#NephMadness 2019: Complement Inhibition in Post-Transplant Thrombotic Microangiopathy

Posted on April 4, 2019 by AJKDblog in NephMadness // 0 Comments

Mythili Ghanta

Mythili Ghanta is an Assistant Professor in the Department of Internal Medicine at UT Southwestern Medical Center and the Associate Medical Director of the Kidney Transplant Program at Parkland Health & Hospital System. She specializes in treating kidney transplant recipients.

Competitors for the Complement Region

One of the diagnoses that remains a substantial challenge in transplant nephrology is post-kidney transplant thrombotic microangiopathy, as the etiology remains heterogenous and tends to poorly responds to therapy, oftentimes leading to graft failure. Better understanding of disease processes and new treatments are greatly needed.

Thrombotic microangiopathy (TMA) post-transplant is a devastating complication, with significant risk of graft loss, morbidity, and mortality. Broadly it can be categorized into recurrent TMA and de novo TMA. Recurrent TMA (mainly recurrent atypical hemolytic uremic syndrome [HUS]) is related to dysregulated activation of alternative complement pathway where complement inhibition plays an important role in preventing graft loss. Eculizumab is used in protocols post-transplant in patients with identified mutations in complement regulatory proteins with atypical HUS to prevent recurrence. However, duration of therapy, cost burden involved with long-term use, and infection risk remain important challenges with eculizumab therapy.

De novo TMA post-transplant remains heterogenous in etiology and is poorly understood. In the presence of well-identified triggers for TMA post-transplant (for example ischemia reperfusion injury, calcineurin inhibitors, antibody-mediated rejection), there is a growing body of literature that suggests a role of dysregulated alternate complement pathway in de novo TMA as well. Hence, it is important to perform genetic testing for mutations in proteins regulating alternate complement pathway in all cases of TMA post-transplantation.

In select cases of post-transplant TMA where a clear mutation associated with dysregulated alternate complement pathway is identified, eculizumab (C5 inhibitor) can offer therapeutic benefit. However, constraints to use eculizumab remains significant including: cost burden, poorly defined duration of therapy, route of administration(infusion) and infection risk. Furthermore, eculizumab resistance has also been described. Several novel complement inhibitors are on the horizon and offer promise for use in post-transplant TMA such as the compstatin analog Cp40 (C3 inhibitor). Cp40 has passed preclinical trials and is currently undergoing clinical trials. There is hope with these evolving novel therapies in the near future for patients with post-transplant TMA. Complement inhibition may also have a role in other post-transplant pathologies involving complement activation such as recurrent glomerulonephritis and antibody-mediated rejection.

For these reasons, team C3-i and Beyond has the talent and promise to go deep in this year’s NephMadness.

– Guest Post written by Mythili Ghanta

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