Torres, Vicente

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 Background and Aims ADPKD is a progressive inherited disease that causes end-stage renal disease (ESRD) in ∼50% of the affected individuals by 60 years of age. TOL, a selective vasopressin V2-receptor antagonist, has been shown in randomized, placebo-controlled trials to slow the progression of renal function decline in ADPKD subjects with an eGFR of 25 mL/min/1.73m2 or higher. The efficacy and safety of TOL in subjects with lower eGFR remain understudied. This post-hoc analysis evaluated the efficacy and safety of TOL in subjects with stage 4 ADPKD (eGFR of <30 mL/min/1.73m2). Method This is a retrospective analysis of a subgroup of ADPKD subjects who enrolled in the TOL long-term open-label extension (OLE) trial (NCT02251275). Included subjects had a baseline eGFR of <30 mL/min/1.73m2, received ≥ 1 TOL dose, and were randomized to the placebo group in the REPRISE trial (NCT02160145). Two subgroups of subjects were analyzed, one with baseline eGFR of 25-30 (Subgroup 1) and one with <25 (Subgroup 2). The variables evaluated included: 1) demographics, 2) adverse event (AE) profile, 3) intra-subject comparison of change in annualized eGFR decline during the open-label study (treatment period) to that during placebo use in the REPRISE trial (control period). Annualized eGFR change slopes in the treatment period were calculated using eGFR values between Month 1 and 12 visits to compensate for the acute hemodynamic effect of tolvaptan. Comparison was made by linear mixed model. Results Of the 1,803 subjects enrolled, 159 (8.8%) subjects (76 in Subgroup 1 and 83 in Subgroup 2) met the selection criteria for analysis. Annualized eGFR change slopes for all subjects (n=148) were -5.28 (SE 0.27) in the control period and -3.16 (SE 0.30) in the treatment period with a treatment effect of 2.11 mL/min/1.73m2/year (95% CI 1.56, 2.66), p<0.0001). Demographic information, baseline eGFR, treatment duration and effects in the 2 subgroups are shown in the Table below. Treatment-emergent AEs were observed in 95% and 90% of the subjects in the 2 subgroups, respectively. Discontinuation due to AEs occurred in 15% and 17% of the 2 subgroups, respectively. The 5 most common AEs for all subjects were thirst (32%), polyuria (30%), renal pain (25%), blood creatinine increase (23%) and nocturia (22%); the rates were similar between the 2 subgroups. One incidence of hepatic enzyme increase, hemodialysis and death (unrelated to TOL) was observed in Subgroup 2, but not in Subgroup 1. Conclusion This post-hoc analysis demonstrated that TOL significantly decreases the rate of eGFR decline in ADPKD subjects with stage 4 CKD, including those with an eGFR of <25 mL/min/1.73m2.