In this prospective analysis of a relatively large cohort of patients with type 2 diabetes, we confirmed the risk association between metabolic syndrome and CKD independent of conventional risk factors including age, male sex, glycemic control, disease duration, and albuminuria. This finding is strengthened by the stepwise increase in HR for CKD with an increasing number of metabolic syndrome components. Among the latter, central obesity, hypertriglyceridemia, and hypertension were the three main metabolic syndrome traits related to CKD in this cohort. These three factors were also found to predict all-cause and cardiovascular mortality in a community-based Hong Kong Chinese cohort (13
Of note, we observed the additive effects of high waist circumference and low BMI on risk of CKD independent of metabolic control. There is now general consensus that waist circumference as a surrogate of visceral adiposity (14
) is more strongly correlated with adverse metabolic risks including high blood pressure, dyslipidemia, and increased insulin resistance (15
). Lamacchia et al. (16
) observed recently in subjects with type 2 diabetes that waist circumference but not BMI was associated with an increased renal resistive index, a parameter that reflects intrarenal arteriosclerosis and glomerulosclerosis. Increased adipose tissue, especially that of visceral origin, is a rich source of inflammatory cytokines and growth factors including leptin, tumor necrosis factor-α, and interleukin-6 (17
). In a separate cohort of Chinese patients with type 2 diabetes with nephropathy, we reported aberrant activation and expression of inflammatory cytokines or adhesion molecules, which can have direct effects on renal hemodynamics and glomerular cellularity (18
). Although low BMI may reflect lipolysis and muscle wasting due to hyperglycemia and insufficient insulin action, the risk conferred by low BMI on CKD in our cohort was independent of A1C. In the Japanese population, obesity is an independent predictor for end-stage renal disease in the general population (19
), although low BMI and increased waist circumference are independent predictors for diabetes (20
). Thus, with the onset of diabetes, the effect of body composition and/or distribution may take on different prognostic significance.
In this cohort, hypertriglyceridemia but not a low HDL cholesterol level was predictive of CKD development. In keeping with the clinical observations on lipotoxicity and renal damage, there are experimental studies showing the stimulatory effects of lipids on mesangial cell proliferation and matrix deposition, in addition to recruitment of inflammatory cells and synthesis of inflammatory cytokines (21
). In a recent meta-analysis of 40,000 individuals, the use of hydroxymethylglutaryl-CoA inhibitors attenuated the rate of progression of renal impairment and reduced proteinuria (22
). In a post hoc analysis of a clinical study comparing the effects of fenofibrate and placebo treatment on progression of coronary atherosclerosis, fenofibrate was associated with a greater reduction in albuminuria in patients with type 2 diabetes (23
Metabolic syndrome is now known to be associated with development of cardiovascular diseases (3
). In our current study of the Chinese diabetic population, we observed that metabolic syndrome increased the risk of CKD. Moreover, CKD per se is an independent determinant of atherosclerotic diseases and the two conditions often coexist. In a separate analyses of this cohort, we have demonstrated that albuminuria (24
) and estimated GFR (25
) were strongly predictive of cardiovascular outcome. We proposed that the same metabolic risk factors are operative in the progression of both conditions. In this connection, increased oxidative stress, chronic inflammation, increased fibrogenic activity, and endothelial dysfunction are common underlying pathological events.
Our study has several limitations. First, baseline measurements of serum creatinine were based on a single collection and may not fully reflect the background renal function, especially in the presence of intercurrent illness. At baseline, all clinical and biochemical assessments were performed in an outpatient setting when the patient was clinically stable. Second, although diabetes may be the main culprit for the new onset of CKD in this prospective cohort, other causes such as ischemic nephrosclerosis, obstructive uropathy, and glomerulonephritis may also contribute to deterioration of renal function. Third, some investigators have suggested overestimation of the prevalence of stage 4 to 5 CKD using the original MDRD equations. However, the current modified MDRD formula has been validated in Chinese populations (11
Despite these limitations, the relatively large sample size of the present cohort with detailed phenotyping and a relatively long observational period, averaging 5 years, is an important strength of our study to support the causal relationship between metabolic factors and renal dysfunction. In summary, the presence of metabolic syndrome is associated with an increased risk of development of CKD. Our study has expanded the current body of knowledge on the possible causes of diabetic nephropathy and highlights metabolic syndrome as a major problem for which individuals with diabetes who are at high risk of cardiorenal complications need treatment.