#6036 CYSTIC KIDNEY PHENOTYPE IS A FREQUENT, AGE- AND EGFR- DEPENDENT FINDING IN ALPORT SYNDROME
Authors: Zeni Letizia , Mescia Federica , Toso Diego , Mazza Cinzia , Dordoni Chiara , Econimo Laura , Cortinovis Roberta , Alberici Federico , Scolari Francesco , Izzi Claudia 
Published: June 2023

Abstract

Background and Aims
Alport Syndrome (AS), the most common genetic glomerular disease, due to pathogenic variants in COL4A3-COL4A5 genes, includes three main forms: X-linked AS (XLAS, COL4A5); autosomal recessive (ARAS, biallelic pathogenic variants in COL4A3 or COL4A4); autosomal dominant (ADAS; heterozygous COL4A3 or COL4A4 variant).
An expanded phenotypic spectrum of AS has been described, including recent reports of multiple kidney cysts in affected patients. The aim of the study was to evaluate the prevalence and characteristics of renal cysts in a cohort of adult patients with AS.

Method
This retrospective study included subjects with AS followed at the Outpatient Nephrogenetic Clinic of Spedali Civili di Brescia (Italy) from 2002 to 2022 and with at least one available renal imaging study (Ultrasonography/CT scan). Genetic testing was performed by using a next generation sequencing multi-gene panel for kidney disease.
Cystic phenotype was defined as the presence of ≥3 cysts in each kidney. The prevalence of renal cystic phenotype was compared between patients (pts) with AS and a group of age- and eGFR-matched pts with sporadic IgA nephropathy (IgA-N). Demographic and clinical features were compared between pts with or without cystic phenotype. Logistic regression was performed to test whether sex, age, type of variant and eGFR (CKD-EPI formula) were independently associated with the cystic phenotype.

Results
A total of 96 AS pts were studied. The pattern of inheritance was AD in the majority of the cohort (56%), XL in 25%, AR in 2% and unknown in the remaining 17%. The cystic phenotype was observed in 36 pts (38%). When compared to a matched IgA-N cohort (n = 79), the cystic phenotype was significantly more common in AS (42% in AS; 19% in IgA-N; p = 0,002). The majority of AS pts with cystic phenotype showed normal/reduced sized kidneys and multiple cortical and/or parapelvic renal cysts. Increased total kidney volume, in keeping with primary cystic kidney disease, was observed in three patients; however, pathogenic variants in known cysto-genes were excluded. At the time of renal imaging, AS pts with cystic phenotype were older and had a more marked reduction in kidney function than their non-cystic counterparts (Table 1). When stratifying patients based on age or eGFR, the prevalence of the cystic phenotype gradually increased in parallel with older age and declining eGFR (Figure 1). Independent predictors of the cystic phenotype were age (HR 1.96 [95% CI 1.31-2.94] per 10 years; p = 0.001) and eGFR (HR 0.75 [95% CI 0.64-0.89] per 10 ml/min/1.73m2;p = 0.001). Serial longitudinal ultrasounds were available for 15 cystic pts, among whom the cystic phenotype was first observed from 40 years of age onwards, at an overall median age of 59 (IQR 46–65).

Conclusion
Our data show that multiple bilateral kidney cysts, with no increase in kidney size, are frequently found in AS patients. The cystic phenotype is associated with older age and eGFR decline, suggesting that it can reflect the severity and/or duration of CKD. However, the higher frequency of cystic phenotype in AS than IgAN, the role of the collagen IV α3 to α5 chains in the basement membranes in the glomerulus and distal tubule, and the occurrence of kidney cysts in a canine model of ADAS, support a possible pathogenetic link between type IV collagen mutations and cystogenesis in AS. Finding kidney cysts should not discourage from considering the diagnosis of AS, particularly in adult patients and in the presence of familial CKD. Future prospective studies will be needed to shed light on the prognostic implications of the cystic phenotype and possible genotype-phenotype associations.