Abstract
Background: The complement system activation and regulation have been linked to post-transplant pathologies including chronic antibody mediated rejection (cAMR) and the recurrence of IgA nephropathy (ReIgAN) but distinct mechanisms remain to be elucidated.Methods: In this retrospective single center study, the outcome of kidney transplantation was studied in 150 patients with late histological diagnosis to be either cAMR or ReIgAN, 14 stable kidney grafts at 3 months and finally 11 patients with native kidney IgAN nephropathy. To study a role of complement cascade and regulation in cAMR and ReIgAN, the RNA was extracted from available frozen kidney biopsy samples and using RT-qPCR transcripts of 11 target genes along with clinical data were determined and compared with stable grafts at 3 months protocol biopsies or IgAN native kidney nephropathy. Immunohistologically, CD46 (MCP), and C5 proteins were stained in biopsies.Results: Interestingly, there were no differences in kidney graft survival between cAMR and ReIgAN since transplantation. cAMR was associated with significantly higher intragraft transcripts of C3, CD59, and C1-INH as compared to ReIgAN (p < 0.05). When compared to normal stable grafts, cAMR grafts exhibited higher C3, CD55, CD59, CFH, CFI, and C1-INH (p < 0.01). Moreover, ReIgAN was associated with the increase of CD46, CD55, CD59 (p < 0.01), and CFI (p < 0.05) transcripts compared with native kidney IgAN. Rapid progression of cAMR (failure at 2 years after biopsy) was observed in patients with lower intrarenal CD55 expression (AUC 0.77, 78.6% sensitivity, and 72.7 specificity). There was highly significant association of several complement intrarenal transcripts and the degree of CKD regardless the diagnosis; C3, CD55, CFH, CFI, and C1-INH expressions positively correlated with eGFR (for all p < 0.001). Neither the low mRNA transcripts nor the high mRNA transcripts biopsies were associated with distinct trend in MCP or C5 proteins staining.Conclusions: The intrarenal complement system transcripts are upregulated in progressively deteriorated kidney allografts.
Highlights
Despite the advances in both the surgical procedures and immunosuppressive protocols, the long-term outcome of kidney transplantation has not substantially changed
We evaluated several gene transcripts and proteins involved in complement regulation in main pathologies influencing the long-term kidney graft outcome, the chronic antibody mediated rejection and recurrent IgA nephropathy (ReIgAN) and showed that intrarenal complement transcripts are upregulated in progressively deteriorating kidney allografts regardless the underlying pathology
Several complement gene transcripts (C3, CD55, CD59, CFH, CFI, and C1-INH) were elevated in chronic antibody mediated rejection (cAMR) compared to stable grafts that underlines the complement overactivity in chronic rejection (Figure 2)
Summary
Despite the advances in both the surgical procedures and immunosuppressive protocols, the long-term outcome of kidney transplantation has not substantially changed. The complement system involvement was shown to play a role in both chronic antibody-mediated rejection and IgA nephropathy pathogenesis [7,8,9,10,11] Both complement and complement regulators have been studied in relation to antibodymediated rejection, and therapies based both on C5 blockade [12, 13] and C1 inhibition using the C1-inhibitor [14] or antiC1 antibody [15] have been considered. We evaluated several gene transcripts and proteins involved in complement regulation in main pathologies influencing the long-term kidney graft outcome, the chronic antibody mediated rejection (cAMR) and recurrent IgA nephropathy (ReIgAN) and showed that intrarenal complement transcripts are upregulated in progressively deteriorating kidney allografts regardless the underlying pathology. The complement system activation and regulation have been linked to post-transplant pathologies including chronic antibody mediated rejection (cAMR) and the recurrence of IgA nephropathy (ReIgAN) but distinct mechanisms remain to be elucidated
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