A Case of Autosomal Dominant Hereditary Nephritis

Introduction: Alport syndrome, or hereditary nephritis, results from genetic mutations in collagen IV protein genes, leading to a basement membrane disorder. It can be inherited through X-linked (COL4A5 gene defect), autosomal recessive (AR), or autosomal dominant (AD) (COL4A3 or COL4A4 gene defects). This disorder causes a progressive glomerular disease and often involves sensorineural hearing loss and ocular abnormalities. Case Description: A 47-year-old woman with Crohn's disease, receiving infliximab, is evaluated for CKD stage IIIA and proteinuria (UACR 838 mg/g Cr). No history of hearing or ocular issues is reported. She has a family history of ESRD in two maternal aunts. Serology shows positive ANA (1:640), and anti-histone antibodies. The kidney biopsy showed variable glomerular basement membrane width; areas of thinning alternated with thickened sections having variable lucency (Fig 1A). No immune complex electron-dense deposits were noted. Irregular staining of the glomerular capillary walls for COLIV alpha5 chain was observed (Fig 1B left) compared to the normal control tissue (Fig 1B right). Genetic testing revealed heterozygous pathogenic variant in COL4A4 c.2402G>T (p.Gly801Val). She was diagnosed with AD Alport syndrome. She was referred for ocular and auditory evaluations. She began treatment with losartan and Empagliflozin. After 6 months, her kidney function remained stable, and UACR improved to 397 mg/g Cr. Discussion: Though her positive serology likely stems from an immunologic effect of infliximab, there's no evidence of immune complex-related kidney disease. The observed GBM abnormalities align with a COL4-related disorder. While variable alpha5 staining hints at COL4A5 gene abnormalities, her family history suggests otherwise; with her maternal grandfather lived longer without ESRD. With a heterozygous genetic mutation, she has AD disease. Her variable COL4A5 staining reflects deficiency of normal A3-A4-A5 trimer formation. AD Alport's is typically less severe than AR and often lacks hearing loss and eye issues (occurs in <10 – 25%).