Dr. James Torain is a second-year nephrology fellow at Duke University Hospital. He currently has an interest in implementation of home dialysis modalities. Health disparities have been a particular interest of his since completing his medical degree at Meharry Medical College.  His fascination with the intricacies of renal physiology and CKD prevention developed during his residency at the University of Tennessee Health Science Center. Outside of medicine, Dr. Torain enjoys running, playing the drums, and speaking at local church health symposiums.

 

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Dr. Matthew Sinclair @mattysincs is currently at Medical Instructor at Duke University School of Medicine and a faculty member at the Duke Clinical Research Institute in Durham, NC. His research focuses on reducing the progression of chronic kidney disease among racial and ethnic minorities both by enhancing recognition of chronic kidney disease risk factors among individuals in the community and developing interventions to optimize evidence-based screening and therapy provision for patients with or at risk for chronic kidney disease. Dr. Sinclair has also been very proud to serve as a member of the NKF Health Equity Advisory Committee since 2023. In addition to his research and advocacy work, Dr. Sinclair greatly values his time working with patients as a nephrologist at both Duke University Hospital and the Durham Veterans Affairs Medical Center. When not at work, Dr. Sinclair enjoys traveling and spending time with his wife and two young sons.

In March of 2013, Canagliflozin became the first sodium glucose cotransporter-2 inhibitor (SGLT2i) approved to improve glycemic control in adults with type 2 diabetes (T2D). In the decade since, numerous cardiovascular outcome trials (CVOTs) examined multiple SGLT2i’s, all of which noted impressive reductions in adverse cardiovascular and kidney outcomes. In 2019, the Canagliflozin and Renal Outcomes In T2D and Nephropathy (CREDENCE) trial became the first CVOT to specifically examine and note a lower risk of kidney failure and cardiovascular events in patients with both T2D and chronic kidney disease (CKD). Since then, multiple other trials have noted similar results, even in patients with advanced CKD with and without T2D, solidifying this medication class as a mainstay of treatment for all patients with CKD. In fact, the recent Kidney Disease: Improving Global Outcomes (KDIGO) 2022 Clinical Practice Guideline for Diabetes Management in CKD recommends SGLT2i’s as first-line therapy.

So, these “miracle drugs” are being prescribed frequently and to those patients who need them most, right? Unfortunately, this is not the case. In a recently published study examining prescribing of SGLT2i’s through 2019 among insured patients with T2D and CKD, initiation rate of SGLT2i’s was only 2.5%.  Perhaps this under-prescribing could be attributed to cost, as these medications are often quite expensive for patients, even those with insurance. Therefore, examining prescribing in a system where price isn’t an issue would be ideal to eliminate cost as a reason for under-prescribing; enter the Veterans Affairs (VA) healthcare system. The VA system offers heavily discounted or free medications to patients, reducing the influence of cost as a factor. This allows us to control for the cost of drugs and evaluate other factors that may cause lack of optimal prescribing of SGLT2i’s.  In 2022, a JAMA trial was published that examined prescribing of SGLT2i’s among adults with T2D in the VA system from January 2019 through December 2020, and unfortunately, prescribing rates remained poor, with only 10.7% of eligible patients receiving an SGLT2i. Furthermore, racial and ethnic minority individuals (most prominently Black and Hispanic patients) were even less likely to receive these medications.

In the recently published July 2023 issue of AJKD, the article a study from L. Parker Gregg and colleagues expanded on the previously described JAMA article to examine prescribing among US veterans with comorbid T2D, CKD, and atherosclerotic cardiovascular disease, who had at last one primary care visit in 2020. The investigators examined the associations of race and sex with prescribing, in addition to facility level variation. Notably, Hispanic ethnicity was not evaluated as a predictor for prescribing in this study. Like the JAMA study, SGLT2i prescribing overall was poor, with only 11.5% of veterans prescribed an SGLT2i. There was a profound racial discrepancy in prescribing, with Black Patients being about 13% less likely to receive an SGLT2i compared to White patients. Furthermore, women were over 40% less likely to receive an SGLT2i compared to men. In terms of facility level variation, there was a residual 58% variation in treatment with SGLT2i’s among two similar patients and two random facilities, indicating large variation of prescribing.

This study also thoroughly evaluated race and sex disparities in prescribing among subgroups. Overall, as comorbidities (ie, CKD, heart failure, and T2D) became more advanced or less controlled, disparities between Black and White patients were attenuated. However, among patients with less advanced disease who would still benefit from an SGLT2i, Black patients were prescribed the medication significantly less. In academic medical centers, there was no difference in prescribing between Black and White patients, but Black patients were less likely to be prescribed SGLT2is at community medical centers. As far as sex disparities, nearly all subgroups of women had lower prescribing than men.

Possible Reasons for Lack of SGLT2 inhibitor Prescribing In VA vs Civilian Systems. © Torain, Sinclair

There are multiple possible reasons for the reasons for the findings in the study. Unconscious bias likely plays a role, as it seems providers recognize the value in prescribing SGLT2is to Black patients more once their disease and comorbidities are advanced, as opposed to earlier on, when these drugs have just as much if not more benefit. Additionally, it’s likely that providers associated with academic medical centers may be more updated with recent evidence that supports prescribing of the SGLT2i’s, compared to their counterparts working in community settings. It should also be noted that trainees at teaching (ie. academic) facilities are being precepted, meaning that there is an active review process for patients that they see. Having multiple providers involved in the decision-making process may lead to improved prescribing. As far as the sex disparities seen in the trial, it’s important to note that the VA population is predominantly male, including >98% of patients in this study. That being said, the lack of prescribing in women is notable, and may be partially attributable to the concern for the SGLT2i’s to cause urinary tract infections, specifically in peri- and post-menopausal women. This concern may be exacerbated by the fact that these female patients are being seen by providers who may not used to be seeing many female patients, and hence may be more hesitant to prescribe these medications that those providers in the community setting.

In conclusion, providers need to do a better job of prescribing SGLT2i’s to all patients. It is especially concerning that racial and ethnic minority individuals, including Black and Hispanic patients, are being prescribed these medications at lower rates than their White brethren, when they are already at a higher risk of progressing to end stage kidney disease. We explored multiple factors that may be associated with reduced prescribing, some of which affect only patients in the VA or the civilian world, but most of which affect all patients (see Figure). Clearly, more studies are needed to better understand all reasons for lack of prescribing of these life-saving medications, so that we may do a better job of addressing the barriers to adequate prescribing and get these medications into the hands of the patients who need them most.

To view Gregg et al (subscription required), please visit AJKD.org.

Title: Predictors, Disparities, and Facility-Level Variation: SGLT2 Inhibitor Prescription Among US Veterans With CKD
Authors: L. Parker Gregg, David J. Ramsey, Julia M. Akeroyd, Shehrezade A. Jafry, Michael E. Matheny, Salim S. Virani, Sankar D. Navaneethan
DOI: 10.1053/j.ajkd.2022.11.017

The author and his father.  © Hassanein

In A Few Words is a recurring AJKD feature that highlights the diverse stories that define kidney disease. In a recent piece, Dr Mohamed Hassanein reflected on his father’s extraordinary journey to becoming an international medical graduate in nephrology. AJKDBlog’s Interviews Editor,  Timothy Yau @Maximal_Change recently sat down with Dr Hassanein @kidneymo to discuss his father’s legacy.

AJKD Interview – Dr. Hassanein, In A Few Words from Timothy Yau on Vimeo.

If the embedded player above doesn’t work, please click here to watch the video interview. Special thanks to Dr. Hassanein!

To view Dr Hassanein’s essay (FREE), please visit AJKD.org.

Title: Honoring My Father’s Legacy as an International Medical Graduate in Nephrology
Author:Mohamed Hassanein
DOI: 10.1053/j.ajkd.2022.11.011

Interested in submitting In A Few Words? Find out more in this Call for Submissions. 

Figure 1 from Bushinsky et al, AJKD © The Authors

In a recent Original Investigation published in AJKD, David Bushinsky and colleagues characterized the effect of patiromer on serum phosphorus in patients with CKD, hyperkalemia, and hyperphosphatemia.

AJKD’s Social Media Editor, Timothy Yau @Maximal_Change recently sat down with his Rush Nephrology colleagues Pravir Baxi @Proximal_Baxi, Roger Rodby @NephRodby, and William Whittier @TWhittier_RUSH, for a deeper dive into hyperkalemia and potassium binders.

If the embedded player above doesn’t work, please click here to watch the video interview. Special thanks to Drs. Baxi, Rodby, and Whittier for lending us their expertise!

To view this Original Investigation [Open Access], please visit AJKD.org.

Title: Patiromer Treatment in Patients With CKD, Hyperkalemia, and Hyperphosphatemia: A Post Hoc Analysis of 3 Clinical Trials
Author:David A. Bushinsky Jeffrey J. Budden Philip A. Kalra Jinwei Yuan Carol Moreno Quinn Murray Epstein
DOI: 10.1053/j.ajkd.2023.01.444

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. Highlights from the September 2023 issue:

Serum Potassium and Risk of Death or Kidney Replacement Therapy in Older People With CKD Stages 4-5: Eight-Year Follow-up by Esther N.M. de Rooij et al [OPEN ACCESS]

From the authors: Abnormal potassium blood levels may increase the risk of death or kidney function decline, especially in older people with chronic kidney disease (CKD). We studied 1,714 patients aged ≥65 years with advanced CKD from the European Quality (EQUAL) study and followed them for 8 years. We found that both low and high levels of potassium were associated with an increased risk of death or start of kidney replacement therapy, with the lowest risk observed at a potassium level of 4.9 mmol/L. In patients with CKD, the focus is often on preventing high blood potassium. However, this relatively high optimum potassium level stresses the potential importance of also preventing low potassium levels in older patients with advanced CKD.

DOI: 10.1053/j.ajkd.2023.03.008

Evaluation of Plasma Biomarkers to Predict Major Adverse Kidney Events in Hospitalized Patients With COVID-19 by Steven Menez et al [OPEN ACCESS]

From the authors:  Patients hospitalized with COVID-19 are at increased risk for long-term adverse health outcomes, but not all patients suffer long-term kidney dysfunction. Identification of patients with COVID-19 who are at high risk for adverse kidney events may have important implications in terms of nephrology follow-up and patient counseling. In this study, we found that the plasma biomarkers soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 measured in hospitalized patients with COVID-19 were associated with a greater risk of adverse kidney outcomes. Along with clinical variables previously shown to predict adverse kidney events in patients with COVID-19, both sTNFR1 and sTNFR2 are also strong predictors of adverse kidney outcomes.

DOI: 10.1053/j.ajkd.2023.03.010

Integrated Analysis of Blood and Urine Biomarkers to Identify Acute Kidney Injury Subphenotypes and Associations With Long-term Outcomes by Pavan K. Bhatraju et al

From the authors: Acute kidney injury (AKI) occurs commonly in hospitalized patients and is associated with high morbidity and mortality. The AKI definition lumps many different types of AKI together, but subgroups of AKI may be more tightly linked to the underlying biology and clinical outcomes. We used 29 different clinical, blood, and urinary biomarkers and applied 2 different statistical algorithms to identify AKI subtypes and their association with long-term outcomes. Both clustering algorithms identified 2 AKI subtypes with different risk of chronic kidney disease, independent of the serum creatinine concentrations (the current gold standard to determine severity of AKI). Identification of AKI subtypes may facilitate linking therapies to underlying biology to prevent long-term consequences after AKI.

DOI: 10.1053/j.ajkd.2023.01.449

Long-term Visit-to-Visit Variability in Hemoglobin A1c and Kidney-Related Outcomes in Persons With Diabetes by Yang Xu et al 

From the authors:  Heart disease and kidney disease are known to interact with each other. In this study, we examined whether cardiac abnormalities, as assessed by echocardiography, were linked to the subsequent progression of kidney disease among people living with chronic kidney disease (CKD). We found that people with abnormalities in heart structure and function had a greater risk of progression to advanced CKD that required kidney replacement therapy and had a faster rate of decline in kidney function. Our study indicates the potential role of abnormal heart structure and function in the progression of kidney disease among people living with CKD.

DOI: 10.1053/j.ajkd.2023.03.007

Case Report from the September 2023 issue:

Antiviral Treatment Failures After Transplantation of Organs From Donors With Hepatitis C Infection: A Report of 4 Cases by Julie M. Steinbrink et al [OPEN ACCESS]

The transplantation of organs from donors with hepatitis C virus (HCV) infection into uninfected recipients has expanded the available organ donor pool. With the advancement of direct-acting antivirals (DAAs), high rates of cure among transplant recipients are possible. Although DAAs are highly effective, treatment failure can occur following an appropriate 12-week course of a pan-genotypic regimen. Here we describe 4 kidney transplant recipients of organs from donors with HCV infection (3 with genotype 3, 1 genotype 1a) in whom first-line DAA treatment with either glecaprevir-pibrentasvir or sofosbuvir-velpatasvir was unsuccessful, started 22-35 days after the day of transplantation. All ultimately achieved sustained virologic response with second- or third-line therapy. Post-treatment resistance-associated substitutions were tested and noted to be present in 2 cases. Additionally, antiviral levels were assessed in 2 cases and found to be therapeutic in each. This article explores possible reasons for treatment failure, including medication interactions, bariatric surgery, viral dynamics, and drug resistance.

DOI: 10.1053/j.ajkd.2022.12.006

On the Cover: The cover image captures the salt pans of Marsaskala, Malta at sunrise, a testament to the intricate process of sea salt crystallization. This meticulous process, beginning with seawater filling coastal crevices and culminating in evaporation and
crystallization in smaller, warmer pans, stands in stark contrast to the pathological retention of salt in the human body. Excessive salt retention, as seen in primary aldosteronism, can lead to hypertension and end-organ damage. In this issue of AJKD, Hernandez and Bhalla summarize the screening and detection of primary aldosteronism, a common yet often underdiagnosed condition, characterized by excessive aldosterone leading to sodium reabsorption and potassium excretion. The review underscores the need for improved screening and diagnostic practices to address this prevalent, consequential, and treatable
disease.

The photograph “Salt flats at sunrise” by Giuseppe Milo is released on Flickr under the CC BY 2.0 license.

Special thanks to Editorial Intern Mengyao Tang for curating the cover image and drafting the
cover blurb for this issue.

SPECIAL COLLECTION: HIGHLY CITED ARTICLES

This special collection highlights the top cited Original Investigations published in 2020 and 2021 that contributed to AJKD’s 2022 Impact Factor of 13.2, our highest IF yet. The editors would like to thank all the authors and reviewers who helped AJKD achieve this milestone..

Dr. Zachary Appelbaum, is a Nephrology fellow in the Renal -Electrolyte and Hypertension Division at the Hospital of the University of Pennsylvania. He matriculated from the University of Miami Leonard M. Miller School of Medicine and completed Internal Medicine residency at George Washington University Hospital. His main academic interests include Nephrology and healthcare policy.
 

 
 

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Dr. Biruh Workeneh, @Ralph__Nader, is an Assistant Professor at the Perelman School of Medicine and a nephrologist in the Renal-Electrolyte and Hypertension Division at the Hospital of the University of Pennsylvania. As part of the Penn Glomerular Center, his main clinical and research interests revolve around glomerular diseases and onconephrology with a special interest in amyloidosis and gammopathies of renal significance.

 

 

Minimal change disease (MCD) is a primary podocytopathy that accounts for approximately 80% and 15% of nephrotic syndrome (NS) in the pediatric and adult populations respectively. A kidney biopsy is necessary in adults, whereas the diagnosis is presumed in children based on clinical presentation. MCD is characterized by normal histology on light microscopy, absence of significant staining by immunofluorescence (IF), and foot process effacement on electron microscopy. Corticosteroids are typically utilized as first line agents in the management of MCD, however other immunosuppressive treatments, including antimetabolites, calcineurin inhibitors, and B cell depleting agents, are used in patients intolerant to corticosteroids or in patients with poorly controlled MCD.

The pathogenesis of MCD likely involves both T and B cell mediated processes. One current hypothesis is that MCD is caused by one or more circulating factors that alter the glomerular filtration barrier’s permeability. While initially this factor was thought to be produced by T cells, based on response to cell-mediated immunity suppression and the absence of antibody deposition found on IF, further research suggests a role for B cells based on the effectiveness of the anti-CD20 agent rituximab and an increase in plasma soluble CD23 during MCD relapses. Recent literature has described a role for anti-nephrin antibodies in the pathogenesis of MCD. Nephrin is a structural component of the slit diaphragm and administration of anti-nephrin antibodies has produced proteinuria in animal models. In an important study by Watts et al, a subset of MCD patients with active disease developed elevated levels of nephrin autoantibodies, which decreased during periods of remission. Kidney biopsies from these patients demonstrated delicate punctate IgG that colocalized specifically with nephrin, possibly representing in situ binding of nephrin autoantibodies. The evidence supporting a pathogenic role for both T and B cells underscores their essential cross-talk and the role that T cells play in orchestrating, maintaining, and amplifying the humoral immune response. In particular, there is polarization of Th2 immune cells that favors propagation of a humoral immune response and may be implicated in MCD relapses. As in other autoimmune conditions, MCD has been associated with a reduced number and function of regulatory T cells – the biology of which continues to be an active area of research.

Because MCD accounts for 80% of NS cases in children , pediatric patients are often treated empirically with corticosteroids without undergoing kidney biopsy. A recent study by Chen et al analyzed the clinical course of childhood and adult-onset MCD from the CureGN cohort. The difference in performing a biopsy can be noted from the time of disease onset until kidney biopsy. Specifically, children and adults were biopsied at approximately 238 and 36 days after disease onset respectively – clearly demonstrating the need for an early tissue diagnosis in adults in whom a workup is indicated to rule out other causes of NS. Moreover, this study comments on the generalizability of the findings noted in the pediatric cohort as those patients underwent a kidney biopsy for a reason. For example, the most common disease classification at enrollment in the childhood-onset group was frequent relapsing/glucocorticoid-dependent disease; this may not necessarily represent the entire spectrum of pediatric MCD cases.

In both children and adults, MCD remission can typically be obtained with a course of corticosteroids. However, approximately 20% of adult patients exhibit steroid resistance. Steroid-sparing agents – calcineurin inhibitors, mycophenolate, and rituximab – are used in subsequent relapses and in patients defined as frequent relapsers, steroid dependent, and steroid resistant. Table 1 summarizes some of the pertinent characteristics of the different immunosuppressive regimens.

In the recent Chen et al study, which analyzed the clinical course of 554 patients – mostly childhood and adult-onset disease – with biopsy proven MCD, childhood-onset MCD exhibited faster times to remission and more frequent relapses compared to adult-onset MCD. Additionally, patients with childhood-onset disease were more likely to enter remission after rituximab initiation as compared to adolescents or adults. This noted difference following rituximab therapy may suggest more responsive lesions and fewer chronic changes in pediatric patients. Given the spectrum of response to treatment and the noted differences in sustained control of NS, important questions arise regarding the possibility of distinct MCD phenotypes, variations in response to treatment at different times in the disease course, and the ongoing need to identify predictive risk factors for remission or relapse.

Furthermore, the authors noted a higher rate of remission in the steroid-sensitive group than the steroid-resistant group after rituximab therapy suggesting that while there is no biomarker available to predict the effect of B cell depletion, response or resistance to previous immunosuppressive agents, such as corticosteroid therapy, can guide the decision to administer rituximab.

The Chen et al study reiterates that the prognosis of MCD remains favorable. In fact, 4% of childhood-onset MCD patients developed ESKD compared to 3% of adult-onset patients. These findings are similar to other studies that suggest less than 5% of adult-onset patients progress to ESKD .

The study by Chen et al illustrates the variety of MCD phenotypes based on response to treatment and subsequent risk of relapse. Certain phenotypes, particularly those found in childhood-onset disease, are initially easier to treat but exhibit higher relapse rates.

Because patients receiving rituximab therapy had higher remission rates amongst the steroid-sensitive cohort as opposed to the steroid-resistant group, pertinent questions arise regarding this specific patient population and their response to B cell depletion. Are these patients being treated earlier before substantial sclerosis has occurred? Is this a subset of patients in whom the humoral immune response is the more predominant driver in the pathogenesis of their disease? Is it possible that these patients have higher anti-nephrin antibodies, or other – yet to be discovered – antibody titers at presentation?

While it may be too early to tell, it seems like the story of MCD is reminiscent of the one re-written for membranous nephropathy in 2009 with the discovery of PLA2R  and the other antigens identified afterward, opening the door to precision medicine in the treatment of glomerular disease.

In their elegant 2022 study, Watts et al identified nephrin auto-antibodies in a subset of patients with MCD, and the paper from Chen et al seems to describe patients with MCD having different phenotypes. As such, given this variety in MCD phenotypes and the heterogeneity in response to treatment, questions arise as to the prevalence of anti-nephrin in this cohort, its possible role in the differences seen in disease phenotypes, and the possibility of other yet-to-be-discovered antigens which may explain the variety seen in MCD.

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

Title: Age of Onset and Disease Course in Biopsy-Proven Minimal Change Disease: An Analysis From the Cure Glomerulonephropathy Network
Authors: Dhruti P. Chen, Margaret E. Helmuth, Abigail R. Smith, Pietro A. Canetta, Isabelle Ayoub, Krzysztof Mucha, Mahmoud Kallash, Jeffrey B. Kopp, Rasheed Gbadegesin, Brenda W. Gillespie, Larry A. Greenbaum, Rulan S. Parekh, Tracy E. Hunley, C. John Sperati, David T. Selewski, Jason Kidd, Aftab Chishti, Kimberly Reidy, Amy K. Mottl, Debbie S. Gipson, Tarak Srivastava, Katherine E. Twombley on behalf of theCureGN Consortium
DOI: 10.1053/j.ajkd.2022.11.012

Dr. Helbert Rondon, @NephroMD, is an Associate Professor of Medicine in the Renal-Electrolyte Division at the University of Pittsburgh School of Medicine where he also serves as the Program Director of the Nephrology Fellowship Training Program. Dr. Rondon has authored several publications in the field of hyponatremia. He is an NIH funded clinical investigator. His research focus on the effects of oral urea on the clinical outcomes of chronic hyponatremia and the use of hypertonic saline and desmopressin for slow correction of chronic severe hyponatremia.

Dr. Biruh Workeneh, @bdubNephro, is a nephrologist at the University of Texas MD Anderson Cancer Center and has contributed to a better understanding of the complex relationship between cancer, electrolyte imbalances, and cancer therapy.

 

 

 

AJKD Interviews Editor Timothy Yau (@Maximal_Change) talks to Dr. Helbert Rondon and Dr. Biruh Workeneh about their recently published AJKD Review on electrolyte and acid-base disorders in patients with cancer.

AJKDBlog: Let’s start with pseudohyponatremia – probably the most well known and most discussed pseudo-electrolyte disorders.  Can you explain the different assays using direct and indirect ion selective electrodes (ISE) and how pseudohyponatremia can be seen when there is higher percent of solid phase proteins in plasma?

First, we should start by saying that both methods used the ISE technique where an electrode that includes a membrane selective for sodium ions is submerged into an aliquot of the serum sample to measure sodium ion activity in water (sodium ions only distribute in the water fraction of serum). The ISE electrode produces a potential change due to the exchange of sodium ions on the surface of the electrode membrane and the serum sample. This potential change is then converted into a concentration using the Nernst equation and a result is produced.

Most clinical laboratories routinely measure serum sodium in automated analyzers using the indirect ISE method. In this method an aliquot of the serum sample first undergoes a significant dilution step (typically dilution of 1:16-1:34) prior to sodium measurement. Dilution is needed to extend the life of the electrode and to decrease the volume of serum sample needed for testing. Under normal conditions, plasma is 93% water and 7% solids (proteins and lipids). After measuring sodium ion activity in the post-dilution serum aliquot and converting it into sodium concentration, the analyzer back calculates the serum sodium concentration in the pre-dilution serum aliquot by multiplying the sodium concentration in the post-dilution serum aliquot by the dilution factor used (Figure 1A).  In patients with severe hyperproteinemia or hypertriglyceridemia, the solid phase of serum is greater than 7%, and hence the water fraction would be less than 93%. (Figure 1B). Because sodium ions only distribute in the water fraction of serum, the sample with a lower water fraction will contain less sodium ions. If this sample undergoes a significant dilution, the effect of the solids coming from the original sample will be negligible here and the electrode will measure then a lower sodium ion activity in water, and hence a lower sodium concentration. Therefore, indirect ISE methods are affected by the distribution of solutes and water in the sample. This phenomenon is known as the “electrolyte exclusion effect” or “volume displacement effect.”

In contrast, direct ISE methods do not involve a dilution step. Electrodes are submerged in a serum aliquot where sodium ion activity will be measured and then converted to sodium concentration. Since sodium ion activity is measured in the water fraction of an undiluted serum sample, the presence of a lower water fraction (<93%), as it occurs in hyperproteinemia or hypertriglyceridemia, will not affect the results. Sodium concentration measured in serum water is expected to be higher than in total serum. To standardize the results with sodium concentration obtained by indirect ISE, sodium concentration in water serum is multiplied by 0.93 to transform the results to sodium concentration in total serum (Figure 2). Sodium concentration using direct ISE methods tends to be 2 mmol/L lower than the one obtained with indirect ISE methods.

AJKDBlog: If this is suspected in diseases such as paraprotein diseases, hypertriglyceridemia, or lymphoproliferative diseases, how can clinicians confirm a true plasma sodium with direct ISE measurements?

In cases where isoosmolar hyponatremia is encountered, clinicians frequently order serum protein electrophoresis and/or lipid profile to rule out common abnormalities leading to pseudohyponatremia. However, isoosmolar hyponatremia is more commonly associated with the presence of ineffective osmoles such as urea or ethanol in the setting of hypotonic hyponatremia (e.g., hyponatremia in ESKD, beer potomania). Therefore, the easiest and most efficient way to confirm pseudohyponatremia is to simply order a whole blood sodium measured in a blood gas analyzer or point-of-care device (i.e., iSTAT).

AJKDBlog: You also discuss a less well-known phenomenon that has a very similar mechanism – pseudohypobicarbonatemia.  It sounds like this is very similar to pseudohyponatremia that can be seen with indirect ISE measurement.  Would this also impact other values in the chemistry panel such as BUN, Cr, and calcium, or are these measured differently in laboratories?

Pseudohypobicarbonatemia shares similarities with pseudohyponatremia, which is the result of interference in the measurement of sodium levels in the context of indirect ion-selective electrode (ISE) methods. Both of these conditions can lead to falsely low measurements of the respective analytes.

Regarding the impact on other values in the chemistry panel such as blood urea nitrogen (BUN), creatinine (SCr), and calcium, these are usually measured differently in laboratories, and thus are not affected by the same mechanism that causes pseudohyponatremia or pseudohypobicarbonatemia. BUN and SCr are commonly measured using enzymatic or kinetic methods (e.g., Jaffe reaction for creatinine), while calcium is often measured using colorimetric methods, atomic absorption spectroscopy, or direct ISE. Because these analytes are measured by different methodologies, they are less likely to be influenced by the same factors causing pseudohyponatremia or pseudohypobicarbonatemia.

AJKDBlog: Let’s move to spurious potassium disorders.  Before we jump into pseudo-diseases, can you explain to our learners the difference between a serum potassium level from a basic chemistry panel versus a whole blood potassium and how these differ?

Whole blood potassium refers to the concentration of potassium ions in the unseparated blood, and usually measured using a blood gas analyzer in hospital settings. Serum potassium is the acellular fraction of blood obtained after blood has been allowed to clot and the clot has been removed. This measurement is the most common method for assessing potassium levels. Plasma potassium is the acellular fraction of blood treated with an anticoagulant to prevent clotting. Typically, the serum potassium level is ~0.4 mmol/L higher than the plasma or whole blood levels because potassium is released during clot formation. The potential for pseudohyperkalemia comes from the significant difference in the extracellular (~4mmol/L) and intracellular (~150mmol/L) potassium concentrations that exists. Due to this difference, even a small release of potassium from blood cells into the plasma or serum fraction after sampling can greatly impact the measured potassium levels.

AJKDBlog: Now that we understand the basics, let’s discuss pseudohyperkalemia, another relatively common phenomenon in patients with leukemia or thrombocytosis.  What are the factors related to collection, transport, and timing that lead to these falsely elevated levels and what can clinicians do to get more accurate values?

The factors related to blood collection, transport, and timing that can lead to pseudohyperkalemia include common causes like hemolysis (e.g., vigorous mixing), prolonged tourniquet time, delayed sample processing, and temperature, which are more pronounced in the presence of hematological malignancies. Serum samples can be particularly elevated in patients with elevated platelet counts > 500×10⁹/L. Plasma potassium values result in more accurate values, but there are rare exceptions to this as well, as in the cases of reverse pseudohyperkalemia typically seen in patients with CLL. Whole blood with careful transport (<10 min) of the specimen to the laboratory can be done when cases of reverse pseudohyperkalemia are suspected. Ultimately, in the setting of malignancy, repeat and simultaneous testing should be encouraged when there is a suspicion of pseudohyperkaelmia.

AJKDBlog: Let’s now talk about spuriously decreased anion gaps.  I would venture that we use the anion gap 99% of the time when talking about metabolic acidosis and whether the AG is high.  Can you discuss some reasons where the serum AG is truly low and why patients with cancer might present with a falsely decreased AG?

A truly low anion gap can result from several factors, including hypoalbuminemia, hypercalcemia, hypermagnesemia, and lithium therapy. There are some rare circumstances where drugs that contain bromide ions interfere with the measurement of chloride ions, leading to a falsely low anion gap calculation. These factors are not unique to cancer patients, but can be seen more commonly, particularly hypoalbuminemia and hypercalcemia. In patients with cancer, a falsely decreased anion gap might be observed due to factors such as paraproteinemias, which can produce large amounts of positively charged monoclonal proteins. It is also worth noting that negatively charged monoclonal protein (IgA) can increase the anion gap.

AJKDBlog: Lastly, let’s talk about pseudo-levels of phosphorus, which is not a phenomenon I was familiar with before reading the article.  It seems that the laboratory reasons for this are quite different from the pseudohyponatremias.  Please give us a brief overview of how phos levels may be falsely low or high.

Factitious levels of phosphorus can be affected by the laboratory analysis and co-administration of agents that can sequester phosphorus in vitro. For example, pseudo-hypophosphatemia can from intravenous administration of glucose or insulin, which may not reflect the patient’s true phosphorus status. There can also be in vitro release of phosphate when there is hemolysis. The methodology for measuring phosphorus is important to understanding how factitious levels can occur. Inorganic phosphate forms an ammonium phosphomolybdate complex in the presence of sulfuric acid, and this concentration is directly proportional to phosphate concentration and is measured photometrically. Paraproteins exert interference usually resulting in factitious hyperphosphatemia. but occasionally in hypophosphatemia. Deproteination can correct this artifact, therefore clinicians should have a suspicion of this phenomenon in the appropriate clinical setting.

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

Title: Spurious Electrolyte and Acid-Base Disorders in the Patient With Cancer: A Review
Authors: Raad Chowdhury, Anna-Eve Turcotte, Helbert Rondon-Berrios, and Biruh T. Workeneh
DOI: 10.1053/j.ajkd.2023.01.441

Review articles cover clinical, translational, or basic science topics of interest to practitioners. Reviews published in the last two years are freely available.

Seolhyun Lee @LeeSeolhyun

Dr. Seolhyun Lee is currently a clinical Assistant Professor at Stanford University. He attended medical school at Chungnam National University in South Korea, and completed internal medicine residency at Cooper University Hospital, NJ. During his postdoctoral research fellowship at Stanford University, he studied clearances of uremic solutes and improving those in hemodialysis, which was funded by American Society of Nephrology. Additionally, he has clinical interests in onco-nephrology. Dr. Lee is a proud father of three children. He shamelessly admits going to work feels like a vacation to him.

“Intravenous (IV) iron can cause clinically significant intra-dialytic hypotension” – many clinicians may believe such a statement. The FDA even labels 36% prevalence of hypotension as a side effect of IV iron sucrose and warns of the risk of significant hypotension following IV iron sucrose administration.

In a recent AJKD article, Singh and colleagues disproved such a statement. They conducted a prospective cohort study of 950 patients who received a total of 135,412 HD sessions. Infusion of IV iron sucrose 100 mg or greater was associated with a 16% lower rate of intradialytic hypotension (incidence rate ratio 0.84 [95% CI, 0.80-0.89]).  Singh and colleagues further showed that IV iron can instead cause hypertension during dialysis; systolic blood pressure was increased 2.5 (95% CI, 2.2 to 2.8) mmHg when IV iron sucrose 100 mg or greater was given. These effects remained significant when adjusted for various risk factors

Hypotension in children secondary to accidental oral iron ingestion, typically greater than 60 g/kg, was traditionally observed in clinical settings, which may have seeded the concept of iron-induced anaphylaxis and hypotension. The pathophysiology of iron-induced hypotension is based on the hypothesis that labile iron can cause hypersensitivity or vascular reaction via oxidative stress and endothelial dysfunction. It has been also supported by clinical studies, such as the systematic review and meta-analysis by Avni and colleagues that demonstrated the association between hypotension and IV iron therapy.

Singh and colleagues suggest two hypothetical mechanisms why IV iron sucrose would prevent hypotension or even cause hypertension during HD. The first mechanism is related to the osmolar effects of IV iron sucrose. Iron sucrose with 100 mg elemental iron, mixed in 100 mL of isotonic saline provides hyperosmolar solution with 404 mOsm/L; hence, a total osmoles contained in a bag of IV iron sucrose infusion is approximately 40 mOsm. Further, IV iron sucrose is not dialyzable, owing to its large mass (34,000–60,000 Da) as a polymer.

The second mechanism is reduced production of nitric oxide, a potent vasodilator, by resolution of iron deficiencies. Although there is evidence of increased nitric oxide production in the setting of iron-deficiency anemia, we do not know whether infusing IV iron would immediately reduce the concentration of nitric oxide and therefore contribute to the hypertension.

In patients with End-stage kidney disease (ESKD) on HD, IV iron is preferred to oral iron, as it is more effective in raising hemoglobin level, more amenable to achieve higher compliance, and more convenient to administer during HD sessions. A consequence of not administering IV iron to a patient with ESKD and severe iron deficiency anemia is a higher chance of requiring blood transfusion, which has a greater risk of adverse outcomes. Based on this study by Singh et al., nephrologists may consider scheduling IV iron infusion specifically on Mondays or Tuesdays for patients on HD if they are on typical thrice weekly HD schedule because those patients may have higher chance of intradialytic hypotension on Mondays or Tuesdays when higher rate of ultrafiltration is required after accumulating significant volume over the weekend.

The least we can learn from the study of Singh and colleagues is that we should not avoid ordering IV iron for patients with ESKD and iron-deficiency anemia just because we fear adverse events, such as intradialytic hypotension. Additionally, we also learned that it makes little sense to start IV iron at a lower dose to avoid possible hypotension as an adverse reaction because only higher dose IV iron sucrose 100 mg or greater significantly reduced the risk of intradialytic hypotension.

Singh and colleagues showed patients with ESKD on HD had a lower prevalence of intradialytic hypotension when they received IV iron sucrose 100 mg or greater. We can use these findings to improve clinical outcome of hemodialysis treatment and inspire future studies to elucidate the mechanisms.

– Post prepared by Seolhyun Lee @LeeSeolhyun

To view Singh et al [OPEN ACCESS], please visit AJKD.org.
Title: Associations of Iron Sucrose and Intradialytic Blood Pressure
Authors: Anika T. Singh, Timothy E. Yen, Suraj Sarvode Mothi, Sushrut S. Waikar, Finnian R. Mc Causland
DOI:10.1053/j.ajkd.2022.11.007

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. Highlights from the August 2023 issue:

Proton Pump Inhibitor Use, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients: Results From the TransplantLines Biobank and Cohort Study by Tim J. Knobbe et al [OPEN ACCESS]

From the authors: In this observational study, we investigated the association of proton pump inhibitors with fatigue and health-related quality of life among kidney transplant recipients. Our data showed that proton pump inhibitors were independently associated with fatigue severity, severe fatigue, and lower physical and mental health-related quality of life. These associations were present among all individually assessed proton pump inhibitor types and were dose dependent. While we await future studies on this topic, proton pump inhibitor use might be an easily accessible target for alleviating fatigue and improving health-related quality of life among kidney transplant recipients.

DOI: 10.1053/j.ajkd.2022.12.012

Ultraprocessed Foods and Kidney Disease Progression, Mortality, and Cardiovascular Disease Risk in the CRIC Study by Valerie K. Sullivan et al 

From the authors: Ultraprocessed foods are industrial formulations produced using ingredients and processes that are not commonly used in culinary preparations and contain few, if any, intact unprocessed foods. Ultraprocessed foods are widely consumed in the United States, and high intakes of such foods have been linked to cardiovascular disease, kidney disease, and mortality in the general population. In this study, we found that greater intake of ultraprocessed foods was associated with higher risk of kidney disease progression and mortality in adults with chronic kidney disease. Our findings suggest that patients with kidney disease may benefit from greater consumption of fresh, whole, and homemade or hand-prepared foods and fewer highly processed foods.

DOI: 10.1053/j.ajkd.2023.01.452

Patient-Reported Outcomes Over 24 Months in Pediatric CKD: Findings From the MyKidneyHealth Cohort Study by Sandra Amaral et al

From the authors: Children with chronic kidney disease (CKD) have many treatment demands and experience many systemic effects. How CKD impacts the daily life of a child is poorly understood. We surveyed 212 children, adolescents, and younger adults with CKD and their parents over 24 months to assess the participants’ well-being over time. Among children, adolescents, and younger adults with CKD we found a very high and persistent burden of psychological distress that did not differ by degree of CKD or type of kidney disease. The participants with CKD endorsed greater impairment in fatigue and global health compared with healthy children, adolescents, and younger adults, and parent-reported sleep problems were associated with poorer patient-reported outcome (PRO) scores across all domains. These findings emphasize the importance of including PRO measures, including fatigue and sleep measures, into routine clinical care to optimize the lived experience of children with CKD.

DOI: 10.1053/j.ajkd.2022.12.014

Cardiac Structure and Function and Subsequent Kidney Disease Progression in Adults With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study by Junichi Ishigami et al 

From the authors:  Heart disease and kidney disease are known to interact with each other. In this study, we examined whether cardiac abnormalities, as assessed by echocardiography, were linked to the subsequent progression of kidney disease among people living with chronic kidney disease (CKD). We found that people with abnormalities in heart structure and function had a greater risk of progression to advanced CKD that required kidney replacement therapy and had a faster rate of decline in kidney function. Our study indicates the potential role of abnormal heart structure and function in the progression of kidney disease among people living with CKD.

DOI: 10.1053/j.ajkd.2023.01.442

Case Report from the August 2023 issue:

Anaphylaxis From Ethylene Oxide–Sterilized Dialysis Tubing and Needles: A Case Report by Clarkson Crane et al [OPEN ACCESS]

Anaphylaxis and hypersensitivity reactions to dialysis equipment in patients undergoing maintenance hemodialysis (HD) have been well described. However, most reports are from the 1980s and describe reactions to dialyzers that were sterilized with ethylene oxide during the manufacturing process. In response to this, most commercial dialyzers are now sterilized with electron beam or steam sterilization. However, many other pieces of routine dialysis equipment, such as tubing and needles, continue to be sterilized with ethylene oxide. The authors report a case of anaphylaxis that initially presented as intradialytic hypotension and was ultimately attributed to an IgE-mediated allergy to ethylene oxide.

DOI: 10.1053/j.ajkd.2022.12.004

On the Cover: The word glomerulus derives from the Latin root, glomus, meaning “ball of yarn”. Glomerular diseases are complex and often considered challenging to understand, diagnose, and treat. Recent advancements in knowledge regarding the pathophysiology of glomerular diseases have improved their classification and catalyzed the development of novel diagnostic and therapeutic approaches for their management. The Kidney Disease Outcomes Quality Initiative (KDOQI) commentary on the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases provides further insight and unravels the tangled strands of our knowledge on glomerular diseases. See p. 121.

The photograph “Confetti in a ball” by inger maaike is released on Flickr under the CC BY 2.0 license.

Special thanks to Editorial Intern Dilushi Wijayaratne for curating the cover image and drafting the cover blurb for this issue

In this piece, AJKD editor Timothy Yau (@Maximal_Change) interviews Dr. Laura Plantinga and Dr. Bernard Jaar on their recent publication looking at burnout and turnover in dialysis patient care technicians (PCTs) in the United States.  Read the full article here.

Dr. Laura Plantinga is an Associate Professor at Emory University in Atlanta, Georgia. She received a PhD in Epidemiology from Emory and a masters in biostatistics from Johns Hopkins University. She serves on the Editorial Board of the American Journal of Kidney Diseases is a Senior Board Member for BMC Nephrology. Her research focuses on multidisciplinary, patient-centered approaches to improving the quality of care among underserved patients with chronic diseases, including patients with chronic kidney disease, end-stage kidney disease, and lupus.

Dr. Bernard Jaar is an Assistant Professor of Medicine at Johns Hopkins University. He holds a Master of Public Health degree from the Johns Hopkins Bloomberg School of Public Health and is a Fellow of the American College of Physicians, of the American Society of Nephrology and of the National Kidney Foundation. He is interested in outcomes research among patients with chronic kidney disease and on dialysis.

AJKDBlog: First of all, thank you for highlighting such an important topic pertaining  to the nephrology healthcare.  So often when we hear “nephrology workforce crisis” everyone thinks of the fellowship training issue, and your paper emphasizes that there has been strain on the workforce for dialysis nurses and PCTs.  Can you tell us from a historical perspective what burnout and turnover among staff in dialysis units has looked like over the past decades?

This is a very important question. It takes the entire dialysis care team to make a program successful. Dialysis patient care technicians are front-line care providers in U.S. dialysis centers. The work they perform, as well as the challenges they face, are too often overlooked by the nephrology community. These issues have been underexplored and there are actually very little data about burnout or turnover in this setting over the years.

Our group recently reported that 23% of nephrologists (as well as 30% of fellows) were experiencing burnout in 2018-2019. Recent, COVID-era surveys by other groups have shown that >60% of dialysis nurses reported burnout and similar percentages intended to leave their jobs. Similar burnout rates are reported at 57% in the U.K. nephrology workforce. While burnout and turnover intention have not been explored in-depth among dialysis social workers and dietitians, factors that increase the risk of burnout are common: social workers averaged around 130 patients in 2017 (vs. National Kidney Foundation recommendations of a maximum of 75 patients per social worker), and 58% of surveyed dietitians were dissatisfied with the amount of work they were assigned; both reported that only ~25% of their time was spent on direct patient care or counseling, the work for which they were trained, which can lessen professional fulfillment and increase risk for burnout.

AJKDBlog: Many people only noticed this issue when COVID-19 put the strain on dialysis care.  Can you briefly tell us how the pandemic unmasked this pre-existing issue?

This is a very good point. The U.S. dialysis care system was already quite strained and the pandemic only made this more apparent by introducing additional barriers to providing patient care in the dialysis centers.  These included:

• Treating and providing guidance to patients who were frightened or isolated
• Providing care without adequate information or personal protective equipment
• Experiencing hostility and threats due to virus misinformation
• Increasing patient caseload and severity beyond system capacity (which was exacerbated by increased rates of turnover at the start of the pandemic).

However, it is important to note that our participants did not cite the pandemic as a major factor contributing to their experiences of professional fulfillment and burnout, suggesting that other pre-existing and often reversible factors may be more strongly associated with these reported experiences.

AJKDBlog: Please walk us through the survey design, some of the questions you asked, and how you obtained responses from dialysis PCTs.

Our survey incorporated items from the Stanford Professional Fulfillment Index, which measures professional fulfillment and two domains of burnout, work exhaustion and interpersonal disengagement. We also asked participants to rank contributors to their feelings of professional fulfillment and burnout and about turnover intention (“Do you think you will still be working as a dialysis technician in 3 years?” and “Do you think you will be working at the same facility?”).

In partnership with the National Association of Nephrology Technicians/Technologists (NANT), we provided the survey link to dialysis PCTs via direct emails to the NANT listserv; on QR codes on postcards distributed at the NANT and National Kidney Foundation annual meetings, and via links/QR codes posted in NANT’s newsletters and on closed social media pages. We chose this method of recruitment because we believed that it was very important to work directly with this group of front-line dialysis providers, rather than through their employers.

AJKDBlog: And can you give us a snapshot of the results you obtained from the quantitative data?  Did anything stand out in particular?

Unsurprisingly we found a high prevalence of burnout, with 58% of dialysis PCTs reporting burnout, while only 37% reported professional fulfillment. For burnout, issues pertaining to work exhaustion, rather than interpersonal disengagement (with patients or other staff), seemed to drive these percentages.

The strongest contributors to their feelings of fulfillment vs. burnout were salary, supervisor support, respect from other staff and patients, sense of purpose, number of hours worked, and level of autonomy in their work. We also found that nearly half (47%) reported turnover intention within 3 years, and interestingly this was even higher among younger dialysis PCTs (68% vs. 40% for those aged <35 vs. ≥50 years). Even among those who planned to continue working as PCTs, only 69% planned to be working at the same facility.

The big takeaway is that the healthcare system need to start paying more attention to these front-line dialysis providers. Our patients, and the nephrology community at large, depend on them to deliver safe, high-quality care to our patients with kidney failure.

AJKDBlog: As someone who reviews student feedback all year, oftentimes I find responses from the qualitative narrative data to be the most helpful in identifying strategies to improve the system.  Did any themes emerge from the free-text responses?

Yes, we agree that qualitative data can be a rich source of data for potential improvement strategies. Our qualitative data (from an open-ended question) highlighted three major themes.

First, participants emphasized low pay, with several participants noting that pay levels were similar to those in retail or fast food, which is shocking when you think about the highly specialized medical service they provide. Second, insufficient staffing and training emerged as a theme, which is unfortunately a problem throughout our health system these days. Finally, participants often voiced opposing feelings of fulfillment vs. burnout, with participants often stating they loved their patients but that the workload and stress were making it hard to continue working in the dialysis environment.

AJKDBlog: Lastly, what changes do you think are needed to mitigate this issue for the future of dialysis care in the US?

This is a loaded question! We likely need multifactorial, multilevel changes to mitigate these issues, which threaten the current and future quality and safety of dialysis care. Addressing low pay requires employers to invest in higher salary and/or other employment incentives such as promotion and educational opportunities. Improving staffing and training will likely require interventions at the level of the employer, healthcare system, and policymaker. For example, standardized training and certification processes and mandated patient-to-PCT ratios (which only exist in some states) should be considered. Improving supervisor support and respect from other staff will likely require interventions at the dialysis care team level and would require both psychosocial (e.g., education in interpersonal teamwork) and organizational components.

Now that we have identified these important issues with our PCTs, more research is needed to develop and implement interventions at these multiple levels. Additionally, it will be important to examine longitudinal associations of these issues with outcomes among both technicians and patients, which may provide a more persuasive evidence base for employers and policymakers to facilitate such interventions.

To view Plantinga, please visit AJKD.org.

Title: Professional Fulfillment, Burnout, and Turnover Intention Among US Dialysis Patient Care Technicians: A National Survey
Authors: Laura C. Plantinga, Fran Rickenbach, Megan Urbanski, Courtney Hoge, Clarica Douglas-Ajayi, Jennifer Craft Morgan, Alexis A. Bender, and Bernard G. Jaar
DOI:10.1053/j.ajkd.2022.12.017

Core Curricula aim to give trainees in nephrology a strong knowledge base in core topics in the specialty by providing an overview of the topic and citing key references, including the foundational literature that led to current clinical approaches. All Core Curricula are freely available on AJKD.org

Eric Ryan, MD

Eric Ryan recently completed fellowship and is joining the nephrology faculty at Oregon Health and Science University. He has an early career interest in medical education, critical care nephrology, and multidisciplinary process improvement.

 

 

Vanderlene Liu Kung, MD PhD 

Vanderlene Liu Kung is a renal pathologist at Oregon Health & Science University. Her research interests are in applying transcriptional techniques to formalin fixed paraffin embedded tissue to understand native and allograft kidney diseases.

 

 

Rupali Avasare, MD

Rupali Avasare is a nephrologist and glomerular disease specialist at Oregon Health & Science University. Her clinical and research interests involve glomerular disease and triggers of autoimmunity.

Isolated microscopic hematuria (>2-5 RBCs / high-powered field) is detected across all populations and has an estimated prevalence of 2.4 – 31.1%. Preliminary workup for microscopic hematuria involves a careful history and physical examination to rule out several common causes, including urinary tract infection, kidney stones, and menstruation. Clues that point to glomerular hematuria include dysmorphic red blood cells or acanthocytes, red blood cell casts, decreased glomerular filtration rate (GFR), and/or proteinuria.

The most common causes of glomerular hematuria are IgA nephropathy (IgAN) and type IV collagen disorders (Figure 1), and less commonly other nephritic processes.  Traditionally, kidney biopsy is recommended in those with high-risk features, such as proteinuria, decline in kidney function, and new hypertension. Experts in Alport syndrome propose genetic testing for COL4A3, COL4A4, and COL4A5 variants in those with persistent hematuria, their first-degree relatives, and those with suspected inherited focal and segmental glomerulosclerosis, familial IgAN, and kidney failure of unknown cause. At minimum, patients with glomerular hematuria should be monitored once or twice yearly.

Urologic evaluation involves a CT urogram – cross sectional imaging both with and without contrast — to evaluate for structural abnormalities, stones, and large masses. Special consideration is necessary for young patients who may not require contrast studies, pregnant patients who may begin with ultrasound evaluation, and advanced chronic kidney disease (CKD) patients who may begin with non-contrast CT or MR urogram. In patients with increased risk for malignancy, cystoscopy is recommended.

A recently published retrospective cohort study by Um et al investigates the association between microscopic hematuria of any cause (four distinct groups, including persistent or single episode) and incident CKD, defined as GFR < 60 mL/min/1.73 m² or proteinuria of 1+ or more on dipstick in relatively healthy Korean adults without known kidney disease or malignancy. The study included 2,392 participants, 58.9% male, with an average age of 38.2 years. The major finding was a strong association between microscopic hematuria and incident CKD with hazard ratios as high as 5.34 (95% CI, 4.15 – 6.59) for the persistent hematuria group and as low as 1.85 (95% CI, 1.35 – 2.53) for those with hematuria that regressed on follow-up urine examination. Notably, the association between persistent microscopic hematuria and incident CKD was higher in men than in women (p < 0.001). This study is in line with other large cohort studies that have demonstrated an association between microscopic hematuria and CKD. Major weaknesses include using dipstick proteinuria, without quantification, as a surrogate for incident CKD which may have led to higher than expected rate of incident CKD.

Um et al., along with others, and the newly proposed guidelines on genetic testing in patients with microscopic hematuria have the potential to transform clinical care of adults with microscopic hematuria. Because screening for asymptomatic hematuria for cancer and/or kidney disease detection is not recommended by any major US-based organization including the American Academy of Pediatrics, the American College of Physicians, and the U.S. Preventive Services Task Force, most US cases of asymptomatic hematuria will be incidentally discovered. We anticipate that because of recent findings and recommendations from expert nephrologists, more patients with asymptomatic microscopic hematuria will undergo genetic testing and that the frequency of proteinuria and GFR monitoring will increase in this population. Future studies evaluating the impact of more rigorous evaluation on incident CKD and end-stage kidney disease in different patient populations is essential to understanding whether glomerular hematuria is ever truly “benign.”

Ultrastructural findings associated with type IV collagen gene mutations. A) Thin glomerular capillary basement membranes (GBMs) are associated with a broad spectrum of clinical phenotypes related to type IV collagen gene mutations, including a “benign/non-progressive” autosomal dominant lesion (thin basement membrane nephropathy), early stage autosomal recessive or dominant Alport syndrome, a heterozygous (carrier) state of autosomal recessive or X-linked Alport syndrome, and a subset of both sporadic and familial cases of IgAN. B) In addition to GBM thinning, ultrastructural features of Alport syndrome include irregular GBM thickening, subepithelial scalloping and lifting, remodelling conferring a basket-weave and lamellated appearance (dotted circles) and lamina densa splitting (arrow).

– Post prepared by Eric Ryan, Vanderlene Kung, and Rupali Avasare.

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

Title: Risk of CKD Following Detection of Microscopic Hematuria: A Retrospective Cohort Study
Authors: Yoo Jin Um, Yoosoo Chang, Yejin Kim, Min-Jung Kwon, Hyun-Suk Jung, Kyu-Beck Lee, Kwan Joong Joo, In Young Cho, Sarah H. Wild, Christopher D. Byrne, and Seungho Ryu.

DOI: 10.1053/j.ajkd.2022.09.012

The AJKD editors are excited to continue the Editorial Internship Program for a sixth year, and thank all the applicants who responded to the recent call for applications.

Please join us in welcoming the AJKD Editorial Internship Class of 2024: Emmanuel Adomako, Michael Granda, George Vasquez Rios, Rachel Shulman, and Megan Urbanski.

Emmanuel Adomako

Emmanuel A. Adomako is currently an Assistant Professor at the University of Kansas Medical Center. He graduated from the Kwame Nkrumah University of Science and Technology in Kumasi, Ghana, where he was the editor of the medical students’ journal. He completed his internal medicine residency at the Englewood Hospital and Medical Center, Englewood, NJ. He moved to Dallas for his clinical/research nephrology fellowship at the University of Texas Southwestern Medical Center. His research interests include kidney stones and mineral metabolism. Follow him @EAAdomako.

Michael Granda

Dr. Michael Granda is a Clinician-Researcher in the Division of Nephrology at the University of Washington. He completed his internal medicine residency at the University of Miami in 2019, and continued his path in nephrology to the University of Washington where he completed his clinical nephrology fellowship in 2021 and has remained ever since. Dr. Granda’s research focuses include proximal tubule secretory clearance and the use of imaging to investigate kidney physiology, and he is currently funded by the American Society of Nephrology. When he’s not pontificating about salt water at work, you can find Dr. Granda at the lake or in the kitchen. 

George Vasquez Rios

Dr. George Vasquez Rios is a graduate of the clinician-scientist track in Nephrology and Glomerular Disease at the Icahn School of Medicine at Mount Sinai. He earned his medical degree from Universidad Peruana Cayetano Heredia, followed by his Internal Medicine training at Saint Louis University School of Medicine. Additionally, he obtained his Master of Science in Clinical Research, graduating with distinction. His research focuses on novel biomarkers, prognostic models of kidney disease, and subphenotype discovery, which has garnered recognition from the NIH/NIDDK, ASN, the NYSN, and the AFMR. He is dedicated to advancing his career as a nephrologist at the intersection of community care and academia, with a specific emphasis on glomerular diseases, precision medicine, and inclusive clinical trials. Beyond his professional endeavors, he enjoys sports, art, and jazz, frequently sharing these passions with his wife. Follow him @GeorgeVasquezR2. 

Rachel Shulman

Dr. Rachel Shulman obtained her medical degree at the University of Pennsylvania where she is currently a clinical and research fellow pursuing a Master of Science in Clinical Epidemiology. Her published research has focused on the epidemiology of essential hypertension, with particular reference to its complex relation to sleep patterns and obesity. Currently she is pursuing her interest in the pathophysiology and pharmacoepidemiology of non-proteinuric CKD with the hope of identifying targeted treatment strategies to prevent its progression. She has been a tutor and lecturer for medical students and residents and hopes to contribute to educational programs for both professionals and the public on vital issues of public health. When she is not enjoying specimens spinning in a centrifuge she can be found with her Puerto Rican cousins enjoying salsa–either on the dance floor or on arroz con gandules. Follow her @shulman_rachel.

Megan Urbanski

Dr. Megan Urbanski is currently an Assistant Professor in the Department of Surgery, Division of Transplantation, in the Emory University School of Medicine. She received a master’s degree in clinical social work from the University of Pennsylvania and worked for several years as a nephrology and transplant social worker prior to obtaining a PhD in Public Health with a concentration in the Social and Behavioral Sciences from Temple University. She also completed a postdoctoral research fellowship in Health Services Research at Emory University. She has experience conducting qualitative, mixed methods, community engaged, and implementation research. Her specific research interests include the kidney failure transition experience, psychosocial evaluation criteria for transplant, and nephrology workforce issues. She is grateful for the opportunity to learn more about the editorial process!  

Dilushi Wijayaratne @Dilushiwijay

Dilushi Wijayaratne graduated from the Faculty of Medicine Colombo in 2010, completed her MD (Medicine) in 2016, and was board-certified as a nephrologist in 2020. She joined the Department of Clinical Medicine as a lecturer in 2020 and serves as an honorary consultant nephrologist at the National hospital of Sri Lanka and the National institute of nephrology, Dialysis and Transplant. Currently she is reading for an MSc in Clinical Trials, University of Oxford. Her research interests include lupus and other glomerular disorders.

One of the biggest challenges we face as nephrologists is prescribing effective safe analgesics to patients with reduced kidney function. The possibility that an analgesic agent can be, not merely non-nephrotoxic, but even renoprotective, and that that could be none other than our common garden acetaminophen (paracetamol) is definitely exciting.

In the December issue of AJKD, authors Xiong et al presented their study exploring the effectiveness of acetaminophen in preventing acute kidney injury (AKI) in patients undergoing cardiac surgery. They conducted a retrospective study using registry data from two sources in the United States (US), the Medical Information Mart for Intensive Care (MIMIC)-III and the eICU Collaborative Research Database (eICU).

The study cohort included patients aged > 18 years who had had coronary artery bypass graft (CABG) surgery, valve replacement or repair, or combined CABG and valvular procedures. The primary study outcome was severe AKI in the first 7 days after surgery, defined as stage 2 or stage 3 AKI according to KDIGO criteria. Secondary outcomes were any-stage AKI, new-onset postoperative kidney replacement therapy (KRT), and in-hospital mortality

The exposure of interest was acetaminophen administration within the first 48 hours of surgery. This was defined as one or more doses of any form of acetaminophen given within 48 hours after surgery. In the primary analysis patients who were only given acetaminophen after 48 hours were considered to be unexposed. Baseline covariates which could influence the outcome were extracted. These included age, sex, ethnicity, body mass index, admission type, surgery type, comorbidities (defined using International Classification of Diseases–9 diagnosis codes), baseline hemoglobin, and baseline estimated glomerular filtration rate (eGFR), SOFA score, SAPS II (MIMIC-III) or APACHE IV (eICU) score, use of high-risk nephrotoxins, intra-aortic balloon pump, and vasopressors, and prolonged mechanical ventilation ≥ 24 h in the first 2 postoperative days. A cause-specific hazards model with time-varying acetaminophen exposure was used to assess the effect of acetaminophen treatment on the outcome.

In this study, after adjusting for relevant covariates, early acetaminophen administration was associated with lower hazard of postoperative severe AKI in both MIMIC-III (adjusted HR, 0.86; 95% CI, 0.79–0.94; P<0.001) and eICU cohorts (adjusted HR, 0.84; 95% CI, 0.72–0.97; P=0.018).

Impressive? As we know too well, a retrospective analysis does not indicate causation. One obvious question is if the group that did not receive acetaminophen received a different analgesic or antipyretic agent, such as a non-steroidal anti inflammatory drug (NSAID). How much of this renoprotection is due to acetaminophen’s analgesic sparing effect? While the authors did consider nephrotoxic agents in the multi regression model, what these agents were is not specified. All we do know is the agents considered did not include NSAIDs. Other important data that are unavailable include the dose and indications for the acetaminophen prescribed.

So… as attractive as the idea is, the case is still very much open.

But, why do we even think acetaminophen may be effective as a renoprotective agent? And why cardiac surgery?

To understand how this might happen we have to step back to biochemistry. Hemolysis induced by cardiopulmonary bypass, suction, transfusion and cell salvage during cardiac surgery releases free hemoglobin. Free heme, released in rhabdomyolysis and hemolysis has been shown to result in oxidative stress. The process involves the oxidation of Fe++ in Heme and involves the production of ferryl heme and superoxide (O₂^. ), i.e  reactive oxygen species. Lipid cell membranes contain polyunsaturated fatty acids such as arachidonic acid which, due to their molecular structure are particularly susceptible to oxidative injury. This generates a class of bioactive molecules called F2 isoprostanes, which are potent vasoconstrictors. Elevated serum F2 isoprostanes have been detected in the serum of patients with rhabdomyolysis and AKI, suggesting that oxidative cell membrane injury may be a mechanism for heme-protein induced acute tubular injury in these situations. As further evidence, animal models of oxidative injury  have demonstrated esterification of isoprostanes to tissue lipids. F2 isoprostane generation is reduced in the setting of high oxygen tension. Isofurans, on the other hand, are another form of lipid peroxidation products which are favorably produced in situations of increased oxygen tension in tissues, such as in the setting of cardiopulmonary bypass (CBP).

Acetaminophen has been shown in in vitro studies and in animal models to inhibit heme protein induced  lipid peroxidation at drug levels which fall within the therapeutic range. In two RCTs by Billings et al  and  Simpson et al, IV acetaminophen started prior to initiation of cardiopulmonary bypass and for every 6 hours for 4 doses was compared to placebo.

In the study by Billings et al, (N=60) the primary outcome was the oxidative stress response as measured by plasma and urine F2-isoprostanes and isofurans. Blood and urine samples were collected at six time points: 1) after induction of anesthesia but prior to cardiopulmonary bypass (CPB) and administration of study drug (baseline), 2) following 30 min of CPB, 3) following 60 min of CPB, 4) after protamine administration (post-bypass), 5) upon arrival in the ICU, and 6) 24 hours after administration of first acetaminophen dose on postoperative day 1 (POD1). Plasma and urinary isofuran and F2-isoprostane concentrations increased during CPB, peaking at 60 min before returning to baseline concentrations within 24 hours (Figure 1).  The increase in plasma isofuran concentrations was lessened by the administration of perioperative intravenous acetaminophen compared to placebo (P = 0.05). However, plasma concentrations of F2-isoprostanes and urinary markers of lipid peroxidation were not significantly affected. The differential effects on isofuran and F2 isoprostanes could be related to the high oxygen tension environment created during CBP, which facilitates isofuran generation over F2 isoprostanes. The authors also suggested that persistent presence of haptoglobin (though lowered) in this study could have related to lesser oxidative injury, and therefore less power to detect a difference between the two arms.

Figure 1: Effect of acetaminophen vs placebo on urine and plasma isofuran and F2-isoprostane concentrations following cardiopulmonary bypass surgery, ICU= intensive care unit, POD1= postoperative day 1. (Billings et al.)

Using a similar protocol, Simpson et al, studied the effect of acetaminophen on children undergoing CBP (N=30).Here too, acetaminophen reduced plasma isofuran concentrations over the perioperative period but did not have any effects on serum F-isoprostane levels or urinary biomarkers.

In both these studies, the absence of any effects on urinary biomarkers does suggest that the effects of acetaminophen on lipid peroxidation may be predominantly extra-renal. Neither study was well-powered to assess clinical outcomes, and available data shows neither an effect on urinary NGAL (a  biomarker of acute tubular injury) nor occurrence of acute kidney injury (defined by creatinine based criteria) with the use of acetaminophen.

What do we know about acetaminophen and prevention of AKI in the clinical setting?

As in the current study, most of the available data is observational, or limited. We found a single open-label RCT which showed a greater reduction in serum creatinine with acetaminophen compared to control in severe malaria. But the numbers here are small, and the clinical implications of this change is not clear. Most other data (Table 1) is retrospective and therefore cannot prove causation and is liable to confounding.

Table 1.  Summary of clinical studies assessing the effect of acetaminophen on prevention of acute kidney injury.

So where do we stand on whether acetaminophen prevents AKI?

The observation data does seem to support a lower risk of AKI with acetaminophen use. But whether AKI can actually be prevented by the administration of acetaminophen remains to be proven. The proof of concept studies have been supportive, but not conclusive. Perhaps it is finally time for a large clinical trial using data from published studies to guide trial design and power calculations.  Acetaminophen is a cheap, widely available, and safe option that would be readily accessible to many patients. Will it be the next wonder drug in AKI prevention? We do not know this yet, but perhaps we can take some comfort in believing it will at least do no harm.

– Post prepared by Dilushi Wijayaratne @Dilushiwijay

To view Xiong et al [OPEN ACCESS], please visit AJKD.org.

Title: Early Postoperative Acetaminophen Administration and Severe Acute Kidney Injury After Cardiac Surgery
Authors: Chao Xiong, Yuan Jia, Xie Wu, Yanyan Zhao, Su Yuan, Fuxia Yan, and Daniel I. Sessler
DOI: 10.1053/j.ajkd.2022.11.009

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. Highlights from the July 2023 issue:

Risk Factors for Incident CKD in Black and White Americans: The REGARDS Study by Katharine L. Cheung et al [OPEN ACCESS]

From the authors: In this longitudinal cohort study of Black and White adults at least 45 years of age followed for approximately 10 years, chronic kidney disease (CKD) developed in 9%, ranging from 4% of those 45-54 years old to 18% of those at least 75 years old. Systolic blood pressure, diabetes, heart disease, body mass index, and residence in the southeastern “stroke belt” were independent risk factors for CKD. Black individuals had higher incidence of CKD than White individuals, but this was attenuated after adjusting for traditional CKD risk factors. Albuminuria was a stronger risk factor for kidney disease in Black compared with White individuals.

DOI: 10.1053/j.ajkd.2022.11.015

Editorial: Unpacking Contributors to CKD Incidence and Progression: Time to Move Beyond Traditional Risk Factors by Panupong Hansrivijit et al [FREE]

Professional Fulfillment, Burnout, and Turnover Intention Among US Dialysis Patient Care Technicians: A National Survey by Laura C. Plantinga et al 

From the authors: Dialysis patient care technicians (PCTs) are essential members of the hemodialysis care team. However, retention of dialysis PCTs is increasingly difficult. We conducted a survey of dialysis PCTs to understand their work experiences and found that more than half reported burnout (job-related mental, physical, and emotional exhaustion), and fewer than half felt fulfilled professionally. Nearly half indicated that they did not plan to still be working as dialysis PCTs in 3 years. Survey respondents identified low salary, lack of respect and support from other staff, and inadequate training as factors that should be addressed to improve dialysis PCT work experiences, retain staff, and, potentially, improve the quality and safety of care delivered by dialysis PCTs.

DOI: 10.1053/j.ajkd.2022.12.017

Editorial: Dialysis Technician Burnout: An Opportunity for Empowerment by Hanna Webb [FREE]

Assessing Fatigue in Patients Receiving Kidney Replacement Therapy Using PROMIS Computer Adaptive Testing by Sumaya Dano et al

From the authors: Patients receiving maintenance dialysis and those who have received a kidney transplant experience many symptoms, including fatigue. Currently, we do not routinely screen for fatigue, which often goes undiagnosed and untreated. Using questionnaires such as the Patient-Reported Outcome Measurement Information System–Fatigue Computer Adaptive Test (PROMIS-F CAT) can help routinely measure fatigue in clinical settings. PROMIS-F CAT relies on a small number of questions and may be more acceptable than longer, validated instruments, including the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) questionnaire. We compared PROMIS-F CAT with FACIT-F to learn whether PROMIS-F CAT is sufficiently accurate and precise to use in the clinical setting. We found that PROMIS-F CAT is a potentially valuable tool for the clinical assessment of people with kidney failure receiving kidney replacement therapy.

DOI: 10.1053/j.ajkd.2022.12.018

Editorial: Measurement of Fatigue in Patients Receiving Kidney Replacement Therapy by Melandrea L. Worsley [FREE]

Acute Kidney Injury and Hair-Straightening Products: A Case Series by Alon Bnaya et al 

From the authors: Exposure to environmental toxins may lead to acute kidney injury (AKI). Nevertheless, chemical products associated with kidney impairment are occasionally overlooked and underreported by clinicians. During a recent 4-year period, episodes of severe AKI following hair straightening have been described in healthy young women in Israel. Clinical symptoms, including abdominal pain, nausea, vomiting, and scalp irritation, appeared during or immediately after the procedure. In 30% of cases, a kidney biopsy was performed, demonstrating deposition of calcium oxalate crystals in the tubules and acute tubular injury. Kidney function recovered spontaneously in most patients. This case series suggest a possible association between hair straightening and AKI, which may in turn result from acute oxalate nephropathy.

DOI:10.1053/j.ajkd.2022.11.016

The Impact of a Wearable Activity Tracker and Structured Feedback Program on Physical Activity in Hemodialysis Patients: The Step4Life Pilot Randomized Controlled Trial by Rakesh Malhotra et al [OPEN ACCESS]

From the authors:  Patients receiving hemodialysis are known to have less physical activity. A sedentary lifestyle is associated with excess illness and death among those on dialysis. We performed a pilot randomized control trial to evaluate the effect of a structured feedback intervention coupled with a wearable activity tracking device to promote physical activity in patients receiving hemodialysis as compared with simply wearing an activity tracker. We found that implementation of a behavior feedback intervention to improve physical activity level is feasible and leads to a greater daily step count, which was sustained over 12 weeks, as compared with simply wearing an activity tracker without the accompanying intervention.

DOI:10.1053/j.ajkd.2022.12.011

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial by Tae Won Yi et al [FREE]

From the authors: The CREDENCE trial demonstrated significant kidney benefits with canagliflozin in participants with diabetic kidney disease. We analyzed the data to see if the safety and efficacy of canagliflozin differed among three age groups (<60, 60-69, and ≥70 years) and between sexes. Canagliflozin reduced the risk of the primary outcome (kidney failure, doubling of serum creatinine concentration, death due to kidney or cardiovascular disease) similarly among the age groups and between sexes. The effect of canagliflozin on kidney outcomes was similar regardless of age or sex but was more pronounced in younger participants, who were at higher risk of these events. Our study demonstrates that canagliflozin appears to be similarly effective and safe among different age categories and between sexes.

DOI:10.1053/j.ajkd.2022.12.015

Research Letter from the July 2023 issue:

Kidney Structure and Reproductive History Among Healthy Female Kidney Donors by Andrea G. Kattah et al [FREE]

Sex hormones may play an important role in the kidney. Shorter duration of a woman’s reproductive lifespan, or the time from menarche to menopause, has been associated with cardiovascular disease and chronic kidney disease (CKD). The authors have recently demonstrated that women with bilateral oophorectomy before the natural age of menopause are at an increased risk of CKD. Pregnancy also causes significant physiologic changes in kidney function, including hypertrophy, hyperfiltration, and proteinuria, though it is not clear if these changes persist. The objective of the study was to determine how past reproductive history can impact kidney function and structure.

DOI: 10.1053/j.ajkd.2022.12.016

On the Cover: Toxins are important preventable contributors to kidney injury. In this issue of AJKD, Bnaya et al identify glycolic acid as a potential toxin in hair-straightening products associated with severe acute kidney injury. Glycolic acid is also present in snail mucus, which was historically used to treat burns and other wounds. See p. 43.

The photograph “Snail” by Raphae¨l Quinet is released on Flickr under the CC BY 2.0 license. Special thanks to Editorial Intern Jeffrey Ha drafting the cover blurb for this issue

SPECIAL COLLECTION: RESEARCH ACROSS THE WORLD

This special collection highlights kidney disease research from around the world. Articles in this collection will be freely available until July 15, 2023.

Allisar El Chediak @alissar_chediak

Dr. Alissar El Chediak is currently 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, before pursuing her nephrology fellowship at Vanderbilt. Her 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.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder. However, there is still a scarcity in treatments that prevent or slow the progression to end stage kidney disease (ESKD). Throughout this blog post, we will revisit some of the available therapeutic medical and non-medical options that have been trialed in ADPKD.

Before delving into specific therapies for managing ADPKD, we should understand the pathways leading to cyst formation and enlargement. These pathways are the target for the different proposed treatments. It all starts with mutations of either the PKD1 gene encoding the Polycystin 1 Complex (PC1) on chromosome 16 or by mutations of the PKD2 gene encoding the Polycystin 2 Complex (PC2). The loss of PC1 and/or PC2 activity leads to measurable biochemical changes in several cellular signaling pathways, including elevated cyclic adenosine 3’,5’-monophosphate (cAMP) levels and increased activation of mechanistic target of rapamycin (mTOR) complex 1, extracellular signal-regulated kinase (ERK), and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling pathways with reductions in intracellular calcium levels and 5ʹ-AMP-activated protein kinase (AMPK) activation. Subsequently, cyst formation, cellular proliferation, and alterations in the level of arginine vasopressin (AVP) as well as other metabolic dysregulation can occur.

Several therapies have emerged to treat ADPKD including vasopressin V2 receptor antagonist (Tolvaptan), mTOR inhibitors (Sirolimus, Everolimus), somatostatin analogue (Octreotide), glucoceramide synthase inhibitor (Venglustat), and much more. However, not all of these treatments have been successful in preventing progression of the disease.

Tolvaptan, a vasopressin receptor antagonist, is the only medication approved to slow kidney function decline in ADPKD patients at risk for rapid progression. As a reminder, vasopressin triggers a cascade of intracellular events that result in cystogenesis. Blocking vasopressin results in lower cyst burden and preserved kidney function. Two landmark trials supporting its use are the TEMPO and REPRISE trials.The TEMPO trial, which was the larger of the two, provided us with data that blockade of vasopressin V2 receptor inhibits cyst growth, thereby delaying additional adverse clinical outcomes. REPRISE trial results also confirmed that tolvaptan slowed disease progression in ADPKD.

Other drugs that have been trialed in ADPKD include mTOR inhibitors, metformin, somatostatin analogues and most recently Venglustat.

The mTOR pathway is central to cyst formation, so mTOR inhibitors were thought to be good options for treatment of ADPKD. Unfortunately, clinical trials failed to show any clinical evidence for their use. While Sirolimus can slow cyst growth, large randomized trials showed no benefit on kidney function or polycystic kidney growth in patients with ADPKD. Similarly, a two-year randomized clinical trial by Walz et al showed that Everolimus slowed the increase in total kidney volume of patients with ADPKD but did not slow the progression of renal impairment.

Metformin is another drug that can potentially slow eGFR decline. Brosnahan et al conducted a feasibility study which tested the safety and tolerability of metformin in ADPKD patients with mildly reduced kidney function. Secondary and exploratory outcomes were the effect of metformin compared with placebo on (1) the percentage change in total kidney volume (TKV) referenced to height (htTKV in mL/m) and (2) the change in eGFR over a 12-month period. At 12 months, eGFR decline was -0.41 vs. 3.35 mL/min/1.73 m² in metformin vs. placebo groups, respectively.  However, the difference was not statistically different. Kidney volume changes were similar in both groups.

Somatostatin and its analogs (octreotide and lanreotide) may reduce kidney and liver cyst fluid accumulation among patients with PKD. However, these agents have not been shown to slow the progression of kidney function decline and produce a variety of undesirable adverse effects. Therefore, these agents aren’t recommended for use in the treatment of ADPKD.

Alterations of glycosphingolipid metabolism and elevated glucosylceramide abundance have been documented in ADPKD. Low kidney glucosylceramide due to glucosylceramide synthase inhibitor resulted in effective inhibition of cystogenesis and fibrogenesis. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. STAGED-PKD was a two-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease. In addition to the primary endpoints below, eGFR slope over 18 months (Stage 1), rate of change in TKV (Stage 2), safety/tolerability, pain, and fatigue (Stages 1 and 2) served as secondary endpoints. Venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (Stage 1) and in fact had a faster rate of decline in eGFR slope over 24 months (Stage 2).

Several other drugs are currently under investigation to determine their efficacy in ADPKD patients. Besides pharmacotherapy, various surgical and interventional management options for ADPKD exist as well. Novel treatment modalities such as celiac plexus blockade and renal denervation appear to be promising in pain relief; however, further studies are needed to confirm their efficacy. Renal cyst decortication seems to have a higher success rate in targeting cyst-related pain compared with aspiration only. In terms of surgical interventions, some patients may benefit from native nephrectomy before or after a kidney transplant. Patients who are not candidates for native nephrectomy may consider transcatheter arterial embolization.

Major research efforts in both the clinical and preclinical setting in the last two decades resulted in a number of pivotal clinical trials aimed to address ADPKD. Several medications have been suggested to alter the course of kidney disease progression. However, the only medication that was proven effective in slowing kidney function decline has been Tolvaptan. mTOR inhibitors (Sirolimus, Everolimus), somatostatin analogue (Octreotide), and glucoceramide synthase inhibitor (Venglustat) have all been studied but proven to be non-effective. We anxiously await new therapies that can improve the outcomes of our patients with ADPKD.

– Post prepared by Allisar El Chediak @alissar_chediak

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

Title: Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: Primary Results of a Double-Blind, Placebo-Controlled, Phase 2/3 Randomized Clinical Trial
Authors: Ronald T. Gansevoort, Ali Hariri, Pascal Minini, Curie Ahn, Arlene B. Chapman, Shigeo Horie, Bertrand Knebelmann, Michal Mrug, Albert C.M. Ong, York P.C. Pei, Vicente E. Torres, Vijay Modur, Igor Antonshchuk, and Ronald D. Perrone.
DOI:10.1053/j.ajkd.2022.10.016

Figure 1 from Genest et al., AJKD © National Kidney Foundation

Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. In a recent Review published in AJKD, Dominique Suzanne Genest and colleagues reviewed the clinical presentation and pathologic hallmarks of renal-limited forms of TMA, disease-specific mechanisms that contribute to TMA lesions, diagnostic approach, and treatment strategies, and the potential role for emerging therapies.

AJKDBlog’s Interviews Editor Timothy Yau @Maximal_Change recently sat down with colleagues Anuja Java @anuja_java and Anna Vinnikova @KidneyWars to discuss these topics further.

If the embedded player above doesn’t work, please click here to watch the video interview. Special thanks to Drs. Java and Vinnikova for agreeing to do the interview!

To view this Review (Freely Available), please visit AJKD.org.

Title: Renal Thrombotic Microangiopathy: A Review
Author: Dominique Suzanne Genest, Christopher J. Patriquin,  Christoph Licht, Rohan John, and Heather N. Reich
DOI: 10.1053/j.ajkd.2022.10.014

Review articles cover clinical, translational, or basic science topics of interest to practitioners. Reviews published in the last two years are freely available.

Jeffrey Ha @_jeffreyha

Dr. Jeffrey Ha is a nephrologist in the Sydney Local Health District. 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.

Carinna Hockham @carinnahockham

Dr. Carinna Hockham is a kidney disease epidemiologist at The George Institute for Global Health, Imperial College London. Her research interests lie in the sex and gender differences (and similarities) in chronic kidney disease and, more recently, multimorbidity.

Sex is a biological construct, defined by our complement of chromosomes at birth, with the physiological influences of our gonads and sex hormones throughout life. Gender, by contrast, is attributed to the social, environmental, cultural, and behavioral factors that influence our identity. Although often used interchangeably due to their high degree of congruence in the population, sex and gender are distinct concepts and should be considered accordingly.

Differences in the burden, progression, and outcomes of kidney disease between females and males and women and men are known to exist. A Special Issue in Seminars in Nephrology states that it is time for a paradigm shift in kidney care and research, which fundamentally “[addresses] the specific sex- and gender-based differences in the physiology, pathophysiology, presentation, choice of therapies, and response to treatments”.

There is a growing body of literature detailing the sex- and gender-based differences and disparities in kidney care and research. Figures 1 and 2—whilst not exhaustive—highlight important differences and disparities between males/females and men/women across the spectrum of kidney disease.

Figure 1 © Jeffrey Ha and Carinna Hockham

Figure 2 © Jeffrey Ha and Carinna Hockham

Notably, these do not highlight the barriers to healthcare and adverse outcomes that transgender, nonbinary, or gender-diverse people face, which are instead nicely summarized in this review. The visual abstract in a review from Drs. Katz-Greenberg and Shah also beautifully illustrates some of the sex and gender differences that are present in kidney transplantation (Figure 3).

Sex and gender differences in kidney transplantation. Figure 1 from Katz-Greenberg et al, Seminars in Nephrology This is an open-access article distributed under the terms of the Creative Commons CC-BY license. 

The meta-epidemiologic study from Dr. Collister et al. on sex and gender in randomized controlled trials (RCTs) involving adults receiving maintenance dialysis is therefore timely. 561 RCTs published in high-impact journals over the last two decades were included.

Key findings

• The RCTs were representative of the general dialysis population with regards to the percentage of females/women in trials (nearly 40% which is consistent with observational data from DOPPS and USRDS). This is in contrast to a previous meta-analysis which suggests that men are more likely than women to be represented in dialysis trials relative to their distribution in the US dialysis population.
• The study did not identify a trial characteristic associated with a greater percentage of female/women participants, apart from the percentage of female/women participants being marginally higher in studies conducted in Asia.
• Sex and gender were reported inconsistently in dialysis trials. Around a third (31%) did not explicitly report the sex or gender of their participants (i.e., did not specifically use the term sex and/or gender but used the descriptors “male/female” or “man/woman” without referring to sex or gender specifically).
• Where the terms “sex” or “gender” were used, authors in the included studies tended to prefer the term sex over gender in recent years.
• The RCTs often did not consider sex or gender in their study design, possibly to the detriment of women. Sex- and/or gender-biased exclusion criteria were commonly used (in 27% of RCTs; usually to exclude female participants based on child-bearing potential, or with stringent contraception requirements) and rarely used as inclusion criteria (3%).
• Sex- and gender-specific outcomes in dialysis RCTs were infrequently reported, and only 16% of studies performed subgroup analyses adjusting for treatment effects according to sex or gender.

What does this study NOT address?

• The study could explore further whether the proportion of females/women in dialysis trials was related to the type of interventions studied (i.e., pharmacological interventions versus non-pharmacological, behavioral interventions, of which the latter may be more likely to attract women).
• Given that sex and gender are often used interchangeably, the correct use of sex and/or gender relative to the descriptors “female/male” and “women/men” was not assessed. Given the different implications that sex- versus gender-based differences might have on our understanding of kidney disease and intervention design, this distinction is important and their interchangeable use highlights a knowledge gap.
• The study also did not include trials with kidney transplant recipients, nor the wider CKD population (which would be an ambitious study!). As a point of reference, a scoping review by Laprise et al. of transplant studies showed that sex or gender was usually applied erroneously or used interchangeably, and only 15% of studies considered sex or gender in the study’s primary question. Most of these studies considered sex and gender variables as confounders, with few studies considering them as modifiers of treatment effects.

What are the implications for clinical practice and future research? How do we remove barriers towards participation of more females/women in kidney research?

Although not directly related to the study’s findings, the paper gives several useful recommendations and future directions for incorporating sex and gender in research involving patients with kidney disease (which are also listed in the accompanying Visual Abstract).

Specific targets to recruit more females/women into nephrology trials may need to be adopted, especially if sex/gender is likely to modify the effect of the intervention. At the very least, the study population should be proportional to and reflect the gender distribution of the target population with the condition, to maintain the generalizability of the study’s results. Inclusivity with regards to transgender, non-binary and gender diverse individuals will also be important. A risk-based approach to eligibility criteria based on sex or gender should also be implemented (so females of child-bearing age for example, should not be excluded by default).

Sex and gender differences should not pose barriers to accessing nephrology care. A better understanding of sex- and gender-specific differences and disparities warrants further research. This enables us to improve outcomes and move towards equity for patients across the spectrum of kidney disease.

– Post prepared by Jeffrey Ha and Carinna Hockham

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

Title: Sex and Gender in Randomized Controlled Trials of Adults Receiving Maintenance Dialysis: A Meta-epidemiologic Study
Authors: David Collister, Lonnie Pyne, Arrti A. Bhasin, Sofia B. Ahmed, Brendan Smyth, William Herrington, Meg Jardine, and Michael Walsh

DOI: 10.1053/j.ajkd.2022.10.015

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. Highlights from the June 2023 issue:

Identification of Novel Genetic Risk Factors for Focal Segmental Glomerulosclerosis in Children: Results From the Chronic Kidney Disease in Children (CKiD) Cohort by Axelle Durand et al 

From the authors: We assessed the genetic risk factors for primary focal segmental glomerulosclerosis (FSGS) by simultaneously testing over 680,000 genetic markers spread across the genome in 140 children, including 32 with FSGS lesions. Fourteen independent genetic regions were significantly associated with pediatric FSGS, including APOL1 and ALMS1-NAT8, which were previously found to be associated with FSGS and chronic kidney diseases in adults. Novel genes with relevant biological functions were also highlighted, such as GRB2 and FGFR4, which play a role in the kidney filtration barrier and in kidney cell differentiation, respectively. Finally, we revealed the importance of immune regulation in pediatric FSGS through associations involving cell surface proteins presenting antigens to the immune system and interacting with T-cell receptors.

DOI: 10.1053/j.ajkd.2022.11.003

Editorial: Genetics of Focal Segmental Glomerulosclerosis in African American Children by Rebecca Levy et al [FREE]

Associations of Iron Sucrose and Intradialytic Blood Pressure by Anika T. Singh et al 

From the authors: Intradialytic hypotension and intradialytic hypertension are common among patients on hemodialysis, and they are associated with morbidity and mortality. Although many factors may contribute to these risks, medications administered during hemodialysis play an important role. We studied the significance of the intravenous iron sucrose used to treat iron deficiency and the impact it may have on blood pressure during dialysis. In our study of 950 outpatient hemodialysis patients, we observed that administration of iron sucrose was associated with higher systolic blood pressure (during and after hemodialysis sessions) as well as a lower risk of intradialytic hypotension. We also observed that higher doses of iron sucrose are associated with the development of intradialytic hypertension.

Editorial: Iron Sucrose and Blood Pressure Patterns During Hemodialysis by Jingyin Yan [FREE]

DOI: 10.1053/j.ajkd.2022.11.007

Muscle Oxygenation and Microvascular Reactivity Across Different Stages of CKD: A Near-Infrared Spectroscopy Study by Marieta P. Theodorakopoulou et al

From the authors: Previous studies in chronic kidney disease (CKD) have shown that vascular dysfunction in different circulatory beds progressively deteriorates with CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with nondialysis CKD versus controls, as well as across different CKD stages. It showed that the microvascular hyperemic response after an arterial occlusion was significantly impaired in CKD and was worst in patients with more advanced CKD. No significant differences were detected in skeletal muscle oxygenation or muscle oxidative capacity at rest or during the handgrip exercise when comparing patients with CKD with controls or comparing across CKD stages. The impaired ability of microvasculature to respond to stimuli may be a component of the adverse vascular profile of patients with CKD and may contribute to exercise intolerance.

DOI: 10.1053/j.ajkd.2022.11.013

Editorial: Strengthening the Link Between Cardiovascular Disease and Sarcopenia in CKD by Matthew K. Abramowitz [FREE]

Characteristics of and Outcomes After Dialysis-Treated Acute Kidney Injury, 2009-2018: A Taiwanese Multicenter Study by Cheng-Chia Lee et al (OPEN ACCESS)

From the authors: The current medical management of severe acute kidney injury (AKI) is primarily limited to supportive care and kidney replacement therapy if indicated, leading to perceptions that outcomes among intensive care unit (ICU) patients with dialysis-treated AKI have not improved. In this multicenter retrospective study of ICU patients with dialysis-treated AKI between 2009 and 2018 in Taiwan, patient mortality decreased over time despite increasing comorbidities. Moreover, the decreasing linear trends remained significant even when considering severity of acute illness at dialysis initiation, which was based on physiologic and laboratory measurements seldom evaluated in previous studies. Further research should explore the basis for these improvements.

DOI: 10.1053/j.ajkd.2022.08.022

Early Postoperative Acetaminophen Administration and Severe Acute Kidney Injury After Cardiac Surgery by Chao Xiong et al (OPEN ACCESS)

From the authors: There is uncertainty about whether antioxidant medications such as acetaminophen may protect against kidney injury. Therefore, we evaluated the associations between acetaminophen use and kidney outcomes in adults recovering from cardiac surgery in 2 large clinical registries. Acetaminophen treatment was significantly associated with a 14%-16% lower risk of severe and any-stage acute kidney injury but similar risks of kidney replacement therapy and in-hospital mortality. Our findings suggest that acetaminophen use may protect against kidney injury in adult patients recovering from cardiac surgery.

DOI: 10.1053/j.ajkd.2022.11.009

Subcutaneous C.E.R.A. for the Maintenance Treatment of Anemia in Pediatric Patients With CKD: A Phase 2, Open-Label, Single-Arm, Multicenter Study by Bradley A. Warady et al 

From the authors: Anemia, a complication of chronic kidney disease, is associated with poor quality of life and an increased risk of hospitalization and mortality. The current treatments for anemia include iron therapy and erythropoiesis-stimulating agents (ESAs); however, the relatively short half-lives of the ESAs epoetin alfa/beta or darbepoetin alfa may require more frequent dosing and hospital visits compared with the ESA known as continuous erythropoietin receptor activator (C.E.R.A.). A previous study demonstrated that children aged 5 years or more with anemia associated with chronic kidney disease who were on hemodialysis could be switched to intravenous C.E.R.A. from their existing epoetin alfa/beta or darbepoetin alfa treatment. This study provides evidence that subcutaneous C.E.R.A. can safely and effectively treat anemia in children, including those aged <5 years and regardless of whether they were on dialysis or the type of dialysis they received (peritoneal dialysis or hemodialysis).

DOI: 10.1053/j.ajkd.2022.11.006

Age of Onset and Disease Course in Biopsy-Proven Minimal Change Disease: An Analysis From the Cure Glomerulonephropathy Network by Dhruti P. Chen et al 

From the authors: Minimal change disease is a biopsy diagnosis for nephrotic syndrome. It is diagnosed in childhood, adolescence, or adulthood. Patients and clinicians often have questions about what to expect in the disease course and how to plan therapies. We analyzed a group of patients followed longitudinally as part of the Cure Glomerulonephropathy Network (CureGN) and describe the differences in disease (relapse and remission) based on the age of onset. We also analyzed rituximab response. We found that those with childhood-onset disease had a higher rate of relapse but also have a higher probability of reaching remission when compared with adolescent- or adult-onset disease. Children and all steroid-responsive patients are more likely to achieve remission after rituximab.

DOI: 10.1053/j.ajkd.2022.11.012

Association of Acute Kidney Injury and Cardiovascular Disease Following Percutaneous Coronary Intervention: Assessment of Interactions by Race, Diabetes, and Kidney Function by Joseph Lunyera et al

From the authors: This study examined differences by race, diabetes, or kidney function in the well-known association of AKI with increased risk for cardiovascular outcomes among patients undergoing percutaneous coronary intervention. The authors found that AKI was associated with a greater risk for cardiovascular outcomes, but this risk did not differ by patients’ race, diabetes status, or level of kidney function before the procedure. That said, the risk for cardiovascular outcomes was numerically highest among Black patients compared with White patients or those of other races. These study findings suggest that future efforts to prevent AKI among patients undergoing the procedure could reduce racial disparities in risk for unfavorable cardiovascular outcomes afterward.

DOI: 10.1053/j.ajkd.2022.12.013

Review from the June 2023 issue:

Nutritional Epidemiology and Dietary Assessment for Patients With Kidney Disease: A Primer by Valerie K. Sullivan and Casey M. Rebholz (FREE)

Nutritional epidemiology seeks to understand nutritional determinants of disease in human populations using experimental and observational study designs. This primer offers an overview of nutritional epidemiology, including study designs, exposure definition, traditional and novel diet assessment methods, sources of error, and statistical considerations, to guide researchers and clinicians in interpreting and conducting investigations of diet in CKD.

DOI: 10.1053/j.ajkd.2022.11.014

Figure 1 from Sullivan et al, AJKD © National Kidney Foundation

On the Cover: Before the advent of modern medicine, danewort (Sambucus ebulus), a form of elder plant, was used to treat nephrotic syndrome. Cornelius Roelans described in 1484 a child with “whole body swelling” and recommended to “take the tops of elder plant and danewort, cook in white wine and wrap the child in hot clothes by applying the poultice in whole or in part, and so cure him”. In this issue of AJKD, 2 studies highlight the evolution in our understanding and effective treatment of childhood nephrotic syndrome. Durand et al identify novel genetic risk factors for focal segmental glomerulosclerosis in children. Chen et al show that the disease course of biopsy-proven minimal change disease differs in patients with childhood-onset compared with adolescent- or adult-onset disease.

The photograph “Fla¨der” by Susanne Nilsson is released on Flickr under the CC-BY-SA 2.0 license.

Special thanks to Editorial Intern Jeffrey Ha for curating the cover image and drafting the cover blurb for this issue.

SPECIAL COLLECTION: RESEARCH ACROSS THE WORLD

This special collection highlights kidney disease research from around the world. Articles in this collection will be freely available until July 15, 2023.

Comparison of centrifugation and membrane separation therapeutic plasma exchange (TPE). Figure 1 from Cervantes et al, AJKD © National Kidney Foundation

In a recent Core Curriculum published in AJKD, C. Elena Cervantes, Evan M. Bloch, and C. John Sperati discuss therapeutic plasma exchange (TPE) from the perspective of a nephrologist responsible for prescribing and managing TPE, as well as nephrologists engaged in the care of patients undergoing the procedure.

AJKDBlog’s Interviews Editor, Timothy Yau @Maximal_Change sat down with Dr. Cervantes @Elena_Cervants for a deeper dive into these topics.

If the embedded player above doesn’t work, please click here to watch the video interview. Special thanks to Dr. Cervantes for taking the time to talk with us!

To view this Core Curriculum (FREE), please visit AJKD.org.

Title: Therapeutic Plasma Exchange: Core Curriculum 2023
Author:C. Elena Cervantes, Evan M. Bloch, and C. John Sperati
DOI: 10.1053/j.ajkd.2022.10.017

Core Curricula aim to give trainees in nephrology a strong knowledge base in core topics in the specialty by providing an overview of the topic and citing key references, including the foundational literature that led to current clinical approaches. All Core Curricula are freely available on AJKD.org

Mengyao Tang @tammyyaotang

Dr. Mengyao Tang is a research fellow at Massachusetts General Hospital, as well as a board-certified nephrologist who has a particular interest in the interplay of CKD, CVD, and diabetes. She is an AJKD Editorial Intern from 2022-2023. She is supported by an AHA postdoctoral grant to study glycemic variability as a novel risk factor for CVD in CKD patients.

The importance of sick day medication guidance (SDMG), defined as “withholding or adjusting specific medications in the setting of acute illness”, has been emphasized in the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline. The rationale seems intuitive at first—most medications can be double-edged swords: taken long-term for cardio-renal-metabolic disease, they are lifesaving and reduce progression to end-stage kidney disease (ESKD), hospitalization rate, and even mortality; however, in acute illness, the same medications can potentially contribute to or aggravate hypotension, acute kidney injury (AKI), or hypoglycemia.

However, 21^st century modern medicine is based on evidence rather than intuition. A fundamental question remains to be answered: does SDMG actually work in preventing or mitigating adverse events? In a systematic review conducted to assess the clinical evidence base for the effectiveness of SDMG, most of the identified documents were educational resources or guidelines, and there were very few primary research studies conducted to answer the question. Furthermore, no studies reported beneficial effects on clinical outcomes.

One challenge to studying the effectiveness of SDMG is that there is a lack of consensus on recommendations for SDMG among researchers and practicing clinicians. In a recent study published in AJKD, Watson et al. seek to develop standardized SDMG recommendations for people with chronic kidney disease (CKD), cardiovascular disease (CVD), or diabetes.

In this study using a modified Delphi process, an international panel of experts on SDMG recruited through purposive and snowballing sampling had a total of 3 rounds to develop, refine, and vote on recommendations via virtual meetings. They focused on 3 main questions:

1) What symptoms or signs of acute illness should trigger SDMG?

2) What should be included in SDMG?

3) What medication instructions should be included in SDMG?

Data were collected and analyzed using a mixed method, including counts and percentages to report agreement and consensus (75% agreement), as well as content analysis to capture contexts and additional considerations (Figure 1).

Modified Delphi Process Flow Diagram. Figure 1 from
Watson et al © 2022 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.

The final expert panel consisted of 26 clinicians from 4 countries (19 of them from Canada, same as the majority of co-authors) and 10 clinical disciplines (including general internal medicine, endocrinology, cardiology, and nephrology) were able to reach a consensus on 42 specific recommendations. Let’s take a closer look at the 3 main questions of interest:

1) What symptoms or signs of acute illness should trigger SDMG?

The experts reached a consensus on 5 recommendations regarding signs and symptoms of volume depletion that should trigger SDMG, including vomiting or diarrhea leading to significant fluid loss, anorexia or nausea leading to a significant decrease in fluid intake, new dizziness, decreased weight, and decreased urine output. In addition, another 6 signs should prompt urgent contact with providers, including reduced level of consciousness, severe vomiting, low blood pressure, presence of ketones, tachycardia, and fever.

2) What should be included in SDMG?

The experts reached a consensus on recommendations for patient self-management VS. seeking assistance from a health care provider VS. emergency/urgent care with 14 different scenarios and strategies, including frequent glucose monitoring, checking ketones, fluid intake, and ensuring food consumption. For example, they recommended contacting health care providers when patients feel they are not coping; their symptoms have not resolved within 3 days; they cannot keep up with food/fluid intakes; they are experiencing recurrent low glucose readings or significant increase in glucose after 1 day of adjusting medications.

3) What medication instructions should be included in SDMG?

Medications such as renin-angiotensin-aldosterone system (RAAS) inhibitors, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), sodium-glucose cotransporter-2 (SGLT2) inhibitors and metformin were recommended to be held temporarily. Insulin, sulfonylureas and meglitinides were recommended to be held only when glucose levels were low. Furthermore, they made 6 recommendations regarding the resumption of these medications within 1-2 days of symptom resolution and return of normal eating/drinking patterns.

The current clinical practice of SDMG varies among medical providers. Even among the 26 experts included in the panel, only 9 of them provided SDMG frequently to their patients. Those who did not follow such practice cited a lack of evidence supporting SDMG as one of the major reasons. To add more complexity, even patients with high health literacy are often confused by the ambiguity of the SDMG recommendations offered by their medical providers. Another practical challenge is to ensure patients restart these potentially life-saving medications once the acute illness is over.

The authors should be applauded for undertaking a crucial step to achieve consensus on these SDMG clinical recommendations. Many research questions remain to be answered on SDMG. This study provides the foundation for future investigations aiming to evaluate whether SDMG interventions work in clinical settings. In parallel, the recommendations can also be used as a helpful resource of reference for clinicians caring for patients with cardio-renal-metabolic diseases.

– Post prepared by Mengyao Tang @tammyyaotang

To view Watson et al [OPEN ACCESS], please visit AJKD.org.

Title: Consensus Recommendations for Sick Day Medication Guidance for People With Diabetes, Kidney, or Cardiovascular Disease: A Modified Delphi Process
Authors: Kaitlyn E. Watson, Kirnvir Dhaliwal, Sandra Robertshaw, Nancy Verdin, Eleanor Benterud, Nicole Lamont, Kelsea M. Drall, Kerry McBrien, Maoliosa Donald, Ross T. Tsuyuki, David J.T. Campbell, Neesh Pannu, Matthew T. James on behalf of the PAUSE (Preventing Medication Complications During Acute Illness Through Symptom Evaluation and Sick Day Guidance) Medication Safety Advisory Panel
DOI: https://doi.org/10.1053/j.ajkd.2022.10.012

NephMadness 2023 ended just a month ago and it’s now time to plan NephMadness 2024!

Which topics would you like to see in next year’s edition of the madness?

Copyright: Ronnaphoom Naksomboon / Shutterstock

We’ve had great fun and success crowdsourcing topic ideas in the past:

Frequency of dialysis treatment
Dialysis innovation region (for an encore!)
Nephrology recruitment
Leadership development in Nephrology
AI to analyze patient data
Developments in transplantation including xenotransplantation
COVID and CKD, dialysis and transplant patients

— Kidney Rebel (@kidneyrebel) May 23, 2022

Many thanks to @KidneyRebel (who won Best Tweeter in 2023) for suggesting the transplantation topic – team Expanding the Organ Pool from Access to Transplantation region ended up winning NephMadness 2023!

Copyright: Gemenacom/Shutterstock

Transitions of care:
Pediatric to adult
Inpatient to outpatient
Nephrology clinic to dialysis unit

— Michelle Rheault (@rheault_m) May 18, 2022

Thanks to @rheault_m for suggesting the team Pediatric to Adult Care for the Transitions of Care Region!

Copyright: FGC/Shutterstock

Want to see your name in next year’s post? Then send us your ideas for NephMadness 2024 via Twitter with the hashtag #NephMadness. Or submit your feedback by commenting on our Facebook page. If you do not have a social media account, send an email to ajkd@pennmedicine.upenn.edu.

Here are all the NephMadness brackets from previous years so you can see which topics have been covered so far:

NephMadness 2023 | Full-size 2022 Bracket PDF

NephMadness 2022 | Full-size 2022 Bracket PDF

NephMadness 2021 | Full-size 2021 Bracket PDF

NephMadness 2020 | Full-size 2020 Bracket PDF

NephMadness 2019 | Full-size 2019 Bracket PDF

NephMadness 2018 | Full-size 2018 Bracket PDF

NephMadness 2017 | Full-size 2017 Bracket PDF

NephMadness 2016 | Full-size 2016 Bracket PDF

NephMadness 2015 | Full-size 2015 Bracket PDF

NephMadness 2014 | Full-size 2014 Bracket PDF

NephMadness 2013 | Full-size 2013 Bracket PDF

NephMadness Champions

The NephMadness Exec Team:

• Matt Sparks @Nephro_Sparks
• Tim Yau @Maximal_Change
• Anna Burgner @anna_burgner
• Samira Farouk @ssfarouk
• Anna Vinnikova @KidneyWars

NephMadness | #NephMadness | @NephMadness