Post-transplant Thrombotic Microangiopathy

Java, A; Sparks, M; Kavanagh, D

doi:10.1681/asn.0000000645

Post-transplant Thrombotic Microangiopathy

Lookup NU author(s): Professor David Kavanagh ORCiD

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Abstract

Thrombotic microangiopathy (TMA) is a challenging and serious complication of kidney transplantation that significantly impacts graft and patient survival, occurring in 0.8–15% of transplant recipients. TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to endothelial damage and microthrombi formation in small vessels. However, clinical features can range from a renal-limited form, diagnosed only on a kidney biopsy, to full-blown systemic manifestations, which include neurological, gastrointestinal, and cardiovascular injury. TMA can arise due to genetic or acquired defects such as in complement-mediated TMA or can occur in the context of other conditions like infections, autoimmune diseases or immunosuppressive drugs, where complement activation may also play a role. Recurrent TMA after kidney transplant is almost always complement-mediated, although complement overactivation may also play a role in de novo post-transplant TMAs associated with ischemia-reperfusion injury, immunosuppressive drugs, antibody-mediated rejection, viral infections, and relapse of autoimmune diseases such as, antiphospholipid antibody syndrome. Differentiating between a complement-mediated process and one triggered by other factors is often challenging but critical to minimize allograft damage since the former is non-responsive to supportive therapy, needs long-term anti-complement therapy and has a high risk of recurrence. Given the central role of complement and impact of genetic defects on the risk of recurrence in many forms of post-transplant TMA, genetic testing for complement disorders is key for proper diagnosis and management. Given that complement activation may also play a role in a subset of TMAs associated with other conditions, prompt recognition and timely initiation of anti-complement therapy is equally important. Additionally, TMA associated with non-complement genes, often part of a broader syndromic process with distinct clinical features, has also been described. Early identification and treatment are essential to prevent graft failure and other severe complications. This review explores the pathophysiological mechanisms underlying various post-transplant TMAs.