An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes

Abstract

Of all kidney transplants, half are still lost in the first decade after transplantation.Here, using genetics, we probed whether interleukin 6 (IL-6) could be a target in kidney transplantation to improve graft survival. Additionally, we investigated if a genetic risk score (GRS) based on IL6 and IL10 variants could improve prognostication of graft loss.In a prospective cohort study, DNA of 1271 donor-recipient kidney transplant pairs was analyzed for the presence of IL6, IL6R, IL10, IL10RA, and IL10RB variants. These polymorphisms and their GRS were then associated with 15-year death-censored allograft survival. The C|C-genotype of the IL6 polymorphism in donor kidneys and the combined C|C-genotype in donor-recipient pairs were both associated with a reduced risk of graft loss (p = .043 and p = .042, respectively). Additionally, the GRS based on IL6, IL6R, IL10, IL10RA, and IL10RB variants was independently associated with the risk of graft loss (HR 1.53, 95%-CI [1.32-1.84]; p < .001). Notably, the GRS improved risk stratification and prediction of graft loss beyond the level of contemporary clinical markers. Our findings reveal the merits of a polygenic IL-6-based risk score strengthened with IL-10-polymorphisms for the prognostication and risk stratification of late graft failure in kidney transplantation.

Synergistic impact of three complement polymorphisms in the donor, not the recipient, on long-term kidney allograft survival

“…Patients receiving a first single kidney transplantation at the University Medical Center Groningen (UMCG) between March 1993 and February 2008 were selected for this study. [31][32][33][34][35][36] Subsequent, exclusion criteria consisted of perioperative technical complications (3 pairs excluded), lack of available DNA (65 pairs excluded), loss of follow-up (4 pairs excluded), retransplantation at the time of recruitment (22 pairs excluded) and simultaneous transplantation of other organs (65 pairs excluded). In summary, we began with 1430 kidney transplant pairs, and after applying exclusion criteria, we included 1271 kidney transplant pairs in this study.…”

Carboxypeptidase B2 gene polymorphisms in the donor associate with kidney allograft loss

“…For this longitudinal cohort study, transplant recipients were enrolled who received a single kidney allograft between March 1993 until February 2008 at the University Medical Center Groningen, as described previously. [28][29][30][31] Exclusion criteria were: Lack of DNA, re-transplantation, technical complications during surgery, and loss of follow-up. In brief, a total of 1,271 out of 1,430 donor-recipient kidney transplant pairs were included.…”

Chronic Active Antibody-mediated Rejection: Opportunity to Determine the Role of Interleukin-6 Blockade

“…26,27 Not only can it act on multiple cell types by both direct and indirect pathways, 28 IL-6 can also be produced by many types of parenchymal cells, especially following ischemia. [29][30][31] IL-6 gene polymorphisms correlate with graft survival, 32 and elevated circulating IL-6 correlates with increased morbidity. 33 Multiple monoclonal antibodies against IL-6 or its receptors are in clinical use and/or studies across a broad spectrum of diseases.…”