The variable course of women with X-linked Alport Syndrome
A 25-year-old white female presented in 2006 at age 19 with nephrotic syndrome. Her serum creatinine (SCr) was 0.9 mg/dL (79.6 μmol/L) with an estimated glomerular filtration rate (eGFR) [] of 74 mL/min/1.73 m2, serum albumin (SAlb) was 2.9 g/dL (29 g/L) and a urinalysis had 4+ protein and large blood by dipstick. A 24-h urine protein was 6.4 g/day. She had no history of gross hematuria, hearing difficulty or visual changes. Family history was negative for proteinuria, renal failure or AS, but was positive for microscopic hematuria in her maternal grandmother and aunt. A kidney biopsy was performed for the evaluation of nephrotic syndrome and microscopic hematuria.\nLight microscopy (LM) contained six glomeruli, one of which was globally sclerotic. The remaining glomeruli had preserved architecture with delicate basement membranes, patent glomerular capillaries and normal mesangial matrix and cellularity (Figure A). Tubular atrophy and interstitial fibrosis involved 5% of the cortex, and interstitial foams cells (Figure B) affected 10–15% of the cortex. IF demonstrated weak mesangial staining for IgM (trace–1+) and C3 (trace). The tissue was stained with antibodies to the alpha 1, 3 and 5 chains of type IV collagen. This revealed 1–2+ segmental/mosaic staining of the GBM with the alpha 3 chain of type IV collagen (Figure ). Staining for the alpha 5 chain of type IV collagen also showed 1+ segmental/mosaic staining of the GBM (Figure ). There was no staining of the dTBM for either the alpha 3 or the alpha 5 chains of type IV collagen. Electron microscopy (EM) demonstrated diffusely thinned GBMs, measuring 124 nm in average thickness (Figure ), but there was no lamellation or splitting. Segmental foot process effacement involved 50% of the total glomerular capillary surface area.\nHeterozygous XLAS was diagnosed based on the ultrastructural findings and the segmental/mosaic IF staining of the GBM and Bowman's capsule and the lack of staining of the dTBM for the alpha 3 and alpha 5 chains of type IV collagen.\nAn angiotensin-converting enzyme inhibitor (ACEi) was started after the biopsy. In 2012, her SCr rose to 1.6 mg/dL (141.4 μmol/L) (eGFR—38 mL/min/1.73 m2), and she remained nephrotic (urine protein creatinine ratio 3.7 g/g) with microscopic hematuria. Additionally, she developed progressive high-tone hearing loss and now requires hearing aids.