Citations

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.

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 Purpose: Relapse is a major cause of failure in human papillomavirus–independent head and neck squamous cell carcinoma. Clinicopathologic criteria for adjuvant treatment remain imprecise and have not changed for decades. We investigated whether ctDNA in lymphatic exudate collected via surgical drains (“lymph”) 24 hours after surgery identified molecular residual disease (MRD) and compared its performance with time-matched plasma. Experimental Design: Using an ultra-sensitive tumor-informed sequencing approach, tumor variants were called in lymph and plasma to classify patients as ctDNA positive or ctDNA negative, trained in an initial cohort of 36 patients, and replicated in an independent cohort of 37 patients. Progression-free survival was compared in ctDNA(+) versus ctDNA(–) patients. Results: Lymph identified MRD in two independent multi-site cohorts (initial cohort sensitivity = 76% and specificity = 63%; log-rank P = 0.01; replication cohort sensitivity = 65% and specificity = 70%; log-rank P = 0.04). Lymph performance was enhanced in locoregional relapse (sensitivity = 78% and specificity = 67%; log-rank P = 0.0004) and generalized to early-stage patients. Analysis of matched plasma collected at this early timepoint was not predictive of recurrence (sensitivity = 35% and specificity = 72%; log-rank P = 0.7). In patients with intermediate-risk pathology, lymph ctDNA was associated with recurrence (sensitivity = 88% and specificity = 67%; log-rank P = 0.0008), suggesting an opportunity for improved stratification of patients who may benefit from additional adjuvant treatment. Conclusions: Postoperative lymph is a novel, proximal, and early source of MRD with the potential to introduce more precision into adjuvant therapy decision-making and improve outcomes, especially for patients with intermediate-risk human papillomavirus–independent head and neck squamous cell carcinoma.

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.