| COMMENTARIES |
Effects of Renal Function and Metabolic Syndrome Components on Cardiovascular and All-Cause Mortality
Kuo-Liong Chien, M.D., Ph.D., Associate Professor, Institute of Preventive Medicine, College of Public Health, National Taiwan University, Department of Internal Medicine, National Taiwan University Hospital, Email: klchien@ntu.edu.tw
Background and Issues
Impaired renal function and metabolic syndrome have been associated with the risk of cardiovascular disease (CVD) [1,2]. We investigated their roles in CVD and all-cause death among ethnic Chinese population. Cross-sectional studies have shown a significant relationship between chronic kidney disease, metabolic syndrome, and atherosclerotic risk among populations, but data on prospective cohorts for further cardiovascular events were limited. In addition, the potential additive effects of the chronic kidney disease and metabolic syndrome, after considering the individual markers, were still unknown in ethnic Chinese populations. The focus of the study was on renal function, uric acid, and metabolic syndrome factors, particularly the potential mediating effects among these risk factors on CVD and all-cause mortality.
Materials and Methods
Two renal function indices were used: serum creatinine levels and estimated glomerular filtration rate (GFR) (ml/min), which was calculated by the Cockroft-Cault equations (i.e. (140-age) x (weight in kg)/(72 x creatinine in mg/dL) for men, and the value multiplied by 0.85 for women due to smaller muscle mass [3]. We defined CVD mortality by the death codes 390 to 459 from the 9th version of the International Classification of Diseases.
Results
We followed up a cohort of 11,429 men and 7,472 women aged 20 years and older for an average 4.9 years (median: 3.5, inter-quartile range: 2.7-7.9) from the tertiary hospital health checkup population and found that 500 subjects died, including 106 due to CVD deaths. CVD death rates increased when the quintiles of each variable progressed. Metabolic syndrome was a significant predictor for CVD death, with relative risk of up to 4.68. Quintiles of serum creatinine concentrations, estimated glomerular filtration rate (GFR), and uric acids were significantly associated CVD death, with the highest relative risk of creatinine concentration (11.22, 95% confidence interval [CI]: 2.43-51.7, P for trend: < 0.001). Serum creatinine concentrations and estimated GFR had the higher areas under ROC curves of CVD death (0.76, 95% CI: 0.71-0.80 for creatinine and 0.76, 95% CI: 0.72-0.81 for estimated GFR). Metabolic syndrome and impaired renal function had the most significant roles in predicting CVD deaths; the multivariate relative risk was 30.6 (95% CI: 3.7-254, P: 0.002) in participants with the highest creatinine and presence of metabolic syndrome compared with those with the lowest and absence of metabolic syndrome.
Role and Renal Function on CVD Risk
Researchers argued that could there be a causal relationship between chronic renal insufficiency and CVD death, or that renal insufficiency is only a marker for co-morbidities or disease severity [4]. Evidence on clustering of renal insufficiency, metabolic syndrome, and atherosclerotic risk factors from observational studies implied renal function was associated with metabolic syndrome components. There is evidence that supports the role of renal impairment in CVD risk, as well as the potential mechanisms for cardio-renal interaction. First, impaired renal function worsens hypertension, activates the renin-angiotensin system, increases sodium and water retention, and induces hyper-coagulation and inflammatory reactions in the body, which aggravates atherosclerotic burden. Second, excess co-morbidities of metabolic syndrome components also contribute to worsening CVD risks among subjects with chronic or end-stage renal disease. Finally, chronic renal disease has multiple effects on vascular dysfunctions, which induce atherosclerosis. Our data showed substantial effects of renal impairment on CVD events, and the results were consistent with other ethnic population-based cohorts, such as U.S.-based and Asian-based studies [1,5]. A nation-wide survey showed a high prevalence of renal impairment but low awareness in the Taiwanese general population; therefore, screening on renal function is mandatory for primary prevention of CVD in the general population.
Role of Metabolic Syndrome and Components on CVD Risk
Previous studies have shown that metabolic syndrome and its components were important risk factors for CVD death [6]. The existence of metabolic syndrome enforced the effects of renal insufficiency on CVD and all-cause death. The interrelationships among obesity, metabolic syndrome, and chronic kidney disease would worsen further CVD events among patients with renal insufficiency. We used traditional NCEP definition of metabolic syndrome, and the other definitions, such as those of the International Diabetes Federation (IDF) and the American Heart Association (AHA) which have similar prognostic implications for the outcomes [7]. Also, prior studies on Asian populations have demonstrated that, while BMI and metabolic syndrome are important predictors of CVD and death, substantially lower values of BMI (even those considered in the “normal” range for US-based populations) are still predictive of increasing poor prognosis. Our data also showed mild obesity still had high risks for CVD mortality.
Role of Uric Acid on CVD Risk
There were inconsistent study results on the relationship between hyperuricemia and CVD risk. Our previous study results, based on a community-based cohort, have demonstrated that uric acid had marginally statistically significant roles for CVD events. Our present data showed that the role of uric acid in CVD death remained significant after multivariate and metabolic syndrome adjustments. Metabolic syndrome induces high oxidative stress and the accompanying hyperuricemia worsens the oxidative stress. Furthermore, uric acid stimulates vascular smooth muscle proliferation and induces endothelial dysfunction. The increase of uric acid decreases endothelial nitric oxide production and consequently makes peripheral tissue resistant to insulin effects and results in endothelial dysfunction. Moreover, high uric acid is associated with increased renal glomerular pressure and increased renal sodium reabsorption, and these renal reactions are greatly enhanced by high insulin concentrations. In addition, hyperuricemia was associated with insulin resistance markers, including triglycerides, microalbuminuria, and impaired glucose tolerance. The combination effects of insulin resistance and hyperuricemia on renal functions resulted in high cardiovascular risk.
Clinical Implications
Our results have several clinical implications. First, mild renal function impairment should be an indicator for clinical monitoring and close follow-up of renal function, such as serum creatinine concentrations or estimated GFR in the general population, should be mandatory. Second, metabolic syndrome and renal function makers had additive risks on CVD and all-cause death. Hence, lifestyle intervention on metabolic syndrome prevention and salt restriction on renal function should be emphasized in the primary care setting and in the public health environment. Further randomized controlled trial designs can address the effects of prevention of metabolic syndrome and renal function deterioration on clinical outcomes.
Conclusion
In summary, renal function indices were strongly associated with CVD and all-cause death rates in the ethnic Chinese who undertook health examinations in one tertiary hospital. We clearly demonstrated the additive risks of impaired renal function, uric acid, and metabolic syndrome components of CVD death risk. Optimal treatments on renal function preservation and prevention of metabolic syndrome are mandatory for the prevention of CVD and all-cause deaths.
References