Complement Activation During Liver Transplantation—Special Emphasis on Patients With Atypical Hemolytic Uremic Syndrome

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy often caused by mutations in complement factor H (CFH), the main regulator of alternative complement pathway. Because CFH is produced mainly by the liver, combined liver-kidney transplantation is a reasonable option in treatment of patients with severe aHUS. We studied complement activation by monitoring activation markers during liver transplantation in two aHUS patients treated extensively with plasma exchange and nine other liver transplantation patients. After the reperfusion, a clear increase in all the activation markers except C4d was observed indicating that the activation occurs mainly through the alternative pathway. Concentration of SC5b-9 was higher in the hepatic than the portal vein indicating complement activation in the graft. Preoperatively and early during the operation, the aHUS patients showed highest C3d concentrations but otherwise their activation markers were similar to the other patients. In the other patients, correlation was found between perioperative SC5b-9 concentration and postoperative alanine aminotransferase and histological changes. This study explains why supply of normal CFH by extensive plasma exchange is beneficial before combined liver-kidney transplantation of aHUS patients. Also the results suggest that perioperative inhibition of the terminal complement cascade might be beneficial if enhanced complement activation is expected.

Eculizumab for Atypical Hemolytic Uremic Syndrome Recurrence in Renal Transplantation

“…Notably, five patients (cases 5–9) were given two consecutive daily anti‐C5 infusions at the time of the transplantation to circumvent the concern of high complement activation triggered by ischemia reperfusion (17,32). Four patients received the starting dose a few hours before surgery and the second dose within the next 24 h (cases 5, 6, 8 and 9).…”

“…Regarding prophylactic regimens, a first dose of anti‐C5 was administered a few hours before surgery and an additional dose within the next 24 h (postoperative day 1) in three patients, as it has been proposed for preventing antibody‐mediated rejections (ClinicalTrials.gov: NCT01399593) (34) and catastrophic antiphospholipid syndrome posttransplant recurrence (ClinicalTrials.gov: NCT01029587) (35). The day 1 infusion, incorporated in prophylactic protocols, stemmed from the finding that complement products are dramatically released following graft reperfusion (17,32). This led to the idea that conventional protocols might not sufficiently block circulating C5 during the early posttransplant course and that a greater anti‐C5 exposure might be needed.…”

Atypical haemolytic uraemic syndrome treated with the complement inhibitor eculizumab: the experience of the Australian compassionate access cohort

“…In the absence of eculizumab the risk of disease recurrence post-transplantation is approximately 50%, with nearly 90% graft loss in such patients. 3,40 The risk of disease recurrence is significantly heightened in those with particular genotypes such as CFH mutations, and thus combined liver-kidney transplantation has been employed in a small number of patients to facilitate prophylactic hepatic endogenous wild-type Complement Factor H. [41][42][43][44][45][46] This remains a high-risk procedure, with intensive PT or eculizumab required in order to facilitate safe transplantation. Various groups now recommend that genetic testing and pre-emptive eculizumab is likely to become the standard of care in renal transplantation for aHUS.…”

Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics

“…TMA associated with transplantation most commonly affects the kidneys but can manifest with gastrointestinal, pulmonary, neurologic or cardiac involvement and typically has normal or mildly low ADAMTS‐13 activity. There are rare case reports of severe deficiency of ADAMTS‐13 activity in the presence of an inhibitor in lung‐ and kidney‐transplant patients . Medications, including CNIs, anti‐VEGF bevacizumab and sirolimus, have been implicated in TMA in this population .…”