Role of cytokine gene polymorphisms in acute rejection and renal impairment after liver transplantation

Abstract

Although immunosuppressive regimens are effective, rejection occurs in up to 50% of patients after orthotopic liver transplantation (OLT), and there is concern about side effects from long-term therapy. Knowledge of clinical and immunogenetic variables may allow tailoring of immunosuppressive therapy to patients according to their potential risks. We studied the association between transforming growth factor-␤, interleukin-10, and tumor necrosis factor ␣ (TNF-␣) gene polymorphisms and graft rejection and renal impairment in 121 white liver transplant recipients. Clinical variables were collected retrospectively, and creatinine clearance was estimated using the formula of Cockcroft and Gault. Biallelic polymorphisms were detected using polymerase chain reactionbased methods. Thirty-seven of 121 patients (30.6%) developed at least 1 episode of rejection. Multivariate analysis showed that Child-Pugh score (P ‫؍‬ .001), immune-mediated liver disease (P ‫؍‬ .018), normal pre-OLT creatinine clearance (P ‫؍‬ .037), and fewer HLA class 1 mismatches (P ‫؍‬ .038) were independently associated with rejection. Renal impairment occurred in 80% of patients and was moderate or severe in 39%. Clinical variables independently associated with renal impairment were female sex (P ‫؍‬ .001), pre-OLT renal dysfunction (P ‫؍‬ .0001), and a diagnosis of viral hepatitis (P ‫؍‬ .0008). There was a significant difference in the frequency of TNF-␣-308 alleles among the primary liver diseases. After adjustment for potential confounders and a Bonferroni correction, the association between the TNF-␣-308 polymorphism and graft rejection approached significance (P ‫؍‬ .06). Recipient cytokine genotypes do not have a major independent role in graft rejection or renal impairment after OLT. Additional studies of immunogenetic factors require analysis of large numbers of patients with appropriate phenotypic information to avoid population stratification, which may lead to inappropriate conclusions. (Liver Transpl 2001;7:255-263.) S urvival after orthotopic liver transplantation (OLT) has steadily improved; overall 1-and 5-year patient survival rates for a primary graft are 88% and 74%, respectively. 1 Acute rejection occurs in up to 50% of patients but does not appear to adversely affect liver allograft survival. 2 Although current immunosuppressive regimens are very effective, concern is increasing about the side effects arising from long-term therapy. More than 50% of all deaths after OLT are caused by infection, 3 and approximately 4% of long-term survivors develop severe chronic renal failure. 4 These adverse consequences of immunosuppression may be reduced by modifying current drug regimens with lower doses of cyclosporine (CsA) and tacrolimus and earlier cessation of corticosteroid therapy. However, it remains difficult to predict the patients least likely to experience graft rejection who can be treated with minimal immunosuppression. In contrast to other solid organs, HLA matching for OLT has only a weak effect on rejection, and information...

GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro

“…In fact, in neither renal nor liver transplant patients was an association between TNF producer genotype and rejection found at the mRNA level (45). In addition, GM-CSF, the TNF-reconstituting agent in our model, has been safely applied following liver transplantation in the treatment of neutropenia (44).…”

Tumor necrosis factor-α promoter polymorphisms and the risk of rejection after liver transplantation: A case control analysis of 210 donor-recipient pairs

“…In a recent study of 121 white OLT recipients, Jonsson et al 21 found that recipient cytokine genotypes did not have a major role in graft rejection or renal impairment. Evans et al 22 found that the observed association between the high TNF-␣ producing allele and chronic rejection in 89 liver transplant recipients was caused by linkage to HLA-DR3.…”

Is there a future for TNF promoter polymorphisms?

“…Most studies that have looked at outcome of disease have found no association with TNF SNPs. 104,[111][112][113][114][115] However, two studies have appeared that did find an association of TNF SNPs with HCV. 116,117 The latter study 117 is curious not because of the reported higher occurrence of the À238A allele among chronic HCV patients, but because the reported frequency in a healthy control group (n ¼ 99) drops from 7 117 to 3.5% in an article published concurrently by the same group.…”