Harris, Peter C.

Autosomal dominant polycystic kidney disease (ADPKD), mainly driven by pathogenic variants in PKD1 and PKD2 , is the most common inherited cause of kidney failure. Details of ADPKD pathogenesis are incompletely resolved, but primary cilia are an integral component. There is also evidence for changes to the tubular basement membrane (TBM) in early disease. In this issue of the JCI , Mazloum and colleagues link cilia-dependent, PKD1-mediated regulation of the TBM to ADPKD pathogenesis. Using in vivo, ex vivo, tubule-on-chip, and cellular models of ADPKD, they connect cilia-dependent tubule dilation and TBM thinning to early-stage cystogenesis. Moreover, they identify a cilia-dependent TBM remodeling expression signature in affected tubules and suggest that PC1 loss compromises TBM stiffness. By integrating roles for cilia at the apical membrane and extracellular matrix at the basolateral membrane in cystogenesis, this work highlights the TBM as an additional area for investigation of therapeutic and biomarker discovery in ADPKD.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder leading to kidney failure. Tolvaptan, the only FDA-approved therapy, modestly slows disease progression but is limited by significant adverse effects, highlighting the need for more effective and better-tolerated treatments. Ciliary polycystins are central to ADPKD pathogenesis. We previously demonstrated that a cilia base-localized pool of CDK6 restricts ciliary polycystin abundance by suppressing axonemal polyglutamylation. However, whether CDK6 inhibition can restore polycystin function and suppress ADPKD progression in vivo remains unknown. Methods: Abemaciclib was tested in in vitro 3D cyst assays and ex vivo metanephric organ cultures. In vivo efficacy of early- and late-stage intervention were assessed in F1(129/B6) Pkd1 R3277C/R3277C mice receiving daily abemaciclib. Tolvaptan served as a therapeutic control. Cyst burden, fibrosis in the kidneys, kidney function, and primary cilia of renal epithelial cells were analyzed at study endpoints. Results: CDK6 was prominently upregulated in cyst-lining cells in human and murine PKD kidneys. At doses substantially lower than those used in oncology, abemaciclib robustly suppressed cyst growth in vitro and ex vivo . In vivo , long-term early treatment arrested cyst progression more effectively than tolvaptan without detectable toxicity. Late intervention largely halted cyst growth in females and reversed cyst progression in males. Mechanistically, abemaciclib restored axonemal polyglutamylation and increased ciliary polycystin levels. Conclusions: Abemaciclib has greater therapeutic efficacy and tolerability than tolvaptan in this preclinical model, largely driven by CDK6 inhibition–mediated restoration of axonemal polyglutamylation and increased ciliary polycystin abundance.

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

Renal water reabsorption is classically regulated by vasopressin V2 receptor (V2R) signaling through cyclic AMP and protein kinase A, driving apical accumulation of aquaporin-2 (AQP2). However, collecting duct water handling is also modulated by vasopressin-independent mechanisms. Here, we examined intracellular soluble urate as a vasopressin-independent regulator of AQP2 trafficking. Intracellular urate accumulation in collecting duct cells was mediated by enhanced apical urate uptake via GLUT9b and reduced apical urate efflux through ABCG2, triggering phosphodiesterase-4 activation, reduced cAMP, and downstream AMP-activated protein kinase (AMPK) activation. The resulting AQP2 accumulation at the apical membrane was independent of V2R signaling, required ongoing endocytosis, and was associated with features of postendocytic apical trafficking of internalized AQP2. In vivo ABCG2 inhibition with probenecid increased apical AQP2 abundance and markedly attenuated tolvaptan-induced polyuria in both wild-type and Pkd1 RC/RC autosomal dominant polycystic kidney disease (ADPKD) mice in a uricase-independent manner while preserving tolvaptan’s ADPKD-modifying efficacy. In a phase II trial with tolvaptan-treated patients with ADPKD, probenecid reduced urine volume and nocturia frequency. Together, these findings support a vasopressin-independent urate/AMPK/AQP2 pathway that regulates renal water handling and, in a preclinical ADPKD model, can uncouple cyst growth attenuation from the dose-limiting aquaretic effects of V2R antagonism.

Key Points In an observational cohort of mostly non-Hispanic White women, pregnancy was not associated with later-life accelerated kidney function decline. Pregnancy occurring during the HALT Progression of Polycystic Kidney Disease (HALT-PKD) trial was not associated with kidney disease progression relative to women who did not become pregnant. Prior evidence indicates that adverse pregnancy outcomes may be involved in autosomal dominant polycystic kidney disease progression; pregnant women should be closely monitored. Background Data are conflicting regarding whether pregnancy influences disease progression in women with autosomal dominant polycystic kidney disease (ADPKD). This study examined whether pregnancy or number of pregnancies was associated with kidney disease progression in women with ADPKD. Methods Women with early- (study A) and late-stage (study B) ADPKD from the HALT Progression of Polycystic Kidney Disease (HALT-PKD) trial were included to examine the association between self-reported number of pregnancies (categorical predictor: no pregnancy versus 1–2 pregnancies and ≥3 pregnancies), annual slope of eGFR, annual percent change in total kidney volume (%ΔTKV), and a composite outcome (kidney failure, 50% decline in eGFR, or death) using multivariable linear regression and Cox proportional hazard models. In addition, women who became pregnant, had full-term pregnancies, and available data during study participation ( n =13) were propensity matched (1:4) to women who were not pregnant during study participation, and a mixed model was applied to determine the association of pregnancy with eGFR slope and %ΔTKV. Results Across all analyses, 455 women with a median age of 45 (interquartile range, 38–50) years and eGFR of 69±25 ml/min per 1.73 m 2 at baseline were included. One hundred ninety-nine women had 1–2 pregnancies, and 165 women had ≥3 pregnancies. There was no association of 1–2 pregnancies or ≥3 pregnancies (versus no pregnancies) with eGFR slope ( β -estimate [95% confidence interval (CI)]; 1–2 pregnancies: 0.22 [−0.44 to 0.89]; ≥3 pregnancies: −0.46 [−1.16 to 0.25]), %ΔTKV ( β -estimate [95% CI]; 1–2 pregnancies: 0.92 [−0.34 to 2.17]; ≥3 pregnancies: 0.69 [−0.67 to 2.04]), or time to composite outcome (hazard ratio [95% CI]; 1–2 pregnancies: 1.04 [0.56 to 1.93]; ≥3 pregnancies: 1.48 [0.78 to 2.77]) in adjusted models. Moreover, there was no difference in annual eGFR slope ( β -estimate: −0.14 [95% CI, −2.72 to 2.44]) and %ΔTKV ( β -estimate: 0.04 [95% CI, −3.74 to 3.82]) in women who became pregnant matched to women who did not became pregnant during their participation in the study. Conclusions Pregnancy was not associated with ADPKD progression among women with early- and late-stage ADPKD enrolled in the HALT-PKD trial.

ABSTRACT Autosomal recessive polycystic kidney disease (ARPKD) leads to severe renal cysts and progressive kidney dysfunction, with no approved treatments. The absence of such cystic phenotypes in Pkhd1 − / − mice underscores the need for novel models that better recapitulate the human disease. We developed kidney organoid‐on‐chip models that mimic patients’ distal‐nephron cysts, identifying RAC1/c‐FOS as potential therapeutic targets. However, critical questions remain regarding RAC1 activation during cyst formation, cyst origins, and underlying molecular mechanisms. Using a multifaceted approach, organoid‐on‐chip models, transgenic mice, and patient kidney samples, we identified reduced levels of SPTAN1, a cytoskeletal spectrin protein, as a key regulator of RAC1 activation and cystic pathology. SPTAN1‐mutant kidney organoids and mice exhibited distal‐nephron cysts, and elevated RAC1/c‐FOS expression, consistent with ARPKD patients. Transcriptomics and live imaging revealed altered calcium signaling and increased intracellular calcium. Single‐cell RNA‐seq identified SLC8A1, a sodium/calcium exchanger, as a marker distinguishing distal/connecting tubules from collecting ducts in human kidneys, predominantly expressed in cystic epithelia in organoids and human ARPKD kidneys. Restoring SPTAN1 in PKHD1 − / − organoids via CRISPR activation alleviated cystic phenotypes, normalized intracellular calcium, and reduced RAC1/c‐FOS expression. These findings position SPTAN1 as a central player in ARPKD pathogenesis and highlight epigenome editing as a potential therapeutic strategy.

Key Points In a cohort of children, 79% of families with kidney cysts had a monogenic diagnosis. Resolved cases were more likely to have a family history of kidney cysts and unresolved cases more often had unilateral cysts. Broad genetic testing revealed genetic diversity and informed prognosis and clinical management in childhood kidney cysts. Background Pediatric kidney cysts may indicate an underlying genetic disorder, yet the full spectrum of causes remains incompletely defined. With advances in genetic testing enabling broader evaluation, this study assessed the diagnostic utility of comprehensive genetic testing in a broad pediatric cohort with kidney cysts and characterized the underlying etiological diversity. Methods This observational cohort study included patients younger than 18 years enrolled between January 2020 and June 2024 at a single tertiary center. Genetic testing used targeted multigene or custom curated exome/genome sequencing panels, with segregation analysis when available. Eligible participants had at least two cysts without family history, one cyst with positive family history, or enlarged echogenic kidneys on prenatal ultrasound; those with congenital anomalies of the kidney and urinary tract associated with cysts were excluded. Clinical presentation was categorized as symptomatic, incidental, prenatal, or family screening. Primary outcomes were diagnostic yield and distribution of pathogenic variants. Results Among 109 patients (median age 7.6 years, 53% female), genetic testing identified a definitive diagnosis in 81 of 100 tested patients (81%) from 72 families (79%; 14 disorders). PKD1 variants were most common (45%), while PKD2 accounted for 7%. Other causes included HNF1B or 17q12 deletions (13%), minor autosomal dominant polycystic kidney disease genes (11%; GANAB, NEK8, IFT140 ), monoallelic PKHD1 (3%), and biallelic PKHD1 (8%), while syndromic ciliopathy genes accounted for 5%. A positive family history of cystic kidney disease was more common among patients with a genetic diagnosis (54% versus 11%; P = 0.008). Patients without an identified genetic diagnosis more often had unilateral cysts (26% versus 4%; P = 0.53). Diagnosis by clinical symptoms was the most genetically diverse category. Conclusions Comprehensive genetic testing in pediatric kidney cysts achieved high diagnostic yield in a selected cohort and identified diverse causes beyond major autosomal dominant polycystic kidney disease/autosomal recessive polycystic kidney disease genes, supporting early evaluation to improve diagnostic accuracy, inform prognosis, and guide management, even in the absence of family history.

Key Points In autosomal dominant polycystic kidney disease, there is a linear relationship between the log-transformed total kidney volume and eGFR. There is a predictable change in the rate of eGFR decline with reduction in kidney growth rate. This framework can be used to determine treatment effect to support accelerated approval of drugs for polycystic kidney disease. Background Total kidney volume (TKV) is accepted by the US Food and Drug Administration as a surrogate end point that is reasonably likely to predict clinical benefit in autosomal dominant polycystic kidney disease and the most commonly used response biomarker for proof-of-concept intervention trials. However, the magnitude of treatment effect on TKV that would be predictive of a meaningful improvement in a clinical outcome, such as eGFR, is unknown. Inference of this from observational studies has previously been approached by examining interindividual variance in the relationship between TKV and GFR slopes over time. Methods We developed a novel approach to modeling the intraindividual relationship between TKV and eGFR. Patients from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease and Halt Progression of Polycystic Kidney Disease Study A dataset were stratified by Mayo Imaging Class (MIC). Linear mixed models were fitted to eGFR with a fixed effect of log(TKV) and random intercepts, and the average slope within each MIC was estimated. Results We found that within each MIC, there is a consistent, linear relationship between log(TKV) and eGFR. The model predicts that within classes 1C–1E, for each 1% point per year reduction in TKV growth rate, the rate of eGFR decline would be reduced by 0.40–0.52 ml/min per 1.73 m 2 per year. Conclusions We have developed a new model that provides a framework for defining the magnitude of treatment effect on TKV that would support accelerated approval of a drug for autosomal dominant polycystic kidney disease. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2026_05_18_CJASNMay.21.5.51820.mp3

Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited disorder characterized by the progressive enlargement of fluid-filled cysts in the kidneys and liver. Since the cystic fibrosis transmembrane conductance regulator (CFTR) Cl– channel may mediate the secretion of Cl– and fluid into the cysts, it is conceivable that coexisting cystic fibrosis (CF) in patients with ADPKD could attenuate their development. We previously reported that two patients with ADPKD coexisting with cystic fibrosis (CF) had a milder cystic phenotype than that of kindred without CFTR mutations. A subsequent report failed to confirm this protective effect. We now have identified another family with coexisting type 1 ADPKD and CF. The kidney volumes and the number and size of renal and hepatic cysts were markedly less in a member of this family with ADPKD (PKD1 mutation C508R) and CF (homozygous ΔF508 mutation) than in her sister with ADPKD alone at comparable ages.

Key Points Data were collected from a cohort of 759 patients with autosomal dominant polycystic kidney disease that were followed for a median of 10.2 years. Prognostic models were developed to predict kidney failure using routinely obtained clinical information and externally validated. Risk predictions had good discrimination and calibration over a time horizon of 15 years. Background Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of kidney failure. Progression is highly variable, and accurate prognostic information is needed to guide early treatment decisions. The objective of this study was to develop a multivariable predictive model for progression to kidney failure. Methods We developed prognostic models using Cox regression for the outcome of kidney failure, defined as eGFR <15 ml/min per 1.73 m 2 , dialysis, or kidney transplantation. The development dataset consisted of participants in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) and Halt Progression of Polycystic Kidney Disease study A (HALT-A) studies. The validation dataset consisted of patients with ADPKD in the Mayo clinical registry aged 15–49 years, with eGFR ≥60 ml/min per 1.73 m 2 . Predictor variables in the base model were age, sex, creatinine or eGFR, ADPKD genotype, and Mayo Imaging Class. Clinical and laboratory data were evaluated in the full model. Results The development cohort included 759 patients with baseline eGFR of 91±29 ml/min per 1.73 m 2 (mean±SD), of whom 16% reached end point after median (interquartile range) follow-up of 10.2 (5.5–16.7) years. The validation cohort included 535 patients with baseline eGFR of 90±31 ml/min per 1.73 m 2 (mean±SD), of whom 11% reached end point after median (interquartile range) follow-up of 5.5 (1.5–13.7) years. The full model, including age, sex, serum creatinine, Mayo Imaging Class, total carbon dioxide, hemoglobin, diastolic BP, and body mass index, had a C-index of 0.81 (95% confidence interval, 0.72 to 0.90) in the validation cohort and 0.75 (95% confidence interval, 0.62 to 0.88) when ADPKD genotype was also included. Risk predictions from base and full models were well-calibrated out to 15 years. Conclusions In persons with early ADPKD and preserved eGFR, a model using routinely obtained clinical information quantified risk of kidney failure over 15 years.