Nephrology Commons^™

Endothelin Receptor Antagonists In Resistant Hypertension And Proteinuric Kidney Disease: Receptor Strategy And Volume Management, Corey Keith Goldman, Jesse M. Goldman

Division of Nephrology Faculty Papers

This narrative review examines how endothelin receptor antagonists (ERAs) can be used at the intersection of difficult-to-control hypertension, chronic kidney disease (CKD), and albuminuria or proteinuria. For clinicians, the central question is not receptor selectivity alone, but whether a specific agent, indication, dose, background therapy, and monitoring plan can deliver meaningful blood-pressure or kidney benefit without unacceptable fluid retention. Pulmonary arterial hypertension established the pharmacology and major safety liabilities of the class; the current implementation questions for hypertension and kidney specialists arise in systemic hypertension and proteinuric kidney disease. Aprocitentan is the first and only ERA approved for hypertension; in …

Improving Vaccination In People With Ckd: Report From A National Kidney Foundation Working Group, Susan F. Massengill, Kenneth A. Andreoni, Keith A. Bellovich, Cheryl Courtlandt, Vimal K. Derebail, David L. Feldman, Gia J. Oh, John W. Sleasman, Kristina A. Bryant, Improving Vaccination In Ckd Working Group

Department of Surgery Faculty Papers

People with chronic kidney disease (CKD) are particularly vulnerable to vaccine-preventable infections. Therefore, the National Kidney Foundation organized a multidisciplinary working group, including people with CKD and family care partners, to develop recommendations to improve vaccination rates, vaccination effectiveness, and health care for the CKD population. A modified Delphi process was used to achieve consensus on the recommendations. Recommendations on vaccination in CKD patients were organized into these categories: (1) patient preferences; (2) assessing the vaccination status of patients with CKD; (3) assessing vaccine response in patients with CKD; (4) vaccination of immunocompromised patients; (5) vaccination in posttransplant patients; (6) …

The Role Of Serum Phosphate Control In Supporting Transplant Readiness In Patients On Dialysis, Laura A Williams, Stephen Z Fadem

Faculty, Staff and Students Publications

Chronic kidney disease affects over 36 million Americans, with more than 800,000 progressing to end-stage kidney disease (ESKD). Treatment with kidney transplantation offers superior survival, quality of life, and cost-effectiveness compared with dialysis, yet access remains limited. Hyperphosphatemia is a highly prevalent and modifiable complication of ESKD that contributes to cardiovascular disease, mineral bone disorder, and potential pulmonary dysfunction. Additionally, elevated serum phosphate has been linked to transplant graft failure and adverse post-transplant outcomes. Although normal phosphate levels are not formally required for transplant eligibility, they are frequently considered as part of transplant readiness assessments. Persistent gaps between clinical guideline …

Disease Activity Of Rheumatoid Arthritis And Kidney Function Decline: A Large Prospective Registry Study, Sho Fukui, Wolfgang C Winkelmayer, Sara K Tedeschi, Javier Marrugo, Hongshu Guan, Leslie Harrold, Heather J Litman, Tomohiro Shinozaki, Daniel H Solomon

Faculty, Staff and Students Publications

Introduction: Chronic kidney disease (CKD) is a common comorbidity of rheumatoid arthritis (RA). The association of longitudinal RA disease activity with long-term kidney function has remained uncertain.

Method: We analysed a multicentre prospective RA registry in the USA from 2001 to 2022. The exposure was updated time-averaged Clinical Disease Activity Index (TA-CDAI) categories from study enrolment. The primary outcome was a longitudinal estimated glomerular filtration rate (eGFR) change. Secondary outcomes included developments of CKD stage G3a (eGFR< 60 mL/min/1.73 m2) and stage G3b (eGFR< 45 mL/min/1.73 m2). Results were adjusted for relevant time-fixed and time-varying covariates.

Results: 31 129 patients (median age: 58.0 years, female: 76.3%, median eGFR: 90.7 mL/min/1.73 m2) contributed 234 973 visits and 146 778 person-years …

A Conceptual Framework To Assess The Health, Socioeconomic And Environmental Burden Of Chronic Kidney Disease, Charlotte Johnston-Webber, Isaac Bencomo-Bermudez, George Wharton, Robin Van Kessel, Salvatore Barone, Francisco Brotons Muntó, Steven Chadban, Juan Jose Garcia Sanchez, Janwillem Kocks, Kyra Obolensky, Petra Sandow, Neil Skolnik, Ming-Hui Zhao, Alexei Volaco, David Wheeler, Alistair Mcguire, Elias Mossialos

Department of Medicine Faculty Papers

Chronic kidney disease (CKD) is a global health challenge that affects patients, caregivers, healthcare systems, the environment and national economies. Despite its far-reaching impact, there is no framework to systematically evaluate national CKD prevention and management programmes or evaluate the societal burden of disease. This paper has two objectives: first, to introduce a comprehensive framework to assess national programmes, which recognises gaps and weaknesses and identifies feasible policy interventions to reduce overall CKD burden; second, to present some key challenges and success stories in delivering CKD services delivered in eight different country settings. A literature review informed an initial version …

Assessing The Predictive Power Of Nutritional Indices On All-Cause And Cardiovascular Mortality In Hemodialysis Patients: A Longitudinal Study, Qian Wang, Zengchun Ye, Jialing Rao, Wenbo Zhao, Jianqiang Liu, Yanru Chen, Juncheng Xiang, Xin Zhen, Jiawen Li, Yunfang Zhang, Xianrui Dou, Zhaoyong Hu, Jun Zhang, Hui Peng

Faculty, Staff and Students Publications

BACKGROUND AND HYPOTHESIS: The prognostic value of nutritional scoring tools in assessing the relationship between nutritional status and prognosis in hemodialysis patients is unclear. This multicenter retrospective cohort study compared the Prognostic Nutritional Index (PNI), Controlling Nutritional Status scores (CONUT), and Geriatric Nutritional Risk Index (GNRI) for predictive accuracy of all-cause and cardiovascular mortality, especially the impact of dynamic changes over time on prognosis.

METHODS: Hemodialysis patients from four hospitals were included. Laboratory data and nutrition scores were collected at the initiation of dialysis, and at 6th, 12th, and 18th months after dialysis initiation. A joint model analyzed the relationship …

National Liver Cancer Screening Trial (Tracer) Study Protocol, Amit G Singal, Neehar D Parikh, Fasiha Kanwal, Jorge A Marrero, Sneha Deodhar, Stephanie Page-Lester, Camden Lopez, Ziding Feng, Nabihah Tayob

Faculty, Staff and Students Publications

BACKGROUND: Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice. …

First Interim Results From Fine-Real: A Prospective, Non-Interventional, Phase 4 Study Providing Insights Into The Use And Safety Of Finerenone In A Routine Clinical Settingfirst Interim Results From Fine-Real: A Prospective, Non-Interventional, Phase 4 Study Providing Insights Into The Use And Safety Of Finerenone In A Routine Clinical Setting, Susanne B Nicholas, Ricardo Correa-Rotter, Nihar R Desai, Lixin Guo, Sankar D Navaneethan, Kevin M Pantalone, Christoph Wanner, Stefanie Hamacher, Samuel T Fatoba, Andrea Horvat-Broecker, Antonio Garreta-Rufas, Alain Gay, Martin Merz, David C Wheeler

Center for Medical Ethics and Health Policy Staff Publications

Background: Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). The FINE-REAL study (NCT05348733) aims to evaluate the characteristics and treatment patterns of participants treated with finerenone in clinical practice.

Methods: FINE-REAL is a prospective, single-arm, non-interventional study of patients initiated on finerenone as part of their routine care in accordance with country-approved labels. The study, initiated in June 2022, is expected to be completed by January 2028. The cutoff for this pre-specified interim analysis was June 13, 2023.

Results: Participants were …

Clonal Hematopoiesis Of Indeterminate Potential Is Associated With Reduced Risk Of Cognitive Impairment In Patients With Chronic Kidney Disease, Cissy Xiao, Manjula Kurella Tamura, Yang Pan, Varun Rao, Celestin Missikpode, Caitlyn Vlasschaert, Tetsushi Nakao, Xiao Sun, Changwei Li, Zhijie Huang, Amanda Anderson, Md Mesbah Uddin, Do-Kyun Kim, Jonathan Taliercio, Rajat Deo, Zeenat Bhat, Dawei Xie, Panduranga Rao, Jing Chen, James P Lash, Jiang He, Pradeep Natarajan, James E Hixson, Kristine Yaffe, Tanika N Kelly, Cric Study Investigators

Faculty, Staff and Student Publications

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) and dementia disproportionately burden patients with chronic kidney disease (CKD). The association between CHIP and cognitive impairment in CKD patients is unknown.

Methods: We conducted time-to-event analyses in up to 1452 older adults with CKD from the Chronic Renal Insufficiency Cohort who underwent CHIP gene sequencing. Cognition was assessed using four validated tests in up to 6 years mean follow-up time. Incident cognitive impairment was defined as a test score one standard deviation below the baseline mean.

Results: Compared to non-carriers, CHIP carriers were markedly less likely to experience impairment in attention (adjusted …

Predicting Wait Time For Pediatric Kidney Transplant: A Novel Index, Alexandra Alvarez, Ashley Montgomery, Nhu Thao Nguyen Galván, Eileen D Brewer, Abbas Rana

Faculty, Staff and Students Publications

BACKGROUND: Over one thousand pediatric kidney transplant candidates are added to the waitlist annually, yet the prospective time spent waiting is unknown for many. Our study fills this gap by identifying variables that impact waitlist time and by creating an index to predict the likelihood of a pediatric candidate receiving a transplant within 1 year of listing. This index could be used to guide patient management by giving clinicians a potential timeline for each candidate's listing based on a unique combination of risk factors.

METHODS: A retrospective analysis of 3757 pediatric kidney transplant candidates from the 2014 to 2020 OPTN/UNOS …

Expanding The Access To Kidney Transplantation: Strategies For Kidney Transplant Programs, Angie Nishio Lucar, Ankita Patel, Shikha Mehta, Anju Yadav, Mona Doshi, Megan Urbanski, Beatrice Concepcion, Neeraj Singh, M. Lee Sanders, Arpita Basu, Jessica Harding, Ana Rossi, Oluwafisayo Adebiyi, Milagros Samaniego-Picota, Kenneth Woodside, Ronald Parsons

Department of Medicine Faculty Papers

Kidney transplantation is the most successful kidney replacement therapy available, resulting in improved recipient survival and societal cost savings. Yet, nearly 70 years after the first successful kidney transplant, there are still numerous barriers and untapped opportunities that constrain the access to transplant. The literature describing these barriers is extensive, but the practices and processes to solve them are less clear. Solutions must be multidisciplinary and be the product of strong partnerships among patients, their networks, health care providers, and transplant programs. Transparency in the referral, evaluation, and listing process as well as organ selection are paramount to build such …

Emerging Evidence For Glucagon-Like Peptide-1 Agonists In Slowing Chronic Kidney Disease Progression, Michael W Holliday, Livia Frost, Sankar D Navaneethan

Faculty, Staff and Students Publications

PURPOSE OF REVIEW: Diabetic kidney disease continues to increase, and several novel therapeutic agents have been shown to slow the progression of chronic kidney disease in those with diabetes. This review summarizes more recent data on the role of glucagon-like peptide-1 (GLP-1) receptor agonists and kidney outcomes.

RECENT FINDINGS: Posthoc analysis of cardiovascular outcome trials, as well as several retrospective studies, demonstrate benefits of GLP-1 receptor agonist therapy for chronic kidney disease progression in diabetics. Although limited randomized clinical trials evidence assessing the effects of GLP-1 receptor agonists on kidney outcomes in diabetic chronic kidney disease patients have been published, …

Acute And Chronic Kidney Injury During Therapy For Pediatric Acute Leukemia: A Report From The Leukemia Electronic Abstraction Of Records Network (Learn), Wendy Hsiao, Yimei Li, Kelly Getz, Lusha Cao, Edward Krause, Mark Ramos, Judy Lee, Maria Monica Gramatges, Karen R Rabin, Michael E Scheurer, Richard Aplenc, Michelle Denburg, Tamara P Miller

Center for Medical Ethics and Health Policy Staff Publications

Children with acute leukemia are at increased risk of kidney injury. Using electronic health record data from three centers between 2010 and 2018, this study retrospectively described acute kidney injury (AKI) and chronic kidney disease (CKD) prevalence in children with acute lymphoblastic or myeloid leukemia (ALL, AML) using Common Terminology Criteria for Adverse Events (CTCAE) and Kidney Disease Improving Global Outcomes (KDIGO) definitions. AKI during therapy was 25% (ALL) and 32% (AML) using CTCAE, versus 84% (ALL) and 74% (AML) using KDIGO. CKD prevalence was low and Grade 1/Stage 2. Further investigation is needed to optimally define kidney injury in …

Market Competition And Anemia Management In The United States Following Dialysis Payment Reform, Anshul Bhatnagar, Vishnupriyadevi Parvathareddy, Wolfgang C Winkelmayer, Glenn M Chertow, Kevin F Erickson

Faculty, Staff and Students Publications

BACKGROUND: Whether market competition influences health care provider responses to national reimbursement reforms is unknown.

OBJECTIVES: We examined whether changes in anemia management after the expansion of Medicare's dialysis payment bundle varied with market competition.

RESEARCH DESIGN: With data from the US dialysis registry, we used a difference-in-differences (DID) design to estimate the independent associations of market competition with changes in anemia management after dialysis reimbursement reform.

SUBJECTS: A total of 326,150 patients underwent in-center hemodialysis in 2009 and 2012, representing periods before and after reimbursement reform.

MEASURES: Outcomes were erythropoiesis-stimulating agent (ESA) and intravenous iron dosage, the probability of …

Trends And Perspectives For Improving Quality Of Chronictrends And Perspectives For Improving Quality Of Chronic Kidney Disease Care: Conclusions From A Kidney Disease: Improving Global Outcomes (Kdigo) Controversies Conference Kidney Disease Care: Conclusions From A Kidney Disease: Improving Global Outcomes (Kdigo) Controversies Conference, Kai-Uwe Eckardt, Cynthia Delgado, Hiddo J L Heerspink, Roberto Pecoits-Filho, Ana C Ricardo, Bénédicte Stengel, Marcello Tonelli, Michael Cheung, Michel Jadoul, Wolfgang C Winkelmayer, Holly Kramer, Conference Participants

Faculty, Staff and Students Publications

Chronic kidney disease (CKD) affects over 850 million people globally, and the need to prevent its development and progression is urgent. During the past decade, new perspectives have arisen related to the quality and precision of care for CKD, owing to the development of new tools and interventions for CKD diagnosis and management. New biomarkers, imaging methods, artificial intelligence techniques, and approaches to organizing and delivering healthcare may help clinicians recognize CKD, determine its etiology, assess the dominant mechanisms at given time points, and identify patients at high risk for progression or related events. As opportunities to apply the concepts …

Chronic Kidney Disease Promotes Atrial Fibrillation Via Inflammasome Pathway Activation, Jia Song, Jose Alberto Navarro-Garcia, Jiao Wu, Arnela Saljic, Issam Abu-Taha, Luge Li, Satadru K Lahiri, Joshua A Keefe, Yuriana Aguilar-Sanchez, Oliver M Moore, Yue Yuan, Xiaolei Wang, Markus Kamler, William E Mitch, Gema Ruiz-Hurtado, Zhaoyong Hu, Sandhya S Thomas, Dobromir Dobrev, Xander Ht Wehrens, Na Li

Faculty, Staff and Students Publications

Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1β, a main effector of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1β levels were elevated in patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL-1β signaling in the pathogenesis of CKD-induced AF, Nlrp3-/- and WT mice were subjected to …

Erythrocyte Ent1-Ampd3 Axis Is An Essential Purinergic Hypoxia Sensor And Energy Regulator Combating Ckd In A Mouse Model, Changhan Chen, Tingting Xie, Yujin Zhang, Yiyan Wang, Fang Yu, Lizhen Lin, Weiru Zhang, Benjamin C Brown, Xin Zhang, Rodney E Kellems, Angelo D'Alessandro, Yang Xia

Faculty, Staff and Student Publications

Significance statement: Hypoxia drives kidney damage and progression of CKD. Although erythrocytes respond rapidly to hypoxia, their role and the specific molecules sensing and responding to hypoxia in CKD remain unclear. In this study, we demonstrated in a mouse model that erythrocyte ENT1-AMPD3 is a master energy regulator of the intracellular purinergic hypoxic compensatory response that promotes rapid energy supply from extracellular adenosine, eAMPK-dependent metabolic reprogramming, and O 2 delivery, which combat renal hypoxia and progression of CKD. ENT1-AMPD3-AMPK-BPGM comprise a group of circulating erythroid-specific biomarkers, providing early diagnostic and novel therapeutic targets for CKD.

Background: Hypoxia drives kidney damage …

Novel Anemia Therapies In Chronic Kidney Disease: Conclusions From A Kidney Disease: Improving Global Outcomes (Kdigo) Controversies Conference, Elaine Ku, Lucia Del Vecchio, Kai-Uwe Eckardt, Volker H Haase, Kirsten L Johansen, Masaomi Nangaku, Navdeep Tangri, Sushrut S Waikar, Andrzej Więcek, Michael Cheung, Michel Jadoul, Wolfgang C Winkelmayer, David C Wheeler, For Conference Participants

Faculty, Staff and Students Publications

Anemia is common in patients with chronic kidney disease and is associated with a high burden of morbidity and adverse clinical outcomes. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline for the diagnosis and management of anemia in chronic kidney disease. Since then, new data from studies assessing established and emerging therapies for the treatment of anemia and iron deficiency have become available. Beginning in 2019, KDIGO planned 2 Controversies Conferences to review the new evidence and its potential impact on the management of anemia in clinical practice. Here, we report on the second of these conferences …

Bioresorbable Mesenchymal Stem Cell-Loaded Electrospun Polymeric Scaffold Inhibits Neointimal Hyperplasia Following Arteriovenous Fistula Formation In A Rat Model Of Chronic Kidney Disease, Allan John R Barcena, Joy Vanessa D Perez, Marvin R Bernardino, Jossana A Damasco, Andrea Cortes, Huckie C Del Mundo, Erin Marie D San Valentin, Carleigh Klusman, Gino Martin Canlas, Francisco M Heralde, Rony Avritscher, Natalie Fowlkes, Richard R Bouchard, Jizhong Cheng, Steven Y Huang, Marites P Melancon

Faculty, Staff and Students Publications

Bioresorbable perivascular scaffolds loaded with antiproliferative agents have been shown to enhance arteriovenous fistula (AVF) maturation by inhibiting neointimal hyperplasia (NIH). These scaffolds, which can mimic the three-dimensional architecture of the vascular extracellular matrix, also have an untapped potential for the local delivery of cell therapies against NIH. Hence, an electrospun perivascular scaffold from polycaprolactone (PCL) to support mesenchymal stem cell (MSC) attachment and gradual elution at the AVF's outflow vein is fabricated. Chronic kidney disease (CKD) in Sprague-Dawley rats is induced by performing 5/6th nephrectomy, then AVFs for scaffold application are created. The following groups of CKD rats are …

Vadadustat For Treatment Of Anemia In Patients With Dialysis-Dependent Chronic Kidney Disease Receiving Peritoneal Dialysis, Mark J Sarnak, Rajiv Agarwal, Neil Boudville, Pradip C P Chowdhury, Kai-Uwe Eckardt, Carlos R Gonzalez, Laura A Kooienga, Mark J Koury, Kwabena A Ntoso, Wenli Luo, Patrick S Parfrey, Dennis L Vargo, Wolfgang C Winkelmayer, Zhiqun Zhang, Glenn M Chertow

Faculty, Staff and Students Publications

BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear.

METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular …

Insulin Resistance And Insulin Handling In Chronic Kidney Disease, Vishnu P Parvathareddy, Jiao Wu, Sandhya S Thomas

Faculty, Staff and Students Publications

Insulin regulates energy metabolism involving multiple organ systems. Insulin resistance (IR) occurs when organs exhibit reduced insulin sensitivity, leading to difficulties in maintaining glucose homeostasis. IR ensures decades prior to development of overt diabetes and can cause silent metabolic derangements. IR is typically seen very early in the course of chronic kidney disease (CKD) and is evident even when the estimated glomerular filtration rate (eGFR) is within the normal range and IR persists at various stages of kidney disease. In this article, we will discuss insulin handling by the kidneys, mechanisms responsible for IR in CKD, measurements and management of …

Barriers And Facilitators To Home Dialysis Among Latinx Patients With Kidney Disease, Katherine Rizzolo, Rebeca Gonzalez Jauregui, Ileana Barrientos, Jade Teakell, Claudia Camacho, Michel Chonchol, Sushrut S Waikar, Lilia Cervantes

Faculty, Staff and Student Publications

Importance: Latinx people have a high burden of kidney disease but are less likely to receive home dialysis compared to non-Latinx White people. The disparity in home dialysis therapy has not been completely explained by demographic, medical, or social factors.

Objective: To understand the barriers and facilitators to home dialysis therapy experienced by Latinx individuals with kidney failure receiving home dialysis.

Design, setting, and participants: This qualitative study used semistructured interviews with Latinx adults with kidney failure receiving home dialysis therapy in Denver, Colorado, and Houston, Texas, between November 2021 and March 2023. Patients were recruited from home dialysis clinics …

Predictors, Disparities, And Facility-Level Variation: Sglt2 Inhibitor Prescription Among Us Veterans With Ckd, L Parker Gregg, David J Ramsey, Julia M Akeroyd, Shehrezade A Jafry, Michael E Matheny, Salim S Virani, Sankar D Navaneethan

Faculty, Staff and Students Publications

RATIONALE & OBJECTIVE: Sodium/glucose cotransporter 2 (SGLT2) inhibitors are recommended for type 2 diabetes mellitus (T2DM) in patients with chronic kidney disease (CKD) or atherosclerotic cardiovascular disease (ASCVD). We evaluated factors associated with SGLT2 inhibitor prescription, disparities by race and sex, and facility-level variation in prescription patterns.

STUDY DESIGN: Retrospective cohort.

SETTING & PARTICIPANTS: A national sample of US veterans with comorbid T2DM, CKD, and ASCVD with a primary care visit between January 1 and December 31, 2020.

EXPOSURE: Race, sex, and individual Veterans Affairs (VA) location.

OUTCOME: SGLT2 inhibitor prescription.

ANALYTICAL APPROACH: Multivariable logistic regression assessed associations of race …

Transcriptome- And Proteome-Wide Association Studies Nominate Determinants Of Kidney Function And Damage, Pascal Schlosser, Jingning Zhang, Hongbo Liu, Aditya L Surapaneni, Eugene P Rhee, Dan E Arking, Bing Yu, Eric Boerwinkle, Paul A Welling, Nilanjan Chatterjee, Katalin Susztak, Josef Coresh, Morgan E Grams

Faculty, Staff and Student Publications

BACKGROUND: The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage.

RESULTS: Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are …

Longer Time To Recovery From Acute Kidney Injury Is Associated With Major Adverse Kidney Events In Patients With Cirrhosis, Kavish R Patidar, Mobasshir A Naved, Shaowli Kabir, Ananth Grama, Andrew S Allegretti, Giuseppe Cullaro, Sumeet K Asrani, Astin Worden, Archita P Desai, Marwan S Ghabril, Lauren D Nephew, Eric S Orman

Faculty, Staff and Students Publications

BACKGROUND: In patients with cirrhosis and acute kidney injury (AKI), longer time to AKI-recovery may increase the risk of subsequent major-adverse-kidney-events (MAKE).

AIMS: To examine the association between timing of AKI-recovery and risk of MAKE in patients with cirrhosis.

METHODS: Hospitalised patients with cirrhosis and AKI (n = 5937) in a nationwide database were assessed for time to AKI-recovery and followed for 180-days. Timing of AKI-recovery (return of serum creatinine7-days. Primary outcome was MAKE at 90-180-days. MAKE is an accepted clinical endpoint in AKI and defined as the composite outcome of ≥25% decline in estimated-glomerular-filtration-rate (eGFR) compared with baseline with …

Steroidal Or Non-Steroidal Mras: Should We Still Enable Raasi Use Through K Binders?, L Parker Gregg, Sankar D Navaneethan

Faculty, Staff and Students Publications

Renin-angiotensin-aldosterone system inhibitors (RAASi) and mineralocorticoid receptor antagonists (MRAs) are important interventions to improve outcomes in patients with chronic kidney disease and heart failure, but their use is limited in some patients by the development of hyperkalemia. The risk of hyperkalemia may differ between agents, with one trial showing lower risk of hyperkalemia with the novel non-steroidal MRA finerenone compared with steroidal MRA spironolactone. Novel potassium binders, including patiromer and sodium zirconium cyclosilicate, are available interventions to manage hyperkalemia and enable continuation of RAASi and MRAs in patients who could benefit from these treatments. These agents bind free potassium ions …

A Parathyroid Hormone/Salt-Inducible Kinase Signaling Axis Controls Renal Vitamin D Activation And Organismal Calcium Homeostasis, Sung-Hee Yoon, Mark B Meyer, Carlos Arevalo, Murat Tekguc, Chengcheng Zhang, Jialiang S Wang, Christian D Castro Andrade, Katelyn Strauss, Tadatoshi Sato, Nancy A Benkusky, Seong Min Lee, Rebecca Berdeaux, Marc Foretz, Thomas B Sundberg, Ramnik J Xavier, Charles H Adelmann, Daniel J Brooks, Anthony Anselmo, Ruslan I Sadreyev, Ivy A Rosales, David E Fisher, Navin Gupta, Ryuji Morizane, Anna Greka, J Wesley Pike, Michael Mannstadt, Marc N Wein

Faculty, Staff and Student Publications

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell–derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, …

Heart Failure-Type Symptom Score Trajectories In Ckd: Findings From The Chronic Renal Insufficiency Cohort (Cric) Study, Carl P Walther, Julia S Benoit, Nisha Bansal, Vijay Nambi, Sankar D Navaneethan, Cric Study Investigators

Faculty, Staff and Students Publications

RATIONALE & OBJECTIVE: Quality of life in chronic kidney disease (CKD) is impaired by a large burden of symptoms including some that overlap with the symptoms of heart failure (HF). We studied a group of individuals with CKD to understand the patterns and trajectories of HF-type symptoms in this setting.

STUDY DESIGN: Prospective cohort study.

SETTING & PARTICIPANTS: 3,044 participants in the Chronic Renal Insufficiency Cohort (CRIC) without prior diagnosis of HF.

PREDICTORS: Sociodemographics, medical history, medications, vital signs, laboratory values, echocardiographic and electrocardiographic parameters.

OUTCOME: Trajectory over 5.5 years of a HF-type symptom score (modified Kansas City Cardiomyopathy Questionnaire …

Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated With Diabetic Kidney Disease, Yang Pan, Xiao Sun, Xuenan Mi, Zhijie Huang, Yenchih Hsu, James E Hixson, Donna Munzy, Ginger Metcalf, Nora Franceschini, Adrienne Tin, Anna Köttgen, Michael Francis, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium Topmed Kidney Function Working Group, Jennifer A Brody, Bryan Kestenbaum, Colleen M Sitlani, Josyf C Mychaleckyj, Holly Kramer, Leslie A Lange, Xiuqing Guo, Shih-Jen Hwang, Marguerite R Irvin, Jennifer A Smith, Lisa R Yanek, Dhananjay Vaidya, Yii-Der Ida Chen, Myriam Fornage, Donald M Lloyd-Jones, Lifang Hou, Rasika A Mathias, Braxton D Mitchell, Patricia A Peyser, Sharon L R Kardia, Donna K Arnett, Adolfo Correa, Laura M Raffield, Ramachandran S Vasan, L Adrienne Cupple, Daniel Levy, Robert C Kaplan, Kari E North, Jerome I Rotter, Charles Kooperberg, Alexander P Reiner, Bruce M Psaty, Russell P Tracy, Richard A Gibbs, Alanna C Morrison, Harold Feldman, Eric Boerwinkle, Jiang He, Tanika N Kelly, Cric Study Investigators

Faculty, Staff and Students Publications

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between …

Metabolomic Markers Of Ultra-Processed Food And Incident Ckd, Donghan Su, Jingsha Chen, Shutong Du, Hyunju Kim, Bing Yu, Kari E Wong, Eric Boerwinkle, Casey M Rebholz

Faculty, Staff and Student Publications

BACKGROUND: High ultra-processed food consumption is associated with higher risk of CKD. However, there is no biomarker for ultra-processed food, and the mechanism through which ultra-processed food is associated with CKD is not clear. Metabolomics can provide objective biomarkers of ultra-processed food and provide important insights into the mechanisms by which ultra-processed food is associated with risk of incident CKD. Our objective was to identify serum metabolites associated with ultra-processed food consumption and investigate whether ultra-processed food-associated metabolites are prospectively associated with incident CKD.

METHODS: We used data from 3751 Black and White men and women (aged 45-64 years) in …