Rapid Progression to ESKD: The Role of Genetic Testing in Diagnosing C3 Glomerulopathy and Atypical Hemolytic Uremic Syndrome (HUS)

Introduction: 45-year-old woman, with no prior history, developed rapid and unexpected kidney failure, progress into ESKD and requiring dialysis within a few months. Findings included renal mass, and severe nephrosclerosis and biopsy raised concerns for secondary causes, but this didn't fully explain the rapid decline. Genetic testing showed C3 glomerulopathy and aHUS, both rare complement-mediated diseases. While these diagnoses are known entities, this case stood out for its abrupt course, emphasizing the value of genetic testing in unexplained disease. Case Description: In October 2023, a 45-year-old woman with no significant history presented with normal renal function. In February 2024, while traveling to Brazil, the symptoms returned, with severe headaches and hypertension. In the ER labs revealed a creatinine of 14 mg/dL, and she was started on hemodialysis. Imaging showed a mass on her left kidney. After returning to the U.S, she continued hemodialysis and had a nephrectomy in September 2024. Pathology showed severe arterial nephrosclerosis, chronic microangiopathy, FSGS likely secondary, and marked interstitial fibrosis. A genetic panel revealed mutations linked to C3 glomerulopathy and aHUS, providing explanation. Discussion: This case shows the diagnostic challenge of complement-mediated renal disease. In the absence of evident triggers, it can be easy to attribute findings to common conditions like hypertensive nephrosclerosis or secondary FSGS. Unfortunately, we made the diagnosis when her kidney function was already lost, too late for eculizumab, which may have preserved kidney function if started earlier. Genetic testing revealed the true underlying mechanism. For patients with atypical or rapidly progressive kidney failure, early consideration of genetic testing can be key, not just for diagnosis, but for guiding timely treatment. We believe that combining genetic testing and biopsy, will help the transplant team choose the best strategy and reduce risk of allograft failure from her specific glomerulopathy.