Harris, Peter C

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.

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.

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

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.

Autosomal dominant polycystic kidney disease is the most common inherited kidney disorder and a leading monogenic cause of kidney failure. Reduction or loss of polycystin-1 and polycystin-2 function disrupts ciliary calcium signaling, elevates cyclic AMP (cAMP), reprograms cellular metabolism, and activates proliferative cascades that drive cyst expansion. Tolvaptan, a vasopressin V2 receptor antagonist, established cAMP modulation as a disease-modifying strategy but is limited by aquaretic effects and hepatotoxicity risk. This review highlights emerging therapeutic strategies in clinical trial development that extend beyond vasopressin antagonism. Gene-directed therapies aim to restore polycystin dosage, including anti–miR-17 oligonucleotides ( e.g ., farabursen) and pharmacochaperones that rescue misfolded polycystin-1 and restore trafficking in select PKD1 missense variants ( e.g ., VX-407). Paracrine signaling can be modulated with anti–pregnancy-associated plasma protein A antibodies that reduce insulin-like growth factor-1 bioavailability in cystic microenvironments. Metabolic reprogramming is targeted by agents such as metformin, bempedoic acid, glucagon-like peptide-1 receptor agonists, and structured dietary interventions. Sodium-glucose cotransporter 2 inhibitors hold theoretical promise but await definitive results from ongoing trials. A novel cAMP-lowering strategy through phosphodiesterase-4 activation is advancing toward clinical testing. Looking ahead, gene therapy, and genome editing offer the potential to raise polycystin levels above the threshold for cystogenesis, although challenges in vector capacity, kidney-specific delivery, and durability remain. Artificial intelligence–guided discovery, coupled with human organoid platforms, is accelerating therapeutic repurposing and rational combination design. Collectively, these advances signal a transition toward a layered, mechanism-guided framework in which vasopressin blockade is integrated with metabolic, other signaling, and genotype-specific therapies. As biomarkers and risk stratification tools mature, autosomal dominant polycystic kidney disease management is poised to become increasingly precise, tolerable, and effective.

Key Points Inositol polyphosphate-5-phosphatase E (INPP5E) and type Ig phosphatidylinositol-4-phosphate 5-kinase (PIPKIγ) coordinated the homeostasis of phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate in primary cilia. Modulating INPP5E or PIPKIγ activity changed the level of polycystin-1 and polycystin-2 in primary cilia. INPP5E inhibition increased the hypomorphic PKD1 variants (PC1-R3277C) in cilia and reduced cystogenesis in the kidney in vitro . Background Autosomal dominant polycystic kidney disease is mainly caused by mutations in PKD1 and PKD2 , which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 assemble a cation channel complex enriched in primary cilium, a sensory organelle associated with various developmental diseases, including polycystic kidney disease (PKD). Accumulating evidence supports the necessity of functional polycystin (PC) complex in cilia to prevent cystogenesis in the kidney, indicating that improving their ciliary levels may ameliorate defects underlying PKD pathogenesis. Yet, molecular mechanisms underlying the ciliary targeting and homeostasis of the PC complex are not fully understood. Methods Indirect immunofluorescence microscopy was used to monitor ciliary levels of PC1 and PC2 in renal epithelial cells. Electrophysiology analysis in oocytes was used to determine the channel activity of the PC complex. Cystogenesis in the kidney was measured using in vitro 3D-Matrigel cell models and ex vivo mouse embryonic kidney models. Results Suppressing inositol polyphosphate-5-phosphatase E (INPP5E) or activating type Ig phosphatidylinositol-4-phosphate 5-kinase raised ciliary levels of the PC complex in both normal renal epithelial cells and cells carrying autosomal dominant polycystic kidney disease mutations that interrupt the trafficking of PCs into cilia, including GANAB inactivation and the trafficking PKD1 mutation p.Arg3277Cys (RC). PC1 RC formed a complex with PC2 and exhibited normal channel activity in vitro . An INPP5E that increases PC1 and PC2 in cilia, suppressed in vitro forskolin-induced cystogenesis of inner medullary collecting duct epithelial cell line 3 cells in 3D Matrigel and ex vivo cyst formation in embryonic Pkd1 RC/RC mouse kidneys. Conclusions Our results demonstrated that increasing the ciliary level of PCs, by manipulating a ciliary phosphoinositide signaling axis, enhanced the functionality of PCs and suppressed cystogenesis of renal epithelial cells in vitro .

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that is caused by mutations in PKD genes. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (GLP‐1RAs) are a class of medications that mimic the actions of the hormone GLP‐1, conferring beneficial effects on weight management and other metabolic conditions. However, whether GLP‐1RA plays a kidney‐protective action in ADPKD remains unknown. In this study, we define the role and mechanisms of one of the most popular GLP‐1RA agonists, Semaglutide, in ADPKD. We show that the expression of GLP‐1R is decreased in Pkd1 mutant renal epithelial cells and kidneys. Treatment with Semaglutide delays cyst growth in aggressive and long‐lasting Pkd1 mutant mouse models. Treatment with Semaglutide (1) decreases glucose uptake, ATP generation, and glycolysis, (2) deactivates PKD‐associated signaling pathways, including Rb, S6, and Stat3, resulting in a decrease in cell proliferation, (3) deactivates NF‐kB signaling pathways, resulting in a decrease in the expression of cytokines and the recruitment of macrophages, (4) normalizes mitochondrial morphology and function, (5) induces Pkd1 mutant renal epithelial cell death, (6) induces ketosis characterized by an increase in serum level of beta‐hydroxybutyrate (BHB) and the activation of AMPK, and (7) alleviates renal fibrosis through deactivation of TGF‐b signaling in Pkd1 mutant mouse kidneys. This study highlights the potential of GLP‐1R agonists as a novel therapeutic strategy for ADPKD treatment.

Key Points Automated cyst segmentation in autosomal dominant polycystic kidney disease could transform care by enabling precise monitoring of cyst progression with minimal manual effort. This technology can facilitate more consistent assessments of cyst burden across patients. Translating these segmentation models from magnetic resonance imaging to computed tomography is crucial for providing comprehensive, modality-independent evaluations. Background Total kidney and liver volumes are key image-based biomarkers to predict the severity of kidney and liver phenotype in autosomal dominant polycystic kidney disease (ADPKD). However, magnetic resonance (MR) imaging-based advanced biomarkers like total cyst number and cyst parenchyma surface area have been shown to more accurately assess cyst burden and improve the prediction of disease progression. The main aim of this study was to extend the calculation of advanced biomarkers to other imaging modalities; thus, we propose a fully automated model to segment kidney and liver cysts in computed tomography (CT) images. Methods Abdominal CTs of patients with ADPKD were gathered retrospectively between 2001 and 2018. A three-dimensional deep learning method using the nnU-Net architecture was trained to learn cyst edges-cores and the noncystic kidney/liver parenchyma. Separate segmentation models were trained for kidney cysts in contrast-enhanced CTs and liver cysts in noncontrast CTs using an active learning approach. Two experienced research fellows manually generated the reference standard segmentation, which were reviewed by an expert radiologist for accuracy. Results Two-hundred CT scans from 148 patients (mean age, 51.2±14.1 years; 48% male) were used for model training (80%) and testing (20%). In the test set, both models showed good agreement with the reference standard segmentations, similar to the agreement between two independent human readers (model versus reader: TCN kidney/liver r =0.96/0.97 and CPSA kidney r =0.98, inter-reader: TCN kidney/liver r =0.96/0.98 and CPSA kidney r =0.99). Conclusions Our study demonstrates that automated models can segment kidney and liver cysts accurately in CT scans of patients with ADPKD.

Key Points Genetic testing of individuals suspected of monogenic urinary stone disease resolved 34% of families with 22 different genes detected. Resolved individuals had a lower baseline and last visit eGFR and earlier age of stone presentation than the unresolved group. Specific phenotypes and younger diagnostic age were associated with a monogenic cause, allowing refinement of future screenings. Background Urinary stone disease with a clear genetic cause, monogenic stone disease (MSD), is increasingly recognized as a significant proportion of the total population. When MSD is suspected, genetic testing provides a firm diagnosis that can alter management and treatment. Here, we present testing results from a large cohort with suspected MSD. Methods Patients with features suggestive of MSD (early onset, family history, frequent stones, nephrocalcinosis [NC], and/or CKD) were recruited by the Rare Kidney Stone Consortium and genotyped for up to 160 known or candidate MSD genes via a targeted massively parallel sequencing panel. We compared clinical and biochemical features between genetically resolved MSD and unresolved individuals. Results Of 426 families (657 patients) enrolled, 145 (34%) were resolved with identified disease associated variants in 22 known MSD genes. Ninety-nine families were biallelic, 37 monoallelic, and two digenic. An additional 21 of the 231 screened family members were resolved. Genes identified in ten or more families include the following: AGXT , HOGA1 , SLC34A3 , CYP24A1 , SLC3A1 , and CLCN5 . Compared with the unresolved group, MSD probands had a lower baseline and last visit eGFR, earlier age of stone presentation, and more stone events and procedures/year of life. The resolve rate was higher in those <16 years, and NC was seen earlier in the MSD group. Overall, NC was a risk factor for lower eGFR. Among the specific disorders, patients with primary hyperoxaluria had the earliest age of stone and NC diagnosis, and as expected, the highest urinary oxalate level. Conclusions Our study emphasizes the value of selecting patients enriched for factors associated with MSD, and comprehensive genetic testing to achieve a high yield of genetic diagnoses. Significant clinical and biochemical characteristics of patients with MSD were defined. A definitive MSD diagnosis facilitates individualized management and strategies to delay disease progression in probands and affected family members.