CAKUT subtypes determine the rate of progression to kidney failure - an adult patient cohort study.

Background And Hypothesis: Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are the leading cause of pediatric kidney failure (KF) and a significant contributor to KF in adults. Progression to KF varies widely. Early renal risk stratification is challenging, due to a lack of data on long-term kidney outcomes during adulthood. This multicenter study, therefore, aims to correlate progression to KF with CAKUT phenotypes, including the extent of extrarenal involvement and genetic findings.

Methods: Observational, retrospective cohort study. 229 adult CAKUT patients with KF either before or after the age of 18 were recruited at two tertiary care centers. Genetic testing was performed in 117 patients.

Results: Genetic testing identified pathogenic variants in 14 patients (12.0%), spanning 10 genes. Extrarenal manifestations were more common in genetically resolved cases (9/14, 64.3%), primarily affecting the genital (3/14, 21.4%) and gastrointestinal systems (5/14, 35.7%). Syndromic patients experienced significantly earlier KF-onset (median age: 22.0 years [14.0; 31.0]; n = 81) compared to those with isolated CAKUT (28.0 years [21.0-38.0]; n = 145). Among CAKUT subtypes, multicystic dysplastic kidneys presented with the fastest rate of progression to KF (median age at KF-onset 18.0 years [5.0; 23.0]; n = 9), whereas horseshoe or ectopic kidneys showed more attenuated outcomes (55.5 years [47.3-62.5]; n = 4). Bilateral kidney and urinary tract involvement was associated with a significantly worse prognosis (median age at KF-onset 22.0 years [15.5-30.0]; n = 143) compared to unilateral involvement (37.0 years [28.0-47.0]; n = 71).

Conclusion: CAKUT is genetically heterogeneous, and the majority of cases remain genetically unresolved. Among patients on kidney replacement therapy, the rate of progression to KF is influenced by extrarenal presentation, bilateral kidney and urinary tract involvement, as well as CAKUT subtypes. Comprehensive interdisciplinary phenotypic characterization is essential and also contributes to a more accurate determination of kidney prognosis.