Our research broadens the knowledge of kidney disease.

Glycemic Variability and KIM-1-Induced Inflammation in the Diabetic Kidney

Katherine R Tuttle, Radica Z Alicic

The need to find better ways to identify and treat DKD has never been more urgent. Recent therapeutic advances with the sodium–glucose cotransporter 2 inhibitors demonstrate clear benefits on top of the standard of care, yet substantial residual risk of kidney failure and death remains Uncovering the biological basis of disease is essential to further therapeutic advancement. While hyperglycemia is a well-recognized DKD risk factor, the traditional biomarker of glycated hemoglobin is an average measure that does not capture glycemic variability, an indicator of more disordered homeostasis.

Toward Norepinephrine as a First-Line Treatment for All Hospitalized Patients With Hepatorenal Syndrome

Cary H Paine, Raimund H Pichler, Laura Evans, Scott W Biggins

Hepatorenal syndrome (HRS) is a devastating complication of advanced liver disease associated with high mortality rates. Despite having been described as a clinical syndrome more than 60 years ago, options for the treatment of HRS remain limited. Medical management of patients with HRS, either those waiting for definitive treatment with liver transplantation or those for whom transplantation is not an option, typically includes the administration of albumin in combination with vasoconstrictor therapy......In this pragmatic, real-life study, acute care patients with HRS were first treated with midodrine and octreotide. Those who failed to demonstrate a full or partial response to treatment were started on norepinephrine, the administration and titration of which was protocolized and overseen by the hepatologist. Of the 20 patients who failed to respond to midodrine and octreotide and went on to receive norepinephrine, 45% had a full or partial response to norepinephrine. This serves to underscore the extent to which norepinephrine is a vastly superior treatment for HRS, and it mirrors observations from our institution in which patients transferred to the ICU for norepinephrine after failing midodrine and octreotide frequently responded well to norepinephrine.

KDOQI US Commentary on the 2020 KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation

Chethan M Puttarajappa, Carrie A Schinstock, Christine M Wu, Nicolae Leca, Vineeta Kumar, Brahm S Vasudev, Sundaram Hariharan 

Evaluation of patients for kidney transplant candidacy is a comprehensive process that involves a detailed assessment of medical and surgical issues, psychosocial factors, and patients’ physical and cognitive abilities with an aim of balancing the benefits of transplantation and potential risks of surgery and long-term immunosuppression. There is considerable variability among transplant centers in their approach to evaluation and decision-making regarding transplant candidacy. The 2020 KDIGO (Kidney Disease: Improving Guidelines Outcome) clinical practice guideline on the evaluation and management of candidates for kidney transplantation provides practice recommendations that can serve as a useful reference guide to transplant professionals. The guideline, covering a broad range of topics, was developed by an international group of experts from transplant and nephrology through a review of literature published until May 2019. A work group of US transplant nephrologists convened by NKF-KDOQI (National Kidney Foundation–Kidney Disease Quality Initiative) chose key topics for this commentary with a goal of presenting a broad discussion to the US transplant community. Each section of this article has a summary of the key KDIGO guideline recommendations, followed by a brief commentary on the recommendations, their clinical utility, and potential implementation challenges. The KDOQI work group agrees broadly with the KDIGO recommendations but also recognizes and highlights the decision-making challenges that arise from lack of high-quality evidence and the need to balance equity with utility of organ transplantation.

Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis

Insa M Schmidt, Mia R Colona, Bryan R Kestenbaum, Leonidas G Alexopoulos, Ragnar Palsson, Anand Srivastava, Jing Liu, Isaac E Stillman, Helmut G Rennke, Vishal S Vaidya, Haojia Wu, Benjamin D Humphreys, Sushrut S Waikar, Kidney Precision Medicine Project (KPMP)

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD.

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.