Noninvasive optical coherence tomography biomarker for Alport syndrome, COL4-related focal segmental glomerulosclerosis, and COL4 variant interpretation.

Abstract

Alport syndrome (AS) is a hereditary glomerulopathy often associated with ocular abnormalities, yet structural retinal biomarkers remain underutilized in nephrology. Here, we evaluated the Temporal Thinning Index Maximum (TTIMax), a subject-level optical coherence tomography (OCT) metric, as a potential diagnostic biomarker for inherited podocytopathies. We evaluated TTIMax derived from OCT in 93 genetically confirmed patients with AS and 136 controls (84 with chronic kidney disease and 52 healthy individuals). Genetic diagnosis served as the reference standard and TTIMax as the index test. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis with calculation of sensitivity and specificity. TTIMax stratified disease severity across genotypes (severe X-linked AS-Male/autosomal recessive AS: 11.8%; intermediate X-linked AS-Female/autosomal dominant AS: 7.3-8.1%; controls: 5.3-5.8%) and remained significantly associated with disease severity after adjustment for age, eGFR, and blood pressure. ROC analysis demonstrated excellent discrimination for severe AS (area under the curve (AUC) 0.98; 95% Confidence Interval 0.96- 1.00) with an optimal threshold of 8.4% (sensitivity 93%, specificity 99%). TTIMax distinguished severe AS from primary immune-mediated focal segmental glomerulosclerosis (FSGS) (AUC 0.97;0.94-1.00) and differentiated COL4A-related FSGS from primary FSGS (AUC 0.91; 0.77-1.00). Longitudinal follow-up (four-14 years) demonstrated stability of TTIMax despite changes in kidney function CONCLUSIONS: TTIMax provides a widely accessible, non-invasive structural biomarker that complements genetic testing and may aid in diagnosing inherited podocytopathies and interpreting COL4 variants of uncertain significance.