Analysis of Glomerular Transcriptomes from Nephrotic Patients Suggest Risk Variants Impact Parietal Epithelial Cells.

The disproportionate risk for idiopathic proteinuric podocytopathies in Black people is explained, in part, by the presence of two risk alleles (G1 or G2) in the gene. The pathogenic mechanisms responsible for this genetic association remain incompletely understood. We analyzed glomerular RNASeq transcriptomes from patients with idiopathic nephrotic syndrome of which 72 had inferred African ancestry (AA) and 152 did not (noAA).

Precision Medicine Proof-of-Concept Study of a TNF Inhibitor in FSGS and Treatment-Resistant Minimal Change Disease.

Background: Focal segmental glomerulosclerosis (FSGS) and treatment-resistant minimal change disease (TR-MCD) are heterogeneous disorders with subgroups defined by distinct underlying mechanisms of glomerular and tubulointerstitial injury. A non-invasive urinary biomarker profile has been generated to identify patients with intra-kidney tumor necrosis factor (TNF)-activation and to predict response to anti-TNF treatment. We conducted this proof-of-concept, multi-center, open-label clinical trial to test the hypothesis that in patients with FSGS or TR-MCD and evidence of intra-renal TNF activation based on their biomarker profile, short-term treatment with adalimumab would reverse the elevated urinary excretion of MCP-1 and TIMP-1.

A transcription factor network regulates proliferation of glomerular endothelial cells in diabetic kidney disease.

The maintenance of a healthy epithelial-endothelial juxtaposition requires cross-talk within glomerular cellular niches. We sought to understand the spatially-anchored regulation and transition of endothelial and mesangial cells from health to injury in DKD. From 74 human kidney samples, an integrated multi-omics approach was leveraged to identify cellular niches, cell-cell communication, cell injury trajectories, and regulatory transcription factor (TF) networks in glomerular capillary endothelial (EC-GC) and mesangial cells.

Virtual Nephron: Evaluation of a Novel Virtual Reality Educational Tool.

Introduction: Recent technological advancements allowed the development of engaging technological tools. Using ASN funding from the ASN, we developed a 3D Virtual Reality (VR) physiology course entitled DiAL-Neph (Diuretic Action and eLectrolyte transport in the Nephron). We hereby present its evaluation.

Protein N-glycans in Healthy and Sclerotic Glomeruli in Diabetic Kidney Disease.

Background: Diabetes is expected to directly impact renal glycosylation, yet to date, there has not been a comprehensive evaluation of alterations in N-glycan composition in the glomeruli of patients with diabetic kidney disease (DKD).

Methods: We used untargeted mass spectrometry imaging to identify N-glycan structures in healthy and sclerotic glomeruli in FFPE sections from needle biopsies of five patients with DKD and three healthy kidney samples. Regional proteomics was performed on glomeruli from additional biopsies from the same patients to compare the abundances of enzymes involved in glycosylation.

Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today.

Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges.

Black Patients Equally Benefit From Renal Genetics Evaluation but Substantial Barriers in Access Exist.

Introduction: Genetic testing is increasingly accessible to patients with kidney diseases. Racial disparities in renal genetics evaluations have not been investigated.

Methods: A cohort of patients evaluated by the Cleveland Clinic Renal Genetics Clinic (RGC) from January 2019 to March 2022 was analyzed.

An atlas of healthy and injured cell states and niches in the human kidney.

Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods. Here we applied multiple single-cell and single-nucleus assays (>400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations.

Kidney Genetics: Continuing Discoveries and a Roadmap to the Clinic.

This article contains a podcast at https://dts.podtrac.com/redirect.

Renal Genetics Clinic: 3-Year Experience in the Cleveland Clinic.

Rationale & Objective: There has been an increasing demand for the expertise provided by a renal genetics clinic. Such programs are limited in the United States and typically operate in a genomics research setting. Here we report a 3-year, real-world, single-center renal genetics clinic experience.

Characteristics of Potential and Actual Living Kidney Donors: A Single-center Experience.

Background: There are limited data and no national capture of barriers associated with initiating and completing the donation process for potential living kidney donors (LKDs).

Methods: We performed a retrospective analysis of 3001 intake forms completed by prospective LKDs from 2016 to 2019 at a single transplant center. We analyzed data from all potential donors who completed the intake until they became ineligible or withdrew or donation was complete.

Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS).

Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study.

T-cell receptor diversity in minimal change disease in the NEPTUNE study.

Background: Minimal change disease (MCD) is the major cause of childhood idiopathic nephrotic syndrome, which is characterized by massive proteinuria and debilitating edema. Proteinuria in MCD is typically rapidly reversible with corticosteroid therapy, but relapses are common, and children often have many adverse events from the repeated courses of immunosuppressive therapy. The pathobiology of MCD remains poorly understood.

Essential role of Wtip in mouse development and maintenance of the glomerular filtration barrier.

Wilms' tumor interacting protein (Wtip) has been implicated in cell junction assembly and cell differentiation and interacts with proteins in the podocyte slit diaphragm, where it regulates podocyte phenotype. To define Wtip expression and function in the kidney, we created a -deleted mouse model using β-galactosidase-neomycin (β-geo) gene trap technology. gene trap mice were embryonic lethal, suggesting additional developmental roles outside kidney function.

A Participant-Centered Approach to Understanding Risks and Benefits of Participation in Research Informed by the Kidney Precision Medicine Project.

An understanding of the ethical underpinnings of human subjects research that involves some risk to participants without anticipated direct clinical benefit-such as the kidney biopsy procedure as part of the Kidney Precision Medicine Project (KPMP)-requires a critical examination of the risks as well as the diverse set of countervailing potential benefits to participants. This kind of deliberation has been foundational to the development and conduct of the KPMP. Herein, we use illustrative features of this research paradigm to develop a more comprehensive conceptualization of the types of benefits that may be important to research participants, including respecting pluralistic values, supporting the opportunity to act altruistically, and enhancing benefits to a participant's community.