Kidney Week 2025 Early Program - Genetics in Clinical Nephrology-Unraveling the Genetics of Thrombotic Microangiopathy

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Video Summary

The speaker explains thrombotic microangiopathy (TMA) as microvascular endothelial injury leading to platelet-rich thrombi, hemolytic anemia, thrombocytopenia, and organ ischemia—often kidney-predominant but potentially systemic or renal-limited. Because clinical features don’t identify cause, TMAs should be classified by etiology. A key genetic form is complement-mediated TMA (atypical HUS), driven by dysregulation of the alternative complement pathway due to heterozygous variants in complement regulators (e.g., factor H, MCP) or gain-of-function variants (e.g., C3, factor B), plus triggers and incomplete penetrance. About 10–15% involve factor H autoantibodies. Structural/copy-number variants in the factor H–related gene cluster can create hybrid proteins that impair factor H surface binding; these require specialized testing (e.g., MLPA) beyond standard sequencing. Risk haplotypes can increase penetrance but aren’t actionable alone.<br /><br />Non-complement genetic TMAs (e.g., DGKE, cobalamin C/MMACHC, RNA exosome genes) often present syndromically and may not respond to complement inhibitors.<br /><br />Genetic testing helps confirm etiology, guide prognosis, transplant recurrence risk, donor selection, and duration of anti-complement therapy. The speaker emphasizes testing TMAs with unclear cause, family history, pregnancy-associated kidney failure, “hypertensive nephrosclerosis,” and post-transplant TMA. For transplant candidates with pathogenic complement variants, prophylactic eculizumab at induction is recommended to prevent graft loss.

Asset Subtitle

Anuja Java

Meta Tag

Module GENE

Speaker Anuja Java

Keywords

thrombotic microangiopathy (TMA)

complement-mediated TMA

atypical hemolytic uremic syndrome (aHUS)

alternative complement pathway dysregulation

CFH (factor H) and MCP (CD46) variants

C3 and factor B gain-of-function mutations

factor H autoantibodies

MLPA testing for CFHR copy-number/hybrid variants