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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. We identify GPRC5A as a marker for cyst-lining collecting duct cells that exhibits increased transcription factor binding motif availability for NF-κB, TEAD, CREB and retinoic acid receptors. We identify and validate a distal enhancer regulating GPRC5A expression containing these motifs. This single cell multiomic analysis of human ADPKD reveals previously unrecognized cellular heterogeneity and provides a foundation to develop better diagnostic and therapeutic approaches. Autosomal dominant polycystic kidney disease (ADPKD) is a complicated disease that involves numerous cell types. Here the authors used a multiomics approach consisting of single nucleus transcriptomes and epigenomes to redefine cell states in ADPKD and to dissect the cellular interactions and molecular mechanisms of ADPKD.

Key Points Intracranial aneurysms (IAs) are the most common vascular manifestation of autosomal dominant polycystic kidney disease (ADPKD) Individuals with ADPKD and increased risk of IA—including those with a family or personal history of IA or subarachnoid haemorrhage—should undergo screening Other vascular abnormalities in ADPKD include aneurysms and dissections of the thoracic aorta, coronary arteries and cervicocephalic arteries, aortic root dilatation and cerebral dolichoectasia; screening is not usually indicated Asymptomatic IAs detected by screening are frequently small and have a low risk of rupture Intervention, either surgical or endovascular, is indicated based on the size and location of the aneurysm The relationship between PKD1 and PKD2 mutations and the development of vascular abnormalities is undefined; modifier genes that increase TGF-β signalling might increase the risk of vascular complications in ADPKD Vascular abnormalities, particularly those associated with rupture of intracranial aneurysms (IAs) or arterial dissections are among the most serious complications of autosomal dominant polycystic kidney disease (ADPKD). In this article, the authors discuss the pathophysiological mechanisms that might be involved in the development of vascular complications in patients with ADPKD and review strategies for screening, diagnosis and treatment of IAs in this population. Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Relentless cyst growth substantially enlarges both kidneys and culminates in renal failure. Patients with ADPKD also have vascular abnormalities; intracranial aneurysms (IAs) are found in ∼10% of asymptomatic patients during screening and in up to 25% of those with a family history of IA or subarachnoid haemorrhage. As the genes responsible for ADPKD— PKD1 and PKD2 —have complex integrative roles in mechanotransduction and intracellular calcium signalling, the molecular basis of IA formation might involve focal haemodynamic conditions exacerbated by hypertension and altered flow sensing. IA rupture results in substantial mortality, morbidity and poor long-term outcomes. In this Review, we focus mainly on strategies for screening, diagnosis and treatment of IAs in patients with ADPKD. Other vascular aneurysms and anomalies—including aneurysms of the aorta and coronary arteries, cervicocephalic and thoracic aortic dissections, aortic root dilatation and cerebral dolichoectasia—are less common in this population, and the available data are insufficient to recommend screening strategies. Treatment decisions should be made with expert consultation and be based on a risk–benefit analysis that takes into account aneurysm location and morphology as well as patient age and comorbidities.

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.

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. Patients on renal replacement therapy were excluded. N  = 66 patients participated in a phone questionnaire from June 2022-December 2022 about ADPKD-related complications, concern about contracting Covid-19, healthcare-seeking behaviors, and telehealth utilization before and after March 2020. Results N  = 34 (51.5%) of participants reported a positive Covid-19 test result. N  = 29 (44%) expressed high concern of contracting Covid-19. Those who avoided medical care at least once ( N  = 17, 25.8%) had similar demographics and ADPKD severity to those who did not, but reported greater telehealth utilization (88.2% vs. 42.9%, p  = 0.002), greater use of non-prescribed medication for Covid-19 treatment or prevention (35.3% vs. 8.2%, p  = 0.01), and were more likely to contract Covid-19 (76.5% vs. 42.9%, p  = 0.02). Among the N  = 53 who reported very good or excellent ADPKD disease management pre-pandemic, N  = 47(89%) reported no significant change during the pandemic. Conclusions In this highly educated, high-income cohort with a mean age of 46.1 years, most people reported well-managed ADPKD prior to the pandemic. This may explain why less than half of participants expressed high concern for contracting Covid-19. Overall, there was no significant pandemic-related decline in self-reported ADPKD management. This was likely due to this cohort’s excellent access to, and uptake of, telehealth services. Notably, 1 in 4 participants reported healthcare avoidant behavior, the effect of which may only be seen years from now. Future studies should investigate potential impacts of avoidant behaviors, as well as expand investigation to a more diverse cohort whose care may not have been as easily transitioned to telehealth.

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 15 , contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1 V/V in which cleavage of Pkd1 -encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD 15 enhances renal cystogenesis without inducing pancreatic cysts in Pkd1 V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD 15 cleavage, crucial for cystogenesis mechanisms. Fibrocystin/Polyductin (FPC) is a large ciliary membrane protein encoded by PKHD1 which, when mutated, causes ARPKD. Here, the authors show that FPC suppresses cyst development in the kidney of mouse models through the release and mitochondrial translocation of its C terminal product.

Primary cilia contain specific receptors and channel proteins that sense the extracellular milieu. Defective ciliary function causes ciliopathies such as autosomal dominant polycystic kidney disease (ADPKD). However, little is known about how large ciliary transmembrane proteins traffic to the cilia. Polycystin-1 (PC1) and -2 (PC2), the two ADPKD gene products, are large transmembrane proteins that co-localize to cilia where they act to control proper tubular diameter. Here we describe that PC1 and PC2 must interact and form a complex to reach the trans -Golgi network (TGN) for subsequent ciliary targeting. PC1 must also be proteolytically cleaved at a GPS site for this to occur. Using yeast two-hybrid screening coupled with a candidate approach, we identify a Rabep1/GGA1/Arl3-dependent ciliary targeting mechanism, whereby Rabep1 couples the polycystin complex to a GGA1/Arl3-based ciliary trafficking module at the TGN. This study provides novel insights into the ciliary trafficking mechanism of membrane proteins. Polycystins (PC) 1 and 2 are large transmembrane proteins that play a vital role in the function of primary cilia. Here, Kim et al. identify the requirements for polycystin trafficking to the cilium, involving a PC1–PC2 interaction, PC1 proteolytic cleavage and a specific trafficking module at the trans -Golgi network.

MiT/TFE gene fusions like SFPQ-TFE3 drive both epithelial (translocation RCC) and mesenchymal (PEComas) neoplasms. However, no mouse models for SFPQ-TFE3 -related tumors exist and the underlying mechanisms of lineage plasticity remain unclear. Here, we demonstrate that constitutive murine renal expression of SFPQ-TFE3 disrupts kidney development with early neonatal renal failure and death, while post-natal induction induces infiltrative epithelioid tumors, that morphologically and transcriptionally resemble human PEComas, with strong activation of mTORC1 signaling via increased V-ATPase expression. Remarkably, SFPQ-TFE3 expression is sufficient to induce lineage plasticity, with down-regulation of the PAX2/PAX8 nephric lineage factors and tubular epithelial markers, and up-regulation of PEComa differentiation markers in transgenic mice, cell lines and human tRCC. mTOR inhibition downregulates SFPQ-TFE3 expression and rescues PAX8 expression and transcriptional activity in vitro. These data provide evidence of an epithelial cell-of-origin for TFE3 -driven PEComas, highlighting a reciprocal role for SFPQ-TFE3 and mTOR in driving lineage plasticity in the kidney. TFE3-fusions are known to drive both epithelial and mesenchymal renal tumors. Here, the authors generate a transgenic mouse model of renal tumorigenesis expressing the human SFPQ-TFE3 fusion, showing that the fusion regulates mTORC1 activity and induces lineage plasticity.

Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of inherited renal failure 1 that is characterized by the progressive formation of renal cysts, which leads to end-stage renal disease in mid-adulthood. Furthermore, massive renal enlargement has a number of untoward consequences, including chronic pain, hypertension, and cyst infections. Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene that encodes a large membrane receptor. The remaining 15% of cases result from mutations in the PKD2 gene, a calcium-permeable channel that binds to PKD1. The accelerated pace of scientific discovery in the field has led to an . . .

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of kidney cysts leading to kidney failure in adulthood. Inhibition of mammalian target of rapamycin (mTOR) slows polycystic kidney disease (PKD) progression in animal models, but randomized controlled trials failed to prove efficacy of mTOR inhibitor treatment. Here, we demonstrate that treatment with mTOR inhibitors result in the removal of negative feedback loops and up-regulates pro-proliferative phosphatidylinositol 3-kinase (PI3K)-Akt and PI3K-extracellular signal-regulated kinase (ERK) signaling in rat and mouse PKD models. Dual mTOR/PI3K inhibition with NVP-BEZ235 abrogated these pro-proliferative signals and normalized kidney morphology and function by blocking proliferation and fibrosis. Our findings suggest that multi-target PI3K/mTOR inhibition may represent a potential treatment for ADPKD.

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. Methods A model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death. Results When treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively. Conclusions The model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression.