Depressive Symptoms in Adults with Autosomal Dominant Polycystic Kidney Disease.

Background: Individuals with autosomal dominant polycystic kidney disease (ADPKD) face mental health challenges linked to disease progression and its heritable nature. Prior studies reported mixed associations between depressive symptoms and ADPKD severity and progression. Here, we assessed depressive symptoms and disease severity over three years in ADPKD patients without end-stage kidney disease.

gene fusion reciprocally regulates mTORC1 activity and induces lineage plasticity in a novel mouse model of renal tumorigenesis.

The MiT/TFE family gene fusion proteins, such as , drive both epithelial (eg, translocation renal cell carcinoma, tRCC) and mesenchymal (eg, perivascular epithelioid cell tumor, PEComa) neoplasms with aggressive behavior. However, no prior mouse models for -related tumors exist and the mechanisms of lineage plasticity induced by this fusion remain unclear. Here, we demonstrate that constitutive murine renal expression of human using Ksp Cadherin-Cre as a driver disrupts kidney development leading to early neonatal renal failure and death.

Multiomics profiling of mouse polycystic kidney disease progression at a single-cell resolution.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to kidney failure. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single-nucleus multimodal atlas of an orthologous mouse PKD model at early, mid, and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes.

Characterizing the impact of the Covid-19 pandemic on adults with autosomal dominant polycystic kidney disease: a cross-sectional study.

Background: The Covid-19 pandemic greatly affected those with chronic diseases, impacting healthcare access and healthcare seeking behaviors. The impact of the pandemic on adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD) has not been investigated.

Methods: Participants were recruited from a cohort of 239 ADPKD patients enrolled in a longitudinal study at the University of Maryland.

Characterizing the Impact of the Covid-19 Pandemic on Adults with Autosomal Dominant Polycystic Kidney Disease: A Cross-Sectional Study.

Background: The Covid-19 pandemic greatly affected those with chronic diseases, impacting healthcare access and healthcare seeking behaviors. The impact of the pandemic on adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD) has not been investigated.

Methods: Participants were recruited from a cohort of 239 ADPKD patients enrolled in a longitudinal study at the University of Maryland.

Multi-omics profiling of mouse polycystic kidney disease progression at a single cell resolution.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to end-stage kidney disease. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single nucleus multimodal atlas of an orthologous mouse PKD model at early, mid and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes.

Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease.

Background & Aims: Autosomal dominant polycystic liver disease is a rare condition with a female preponderance, based mainly on pathogenic variants in 2 genes, PRKCSH and SEC63. Clinically, autosomal dominant polycystic liver disease is characterized by vast heterogeneity, ranging from asymptomatic to highly symptomatic hepatomegaly. To date, little is known about the prediction of disease progression at early stages, hindering clinical management, genetic counseling, and the design of randomized controlled trials.

Vascular Complications in Autosomal Dominant Polycystic Kidney Disease: Perspectives, Paradigms, and Current State of Play.

Autosomal dominant polycystic kidney disease (ADPKD) is the leading cause of inherited kidney disease with significant contributions to CKD and end-stage kidney disease. The underlying polycystin proteins (PC1 and PC2) have widespread tissue expression and complex functional roles making ADPKD a systemic disease. Vascular complications, particularly intracranial aneurysms (ICA) are the most feared due to their potential for devastating neurological complications and sudden death.

Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis.

Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria.

Polycystin-2-dependent transcriptome reveals early response of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in polycystin genes, and , but the underlying pathogenic mechanisms are poorly understood. To identify genes and pathways that operate downstream of polycystin-2 (PC2), a comprehensive gene expression database was created, cataloging changes in the transcriptome immediately following PC2 protein depletion. To explore cyst initiation processes, an immortalized mouse inner medullary collecting duct line was developed with the ability to knock out the gene conditionally.

Association of Longitudinal Urinary Metabolic Biomarkers With ADPKD Severity and Response to Metformin in TAME-PKD Clinical Trial Participants.

Introduction: Dysregulated cellular metabolism contributes to autosomal dominant polycystic kidney disease (ADPKD) pathogenesis. The Trial of Administration of Metformin in Polycystic Kidney Disease (TAME-PKD) tested the effects of metformin treatment over 2 years in adult ADPKD patients with mild-moderate disease severity. Metformin was found to be safe and tolerable with an insignificant trend toward reduced estimated glomerular filtration rate (eGFR) decline compared to placebo.

Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis.

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease characterized by progressive expansion of kidney cysts. To better understand the cell types and states driving ADPKD progression, we analyze eight ADPKD and five healthy human kidney samples, generating single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. Activation of proinflammatory, profibrotic signaling pathways are driven by proximal tubular cells with a failed repair transcriptomic signature, proinflammatory fibroblasts and collecting duct cells.

A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease.

Background: Tolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking.

Design and Basic Characteristics of a National Patient-Powered Registry in ADPKD.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease worldwide. Over the past five years, the therapeutic pipeline for ADPKD has expanded, leading to a growing need for patient enrollment in clinical trials and improved understanding of patient-centered outcomes that can be used in trial design. To advance these goals, the Polycystic Kidney Disease Foundation (PKDF) established a national web-based ADPKD Registry.

Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype.

Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive cyst formation/expansion, results in enlarged kidneys and often end stage kidney disease. ADPKD is genetically heterogeneous; PKD1 and PKD2 are the common loci (∼78% and ∼15% of families) and GANAB, DNAJB11, and ALG9 are minor genes. PKD is a ciliary-associated disease, a ciliopathy, and many syndromic ciliopathies have a PKD phenotype.

Polycystin-1 dependent regulation of polycystin-2 via GRP94, a member of HSP90 family that resides in the endoplasmic reticulum.

Autosomal dominant polycystic kidney disease is a common inherited renal disorder that results from mutations in either PKD1 or PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Downregulation or overexpression of PKD1 or PKD2 in mouse models results in renal cyst formation, suggesting that the quantity of PC1 and PC2 needs to be maintained within a tight functional window to prevent cystogenesis. Here we show that enhanced PC2 expression is a common feature of PKD1 mutant tissues, in part due to an increase in Pkd2 mRNA.

Association of Baseline Urinary Metabolic Biomarkers with ADPKD Severity in TAME-PKD Clinical Trial Participants.

Background: Recent work suggests that dysregulated cellular metabolism may play a key role in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). The TAME-PKD clinical trial is testing the safety, tolerability, and efficacy of metformin, a regulator of cell metabolism, in patients with ADPKD. This study investigates the cross-sectional association of urinary metabolic biomarkers with ADPKD severity among TAME-PKD trial participants at baseline.

Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD).

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by growth of kidney cysts and glomerular filtration rate (GFR) decline. Metformin was found to impact cystogenesis in preclinical models of polycystic disease, is generally considered safe and may be a promising candidate for clinical investigation in ADPKD. In this phase 2 two-year trial, we randomly assigned 97 patients, 18-60 years of age, with ADPKD and estimated GFR over 50 ml/min/1.

TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

Background: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia.

Baseline Characteristics and Patient-Reported Outcomes of ADPKD Patients in the Multicenter TAME-PKD Clinical Trial.

Background: Autosomal dominant polycystic kidney disease (ADPKD) has been associated with metabolic disturbances characterized by downregulation of AMP-activated protein kinase (AMPK), a critical sensor of the cellular energy status. Therapeutic activation of AMPK by metformin could inhibit cyst enlargement by inhibition of both the mammalian target of rapamycin pathway and fluid secretion the CFTR chloride channel.

Methods: We designed a phase-2, randomized, placebo-controlled, clinical trial to assess the safety, tolerability, and efficacy of metformin on total kidney volume in adults without diabetes (age 18-60 years) with ADPKD and eGFR of ≥50 ml/min per 1.

A genetic screen in Drosophila reveals an unexpected role for the KIP1 ubiquitination-promoting complex in male fertility.

A unifying feature of polycystin-2 channels is their localization to both primary and motile cilia/flagella. In Drosophila melanogaster, the fly polycystin-2 homologue, Amo, is an ER protein early in sperm development but the protein must ultimately cluster at the flagellar tip in mature sperm to be fully functional. Male flies lacking appropriate Amo localization are sterile due to abnormal sperm motility and failure of sperm storage.

GDNF drives rapid tubule morphogenesis in a novel 3D model for ADPKD.

Cystogenesis is a morphological consequence of numerous genetic diseases of the epithelium. In the kidney, the pathogenic mechanisms underlying the program of altered cell and tubule morphology are obscured by secondary effects of cyst expansion. Here, we developed a new 3D tubuloid system to isolate the rapid changes in protein localization and gene expression that correlate with altered cell and tubule morphology during cyst initiation.

Left ventricular hypertrophy in a contemporary cohort of autosomal dominant polycystic kidney disease patients.

Background: Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) often develop hypertension in childhood or early adulthood. Although this could result in left ventricular hypertrophy (LVH), a major risk factor for cardiovascular morbidity and mortality, prior studies of LVH in ADPKD have yielded conflicting results. We estimated the prevalence of LVH using consensus echocardiography criteria and examined the independent association of ADPKD severity with LV mass in a contemporary cohort of ADPKD patients.

Alterations of Proximal Tubular Secretion in Autosomal Dominant Polycystic Kidney Disease.

Background And Objectives: In autosomal dominant polycystic kidney disease (ADPKD), the GFR often remains normal despite significant nephron loss. Proximal tubular secretory clearance may be reduced in ADPKD before detectable changes in GFR.

Design, Setting, Participants, & Measurements: We used targeted mass spectrometry to quantify secretory solutes from blood and urine samples from 31 patients with ADPKD and preserved GFR (mean eGFR =111±11 ml/min per 1.