Jonsson J R, Hong C, Purdie D M, Hawley C, Isbel N, Butler M, Balderson G A, Clouston A D, Pandeya N, Stuart K, Edwards-Smith C, Crawford D H, Fawcett J, Powell E E
Department of Surgery, The University of Queensland, The Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia.
Liver Transpl. 2001 Mar;7(3):255-63. doi: 10.1053/jlts.2001.22450.
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-beta, interleukin-10, and tumor necrosis factor alpha (TNF-alpha) 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 reaction-based 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-alpha-308 alleles among the primary liver diseases. After adjustment for potential confounders and a Bonferroni correction, the association between the TNF-alpha-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.
尽管免疫抑制方案有效，但原位肝移植（OLT）后仍有高达50%的患者发生排斥反应，且人们担心长期治疗的副作用。了解临床和免疫遗传变量可能有助于根据患者的潜在风险为其量身定制免疫抑制治疗方案。我们研究了121名白种人肝移植受者中转化生长因子-β、白细胞介素-10和肿瘤坏死因子-α（TNF-α）基因多态性与移植排斥反应及肾功能损害之间的关联。回顾性收集临床变量，并使用Cockcroft和Gault公式估算肌酐清除率。采用基于聚合酶链反应的方法检测双等位基因多态性。121例患者中有37例（30.6%）至少发生1次排斥反应。多变量分析显示，Child-Pugh评分（P = 0.001）、免疫介导的肝病（P = 0.018）、OLT前肌酐清除率正常（P = 0.037）以及较少的HLA-Ⅰ类错配（P = 0.038）与排斥反应独立相关。80%的患者出现肾功能损害，其中39%为中度或重度。与肾功能损害独立相关的临床变量为女性（P = 0.001）、OLT前肾功能不全（P = 0.0001）和病毒性肝炎诊断（P = 0.0008）。原发性肝病之间TNF-α -308等位基因频率存在显著差异。在对潜在混杂因素进行校正并采用Bonferroni校正后，TNF-α -308多态性与移植排斥反应之间的关联接近显著水平（P = 0.06）。OLT后受者细胞因子基因型在移植排斥反应或肾功能损害中没有主要的独立作用。对免疫遗传因素的进一步研究需要分析大量具有适当表型信息的患者，以避免可能导致不恰当结论的群体分层。
