Clinical Variability and Genetic Variants in Alport Spectrum: A Retrospective Cohort Study
Background: Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are hereditary disorders characterized by glomerular basement membrane (GBM) abnormalities. Differentiating between them remains challenging due to overlapping clinical, and genetic features.Methods: We retrospectively analyzed a national cohort of 95 adult patients (39 males, 56 females) diagnosed with AS or TBMN between 2010 and 2024, evaluating their clinical course, histopathology, and genetic findings.Results: GBM abnormalities were found in 3.4% of native kidney biopsies, with 10 patients (11%) diagnosed with AS and 85 (89%) with TBMN. At biopsy, AS patients had higher serum creatinine (p = 0.002), while estimated glomerular filtration rate (eGFR), proteinuria, and hematuria were comparable between groups. Additional renal pathology was more frequent in TBMN than AS (p = 0.01). TBMN patients showed less glomerulosclerosis (p = 0.02) and interstitial fibrosis/tubular atrophy (p = 0.008). Genetic variants were detected in 100% of AS and 42% of TBMN patients (p < 0.001). Positive genetic findings were associated with more hematuria (p = 0.02), lower proteinuria (p = 0.01) and more frequent positive family history (p = 0.006). Disease progression occurred in 60% of AS and 25% of TBMN patients, with 45% of progressing cases showing genetic variants. Progression correlated with baseline eGFR (p < 0.001), not with genetic findings (p = 0.26) or variant pathogenicity (p = 0.58).Conclusions: AS and TBMN represent a clinical and genetic continuum within the Alport spectrum. While genetic testing aids diagnosis, it does not predict disease progression, highlighting the importance of clinical parameters in long-term renal outcomes.