Our research broadens the knowledge of kidney disease.

Overdiagnosis of Chronic Kidney Disease in Older Adults—An Inconvenient Truth

Since its publication in 2002, the National Kidney Foundation (NKF)’s clinical practice guideline on the evaluation, classification, and stratification of chronic kidney disease (CKD) dramatically altered how we think about kidney disease and how we care for people with this condition. Almost 2 decades later, many of the practices recommended in this guideline have been fully integrated into clinical practice, such as using a prediction equation to estimate glomerular filtration rate (eGFR) rather than serum creatinine alone, an eGFR-based classification system to define and gage the severity of CKD, and a risk-based approach to managing CKD based on the level of eGFR and albuminuria. The 2002 guideline was in many ways a breath of fresh air. It offered a formal case definition where none had existed previously, a common language to describe the presence and severity of CKD, and a powerful organizing structure to guide clinical care, scientific research, and patient advocacy. Nonetheless, these sweeping changes to the recommended conceptual and pragmatic approach to defining and managing CKD had some unanticipated and unintended adverse consequences. In this issue of JAMA Internal Medicine, Liu et al spotlight one of these.

Arterial Stiffness is Independently Associated with Acute Kidney Injury in SPRINT

Michelle Pengshung, Nina Bispham, Zhiying You, Ester Oh, Mark Supiano, Michel Chonchol, Kristen Nowak, Anna Jovanovich

CJASN August 2021, CJN.06420521; DOI: https://doi.org/10.2215/CJN.06420521 CJN.06420521 DOI https://doi.org/10.2215/CJN.06420521 PubMed 34452880 Published By American Society of Nephrology Print ISSN 1555-9041 Online ISSN 1555-905X Copyright & Usage © 2021

Microphysiological Systems in ADME Sciences

Kirk P. Van Ness, Francine Cesar, Catherine K. Yeung, Jonathan Himmelfarb, Edward J. Kelly

The use of microphysiological systems (MPS) to support Adsorption, Distribution, Metabolism, and Elimination (ADME) sciences has grown substantially in the last decade in part driven by regulatory demands to move away from traditional animal-based safety assessment studies and industry desires to develop methodologies to efficiently screen and characterize drugs in the development pipeline. The past decade of MPS development has yielded great user-driven technological advances with the collective fine-tuning of cell culture techniques, fluid delivery systems, materials engineering, and performance enhancing modifications. The rapid advances in MPS technology have now made it feasible to evaluate critical ADME parameters within a stand-alone organ system or through interconnected organ systems. This review surveys current MPS developed for liver, kidney, and intestinal systems as stand-alone or interconnected organ systems, and evaluates each system for specific performance criteria recommended by regulatory authorities and MPS leaders that would render each system suitable for evaluating drug ADME. While some systems are more suitable for ADME type research than others, not all system designs were intended to meet the recently published desired performance criteria and are reported as a summary of initial proof-of-concept studies.

Safety and Efficacy of GFB-887, a TRPC5 Channel Inhibitor, in Patients With Focal Segmental Glomerulosclerosis, Treatment-Resistant Minimal Change Disease, or Diabetic Nephropathy: TRACTION-2 Trial Design

Liron Walsh, John F. Reilly, Caitlin Cornwall, Gregory A. Gaich, Debbie S. Gipson, Hiddo J.L. Heerspink, Leslie Johnson, Howard Trachtman, Katherine R. Tuttle, Youssef M.K. Farag, Krishna Padmanabhan, Xin-Ru Pan-Zhou, James R. Woodworth, Frank S. Czerwiec

A critical unmet need exists for precision therapies for chronic kidney disease. GFB-887 is a podocyte-targeting, small molecule inhibitor of transient receptor potential canonical-5 (TRPC5) designed specifically to treat patients with glomerular kidney diseases characterized by an overactivation of the TRPC5-Rac1 pathway. In a first-in-human study, GFB-887 was found to be safe and well tolerated, had a pharmacokinetic (PK) profile allowing once-daily dosing, and dose dependently decreased urinary Rac1 in healthy adults.

Breaking New Ground with Incretin Therapy in Diabetes

The number of persons with diabetes is projected to grow from 463 million to 700 million worldwide between 2019 and 2045, with the greatest effect occurring in low- and middle-income countries.1 Given the growing number of cases of diabetes (90% of which are type 2), an increased incidence of complications of diabetes, particularly cardiovascular disease and chronic kidney disease, is anticipated.2,3 The need is urgent to develop and deploy effective therapies for diabetes — especially those that reduce the risks of serious complications — across populations. The novel concept of combining a glucose-dependent insulinotropic polypeptide with a glucagon-like peptide-1 (GLP-1) receptor agonist takes incretin therapeutic agents to a new level. This combination has a solid basis in mechanistic underpinnings.

Urine creatinine concentration and clinical outcomes in older adults: The Cardiovascular Health Study.

Joshua I. Barzilay, Petra Buzkova, Michael G. Shlipak, Mary F. Lyles, Nisha Bansal, Pranav S. Garimella, Joachim H. Ix, Jorge R. Kizer, Elsa S. Strotmeyer, Luc Djousse, Mary L. Biggs, David Siscovick, Kenneth J. Mukamal

Purpose: Loss of muscle mass and strength are associated with long-term adverse health outcomes in older adults. Urine creatinine concentrations (Ucr; mg/dl) are a measure of muscle tissue mass and turnover. This study assessed the associations of a spot Ucr level with muscle mass and with risk of hospitalization, mortality, and diabetes mellitus in older adults. Methods: We examined 3424 participants from the Cardiovascular Health Study who provided spot urine samples in 1996–1997 and who were followed through June 2015. All participants underwent baseline measurement of grip strength. In a sub-cohort, 1331 participants underwent dual energy X-ray absorptiometry (DEXA) scans, from which lean muscle mass was derived. Participants were followed for a median of 10 years for hospitalizations and mortality, and 9 years for diabetes mellitus.

Association Between Self-reported Importance of Religious or Spiritual Beliefs and End-of-Life Care Preferences Among People Receiving Dialysis.

Jennifer S Scherer, Kaylin C Milazzo, Paul L Hebert, Ruth A Engelberg, Danielle C Lavallee, Elizabeth K Vig, Manjula Kurella Tamura, Glenda Roberts, J Randall Curtis, Ann M O'Hare

Question: Is there an association between the self-reported importance of religious or spiritual beliefs and serious illness preferences among people who receive dialysis? Findings: In this cross-sectional survey study of 937 patients receiving dialysis, most participants indicated that their religious or spiritual beliefs were behind their whole approach to life. Those for whom these beliefs were more important were more likely to favor resuscitation and a shared (vs patient-centered) decision-making role and less likely to have ever thought or spoken about stopping dialysis. Meaning: These findings highlight the importance of religious or spiritual beliefs and the potential value of an integrative approach that includes spiritual care for people who receive dialysis.

Advance Care Planning Documentation and Intensity of Care at the End of Life for Adults with Congestive Heart Failure, Chronic Kidney Disease, and Both Illnesses.

Gwen M. Bernacki, Cara L. McDermott, Daniel D. Matlock, Ann M.O 'Hare, Lyndia Brumback, Nisha Bansal, James N. Kirkpatrick, Ruth A. Engelberg, J. Randall Curtis

Context: Heart failure (HF) and chronic kidney disease (CKD) are associated with high morbidity and mortality, especially in combination, yet little is known about the impact of these conditions together on end-of-life care. Objectives: Compare end-of-life care and advance care planning (ACP) documentation among patients with both HF and CKD to those with either condition. Methods: We conducted a retrospective analysis of deceased patients (2010-2017) with HF and CKD (n=1673), HF without CKD (n=2671), and CKD without HF (n=1706), excluding patients with cancer or dementia. We compared hospitalizations and intensive care unit (ICU) admissions in the last 30 days of life, hospital deaths, and ACP documentation >30 days before death.

Monoclonal Gammopathy of Renal Significance Causes C3 Glomerulonephritis Via Monoclonal IgG Kappa Inhibition of Complement Factor H

Christopher K. Johnson, Sandra Carias Zuniga, Tejaswini Dhawale, Yuzhou Zhang, Richard J.H. Smith, Christopher D. Blosser

Monoclonal gammopathy of renal significance (MGRS) describes a causal relationship between abnormal circulating monoclonal immunoglobulins (MIg) and kidney disease in the absence of multiple myeloma.Treatment targeting MIg has improved outcomes. Kidney disease associated with MGRS commonly recurs after kidney transplantation if not adequately treated; therefore, an accurate pretransplantation diagnosis is essential to guide therapy and mitigate recurrence risk. A high-risk subset of MGRS with dominant glomerular C3 glomerulopathy (C3G) has been reported. In MGRS-C3G, abnormal paraproteins are not deposited in the kidney; rather, injury occurs via dysregulation of the alternative complement pathway. The resulting acute kidney injury or recurrence is often rapid and severe, with poor prognosis. We report a patient and the specific mechanism for MGRS-C3G that resulted in end-stage renal disease due to immunoglobulin G (IgG) kappa light chain anti–factor H antibodies. Once an accurate diagnosis was made, appropriate treatment of the acquired mechanism enabled successful kidney transplantation. This case shows the importance of accurate diagnosis and appropriate treatment of MGRS.

Prediction of Incident Atrial Fibrillation in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort Study

Leila R. Zelnick, Michael G. Shlipak, Elsayed Z. Soliman, Amanda Anderson, Robert Christenson, James Lash, Rajat Deo, Panduranga Rao, Farsad Afshinnia, Jing Chen, Jiang He, Stephen Seliger, Raymond Townsend, Debbie L. Cohen, Alan Go, Nisha Bansal

Atrial fibrillation (AF) is common in CKD and associated with poor kidney and cardiovascular outcomes. Prediction models developed using novel methods may be useful to identify patients with CKD at highest risk of incident AF. We compared a previously published prediction model with models developed using machine learning methods in a CKD population.