Harris, Peter C.

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 Background and Aims Patients with ADPKD exhibit an increased prevalence of kidney stones with a significant overrepresentation of uric acid (UA) stones which has led to the previous suggestion that UA may be associated with disease progression in ADPKD. However, available results are controversial and the exact mechanism remains unknown. Since we have previously reported that calcium-based microcrystals worsen ADPKD disease progression we hypothesized that renal UA crystallization could affect PKD disease progression and aimed to investigate this in animal models of PKD and the AD(H)PKD registry at the University Hospital Cologne. Method WT and Pkd1+/− rats were supplemented with UA and the uricase inhibitor oxonic acid from 8 to 10 weeks of age to induce moderate hyperuricemia causing renal UA crystal deposition. This was followed by washout from 10 to 18 weeks to analyze crystal clearance. For additional treatment with the ketone beta-hydroxybutyrate (BHB) and alkaline Citrate, adult rats received a solution containing 2.1% BHB and 13.75 mM tripotassium citrate/16.75 mM citric acid in the drinking water from 14 to 18 weeks of age. Human data including eGFR, UA levels in serum, spot urine and 24-hour urine and urine pH were used from the AD(H)PKD study (Clinical Trials ID: NCT02497521) and analyzed using multivariable linear models. Results UA crystal deposition in Pkd1+/− rats led to significantly increased kidney growth, tubule dilation and UA crystal burden compared to UA-treated WT controls. Dilated tubules exhibited strong TLR-4 expression, NLRP3 activation, recruitment of peritubular macrophages and intraluminal neutrophils undergoing NETosis. Strikingly—although untreated heterozygous Pkd1+/− rats fail to develop a polycystic phenotype—UA-treated Pkd1+/− rats developed polycystic kidney disease after 8 weeks washout period with persistent activation of TLR4, NLRP3, pericystic macrophages and intracystic neutrophils. UA-treated WT rats displayed a normalization of renal tubules. Previously, we demonstrated that treatment with BHB and Citrate can ameliorate PKD disease progression. BHB has been reported to inhibit TLR4-NLRP3 signaling and citrate can prevent UA deposition due to urine alkalinization. Therefore, we induced UA crystal deposition in Pkd1+/− followed by 4 weeks of normal diet to allow crystal clearance, followed by treatment with BHB/Citrate in the drinking water. Remarkably, BHB/Citrate potently inhibited the progression to PKD in Pkd1+/− rats by ameliorating cyst growth, TLR4-NLRP3 activation, and macrophage and neutrophil recruitment. Translational analysis of UA stone forming parameters in the AD(H)PKD patient registry showed a correlation of serum and urine UA concentration with eGFR slope. However, significance of this association was lost after adjusting for eGFR, age and sex. In contrast, analysis of the Marshal lithogenic risk score which combines urine UA with urine pH to predict the risk for UA crystal/stone formation showed a significant and independent impact on eGFR slope. Conclusion Our results suggest that UA exposure is a sufficient environmental hit to induce cystogenesis in a heterozygous Pkd1 rat model. A heterozygous Pkd1 gene mutation as observed in ADPKD patients creates a hyperresponsive renal phenotype upon UA crystal formation leading to exaggerated tubule dilation, persistent inflammation, fibrosis and progression to PKD. Treatment with BHB/Citrate significantly reduces TLR4-NLRP3 activation and macrophage/ neutrophil recruitment leading to a significant amelioration of UA-induced cystogenesis. We conclude that UA crystal deposition could accelerate PKD disease progression by NLRP3-mediated and macrophage/neutrophil-based hyperinflammation. BHB/Citrate could not only prevent UA crystallization but ameliorate UA-associated kidney injury and ADPKD disease progression. Finally, the translational analysis in the AD(H)PKD patient registry suggest that, although not showing serum uric acid as independent risk factor, the lithogenic risk- largely driven by the combination of urine uric acid and urine pH- could be a driver of PKD disease progression.

Abstract Background and Aims PKD1 and PKD2 are the two major genes in autosomal dominant polycystic kidney disease (ADPKD). Up to 15% of patients with ADPKD-like phenotype are genetically unresolved (GUR) or carry variants in minor cystogenes including IFT140. Here, we describe features of an ADPKD-like phenotype linked to monoallelic predicted loss-of-function (pLoF) variants in a new candidate cystogene, IFT172. The IFT172 protein is part of the IFT-B subcomplex and plays a role in protein trafficking within primary cilia. Biallelic variants in IFT172 cause a severe ciliopathy. Method A total of ∼3200 unrelated individuals with cystic kidney disease (CyKD) underwent genetic testing employing whole-exome sequencing (WES) or massive-parallel-sequencing (MPS) gene panels in Brest, Lyon and in Rochester, MN. In addition, 185 individuals ICD coded as CyKD from Mayo Clinic Biobank (MCBB) underwent WES. Clinical and genetic data of individuals with predicted loss-of-function variants of IFT172 were collected and analyzed. Also, the Genomics England 100kG Project cohort was screened for pLoF variants in IFT172. Results In the CyKD population, 18 patients with a monoallelic pLoF variant in IFT172 were identified. In the MCBB CyKD cohort, 3 individuals had IFT172 pLoF variants. We describe the clinical presentation of these 21 affected individuals (15 males). Median age at CyKD diagnosis was 67 (range 34–88) years. Family history for CyKD was positive in 10 (48%), negative in 9 (42%) and not known in 2 (10%) individuals. Arterial hypertension was present in 9 (45%) patients, in three of them diagnosed before age of 50 years and in 6 at a later age. Hypertension status was not known in 10 of them. A majority of the patients presented with multiple bilateral cortical kidney cysts with moderate kidney enlargement or normal-sized kidneys with large, exophytic kidney cysts and were classified as Mayo Imaging Class 2A. In one patient, unilateral CyKD was present with >10 cysts. Liver cysts were present in 4 (19%) and gout in three (15%) patients. None of the three patients who underwent screening were found to have intracranial aneurysm. Median eGFR at diagnosis (N = 19) was 53 (range 29–119) ml/min/1.73 m2. Of 15 patients older than 60 y, one had CKD stage G1, 5 stage G2, 3 stage G3a, 5 stage G3b and one G4. Only one patient of African descent (APOL1 G1/G0) reached kidney failure at age of 43 y, likely due to additional contribution of uncontrolled hypertension and poorly controlled diabetes. In addition, in two patients, the IFT172 pLoF variant was identified alongside a pathogenic variant in PKD1 (p.Gln2519*) or PKD2 (c.844-1G>T). Both progressed to kidney failure at an earlier age than typically observed with PKD1 or PKD2 alone, at 29 and 52 years, respectively. Familial segregation is ongoing. Of the total of 94,799 patients recruited in “rare disease program” within 100kG Project, 51 carried monoallelic pLoF variants in IFT172 (genetic prevalence: 5.38 [0.95 CI 3.9–6.86] per 10,000). Four of them (7.8%) had CyKD. Conclusion Carriers of monoallelic pLoF variants in IFT172 are likely to develop cystic kidney disease (CyKD) that is atypical of classical ADPKD, generally associated with a favorable kidney prognosis. Nonetheless, individuals over the age of 60 may have an increased risk of progressing to CKD stage G3 or worse. Disease penetrance in IFT172 pLoF variant carriers appears to be incomplete, similar to what is observed in IFT140.

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.