Unveiling X-linked Alport Syndrome: Genetic Testing in FSGS

Introduction: FSGS is often considered in the evaluation of patients with CKD and proteinuria. As a histopathologic pattern of injury with various causes, investigating the underlying etiology of podocyte injury is crucial, given its potential therapeutic implications. Recent advances in genetic testing have revealed pathogenic variants of Alport’s syndrome (AS) in patients presenting with biopsy findings of FSGS. Here, we present a patient with biopsy proven FSGS subsequently found to have X-linked AS. Case Description: An 18 y/o man with CKD was evaluated for HTN at age 7, at which time he had a normal creatinine (Cr) and microscopic hematuria without proteinuria. He was started on an ACE-i. At age 16, he developed proteinuria, with a biopsy showing FSGS and acute interstitial nephritis (AIN). There was insufficient sample for EM analysis. A course of steroids was prescribed for the AIN. Now, he has developed significant HTN, rising Cr, and worsening proteinuria. He had no history of vision or hearing issues. Further evaluation of his family revealed siblings with microscopic hematuria. Genetic testing was done now 11 yrs after the biopsy and showed a mutation within the COL4A5 gene, consistent with X-linked AS. Discussion: FSGS of genetic origin can appear at different ages and exhibit varying degrees of proteinuria and foot process effacement. Recent advancements have shed light on the role of COL4A3-5 mutations in the development of FSGS amongst patients diagnosed with primary FSGS or steroid-resistant nephrotic syndrome. AS diagnosis has significant implications not only for the patient but also their family members who are at risk for the spectrum of systemic manifestations of the condition. Early diagnosis also allows for patients to be enrolled in clinical trials to help our therapeutic options. This case underscores the importance of accurately classifying patients with FSGS and highlights the pivotal role of genetic testing in managing CKD.PAS stain showing segmental scar (arrow)