Complement Blockade in Recipients Prevents Delayed Graft Function and Delays Antibody-mediated Rejection in a Nonhuman Primate Model of Kidney Transplantation

Abstract

Original Basic ScienceBackground. Complement activation in kidney transplantation is implicated in the pathogenesis of delayed graft function (DGF). This study evaluated the therapeutic efficacy of high-dose recombinant human C1 esterase inhibitor (rhC1INH) to prevent DGF in a nonhuman primate model of kidney transplantation after brain death and prolonged cold ischemia. Methods. Brain death donors underwent 20 h of conventional management. Procured kidneys were stored on ice for 44-48 h, then transplanted into ABO-compatible major histocompatibility complex-mismatched recipients. Recipients were treated with vehicle (n = 5) or rhC1INH 500 U/kg plus heparin 40 U/kg (n = 8) before reperfusion, 12 h, and 24 h posttransplant. Recipients were followed up for 120 d. Results. Of vehicle-treated recipients, 80% (4 of 5) developed DGF versus 12.5% (1 of 8) rhC1INH-treated recipients (P = 0.015). rhC1INH-treated recipients had faster creatinine recovery, superior urinary output, and reduced urinary neutrophil gelatinase-associated lipocalin and tissue inhibitor of metalloproteinases 2-insulin-like growth factor-binding protein 7 throughout the first week, indicating reduced allograft injury. Treated recipients presented lower postreperfusion plasma interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and IL-18, lower day 4 monocyte chemoattractant protein 1, and trended toward lower C5. Treated recipients exhibited less C3b/C5b-9 deposition on day 7 biopsies. rhC1INH-treated animals also trended toward prolonged mediated rejection-free survival. Conclusions. Our results recommend high-dose C1INH complement blockade in transplant recipients as an effective strategy to reduce kidney injury and inflammation, prevent DGF, delay antibody-mediated rejection development, and improve transplant outcomes.

The Rational Use of Complement Inhibitors in Kidney Diseases

“…In animal models, complement depletion or inhibition attenuates myoglobin 34 , proteinuria 29 and ischemia/reperfusion [35][36][37][38] -induced tubular damage and interstitial fibrosis. However, clinical data are particularly scarce and limited to trials assessing C5 blockade in renal transplantation associatedischemia reperfusion and that has yielded disappointing results 39 .…”

Microvascular Inflammation of the Renal Allograft: A Reappraisal of the Underlying Mechanisms

“…Although these three pathways are engaged by distinct molecular mechanisms, all of them lead to the cleavage of the C3 protein, generating the C3a and C3b fragments ( 118 ). Two recent studies have demonstrated that in a nonhuman primate model, C3 complement inhibition can prevent antibody-mediated injury and improve transplant outcomes ( 119 , 120 ). Ultimately, full complement cascade activation leads to the cleavage of C5, generating the soluble C5a and C5b fragments.…”

Protein therapeutics and their lessons: Expect the unexpected when inhibiting the multi‐protein cascade of the complement system

“…Thus far, the clinical need for plasma purified or recombinant (which has become available) C1‐INH is not in a complement disease but rather in hereditary or acquired angioedema, which is characterized by uncontrolled generation of bradykinin. However, clinical trials have been or are underway to investigate if C1‐INH may be efficacious in complement diseases with a substantial CP component, such as antibody‐mediated rejection after kidney transplantation or overshooting inflammation after severe traumatic brain injury 79,80 . Future studies will show whether C1‐INH, which inhibits more than one physiological pathway, warrants in depth investigation as a complement inhibitor in diseases with a substantial CP involvement now that a specific monoclonal antibody directed against C1s has been approved for clinical use.…”