Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome?

Abstract

Background/Aims: Complement activation is important in post-transplantation renal injury, but data on its role as predictor of transplant outcome/complications when assessed in donor kidneys are lacking. Methods: In human renal transplant biopsies with delayed graft function (DGF, n=12), antibody mediated rejection (ABMR, n=8), T-cell mediated rejection (TCMR, n=11), 1 year protocol biopsies (control, n=10) and corresponding zero-biopsies we performed immunohistochemical analyses of 6 complement factors using FFPE sections and correlated the findings with kidney function, as assessed by serum creatinine, and morphological changes including interstitial fibrosis and tubular atrophy (IF/TA). Results: In DGF, TCMR and ABMR significant complement deposition was observed, which was less pronounced in corresponding zero-biopsies. Zero-biopsies with subsequent ABMR showed glomerular complement factor D and C3c expression. Moreover, glomerular C3c and C9 and tubular MASP-2 and Collectin-11 expression in zero-biopsies significantly correlated with serum creatinine at diagnosis of DGF, TCMR or ABMR. Glomerular C1q was significantly increased in ABMR, but not in DGF and TCMR. In contrast, peritubular C1q was significantly enhanced in DGF and TCMR compared to zero-biopsies. Using C3d as a surrogate marker for complement activity we could confirm that stained complement factors are frequently associated with complement activity. Conclusion: Complement deposition strongly correlated with histopathological changes observed in renal transplants. All 3 complement pathways were operational in biopsies with DGF, TCMR and ABMR albeit with differential abundance and localization. Since complement deposition in zero-biopsies correlated with graft function and morphological changes, early specific complement inhibition in renal transplantation may be a new therapeutic option to prevent graft loss.

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

“…Bobka S. et al also demonstrated an increased Complement activation in pre-transplant biopsies from diabetic, hypertensive, or smoking donors, suggesting a predictive value of Complement activation in donor biopsies for later outcome [ 98 ]. Expression of these Complement components at time of diagnosis of ABMR was associated with higher serum creatinine and more severe morphological changes.…”

Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage

“…Interestingly, a significant complement activation has been observed also in these conditions. Bobka et al demonstrated an increased complement activation in pretransplant biopsies from diabetic, hypertensive, or smoking donors (97). The authors showed a predictive value of complement activation in donor biopsies for later outcome; effective analyses of these deposits in the donor were characterized by C1q, factor D, C3c, and C5b-9 and tubular MASP2 and Collectin-11 in kidney that would have developed ABMR.…”

“…Consistently, pathogenic roles for C5aR1 in renal tubulo-interstitial fibrosis have been reported in different models of renal IRI (66,(87)(88)(89)(90)(91), murine model of unilateral ureteral obstruction (UUO) (92), and chronic pyelonephritis (93). Remarkably, in clinical settings, donor urinary C5a concentrations before transplantation has been shown to be higher in the recipients with risk of DGF (92,94).…”

“…key role (96,97). ABMR is characterized by glomerulitis, peritubular capillaritis, acute thrombotic microangiopathy tubular injury, C4d deposition in the peritubular capillaries, and microvascular inflammation (98,99).…”

“…By performing renal transplantation of a donor C3 −/− kidney in a wild-type recipient mice (donor, C3 −/− ; recipient: wild type), Pratt et al demonstrated a significant increased long-term survival and less rejection incidence compared to wild-type mice recipients transplanted with allogenic wild-type kidney (Wtype/Wtype). Therefore, locally synthesized C3 is the most important trigger of rejection than circulating C3 and a powerful inducer of chronic damage (92). Other experimental evidence to support the role of complement in rejection were provided by Wang et al (114).…”