Two Hits, One Target: Endothelial and Podocyte Injury in a Dual Kidney Pathology

Introduction: Podocytopathy is an immune mediate diffuse pdocyte injury resulting in nephrotic syndrome. Whereas thrombotic microangiopathy (TMA) is characterized by endothelial damage and microvascular thrombosis, typically presenting with acute kidney injury (AKI). Herein, we present a rare case of concurrent anti-nephrin mediated podocytopathy and TMA. Case Description: A 43-year-old Vietnamese male patient with history of nephrotic syndrome (unknown diagnosis) presented with anasarca. Laboratory evaluation revealed AKI and portienuria (24 g/day). He had worsening anemia and thrombocytopenia with high LDH, low haptoglobin, and schistocytes concerning for TMA. Kidney biopsy showed TMA involving glomeruli and arterioles with a collapsing lesion by light microscopy, IF showed punctate IgG staining within the podocytes, and EM showed diffuse podocyte effacement and global subendothelial lucency without depositis. Further evaluation by IF revelaed clusterd nephrin staining overlapping with the punctate IgG compatible with anti-nephrin medicated podocytopathy. The patient required temporary dialysis and later started empirically on eculizumab and rituximab, aHUS panel was nondiagnostic and genetic testing revealed a variant of undetermined significance in CFHR2 gene. The patient recovered with improvement in proteinuria to subnephrotic range in 2 months and creatinine to 1.1 mg/dL in 3 months. Discussion: This case highlights the critical importance of meticulous histopathologic evaluation in kidney biopsy interpretation, where subtle findings led to the identification of a rare dual pathology—anti-nephrin antibody–mediated podocytopathy superimposed on thrombotic microangiopathy (TMA). Recognition of this uncommon association was pivotal in guiding targeted therapy, resulting in an excellent clinical response.