ACE gene polymorphism, left ventricular geometry, and mortality in diabetic patients with end-stage renal disease

Abstract

The objectives of this study were to determine the association between angiotensin converting enzyme (ACE) gene polymorphism and left ventricular (LV) geometry, and to clarify independent effects of ACE genotype on mortality after commencing dialysis in diabetic patients with end-stage renal disease (ESRD). A total of 106 diabetic patients, 71 men and 35 women, 11 type 1 and 95 type 2 diabetic, 57±12 ($\text{mean}\text{±}\text{standard}\text{deviation}\text{(}\text{S.D.}\text{)}$) years of age, who started dialysis were studied. Patients with cardiac diseases and those treated with ACE inhibitors were excluded because of potential effects on LV performance. Echocardiographic examination was performed within ±2 months of the start of dialysis. Relation between ACE genotype and LV mass index (LVMI) or relative wall thickness (RWT) at onset of dialysis, and impact of ACE genotype on survival after commencing dialysis were evaluated. There were no significant differences in LVMI or RWT in the three ACE genotype groups at onset of dialysis. However, mortality of patients with the ACE–DD genotype was significantly higher than patients with the DI and II genotypes (hazard ratio, 2.318; P=0.043), based on a survival analysis with a mean follow-up duration of 60 months. The higher mortality in patients with the DD genotype was confirmed to be independent of LV hypertrophy and increases in RWT. In diabetic patients with ESRD, ACE genotype has no association with LV mass or RWT at the start of dialysis, but does have an independent impact on patient survival thereafter.

Introduction

Diabetic nephropathy is the leading cause of renal disease among incident dialysis patients in most industrialized countries, including Japan [1], [2]. Diabetic nephropathy is associated with a higher mortality during renal replacement therapy (RRT) than are non-diabetic renal diseases [1], [2]. This excess mortality results mainly from higher prevalence of cardiovascular disorders even at the onset of RRT [1], [3], [4]. Left ventricular (LV) hypertrophy, commonly seen in both diabetic and non-diabetic patients with end-stage renal disease (ESRD) [5], [6], [7], is one of the most crucial determinants in the prognosis of ESRD patients. Diabetes mellitus per se also is an independent risk factor for left LV hypertrophy [8], [9], the prevalence of which appears to increase according to the progression of diabetic nephropathy [10], [11].

In addition to several environmental factors, genetic determinants may be associated with LV hypertrophy [12], [13]. The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has been most extensively studied among the candidate genes implicated in the pathogenesis of LV hypertrophy, though yielding conflicting results to date [14], [15], [16]. In patients with ESRD, Osono et al. reported a significant relationship between ACE genotype and LV hypertrophy [17], although further studies found opposite results [18], [19]. Association has been also repeatedly examined between ACE genotype and the development and/or progression of diabetic nephropathy, yielding conflicting results [20], [21], [22], [23], [24]. ACE genotype has been reported to correlate with risk for death in patients with myocardial infarction [25], atherosclerotic renovascular disease [26], and in patients treated with dialysis [27]; however, this relationship has not been previously investigated in diabetic patients with ESRD. Accordingly, there remains considerable obscurity in the linkages among ACE genotype, LV hypertrophy, and survival in diabetic patients with ESRD. We therefore conducted this study (1) to evaluate cross-sectionally the association between ACE gene polymorphism and LV geometry in diabetic patients with ESRD, and (2) to determine prospectively the independent effects of ACE genotype on mortality of diabetic patients after the commencement of dialysis.