Our research broadens the knowledge of kidney disease.

A genome-wide association study suggests correlations of common genetic variants with peritoneal solute transfer rates in patients with kidney failure receiving peritoneal dialysis

Rajnish Mehrotra, Ian B. Stanaway, Gail P. Jarvik, Mark Lambie, Johann Morelle, Jeffrey Perl, Jonathan Himmelfarb, Olof Heimburger, David W. Johnson, Talha H. Imam, Bruce Robinson, Peter Stenvinkel, Olivier Devuyst, Simon J. Davies, on behalf of the Bio-PD Consortium

Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD.

Multivalent designed proteins protect against SARS-CoV-2 variants of concern

Andrew C Hunt, James Brett Case, Young-Jun Park, Longxing Cao, Kejia Wu, Alexandra C Walls, Zhuoming Liu, John E Bowen, Hsien-Wei Yeh, Shally Saini, Louisa Helms, Yan Ting Zhao, Tien-Ying Hsiang, Tyler N Starr, Inna Goreshnik, Lisa Kozodoy, Lauren Carter, Rashmi Ravichandran, Lydia B Green, Wadim L Matochko, Christy A Thomson, Bastain Vögeli, Antje Krüger-Gericke, Laura A VanBlargan, Rita E Chen, Baoling Ying, Adam L Bailey, Natasha M Kafai, Scott Boyken, Ajasja Ljubetič, Natasha Edman, George Ueda, Cameron Chow, Amin Addetia, Nuttada Panpradist, Michael Gale, Benjamin S Freedman, Barry R Lutz, Jesse D Bloom, Hannele Ruohola-Baker, Sean P J Whelan, Lance Stewart, Michael S Diamond, David Veesler, Michael C Jewett, David Baker

Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers of single minibinders and fusions of three distinct minibinders were designed to geometrically match the SARS-CoV-2 spike (S) trimer architecture and were optimized by cell-free expression and found to exhibit virtually no measurable dissociation upon binding. Cryo-electron microscopy (cryoEM) showed that these trivalent minibinders engage all three receptor binding domains on a single S trimer. The top candidates neutralize SARS-CoV-2 variants of concern with IC 50 values in the low pM range, resist viral escape, and provide protection in highly vulnerable human ACE2-expressing transgenic mice, both prophylactically and therapeutically. Our integrated workflow promises to accelerate the design of mutationally resilient therapeutics for pandemic preparedness. We designed, developed, and characterized potent, trivalent miniprotein binders that provide prophylactic and therapeutic protection against emerging SARS-CoV-2 variants of concern.

Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis

Janani Gopalan, Mitchell H Omar, Ankita Roy, Nelly M Cruz, Jerome Falcone, Kiana N Jones, Katherine A Forbush, Jonathan Himmelfarb, Benjamin S Freedman, John D Scott

Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.

Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes

Farsad Afshinnia, Thekkelnaycke M. Rajendiran, Chenchen He, Jaeman Byun, Daniel Montemayor, Manjula Darshi, Jana Tumova, Jiwan Kim, Christine P. Limonte, Rachel G. Miller, Tina Costacou, Trevor J. Orchard, Tarunveer S. Ahluwalia, Peter Rossing, Janet K. Snell-Bergeon, Ian H. de Boer, Loki Natarajan, George Michailidis, Kumar Sharma, Subramaniam Pennathur

Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D. In a case-control study, 817 patients with T1D from three large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m2 per year decline in estimated glomerular filtration rate (eGFR), while control was defined as <1 mL/min/1.73 m2 per year decline over a minimum 4-year follow-up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform.

Body Composition Changes Following Dialysis Initiation and Cardiovascular and Mortality Outcomes in CRIC (Chronic Renal Insufficiency Cohort): A Bioimpedance Analysis Substudy

Ke Wang, Leila R Zelnick, Glenn M Chertow, Jonathan Himmelfarb, Nisha Bansal

Bioelectrical impedance analysis (BIA) provides a noninvasive assessment of body composition. BIA measures of nutritional (phase angle) and hydration (vector length) status are associated with survival among individuals with chronic kidney disease (CKD), including those receiving maintenance dialysis. However, little is known regarding changes in these parameters with CKD following the high-risk transition to maintenance dialysis.

Ambulatory and Home Blood Pressure Monitoring in Hemodialysis Patients: A Mixed-Methods Study Evaluating Comparability and Tolerability of Blood Pressure Monitoring

Jordana B. Cohen, Chi-yuan Hsu, David Glidden, Lori Linke, Farshad Palad, Hanna L. Larson, Rajnish Mehrotra, Raymond R. Townsend, Nisha Bansal

Out-of-dialysis unit blood pressure (BP) measurement is a better predictor of adverse outcomes compared with traditional dialysis unit BP measurement among patients receiving thrice-weekly in-center hemodialysis. Forty-four–hour ambulatory BP monitoring in maintenance hemodialysis patients provides valuable prognostic information but is often not practical in clinical practice.5 Home BP monitoring may be better suited for longitudinal BP monitoring to guide hypertension management. However, limited evidence exists regarding the tolerability of ambulatory versus home BP in hemodialysis patients.

Triglyceride-Rich Lipoproteins, Apolipoproteins, and Atherosclerotic Cardiovascular Events Among Patients with Diabetes Mellitus and End-Stage Renal Disease on Hemodialysis

Julio A Lamprea-Montealegre, Ronit Katz, Hubert Scharnagl, Günther Silbernagel, Winfried März, Christiane Drechsler, Cristoph Wanner, Ian H de Boer

In this observational post–hoc analysis of the “Die Deutsche Diabetes Dialyse Studie (4D study)” clinical trial8, we examined associations of triglycerides, VLDL–cholesterol (VLDL–C), and apolipoproteins B (Apo B) and C–III (Apo C–III) with ASCVD events among patients with type 2 diabetes and ESRD on HD.

Calculating estimated glomerular filtration rate without the race correction factor: Observations at a large academic medical system

Junyan Shi, Edwin G. Lindo, Geoffrey S. Baird, Bessie Young, Michael Ryan, J.  Ashley Jefferson, Rajnish Mehrotra, Patrick C. Mathias, Andrew N. Hoofnagle

Creatinine-based MDRD and CKD-EPI equations include a race correction factor, which results in higher eGFR in Black patients. We evaluated the impact on our patient population upon adoption of the CKD-EPI equation and the removal of the race correction factor from the equation. Retrospective analysis of blood creatinine results and respective eGFR values calculated by the MDRD or CKD-EPI equation without the race correction factor (CKD-EPINoRace) in a large academic medical system over a 20.5-month period.

An Introduction to Qualitative Inquiry

Many aspects of care for people with kidney disease cannot be meaningfully understood in numerical terms, and benefit from a qualitative approach to inquiry. Qualitative methodologies were originally developed in the social sciences, but are increasingly used in medical research to address questions related to people's lived experiences of illness and care, the meanings they attribute to these experiences, and how health care processes and systems function. In the nephrology literature, qualitative work has helped to identify those health outcomes that matter most to people with kidney disease and their families, which has informed the design and testing of clinical interventions. Other studies have shed light on complex health care processes, such as kidney transplant donation and medical decision making, helping to identify targets for process improvement. Qualitative work may also offer a view into the lives of people with kidney disease, which supports clinicians in better understanding, communicating with, and caring for this group.

DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

Pamela R. Matías-García, Cavin K. Ward-Caviness, Laura M. Raffield, Xu Gao, Yan Zhang, Rory Wilson, Xīn Gào, Jana Nano, Andrew Bostom, Elena Colicino, Adolfo Correa, Brent Coull, Charles Eaton, Lifang Hou, Allan C. Just, Sonja Kunze, Leslie Lange, Ethan Lange, Xihong Lin, Simin Liu, Jamaji C. Nwanaji-Enwerem, Alex Reiner, Jincheng Shen, Ben Schöttker, Pantel Vokonas, Yinan Zheng, Bessie Young, Joel Schwartz, Steve Horvath, Ake Lu, Eric A. Whitsel, Wolfgang Koenig, Jerzy Adamski, Juliane Winkelmann, Hermann Brenner, Andrea A. Baccarelli, Christian Gieger, Annette Peters, Nora Franceschini, Melanie Waldenberger

The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.