Abstract: FR-PO0433
Second Hit Causing Renal Thrombotic Microangiopathy: Unmasking Pathogenic MCP/CD46 Variant
Session Information
- AKI: Case Reports - TMA, Vasculitis, Immune-Mediated Injury, and Systemic Disease
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 102 AKI: Clinical, Outcomes, and Trials
Authors
- Patel, Vraj, Temple University, Philadelphia, Pennsylvania, United States
- Cheng, Derek, Temple University, Philadelphia, Pennsylvania, United States
- Gillespie, Avrum, Temple University, Philadelphia, Pennsylvania, United States
Introduction
Thrombotic microangiopathy (TMA) is a rare but life-threatening complication of carfilzomib, a second-generation proteasome inhibitor used in relapsed/refractory multiple myeloma. While the mechanism is not completely understood, genetic susceptibility via complement regulatory gene variants may lower the threshold for drug-triggered endothelial injury and uncontrolled complement activation.
Case Description
A 62 years old male with relapsing IgG kappa multiple myeloma presented to the hospital with delirium and was found to have acute kidney injury, profound anemia, and thrombocytopenia. He had received Daratumumab-Carfilzomib for the last 9 months with his last treatment was one week prior to admission. His serum creatinine was 18.69 mg/dl (baseline 1.1 mg/dl) and a urea nitrogen 233 mg/dl. His hemoglobin was 6.3 g/dl, platelet count was 71.8 k/mm3, lactate dehydrogenase was 2817 U/Lm, and haptoglobin < 10. Peripheral blood smear showed >15 schistocytes/high power field. Carfilzomib induced TMA was suspected. He was started hemodialysis (HD) and a week later he was started on eculizumab for Carfilzomib induced TMA despite mixed evidence. His genetic testing for complement mediated TMA was sent. Two days after eculizumab, he came off HD and creatinine returned to 1 mg/dl. His genetic testing later came back positive for a MCPggaac/CD46 risk haplotype- heterozygous which increases risk for atypical hemolytic uremic syndrome (aHUS). He received a total 6 doses of Eculizumab and carfilzomib was discontinued.
Discussion
Carfilzomib induced TMA usually occurs within 3 months of onset of treatment regimen. A recent study showed no benefit from eculizumab; however, that study did not test genetic variants. Complement inhibitors may be beneficial in those with complement mutations such as our case. MCP (CD46) is a ubiquitously expressed type-I membrane glycoprotein that serves as a cofactor for the serine protease factor I to mediate inactivation of C3b and C4b deposited on host cells. Pathogenic variants in MCP impair this surface-level complement inhibition, leaving endothelial cells exposed to unopposed amplification loop activity. The superimposed Carfilzomib mediated endothelial injury functions as the critical "second hit" that precipitates overt TMA and reframes carfilzomib-TMA not merely as a drug toxicity, but as a pharmacogenomically-triggered complement-mediated disease.