Challenging the narrative of Alport syndrome spectrum: no link with cystic phenotype

ABSTRACT Background Alport syndromes (AS) are the second leading genetic cause of kidney failure. Whether the multiple kidney cysts (MKC) phenotype belongs to the AS spectrum remains debated. Methods This multicenter retrospective study focused on patients genotyped with pathogenic COL4A3, COL4A4, or COL4A5 variants (classified as ACMG-AMP 4 or 5) between January 2011 and January 2023 across four French university hospitals. The study aimed to compare characteristics between two groups based on the presence or absence of MKC, defined by three or more cysts per kidney. The MKC group was compared to a control group with negative exome sequencing results for undetermined kidney disease (ES-UKD) to assess the association between MKC and AS. Results Among the 257 AS patients included, 38 (14.8%) presented MKC without variation from hereditary cystic kidney panel. MKC showed a significant association with male gender (P = 0.004), cardiovascular risk factors, and loss of function variants (P = 0.012). Kidney failure onset appeared significantly later, by 6 years, in MKC patients (P = 0.035). Comparison with the ES-UKD (n = 990) control group showed no significant association between AS and MKC by univariate and multivariate analysis. Multivariate analysis identified patient age and male gender (P < 0.001) as factors linked to MKC. Conclusions A 14.8% prevalence of MKC was found in our cohort of 257 patients with AS. MKC-AS patients exhibited clinical and histological characteristics akin to nephroangiosclerosis. Our comprehensive analysis, incorporating a sizable ES-UKD cohort, revealed no significant association between MKC and AS, thus questioning the inclusion of MKC within the spectrum of AS.