Sylvia E. Rosas @sylviaerosas

Sylvia E. Rosas, MD, MSCE is a nephrologist and epidemiologist at the Joslin Diabetes Center and an Associate Professor of Medicine at Harvard Medical School. Dr. Rosas has evaluated health disparities in individuals with CKD particularly in those of Hispanic/Latino background.  She is the President of the National Kidney Foundation and chairs the NKF Health Equity Advisory Committee.

 

March is National Kidney Month, with the purpose of raising awareness about kidney health. At the National Kidney Foundation (NKF), we kicked it off with our 10^th Kidney Patient Summit in Washington, DC. About 125 advocates from 37 States, the District of Columbia, and, for the first time, Puerto Rico visited with our legislators and their staff on Capitol Hill to urge support for:

a) Living Donor Protection Act(LDPA), which would protect kidney living donors from discrimination in insurance coverage, higher health insurance premiums, and job loss;

b) the Improving Access to Home Dialysis Act, which would expand access to home dialysis by providing trained, professional staff assistance to patients in their home; and

c) increased investment in priority kidney health programs such as the Chronic Kidney Disease program at the Centers for Disease Control and Prevention (CDC) and kidney related research at the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK).

NKF also continues to support efforts to achieve kidney health equity in transplantation. The Organ Procurement and Transplantation Network (OPTN) policy “Modify Waiting Time for Candidates Affected by Race-Inclusive eGFR Calculations” took effect on January 5, 2023. Using a restorative justice framework, the goal over the next year is to improve transplant equity by backdating the waiting times of Black kidney transplant candidates who were affected by the race-based estimated glomerular filtration rate (eGFR) calculation. Because race is a social construct, it is also imperative to remove race from the Kidney Donor Risk Index (KDRI). We commend the OPTN and the OPTN Minority Affairs Committee for prioritizing this effort.

Earlier this year, NKF responded to the United States Preventive Services (USPSTF) draft research plan to assess screening, interventions, outcomes, and disparities in CKD. We recommended a systematic review that allows for stratification of screening, focused where the evidence is strongest—people with diabetes and/or hypertension. Preservation of kidney function is the goal, and can only be achieved if we are able to identify individuals with kidney disease early so that they can benefit from treatment options. When detected early, targeted therapies can significantly improve patient outcomes by attenuating the progression of CKD to kidney failure, and decreasing the risk of cardiovascular disease and death.

NKF also provided recommendations to the Centers for Medicare and Medicaid Services (CMS) to improve the End-Stage Renal Disease Medical Evidence Report Medicare Entitlement and/or Patient Registration (referred to as the CMS-2728 form). While a seemingly minor administrative change, by collecting better information we can identify barriers to transplantation or home dialysis therapies such as housing insecurity, immigration status, or language barriers. By taking a data-driven approach, we can focus resources on the areas where gaps are most significant and where policy can have the biggest impact.

During this month, I invite all of you to participate and to raise awareness of kidney health. Wear your kidney socks, but also take action to promote kidney health. Here are some suggestions:

1. Participate in or hold a Nephmadness event. NephMadness is a competition between a selection of the hottest topics in nephrology. For 2023, there are 8 main nephrology regions with teams competing against each other.
2. Become a voice for kidney health and encourage your patients to become advocates themselves.
3. Become an organ donor.
4. Highlight your work to raise awareness and eliminate kidney disease on social media. Use hashtag #mykidneyvoice so we can amplify your work.
5. Ensure your clinical lab reports race-free eGFR using the CKD-EPI creatinine refit equation.
6. Participate in NKF regional or national events to celebrate Kidney Month.
7. Become an NKF volunteer.
8. Donate to your favorite kidney foundation.

At the NKF, every day is kidney day.  Happy Kidney Month to all of you! See you April 10-15 in Austin, Tx for our Spring Clinical Meeting.

– Post prepared by Sylvia E. Rosas.

AJKD March 2023 cover celebrating World Kidney Day

Submit your picks! | NephMadness 2023 | #NephMadness | #KidneyTransplant

Tanjala Purnell @tpurnell1908

Tanjala Purnell is an Associate Professor of Epidemiology and Surgery at Johns Hopkins University, where she conducts research to advance equity in kidney health, transplantation, and organ donation. She is the 2023 recipient of the National Kidney Foundation’s (NKF) Excellence in Transplantation Award.

Competitors for the Kidney Transplantation Region

Journey to the Wait List vs Organ Pool

Copyright: Gemenacom/Shutterstock

As an advocate for kidney health equity, I am very excited to participate in #NephMadness 2023. Specifically, I am happy to lend my voice in support of the Access to Kidney Transplant region. But first, I have a confession to make.  I am a huge fan of Dawn Staley, who is an Olympic gold medalist, American Basketball Hall of Famer, and award-winning head coach for the South Carolina Gamecocks Women’s Basketball team. Recently, a close friend and I traveled to Hartford, CT to cheer on South Carolina as they faced off against the UConn Huskies Women’s Basketball team. So far, so good, right? Well, I did not realize beforehand that our seats were in a section surrounded by UConn Huskies fans! Lol, thankfully it all worked out fine and we had a great time at the game, especially since the Gamecocks maintained their undefeated regular season record.

By now, you may be wondering what that story has to do with NephMadness and kidney transplants. There are at least three quick parallels that come to mind: 1) access to resources, 2) support to overcome barriers, and 3) a sense of belonging.

Access to Resources

Just as it takes a concerted effort and baseline level of resources to travel across states to attend a sold-out game in support of one of your favorite collegiate basketball teams, it takes an in-depth understanding of the complex journey to the waitlist (or living donation), as well as access to resources at several steps along the path to successful kidney transplantation. These steps include timely education and referral, completion of the evaluation process, and active waitlisting or receipt of a living donor kidney transplant. Tangible resources are needed to successfully make it through the journey, such as health insurance and financial expenses (e.g., medications, exams, travel expenses, and other opportunity costs, such as childcare and lost wages). Patients have also expressed concerns about future financial risks, insurance eligibility, and medical coverage for potential living donors.

Support to Overcome Barriers

When we arrived at the basketball game, the first barrier we encountered was uncertainty around where to park. Most of the parking lots and garages were already full. After riding around in circles for several minutes, we finally spotted a sign that indicated there was space available.  Although we were relieved to finally find a spot, this unexpected barrier contributed to us missing the opening tip-off. In a similar manner, patients and potential donors may encounter barriers at several steps along the path to transplant, and these barriers operate at multiple levels related to potential recipients and donors, health care providers, health system structures, and communities. Comprehensive and tailored support to increase transplant access and overcome barriers to the process is needed. Excitedly, the transplant community has recently made some progress, such as the Organ Procurement and Transplantation Network (OPTN) policy changes using race-free eGFR equations to determine waitlist eligibility, the 2014 OPTN Kidney Allocation System changes to improve efficiency and equity in organ allocation, and legislation to protect living donors by prohibiting insurance companies from denying or limiting life, disability, and long-term care insurance. However, continued efforts are needed to overcome remaining barriers that perpetuate disparities in access to kidney transplantation.

A Sense of Belonging

When it finally made it to our seats, I was thrilled and looked forward to cheering on the Lady Gamecocks. Then, I realized we were surrounded by Huskies fans. Lol. My initial thoughts were, “Did we sit in the correct section, and do we belong here?” Similarly, while navigating the complex processes of transplantation and donation, many Black and Hispanic patients may find themselves wondering, “Do I belong here?” To increase transparency, remove barriers, and redress inequities, targeted interventions are needed that are designed to reduce transplant disparities through appropriate and respectful engagement of diverse communities and patients with lived experiences. It is important to incorporate patient and family engagement in the design and implementation of approaches to overcome barriers to transplant and donation. Provider and center practices that promote shared decision-making and that are respectful of cultural differences in family and social network dynamics are crucial. Meaningful partnerships between health systems and community resources to address barriers are also paramount.

Conclusion

In summary, I am very proud of recent efforts within the nephrology and transplant communities to increase access to kidney transplantation. Although continued efforts to remove remaining barriers and redress long-standing inequities are needed, this is an exciting time for the field. Therefore, I support the Access to Kidney Transplant Region as this year’s #NephMadness champion! P.S. Go Coach Dawn and the Lady Gamecocks!

– Guest Post written by Tanjala Purnell @tpurnell1908

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

Click to read the Kidney Transplantation Region

Submit your picks! | #NephMadness | @NephMadness | #KidneyTransplant

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John Sperati @JohnSperati

Dr. John Sperati is an Associate Professor of Medicine and an adult nephrologist at The Johns Hopkins University School of Medicine. He serves as the director of the Nephrology Fellowship Training Program, and his clinical and research interests focus on complement inhibitors and thrombotic microangiopathy.

Competitors for the Thrombotic Microangiopathy (TMA) Region

Primary TMA vs Secondary TMA

Copyright: ShaiKu/Shutterstock

What’s in a name? That which we call a rose

By any other name would smell as sweet

-William Shakespeare, Romeo and Juliet

Hemolytic uremic syndrome.  Atypical hemolytic uremic syndrome. Primary. Complement mediated TMA. Malignant hypertension induced TMA. Secondary. We-don’t-think-this-is-complement-and-it’s-not-a-TMA-but-it-looks-like-a-TMA. Maybe-it’s-complement-mediated-maybe-it’s-not-complement-mediated-TMA. Oh my! What is more maddening– other than those squeaking sneakers on the courts throughout the month of March- than our current, arbitrary classification of thrombotic microangiopathies?

The term “atypical hemolytic uremic syndrome” may have been first used in 1965 to differentiate diarrheal-associated HUS from non-diarrheal. By 1978, there was a call for an etiologic based classification of HUS while acknowledging that specific molecular mechanisms likely remain unknown. Nevertheless, aHUS evolved into the preferred term for all TMAs that were not Shiga toxin HUS or TTP. This was eventually further ensconced in our collective lexicon by the product labeling for eculizumab that restricted its use to aHUS.  But what is aHUS? The term does not convey mechanism or etiology. It lacks a precise definition. There are kidney limited forms that lack the “H,” and kidney injury is at times sufficiently mild such that the “U” is not present either.

Recognizing the limitations of aHUS as a classifying term, and to better orient the focus on endothelial injury as the foundational event in these disease processes, TMA has emerged as a better but still imperfect rubric. Yet, this field is complicated, and old habits die hard. Over the past several years, for many experts in the field, aHUS has become synonymous with complement. The KDIGO controversies conference included primary aHUS as a complement-mediated etiology of HUS, distinct from other causes (yet with many interconnected arrows).

Another group maintained the primary aHUS label while subcategorizing others (including some associated with complement) under a secondary header.  Still others move secondary causes to the primary category and then further subdivide by hereditary and acquired. Now, in 2023, we find ourselves watching Primary (complement-mediated) vs Secondary (maybe complement mediated) TMA in the Sweet 16. Unlike Chris Webber, I’m calling a real timeout.

As nephrologists, we are abandoning primary membranous, primary FSGS, primary MPGN…this is an opportunity to think mechanistically about TMA as well. TMA due to pathogenic genetic variants in complement is estimated to occur in approximately 1 per million individuals, with a familial penetrance well below 50% in many studies (Sansbury et al, Arjona et al, Ardissino et al). Variants are identified in only 50-60% of affected individuals, and many of these variants are of uncertain significance and potentially non-contributory to disease pathogenesis. Thus, pathogenic complement variants are like a well-positioned defender– they need to be poked for a foul to occur. If a multi-hit mechanism (i.e., infection, medication, pregnancy, etc.) is likely required, then how do we draw a dividing line between primary and secondary etiologies of TMA?

When carefully phenotyped, “secondary” TMA are more common than “primary.” While subject to biases of small cohorts, patients with “secondary” TMA are oftentimes not enriched for rare complement variants. Yet despite the absence of identifiable genetic changes, dysregulated complement activity may nevertheless underlie many “secondary” TMAs, such as gemcitabine, malignant hypertension, and antiphospholipid antibody syndrome, to name a few. On the other hand, “secondary” TMAs such as hematopoietic stem cell transplant associated TMA and pregnancy associated TMA do have a high prevalence of germline complement variants. Should these be “primary?” It is also important to remember that not all TMAs are associated with complement activation.  Given this, focusing on mechanisms, triggers, and response to therapy is a more meaningful approach than primary versus secondary.

It is estimated that over 300 compounds contribute to the lovely scent we know as rose. Some are even detectable by the human nose at the parts per billion level. Is the rare molecule any less important than the most common to that scent? The amplification loop of the alternative pathway of complement can generate 10,000,000,000 C3b molecules in 15 minutes. If it smells like complement, why call it by any other name? At 500 million years old, complement/TMA is clearly the most senior and wisest competitor in this year’s lineup. Primary (complement mediated)– if I must use that term– for the win!

– Guest Post written by John Sperati @JohnSperati

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

Click to read the Thrombotic Microangiopathy (TMA) Region

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Submit your picks! | NephMadness 2023 | #NephMadness | #KidneyTransplant

Morgan Reid @_morganreid

Morgan Reid is the Director of Transplant Policy and Strategy with the National Kidney Foundation. She is a kidney transplant recipient who is passionate about creating policies that ensure everyone has equitable access to kidney transplantation.

Competitors for the Kidney Transplantation Region

Journey to the Wait List vs Organ Pool

Copyright: Gemenacom/Shutterstock

The National Kidney Foundation (NKF) is ecstatic to see that kidney transplantation has made its way back into the NephMadness tournament in 2023! Not only is kidney transplantation a hot topic for NephMadness, but it’s also a hot topic for us at NKF. We firmly believe in transplants for all; everyone should have equitable access to kidney transplantation. We are cheering for both teams in the Access to Kidney Transplant region. We applaud Journey to the Waitlist and Organ Pool for presenting timely and compelling perspectives on kidney transplantation. We would definitely say they both brought their A-game and slam-dunked it!

Patients are truly the heart of all we do at NKF. As a patient advocacy organization, we are committed to playing our position and applying full-court press to ensure patient-centricity becomes a priority in our transplant ecosystem. The journey to the waitlist is not a layup for many people, especially for historically marginalized communities. One victory we believe is a giant leap forward in health equity is removing race from the eGFR equation, an initiative NKF championed in partnership with the American Society of Nephrology (ASN) through a joint task force to make referrals to transplantation fair and ethical for Black patients.^[1] We took a shot, and we’d say that the Organ Procurement and Transplantation Network (OPTN) ally-ooped it when they unanimously decided to mandate that all transplant centers adopt race-free equations to assess kidney function. Using race in clinical algorithms? Ref, call a technical foul! Flagrant Foul! Flag on the play—wait, that’s football, but you get where we are going.

We know all too well the non-medical obstacles people experience at the patient, provider, and system levels, such as medical mistrust, patient education and knowledge, provider communication, and bias in receiving a referral to a transplant program and during the evaluation phase once that referral happens.^[2] People with kidney failure want to feel better. They want to be back in the game; no one wants limited (living) time, and no one wants to be benched. Patients want what we are all looking for: to be seen, heard, and to have an advocate to ensure they complete their transplant journey successfully.

Healthcare providers and professionals are uniquely positioned to provide patient advocacy on several levels–individual, adjacent, and structural– to influence practice, community, and government.^[3] If we, as a community, are genuinely invested in improving the patient experience in kidney transplantation, patients need your advocacy for a transparent, equitably accessible, patient-centric transplant system that prioritizes inclusion, cultural sensitivity, awareness, seamless care coordination, and shared decision-making. Kobe Bryant said, “We can’t always be average and just do what’s normal. I’m not it this to do what’s normal”. Lives are at stake. Patients do not have the luxury of time for us to do what is normal anymore; it’s time for new plays to challenge the status quo and push boundaries to ensure the transplant journey has few turnovers to get to the winning shot.

It is safe to say that the Journey to Transplant has won this round (insert airhorn)! Improving access to transplantation is vital for the health and well-being of kidney failure patients. Patients deserve to have anyone working in and devoted to kidney transplant advocating on their behalf to make the transplant process easier. We cannot just talk the talk, but it is critical that we also walk the walk.

NKF would love to give a shout-out to the Organ Pool team, who shared incredibly sobering information on organ non-use. Thank you for highlighting this issue; it is also one of immense importance to our organization. We know that people die each day awaiting a life-saving kidney transplant, yet so many recovered kidneys go to waste. We are eager to solve this problem and support initiatives to increase transplantation and reduce the non-utilization of recovered kidneys.

A special thank you to Dr. Samira Farouk and the American Journal of Kidney Diseases for the wonderful opportunity to participate in NephMadness.

^[1] Delgado, Cynthia, et al. “A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on

Reassessing the Inclusion of Race in Diagnosing Kidney Disease.” American Journal of Kidney Diseases, vol. 79, no. 2, 2022,

https://doi.org/10.1053/j.ajkd.2021.08.003.

^[2] Harding JL, Perez A, Snow K, et al. Non-medical barriers in access to early steps of kidney

transplantation in the United States – A scoping review. Transplant Rev (Orlando). 2021;35(4):100654.

^[3] Earnest, M., Wong, S.L., Federico, S. et al. A Model of Advocacy to Inform Action. J GEN INTERN MED 38, 208–212 (2023). https://doi.org/10.1007/s11606-022-07866-x

– Guest Post written by Morgan Reid @_morganreid

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

Click to read the Kidney Transplantation Region

Submit your picks! | #NephMadness | @NephMadness | #KidneyTransplant

Submit your picks! | NephMadness 2023 | #NephMadness | #TransitionsRegion

Kelly Li

Dr. Kelly Li is a dual-trained nephrologist and palliative care physician from St George Hospital in Sydney, Australia, and the University of New South Wales. Her academic interests include kidney supportive care, bioethics, advance care planning, and communication skills in the healthcare setting.

Jeffrey Ha @_jeffreyha

Dr. Jeffrey Ha is a nephrology fellow at St George Hospital, Sydney. He attended medical school at University of Sydney and completed his nephrology training in the East Coast Renal Network in Sydney. He is currently undertaking a PhD through The George Institute for Global Health, to better understand and manage the high burden of cardiovascular disease in patients with chronic kidney disease (CKD). His research interests are in epidemiology, clinical trials, and expertise in anticoagulation and the treatment of cardiovascular disease in CKD. He is passionate about teaching and quality improvement

Competitors for the Transitions of Care Region

Team 1: Supportive Care for Kidney Failure vs Team 2: Pediatric to Adult Care

Copyright: FGC/Shutterstock

Kidney supportive care: supporting all transitions in kidney disease

Transitions of care, like major transitions in life, involve decisions that are daunting, uncomfortable, and difficult to navigate. How we assist patients transition into a different phase of illness and treatment can have profound impacts on how they live their life. We are cheering on the transition to kidney supportive care, because as nephrologists, we believe this is core business, and we all need the skills and institutional support to do it well.

Dialysis is not always the answer

Like it or not, our patients with chronic kidney disease (CKD) are part of an ageing population, as people live longer with chronic diseases. Mortality on dialysis remains high, even more so for those who are older, reside in a nursing home, or with high co-morbidity burden. For some, survival may not be longer with dialysis. Further, dialysis doesn’t alleviate the common and distressing symptoms of kidney failure. So it shouldn’t come as a surprise that dialysis is unsuitable or undesirable for many of our older patients. What happens when a patient chooses to forego dialysis?

Kidney supportive care

We work in a well-established kidney supportive care program in an Australian nephrology unit. We started this program because many patients were troubled by distressing symptoms, despite our unit performing above benchmarks in traditional key performance indicators (KPIs). To foster a successful service, we took a page out of the palliative care rulebook. According to the World Health Organisation, palliative care is an approach that improves quality of life of patients with life-limiting illnesses, addressing suffering which can be physical, psychosocial or spiritual. Kidney failure is life-limiting, and associated with high symptom burden and reduced quality of life. Effort and commitment to relieve suffering in this population is long overdue.

A main aspect of kidney supportive care is conservative kidney management – active symptom management and holistic, psychosocial, multidisciplinary support, alongside interventions to delay CKD progression. It is an important alternative to dialysis, one that foregoes sophisticated machines and cocktails of dialysate, instead prioritising individual values, quality of life, and time spent outside of the healthcare setting. Doing this well requires dedication from a whole team of medical, nursing, and allied health providers, and a commitment to not abandon our patients at all stages of illness.

Patients in our program with median age 84 years managed conservatively, lived 15 months (median survival) from eGFR <15ml/min/1.73m², and 6 months from eGFR <10ml/min/1.73m². They also had less hospitalized days than younger, less co-morbid patients who opted for dialysis, and their symptoms improved over time with active management, despite worsening GFR. All were co-managed by nephrologists and kidney supportive care. We think it’s time patients in every nephrology unit have access to and the opportunity for such a program, and clinicians and institutions need to facilitate it.

Non-abandonment

Kidney supportive care can be integrated across a spectrum of kidney diseases, through many complex and life-changing transitions, not just conservative management. Older dialysis patients need proactive symptom management and advance care planning. Patients with a failing graft may not wish to return to life on dialysis. Those faced with the difficult decision to withdraw from dialysis – whatever the reason – need the support of their nephrology team. Dialysis or transplant patients diagnosed with advanced malignancies need palliative care input integrated with their existing nephrology care. Kidney supportive care can look after patients through each of these stages within their nephrology unit, where their nephrologist continues to guide and support them. This holistic care is what our patients need and value, and is what makes kidney-supportive care a strong contender for this year’s NephMadness competition.

– Guest Post written by Kelli Li and Jeffrey Ha @_jeffreyha

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

Click to read the Transitions of Care Region

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Sean Pickthorn, MD @SeanPickthorn

Dr Sean Pickthorn is currently first-year Nephrology fellow at the University of Minnesota. His interests include hypertension, diabetic kidney disease, and AKI.

 

 

Sabine Karam, MD @SabineKaram6

Dr Sabine Karam is currently an assistant professor of medicine in the division of Nephrology and Hypertension at the University of Minnesota. She is also the deputy chair of the Young Nephrologists Committee of the Internal Society of Nephrology (ISN) and a member of the 2021 cohort of the Emerging Leaders Program of the ISN. Her clinical and research interests include Onco-Nephrology, Hypertension and Peritoneal dialysis.

World Kidney Day, established in 2006, is an initiative to raise awareness about the health burden of kidney disease. The theme for World Kidney Day 2023 is “Kidney Health for All”.

AJKD March 2023 Cover Celebrating World Kidney Day

Over the past few years, the world has experienced a rollercoaster of emotions as it has been shaken by major disruptive events and unprecedented crises. Examples include the Covid-19 pandemic and the war in the Ukraine which has instigated the largest refugee crisis in Europe since World War II. This has contributed to the acceleration of major economic crises in several countries around the world such as Lebanon and Sri-Lanka, among others. Most recently, the earthquake in Turkey and Syria, besides putting an end to more than 50,000 lives, has affected over 10 million people and displaced 2.2 million. Unexpected disasters and crises can shake healthcare systems and cause incredible harm to all patients. Patients with chronic conditions are often disproportionately affected, most notably the 850 million patients with kidney disease as of 2020.

This World Kidney Day, it is more important than ever to take a moment to reflect on the impact of these events on the global kidney population. It takes a village to arrange the care and support that our kidney patients need on a routine basis. This is especially true for those patients requiring kidney replacement therapy (KRT). In times of disruption, patients in low resource settings are the most vulnerable.

Within the last few weeks, the war in Ukraine has surpassed one year of duration. An emotional perspective by Stepanova et al describes the multiple challenges faced by the kidney community. With several areas receiving active bombardment, numerous health facilities (including dialysis centers) and medical warehouses stocking PD supplies have been heavily damaged, interrupting medical care to patients that often lack reliable humanitarian corridors for evacuation. The perspective describes one KRT patient who was able to escape to a neighboring country, while 49 out of the 50 patients in his dialysis center passed away. The report also acknowledges the heroic efforts deployed by local and international health communities, with numerous dialysis centers deployed in areas that were less frequently under attack to provide free hemodialysis services, and courageous nephrologists and staff remaining in their clinics—sometimes moving dialysis equipment into basements—to continue treating their patients.

“Anti-terrorist operation in eastern Ukraine” is from Ministry of Defense of Ukraine on Flickr

In their most recent update, the World Health Organization (WHO) reports that 7.9 million people have been displaced from their homes due to this conflict, with many of them seeking refuge in neighboring countries. While access to KRT in most European countries is a universal right for citizens, the access for refugees is less straightforward and is highly dependent on their legal status and whether tor not hey are registered. In addition, the financial burden of dialysis remains a concern in many hosting countries.

In the aftermath of the recent earthquake in Turkey and Syria, countless people are surviving in homeless camps with poor access to care while the country seeks to rebuild. In this case as well, not only were homes destroyed but also clinics and healthcare centers, jeopardizing access to adequate management of acute kidney injury (AKI) following crush injury and rhabdomyolysis in patients being trapped under the debris of collapsed buildings. Buckled and impassable roads don’t make it any easier for medical organizations trying to provide relief. Moreover, in the case of Syria, the country had already been struggling with a chronic conflict since 2011, leading not only to massive population migration and healthcare infrastructure destruction but also to a dramatic reduction in the nephrology workforce.

“Turkey earthquake – a glimpse of the ECHO assessment” is from EU Civil Protection and Humanitarian Aid on Flickr

The WHO has been at the forefront of emergency preparedness and response. They aim to contribute nearly 85 million USD in supplies and assistance to help manage the catastrophic damage. Despite their assistance in initiating the rebuilding process, it will be several years before there is any semblance of what life was like prior to the disaster.

Preparedness is the key to best assist our kidney population in times of disaster. For instance, a Lancet commission has estimated that readiness in the case of the Covid-19 pandemic could have avoided around 200,000 deaths in the United States in 2020 alone.

For this year’s World Kidney Day, we aim more than ever to raise awareness of the importance of achieving sustainable global kidney health for the most vulnerable, and under all circumstances. This can only be attained through the elaboration and implementation of meticulously planned emergency preparedness plans. A recent publication from the World Kidney Day Joint Steering Committee has addressed this with the intent to target populations across all levels of wealth and resources through a map of 11 points that provide guidance for adequate governance and leadership, effective planning, vigorous community engagement, accurate risk analysis, careful surveillance and monitoring, extensive practice and experience, resource optimization, workforce capacity building, timely communication, and prompt learning and evaluation in times of unexpected crises and disasters.  Additional details to consider in a kidney specific population are also provided.

Finally, we would like to recognize all of the individuals that have worked tirelessly to provide undisrupted care to patients affected by disasters, often at the expense of their own safety. This is especially true for those who help arrange care for patients who require a dialysis modality (approximately 4 million patients worldwide). The personnel who continue to make this happen deserve our utmost appreciation.

– Post prepared by Sean Pickthorn and Sabine Karam.

Submit your picks! | NephMadness 2023 | #NephMadness | #TransgenderRegion

Murdoch Leeies @MLeeies

Leeies is an organ donation, critical care medicine and emergency medicine specialist physician.  Trained as a clinician investigator, he serves as the Director of Research for the Department of Emergency Medicine at the University of Manitoba.

Dr. Leeies leads a collaborative program of research with a focus on promoting health equity in organ and tissue donation and transplantation. To ensure this work is informed by the population it aims to serve, Dr. Leeies has led the formation of a 2SLGBTQIA+ Patient & Public Advisory Team which partners in the development of patient-centered research that explores the inequities that 2SLGBTQIA+ persons face in the organ and tissue donation and transplantation system.  Through this work Dr. Leeies hopes to generate knowledge that can inform the reformation of structural and systemic elements of the health system that uphold these inequities.

This intersectional research program pairs with his clinical work as an organ donation specialist physician with the Transplant Manitoba Gift of Life program.  Dr. Leeies extends his commitment to the principles of equity, diversity, decolonization, and inclusion (EDDI) through academic and clinical service as the Director of EDDI for the Canadian Critical Care Society.

Competitors for the Transgender Health Region

Team 1: Kidney Care for the Transgender Patient vs Team 2: Gender-Affirming Care

Copyright: nito/Shutterstock

Sexual orientation and gender identity (SOGI)-diverse populations include Two-Spirit, lesbian, gay, bisexual, transgender and queer plus (2SLGBTQ+) persons and represent approximately 5% of the global population. Specifically, structural discrimination against SOGI-diverse populations is embedded in our organ and tissue donation and transplantation (OTDT) system. Policies that originated in reaction to the Human Immune-deficiency Virus (HIV) epidemic of the 1980’s have not been adequately updated in-line with our evolving understanding of the likelihood of transmission of HIV or viral hepatitis. By failing to keep pace with evolving science we continue to unnecessarily exclude or restrict organ and tissue donors based on their sexual orientation and/or gender identity, as opposed to evidence-based behavioral factors associated with transmission of HIV or viral hepatitis. These policies are stigmatizing and harmful to SOGI-diverse populations and ultimately result in reduced availability of needed organs and tissues for all patients regardless of social identity.

Transgender and gender diverse persons represent a unique population within the SOGI-diverse umbrella who have been historically underrepresented, systemically marginalized and oppressed, even within SOGI-diverse communities. Recognition of diversity of gender identities, the importance of respecting the individual through appropriate self-identified pronoun use, and identification of transgender and gender diverse-specific knowledge gaps (e.g., interactions between gender-affirming medical and surgical therapies with other renal health considerations) is a critical first step in enhancing the care of transgender and gender diverse persons. Many structural barriers, such as the need to update health information systems in order to appropriately collect and document gender identity and other variables, are simple solutions that could meaningfully enhance our ability to provide person-centred care but require attention and resourcing.

I was thrilled to see that the American Journal of Kidney Disease (AJKD) is amplifying the calls to action made by the two teams in the Transgender region this year. By focusing a region on transgender and gender diverse health, the AJKD is acknowledging the inherent value and lived experiences of transgender and gender diverse persons. Our competitors should both be celebrated as winners for championing the need for enhanced epidemiologic collection of sexual orientation and gender identity at the population level, for improved healthcare worker training in cultural humility, and for further research on the interactions between gender-affirming therapies and renal health care.

Team 1 did an excellent job of summarizing inequities, potential harms, and opportunities for improvement specific to SOGI-diverse patients. Team 2 provided an overview of gender-affirming care and highlighted relevant intersections with renal care. Both have described important issues relevant to enhancing the care of transgender and gender diverse populations interfacing with renal care teams. While I applaud both teams my choice is Team 2 for including both education about transgender and gender diverse -specific care and specific opportunities for improvement.

If I were to make one final point it would be to emphasize that appropriately resourced patient-/caregiver-/community-engagement with SOGI-diverse individuals who have lived experiences in the renal health system must be facilitated to ensure that policy revisions, research priorities, and funding allocation decisions are informed by the individuals they are intending to benefit. All human lives have value and I believe it is our duty as physicians, researchers, and leaders in the health system to work to ensure that all our patients achieve their best possible outcomes through our care.

– Guest Post written by Murdoch Leeies @MLeeies

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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Ben Humphreys @HumphreysLab 

Dr. Humphreys is Chief of the Division of Nephrology and the Joseph Friedman Professor at Washington University in St. Louis as well as President-elect for the American Society of Clinical Investigation. His research focuses on kidney injury and fibrosis using single cell multi-omics and spatial transcriptomics as approaches. He has a clinical interest in onco-nephrology.

Competitors for the Onconephrology Region

Chemotherapy-Associated Hypomagnesemia vs Immune Checkpoint Inhibitor-Associated Acute Kidney Injury

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The onconephrology matchup this year features two heavyweights: EGFRi-induced hypomagnesemia vs. ICI-induced AKI. If this were a boxing match, it would be the precision of Muhammed Ali (“Float like a butterfly, sting like a bee”) vs. the power of Mike Tyson (“Everyone has a plan until they get punched in the mouth”). If these were digital tools, EGFRi’s are a hypersegmented facebook precision advertising campaign and ICIs are an email spam filter that keeps unwanted emails out but sometimes blocks your friends and family too.

This year’s contest reflects the growing depth and maturity of the onconephrology subspecialty itself. In one corner, we have a highly accurate, targeted therapy – anti-EGFR inhibitors – that exerts anticancer effects by inhibiting a signaling pathway that some tumors require for survival and expansion. But these drugs are both specific and highly potent, so toxicities result from inhibition of the same biologic pathway in a non-cancer tissue, where the pathway regulates some aspect of organ homeostasis. As eloquently described by Stockholm and Schoer, inhibition of basolateral EGFR in the distal tubule suppresses the magnesium channel TRPM6, causing magnesium wasting and hypomagnesemia.

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What other examples of “on-target” toxicities exist in onco-nephrology? Antiangiogenic therapies target the vascular endothelial growth factor (VEGF) molecule, its receptor or downstream pathways. FDA approved antiangiogenic agents include bevacizumab, a recombinant, humanized monoclonal antibody that binds and sequesters the VEGF molecule, and multi-targeted tyrosine kinase inhibitors (TKI), small molecules that inhibit the VEGFR intracellular intrinsic kinase activity, such as sunitinib, sorafenib, axitinib and pazopanib. Antiangiogenic therapies are first line therapy for cancers such as metastatic renal cell carcinoma and they act by inhibiting tumor-induced angiogenesis – effectively starving the cancer of needed oxygen and nutrients.

Anti-angiogenic therapies can cause proteinuria that is most commonly the consequence of renal thrombotic microangiopathy (TMA). The clinical syndrome is characterized by hypertension, microangiopathic hemolysis, kidney injury, sub-nephrotic proteinuria and microscopic hematuria.  On kidney biopsy, endotheliosis is the most prominent feature, and endothelial injury is reflected by thickened basement membranes with double contours. The pathophysiology of this syndrome involves VEGF expressed by podocytes and blockade of the VEGF signal on glomerular endothelial cells. Eremina, et al. elegantly recapitulated a renal limited TMA in mice by ablating VEGF from podocytes alone. Thus, antiangiogenic therapies act by blocking the effect of podocyte-derived VEGF on adjacent glomerular endothelial cells, resulting in disruption of the glomerular filtration barrier with proteinuria, as well as enhanced clotting.

What these toxicities reveal – both EGFRi-induced hypomagnesemia – and antiangiogenic therapy-induced TMA – is how the toxicities of targeted therapies in the modern era can help us understand human biology by revealing unanticipated roles for the signaling pathways these drug block in kidney homeostasis.

The lessons of ICI for onconephrology are quite distinct from EGFRi. While technically also a targeted therapy, the consequences of ICI are to unleash the full power of the human immune system in a much less predictable way. The anticancer effects of this drug class are remarkable but immune-related adverse events (irAE’s) are common; we do not fully understand their pathogenesis and they pose challenges in clinical management. In this sense the experience we have gained concerning ICI-related AKI over the last decade reflects the real-world generation of new medical knowledge initially through observation and trial and error and later through careful investigation with larger and larger patient cohorts.

Copyright: Grigvovan/Shutterstock

While we have come a long way in understanding the kidney effects of ICI, many important and fascinating questions remain. If acute tubulointerstital nephritis (ATIN) is the most common pathology caused by ICI, how common are other glomerular injury patterns, and what are the risk factors for their development? How safe is it to rechallenge patients with ICI after a kidney complication from the therapy? Are we not biopsying enough, or biopsying too much? Are ICI safe in transplant recipients? These are all important questions that are outlined by the region and require further investigation in order to generate evidence-based guidelines to achieve the best outcomes for our patients.

It is hard to call a winner in this onconephrology veteran bout. After 12 rounds, ICI-induced AKI takes the win (in a split decision) for exemplifying the way that a new class of cancer therapy can force the onconephrology community to come together, gather data, test hypotheses and ultimately advance medical science.

– Guest Post written by Ben Humphreys @HumphreysLab 

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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Selection Committee Member: Rasheeda Hall @Rasheeda_HallMD

Rasheeda Hall is a physician-scientist in the Division of Nephrology at Duke University. Her research focuses on adapting geriatric models of care into kidney care settings. Dr. Hall’s geriatric nephrology clinic at the Durham Veterans Affairs Healthcare System uniquely emphasizes geriatric assessment and conservative kidney management.

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Writer: Alissar El Chediak @alissar_chediak

Dr. Alissar El Chediak is a transplant nephrology fellow at Vanderbilt University Medical Center. She was born and raised in Lebanon where she attended medical school and completed her internal medicine residency at the American University of Beirut. After that, she moved to the United States to pursue her nephrology fellowship at Vanderbilt. Dr. El Chediak’s research interests include increasing organ access to minorities, ABO-incompatible kidney transplant, treatment of COVID in kidney transplant patients, and simultaneous kidney and pancreas transplant.

Competitors for the Transitions of Care Region

Team 1: Supportive Care for Kidney Failure versus Team 2: Pediatric to Adult Care

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Patients with kidney disease can undergo a lot of transitions throughout their care, whether it’s from pediatric to adult care, from chronic kidney disease (CKD) to end-stage kidney disease (ESKD), or from ESKD to transplantation. As nephrologists, we are perhaps most well-versed in the transition from advanced kidney disease to dialysis. In this region, we wanted to focus on two other critical transition periods: 1) the transition from advanced kidney disease to kidney supportive care, and 2) the transition from pediatric to adult care for the patient with kidney disease. 

Team 1: Supportive Care for Kidney Failure

Dialysis is the default treatment for patients with advanced kidney disease, and it is relatively uncommon for patients who develop uremic signs and symptoms NOT to be initiated on dialysis. At the same time, observational studies show that for patients with significant comorbidities including advanced age, dialysis does not offer a survival advantage. 

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Kidney supportive care varies amongst different levels of kidney disease. There are two models of management to focus on: first, conservative care of a patient with advanced CKD (ie, not initiating dialysis), and second, palliative care in patients with ESKD (ie, dialysis withdrawal).

Conservative management is a treatment option for patients with ESKD that, through shared decision-making and patient-centered approach, emphasizes quality of life without pursuing dialysis or transplantation. The focus is on slowing the decline in kidney function, active symptom management, advance care planning, and the provision of palliative care (Figure 1). Moreover, the goal is alleviation of suffering through empathic communication and support for psychosocial distress, especially since patients with advanced kidney disease have heavy symptom burden (whether physical or psychological). 

Figure 1. Domains of kidney supportive care (adapted from Figure 1 in Kidney Supportive Care. Core Curriculum 2020) 

Conservative care for patients with advanced CKD is a form of supportive care for those who choose not to initiate dialysis or pursue kidney transplantation.  An example can be found at the University of Rochester Medical Center, where authors described their practice with shared decision-making in the cases of 13 patients who had chosen conservative management. The aim of the study was to test the authors’ hypothesis that offering conservative management depends on the willingness of nephrologists to learn and use primary palliative care skills. The study was a retrospective chart review conducted by two reviewers who determined the status of advance care planning, hospice referral, and place of death. One of the important findings was the participants’ perceptions of conservative management and their reasons for choosing it. These included poor prognosis, a wish to maintain their quality of life, a desire for a dignified life closure, and the intention to protect family members from having to see them suffer based on their own memory of having witnessed a relative on dialysis previously. Advance care planning was completed in 100% of the cases. Symptoms were managed in collaboration with primary care physicians. In this group of patients, their decisions to choose conservative management were influenced by their values and by previous experience with dialysis, in addition to their comorbidities and limited prognoses. 

For a better understanding of patients who choose conservative care, a qualitative study at the University of Washington was conducted to determine their perception of conservative care, as described in decision aids developed outside the United States (Figure 2).

Conclusions from that study include the following:

1) Aspects of conservative care that were appealing to participants included a whole-person, team-based, and structured approach to care that focused on symptom management, maintaining current lifestyle, and managing health setbacks. 

2)  Participants were more receptive to conservative care when this was framed as an active rather than passive treatment approach, and were receptive to statements of uncertainty about future course of illness and prognosis. 

3) Participants believed decisions about conservative care and dialysis should address considerations about risks and benefits of treatment options, family and clinician perspectives, and patient’s goals, values, and preferences.

4)  Participants did not see conservative care and dialysis as mutually exclusive. To reiterate, older US patients with advanced kidney disease and their family members had difficulty with the notion of conservative care and dialysis as mutually exclusive care models.

Figure 2. Perceptions of conservative care among patients with advanced kidney disease

As for the second management option for patients with ESKD, some might choose the palliative route, wherein they stop dialysis. The lack of understanding of palliative care and/or negative perceptions among patients, caregivers, and providers alike may function as a barrier to a palliative approach in patients with advanced kidney disease. Few dialysis patients report having had even limited discussions about their wishes. The lack of discussions is likely fueled by provider uncertainty about prognosis and decreased exposure. System barriers include time constraints on patient visits, complexities associated with care coordination, lack of a supportive institutional culture, and an absence of appropriate financial reimbursement for conservative management in comparison to dialysis. One component of avoiding end-of-life discussion is the fear of abandonment and death. Particularly, family members feel as if they’re contributing to their loved one’s death, which is not the case. This is often fueled by a culture of medicine that values extension of life over quality of life.

As previously mentioned, many dialysis patients with life expectancy of <1 year may desire a palliative approach, which focuses on aligning patient treatment with patient’s informed preferences and discontinuing dialysis. This is described as a transition from conventional disease-oriented focused treatment to “patient- and family-centered care that optimizes quality of life by anticipating, preventing and treating suffering” as defined by the Centers for Medicare and Medicaid. The Kidney Disease: Improving Global Outcomes (KDIGO) and Renal Physicians Association/American Society of Nephrology (RPA/ASN) outlined recommendations regarding withdrawing dialysis for patients who fit certain criteria (Figure 3).

Figure 3. Shared decision-making in dialysis 

Even though the transition to palliative care in ESKD patients is more common nowadays, there are several barriers hindering that transition. Figure 4 outlines the decision-making process for choice-driven dialysis withdrawal. Numerous barriers currently exist in the process and can be further categorized according to personal preference, cultural and religious beliefs, ethico-legal concerns, and policymaking priorities. 

Figure 4. Decision-making process for choice-driven dialysis withdrawal.

In addition to identifying which patients might benefit from dialysis withdrawal, KDIGO, and RPA/ASN have also outlined recommendations regarding the approach to dialysis withdrawal. First, decision-making capacity is determined. Among patients with decision-making capacity, a multidisciplinary approach is taken to clarify their understanding of withdrawal from dialysis and to verify their intent. In those patients who don’t have decision-making capacity, any previously completed advanced directive or description of well-known, strongly held beliefs or values that would be inconsistent with dialysis (as verified by the health care surrogate or proxy) should be identified to guide further decisions. A systematic approach to discussing prognosis, treatment options, and goals of care should be implemented.

In conclusion, kidney supportive care aims to prevent and relieve suffering and enhance the quality of life of ESKD patients. Patients with kidney diseases can elect not to pursue further kidney replacement therapies (conservative care) or to discontinue them (dialysis withdrawal). These patients will need discussions on prognosis and end-of-life to be able to make decisions and plan according to their personal values. Unfortunately, there are barriers to transitioning to kidney supportive care in patients with advanced CKD. An integrated multidisciplinary approach involving patients, caretakers, and other members of the healthcare team is recommended. 

Team 2: Pediatric to Adult Care

The transition from pediatric to adult renal care is an intricate process requiring a multidisciplinary approach and thorough planning. The position paper from the Society for Adolescent Medicine in 1993 defined transition “as a process that involves purposeful, planned efforts to prepare the pediatric patient to move from caregiver-directed care to disease self-management in the adult unit.” This transition of care most often occurs in patients between 18 and 24 years of age, a critical time in the lives of young adults, when they experience unique challenges and when there is a substantial risk for nonadherence and poor outcomes.

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To young patients, an effective transition is important because it reinforces patient independence during early adult care visits. As for healthcare systems, high morbidity, and mortality are observed in unprepared patients after they transition their care to adult nephrologists, as demonstrated by a Canadian study of kidney transplant recipients (Figure 5).

Figure 5. Usefulness and cost-effectiveness of a kidney transplant transition clinic

Several barriers exist to a successful transition toward adult care. Adult nephrologists often feel ill-equipped to facilitate a successful transition and most centers do not have protocols in place. As per the 2020 US Renal Data System (USRDS),<5% of patients with kidney failure in the United States are children or young adults. Adult providers face difficulties when dealing with adolescent patients who have chronic illness in addition to all of the other physical, psychological, and sexual changes in their development. All of that can make the management and transition difficult for the patient, families, and staff. As for the pediatric patients, they face their own set of challenges. These include difficulty navigating adult healthcare systems, gaps in insurance coverage, lack of health self-efficacy, and limited experience in self-management. After the transition to adult care, patients might feel isolated and disconnected from their new community of patients, providers, and other participants in the healthcare system. This can have a profound psychological impact on young patients with chronic kidney disease or kidney failure who are at high risk of depression, low self-esteem, and high-risk behavior.

The councils of both the International Society of Nephrology (ISN) and the International Pediatric Nephrology Association (IPNA) published a consensus statement describing the transition from pediatric to adult renal services, “Transfer should occur from pediatric to adult nephrology services only after efforts to assess and prepare the adolescent/young adult have occurred.” In short, not only should the physical aspects of the illness be addressed in the young patient, but also the impact upon educational, social, and psychological functioning. Only after all these issues have been tackled and the milestones of adolescence completed is it appropriate to transfer to the adult unit. This transfer should be individualized, taking into consideration psychological, educational, and financial factors. Collaboration between the patient, parents/caregivers, and physicians from both the adult and pediatric clinics must be attained. Transition of care should be gradual. As per the consensus statement, a transition clinic is recommended as an ideal method to endorse a successful transfer of care. Also, they suggested a Transition Scale as a tool to assess and monitor the attainment of goals of transition. Components of the Transition Scale include type of illness, treatment, adherence, nutrition, self-management skills, informed reproductive health, trade/school, insurance, ongoing support, and new health care providers.  

Another published simplified approach to facilitate the transition from pediatric to adult renal care is the PREP approach (Figure 6).

Figure 6. PREP approach for pediatric to adult kidney care transition

Some centers have established transition programs and clinics. Northwestern Medicine Nephrology implemented a pilot transition-of-care program for young adults with kidney disease. This program provided coordination of care between pediatric and adult nephrology teams through a formal transition process. After 18 months, they evaluated the patients’ perception of the program and published their experience.

The authors also defined a successful transition as when a patient returned for follow-up at Northwestern Medicine at least once after the initial transfer visit. 71% of patients successfully transitioned to adult care, which is significantly higher than that reported in the literature. Patients were also asked to take an established survey to evaluate their perception of this process and assess their readiness for the transition. 82% of the participants that filled the questionnaire felt ready to transfer to adult care and 88% felt having a transition appointment and meeting the adult care providers in the pediatric setting to be valuable (Figure 7).

Figure 7. A nephrology pediatric to adult transition clinic pilot program

Another example of a transition program was that of the dialysis and kidney transplant program at Children’s Mercy Hospital. They created the K.E.Y.S  (Kidney Education for Your Success) program, which consists of four phases (Figure 8).

Figure 8. The K.E.Y.S program

Transitioning is a longitudinal process beginning in childhood and continuing through early adulthood. Barriers to this transition include delays in psychosocial milestones, academic challenges, and lack of collaboration between adult and pediatric teams in addition to the normal age-related vulnerability of the young adult years. Extra support in adult care for this vulnerable group is essential to help them successfully navigate their journey and can be accomplished using transition clinics. Building an effective transition program is not done overnight; it begins with small steps that progressively lead toward the defined goal with repeated cycles of assessment, analysis, and improvement.

– Executive Team Members for this region: Pascale Khairallah @Khairallah_P and Anna Vinnikova @KidneyWars

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on June 1, 2023.

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Selection Committee Member: Mitchell R. Lunn @MitchellLunn

Mitchell R. Lunn (he/him) is an Assistant Professor of Medicine (Nephrology) and of Epidemiology and Population Health at Stanford University School of Medicine. He combines his interest in sexual and gender minority (SGM) health and technology to design and deploy digital solutions for address issues related to participant engagement, recruitment, and retention. Dr Lunn is the co-director of PRIDEnet, a national community engagement network focused on catalyzing SGM health research including for the NIH’s All of Us Research Program. He also co-directs The PRIDE Study, a national longitudinal cohort study of SGM adult health.

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Writer: Sehrish Ali @sehrish_alii

Sehrish Ali is an Assistant Professor at Baylor College of Medicine in Houston, TX, where she completed her fellowship under the Transition of Care clinical pathway. At BCM, she serves as the Associate Program Director of Nephrology Fellowship. Her clinical interests include women’s health and kidney disease, gender disparities and kidney disease, education, and wellness.

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Writer: Totini Chatterjee

Totini Chatterjee is a nephrology fellow at the Baylor College of Medicine. She completed medical school at Texas Tech University in Lubbock. She is a graduate of the combined Internal Medicine-Geriatrics residency and fellowship program at the Medical College of Wisconsin. Her clinical interests include disparities in kidney care.

Competitors for the Transgender Health Region

Team 1: Kidney Care for the Transgender Patient versus Team 2: Gender-Affirming Care

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The term “sexual and/or gender minority” (SGM) describes a diverse range of individuals, including those with a difference in sex development and individuals that may identify themselves as asexual, two-spirit, intersex, lesbian, gay, bisexual, transgender, queer, or other minority sexual and/or gender identities (LGBTQ+) (Table 1). 

The sex assigned to someone at birth, usually based on a person’s primary sexual characteristics (eg, external genitalia), may not correspond with an individual’s gender or sexual identity or expression. Table 1 summarizes the terms individuals may use to self-identify. 

Table 1. Commonly used terms and definitions to describe gender and sex.

Health inequities and unequal access to healthcare are prevalent in the LGBTQ+ community. In a recent study by the Center of American Progress, 15% of 1528 self-identified LGBTQ+ respondents endorsed postponing or avoiding medical treatment due to fear of discrimination. The respondents who identified as transgender reported an even starker reality, with 30% reporting postponing or avoiding medical treatment due to fear of discrimination. One-third of respondents reported the need to teach healthcare providers about their sexual identity to receive adequate care (Figure 1). Care for patients with kidney disease is unfortunately impacted by various social determinants and health disparities, and LGBTQ+ patients are susceptible to added barriers and negative physical, mental, and behavioral consequences. Greater awareness and education are necessary to overcome these added factors. 

Figure 1. Discrimination prevents LGBTQ people from accessing healthcare

Many LGBTQ+ individuals may conform to societal pressures by hiding their sexual orientation and gender identity. In the United States (US), health surveys offer a limited assessment of the LGBTQ+ community, as they do not regularly include questions on sexual orientation and gender identity. Based on the current collected data, 0.7% of the US population identifies as transgender. Out of 26 million people with chronic kidney disease (CKD) in the United States, 78,000 people (0.3%) identify as transgender, and approximately 2,500 transgender people receive dialysis. 

Over the last several years, there has been growing awareness of gender-affirming care. It is everyone’s responsibility to create a more inclusive environment by examining the roots of the discrimination, stigma, and violence that the LGBTQ+ community continues to face. This NephMadness region, making its debut in the tournament, highlights both kidney care for the transgender patient and the impact of gender-affirming care on kidney health, with the ultimate goal being to ensure health equity and improved access to healthcare.

Team 1: Kidney Care for the Transgender Patient

In the current healthcare system disparities exist based on socioeconomic class, ethnicity/race, educational status, and gender identity. In medical school, there is a lack of education on how to address and acknowledge individuals in the LGBTQ+ community. Similarly, graduate medical education programs such as residencies and fellowships offer limited training on how to address some disparities, which can result in non-comprehensive care. 

Transgender individuals may begin their social transition in the community by using a new name or pronoun. Individuals may use gender-based pronouns such as he/him/his or she/her/hers, or gender-neutral pronouns like they/them/their or ze/zir/zirs. Some may express their gender through their clothing, hair, make-up, mannerisms, etc. If the sex listed on a person’s medical record differs from their gender identity, the medical staff and/or the physician may incorrectly address a patient with the wrong pronouns. This could damage rapport between the patient and healthcare team, lead to the patient feeling disrespected, and ultimately result in mistrust of their healthcare providers. The ramifications of this mistrust can further lead to substandard patient outcomes. Understanding and being comfortable caring for those identifying as LGBTQ+ is one way to create a safe and affirming environment for patients. 

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Patients in the LGBTQ+ community may already be susceptible to barriers such as neglect, financial instability, and discrimination, along with a lack of acceptance by healthcare providers who are not well informed/trained about the LGBTQ+ community. In a study of transgender patients who visited a physician in the past year, 29% were refused to be seen due to their gender identity, and 29% experienced unwanted physical contact from a healthcare professional. 

Along with disparities in receiving and/or accessing healthcare, the LGBTQ+ community faces mental health challenges. Some individuals face gender dysphoria, a term describing uneasiness perceived by a person due to the mismatch between their gender identity and sex assigned at birth. This may be seen in transgender and gender minority individuals who may use negative coping mechanisms and become prone to suicidal thoughts, mood disorders including anxiety, and eating disorders such as anorexia nervosa. Patients with anorexia nervosa are more likely to have electrolyte derangements and to develop acute kidney injury and CKD. It is imperative for us as nephrologists to be aware and proactive in addressing these concerns with our patients to improve overall care. 

Bathrooms are a concern of homophobic or transphobic people. Traditionally, bathrooms have been gender-based (ie, men or women), a reflection of society’s cisnormative expectation that people will use bathrooms based on their assigned sex at birth. As a result, someone who is transgender or identifies as non-binary may not feel comfortable going to the bathroom consistent with their gender identity due to the fear of harassment, embarrassment, or negative reception by others. More recently, many hospitals have started adopting policies where patients may use whichever restroom matches their gender identity. Other hospitals and institutions have adopted the use of gender-neutral bathrooms, which can be used by anyone regardless of gender identity. The harassment of patients using hospital bathrooms in accordance with their gender identity is not to be tolerated; however, almost 60% of transgender Americans have avoided using public restrooms for fear of confrontation due to harassment and assault. Additionally, to our knowledge, dialysis facilities, and clinics have yet to incorporate gender-neutral restrooms, which can provide inclusiveness and a welcoming atmosphere for transgender patients receiving dialysis. 

As in the general population, it is equally important to understand the prevalence of other comorbidities for LGBTQ+ individuals with CKD and end-stage kidney disease (ESKD), especially for those who receive gender-affirming hormonal therapy (GAHT).

For example, although the risk of fractures is elevated in the general CKD population, this risk may be variable by the sex assigned at birth and can be influenced by the use of exogenous hormones in GAHT. In a study of transgender individuals who received long-term GAHT, fracture risk was found to be higher in younger (age <50 years) transgender women compared to a cohort of age-matched cisgender women. Conversely, fracture risk was not increased in younger transgender men compared to age-matched cisgender men.

Furthermore, there have been various studies showing the increased prevalence of hypertension, diabetes mellitus, human immunodeficiency virus (HIV), and cardiovascular-related outcomes in transgender men and women in comparison to cisgender men and women. GAHT may affect the risk of many chronic conditions. For example, transgender women have a decrease in blood pressure after receiving GAHT, whereas transgender men have an increase in blood pressure. Cerebrovascular complications such as venous thromboembolism, cerebrovascular accident, myocardial infarction, and unstable angina have been noted to be higher in transgender women who have received gender-affirmation therapy compared to cisgender women. These same complications are lower in transgender men, who have received gender affirmation therapy, in comparison to cisgender men. Diabetes risk is higher in transgender women and men on GAHT in comparison to matched cisgender women and men, respectively.

About 13.7% of transgender individuals in the United States have HIV. The risk of HIV is increased in transgender individuals; however, there is a disparity in the access to care and prevention between transgender and cisgender individuals. Preventative medications and treatments for HIV have been understudied in transgender individuals on GAHT. While there may be concern for interaction between these drugs and the metabolism of GAHT, additional information and research is needed to improve care for the transgender population. 

Kidney Function Estimation 

Another challenging area of clinical interest is the lack of evidence-based guidelines on assessing the estimated glomerular filtration rate (eGFR) via serum creatinine for a transgender person who is receiving GAHT. The effect of sex is known on serum creatinine in the cisgender population. However, for a transgender person on GAHT, muscle mass or body fat distribution may be affected, which would make it difficult to correlate the serum creatinine between transgender patients and their age-matched cisgender counterparts. Studies have shown changes in serum creatinine in transgender individuals who have received GAHT. Calculated equations for eGFR using serum creatinine currently use a sex coefficient based on cisgender data, which may underestimate kidney function in transgender adults on GAHT. Future research on the use of 24-hour urine collection for creatinine and urea in the LGBTQ+ population may provide more accurate renal function measurements than spot serum measurements. 

Additionally, using a sex-based rather than a gender-based reference range for serum creatinine may be viewed as offensive. Non-sex dependent biomarkers may be more inclusive of the LGBTQ+ community in measuring kidney function. Utilizing serum cystatin C is one alternative marker to assess eGFR for transgender patients independent of muscle mass. However, other factors such as infection, obesity, tobacco use, corticosteroids, and hyperthyroidism may influence serum cystatin C and would need to be taken into account for each patient. To directly measure GFR, filtration markers such as iohexol, iothalamate, chromium-51 ethylenediamine tetraacetic acid (Cr-EDTA), or “gold standard” inulin can be administered. Limitations of using exogenous filtration markers like inulin may include limited availability, invasiveness, and cost.

Until standardized surveys and tools are created to effectively assess gender and sexual identity for each individual in a culturally sensitive manner, we can collect this information from our patients ourselves. This can be done by creating a welcoming, interpersonal environment and avoiding assumptions of gender identity. Starting a conversation by sharing one’s own pronouns and respectfully asking about the patient’s pronouns is one way to collect this information. Additionally, documentation of both current gender identity and sex assigned at birth in the medical records at the beginning of every visit will promote the delivery of high-quality care to transgender individuals. Strategies to nurture a welcoming LGTBQ+ environment within clinics and outpatient dialysis centers include hiring LGBTQ+ staff, displaying physical LGBTQ+ symbols (such as flags, pins, and stickers), creating non-gendered restrooms, and including LGBTQ+ people on posters or signs. 

In conclusion, as the transgender population grows, nephrologists must stay informed on not only the challenges this population faces but also the ways in which we can improve their care. It is of utmost importance to become more familiar with the unique challenges that may be affecting their mental and physical health. 

Team 2: Gender-Affirming Care

Gender-affirming care is multifaceted and encompasses social, medical, and surgical changes which transgender and other gender-diverse individuals may choose to navigate. While some choose medical or surgical treatments, others may elect to avoid medical or surgical transition; some non-binary individuals may microdose during the medical transition. Hence, the path of each person is unique. Nephrologists and kidney care professionals have a responsibility to understand the importance of gender-affirming therapies and their implications for our transgender patients. 

Copyright: New Africa/Shutterstock

Undergoing gender-affirming therapy is a major change in a patient’s life, both physically and mentally. GAHT for transgender men typically consists of injectable or transdermal testosterone therapy, and GAHT for transgender women includes exogenous sublingual, oral, transdermal, or injectable estradiol, typically along with anti-androgen therapy. Studies have found that initiating this treatment can lead to improvements in quality of life, anxiety, and depression in transgender patients (Figure 2). 

Figure 2. Hormone therapy, mental health and quality of life among transgender people

GAHT may have a direct and indirect effect on creatinine because it may impact muscle mass and body fat. Since, as previously discussed, GAHT has been linked with changes in kidney function and can impact eGFR, it will be important to ensure accurate measurement of kidney function in these individuals. This can be accomplished by knowing when and how to employ techniques such as 24-hour urine creatinine and urea collection, cystatin C, or direct (eg, inulin, iohexol) clearance measurement.

Testosterone therapy has been associated with changes in serum creatinine, but there are limited studies to show its effect on kidney disease. One relationship between testosterone and kidney function was illustrated in a case report of a 14-year-old cisgender boy who received testosterone therapy, which resulted in a rise in both serum cystatin C and creatinine. After cessation of testosterone injections, both kidney biomarkers decreased and remained stable for six months. This change in serum cystatin C and creatinine is thought to be induced by testosterone-mediated changes in intrarenal hemodynamic parameters. Alternatively, another observational cohort study showed long-term testosterone therapy to be associated with an improvement in kidney function for cisgender men with low endogenous testosterone levels (Figure 3). This study did not specifically target individuals with established CKD. While the evidence may not be clear, testosterone may impact kidney function. 

Figure 3. The impact of long-term testosterone therapy on renal function among hypogonadal men

In a research trial studying the effect of estradiol on serum creatinine in transgender patients, transgender women participants had a decrease in their serum creatinine within six months of starting estradiol treatment. Conversely, in transgender men participants, their serum creatinine increased within six months of starting testosterone treatment. After twelve months of receiving GAHT, serum creatinine levels were more similar when compared by gender identity rather than by sex assigned at birth. The changes in serum creatinine correlate with individual changes in body composition and lean body mass, which occurs in response to GAHT. 

In a recent study, the effect of GAHT on transgender patients (488 adult transgender men and 529 transgender women) was evaluated. With the initiation of GAHT, the serum creatinine increased in transgender men but did not significantly change for transgender women (Figure 4). Whether these changes in creatinine are representative of true changes in GFR remains to be seen. Further studies are needed to elucidate other underlying changes associated with kidney function (eg, other biomarkers) that are important for estimating kidney function. 

Figure 4. The effect of gender-affirming hormone therapy on measures of kidney function

Furthermore, certain GAHT therapies may be associated with other factors that impact kidney health such as changes in hemoglobin and hematocrit. Transgender men receiving testosterone therapy may have stimulated erythropoiesis and cessation of menses. However, if a non-binary person assigned female sex at birth on low-dose testosterone therapy still has menstruation, the hemoglobin levels may be impacted by menstrual blood loss. Transgender women, on the other hand, may receive exogenous estradiol, which will cause testosterone levels to fall. Consequently, these individuals often experience some testicular atrophy. However, others may still have some residual testicular function, which may release pulsatile androgen activity and improve hemoglobin levels.  

Spironolactone is a commonly used anti-androgen component of GAHT therapy in transgender women which blocks testosterone’s effect at the tissue level; this blockade helps promote breast development. In those with advanced CKD, close monitoring of kidney function, electrolyte derangements, and hypertension management is essential for those on spironolactone, given its association with hyperkalemia and acute kidney injury. 

Although GAHT alone may be an acceptable option for some individuals, others may opt for a surgical component as part of their gender transition (Tables 2, 3). Genital surgeries including the removal of genital organs are additional surgical procedures that may be pursued. There are over 25 different gender-affirming procedures and surgeries that individuals can receive. Description and complications of selected surgical procedures available for transgender men and women are listed in Tables 2 and 3. Other common procedures include masculinizing chest reconstruction, facial masculinization/feminization surgery, orchiectomy, or chondrolaryngoplasty (“tracheal shave”).

Table 2. Common reconstructive procedures for transgender men

Table 3. Common reconstructive procedures for transgender women

Impact of GAHT on AKI & CKD 

Gender-affirming medical and surgical therapies are becoming more prevalent in our community. However, they have a unique set of risks and side effects. 

A recent cross-sectional study showed a lower prevalence of acute kidney injury and CKD in transgender individuals on GAHT in comparison to those not on GAHT. However, ongoing investigation and research is needed in this arena to determine how best to assess kidney function in transgender individuals, as current data are limited. This evaluation has important implications for dosing medications and for guiding prognostication and management of a transgender patient with kidney disease.

The impact that GAHT may potentially have on kidney biomarkers is important to recognize in the nephrology community as we classify our patients in different stages of CKD, give recommendations on medication dose adjustments, initiate them on renal replacement therapy, and evaluate them for kidney transplantation. Furthermore, estrogen therapy (especially oral formulations) may increase the risk for venous thromboembolism and cardiovascular disease in patients that have CKD, who are already at risk for these disease processes without estrogen therapy. Educating these patients on the risks and benefits of gender-affirming care and its impact on their kidney health is crucial. This may have an additional positive impact on patient adherence and satisfaction. 

Adequate social and structural support is also crucial. The transitioning process may feel stressful, daunting, and isolating. Patients with kidney disease are already identified as having an increased risk of depression and other mental health illnesses. They may feel alone and without support or an advocate. Gender-affirming care (whether medical or surgical) with the proper social and structural support may improve mental health. This may be due to improved trust, access to care, and all-together well-being. It may also improve overall patient outcomes and encourage freedom of expression. With this population seeking more medical care, chronic disease prevention, and acute illnesses may be treated earlier. It may be beneficial to collaborate and develop a multidisciplinary team approach to improve the knowledge, satisfaction, and medical outcomes of these vulnerable patients. This will allow shared decision-making, reduce societal stigma, and improve quality of life by eliminating barriers and empowering a community that may otherwise feel neglected. 

Conclusion

In summary, gender-affirming care may include the medical and surgical interventions described above for some individuals, though others may opt not to pursue these options. Gender-affirming care has implications for all elements of kidney care, including kidney function estimation, CKD, and transplantation. Kidney care professionals will be better equipped to provide high-quality care to all our patients with a greater understanding of gender-affirming therapies and their implications for kidney health. 

– Executive Team Members for this region: Pascale Khairallah @Khairallah_P and Samira Farouk @ssfarouk

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on June 1, 2023.

More NephMadness 2023 Regions

Submit your picks! | #NephMadness | @NephMadness | #TransgenderRegion

Submit your picks! | NephMadness 2023 | #NephMadness | #CardiacDevices

Selection Committee Member: Nisha Bansal @NishaKidneyDoc

Nisha Bansal is an Associate Professor and the Arthur Stach Family Endowed Professor in the Division of Nephrology at the University of Washington (UW). She is also an investigator in the Kidney Research Institute, the Associate Fellowship Program Director and the Director of the Kidney-Heart Service at UW. She is an expert in the pathophysiology, diagnosis and treatment of hypertension and cardiovascular disease in patients with chronic kidney disease and those treated with dialysis.

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Writer: Jen Bergeron @DrJennyBee

Jen Bergeron is a chief and second-year nephrology fellow at Vanderbilt University. She is a graduate of Tufts University School of Medicine- Maine Track and completed her residency at the University of Vermont. Her clinical and research interests include palliative nephrology and ESRD care, sharing her love of renal physiology, and mentorship.

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Writer: Jefferson Triozzi @nepherson

Jefferson L. Triozzi is a nephrology fellow at Vanderbilt University Medical Center where he also serves as a chief fellow. He now pursues a Master’s of Science in Clinical Investigation at Vanderbilt University School of Medicine. His interests are CKD and cardiometabolic diseases.

Competitors for the Heart Failure Devices Region

Team 1: Cardiac Devices in AKI versus Team 2: Cardiac Devices in ESKD

Copyright: zimmytws/Shutterstock

Amidst the political and cultural upheaval of the 1960s, a new era began in medicine—that of heart failure devices. In 1963, Dr. Michael E. DeBakey and colleagues successfully implanted an air-powered pump into the heart of a 37-year-old woman, allowing her to survive cardiogenic shock after open-heart surgery. We’ve come a long way since then, with the emergence of numerous cardiac devices indicated for acute and chronic settings (Table 1). Many technical advancements have been made in the last decade alone. Non-durable cardiac devices provide temporary support for the heart and restore systemic hemodynamics, such as those used during high-risk cardiac interventions or cardiogenic shock. Durable devices offer longer-term options and can serve as a bridge to transplantation or destination therapy. There are a number of factors a nephrologist must consider when caring for patients with a cardiac device. It’s no secret—heart, and kidney function are intricately linked, as we saw in the NephMadness 2022 Cardiorenal Region. Cardiac devices can offer benefits to patients with kidney disease, while simultaneously presenting challenges to the care of our patients. 

Table 1. Non-durable and durable mechanical circulatory support devices.

Team 1: Cardiac Devices in AKI

Acute kidney injury (AKI) is a common complication in patients with advanced heart failure and often leads to long-term kidney dysfunction. In theory, a device that improves cardiac output and kidney perfusion should reduce the risk of AKI. But the story is not so straightforward. 

Copyright: yevgeniy11/Shutterstock

Non-durable devices may reduce the risk of AKI in specific settings 

Cardiac devices used in acute settings include the intra-aortic balloon pump, percutaneous ventricular assist devices (Impella, TandemHeart), and extracorporeal membrane oxygenation (ECMO) machines (Image 1).

a, The intra-aortic balloon pump uses counterpulsation to provide circulatory support and is commonly inserted via the femoral or axillary artery. b, Microaxial flow devices traverse the aortic valve via the femoral or axillary artery and continuously remove blood from the left ventricular (LV) cavity to achieve unloading. c, Transseptal percutaneous assist devices are powered by a centrifugal pump and are inserted via the femoral vein, across the intra-atrial septum and into the left atrium, with an outflow cannula in the femoral artery. Devices using centrifugal pumps require a separate control and monitoring module. d, Venoarterial extracorporeal membrane oxygenation uses a centrifugal pump to pull venous blood from the right atrium, through an oxygenator and into the arterial circulation via the outflow cannula in the aorta. Common cannulation sites include the femoral or axillary vessels or via central cannulation by thoracotomy or sternotomy. Extracorporeal membrane oxygenation can be used for left, right or biventricular support. e, Surgical extracorporeal centrifugal devices provide LV support via sternotomy or minimally invasive thoracotomy. Inflow cannulation is from the left ventricle or left atrium, and outflow cannulation is into the aorta. Figure 1 from Salter et al, Nat Rev Cardiol Copyright © 2022, Springer Nature Limited

Observational data suggests the Impella System lowers the risk of AKI in cardiogenic shock or high-risk cardiovascular interventions. In a case-control study, Impella use during high-risk percutaneous coronary intervention was associated with a lower risk of AKI (adjusted odds ratio = 0.13; 95% confidence intervals = 0.09–0.31, P<0.001) (see Visual Abstract 1 below). In a separate single-center study of patients with all-cause cardiac shock, the subset of patients with AKI demonstrated a significant decrease in serum creatinine with Impella-supported cardiac catheterization. Although these findings are hypothesis-generating and subject to confounding factors, several nephroprotective mechanisms have been proposed. One explanation is that devices maintain continuous kidney blood flow, thereby reducing ischemic tubular necrosis and ensuring an adequate glomerular filtration rate to prevent accumulation of contrast agents. A study in swine found a link between left ventricular unloading and a reduction in the proinflammatory cardiorenal response by placing this device prior to reperfusion in the setting of an acute myocardial infarction. Either way, supporting cardiac output could limit kidney damage when hemodynamics are compromised, at least in the short term.

AKI reversal after durable device placement

LVAD (left ventricular assist device) placement may initially lead to improved kidney function after placement. In a single-center observational study of 131 patients, kidney function improved in 75% of patients within the first month after LVAD placement (Visual Abstract 1). A multivariate analysis found that early AKI reversal was more likely among younger patients with lower baseline kidney function. Reversibility of AKI suggests impaired hemodynamics rather than intrinsic kidney damage as the main driver of kidney injury. Thus, lower baseline kidney function could represent greater potential for improvement due to the relief of venous congestion and the optimization of cardiac output that an LVAD provides. Cardiac devices may even help patients with reversible AKI to wean off of dialysis. In a small cohort of 68 LVAD patients, 5 out of 6 patients on dialysis pre-operatively recovered their kidney function within one month after LVAD placement. One of these patients was able to discontinue dialysis immediately after LVAD placement. The results of a separate meta-analysis examining AKI patients needing dialysis suggested that one-half will recover kidney function (defined as independence from dialysis within two weeks of injury) after the placement of an LVAD. 

The data above suggest that younger patients and those with reversible, hemodynamic forms of AKI have potentially excellent short-term kidney outcomes after durable cardiac device placement. But what happens months and years down the line? Multi-center observational data demonstrates an interesting pattern of change in eGFR over two years after LVAD placement (Image 2). Kidney function improves at first but then declines. Why would this happen?

Image 2. An interesting trend in eGFR after device placement; initially kidney function improves, ultimately kidney function declines.

Durable devices can reverse AKI, but not for long… 

For patients with advanced heart failure refractory to medical interventions, cardiac devices may be needed for the long haul. Ultimately, heart transplantation is the only curative therapy. Originally designed as a temporary “bridge” for those waiting for transplants, LVADs have evolved to become an essential long-term treatment option for patients ineligible for transplantation. The technology behind these devices has improved drastically—they have become smaller and more efficient (Image 3), allowing patients to live active lifestyles while receiving aid from the device. Additionally, LVADs can assist in cardiac recovery, providing hope to those suffering from heart failure. 

There are many factors that ultimately lead to a decline in kidney function after cardiac device placement. The risk of AKI after LVAD placement is estimated between 5.1 to 33.3%. Not unexpectedly, those who develop AKI after device placement have decreased survival. There are many factors that could contribute to AKI, including perioperative factors, hemodynamic changes, vascular injury and non-pulsatile flow, hemolysis, and other much rarer tubular and glomerular pathologies. 

We also note the challenges in measuring and monitoring kidney function in patients with advanced heart failure. Traditional creatinine-based formulas may not be accurate due to reduced muscle mass and creatinine production in these patients. Alternative markers, such as cystatin-C and NGAL, have modest success in this patient population. Ongoing research is seeking to better understand the unique challenges of kidney function assessment in the setting of advanced heart failure disease and to develop more reliable methods for measurement.  

Perioperative & Hemodynamic Factors

Placing an LVAD is no walk in the park. LVAD implantation remains a high-risk surgery, with life-threatening complications potentially occurring in the perioperative phase. The use of cardiopulmonary bypass during LVAD placement increases the risk of AKI by triggering systemic inflammation, impairing vasomotor tone, and potentially creating microemboli in the renal capillaries. Excessive bleeding during surgery or the need for surgical revision could also contribute. 

The tenuous hemodynamic status of patients with cardiac devices further predisposes patients towards AKI. Patients with an LVAD can develop right ventricular dysfunction, which may lead to kidney venous congestion and nephrosarca. It is estimated that 20%-50% of LVAD implantations are complicated by right heart failure (RHF). Therefore, RHF preventative strategies focus on managing the preload and afterload of the right ventricle and using vasodilators to reduce pulmonary vascular resistance. In extreme cases, surgery to also implant an RVAD (right ventricular assist device) may be necessary. However, RVAD placement in the setting of clinically severe right heart failure is often unsuccessful, leading some to advocate for RVAD placement much earlier.

Vascular injury

While early LVAD iterations attempted to mimic the pulsing action of a healthy heart, subsequent devices using continuous flow demonstrated superior patient outcomes and device durability. However, novel studies suggest the continuous blood flow generated by the LVAD may harm the kidneys over time. In a calf animal model, investigators showed that reduced pulsatility produced severe periarteritis in the kidneys (make sure to check out the pathology pictures in this article), which was associated with an upregulation of the local renin-angiotensin system and inflammation. Other vascular changes, such as increased stiffness of the aorta, may be related to non-pulsatile blood flow.

Hemolysis

Hemolysis is common in cardiac devices due to the level of shear stress on red blood cells. Additionally, turbulent blood flow, such as from clot formation in the LVAD pump or inadequate pump speed settings, exacerbates damage to red blood cells. Hemolysis, whether overt or subclinical, can lead to worsening kidney function in several ways. Pigment nephropathy due to LVAD-related hemolysis has been reported. Recently, investigators have identified a proximal tubulopathy related to chronic hemolysis in LVAD patients. The authors identified LVAD patients with proteinuria, glycosuria, and potassium and phosphorus wasting. The authors speculated that the mechanism of proximal tubulopathy was due to LVAD-related hemolysis, similar to the Fanconi-type syndrome seen in hemolytic conditions like sickle cell disease or paroxysmal nocturnal hemoglobinuria. In addition to increasing the risk of AKI, hemolysis is associated with both increased risk for cerebrovascular accident and death. Therefore, some centers routinely monitor plasma-free hemoglobin to proactively detect hemolysis and prevent complications, though it is unclear if this practice improves outcomes. When hemolysis is identified, echocardiography can help to identify mispositioning that may be causing obstruction to the device’s inlet or outlet. In cases where hemolysis is accompanied by a drop in effective blood volume, blood transfusions or volume expansion may also be necessary. 

Glomerulonephritis

Subepithelial hump-like deposits in postinfectious glomerulonephritis. The deposits are irregularly spaced and frequently mottled. The deposits sit on top of the basement membrane with limited or no adjacent basement membrane reaction (electron microscopy). Figure 6 from Fogo et al, AJKD © National Kidney Foundation.

Lastly, development of glomerulonephritis has been described in a case series of patients with LVAD. The authors describe a rare form of “LVAD vasculitis” which presents with infection, skin rash, and AKI. Kidney biopsies of these patients demonstrated infection-associated glomerulonephritis (Image 4). Of note, drive-line infections are the most common non-surgical complication after implantation. 

Device innovation

Image 5. Comparing axial flow pumps with centrifugal flow pumps.

Newer iterations of ventricular assist devices using different flow techniques may prove beneficial for patient outcomes. There have been notable changes in technologies, including a shift from axial to centrifugal flow (Image 5). The landmark REMATCH trial brought axial flow technology to the masses in 2001. Axial flow pumps work by a propeller in a pipe screwing itself into the incoming blood and pushing it towards the outlet. More recently, the MOMENTUM 3 trial showed that a novel magnetically levitated centrifugal continuous-flow LVAD (HeartMate3) had better outcomes than axial pumps. Centrifugal flow pumps more gently capture incoming blood in a centrifuge and sweep it tangentially off the blade tips into the outlet pipe. 77% of patients who received the centrifugal LVAD remained alive and free of disabling stroke or reoperation to replace/remove a malfunctioning device at two years compared to 65% of patients with axial LVADs (relative risk 0.84, 95% confidence intervals = 0.78–0.91). Centrifugal flow pumps had improved hemocompatibility which decreased the occurrence of de novo pump thrombosis, ischemic and hemorrhagic strokes, and nonsurgical bleeding. The HeartMate3 introduced another interesting feature—an artificial pulse created by alternating the speed of the pump every two seconds. Whether this technology will positively impact kidney outcomes is unclear. Regardless, HeartMate3 has largely replaced previous models in practice.

Patient Selection and Prognosis

As discussed above, LVAD implantation is a complicated procedure with high morbidity and mortality. Real-world data after Momentum 3 showed that 5-year survival was 59% in the centrifugal-flow pump group and 44% in the axial-flow pump group (p=0.003), suggesting that newer LVADs might have a slight survival benefit, though overall outcomes are still poor. The HeartMate 3 Risk Score was validated to predict mortality after LVAD placement. Not surprisingly, kidney biomarkers (identified by serum sodium and BUN) are the strongest predictors. Whereas younger patients with reversible AKI may have lower risks, older patients with baseline chronic kidney disease may have higher risks. Traditionally, baseline eGFR < 30 mL/min was a relative contraindication to LVAD placement, but as device placement has become increasingly commonplace there are more patients with more advanced kidney disease who qualify for a device. Optimizing nephrology care before and after surgery is vital to improve outcomes.

Team 2: Cardiac Devices in ESKD

The number of patients with LVADs who require long-term dialysis is on the rise. The risk of requiring kidney replacement therapy after LVAD placement ranges from 9.0% to 38.1%. This is mostly due to the high prevalence of chronic kidney disease in heart failure patients and the risk of irreversible AKI after device implantation. And although “irreversible kidney disease” is listed as a contraindication for device placement per the American College of Cardiology, we are starting to see small but growing numbers of LVAD placements in patients with end-stage kidney disease (ESKD).

Copyright: ded pixto/Shutterstock

Outcomes are poor—how can we improve them?

Outcomes for patients with LVADs are tracked by two large registries: INTERMACS (US patients with FDA-approved devices) and EUROMACS (European registry for patients with mechanical circulatory support devices). The data are clear: Patients with LVADs who require kidney replacement therapies have poor outcomes. Early studies revealed 30% mortality within 3 months for patients with ESKD after LVAD implantation. In one study of Medicare claims and USRDS data that included 155 patients with ESKD, patients with ESKD and an LVAD survived a median of 16 days compared to a median of 2,125 days for patients with an LVAD but without ESKD (Visual Abstract 3). How can we improve these outcomes and support patients until transplant? 

Hemodialysis

Patients with LVADs can safely receive hemodialysis but face unique challenges. One important issue is that most outpatient dialysis units do not admit LVAD patients as part of their patient population, due in large part to uncertainty around dialysis staff’s technical expertise. Nevertheless, some dialysis centers have developed structured programs to successfully provide dialysis care for LVAD patients. In a retrospective case series of LVAD patients requiring outpatient hemodialysis, most patients survived to transplantation or kidney recovery (Image 6). This study reported that dialysis was well-tolerated (~90% of dialysis sessions free of symptoms) with low dialysis-related adverse events (~5% of treatments with symptomatic hypotension). Below, we will review some considerations related to hemodynamics and blood pressure, vascular access, infection risk, and anemia management that are unique to LVAD patients requiring outpatient hemodialysis.

Timeline for patients receiving outpatient hemodialysis with left ventricular assist device (LVAD) support. Figure 1 from Franz et al, AJKD © National Kidney Foundation.

Hemodynamics and Blood Pressure

Continuous flow devices do not generate a palpable thrill or bruit…or pulse, for that matter! Point-of-care ultrasound can be used to assess flow, and ultrasound/doppler-guided blood pressure techniques are also possible. Patients with cardiac devices may be more sensitive to hemodynamic shifts that occur related to intermittent dialysis. Nursing and staff must be trained to understand the LVAD settings to ensure safe limits are maintained for parameters (including the pump speed, flow, and pulsatility index) which are affected by changes in preload and afterload. 

Access

Fistulas are a safe and effective way to provide dialysis access in patients with LVADs. It was previously thought that the non-pulsatile blood flow of continuous flow devices would impair fistula maturation, but this did not turn out to be the case in several reports. In 2020, a case series showed that arteriovenous grafts were also safe in patients with LVADs (Image 8). Moreover, HD central venous catheters have a significantly increased risk of developing bacteremia. The presence of a catheter and an intravascular device puts these individuals at especially high risk for infection. Alternative options such as arteriovenous fistulas or arteriovenous grafts could provide safer and more efficient means of access than catheters (Image 7).

Timeline of arteriovenous graft (AVG) placement and use. Abbreviation: VAD, ventricular assist device. Figure 1 from Toma et al, Kidney Medicine © National Kidney Foundation.

Risk of Infection

We know that patients requiring long-term renal replacement therapies are vulnerable to infections, often related to vascular access. Infections remain the most common complication of LVAD devices, too. These include infective endocarditis, bloodstream infections, mediastinitis, and contamination of the soft tissue at or near the site of cardiac device implantation. Driveline infections are the most common cause. The driveline connects the LVAD controller and batteries, which remain outside of the body, to the internal thoracic pump. The driveline is tunneled in the subcutaneous space, providing a focus of entry for microbes to colonize the device and form biofilms. Management of such driveline infections includes 2-4 weeks of targeted antimicrobial therapy, but severe or refractory cases may require chronic suppressive antibiotics or driveline exchange for source control. The risk of infection from vascular access and drivelines combined represents a considerable morbidity and mortality in these patients.

Anemia

Patients requiring both dialysis and a heart failure device have a compounding risk for severe anemia (related to anemia of chronic disease), gastrointestinal bleeding due to anticoagulant requirements, and hemolysis (explored above). In addition, both dialysis and heart failure devices raise challenges related to managing anemia. Blood transfusions come with the risk of sensitization prior to solid organ transplantation. And while the use of erythropoiesis-stimulating agents (ESAs) with LVAD can help address low red blood cell levels, the thrombosis risk may be heightened for patients with cardiac devices (Visual Abstract 4). A retrospective study identified increased pump thrombosis in LVAD patients receiving ESAs. This finding was dose-responsive and even found that the use of ESAs was associated with a higher rate of all-cause mortality (HR 1.62). Although these data are subject to residual confounders, it is something we should be cautious about.

Peritoneal dialysis 

Peritoneal dialysis (PD) was traditionally contraindicated for patients with LVADs because the driveline disrupted the peritoneal membrane. Newer devices leave the peritoneal cavity intact, allowing for safe PD. PD may offer several potential benefits for patients with LVADs, including gentle ultrafiltration and a lower risk of catheter-related infections. PD may also preserve residual kidney function which has been shown in several studies to impact survival and patient quality of life. Given the frequent vascular interventions that LVAD patients often undergo, finding adequate anatomy for creating an arteriovenous fistula or graft may not be feasible—making PD a great option. Additionally, PD allows for the possibility of providing dialysis care at home, which can be particularly advantageous since many outpatient facilities may not have experience safely dialyzing LVAD patients (as above). 

Practical Hurdles

Outpatient dialysis care for patients living with heart failure devices poses unique practical challenges. It is also of utmost importance that nephrologists work closely with advanced heart failure physicians to make sure all available treatment options are discussed and weighed for each patient. Many patients, such as those in rural areas, may not have easy access to centers providing this highly specialized care. Furthermore, the existing dialysis centers rural patients have access to likely do not have staff with the special training to adequately care for patients with heart failure devices. Education and training programs for dialysis staff on working with patients with LVADs is required. The emphasis on home dialysis modalities, including PD and home hemodialysis (HHD), have been successful in circumventing these hurdles. Novel approaches using telemonitoring could prove beneficial by expanding access and monitoring for these patients. 

Ethical Issues

The use of advanced cardiac devices, much like that of dialysis, has raised several ethical questions since its creation. These issues are magnified when patients require not one, but two forms of life-support for the heart and kidneys. Care teams must weigh the risks and benefits of life-sustaining modalities in terms of beneficence/non-maleficence, futility, and respect for patients’ autonomy in deciding if this new condition is acceptable to them or not. Deactivation of LVADs, much like discontinuation of dialysis, is an ethical quagmire. Health and legal systems worldwide vary on end-of-life care for patients with devices, with nuances between “allowing a patient to die” and physician-assisted suicide. There are many other unanswered questions. For example, if a dialysis patient is receiving a cardiac device as a bridge to transplantation, but then develops a contraindication for transplantation, should terminal deactivation of the cardiac device be discussed? When is the treatment considered futile? What if the patient asks for deactivation? How do we best evaluate patients with dual organ failure for transplantation? Both dialysis and cardiac devices are costly—should we factor in societal justice into the care of these patients?

Shared decision-making with nephrologists, cardiologists, transplant teams, and our patients is important when considering the appropriateness of cardiac devices for patients with ESKD. Although irreversible kidney failure is a contraindication for device placement, perhaps some dialysis patients would indeed benefit from device placement, such as those likely to survive until transplantation. In one study, the median time to death after LVAD placement in ESKD was an abysmal 16 days, with very few making it alive long enough to transplant. A closer look at the data reveals that the interquartile range of survival spans up to 447 days. Identifying the subset of patients with ESKD in which device placement may prolong life in a meaningful way is critical to promoting their care.

Conclusion

The use of cardiac devices has grown rapidly in recent years, with many areas needing improved care that nephrologists can provide. As we discuss the role of cardiac devices in AKI and ESKD, there are a few key points to consider. On one hand, we have the potential benefits—using short-term devices during cardiogenic shock or high-risk interventions, or long-term devices as a bridge to transplantation or destination therapy. On the other hand, we must consider the increased risks of complications, including death, especially for patients with advanced kidney disease or those requiring chronic dialysis. Caring for these patients presents challenges related to complex hemodynamic needs. It can be tricky to navigate, but ultimately teamwork and collaboration are key in ensuring that cardiac devices are used effectively. 

– Executive Team Members for this region: Anna Burgner @anna_burgner and Samira Farouk @ssfarouk

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on June 1, 2023.

More NephMadness 2023 Regions

Submit your picks! | #NephMadness | @NephMadness | #CardiacDevices

Submit your picks! | NephMadness 2023 | #NephMadness | #MRAregion

Selection Committee Member: Matt Luther @DrJMLuther

Matt Luther is Associate Professor at Vanderbilt Medical Center, where he directs the Hypertension Center. He completed Internal Medicine, Nephrology, and Clinical Pharmacology training at Vanderbilt prior to joining the faculty there. His research program investigates the role of aldosterone, epoxyeicosatrienoic acid, and related hormones in the pathogenesis of hypertension and diabetes.

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Writer: Micah Schub @AcidBassMD

Micah Schub is a second-year nephrology clinical fellow at Duke University. He is a graduate of University of Pittsburgh School of Medicine in Pittsburgh, PA, and completed his residency at Duke University in Durham, NC. His clinical and research interests include kidney transplantation, clinical reasoning, and medical education.

Competitors for the Mineralocorticoid Receptor Antagonists (MRAs) Region

Team 1: Steroidal MRA versus Team 2: Nonsteroidal MRA

Copyright: chaoss/Shutterstock

Introduction

What if I told you that the one you were meant to spend your life with is from your past? They were right under your nose the whole time. Now, you’ve both grown up, dated others and found purpose outside of your past relationship. Is now the time to rekindle that old flame? You may think that I’m describing the premise of the reality television show “The One That Got Away” on Amazon Prime, but clearly we are talking about mineralocorticoid receptor antagonists (MRAs) for the treatment of chronic kidney disease. In this region we will be pitting the old flame against the shiny new thing—steroidal versus nonsteroidal MRAs.

The global prevalence of chronic kidney disease (CKD) is roughly 9.1% of the world’s population, which equates to approximately 800 million people, highlighting the massive scale of this problem. Since the early 1990s, it’s been well established that renin-angiotensin system (RAS) inhibition with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), slows the progression of chronic kidney disease in patients with proteinuria. This benefit is present in patients with and without diabetes.

Within the last 10 years, sodium-glucose cotransporter 2 (SGLT2) inhibitors have burst onto the scene, further slowing the progression of CKD in patients on ACEi and ARB therapy. Despite these medical success stories, two thirds of patients with CKD will have a decline in their kidney function over time, and 1%-2% of these patients will progress to kidney failure. This epidemiologic data highlights the clear need for additional treatments to slow the progression of CKD. Enter MRAs.

There are many proposed mechanisms to explain the kidney protective effects of MRAs, here are but a few: 

1. Decreased intraglomerular pressure – This prevents podocyte injury and ameliorates proteinuria, and is mediated by a decrease in renal vasoconstriction and overall improvement in intraglomerular hemodynamics. As has been seen in studies of RAS inhibitors and SGLT2 inhibitors, there is an initial drop in estimated glomerular filtration rate (eGFR) followed by a slowing of kidney function decline over time. There may also be a contribution from the renoprotection afforded by decreased systemic blood pressure.
2. Attenuating aldosterone breakthrough – Up to 50% of patients treated with RAS inhibitors will have an increase in their serum aldosterone levels after starting treatment. This is known as “aldosterone breakthrough.” Not only do aldosterone levels increase in these patients, but urinary albumin excretion was higher. The addition of spironolactone in patients with aldosterone breakthrough led to a further reduction of urinary albumin excretion. Other studies have also shown a trend toward improved kidney protection afforded by MRAs in patients on RAS inhibition compared to patients not on RAS inhibition. It is tempting to think that it is the patients with aldosterone breakthrough that are responsible for this difference. All of this clinical and preclinical data goes to show that aldosterone is a potent mediator of kidney dysfunction independent from angiotensin II.
3. Cardiovascular protective effects – This is not only due to the improved decongestion secondary to MRAs diuretic properties, but also direct cardiac benefits aimed at reducing perivascular inflammation and interstitial fibrosis. Furthermore, there is evidence of smooth muscle MR activation in the pathogenesis of hypertension, atherosclerosis, and vascular aging.
4. Reduced oxidative stress and inflammation in the kidney – Aldosterone leads to MR-dependent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and reactive oxygen species generation. Endothelial MR receptors facilitate an inflammatory response mediated by perivascular infiltration and increased expression of inflammatory mediators. In mouse models of salt and aldosterone-induced hypertension, kidney biopsies showed severe vascular and glomerular sclerosis, fibrinoid necrosis, and thrombosis consistent with hypertensive kidney disease. There was also a significant inflammatory component of leukocytic infiltration and a myriad of inflammatory mediators. Treatment of these mice with the steroidal MRA eplerenone decreased leukocytic infiltration and decreased gene expression of inflammatory mediators including osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, and IL-1.

Compared with controls treated with (left) vehicle alone, (right) aldosterone (8 μg/kg/d) is capable of inducing early fibrotic interstitial changes in both cortex and medulla after only 1 week in adrenalectomized mice without pre-existing hypertension or kidney injury. Blue staining represents collagen matrix. (Original magnification, ×400.) Figure 2 from Huml et al, AJKD © National Kidney Foundation.

Of course, the elephant in the room when discussing MRAs is the dreaded side effect of hyperkalemia. This is due to downregulation of epithelial sodium channels (ENaC) in the principal cell of the collecting duct and decreased activity of sodium-potassium (Na/K) ATPase. This leads to decreased intracellular potassium and a more positive luminal electrochemical gradient, and ultimately to decreased potassium secretion into the tubular lumen. Hyperkalemia thus is an on-target effect, and when present indicates adequate blockade of the MR. Now that we’ve discussed the basis for mineralocorticoid receptor antagonism, let’s get to the matchup.

Team 1: Steroidal MRA

2001 was a year of numerous important events: Wikipedia was launched, the Microsoft Xbox was released, Harry Potter and the Sorcerer’s Stone burst into theaters, Justin Timberlake and Britney Spears wore all denim to the MTV VMAs. But perhaps most significantly, this was the year that spironolactone was first shown to reduce proteinuria in patients with reduced kidney function already on RAS inhibition. Patients in this study had proteinuria >1 g/day despite treatment with enalapril for 1 year. After 4 weeks of taking a modest 25 mg dose of spironolactone, a 54% reduction in proteinuria was observed. The improvement couldn’t be attributed to blood pressure, as it did not change. Despite this being a small, uncontrolled, observational study (only 8 patients), the reduction in proteinuria was hard to ignore. Furthermore, these findings have held up in larger studies and controlled trials.

Copyright: Maksim Shmeljov/Shutterstock

Proteinuria reduction is nice, and multiple studies have shown that reducing proteinuria correlates with kidney protection. Despite proteinuria reduction, hard data on eGFR decline and reducing need for kidney replacement therapy (KRT) is needed to convince the masses that steroidal MR antagonism is truly kidney protective. The good news is, those studies have existed for years. In a trial of 165 patients comparing spironolactone 25 mg versus standard of care treatment with RAS inhibition, the spironolactone arm showed a decrease in eGFR over the first month but then a stabilization of eGFR. After the first month, the control arm experienced a progressive decline in eGFR. When the study ended at 1 year, there was no difference in eGFR giving this trial the label of “negative study”. But similar to our other renoprotective medicines (RAS inhibitors, SGLT2 inhibitors), the initial drop in eGFR muddied the picture and the primary outcome. 1 year was not long enough to see a benefit when studying these medicines. The spironolactone group had begun moving toward an improved eGFR, and had the trial continued, the groups likely would have separated. 

Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int. 2006;70(12):2116-23.

The spironolactone group did show an increased incidence of hyperkalemia, including severe hyperkalemia (K >5.5 mg/dL), although more than half the patients were on combination ACE inhibitor and ARB therapy and this appeared largely responsible for the hyperkalemia. 

Now we know what you’re thinking when you hear about 10-year-old studies and proteinuria reduction—does any of this matter now that SGLT2 inhibitors have become standard of care? The short answer is “probably.” The Rotate 3 trial aimed to address this with 2 important questions: 

1. Does the addition of a MRA (eplerenone) to an SGLT2 inhibitor (dapagliflozin) reduce albuminuria
2. Will some patients respond to one drug and not the other? 

With regards to question #1, the answer was “yes.” The trial showed an additive reduction of albuminuria when the medication classes were used in combination. This additive effect was similar to findings in DAPA-CKD for patients already on an MRA. The combination group also saw a reduction in hyperkalemia compared to the eplerenone alone group, demonstrating another benefit of combination treatment. Interestingly, there was no association between individual UACR changes during the dapagliflozin and eplerenone periods. The fact that the same patient would respond to one class but not the other indicates an important role for both MRAs and SGLT2 inhibitors. These results not only support an additive effect of combined SGLT2 inhibitor and steroidal MRA treatment, but also a role for MRAs in patients who don’t see a reduction in albuminuria with SGLT2 inhibitor therapy alone.

https://pubmed.ncbi.nlm.nih.gov/35257056/

The greatest barrier limiting uptake of Team Steroidal MRAs for kidney disease is that pesky side effects, namely hyperkalemia. The RALES trial was published in 1999 showing a reduction in all cause mortality by treating heart failure with reduced ejection fraction (HFrEF) with 25 mg of spironolactone. Hyperkalemia leading to discontinuation of the drug was not higher in the spironolactone group. Unfortunately, publication of this trial led to a massive spike in spironolactone prescriptions and hospitalizations for hyperkalemia increased, indicating that hyperkalemia outside of a trial was a significant risk. Similar issues with hyperkalemia have been seen in the resistant hypertension population, indicating that this is not isolated to the heart failure population. These findings have largely limited the uptake of these drugs.

Since that time, safe and effective potassium binders have been introduced, calling into question the applicability of a study like this. The use of potassium binders to allow for continued MRA use in the CKD population was studied in the AMBER trial. Patients in the trial all had an eGFR between 25 and 45 and were being treated for resistant hypertension. The investigators were able to show that use of patiromer in conjunction with spironolactone decreased the rate of spironolactone discontinuation when compared to spironolactone alone. The difference in the rate of discontinuation between the 2 groups was more profound at lower eGFRs, indicating a particular benefit to using potassium binders in advanced CKD. With increased monitoring and the use of potassium binders, steroidal MRAs are safer than ever. The increasing efficacy and safety profile of these medicines has to make one wonder, “Was true love in plain sight?”

Team 2: Nonsteroidal MRA

Copyright: Petair/Shutterstock

Ludwig Van Beethoven is arguably the greatest classical composer to ever live. He was prolific in his contribution to the orchestral and instrumental literature, but only wrote one opera (We promise this will come back to MRAs, bear with us). Originally titled “Leonore”, the story follows the politically imprisoned Florestan and his wife Leonore’s exploits in trying to free him. Leonore disguised herself as a boy named Fidelio in order to infiltrate her husband’s prison and free him. The opera underwent 2 revisions after lackluster premieres, and was later rebranded as “Fidelio” to rave reviews and a permanent place in the operatic zeitgeist.

http://www.lvbeethoven.com/Cartes/Cards03Fidelio.html

Finerenone, the most prominent member of Team Nonsteroidal MRA, has a history as an imposter not dissimilar to Leonore. In the search for new antihypertensive medicines, it was discovered that dihydropyridine calcium channel blockers display mineralocorticoid receptor antagonist activity. Finerenone is a dihydronaphthyridine and a close cousin of nimodipine, a calcium channel blocker. The specific configuration of finerenone was found to have potent and selective inhibition of the mineralocorticoid receptor. Thus, an obscure relative of a calcium channel blocker was rebranded as a nonsteroidal MRA, and a successful premier followed.

In 2010, initial interest in MRAs as kidney protective agents had lost steam, and gave way to SGLT2 inhibitors as the nephrology community’s primary pharmacologic focus. The introduction of finerenone and the nonsteroidal MRAs has reignited the conversation around mineralocorticoid receptor antagonism as a kidney protective strategy. Early trials on finerenone showed that when compared to placebo, finerenone led to decreased proteinuria. Although these studies demonstrated promise for CKD treatment they did not include patients with low eGFR or assess hard kidney outcomes (due to short duration), obscuring both the true risk of hyperkalemia and the benefit in addressing a composite kidney outcome. 

FIDELIO-DKD enters, stage right (the intro to this section is finally making sense). This trial explored the effect of finerenone with primary kidney endpoints in patients with type 2 diabetes. It was a multi-centre, international, randomized, double-blinded, interventional trial comparing finerenone to placebo. Participants had a urinary albumin to creatinine ratio (UACR) between 300 and 5000 mg/g and an eGFR ≥ 25 but < 75 mL/min/1.73 m². UACRs down to 30 mg/g were included if diabetic retinopathy was present. Almost 90% of patients in the trial had an eGFR <60 mL/min/1.73 m². The primary outcome was a composite of death from kidney causes, kidney failure (dialysis ≥ 90 days, transplantation, or eGFR < 15 ml/min), and a sustained decrease of at least 40% in the eGFR from the baseline. The primary outcome occurred in 17.8% of patients in the finerenone group and 21.1% in the placebo group. The absolute, between-group difference was 3.4% after 3 years (hazard ratio 0.82 [0.73-0.93; P=0.001]), yielding a Number Needed to Treat of 29 over 3 years. The primary outcome was driven mostly by the 40% decrease in eGFR, as this was responsible for more than two thirds of total events. It should also be noted that in contrast to the large Flozin trials, including DAPA-CKD and EMPA-KIDNEY, there was no significant difference found in progression to kidney failure. As of now, these results are only applicable to the diabetic kidney disease population, but the FIND-CKD trial that is currently underway will address the efficacy of finerenone in patients with CKD without diabetes and UACR of 200-3500 mg/g and eGFR 25-90 mL/min/1.73 m².

https://pubmed.ncbi.nlm.nih.gov/33264825/

Rates of hyperkalemia were more common in the finerenone group (18.3%) than placebo (9%). Serious hyperkalemia occurred in an overall small subset of the population (1.6% on finerenone versus 0.4% on placebo). 2.3% of participants receiving the study drug discontinued the trial because of a high potassium, compared to 0.9% in the placebo arm. While these results appear to present a favorable picture of the hyperkalemia risk, this may be obscured by the trial’s run-in period. 13,911 patients were enrolled in the trial and 2,181 patients were excluded due to a serum potassium >4.8 mmol/L. A total of 7,114 patients made it to the run-in period where, over 12 weeks, the doses of ACE inhibitors and ARBs were escalated to maximally tolerated doses. A further 640 patients (9.0%) had serum potassium >4.8 mmol/L at the end of this period and were excluded from the trial. This run-in period has been referred to as a hyperkalemia stress test (primarily by the authors of this region). The uptitration of ACE inhibitors and ARBs to maximal doses may have exposed patients who would have been susceptible to hyperkalemia with the addition of an MRA. The exclusion of these patients from the trial could be part of the explanation for why the hyperkalemia side effect profile appeared so favorable. Additionally, use of potassium binders was not equal between the 2 groups. After the start of the study 307 patients (10.8%) in the finerenone group and 184 patients (6.5%) in the placebo group were started on potassium binders. Without any head-to-head trials between steroidal and nonsteroidal MRA, we cannot be certain of the hyperkalemia risk, although the data from FIDELIO-DKD is promising and gives a framework for helping to identify the patients at risk and strategies to mitigate hyperkalemia. Gynecomastia was all but absent in FIDELIO-DKD, similar to studies of eplerenone. This is in contrast to high dose spironolactone, where prevalence of gynecomastia reaches upwards of 50% (see figure below showing the specificity of MR antagonists to various receptors).

Only 5% of patients were on SGLT2 inhibitors in FIDELIO-DKD, as the recruitment period was from 2015-2018, prior to publication of the large flozin trials. Now that flozination has become standard of care, it becomes difficult to interpret the results of this trial. Unlike steroidal MRAs and the ROTATE-3 study, there has yet to be a larger randomized trial with primary kidney endpoints assessing the use of finerenone in conjunction with SGLT2 inhibitors. Fortunately the CONFIDENCE trial, which will be assessing finerenone in combination with empagliflozin, is currently enrolling. We are hopeful that combination therapy will lead to not only a reduction in albuminuria, but also a mitigation of hyperkalemia. FIDELIO-DKD is a large, well-designed randomized control trial clearly showing the kidney protective effects of nonsteroidal mineralocorticoid receptor antagonists. It’s also well argued that these drugs are safe with appropriate monitoring. The cardiovascular effects of finerenone are also demonstrated in the 7,437-patient RCT FIGERO-DKD. This study examined cardiovascular primary outcomes in patients with type 2 diabetes and CKD (eGFR 25-90 and UACR of 30-300 mg/g or and eGFR >60 mL/min/1.73 m² and UACR of 300-500 mg/g). The composite cardiovascular outcome in this trial was positive driven by decreased hospitalization for heart failure. Key secondary kidney outcomes were not positive but close. 

While finerenone is the most prominent and well-studied nonsteroidal MRA, this class of medications is growing. Exaserone has been approved in Japan for the treatment of hypertension with growing use in heart failure and ocedurenone is currently being studied for the treatment of poorly controlled hypertension in CKD. With the promising findings in FIDELIO and the ongoing studies of new agents, it does appear that the time is now for this exciting class of medications. Nonsteroidal MRAs have reignited the conversation around the renoprotective benefits of MRA, and thrust this class of medicines into the next frontier of renoprotection.

– Executive Team Members for this region: Matt Sparks @Nephro_Sparks, Anna Burgner @anna_burgner

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Selection Committee Member: Dana Rizk @DanaRizk1

Dana Rizk is Professor of Medicine in the Division of Nephrology at the University of Alabama at Birmingham. Her main clinical and research interests revolve around IgA Nephropathy focusing on multi-disciplinary translational projects of diagnostic and prognostic disease biomarkers. She is also site principal investigator on many IgAN clinical trials.

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Writer: Dana Larsen  @dana_m_larsen

Dana Larsen is a nephrologist at University of California, San Francisco, after completing her fellowship there while earning her Master of Arts in Education from the University of California, Berkeley, in 2022. Her research focuses on understanding how learners are engaging with Free Open Access Medical education (FOAMed) resources. She is a 2022 graduate of NSMC.

Competitors for the IgA Nephropathy Region

Team 1: Non-immunosuppressive Therapy in IgA Nephropathy versus Team 2: Supportive Care with Immunosuppression

Copyright: Ethan Daniels/Shutterstock

“Put me in, coach!” – Immunosuppression as a playmaker for the treatment of IgA nephropathy

This bracket highlights an age-old rivalry, like the ones between Indiana and Purdue or Duke and North Carolina. In its long history, each side has held the advantage at times, so this year’s match is sure to be a close one. The players are on the court; now it’s time for tip-off.   

Overview

IgA nephropathy is the most common cause of primary glomerulonephritis worldwide (obligatory opening sentence). Peak incidence occurs in the second and third decade of life with a 2:1 male-to-female predominance in the United States versus a 1:1 sex distribution in Asia. While it was once considered “benign hematuria,” IgA nephropathy is now recognized as a major contributor to the global kidney health burden with 15%-20% reaching kidney failure within 10 years of kidney biopsy diagnosis and 20%-40% doing so within 20 years.  

Defining the pathogenesis of IgA nephropathy is important for understanding the potential role of immunosuppression and supportive care measures. It is thought to comprise 4 key elements in a multi-hit process (Figure below).

The etiology of primary IgA nephropathy is still being elucidated, with current research seeking to identify triggers from amongst broad potential factors: infection, environment, etc. The disease is now identified as an autoimmune process that occurs in the genetically predisposed host. IgA nephropathy has also been associated with various clinical diseases including cirrhosis, inflammatory bowel disease, psoriasis, Sjogren syndrome, and HIV infection, and in those instances is referred to as secondary IgA nephropathy. IgA nephropathy can also occur in the context of systemic IgA vasculitis (previously known as Henoch Schonlein purpura) with dermal, gastrointestinal, and articular manifestations. While IgA vasculitis is more common in children, it tends to be a self-limiting disease when compared to adult onset.

The clinical presentation of IgA nephropathy is highly variable. Adults generally present with proteinuria, microscopic hematuria, hypertension, and elevated serum creatinine, whereas children and young adults most commonly present with macroscopic hematuria during an upper respiratory tract infection (“synpharyngitic hematuria”). Less than 10% of patients present with rapidly progressive glomerulonephritis (RPGN) or nephrotic syndrome. In IgA vasculitis with nephritis, well-described extra-kidney manifestations include palpable purpura, arthritis, and abdominal pain. Definitive diagnosis of IgA nephropathy requires a kidney biopsy. The hallmark of IgA nephropathy is IgA-dominant deposits in the glomerular mesangium, though it commonly also presents with C3 positivity (about 90% of cases) and IgG (up to 60%). Pathology specimens in IgA nephropathy and IgA vasculitis with nephritis are indistinguishable.

Stratification of relative risk for disease progression in patients with IgA nephropathy is crucial in management decisions. Clinical stratification can be determined at time of biopsy via the International IgA Nephropathy Prediction Tool (IIgAN-PT), which calculates the five-year risk of a 50% decline in eGFR or progression to kidney failure using the following information:

• There is a decreased risk of progression with < 1g/day proteinuria and perhaps even greater risk reduction for those with <0.5g/d
• Hypertension > 140/90 mmHg is predictive of a worse outcome 
• Decreased eGFR at the time of diagnosis and during the course of disease is predictive of worse outcomes
• Pacific Asian origin has been associated with an increased risk of end-stage renal disease (adjusted HR 1.56)
• Histologic features are evaluated using the Oxford classification system

The Oxford classification system was developed in 2009 by the International IgA Nephropathy Network. Aiming to standardize IgA nephropathy grading and provide histological risk stratification to accompany clinical risk, the Oxford score initially comprised 4 key categories: mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, and tubular atrophy and interstitial fibrosis (MEST). Each has independently been validated to be predictive of kidney outcomes in independent studies, though the largest validation trial (the VALIGA cohort) did not confirm endocapillary hypercellularity as an independent risk factor for progression. The impact of crescents (C) remains challenging in this classification system due to the exclusion of RPGN from the original classification development cohort. By combining four large cohorts retrospectively, however, the presence of crescents was found also to be a significant and independent predictor of kidney failure risk. The overall metric is validated in both adults and children with a minimum requirement of an adequate biopsy specimen of 8 glomeruli. Patients with eGFR <30 mL/min/1.73 m² were excluded and the primary outcome of risk stratification was progression to kidney failure or a decrease in eGFR by more than 50%.

Treatment goals in all patients with IgA nephropathy are to slow down eGFR loss. Higher levels of proteinuria have been associated with more rapid progression of kidney disease in patients with IgA nephropathy, and reduction of proteinuria has been shown to be protective. In clinical practice, a resolution in microscopic hematuria is also targeted, though the use of this as a marker for treatment efficacy is unproven. 

The opponents in this matchup both start the game with their supportive therapy treatments on the court. The decision on whether (and when) to bring immunosuppression off the bench and the amount of playtime allotted will be critical in determining the winner of this matchup. 

Copyright: Dariia Belkina/Shutterstock

Team 1: Non-immunosuppressive Therapy in IgA Nephropathy

Supportive therapy has been the tried-and-true treatment for IgA nephropathy, with excellent data to support its use. Summarized in the table below, these treatments and supporting data highlight just how integral these agents are for IgA nephropathy treatment. 

Summary of supportive care treatments for IgA nephropathy:

As the backbone for treatment in all patients with IgA nephropathy, optimized supportive care was considered the ultimate victor in the STOP-IgAN trial, which assessed supportive care with and without the addition of steroids. During the 6 month run-in phase, all patients received comprehensive supportive care including renin-angiotensin system (RAS) blockade to a target blood pressure less than 125/75 mm Hg. Approximately one-third of participants (94/309) achieved remission and were no longer eligible for enrollment, thus showing the power of supportive care in this disease process. You read that right, 30%! Furthermore, patients in the supportive care arm of the trial had an annual eGFR decline of only 1.6 mL/min/1.73 m², which was about the same as in the immunosuppression arm split into two groups.

• Those with eGFR >60 mL/min/1.73 m² received intravenous methylprednisolone with oral prednisone alone (average eGFR 73 mL/min/1.73 m²) 
• Those with eGFR 30-59 mL/min/1.73 m² received prednisone with cyclophosphamide followed by azathioprine (average eGFR 36 mL/min/1.73 m²) 

Notably, the overall rate of eGFR decline in either group was significantly lower when compared with prior trials in IgA nephropathy, and was thought to be related to aggressive supportive care in this trial.  

There are several novel agents recently or currently under investigation in addition to this all-star supportive therapy of RAS blockade and blood pressure control. We’ll start with the recently published data on sodium-glucose co-transporter 2 (SGLT2) inhibitors. DAPA-CKD, published in October 2020, enrolled 270 patients (of 4,303 total) with IgA nephropathy (diagnosed by kidney biopsy in 94%) both with and without diabetes. The eGFR was 25-75 mL/min/1.73 m² and urine albumin-creatinine ratio (UACR) 200-5000 mg/g for those enrolled. Overall, treatment with the SGLT2 inhibitor dapagliflozin was associated with a significant reduction in the primary composite endpoint of 50% reduction in eGFR, kidney failure, or death. In a pre-specified analysis of DAPA-CKD, patients with IgA nephropathy treated with dapagliflozin had decreased in UACR by 26%, mean rates of eGFR decline (-3.5 mL/min/1.73 m² in dapagliflozin vs -4.7 mL/min/1.73 m² in controls), and decreased primary outcome events (HR 0.29, CI 0.12-0.73) compared to those treated with placebo. As of November 2022, EMPA-KIDNEY became the largest randomized control trial of patients with IgA nephropathy. Published in a systematic review and meta-analysis in the Lancet, SGLT2 inhibitors were found to decrease the risk of kidney disease progression by 40% (95% CI 0.46-0.78) across patients with any type of glomerular disease. No heterogeneity was identified amongst those with IgA nephropathy, focal segmental glomerulosclerosis, or other glomerulonephritis. 

Additional novel agents, endothelin receptor inhibitors, are currently under investigation. These agents have been proposed to decrease kidney cell injury and fibrosis in experimental models and reduce proteinuria in addition to maximal renin-angiotensin system blockade, though known side effects of sodium retention and heart failure have resulted in limited use. Following on the heels of SONAR, atrasentan, a selective endothelin A receptor antagonist, is currently being investigated as a treatment for IgAN in a phase 3 trial, Atrasentan in Patients with IgA Nephropathy (ALIGN). A multicenter randomized controlled trial (RCT), ALIGN seeks to assess change in proteinuria in 320 patients after 24 weeks and change in eGFR after 2.6 years of study drug versus placebo. Uniquely, it is enrolling additional subjects currently on stable doses of SGLT2 inhibitors for secondary analysis. ALIGN is anticipated to conclude in December 2025. Additionally, the Effect and Safety of Sparsentan in the Treatment of Patients With IgA Nephropathy (PROTECT) trial compares sparsentan (a novel dual-acting angiotensin receptor blocker and endothelin type A receptor antagonist) with irbesartan using a primary outcome of change in 24-hour urine protein to creatinine ratio (UPCR) after 36 weeks. PROTECT aims to enroll 380 patients with biopsy-proven IgA nephropathy considered at high risk for progression with eGFR greater than 30 and greater than 1g/d proteinuria who have already had 12 weeks of RAS blockade, with results anticipated in August 2023. On February 17, 2023, the FDA granted conditional approval for the use of sparsentan in patients with IgAN at high risk of disease progression with UPCR≥ 1.5 g/g despite optimized medical care.

Sparsentan (FILSPARI) is a once-a-day oral medication that acts as a dual endothelin and angiotensin II receptor antagonist. In the phase 3 PROTECT trial, sparsentan was associated with 49.8% reduction in proteinuria from baseline at 36 weeks compared to 15.1% in the Irbesartan comparator arm. The conditional approval was based on these primary outcome results. Because of the risk of hepatotoxicity with endothelin receptor antagonists, FDA required FILSPARI-treated patients to be enrolled in REMS program for monthly liver function testing for the first year of therapy and then quarterly thereafter. 

As exciting as all these existing and emerging therapies are, we must give due respect to our opponent by further examining immunosuppression in IgA nephropathy. Before doing so, however, we give some last considerations, specifically reasons to avoid immunosuppression in the treatment of IgA nephropathy:

• Immunosuppressives have well-known side effects to avoid – Complications from glucocorticoid therapy are well-described and include the following: infection, diabetes and hypertension exacerbation, osteoporosis, avascular necrosis, peptic ulcers, hyperlipidemia, myopathy, cataracts and suppression of the HPA axis.
• Use of immunosuppression does not predict outcomes – The combination of MEST and cross-sectional clinical data at biopsy was able to predict adverse outcomes independent of treatment with immunosuppression. 
• IgA nephropathy still recurs during transplant – A 23% risk of recurrence of IgA nephropathy in kidney transplant recipients has been reported despite high doses of immunosuppressives aimed to prevent this.
• Immunosuppression has a poor track record – Several immunosuppressive agents, including rituximab and CNIs, have failed to show any benefit in IgA nephropathy despite their widespread use in other immune-mediated kidney diseases.

Perhaps most convincingly, in its 2012 clinical practice guidelines on glomerulonephropathy, KDIGO recommended a trial of steroid therapy for those patients with IgA nephropathy and persistent proteinuria greater than 1 g/day despite 3 months of optimized supportive care. The revised 2021 KDIGO guidelines now recommend inclusion in a clinical trial if possible prior to consideration of glucocorticoid therapy which “may reduce the risk of kidney failure” due to “uncertainty over the safety and efficacy of existing immunosuppressive treatment choices.” The evidence for supportive care is strong, and with new therapies continuing to be developed and evaluated, there are numerous arguments for avoiding immunosuppression and its known risks in the treatment of IgA nephropathy. This team leaves it all on the court.

Copyright: khuncho24/Shutterstock

Team 2: Supportive Care with Immunosuppression

“You miss 100% of the shots you don’t take.” – Wayne Gretzky

While acknowledging the benefit of supportive care for all with IgA nephropathy, ongoing research into immunosuppressive therapies may hold the key to improved outcomes for this heterogeneous disease. 

The therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study followed the STOP-IgAN trial (as discussed in the supportive treatment section above) and provides substantial grounds for the use of corticosteroids, after study modifications. This investigator-initiated study, funded by government agencies in Australia and China, also began with a 3-month run-in of maximally tolerated RAAS blockade. Those patients with persistent proteinuria greater than 1g/d and GFR 20-120 mL/min/1.73 m² were eligible for study enrollment. The initial study, TESTING High Dose (2017), was terminated due to significantly increased risk of serious adverse events in the steroid arm, specifically infections (11 vs 0 with two deaths). At the time of study discontinuation, an early analysis performed on 262 patients after 2.1 years identified potential early efficacy for steroids with a decreased composite outcome of kidney failure, death, or 40% loss of eGFR (15.9% vs 5.9%; HR 0.37). A revised protocol, TESTING Low Dose (combined), raised the lower limit of GFR inclusion to 30 mL/min/1.73 m², lowered the dose of steroids (a reduction in methylprednisolone from initial 0.6-0.8 mg/kg/d to 0.4 mg/kg/d), and included the routine use of Pneumocystis jirovecii (PJP) prophylaxis. The trial resumed with the new protocol and was completed in May 2022. At the completion of the revised protocol, the combined results were statistically powered to show significance in the primary endpoint a composite of 40% eGFR decline, kidney failure (by dialysis or transplant), or death due to kidney disease over the 4.2-year follow-up. The steroid arm did better with respect to the primary outcome, with a HR of 0.58 (95% CI, 0.41-0.81) for full-dose and 0.27 (95% CI, 0.11-0.65) for reduced-dose methylprednisolone. The authors did, however, concede a significant increase of serious adverse events in the steroid arm, mainly with high-dose therapy.

Why different outcomes between TESTING and STOP-IgAN? Potential explanations for differences have been hypothesized to be secondary to underlying patient characteristics and baseline eGFR decline. Notably, the rate of eGFR decline in the supportive care arm of both studies was considerably different, with a mean yearly eGFR loss of 1.6 mL/min/1.73 m² in STOP-IgAN vs 6.95 mL/min/1.73 m² in TESTING which may have contributed to the lack of benefit in the steroid arm of STOP-IgAN. Given that participants in TESTING entered with greater baseline proteinuria (1.8 g/day in TESTING vs 2.5 g/day in STOP-IgAN), the reduction in proteinuria between these studies highlights the importance of this marker for kidney function preservation and suggests that steroids may be important for kidney preservation for those with greater than 2 g/day proteinuria. 

Additionally, STOP-IgAN showed some benefit with regard to immunosuppression. Despite no significant difference in the proportion of patients with a reduction in their eGFR greater than 15 mL/min/1.73 m² after 3 years, there were more patients in the steroid arm who met full clinical remission criteria, defined as UPCR less than 0.2 g/g and stable eGFR less than 5 mL/min/1.73 m² from baseline (17% vs 5% p=0.01). As these were not primary outcomes, the clinical significance of this has yet to be determined.

Whether you’re sold on steroids for IgA nephropathy or not, team immunosuppression has a deep bench of supporting players. Additional immunosuppressive agents have and are currently undergoing further investigation, giving this team the chance to pull off an upset win. 

In an attempt to decrease steroid dose and thereby decrease side effects while still realizing immunosuppressive benefits, mycophenolate mofetil (MMF) has been tried as a treatment for IgA nephropathy. The 2023 MAIN trial was an RCT of 170 patients randomized to either MMF (for 1.5 years) in addition to optimized supportive care or optimized supportive care alone. It found a decrease in the primary composite outcome (doubling of serum creatinine, ESKD, or death due to cardiovascular cause). Secondary outcomes also demonstrated a reduction in the progression of chronic kidney disease, defined as mean eGFR loss without an increase in serious adverse events. Prior to this study, only three prospective trials had evaluated the benefit of MMF vs placebo, with only the largest of those showing a potential role for MMF as a steroid-reducing agent. While no difference in proteinuria reduction at 6 and 12 months was seen when MMF was combined with steroids for induction therapy, fewer adverse events (such as diabetes) were noted. 

Other strategies are being developed in order to decrease the adverse risk of steroids in IgA nephropathy treatment. A notable one is the targeted-release steroidal formulation (TRF) of budesonide. This formulation is supposedly aimed at the Peyer patches of the distal ileum where B cells are primed to produce abnormally glycosylated Gd-IgA1. TRF-budesonide seeks to intensify steroid exposure at this site while limiting systemic exposure. A phase 2b double-blinded RCT of 16 mg vs 8 mg of TRF-budesonide vs placebo, NEFIGAN, enrolled patients with persistent proteinuria greater than 0.75 g/day  or UPCR > 500 mg/g and eGFR ≥ 45 mL/min/1.73 m² after a 6-month run-in of RAS inhibition, and found that those receiving budesonide had a 24% decrease in UPCR compared with 3% decrease in placebo group, as well as stable eGFR vs 9.8% reduction in eGFR in the placebo group. Furthermore, no serious infections were reported. As also discussed by NephJC, the follow-up phase 3 trial, NefIgArd, using the 16 mg TRF-budesonide dose, confirmed these findings from the 2b trial with 199 patients with 27% reduction (absolute change from baseline 221 mg/g) in UPCR at 9 months and 3.87 mL/min/1.73 m² difference vs placebo in eGFR preservation. This has led to conditional approval by the Food and Drug Administration in the United States and European Medicines Agency in Europe of TDF-budesonide (under brand names Tarpeyo and Kinpeygo, respectively). The final results of the trial on eGFR outcome at 12 months follow-up are still being awaited. Adverse events were similar across all treatment groups. Notably, both 16 mg TRF-budesonide and placebo had two serious treatment-emergent adverse events recorded by blinded investigators—DVT and progressive kidney disease in the TRF-budesonide group and increased proteinuria and progressive kidney disease in the placebo group. Classic steroid-associated side effects of weight gain, hypertension, and worsening of diabetes were not seen during the 12-month trial period, though patient-solicited corticosteroid-related symptoms (including swelling of the ankles, acne, striae, depression, and hair loss) were more common in the TRF-budesonide group and most patients who discontinued the treatment experienced corticosteroid-related adverse events.

Summary of immunosuppression agents for IgA nephropathy:

Several novel immunosuppressive agents are under investigation for IgA nephropathy treatment at this time. Leflunomide is an immunosuppressive agent currently used in rheumatoid arthritis and is thought to reduce glomerular deposition of autoantibodies and immune complexes. Currently, a phase 4 trial of leflunomide in addition to low-dose glucocorticosteroids and conservative treatment is ongoing. Additionally, multiple trials are underway investigating the role of complement inhibitors including narsoplimab (lectin pathway inhibitor), ipatacopan LNP023 (factor B inhibitor), cemdisiran (RNAi for C5), and avacopan (C5a receptor antagonist). In disrupting the formation of immune complexes by the alternative complement pathway, these agents were specifically developed to target the pathophysiologic mechanism of IgA nephropathy. Bortezomib, approved for multiple myeloma, is a proteasome inhibitor targeting plasma cells. It has been proposed to modulate IgA nephropathy by depleting antibodies produced by these plasma cells. Bortezomib recently completed a pilot study with 8 patients and is currently in a phase 4 trial with 11 patients. Finally, despite the failure of rituximab in mitigating B-cell dependent pathways for IgA nephropathy progression, two B-cell modulating therapies are currently being evaluated. VISIONARY, a phase 3 trial, seeks to evaluate the effect of sibeprenlimab, a monoclonal antibody against a proliferation-inducing ligand (APRIL) which is a proliferation-inducing ligand cytokine thought to be involved in B cell maturation. VISIONARY will add sibeprelimab to patients on max standard of care therapy to evaluate the impact on proteinuria and eGFR, and is anticipated to complete in 2026. Atacicept, a pharmacologic antagonist for both APRIL and the cytokines B lymphocyte stimulator (BLyS), aimed at reducing B cell activation and class switching, will be evaluated by ORIGIN (Atacicept in Subjects with IgA Nephropathy). Anticipated to complete 2024, ORIGIN will assess change in proteinuria after 36 weeks as well as galactose deficient (gd)-IgA1 levels.

These existing and ongoing trials supportive of immunosuppression for IgA nephropathy all focus on primary IgA nephropathy; less is known about other forms. For IgA nephropathy with apparent minimal change disease, there are convincing arguments that immunosuppression is beneficial, and KDIGO 2021 continues to recommend treatment with corticosteroids as well as steroid-sparing agents for long-term steroid dose reduction. Similarly, in patients with systemic IgA vasculitis also affecting the kidney, anecdotal reports have shown promise for the use of rituximab, though overall there is very little data to guide treatment of these IgA nephropathy-plus entities. 

Additional arguments for immunosuppression:

• Kidney histology improves after steroid exposure – A repeat kidney biopsy study in 2002 included 35 patients with IgA nephropathy treated with combination tonsillectomy and steroid pulse with resultant remission in microscopic hematuria. They found improvement in all glomerular lesions excluding global sclerosis and tubulointerstitial markers. 
• Retrospective analyses of those treated with steroids suggest improvement – 184 patients from the VALIGA cohort were found to have improved outcomes when treated with corticosteroids compared to patients with matched propensity scores. Outcomes were measured by ESKD progression, 50% decline in kidney function. and proteinuria. 
• Existing trials exclude “high-risk” patients – Existing data must be interpreted for specific study populations only. The STOP-IgAN trial, for example, excluded patients with persistent proteinuria > 3.5 g/d. Improved risk stratification and incorporation of “high-risk” patients in trials may identify those patients in whom benefits might outweigh the risks. 

With major 2022 publications for both opponents in this bracket, as well as several trials in the pipeline, this rivalry is heating up on the court, and whoever wins today may or may not be the clear victor next year. Should immunosuppression be employed, or are the developments in supportive care alone sufficient while avoiding treatment-related toxicities for IgA nephropathy?

– Executive Team Members for this region: Matt Sparks @Nephro_Sparks and Tim Yau @Maximal_Change

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on June 1, 2023.

More NephMadness 2023 Regions

Submit your picks! | #NephMadness | @NephMadness | #IgAN

Submit your picks! | NephMadness 2023 | #NephMadness | #OncoNephrology

Selection Committee Member: Matthew Abramson @M_Abramson

Matthew Abramson is an academic nephrologist at Icahn School of Medicine at Mount Sinai in Manhattan, NY. He completed nephrology fellowship training at Weill Cornell Medicine, followed by additional subspecialty training in onco-nephrology at Memorial Sloan Cancer Center. He was a runner-up in NephMadness 2022. His passions include improving quality of care for oncology patients who suffer from kidney-related issues.

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Writer: Scott Stockholm

Scott Stockholm is a nephrology fellow at Washington University in St. Louis. He completed residency at Cape Fear Valley in Fayetteville, NC. His areas of interest include acid-base physiology and electrolyte disturbances.

 

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Writer: Morgan Schoer

Morgan Schoer is a second-year nephrology fellow at Washington University in St. Louis, where she currently serves as chief fellow. She will remain on faculty next year as an assistant professor. Her clinical and research interests include home modalities and urine microscopy.

Competitors for the Onconephrology Region

Team 1: Chemotherapy Associated Hypomagnesemia versus Team 2: Immune Checkpoint Inhibitor-Associated Acute Kidney Injury

Copyright: Antoine2K/Shutterstock

Team 1: Chemotherapy Associated Hypomagnesemia

Introduction

Who doesn’t love electrolytes? Sodium, potassium, chloride, bicarb, and calcium all make it onto the basic metabolic panel, but why does magnesium end up on the bench?  After all, it is the second most abundant intracellular cation after potassium and is not only an invaluable cofactor for innumerable reactions in the body, but also forms protein and nucleic acid structures.  When patients don’t have enough magnesium, they can experience a range of symptoms including nausea, fatigue, muscle tetany, seizures, and even cardiac arrhythmias.

One population that is particularly prone to the development of hypomagnesemia is that of patients with cancer. With the advent of new agents such as anti-epidermal growth factor receptor (EGFR) inhibitors, which have a high prevalence of magnesium wasting, understanding the balance of this electrolyte in our body becomes even more crucial.  This year’s team makes an argument for magnesium to be included with the starting five of the chemistry panel.

Copyright: Wooden Owl/Shutterstock

 Magnesium Homeostasis

Like potassium, magnesium is primarily an intracellular cation stored in bone, muscle, and soft tissue, with only 1% of magnesium present in the extracellular fluid. Of this 1%, about ⅓ is plasma protein bound, and the remaining ⅔ is freely filtered through the kidney. In the gastrointestinal tract, foods high in magnesium such as meats, cereals, and dairy products are responsible for replenishing magnesium stores (30%-80% can be absorbed). Bulk absorption occurs in the small intestine and is modulated by paracellular tight junction proteins claudin 2, claudin 7, and claudin 12. The absorption in the colon is transcellular via TRPM6 and TRPM7. We’ll see similar junctions and channels in the kidney as well!

Magnesium that is not protein bound is readily filtered across the glomerulus. Approximately 2.4 g of magnesium is freely filtered through the kidneys with the majority of this filtrate being reabsorbed. In the setting of hypomagnesemia, the kidneys are able to reduce this amount of excretion to less than 12 mg per day. For most other components of glomerular filtrate, the proximal tubule is the workhorse and reabsorbs about ⅔ of what it sees. However, the proximal convoluted tubule is only responsible for 15% of magnesium resorption through a paracellular mechanism.  The majority of magnesium reabsorption occurs in the thick ascending loop of Henle.  Here, around 70% of magnesium is reabsorbed paracellularly with claudin 16 and claudin 19. A final 15% of magnesium is absorbed in the distal convoluted tubule transcellularly through the TRPM6 channel. With this in mind, let’s consider the mechanisms of hypomagnesemia related to several older agents before diving into the anti-EGFR inhibitors.

Hypomagnesemia in Cancer Patients

Patients with cancer are at particular risk for developing hypomagnesemia.  In addition to potential decreased intake due to appetite loss or poor GI absorption due to bowel resection, medications can have an impact on magnesium homeostasis.  Several adjunctive medications other than chemotherapy can impact magnesium. These include but are not limited to bisphosphonates, aminoglycosides, amphotericin, calcineurin inhibitors, and proton pump inhibitors (PPIs).  The mechanistic impact of these drugs on magnesium varies from cellular shift and disruption of cation-sensing receptors to reducing the expression of magnesium channels like TRPM6.  In many of these cases, hypomagnesemia is associated with hypokalemia. If you don’t understand the mechanism, this Tony Breu Tweetorial will show you the light.

An older class of chemotherapy that is highly associated with hypomagnesemia is the heavy metals cisplatin and, less frequently, carboplatin.  In the earliest phase 1 trials from the 1980s, 10% of patients treated with carboplatin developed hypomagnesemia.  Patients treated with cisplatin were at even higher risk, with more than half of the patients developing hypomagnesemia.  What is striking here is that hypomagnesemia can also persist for more than 5 years after therapy is completed, suggesting irreversible tubular damage from direct injury to cells in the loop of Henle and distal collecting tubule.

The newest chemotherapy agents making a splash in magnesium are the aforementioned anti-EGFR inhibitors. Anti-EGFR inhibitors have been shown to impede cellular apoptosis and promote cell proliferation, angiogenesis, and metastases of malignancy.  These receptors are commonly overexpressed in breast, lung, colorectal, pancreatic, and head and neck cancers, and were the first growth factor receptors proposed as a target for cancer therapy.  Of these agents, the monoclonal antibody agents cetuximab (Erbitux, chimeric IgG1 Ab) and panitumumab (Vectibix, human IgG2 Ab) are most highly linked to hypomagnesemia.  A meta-analysis of over 23,000 patients showed that 34% of patients treated with these two agents developed hypomagnesemia, although the severity was quite variable between studies.  A fascinating study of 98 patients with colorectal cancer showed that nearly all (97%) of patients treated with anti-EGFR inhibitors had a negative slope of serum magnesium over time versus a stable slope in controls treated with other chemotherapy.  They even performed 24-hr urinary magnesium and fractional excretion of magnesium (FeMg) in select patients who received anti-EGFR inhibitors and found mean FeMg levels of 5%, which is inappropriately high in the setting of hypomagnesemia.  IV magnesium load testing in 5 patients was comparable to patients with TRPM6 mutations, implicating renal magnesium wasting as the culprit for the clinical picture.

What explains the profound rate of hypomagnesemia when using anti-EGFR inhibitors?  Remember from earlier that the final location of magnesium absorption is the distal convoluted tubule via TRPM6.  Under normal circumstances, pro-EGF undergoes cleavage with extracellular proteases to form EGF in the distal tubule. This then binds EGFR at a basolateral membrane which activates tyrosine kinase and increases TRMP6 expression.  Anti-EGFR inhibitors suppress TRMP6 expression and subsequently impede the final 15% of magnesium absorption.

Diagnosis and Treatment

Measuring a serum magnesium is easy enough, but it’s important to remember that hypomagnesemia is frequently overlooked due to the vague course of symptom onset and range in severity of symptoms.  When obtaining general labs, other electrolyte abnormalities such as hypocalcemia or hypokalemia often prompt the clinician to check for hypomagnesemia.  Clinicians should have a high index of suspicion and should check for magnesium regularly in patients on any of the above therapies.  In scenarios where there are both renal and GI losses, calculating a fractional excretion of magnesium can be helpful.  FeMg values greater than 2% with preserved GFR strongly suggest a component of magnesium wasting in the kidney.

Magnesium repletion by any route of administration has unique pharmacodynamics to be aware of.  Patients with mild hypomagnesemia (1.2-1.7 mg/dL) and minimal symptoms can be given oral magnesium.  Several formulations are available, each with different dosing schedules and amounts of elemental magnesium.  The most important side effects of any oral magnesium supplement are gastrointestinal effects such as nausea and diarrhea.  Severe (< 1 mg/dL) or symptomatic hypomagnesemia usually requires intravenous administration.  A typical dose is 1-2 grams of magnesium sulfate over 15 minutes, but repeated doses may be required.  Patients with preserved renal function will excrete more than 80% of IV magnesium, so higher doses of IV repletion over a short period of time do not raise the serum Mg significantly.  Instead, the administration of small IV doses over several days is often the best therapy for severe hypomagnesemia.  Interestingly, rapid increases in plasma magnesium have been shown to stimulate the calcium-sensing receptor in the loop of Henle, which subsequently inhibits paracellular magnesium transport and promotes magnesium wasting. On the other side of the court, patients with chronic kidney disease are at risk for developing hypermagnesemia with large IV doses of replacement.

Let’s not forget about dietary ways to supplement magnesium.  An 8 oz glass of 1% milk has 39 mg of magnesium, and 2 tbsp of peanut butter has 50 mg.  A quick after-school snack of both of these will net nearly 100 mg of magnesium and won’t give you any diarrhea; diet modifications like this can be very helpful for patients with mild hypomagnesemia!

Lastly, there are adjunctive therapies to assist with improving magnesium levels in addition to replacement alone. Amiloride is a potassium-sparing diuretic that acts to block sodium reabsorption in the distal convoluted tubule and collecting duct, which can conserve magnesium. This strategy is particularly effective for patients with nephrotoxicity after amphotericin and cisplatin therapy. The rising star of drug classes, Sodium Glucose Transporter-2 Inhibitors can slow down magnesium wasting. A meta-analysis showed that there were small but significant increases in magnesium (0.15-0.24 mg/dL) across all SGLT2-inhibitors without causing changes to potassium or calcium.  The precise mechanism of this remains unknown.

With the increased usage of anti-EGFR inhibitors and incidence of hypomagnesemia being recognized in this population, it’s increasingly important to understand, recognize, and treat this disorder.  Magnesium is emerging as a dark horse candidate to win this year’s onconephrology matchup!

Team 2: Immune Checkpoint Inhibitor-Associated Acute Kidney Injury

Introduction

Immune checkpoint inhibitors (ICI’s) have been reforming cancer treatment since their introduction in the early 2000s (with the Food and Drug Administration’s approval of ipilimumab in 2011). They are now first- and second-line therapies for more than 50 types of cancer. The ability to achieve long-standing or complete remission in previously nearly incurable cancers (eg, melanoma) has been revolutionized by these drugs. 

Copyright: Grigvovan/Shutterstock

Normally, T-cells have immunologic brakes that prohibit them from attacking “self” tissue of the host organism. ICI’s remove these brakes to permit T-cells to target and destroy cancer cells. There are three major categories of ICI’s: CTLA-4 inhibitors, PD1 inhibitors, and PD-L1 inhibitors (see Table 1 for examples and uses, Figure 1 for mechanism of action). 

Schematic representation of T-cell activation regulated by checkpoint inhibition with 3 hypothetical mechanisms of acute tubulointerstitial nephritis. Antigen carried by the antigen-presenting cell (APC) activates a T-cell receptor (TCR) with intracellular signal transduction by CD3 resulting in T-cell proliferation, survival, and differentiation. This signal also stimulates the expression of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), which competes for binding CD80/86 with CD28, the costimulatory protein required for T-cell activation, thereby leading to T-cell anergy. Programmed cell death 1 ligand (PD-L1) is variably expressed by many native and tumor cells. By binding to PD-1 on a T cell, it suppresses its activation and promotes immunotolerance leading to T-cell exhaustion. A T cell can be activated peripherally by an immunogenic checkpoint inhibitor, an immunogenic metabolite presented by the tubuloepithelial cells, or exhibit lesser immunotolerance for native kidney antigen. Figure 2 from Shingarev et al, AJKD © National Kidney Foundation.

However, in the process of unleashing these immunological checkpoints, autoimmune phenomena can occur (termed immune-related adverse events, or irAE’s). These commonly take the form of dermatitis, hepatitis, colitis, or thyroiditis. Unsurprisingly, in the kidney, ICI-associated acute kidney injury (ICI-AKI) most commonly takes the form of acute tubulointerstitial nephritis (ATIN).  Although ICI-AKI is less common (incidence ~3%) than irAE’s of other organs, it can dramatically affect cancer treatment options and thus, potentially, survival. Therefore, especially in this population with numerous other reasons for AKI (vomiting, diarrhea, hypotension, urinary retention, tumor lysis, other nephrotoxins, etc), it is very important to be able to differentiate ICI-AKI from non-ICI AKI in order to both administer and withhold medications appropriately. 

While there are no definite clinical features to differentiate ICI-AKI from non-ICI AKI, certain characteristics are suggestive, including sterile pyuria (~50%), subnephrotic-range proteinuria (~70%), latency period ~3.5 months (interquartile range 1.5-11 months), preceding or concomitant extrarenal irAEs (40%-90%, commonly dermatitis, hepatitis, thyroiditis, or colitis), simultaneous acute interstitial nephritis (AIN) drug culprit (~70%, mostly PPI use, less commonly non-steroidal anti-inflammatories or antibiotics), and combination therapy with multiple ICI’s. Fever and eosinophilia are only observed in 20% of patients.  Concomitant ATIN-causing drugs portend a favorable renal prognosis, while extrarenal irAE’s are associated with worse kidney outcomes. 

There are numerous lingering questions and debates surrounding the ideal diagnosis and management of ICI-AKI. Guidelines from oncologic societies frequently conflict with expert nephrology opinion. This year, we will address several controversies including the spectrum of disease, determining whether to biopsy, if and when it’s safe to rechallenge the ICI, and whether ICI’s can be used safely in a transplant population. 

 Spectrum of Acute Kidney Injury 

The vast majority (up to ~90%) of biopsied lesions of ICI-AKI are from ATIN, either alone or in combination with another disease process. It is hypothesized that some people have immunologically inactive T-cell populations with specificity for tubular antigens that are released by ICI’s, leading to tubulitis and interstitial inflammation.  

Kidney biopsy specimens from the patient with acute kidney injury while undergoing treatment with programmed cell death 1 checkpoint inhibitor. Light microscopy: (A) low power, (B) higher power. Hematoxylin and eosin stain shows severe acute interstitial nephritis with tubulitis accompanied by acute tubular injury (images courtesy of Dr. Surya V. Seshan). Figure 1 from Shingarev et al, AJKD © National Kidney Foundation.

However, there are numerous other ICI-AKI-associated pathological lesions (T-cell mediated, B-cell mediated, and non-immunologic) that can either co-occur with ATIN or occur independently.  In a 2018 retrospective review, 12 patients on pembrolizumab who developed AKI or proteinuria were biopsied. Five (42%) of them had acute tubular necrosis (ATN) alone; five were noted to have ATIN; two had minimal change disease (MCD). This stands in stark comparison to the two largest series to date: (1) a 2020 multicenter retrospective review of 60 biopsied patients, in which 56 (93%) had ATIN as the predominant lesion (of the other 4, one each had MCD with acute tubular injury, ANCA-negative pauci-immune crescentic GN, anti-GBM disease, and C3 glomerulonephritis), and (2) a 2021 retrospective review of 30 sites in 10 countries, which identified ATIN in 125 of 151 (82%) patients biopsied. Additionally, a 2019 retrospective single-center study highlighted potential frequency of concomitant lesions. Of their 16 biopsied patients, although 14 (88%) had ATIN, 9 had a coexisting glomerular injury, which included IgA nephropathy (IgAN), membranous nephropathy (MN), pauci-immune vasculitis (3 cases, two ANCA-negative), C3 glomerulopathy, focal segmental glomerulosclerosis (FSGS), and AA amyloidosis. Interestingly, the case of MN was noted to resolve completely with removal of the ICI and a course of corticosteroids, differentiating it from malignancy-associated MN.  Lastly, there are case reports of lupus nephritis, thrombotic microangiopathy (TMA), and even renal tubular acidosis associated with ICI exposure, although they collectively comprise a small minority of ICI-AKI.

To Biopsy or Not to Biopsy

There are conflicting opinions without clear guidelines regarding who to biopsy and when in expected ICI-AKI. While variable biopsying practices have likely contributed to the heterogeneous data presented above, heterogeneous interpretation of this data appears to perpetuate variable biopsying practices.

Due to the high incidence (>90% in the largest case series) of ATIN, an argument can be made to empirically hold the ICI and administer corticosteroids, with eventual biopsy if the AKI does not improve.  Most cases of glomerular lesions had nephrotic-range proteinuria, hematuria, and/or were oliguric, all of which should be screened for and would remain indications for biopsy.  On the other hand, there may be substantial diagnostic uncertainty in this complex patient group and the only reliable way to determine an ICI-AKI from ATN is a kidney biopsy.  Empiric steroid treatment could lead to unnecessary ICI discontinuation (with later questionable ICI reintroduction), and thus suboptimal oncologic outcomes. Furthermore, inappropriate addition of corticosteroids could lead to avoidable adverse events (eg, sepsis, VTE, fractures). A recent three-case series highlighted examples of ATN that presented like ATIN (and would not have been biopsied based on the current guidelines). The pro-biopsy argument also recognizes the concomitant glomerular processes that may accompany the ATIN, and argues for prompt diagnosis to assist with earlier appropriate therapy. In the end, the aforementioned 2020 multicenter retrospective study showed no differences in renal recovery outcomes between biopsied and non-biopsied patients.

Re-introduction of Immune Checkpoint Inhibitor After Resolution of AKI

This is yet another area of ICI-AKI with clinical uncertainty; can you try using ICIs again after resolution of AKI?  Currently, there are no reliable clinical features or biomarkers to help determine which patients will respond poorly to re-challenge. Furthermore, not all guidelines agree, with the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommending permanent discontinuation of ICI therapy w/ grade 3 or higher toxicity. In the 2020 multicenter retrospective review mentioned above, 31 patients were rechallenged with an ICI after resolution of their initial ICI-AKI, with 7 recurrences (23%). Six of those patients responded when re-treated with steroids. In an international 2021 retrospective review previously introduced, 121 patients were rechallenged, 16% of which had recurrent AKI.  

 Previously we mentioned that if the AKI occurred in the presence of another ATIN-causing medication, this portended a more favorable prognosis. However, it remains unclear whether a rechallenge is any safer in this population after concomitant drug discontinuation.  What little data we have suggests that repeat AKI can occur in about 20% of patients who are rechallenged with the drug and that alternatives should be used if at all possible.

Immune Checkpoint Inhibitor Use in Transplant

Transplant patients have a cancer incidence rate up to four times higher than the general population, and cancer represents the second leading cause of death (~30%) for this population behind cardiovascular disease. This phenomenon is largely due to their immunosuppressive regimens which, while decreasing T-cell-mediated rejection of their organ, simultaneously decreases T-cell immune surveillance of early cancers, as well as allow proliferation of oncogenic viruses. In this era of increasing ICI use, can these drugs be used safely in transplant patients without substantially increasing their risk of rejection? 

 It should be noted up front that all data comes from systematic reviews of case reports and case series, as transplant patients have been excluded from prospective studies on ICI use. Analysis of rejection rates is further complicated by heterogeneously decreased immunosuppressive regimens implemented at the time of cancer diagnosis or ICI initiation.

 Similar trends of rejection, allograft loss, and ICI response were noted across two recent studies. One is a 2020 systematic review of 27 articles with 44 kidney transplant patients treated with ICI’s, while the other is a 2021 multicenter retrospective cohort study with 69 patients treated with ICI’s between 2010 and 2020 (matched to a non-ICI group). Both studies noted an acute rejection rate of 40%-45%, occurring on average 24 days after initiation of the ICI (with IQR 20-56 days in the retrospective study). Rejection was noted to be half T-cell mediated, and half mixed rejection (antibody and T-cell mediated) or unknown. Of the patients with rejection, 65%-85% had resultant allograft failure. However, these studies also noted a significant benefit of ICI therapy for the underlying malignancy, with 35%-50% of patients responding with stable or improved disease.

Insufficient data exist for recommendations on immunosuppression regimens (calcineurin inhibitors [CNIs], mechanistic target of rapamycin [mTOR] inhibitors, etc) prior to ICI initiation. CNI’s, which are a mainstay of transplant immunosuppression, both increase allograft survival and increase cancer risk. Thus, unsurprisingly, in both of these studies patients on CNI’s had less rejection, but more disease progression. mTOR inhibitors have lower cancer risk than CNI’s, and were also noted to have a lower risk of rejection in ICI use. It is thought that mTOR inhibitors have “dynamic immunosuppression” by “helping to maintain graft tolerance and achieve tumor immunity.” Further studies are required to determine the optimal immunosuppressive strategy in patients who may need ICI administration.

ICIs have now been around since 2011 and are proving to be the veteran leaders on the onconephrology court.  Nothing else comes close to matching their impact over the last ten years, and the team is a strong contender for making it deep into this year’s bracket!

– Executive Team Members for this region: Timothy Yau @Maximal_Change and Anna Vinnikova @KidneyWars

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on June 1, 2023.

More NephMadness 2023 Regions

Submit your picks! | #NephMadness | @NephMadness | #OncoNephrology

Submit your picks! | NephMadness 2023 | #NephMadness | #KidneyTransplant

Selection Committee Member: Vineeta Kumar @VineetaKumar8

Vineeta Kumar is Professor of Medicine, Robert and Cutessa Bourge Endowed Professor in Transplant Nephrology, and the Medical Director of the Incompatible Solid Organ Transplant Program for the University of Alabama at Birmingham. She is the lead nephrologist for UAB’s Living Donor Transplant Program and UAB’s Xenotransplantation efforts. Her mission is to improve the care and outcome of living organ donors and the medically complex transplant patient through direct care, education, and clinical research.

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Writer: Margaret DeOliveira @MargaretD128

Margaret DeOliveira is a second-year nephrology fellow at Mount Sinai Hospital. She is a graduate of Cooper Medical School of Rowan University in Camden, NJ, and completed her combined residency in internal medicine and pediatrics at Duke University Medical Center in Durham, NC. She is interested in transitions of care and glomerular disease. She is currently a Fellow Editor for Renal Fellow Network.

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Writer: Jeffrey Kott @jrkott27

Jeffrey Kott is a second-year clinical nephrology fellow at Mount Sinai Hospital. He completed his Residency and Chief year at Stony Brook Medicine. His interests include critical care nephrology, transplant nephrology, improving access to medical care, and medical education. He is a 2021 graduate of the NSMC.

 

Competitors for the Access to Kidney Transplantation Region

Team 1: Journey to the Waitlist versus Team 2: Organ Pool

Copyright: Gemenacom/Shutterstock

After another one-year break, kidney transplantation (KT) is back in the tournament and ready to rumble! In 2020, Biomarkers in Rejection advanced to the Effluent 8 but could not keep up with Consumable Waste in Hemodialysis (and we still haven’t forgotten that KT was the inaugural NephMadness champion in 2013). This year, two teams representing KT have suited up and come to the tournament with one shared goal: timely and successful KT for all patients who need them.

Copyright: kikujungboy CC/Shutterstock

Team 1: Journey to the Waitlist

Currently, there are more than 100,000 patients on the deceased donor kidney transplant (DDKT) waitlist in the United States (US), with an average waitlist time of 3-5 years (longer in some parts of the US). Like the journey of the basketball into the hoop from the 3-point line, so is the journey for the patient with advanced chronic kidney disease (CKD) to the waitlist, and ultimately to a successful KT. Before one can even attempt the shot, the player must get on the court. Let’s start at the beginning. 

Referral to Kidney Transplantation 

Primary care providers and nephrologists both play pivotal roles in the referral of eligible patients to transplant clinics evaluation. Why kidney transplant? Most individuals living with end-stage kidney disease (ESKD) who receive a KT live longer and have a better quality of life compared to those who do not. 

Early referral is key to educate potential KT recipients about living donors and waitlist options. Per the Organ Procurement and Transplantation Network (OPTN) guidelines, the optimal timing of referrals to a transplant center is when estimated glomerular filtration rate (eGFR) is less than 30 mL/min/1.73 m². Waitlist time accrual begins once a patient is registered on the kidney transplant waitlist and the eGFR is less than or equal to 20 mL/min/1.73 m², or once the patient initiates dialysis, whichever comes first (Figure 1). The race-free eGFR calculation for transplant candidate listing has been adopted and was approved in June 2022. 

Unfortunately, a majority of patients with advanced CKD are not referred to general nephrology for their kidney care, and thus are likely not referred for transplantation either. How can you make the shot if you don’t have access to the court? A large 2020 retrospective study of 1,119 patients with advanced CKD found that 55% of patients had not been referred to general nephrology for evaluation. 

In 2014, the National Kidney Allocation System (KAS) redefined parameters for calculating waitlist time in an attempt to address disproportionately long waitlist times for highly sensitized patients (i.e. those with high calculated panel reactive antibody [cPRA]) and racial and ethnic minorities. A significant change to the existing waitlist time calculation was having time accrued on the waitlist include the time from dialysis initiation for those actively listed after initiating dialysis. In other words, if an individual was referred and listed for KT after receiving dialysis for 5 years, waitlist time would begin at 5 years. For patients not yet on dialysis, waitlist time begins at the time of listing (after evaluation). A cohort of 37,676 incident patients in Georgia, North Carolina, and South Carolina from 2012-2016 found that KAS had increased referrals and evaluation starts, decreased overall waitlisting, and lowered rates of active waitlisting when compared to the “pre-KAS” era. There was also an increase in the percentage of preemptive transplants after KAS, though there were continued disparities in access, with the rate of preemptive transplants persistently lower in minoritized populations. 

Disparities in Referrals & Waitlisting 

US Citizenship

2020 NephMadness champion Inequities Region describes in-depth the factors that contribute to disparities in kidney care, including referrals to KT and subsequent waitlisting. Figure 2 illustrates the history of citizenship-based access policies and the evolution of the “5% guideline.” In 1986, OPTN released a policy recommending that at each transplant center’s kidney transplant recipients (KTR) who were non-US citizens be less than 10% of all KTR. In 1994, 10% was lowered to 5%, and a policy was implemented to potentially audit transplant centers in violation. In 2012, the 5% guideline was replaced with a review of US citizenship and US residency data of KTR. 

Timeline of transplant policies related to US citizen and residency status. ∗Transplant tourism is “organ trafficking and/or transplant commercialism, or if resources (organs, professionals, and transplant centers) devoted to providing transplant to patients from outside a country undermine the country’s ability to provide transplant services for its own population.” Figure 1 from Cervantes et al, AJKD © National Kidney Foundation.

Race-Based eGFR Calculations

As eGFR determines active waitlisting eligibility, it is not surprising that race-based eGFR calculations have been a driver of disparities. In September 2021, a National Kidney Foundation/American Society of Nephrology Task Force released a special report urging the elimination of race-based eGFR equations and adoption of the 2021 CKD-EPI equation, which does not include race. The report also recommended national efforts to increase the use of cystatin C as a biomarker, as consideration of both creatinine and cystatin C is more accurate than creatinine alone. Calculation of eGFR using the 2009 CKD-EPI equation with a race coefficient increases the eGFR by 16% for those labeled as “Black.” A 2021 cohort study of self-identified Black adults with CKD (Figure 3) found that estimation of kidney function without a race coefficient was significantly associated with a shorter time to referral and DDKT waitlist eligibility. As Black patients have been shown to have faster progression of kidney disease, a recent study proposed a higher eGFR listing threshold for Black patients that could potentially improve racial disparities. 

Obesity

Obesity can delay patients from being listed, although body mass index (BMI) cut-offs vary from center to center. The “obesity paradox” (or the commonly seen U-shaped relationships in medicine which follow the Goldilocks principle) tells us that survival on dialysis is highest in patients with BMI less than 18.5 kg/m² or greater than 40 kg/m². (Figure 4), with improved survival for the rest. Together, these data underscore that it may not always be prudent to require weight loss in potential recipients of KT on dialysis, especially in older patients who are greater than 65 years of age.  

Figure 4. The “obesity” paradox, figure adapted from Park J et al. (2014) by Joel Topf

A study of the Scientific Registry of Transplant Recipients (SRTR) from 2015-2020 found significant variation in the proportion of recipients with BMI greater than 35 kg/m² at transplant centers; 11% of transplant centers had more than 20% of recipients with BMI greater than 35 kg/m² while 14% of centers had fewer than 5% (Figure 5). For patients with BMI greater than 35 kg/m², center-specific cut-offs may significantly impact access. Similarly, living donor evaluation may be restricted to those with a BMI less than 30-35 kg/m².

Proportion of morbidly obese adult recipients by kidney transplant center in the United States. Unpublished data from January 1, 2015 to December 1, 2020 among adult kidney transplant centers from the Scientific Registry of Transplant Recipients, based on a request for information on December 2, 2020. Figure 1 from Huml et al, AJKD © National Kidney Foundation.

A 2021 meta-analysis of UNOS data (Figure 6) with adults that were first-time deceased donor kidney transplant recipients from 2000-2016 compared BMI categories (less than 25 kg/m², greater than 25-30 kg/m², greater than 30-35 kg/m² and greater than 35 kg/m²). There was an increase in delayed graft function in patients with BMI greater than 35 kg/m² and those BMI  greater than 30-35 kg/m². Though allograft outcomes were better for those with BMI less than 30 kg/m² compared to those greater than 35 kg/m², there was no difference in graft or patient outcomes between BMI greater than 30-35 kg/m² and BMI > 35 kg/m².  There was no difference in patient survival or hospital length of stay following transplant across BMI categories. This study supports the idea of greater flexibility in BMI inclusion criteria for potential KT recipients. 

​The Evaluation

Once a potential KT recipient has been referred for evaluation, the journey has really just begun. The pre-transplant evaluation seeks to assess not only if the individual can safely undergo the surgical procedure and then subsequently tolerate immunosuppression, but also if KT is the best treatment option for that individual. The evaluation process begins with a large, multidisciplinary team of nurse coordinators, social workers, dieticians, financial coordinators, pharmacists, nephrologists, and surgeons. In addition to the laundry list of screening and diagnostic tests patients must complete (and subsequent follow-up assessments, pending the results), assessment of cardiac health is a critical step in the evaluation process, given the high burden of cardiovascular disease in patients with CKD, though it is not so clear whether intervention (eg, percutaneous coronary intervention) in patients without symptoms and good functional status improves outcomes. Pre-KT cardiac evaluation guidelines differ slightly among organizations, though some suggest using a non-invasive cardiac stress test in asymptomatic, “high-risk” individuals. A recent United Kingdom study even suggested that non-invasive cardiac stress tests, often a mainstay of the pre-transplant evaluation process, may not provide any benefit while increasing the time to waitlisting. If a patient who has been able to successfully complete their evaluation makes it to the waitlist, some of the pre-evaluation testing may need repeating as they wait, driven by either screening guidelines (eg, mammography, colonoscopy) or changes in clinical status. 

Time on the Waitlist  

What is the “waitlist” anyway? It’s not really a linear list, per se. It is a pool of candidates waiting for an organ based on different characteristics. When a donor becomes available, a list is generated and that dynamically created list determines how organs are allocated. The more donors we have, the more lists we can generate, and the more offers we can make. Dialysis has the biggest impact on waitlist time, along with sensitization from previous blood transfusions, and blood type (B and O have the longest waitlist times). There are regional variations in wait times as well. The cPRA is used to determine a percentage score estimating the amount of antibodies a patient has in their blood. The higher the percentage, the harder it will be for a patient to find a suitable match (without high levels of donor-specific antibodies), leading to longer wait times. Since the implementation of KAS, sensitized candidates (those that have a cPRA greater than 98%) have been given increased priority. The net impact of the KAS in the highly sensitized group varied across cPRA categories, such that candidates with cPRA 80%-89% received fewer kidneys than those with cPRA 98%-100%. Interestingly, the same study found that KAS implementation was associated with decreased rates of living donor KT (both for kidney paired donation [KPD], and non-KPD) in highly sensitized patients. 

A 2022 National Academies of Sciences, Engineering, and Medicine report found the US organ transplant system to be “demonstrably inequitable.” OPTN has also recently stated the need for increased transparency in waitlist selection and described a need for autonomy, procedural justice, equity, and utility. Transparency is a must as we strive toward a more equitable transplantation system.

In an effort to improve equitable access to kidney transplant, the Board of Directors of the Organ Procurement and Transplantation Network (OPTN) unanimously approved a new policy, effective January 5, 2023, whose goal is to backdate waiting times for those Black kidney transplant candidates who were disadvantaged by previous use of a race-inclusive eGFR. For Black candidates registered on the kidney transplant waitlist, this change back dates waitlist time to the earliest documentation of a race-neutral eGFR less than or equal to 20 mL/min/1.73 m^2.

So what happens during the long timeout between waitlisting and the KT? Each center’s care of the pre-transplant patient varies, with many centers seeing patients yearly prior to transplantation to evaluate potential clinical changes. Pre-transplant care costs (initial evaluation, waitlist management, evaluations of living donors, and donor aftercare) are funded via the Organ Acquisition Cost Center (OACC). The costs per transplant have increased from $81,000 to $100,000 between 2012 and 2017 due to increasing waitlist pools and comorbidities. 

In summary, the journey to the waitlist is long and arduous, with numerous defenders protecting the hoop. Though the transplant community has made some progress in improving this process by encouraging transparency and beginning to address disparities through the use of race-free eGFR for waitlisting eligibility, several barriers remain to making this journey easier to navigate for those who need to undertake it. 

Copyright: Ratchat/Shutterstock

Team 2: Organ Pool

Given the more than 100,000 individuals waiting on the KT list in the United States alone, to paraphrase Steven Speilberg’s 1975 “Jaws”: “We’re gonna need a bigger pool.” The paucity of organs has led to lower percentages of individuals transplanted within 5 years of being listed for organ transplant. Expanding the available organ pool has become a priority for many involved in kidney transplantation. This team will review the current deficiencies as well as developments aimed at making KT more accessible.

Reducing Discard

Throwing away organs that can potentially be used is essentially a technical foul. Discard or non-utilization of organs has been high, recently reaching a peak percentage of 21.3% in 2020. To meet the demands of an increased KT list, there has been a need to use conventionally “less ideal” organs, including those from donors with complex medical comorbidities, surgical complication, or histologic findings. 

In the mid-1990s, the idea of using “expanded or extended donor” criteria for organs from donors thought to be suboptimal candidates (compared to standard criteria donors [SCD]) was proposed, and in 2002 “expanded-criteria kidneys” donors (ECD) were defined as in Figure 1 in an effort to increase the organ pool.

Retrospective analyses of the ECD program found that the most common reason for discard of these organs was due to biopsy findings. However, at the time the rationale for rejecting biopsy findings (>20% glomerulosclerosis) was based on data that was felt to be insufficient in determining long-term function of an allograft, especially as subsequent data found that biopsies of organs with >25% glomerulosclerosis has a 3-year graft survival rate of 75%. Not surprisingly, graft survival of ECD kidneys was lower compared to non-expanded criteria kidneys (Table), with prior sensitization contributing to this outcome. 

Table. Graft Survival of Expanded Criteria Kidneys versus Non-Expanded Criteria Kidneys. Adapted from American Journal of Transplant

Though the ECD program had strengths, ECD organs only accounted for 17% of kidney transplantations by 2005. The consensus became that a more concrete means of discussing risk would be beneficial for physicians, patients, and health policymakers. This movement culminated in the development of the Kidney Donor Risk Index (KDRI), which is used to graph the now more commonly known Kidney Donor Profile Index (KDPI). Though the KDRI initially combined 10 donor characteristics and 4 transplant characteristics (cold ischemia time, degree of HLA mismatch, en bloc transplant, and double kidney transplant), the KDPI excluded the transplant characteristics due to their uncertainty at the time of organ offer (Figure 1). KDPI has since become the preeminent tool used in discussing risk of organ survival and has an inverse relationship with graft survival (Figure 2). The full KDPI calculator is available here.

Figure 2. Survival of deceased donor kidney-alone transplants, by kidney donor profile index (KPDI). Figure adapted from OPTN

Organ discard may occur for several reasons, including characteristics of donated organs, failure to convert potential organ donors (with conversion meaning that a deceased individual actually becomes an organ donor), or just because it’s the weekend! Organs procured during the weekend were 20% more likely to be discarded, even though these organs were of higher quality than those procured and used Monday-Friday. Organs from donors older than 55 years old or with diabetes mellitus, hypertension, or obesity are discarded at higher rates. Organs for which biopsies were obtained continue to have high rates of organ discard, and high KDPI kidneys (>85%) are also more frequently discarded compared to others. Based on these figures, despite efforts to reduce organ discard, there remains work to be done to more effectively expand the organ pool. This need has now become a part of United States governmental policy, as an ambitious target of doubling available organs by 2030 was signed into law in the Advancing American Kidney Health Initiative in 2019. 

While the KDPI was introduced to help provide a more accessible means of categorizing risk for donor organs in both centers and individuals, it has its flaws.  Compared to the ECD vs SCD categorization, KDPI may introduce a bias when an organ is quantified as worse than some percentage, leading to further organ discard. One study, for instance, found that organs categorized as SCD (but with KDPI >85%) were rejected at higher rates once only KDPI was presented, despite use of these organs lowering risk of mortality at 2 years. Mortality benefit of high KDPI organs has since been replicated in additional studies (which include the elderly, though notably not the pediatric population). To maximize the use of high KDPI organs, systems have been proposed to improve informed decisions and mitigate bias introduced by KDPI, and OPTN changed the Kidney Allocation System to increase the geographic area in which high KDPI organs are offered. Still despite these efforts, there remains significant discard of high KDPI organs.

Additionally, variables that increase KDPI though may not ultimately impact allograft function have come into question:

1. Race: Though the discard rates vary between races,  Black is the only race that increases KDPI, more than medical conditions, donation after cardiac death (DCD) status, or cerebrovascular accident (CVA). As race is a social construct, rather than a biological variable, it has already been removed from eGFR questions. Further, removal of race from the KDPI has repeatedly demonstrated restratification of high-risk organs to the lower-risk categories (and thus likely decreased organ discard). Some have proposed that APOL1 genotype should be included in KDPI, as donor high-risk APOL1 genotypes are associated with poorer allograft outcomes in kidney recipients.
2. Hepatitis C Virus (HCV): Presence of HCV in the donor significantly increases the KDPI, and thus can increase discard of these organs. The past 10 years have seen significant breakthroughs in anti-virals that induce a sustained virologic response (cure!), so it seems anachronistic that HCV remains in the KDPI. Single–center exploration into the use of donor HCV+ kidneys in combination with administration of the anti-virals (eg, elbasvir/grazoprevir, glecaprevir/pibrentasvir) at the time of transplant have had promising outcomes with respect to both organ function and recipient HCV cure, if transmitted from the donor. Reproduced in larger, multicenter trials (Figure 3), this has led to a decline in the discard of HCV+ organs (from over 40% in 2016 to about 20% in 2020), though we can likely do better by removing HCV from the KDPI. 

Despite all efforts thus far to reduce organ discard and a significant decrease in the discard of HCV+ kidneys, organ discard continues to increase. One solution that has been proposed in Europe is the Eurotransplant Senior Program (older donors for older recipients), which has been shown to be beneficial in the long term with respect to decreasing organ discard and outcomes. While this system can theoretically disadvantage the elderly, who may otherwise receive younger donor organs, it yields a shorter wait time for the elderly and has demonstrated a survival benefit over dialysis. Given its success, this program has been implemented in various countries across Europe, and would be projected to significantly decrease the number of discarded organs in the United States. 

Organ Procurement Organization (OPO) Performance 

OPOs are non-profit organizations distributed geographically that are responsible for the procurement of organizations for transplantation. They are governed by the provisions laid out in the National Organ Transplant Act (NOTA), which defines the federal oversight by the Center for Medicaid and Medicare Services (CMS) as well as the OPTN, and the Uniform Anatomical Gift Act (UAGA), which defines guidelines by which organ donations occur. There are currently 57 OPOs in the United States which have numerous responsibilities along the entirety of organ allocation.

The CMS governs OPOs, ensuring appropriate adherence through the meeting of certain conditions to maintain reimbursement and certification. Two metrics (donation rate and organ yield rate) have historically been used to evaluate OPO performance, and both rely on the variable known as “eligible deaths” (ED). The donation rate (patients with at least one organ transplanted/ED) and the organ yield rate (organs transplanted/ED) are used to target OPOs outside the top 25% with quality assurance and improvement programs. OPOs deemed not efficient can ultimately be redesignated or de-certified. However, a review of OPO performance from 2011-2018 demonstrated that OPO performance ranking largely did not change despite programs and interventions aimed at rapid improvement. 

Unfortunately, donation rate and organ yield rate do not reflect the full potential of donors. ED is used to estimate a potentially deceased donor pool, but does not include all groups those older than 70 years and DCD donors, thus underestimating the true potential donors. CMS quality metrics have attempted to address some of the deficiencies in ED by incentivizing pursuit of single organ donors. Use of the proposed variable ”potential donors” instead of ED, would allow for more uniformity across OPOs, remove self reporting, and also account for geographic differences, all while capturing the actual upper limit of the possible organ pool. A more recent study proposed the incorporation of administrative data on potential donors into OPO performance measures, such as a donation percentage (Actual Donors/Potential Donors) and Organs Transplanted per Potential Donor. 

Another point of improvement for OPOs would be identifying patterns in donor authorization, which varies significantly. While OPOs certainly drive organ donation consent, and internal methods such as having an in-house coordinator have shown improvements in donor authorization, external methods, (eg, Organ Donor Breaththrough Collaborative) have shown some short-term success in increasing organ consent rates. 

Xenotransplantation (XT)

Think of “xeno” as a heave from half-court to beat the buzzer. XT, the human transplantation of organs from non-humans (cross species), is probably the most exciting and innovative prospect for increasing the organ pool. While we have to look back a few thousand years to the earliest documented case report of XT (and subsequent rejection), use of non-human organs has actually been an area of interest since the 1960s, when a series of chimpanzee-to-human kidney transplants were first described, with one organ lasting 9 months! Additional attempts were made using baboon kidneys, due to declining populations of chimpanzees, though all transplanted organs failed quickly. Fast forward to the 1980s, when deceased donor organ supply could not be met by the demand for organs. Advancements in immunosuppression, coupled with the outlawing of use of chimpanzees as organ sources and various issues with other non-human primates (viruses, size, ethics), made it clear that another animal source needed to be found. Enter the pig, whose physiology, immunology, availability, organ size, and breeding profile made them a viable option to become the main organ provider from the animal kingdom. While initially limited by natural antibodies (NAbs) to porcine antigens such as 1-3,Galactose (Gal) leading to hyperacute rejection (HAR), significant progress has been made for the first time to modify the donor (Pig) to be “more human like” through several advances in genetic modification. This may one day make porcine XT the solution to the organ shortage.  These advances led to the development of a xenograft with 10 gene edits, to minimize chance of rejection, blood clot formation, inflammation, and organ growth. 

These advancements in genetic modification were enough to allow for the first documented XT of a porcine kidney in a deceased human model (Figure 4).  Both kidneys from the 10-gene-edited pig were transplanted into a nephrectomized decedent brain-dead for 72 hours. The study was successful in some ways, and porcine xenografts were transplanted without surgical complications, histologic changes of HAR or acute rejection (with correlating negative prospective crossmatch), transmission of porcine viruses, or reperfusion complications (pig blood pressure is significantly lower than human). While the xenografts produced urine, serum creatinine did not improve and there were early histologic changes of thrombotic microangiopathy as well as severe acute tubular injury. A second publication reported similar results following transplantation of a single-gene modified (Gal knockout) pig kidney with autologous subcapsular thymus implantation (to induce a model of tolerance) into a brain dead decedent. This study reported creatinine clearance, though the native kidneys in the decedent were not removed and the xenograft kidney was left outside the body and on top of the thigh. 

Given the brevity of these studies, it is impossible to conclude that this model of porcine xenograft will be sufficient to prevent chronic rejection.  The establishment of porcine XT as a safe procedure (albeit in a brain-dead decedent) certainly yielded enough promise to serve as a springboard for future research, however many steps still remain. Will these kidneys provide clearance? And in which live patient population can porcine XT be studied safely and ethically? 

Though this is NephMadness, we’d be remiss to exclude a heavily documented cardiac XT from a 10-gene-edited pig into a 57-year-old living man with non-ischemic cardiomyopathy. The pig heart lasted 48 days prior to failing (though initially due to a mechanism not related to rejection), and after almost two weeks on veno-arterial extracorporeal membrane oxygenation (ECMO), care was withdrawn. While this was truly momentous as the first living recipient of XT, it did bring forth several ethical concerns.  First, as animals are sentient, intelligent, have a capacity for suffering, and lack the ability to give consent, there are clear ethical challenges that must be addressed.  Second, there is a possibility that XT may worsen the allocation landscape, as the potential for high cost may lead to easy access to those who are financially well off, ultimately adding another avenue of socioeconomic disparities that already exist in modern-day medicine. Third, there has been a significant ethical discussion categorizing XT recipients as chimeras with potential subsequent negative effects. And finally, the risks of zoonotic infection remain unknown. While porcine viruses have been fairly well-categorized and thus far prevented due to pathogen-free breeding (except for porcine endogenous retroviruses), the unknown long-term effects of potential zoonotic infection remain uncertain. As we have seen in recent zoonotic infections that have undergone human-animal transmission, these effects could spread beyond the recipient. Lastly, there are ethics around the candidates for XT, especially as further advances are made and we move toward clinical trials on living humans. The live recipient of the cardiac XT was ineligible for a human donor. While we have learned from his contribution to science, there certainly is a question as to whether it is ethical to provide an untested medical service to a living human. The Food and Drug Administration allowed for this procedure to proceed as “the outcome of the experimental transplantation was not likely to be inferior to continuation of medical therapy and venoarterial ECMO”. Ultimately, XT has tremendous promise to provide the answer to the organ shortage. However, we’re still far from the championship and have a way to go in terms of both the science and the ethics of XT.

Conclusion

The kidney donor shortage has been and continues to be an insurmountable barrier to providing effective and optimal care for those with end-stage kidney disease. Stemming from increased and potentially unnecessary organ discard and inefficiencies in the obtaining and allocation of deceased donor organs by OPOs, new methods are needed to help optimally allocate organs. Though XT is exciting and has the potential to greatly increase the organ supply, we must first clear medical and ethical hurdles before this can become a strategy to improve access to transplantation—for all.

– Executive Team Members for this region: Samira Farouk @ssfarouk and Anna Burgner @anna_burgner

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on June 1, 2023.

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Selection Committee Member: Anuja Java @anuja_java

Anuja Java is a transplant nephrologist at Washington University in St. Louis, MO. Her research involves functional characterization of genetic variants in complement-mediated diseases. She co-chairs the ClinGen complement gene curation expert panel, is a councilor in Women in Nephrology, has served on the ASN career advancement committee, and received the 2022 NKF “Award of Excellence”.

 

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Writer: Viralkumar Amrutiya @viral_nephro

Viralkumar Amrutiya is a second-year nephrology fellow at Virginia Commonwealth University, Richmond, VA. He is a graduate of Hebei Medical University, Shijiazhuang, Hebei, China, and completed his residency and chief year at Hackensack Meridian Health – Palisades Medical Center in North Bergen, NJ. He has special clinical interest in management of CKD and transplant nephrology. He would like to work towards minimizing disparities and bringing equality in kidney care.

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Writer: Nouman Akbar @AkbarNouman

Nouman Akbar is a second-year nephrology fellow at Virginia Commonwealth University. He is a graduate of Providence Hospital, Washington, DC, where he completed his residency and chief year. His clinical interests include lupus, C3GN, TMA, and transplant nephrology.

Competitors for the

Thrombotic Microangiopathy (TMA) Region

Team 1: Primary TMA versus Team 2: Secondary TMA

Introduction

The Thrombotic Microangiopathy (TMA) region encompasses disorders with microvascular endothelial injury associated with thrombotic, hemolytic, and ischemic complications. TMA presents a number of clinical challenges on the court such as thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and organ damage including AKI.  

These teams’ lineups are based on the evolving classification of TMA. Here we use Primary TMA (complement-mediated, replacing the older term Atypical HUS) and Secondary TMA (triggered by another disease), as suggested by our region’s expert Dr. Anuja Java in a recent book (Fig 1). Interestingly, there is a long history of trades between these teams, with multiple players having played for both sides. Indeed, the presence of a complement mutation may not become significant without the stress of a clinical trigger. An otherwise strong thrombotic thrombocytopenic purpura (TTP) team missed the cut for the NephMadness bracket because of its underwhelming effect on the kidneys. 

Figure 1.

When should you suspect TMA? 

You are admitting a patient with AKI, proteinuria, and hematuria. You notice thrombocytopenia, anemia, and an elevated reticulocyte count. Could this be microangiopathic hemolytic anemia (MAHA)? You look for elevated lactate dehydrogenase (LDH), low haptoglobin, schistocytes on the peripheral smear, and increased reticulocytes. Check! Direct antiglobulin (or Coombs test) is negative, excluding autoimmune hemolysis. Coagulation parameters are normal, excluding disseminated intravascular coagulation (DIC). Yes, this is the classic presentation of TMA. However, any or all of the MAHA features can be absent, especially in renal-limited disease, and this is when a high index of suspicion is called for. The presence or absence of schistocytes is a particularly debatable disease marker. 

Can biopsy help? 

Kidney biopsy is not a requisite when distinct hematologic features of MAHA are in plain view, as histopathology is unlikely to supply the exact cause of TMA. Moreover, thrombocytopenia and anemia can sometimes make the biopsy a risky game. In classic cases, successful empiric treatment itself would clinch the diagnosis. On the other hand, it’s been observed that arterial wall changes are more specific for malignant hypertension (HTN) or scleroderma renal crisis, whereas glomerular changes are more specific for CM-TMA. In addition, renal-limited disease can only be diagnosed by pathology. Therefore, a biopsy should be considered when the clinical picture is ambiguous, there is no response to definitive therapy, the degree of reversibility of kidney injury is unclear, or a second pathology is suspected. 

For histopathologic manifestations of renal TMA, we would like to refer fans to this excellent Renal Fellow Network post. Acute vascular lesions associated with such TMAs as malignant HTN or scleroderma showcase mucoid intimal edema and fibrin deposition, while chronic recurrent injury boasts concentric myointimal proliferation (onion-skinning). In the glomeruli, the telltale lesions are microthrombi (fibrin-platelet plugs) in the capillaries or vascular pole. Acute cases might also flaunt endotheliosis (swelling of endothelial cells) and mesangiolysis (loosening of the mesangium), while double GBM contours and segmental glomerulosclerosis are signs of chronicity. As mentioned, histopathologic evidence of TMA can be a surprise finding in a number of glomerular and autoimmune diseases, without the hematologic features. 

Copyright: RaiDztor/Shutterstock

Team 1: Primary TMA

“An alternative way

To find a complement

Can be quite quirky!”

Haiku by app/writeme.ai

“…Alice soon came to the conclusion that it was a very difficult game indeed.”

Lewis Carroll, Alice’s Adventures in Wonderland

Alternative Pathway of Complement Activation

Complement-mediated TMA (CM-TMA) results from dysregulation of the complement system, mainly the alternative pathway, which then leads to inappropriate activation of the terminal pathway. In Primary TMA, alternative pathway dysregulation can be genetic (due to mutations in complement proteins), acquired (due to autoantibodies against complement proteins), or idiopathic. The alternative pathway was an MVP in NephMadness 2019 for the Complement Region. To refresh our memory, let’s play a game of “Alternative Basketball” (Figure 2). Initially, the teams are Self vs Pathogens. On the Self team, alternative pathway complement activation is the “offense”, alternative pathway complement regulation is the “defense”, and formation of C3 convertase is the “basket”. 

The game starts with a jump ball, C3. The alternative pathway is constitutively active due to spontaneous hydrolysis of small amounts of C3, the so-called C3 tick-over. This auto-activated C3 will deposit on pathogens. To score a point, the “offense” (two proteases, Factors B and D, and a stabilizing protein, Properdin [P]) will engage with C3 basketball to create the powerful alternative pathway C3 convertase. Once C3 convertase is formed, a series of slam dunks via an efficient amplification loop generates large amounts of C3b on the surface of the pathogen. This will opsonize the hapless pathogen and activate the terminal pathway with its lethal weapon, membrane attack complex (MAC) C5b-9. 

Following the game so far? The problem is, the auto-activated C3 will also deposit on self-cells. The offense will go rogue and try to score points by threatening cells on its own Self team! Our body must keep a strong defense to avoid damage from our own complement system. This defense consists of plasma proteins (Factors H and I) and membrane proteins (cell defense players CD46/MCP [membrane cofactor protein], CD35/CR1 [complement receptor 1], CD55/DAF [decay accelerating factor] and CD59/MAC-IP [MAC-inhibitory protein]). One example of defensive play is when either Factor H or MCP holds down C3b, allowing serine protease Factor I to inactivate it.  A normal complement system, an all-star basketball team, is finely tuned and prepared to deal with any offense, even coming from within. In CM-TMA, weak defense (due to loss of function of regulators) or excessive offense (due to gain of function of complement components) will end up with a series of “self-baskets”. The Pathogen team can sit on the sidelines and cheer as the game turns into Self vs Self!

Figure 2. Alternative Basketball.The complement is on the Self team, and its offense against pathogens consists of factors B, D and P (depicted by player BaD Pee), propelling hydrolyzed C3 (basketball) through the C3 convertase (basket) to produce C3b (to score). Before you know it, the amplification loop repeats this multiple times, producing tons of C3b. However, offense can also go rogue against self cells. To contain its offense, the Self team has a robust complement defense, consisting of factors H and I in plasma and CD 46/MCP, CD55, CD35 and CD 59 on cell surface. This “alternative” version of basketball is the real game played by the complement alternative pathway inside our body every day!

Genetic CM-TMA 

The etiology of genetic CM-TMA is typically a heterozygous, loss-of-function mutation in a defense protein of the alternative pathway. Such mutations lead to haplo-insufficiency (the protein is either not made or, if made, does not function properly) and weaken the defense. Less frequently, a gain-of-function mutation in a complement activator is identified. Approximately 60% of patients with CM-TMA carry a rare genetic variant in one of the five complement proteins playing our game (Figure 2):

Loss-of-function mutation of complement Factor H 

Loss-of-function mutation of complement Factor I  

Loss-of-function mutation of CD46/MCP 

Gain-of-function mutation of C3  

Gain-of-function mutation of complement Factor B 

Of note, approximately 10% of affected patients carry more than one variant. Disease penetrance is approximately 50%, therefore a precipitating event (ie, infection in children, pregnancy in adults) may be necessary to manifest the disease. 

If not identified and treated in a timely manner, prognosis is the worst in patients with Factor H mutations, with 60%-70% reaching kidney failure within a year of disease onset. The prognosis in patients with Factor I and C3 mutations is also poor. Patients with CD46 mutations have a better prognosis, with approximately 80% remaining dialysis-independent.

Acquired CM-TMA

Acquired deficiency due to autoantibodies against Factor H is observed in approximately 5%-10% of patients with CM-TMA. A deletion in CFHR1 and CFHR3 (Complement Factor H-related 1 and 3) may indicate a genetic predisposition to the development of Factor H autoantibodies. Autoimmune diseases, usually playing for the Secondary TMA team, can switch sides to cause this entity. 

Workup of Primary TMA

How does one join the CM-TMA team? Coaches and scouts (or you, our reader) can use several tests to evaluate the presence of functional complement dysregulation in addition to testing for genetic complement mutations (Figure 3).

Figure 3. From New Insights into TMA in Kidney Transplantation in: Kidney News Volume 14 Issue 8 (2022), by Anuja Java.

The mutations reported as “pathogenic” or “likely pathogenic” are known to cause dysregulation of complement activation. However, less than 50% of the genetically identified variants have a known functional consequence. Computational prediction algorithms are used to predict the potential impact of these “variants of uncertain clinical significance” (VUS) on the mature protein. The presence of such variants is particularly vexing for clinical management. Functional analysis of VUSs can assist in defining the significance of the variant and helping to re-classify them as pathogenic or benign.

Treatment of Primary TMA

Terminal pathway blockade is the best therapy at this time. Two C5 inhibitors, eculizumab and ravulizumab, administered as infusions, have greatly improved disease outcomes with extensive clinical trial- and real-world-evidence of efficacy and safety. Studies are on the way with another C5 blocker, crovalimab, which should simplify therapy with subcutaneous injection. Alternative pathway inhibitors in development (see illustration) are pegcetacoplan (anti-C3), iptacopan (anti-factor B) and danicopan (anti-factor D).  

Acquired CM-TMA secondary to Factor H autoantibodies often responds to plasma exchange and immunosuppression.  

Liver transplantation can be curative in genetic CM-TMA caused by mutations since a majority of the complement regulatory proteins are of hepatic origin. Therefore, combined liver-kidney transplant may be a feasible option for kidney failure in younger patients, though not commonly used due to the effectiveness of anti-complement therapy. A concern that liver allograft may not initially produce sufficient amounts of the regulatory factors may be circumvented by plasmapheresis in the perioperative time to restore levels of the complement proteins. 

Copyright: Amelia Martin/Shutterstock

Team 2: Secondary TMA

“Of secondary thrombotic

microangiopathy beware.

It’s a tricky affair!

Haiku by app/writeme.ai

Secondary TMA is associated with specific disorders. This roster deploys a diverse set of skills. So what do all these players have in common? The answer is a multi-hit endothelial injury, which renders endothelium vulnerable in the absence of concerted action of plasma and membrane-bound complement regulators. If this team is able to outwork the Primary TMA team (harboring complement mutations) they may be able to exploit certain players (eg, pregnancy, malignant HTN etc.), and generalized complement activation can ensue. 

Secondary TMAs are best managed by treating the underlying causes. Or are they? 

Evaluation of Secondary TMA

Figure 4. When secondary TMA is suspected, the following tests will help with the differential diagnosis.

Hypertension-associated TMA

Features of TMA can be observed in up to 40% of patients with malignant hypertension, viewed as the proverbial vascular damage from shear stress. Patients with clear precipitants such as cocaine use usually respond to antihypertensives with quick resolution of TMA. However, there is growing evidence that complement activation is the underlying disorder behind the majority of malignant hypertension cases, particularly in young patients. This player might soon be switching teams! Genetic testing is recommended in all patients with recurrent episodes of hypertensive emergency, TMA, and progressive kidney disease. Such patients have high rates of progression to kidney failure and disease recurrence after transplantation. Complement blockers may improve clinical outcomes. In a large study by Cavero et.al (Figure 5), 20% of the patients with malignant hypertension had TMA, and 60% of those were due to aHUS. Over 70% ultimately required dialysis, much worse than those without TMA.

Figure 5. Thrombotic microangiopathy in patients with malignant hypertension – PubMed (nih.gov)

In a small earlier study of 26 patients with hypertensive emergency and TMA on kidney biopsy, 69% had evidence of complement activation, and half had pathogenic variants in complement genes. C5 inhibition successfully restored kidney function in 83% of patients with evidence of complement activation, while HTN control did not make a difference.

Pregnancy-associated TMA 

This team features a “big 3” in stars, Preeclampsia/HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets), TTP, and CM-TMA. Telling these triplets apart is a challenge even without factoring in players like Catastrophic Antiphospholipid Syndrome or Renal Cortical Necrosis with DIC.

Preeclampsia results from abnormal placentation with production of anti-angiogenic (i.e., anti-VEGF) factors triggering complement activation. This typically occurs later in the pregnancy; helpful diagnostic tests are abnormal uterine doppler and elevated sFlt-1/PlGF ratios (the latter are not yet available in the United States). Failure of TMA to resolve upon delivery is suggestive of other etiologies.

TTP is diagnosed by ADAMTS13 deficiency and responds to plasma exchange (congenital TTP) or immunosuppression (immune-mediated TTP). In unusually severe cases of pregnancy-associated TMA, especially those that fail to improve after delivery, plasma exchange should be started empirically until TTP is ruled out. 

CM-TMA can be triggered by high risk events late in pregnancy or especially in the postpartum period, and complement gene variants can be found in approximately half of these cases. If untreated, pregnancy outcomes are severe, with two thirds of the patients reaching kidney failure and experiencing a high rate of fetal loss. Recurrence risk in subsequent pregnancies is approximately 25%. Treatment with a C5 inhibitor is associated with improved maternal outcomes without evidence of increased fetal risks. Therefore, patients with undifferentiated pregnancy-associated TMA who fail to respond to plasma exchange and delivery should be started on complement blockade.  See Figure 6.

Figure 6. Differentiating Hemolysis, Elevated Liver Enzymes, and Low Platelet Count Syndrome and Atypical Hemolytic Uremic Syndrome in the Postpartum Period | Hypertension (ahajournals.org)

Drug-induced TMA

Drug-induced TMA can be mediated by antibodies or direct toxicity. A comprehensive registry compiled by George et al can help with differential diagnosis.

Immune-mediated drug-induced TMA is due to an antibody (Ab) formation against a drug or its metabolite. This team’s MVP, quinine, an alkaloid derived from the bark of cinchona trees, can stimulate Ab cross-reactive with platelets. Ever since its fall from grace for dabbing in drug induced-TMA, some US nephrologists are nostalgic for the days when this antimalarial agent was used as a remedy for leg cramps. Quinine is responsible for the flavor of gin and tonic and for the fluorescence of glow-in-the dark jello shots. Beware, consumption of these drinks can lead to TMA! Multiple other medications like trimethoprim, ciprofloxacin, metronidazole, and quetiapine can play this game. 

Non-immune-mediated drug-induced TMA occurs due to direct drug toxicity to the endothelium by multiple mechanisms. Notorious culprits include calcineurin inhibitors like tacrolimus, chemotherapy drugs like mitomycin C, VEGF inhibitors like bevacizumab, and tyrosine kinase inhibitors like sunitinib. Inappropriate intravenous use of oxymorphone (Opana ER) or oxycodone ER (OxyContin) can lead to drug induced-TMA due to postulated toxicity of polyethylene oxide, a high molecular weight filler intended to make the pills tamper-resistant.

TMA in autoimmune conditions and GNs

Disorders like systemic lupus, antiphospholipid syndrome, systemic sclerosis, C3G, focal segmental glomerulosclerosis, ANCA vasculitis and IgA nephropathy can be associated with TMAs, which portends poor kidney outcome. For example, 80% of patients with systemic lupus erythematosus (SLE) and TMA on kidney biopsy develop kidney failure in 5 years. 

Pathogenesis is multifactorial, including fascinating Neutrophil Extracellular Traps, aptly called NETs, akin to basketball nets catching alternative pathway basketballs. 

Management is typically geared towards the underlying disorder. Complement blockers may be helpful in select cases, and trials in this disease space are ongoing.

Infection-associated TMA

TMA can be associated with a wide range of viral (HIV, Influenza, COVID19), bacterial, fungal and parasitic infections. The star player, Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) was once called the “typical HUS” and wielded more power than the entire “atypical HUS” team. STEC-HUS is most common in children and is associated with Shiga toxin-producing E coli (more severe cases can be caused by Shigella spp). Not to be outdone, Strep pneumo can cause TMA called Strep pneumo-HUS, associated with high morbidity and mortality. 

In STEC-HUS, Shiga toxin translocates from the gut, combines with glycolipid Gb3 in the circulation, enters endothelial cells via GB3 receptor, and creates havoc disrupting protein synthesis and egging on tissue factor and von Willebrand factor release. In a fascinating move, Shiga toxin can also bind to Factor H on endothelial surfaces, thus bringing complement into the game. Pathogenesis of Strep pneumo-HUS is attributed to pneumococcal neuraminidase, which cleaves sialic acid residues exposing a cell surface component called T-antigen and initiating complement activation.

Diagnosis is made by stool cultures, PCR testing, and viral serologies. Genetic testing for complement proteins is reserved for severe cases.  

Treatment is usually supportive. The role of eculizumab requires further randomized controlled trials.

Malignancy-associated TMA 

This form of TMA can be seen with mucin-producing adenocarcinomas as well as disseminated malignancies. What occurs is microvascular obstruction with cancer cells, consumption of platelets in tumor microthrombi, and fragmentation of the passing red blood cells. As we learned in the drug-induced TMA section, chemotherapy agents like mitomycin-C, cisplatin, gemcitabine, or bevacizumab can cause TMA which will typically resolve with the withdrawal of the offending drug. 

Eculizumab has been used along with supportive measures in some cases. The mortality rate of cancer-related TMA is high due to its association with disseminated malignancies or withdrawal of chemotherapy.

Transplant-associated TMA

After kidney transplantation, 25%–50% of CM-TMA will recur. In fact, CM-TMA is responsible for most of the recurrent cases and up to a third of the de novo cases. A complement genetic panel is therefore recommended for all patients with transplant-associated TMA. The rest of the cases are broadly caused by the following:

Drugs, such as calcineurin or mTOR inhibitors. The mechanism is direct endothelial injury with release of von Willebrand factor multimers, which overwhelm ADAMTS13 capacity and activate coagulation-complement crosstalk.

Viral infections, such as CMV, Parvovirus B19, SARS-CoV-2. The mechanism is direct endothelial injury by virus with platelet aggregation, generation of thrombin, development of ADAMTS13 inhibitors, and complement activation. 

Acute antibody-mediated rejection. This happens via a postulated mechanism wherein a donor-specific antibody (DSA) binds to HLA antigen on endothelial cells and activates complement. Diagnosis of AMR is confirmed by detection of DSA and positive C4d staining on allograft biopsy. AMR-associated TMA harbingers a high risk of graft loss. Transplant glomerulopathy, a chronic smoldering form of TMA, can produce MPGN pattern on biopsy. 

Figure 7 New Insights into TMA in Kidney Transplantation in: Kidney News Volume 14 Issue 8 (2022)

Non-kidney solid organ transplants can rarely develop TMA. 

Ischemia-reperfusion, immunosuppressive drugs, acute interfering disease, and a relative deficiency of the von Willebrand factor cleaving protease (ADAMTS13) appear to play a major role in its pathogenesis.  

Hematopoietic stem cell transplantation (HSCT) is no stranger to TMA, with an occurrence rate of 3%-39%. A popular 3-hit hypothesis suggests that hit 1 is an underlying predisposition (eg, genetic variant or prior endothelial injury), hit 2 is new endothelial injury (eg, HSCT conditioning regimen), and hit 3 is complement activating triggers described above. 

Management of transplant-associated TMA varies from supportive, like withdrawal of the offending agents or use of antivirals, to complement blockade per genetic or clinical evidence.

Metabolism- and coagulation-mediated TMAs and their mimics

These players do not get a lot of court time, but are a force to be reckoned with, as they can mimic or provoke TMA. 

Acquired cobalamin deficiency-induced pseudo-TMA from pernicious anemia or malabsorption is as easily missed as it is treated. It mimics TMA like netball does basketball. The hemolysis is not intravascular but intramedullary: macrocytic nucleated RBCs, like over-inflated basketballs, are fragile and susceptible to shredding, especially in the setting of high homocysteine levels. 

Pancytopenia, elevated LDH, and peripheral schistocytes can all be seen. There is an absence of the usual degree of endothelial dysfunction or platelet microthrombi. AKI, if it happens, is due to ATN/pigment injury. The best clue to this pseudo-TMA is reticulocytopenia, while low B12 with high MMA and homocysteine levels are diagnostic. The best therapeutic approach is repletion of Vitamin B12, folate, CoQ-10, and carnitine.

Methylmalonic aciduria and homocystinuria, cobalamin C type (MMACHC), or simply cobalamin C disease, is ultra-rare, but is the most common genetic type of functional B12 deficiency. Genetic testing should be considered in all young patients with evidence of intravascular hemolysis, even in the absence of concomitant renal and neurological impairment. B12 levels are notoriously unreliable unless accompanied by elevated homocysteine and MMA. Treatment with hydroxocobalamin and betaine is effective in preventing progression of kidney disease and recurrent TMA.

Diacylglycerol Kinase ε (DGKE)-TMA manifests in infants with progressive CKD and kidney failure. Loss-of-function DGKE mutation can cause endothelial damage with activation of protein kinase C, upregulation of prothrombotic factors, downregulation of the VEGF receptor, podocyte injury, and TMA. There is insufficient data to determine optimal management.

Variants in Thrombomodulin (THBD), a transmembrane glycoprotein with anticoagulant properties and a negative regulator of the complement system on vascular endothelial cells, may lead to a TMA.

Plasminogen (PLG) is a circulating glycoprotein known to hinder platelet aggregation through its protease form, plasmin. PLG variants can decrease proteolytic activity of plasmin and trigger TMA.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive condition that occurs due to mutations in G6PD, and is another TMA mimic. Patients typically present with hemolysis after exposure to an infection or drug, sometimes accompanied by thrombocytopenia and ATN. Finding G6PD deficiency by measuring G6PD activity in red blood cells once TMA is in remission can spare a patient with TMA the risk and cost of long-term complement blockade.

– Executive Team Members for this region: Anna Vinnikova @KidneyWars and Timothy Yau @Maximal_Change

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on June 1, 2023.

More NephMadness 2023 Regions

Submit your picks! | #NephMadness | @NephMadness | #TMAregion

AJKDBlog is excited to bring you the 11th edition of NephMadness!

If you’re a #NephMadnessNewbie, this post is for you…

What is NephMadness?

NephMadness is a free online, CME-granting, evidenced-based, noncommercial learning initiative that leverages the tools of social media to teach about the latest and greatest breakthroughs in the field of nephrology! (From the 2017 explainer post)

The idea is based on March Madness, the annual US college basketball tournament. Instead of basketball teams, we selected the hottest nephrology topics to compete in NephMadness. More on the history of the madness in this Editorial: NephMadness 2015: Nephrology as a Cornerstone of Medicine. Also, check out @KidneyCathy‘s short video explainer:

What do I need to do?

1. Read this year’s region posts here.
2. Submit an individual or team bracket here.
3. Discuss your picks with #NephTwitter!

Helpful illustration by Omar Taco @errantnephron:

What are the teams and regions?

There are 8 main nephrology topics (REGIONS) with 2 subtopics (TEAMS) in the tournament.

• Access to Kidney Transplantation: Vineeta Kumar @VineetaKumar8 | Margaret DeOliveira @MargaretD128 | Jeffrey Kott @jrkott27
• Heart Failure Devices: Nisha Bansal @NishaKidneyDoc | Jen Bergeron @DrJennyBee | Jefferson Triozzi @nepherson
• Thrombotic Microangiopathy: Anuja Java @anuja_java | Viralkumar Amrutiya @viral_nephro | Nouman Akbar @AkbarNouman
• IGA Nephropathy: Dana Rizk @DanaRizk1 | Dana Larsen @dana_m_larsen
• Mineralocorticoid Receptor Antagonists: Matt Luther @DrJMLuther | Micah Schub @AcidBassMD
• Onconephrology: Matthew Abramson @M_Abramson | Morgan Schoer | Scott Stockholm
• Transgender Health: Mitchell R. Lunn @MitchellLunn | Sehrish Ali @sehrish_alii
• Transitions of Care: Rasheeda Hall @Rasheeda_HallMD | Alissar El Chediak @alissar_chediak

This year’s official bracket:

Resources for groups:

DOWNLOAD NEPHMADNESS 2023 BRACKET

DOWNLOAD POWERPOINT PRESENTATION

DOWNLOAD PDF PRESENTATION

PRESENTATION ON GOOGLE SLIDES

If you’re organizing a virtual party, here are instructions on how to fill out your bracket as a group with Zoom polls:

In Step 2 above, the A-B choices would look like this in the bracket:

Who picks the NephMadness champion?

A 9-member Blue Ribbon Panel selects the winners of each round in NephMadness. For each matchup, they are asked to pick the team that, in their opinion, will cause the most practice change in nephrology over the next 5 years. Here are the members of this year’s BRP:

• Naief AbuDaff
• Michelle A. Josephson @MichelleJTx
• Katarzyna Kakareko @kponikwicka
• Peter Kerr
• Abdul Qader @md_abdulqader83
• Sylvia E. Rosas @sylviaerosas
• Shilpi Shah @sshah713
• Jodi Smith @jodismith0820

Read more about the rationale behind the BRP in this Editorial: NephMadness After 5 Years: A Recap and Game Plan for the Future

What’s the Schedule?

• March 1: Bracket entry opens
• March 31: Deadline for bracket submission 
• April 3: First round results | Effluent 8 named
• April 5: Effluent 8 results | Filtered 4 named
• April 7: Filtered Four results | Finalists named
• April 10: NephMadness 2022 Champion crowned

CME and MOC

US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on June 1, 2023.

Competitions

Group Competitions: Highest Score, Most Entries, and Best Party

Winners will be featured on the Winners blog post at the conclusion of NephMadness

• Highest Score: Complete the question on the bracket submission site on whether you are submitting an entry on behalf of a group, adding “OFFICIAL” to the group name
• Most Entries: Complete the question on the bracket submission site on whether you are part of a group and add the group name (everyone in the group should use the same group name to avoid confusion)
• Best Party: Take a photo (or multiple) of your party and tag #NephMadnessParty

Social Media Competitions: Best Tweeter and Best Blogger

Winners will be featured on the Winners blog post at the conclusion of NephMadness

What are the Prizes?

Grand Prizes: Top Overall Score, Top Medical Student Score, Top Resident Score, Top Fellow Score, and Top Attending Score

Each Grand Prize winner will receive complimentary year-long personal subscription to Advances in Kidney Disease and Health and Nature Reviews Nephrology

That’s it – we hope you’ll enjoy the fun and learning during NephMadness 2023!

The 2023 NephMadness Executive Team:

• Matt Sparks @Nephro_Sparks
• Tim Yau @Maximal_Change
• Anna Burgner @anna_burgner
• Samira Farouk @ssfarouk
• Pascale Khairallah @Khairallah_P
• Anna Vinnikova @kidneywars

Submit your picks! | NephMadness 2023 | #NephMadness | @NephMadness

Editor’s Note: We asked authors of Original Investigations to provide short plain-language summaries that would briefly summarize what inspired their study, the basic approach taken, what was learned, and why it matters. We hope our readers will find this valuable in helping them keep up with the latest research in the field of nephrology. From the March 2023 issue:

Association of Kidney Function Measures With Signs of Neurodegeneration and Small Vessel Disease on Brain Magnetic Resonance Imaging: The Atherosclerosis Risk in Communities (ARIC) Study by Johannes B. Scheppach et al 

From the authors: Cognitive decline is a major public health issue and common in patients with kidney disease. To better understand this condition, we measured kidney function and albuminuria in 1,527 participants from the Atherosclerosis Risk in Communities Study. The participants were also scanned for different types of brain damage using magnetic resonance imaging. We found that low kidney function and albuminuria are associated with various structural brain pathologies, such as brain atrophy, microvascular damage, and white matter defects. These results confirm the connection between kidney function and albuminuria with brain damage and provide new information about its cause and its localization in the brain.

DOI: 10.1053/j.ajkd.2022.07.013

Editorial: Kidney Disease and Brain Health: Current Knowledge and Next Steps by Anne M. Murray et al.

Parathyroidectomy and Cinacalcet Use in Medicare-Insured Kidney Transplant Recipients by Aileen X. Wang et al 

From the authors: The treatment options for hypercalcemic hyperparathyroidism after kidney transplantation include cinacalcet and surgical parathyroidectomy, but best practice remains unclear. Using a large database of US kidney transplant recipients, we examined cinacalcet and parathyroidectomy treatment practices, associations, and outcomes in the first 3 years after kidney transplant. We found that 18% of patients used cinacalcet and 1.8% underwent parathyroidectomy after transplant. For patients transplanted in 2007-2013, the rate of parathyroidectomy remained stable. By contrast, cinacalcet use increased during the study period. A longer time on dialysis and cinacalcet use before transplant were strongly associated with both parathyroidectomy and cinacalcet use subsequent to transplant. Hypocalcemia was a common early complication of parathyroidectomy.

DOI: 10.1053/j.ajkd.2022.07.015

Editorial: Persistent Hyperparathyroidism: A Reality Calling for Additional Evidence by Hanne Skou Jørgensen et al.

Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials by David H. Alpers et al. [OPEN ACCESS]

From the authors: In early clinical trials of tolvaptan (TEMPO 3:4 and TEMPO 4:4), liver enzyme level increases in tolvaptan-treated participants indicated risk for drug-induced liver injury. We evaluated data from 2 subsequent large-scale clinical studies (REPRISE and a long-term extension of all 3 trials) that were conducted after monthly liver enzyme testing became required for patients enrolled in tolvaptan trials. No additional liver enzyme level increases meeting the criteria for greatest risk (ie, “Hy’s Law” cases) were reported, and the less severe increases that did occur were seen mainly during the first 18 months of treatment. These results support the conclusion that monthly liver enzyme testing of tolvaptan-treated patients during the first 18 months of therapy enabled timely detection and intervention before severe drug-induced liver injury could occur.

DOI: 10.1053/j.ajkd.2022.08.012

Editorial: Much Ado About Something: The Clinical Pattern of Tolvaptan-Associated Liver Injury in Participants With ADPKD by Merve Postalcioglu et al.

Efficacy and Safety of Belimumab in Patients With Lupus Nephritis: Subgroup Analyses of a Phase 3 Randomized Trial in the East Asian Population by Xueqing Yu et al. [OPEN ACCESS]

From the authors: Lupus nephritis (LN) is a severe complication of the kidneys in patients with the autoimmune disease systemic lupus erythematosus. Belimumab is used in combination with standard therapy for treatment of patients with LN. As data on belimumab treatment of East Asian patients with LN are limited, we assessed the efficacy and safety of belimumab in a subgroup of East Asian patients from the BLISS-LN study. Patients received monthly belimumab or placebo in addition to standard therapy. After 104 weeks, patients who received belimumab showed earlier and more sustained improvements in kidney outcomes compared with patients who received placebo, while no new safety concerns were raised. These results support the use of belimumab treatment for East Asian patients with LN.

DOI: 10.1053/j.ajkd.2022.06.013

Cardiorenal Outcomes Among Patients With Atrial Fibrillation Treated With Oral Anticoagulants by Marco Trevisan et al. [OPEN ACCESS]

From the authors: The relative safety of anticoagulation with direct oral anticoagulants (DOACs) or vitamin K antagonists like warfarin remains inconclusive, particularly with regard to outcomes related to kidney disease on injury. In a cohort of patients with nonvalvular atrial fibrillation from Sweden, we observed that initiation of a DOAC compared with warfarin was associated with a lower risk of the composite of kidney failure and sustained 30% decline in kidney function, as well as a lower risk of occurrence of acute kidney injury. In agreement with trial evidence, DOAC versus warfarin treatment was associated with a lower risk of major bleeding but a similar risk of the composite of stroke, systemic embolism, or death. Collectively, these findings add to the emerging evidence on the safety and effectiveness of DOAC administered for atrial fibrillation.

DOI: 10.1053/j.ajkd.2022.07.017

Racial and Ethnic Disparities in Acute Care Utilization Among Patients With Glomerular Disease by Jill R. Krissberg et al. 

From the authors:  Racial and ethnic disparities have been described in many aspects of kidney disease, but little is known about disparities in glomerular disease. This large multinational cohort study of the Cure Glomerulonephropathy Network describes differences in acute care utilization for patients with glomerular disease across racial and ethnic groups and explores potential underlying reasons for any observed differences. We found that Black race was associated with higher rates of acute care utilization, whereas Asian race was associated with lower rates of acute care utilization. These associations may be explained by differences in socioeconomic status and disease severity among these groups. Efforts to improve health equity should consider socioeconomic factors contributing to disease severity or reliance on hospital over ambulatory care.

DOI:10.1053/j.ajkd.2022.08.010

Review from the March 2023 issue:

Intensive Care Unit–Acquired Weakness in Patients With Acute Kidney Injury: A Contemporary Review by J. Pedro Teixeira et al (FREE)

Acute kidney injury (AKI) and intensive care unit–acquired weakness (ICU-AW) are 2 frequent complications of critical illness that, until recently, have been considered unrelated processes. The adverse impact of AKI on ICU mortality is clear, but its relationship with muscle weakness—a major source of ICU morbidity—has not been fully elucidated. Furthermore, improving ICU survival rates have refocused the field of intensive care toward improving long-term functional outcomes of ICU survivors. The authors begin the review with the epidemiology of AKI in the ICU and of ICU-AW, highlighting emerging data suggesting that AKI and AKI treated with kidney replacement therapy (AKI-KRT) may independently contribute to the development of ICU-AW. The authors then delve into human and animal data exploring the pathophysiologic mechanisms linking AKI and acute KRT to muscle wasting, including altered amino acid and protein metabolism, inflammatory signaling, and deleterious removal of micronutrients by KRT. They next discuss the currently available interventions that may mitigate the risk of ICU-AW in patients with AKI and AKI-KRT. They conclude that additional studies are needed to better characterize the epidemiologic and pathophysiologic relationship between AKI, AKI-KRT, and ICU-AW and to prospectively test interventions to improve the long-term functional status and quality of life of AKI survivors.

DOI: 10.1053/j.ajkd.2022.08.028

On the Cover: On March 9, 2023, the 18th annual World Kidney Day (WKD) will raise awareness on the global burden of kidney disease. This year’s theme, “preparing for the unexpected and supporting the vulnerable,” highlights the need for all members of the kidney community to plan ahead for care disruptions that occur during unpredictable times of disaster. Further information on the 2023 WKD campaign is available at www.WorldKidneyDay.org.

Image adapted from the WKD 2023 campaign image, World Kidney Day 2006-2023.

Only a few more days until we reveal the NephMadness 2023 bracket on Wednesday, March 1!

FRIENDLY REMINDER: Have you scheduled a date to complete your group bracket yet?

Until then, catch up on the Top Ten Region Posts from the last 11 years of NephMadnesses!

Photo: lkeskinen / 123RF

        10. SGLT2i (2020)

Writer: Meg Jardine

Expert: Harish Seethapathy

Exec: Joel Topf

Copyright: Who is Danny / Shutterstock

9. Hyperkalemia (2020)

Writer: Ryann Sohaney

Expert: Deborah Clegg

Exec: Joel Topf

Copyright: bergamont / Shutterstock

8. Volume Assessment (2019)

Writer: Devika Nair

Expert: Tariq Shafi

Exec: Anna Burgner

Copyright: Meryll / Shutterstock

7. Hospitalist Nephrology (2019)

Writer: Pascale Khairallah

Expert: Charlie Wray

Exec: Joel Topf

Copyright: Vladimir Mucibabic / Shutterstock

6. Hypertension (2019)

Writer: Swapnil Hiremath

Expert: Susan Steigerwalt

Exec: Matthew Sparks

5. Contrast (2018)

Writer: Swapnil Hiremath, Anitha Vijayan, Natasha Dave, and Rajeev Raghavan

Expert: Paul M. Palevsky

Exec: Matthew Sparks

Copyright: Lightspring / Shutterstock

4. Anemia (2021)

Writer: Arun Rajasekaran

Expert: Nupur Gupta

Exec: Pascale Khairallah

Copyright: Vladimir Mucibabic / Shutterstock

3. Artificial Kidney (2021)

Writer: Krishna Agarwal

Expert: Bill Fissell

Exec: Timothy Yau

Copyright: Yurchanka Siarhei / Shutterstock

2. Hyponatremia (2018)

Writer: Swapnil Hiremath

Expert: Richard H. Sterns

Exec: Joel Topf

Copyright: CK Foto / Shutterstock

1. Cardiorenal (2022)

Writer: Caitlyn Vlasschaert

Experts: Nisha Bansal and Sadiya Khan

Execs: Samira Farouk and Anna Burgner

Copyright: Sri J / Shutterstock

Happy reading!

*Note: The Top Ten posts do not include helpful guides such as Welcome to #NephMadness 2021

#NephMadness | @NephMadness | NephMadness 2023

Melandrea Worsley @MWorsleyMD

Dr. Melandrea Worsley is a current nephrology fellow at Baylor College of Medicine in Houston, Texas. She is passionate about addressing disparities in hemodialysis vascular access.

 

 

L. Parker Gregg @LParkerGregg1

Dr. L. Parker Gregg is an Assistant Professor at Baylor College of Medicine, the Michael E. DeBakey VA Medical Center, and the Center for Innovations in Quality, Effectiveness and Safety. Her primary interests are in non-traditional risk factors in CKD.

For patients with kidney failure who require hemodialysis (HD), vascular access becomes their lifeline. Obtaining and maintaining vascular access with an arteriovenous fistula (AVF), arteriovenous graft (AVG), or a central venous catheter have unique risks and benefits. The risks associated with the creation and maintenance of an AVF or AVG include bleeding, nerve damage, maturation failure, infection, steal syndrome, and high-output heart failure.^[1] These vascular accesses can be complicated by clotting, stenosis, aneurysms, or pseudoaneurysms, which can require additional procedures to maintain access patency and function.^[2] Dialysis catheters, on the other hand, are considered to have a higher risk of bloodstream infections, may achieve slower blood flow rates with effects on clearance, and can have problems of patency that require placement of a new catheter.^[3]

Prior clinician-driven policies focused on a fistula-first approach to creating HD vascular access, with the rationale that AVFs were thought to have fewer complications than other vascular access types. In 2003, the Centers for Medicare and Medicaid Services (CMS) assembled a task force of vascular access experts, nephrologists, and nurses for the Fistula First National Vascular Access Improvement Initiative. This group was formed to develop and implement systemic changes to support the creation of AVFs for HD. This practice pattern revealed high rates of AVF maturation failure. To address this, in 2015 the Fistula First Catheter Last Workgroup Coalition was formed to reduce the number of catheters that were being used for HD access, as well as to implement further systemic changes needed to increase the rate of successful AVF creation. Despite initiatives and incentives put into place to decrease catheter use, between 2009 and 2018 the rate of HD initiation with a catheter only decreased from 82.4% to 80.8%. Among patients who initiated HD in 2017, 68% of patients were still dialyzing via a catheter 3 months after initiation.^[4] More recently it has been recognized that many patient-level factors also affect HD vascular access decision-making. Consequently, a more patient-centered approach of individualized decisions about vascular access in the context of strategizing for living with kidney failure is now recommended.^[5]

In a recent qualitative study, Elliott, et al. interviewed 19 patients on chronic HD, two caregivers, eight nephrologists, and 13 HD or vascular access nurses at five adult in-center HD units in Alberta, Canada to better understand how these groups perceive the process of shared decision making about vascular access. They identified that shared decision-making about vascular access begins with foundational conversations about prognosis and dialysis modality, which should incorporate the patient’s values, abilities, and priorities. This puts future conversations about vascular access into a meaningful context. The authors note that the process of shared decision-making was undermined in cases of unplanned dialysis initiation, lack of a decision about vascular access prior to the need to start dialysis, or an inability to achieve the patient’s desired vascular access type. This analysis demonstrates that multiple important decisions, beginning with goals of care and prognosis, set the stage for effective shared decision-making about vascular access. Repeated discussions are often necessary, and a patient’s decision about vascular access can be readdressed even after HD initiation.^[6]

Discussions concerning vascular access placement should incorporate patient education about factors that may influence this decision, while also encouraging patients to educate clinicians on their personal healthcare priorities. Several crucial factors impact the decision-making process, including the timing and context of discussions of prognosis and vascular access, patient priorities, biological and surgical factors, and sociocultural considerations (Figure 1). As for the timing of these discussions, it may be difficult for clinicians to anticipate the amount of time a patient has prior to initiating dialysis, which can complicate pre-dialysis planning. In some cases, depending on the patient’s rate of decline in kidney function, a late referral to nephrology when estimated glomerular filtration rate (eGFR) is already low may not provide adequate time for a patient to accept that they may ultimately need dialysis, determine their desired dialysis modality, and have a vascular access placed and ready to use in time. Acute kidney injury may necessitate dialysis initiation sooner than anticipated. In such cases, patients may pursue urgent HD with a catheter as their only available option at the time of initiation.

Patients’ personal healthcare priorities must also be considered when vascular access is selected. A trusting clinician-patient relationship that enables the patient to safely express their priorities is key. Patients’ individual goals should be considered; for example, those who anticipate forthcoming kidney transplantation may elect to defer AVF placement given the brief expected time on HD. Patients’ concerns, such as fear of needles or cosmesis, must be considered as well. Surgical placement of a vascular access results in scarring, and over time AVFs may enlarge having an undesirable cosmetic effect. Priorities such as these may have striking impact on a patient’s decision-making process and should be acknowledged by clinicians and incorporated into patient-centered discussions.

Biological and surgical factors also contribute to the patient’s eligibility for vascular access creation and can undermine shared decision-making when a patient is not able to receive their preferred access type. In order for an AVF to be placed, a patient must have adequate vasculature to allow for access placement and maturation. Many patients have insufficient vasculature due to comorbidities, such as diabetes mellitus and hypertension.^[7] Access to experienced surgeons may also impact decision-making about access eligibility. In one study, surgeons with more than 30 years of clinical experience and vascular surgeons (vs. general or cardiothoracic surgeons) were more likely to place an AVG as a patient’s initial HD access, independent of patient-level factors.^[8]

Sociocultural factors may also influence the type of HD access a patient receives. For example, racial and ethnic healthcare disparities have been identified regarding HD vascular access. Black patients are less likely to receive an AVF and more likely to require a second access when compared to White patients.^[9] Black patients are also less likely to initiate HD with an AVF, despite being younger and having less coronary artery disease, when compared to White patients.^[10] Black patients are less likely to receive nephrology care prior to kidney failure when compared to their White counterparts, which likely contributes to these disparities. Education level, employment status, and the availability of caregiver support may also impact vascular access decision-making. Further qualitative research will be important to understand the extent to which such sociocultural factors influence HD vascular access decision-making.

The nature of vascular access decision-making is complex and requires integration of that decision into repeated conversations starting from the foundational discussions about prognosis to help patients understand and accept the need to plan for dialysis. Prior policies prioritizing one access type over another did not account for this complexity, which may have contributed to the less-than-anticipated success in reducing the use of dialysis catheters. The analysis by Elliot, et al. suggests we should integrate the vascular access decision process into earlier discussions and consider the upstream clinician-patient relationships and conversations that lay the critical foundation for vascular access shared decision-making. Thoughtful communication between clinicians and patients is important to individualize vascular access decision-making and ensure that patients’ priorities and goals are considered in their care plan. The shift toward individualized vascular access decisions represents a patient-centered transition in thinking that will ultimately improve the quality of care that is provided to patients with kidney failure.

Figure 1. Factors impacting HD vascular access shared decision-making.

–Post prepared by Dr. Melandrea Worsley and Dr. L. Parker Gregg. 

To view Elliott et al, please visit AJKD.org.

Title: Patient and Clinician Perspectives on Shared Decision-Making in Vascular Access Selection: A Qualitative Study

Authors: Meghan Elliott, Pietro Ravani, Robert Quinn, Matthew Oliver, Shannan Love, Jennifer MacRae, Swapnil Hiremath, Sarah Friesen, Matthew James, and Kathryn King-Shier.

DOI: 10.1053/j.ajkd.2022.05.016