Yoshida H, Mitarai T, Kawamura T, Kitajima T, Miyazaki Y, Nagasawa R, Kawaguchi Y, Kubo H, Ichikawa I, Sakai O
Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
J Clin Invest. 1995 Nov;96(5):2162-9. doi: 10.1172/JCI118270.
Studies conducted over the last decade demonstrated variable therapeutic efficacy of angiotensin converting enzyme (ACE) inhibitor on the progression of glomerular diseases, including IgA nephropathy. In this study, among patients with biopsy-proven IgA nephropathy, 53 patients in whom creatinine clearance had been monitored over 5 yr were recruited for study. These patients were classified into two groups according to whether or not renal function had declined as determined by the slope of creatinine clearance against time: group 1 had stable renal function; group 2 had declining renal function (average: -6.7 +/- 1.3 ml/min/yr). 21 of 53 patients were treated with ACE inhibitor and followed for 48 wk. Gene polymorphism consisting of insertion (I) or deletion (D) of a 287-bp DNA fragment (presumed to be a silencer element) of the ACE gene was determined by PCR. 46 age-matched individuals without history of proteinuria were analyzed as controls. The DD genotype was significantly more frequent in group 2 (43%) than in controls (7%) or group 1 patients with stable renal function (16%). 48 wk after ACE inhibitor administration, proteinuria significantly decreased in patients with DD genotype but not in those with ID or II genotypes. The results indicate that deletion polymorphism in the ACE gene, particularly the homozygote DD, is a risk factor for progression to chronic renal failure in IgA nephropathy. Moreover, this deletion polymorphism predicts the therapeutic efficacy of ACE inhibition on proteinuria and, potentially, on progressive deterioration of renal function.
过去十年进行的研究表明，血管紧张素转换酶（ACE）抑制剂对包括IgA肾病在内的肾小球疾病进展的治疗效果存在差异。在本研究中，选取了53例经活检证实为IgA肾病且肌酐清除率已监测5年的患者进行研究。根据肌酐清除率随时间变化的斜率所确定的肾功能是否下降，将这些患者分为两组：第1组肾功能稳定；第2组肾功能下降（平均：-6.7±1.3 ml/min/年）。53例患者中有21例接受了ACE抑制剂治疗，并随访48周。通过聚合酶链反应（PCR）确定ACE基因287bp DNA片段（推测为沉默元件）的插入（I）或缺失（D）组成的基因多态性。分析了46例无蛋白尿病史的年龄匹配个体作为对照。第2组中DD基因型的频率（43%）显著高于对照组（7%）或肾功能稳定的第1组患者（16%）。给予ACE抑制剂48周后，DD基因型患者的蛋白尿显著降低，而ID或II基因型患者则未降低。结果表明，ACE基因的缺失多态性，尤其是纯合子DD，是IgA肾病进展为慢性肾衰竭的危险因素。此外，这种缺失多态性可预测ACE抑制对蛋白尿以及潜在的肾功能进行性恶化的治疗效果。
