In this prospective study, a lower annual eGFR is predictive of all-cause as well as expanded and non-expanded CVD-related mortalities in patients with diabetes. The predictive ability of a lower annual eGFR values was based on the presence of proteinuria. Similarly, the predictive ability of proteinuria was based on the stages of renal function measured by eGFR. This finding is important because the current guidelines for the classification and staging of chronic kidney disease are based on eGFR, without considering concomitant proteinuria. Our findings provide the estimates of the risk stratification by eGFR along with proteinuria for Chinese patients with type 2 diabetes.
Our finding that lower GFR values are associated with a higher risk of all-cause mortality is consistent with previous studies[13, 14, 29–31]. In addition, studies have shown that lower eGFR values are associated with about a 3-fold higher risk of CVD mortality. Similar results were observed between the current study and those of Casale Monferrato Study and Nag et al., and the association in the Casale Monferrato Study did not reach statistical significance. In addition to more precise results, three major advantages were obtained using the methodology in the present study. One is that we measured time-varying mean annual eGFR. Second, previous studies did not consider co-morbidities and complications when they explored these associations. The possibility that co-morbidities and complications may explain the relationships observed was ruled out by further considering the effects of co-morbidities and complications. The associations still remained significant, although the effect was attenuated. Third, previous studies did not use both proteinuria and eGFR to predict mortality. This information would be potentially useful in informing ongoing discussions about how best to stratify the risk of mortality among patients with type 2 diabetes using both proteinuria and eGFR.
Several plausible explanations for the association between decreased renal function and mortality were identified. First, diabetic patients with decreased renal function have a higher prevalence of several CVD risk factors, including hypertension, dyslipidemia, and obesity, as well as complications. In our study, the prevalence of hypertension was 2.14 times higher, 1.29 times higher for dyslipidemia, 1.12 times higher for obesity, 3.55 times higher for stroke, 4.00 times higher for coronary artery disease, and 1.71 for myocardial infarction among patients with eGFR < 60 mL/min/1.73 m2 than among patients with eGFR ≥90 mL/min/1.73 m2. These chronic conditions resulted in decreased renal function. Decreased renal function itself may exert an independent effect on mortality. Another possible explanation is that decreased renal function results in lower clearance and higher plasma levels of inflammatory and oxidative stress factors, such as homocysteine and asymmetric dimethylarginine. These unmeasured factors may explain the higher risk of mortality in patients with decreased renal function. In addition, decreased renal function may exacerbate hypertension and activate the rennin-angiotensin system, which may also increase the risk of mortality. These two biological mechanisms both aggravate atherosclerotic burden and potentially increase the risk of CVD.
Our findings have several clinical implications. First, decreased renal function is an important indicator of renal function in patients with diabetes. Proteinuria status, serum creatinine concentrations, and eGFR values of these patients should be routinely monitored. Second, lifestyle intervention and use of medications that can prevent the deterioration of renal function should be emphasized in diabetes care.
Our study has several strengths, including a large number of patients with diabetes, a long follow-up period, the use of a standardized procedure for data collection, and available information on a large number of potential confounding factors. In addition, we averaged repeated eGFR measurements to reduce random variation of measurement errors and improve precision. We also used time-varying eGFR to increase the accuracy of renal function measurement.
Our study has several limitations that need to be considered when interpreting our results. First, we did not screen other measures of impaired kidney function, such as microalbuminuria or cystatin C. Microalbuminuria may be a better marker of early kidney dysfunction, and cystatin C may be a better marker of chronic kidney disease than creatinine. Second, we used the MDRD equation to estimate GFR based on serum creatinine levels. Creatinine levels are affected by differences in muscle mass, and muscle mass distribution varies across gender and age. Although the MDRD equation was developed to consider population differences in muscle mass by age and gender, it does not consider individual differences. Third, despite adjustments for a large number of potential confounders, including lifestyle behaviors, medications, and complications, residual and unrecognized confounding may be present because of the observational nature of our study. Lastly, all patients with type 2 diabetes in this study were enrolled in a Diabetes Care Management Program at a single medical center; thus, they may not be representative of all diabetic patients in Taiwan. In order to evaluate generalizability, we compare the age and gender distributions between the age and gender structure in our study and the national population with type 2 diabetes that was enrolled in the Nation Health Insurance program, which has a coverage rate of more than 99%. Similar distributions were found; the differences in proportions for categories of age and gender distributions between these two groups ranged from 0.56% to 5.24%. The non-differential distributions in age and sex indicate the representativeness of our study sample.
In conclusion, proteinuria and eGFR are independently predictive of all-cause and both expanded and non-expanded CVD-related mortalities in patients with type 2 diabetes, supporting the importance of renal function in mortality prevention. Furthermore, risk stratification by eGFR alone may be relatively insensitive to clinically relevant risk gradients. Therefore, the use of proteinuria measurement with eGFR increases the precision of risk stratification for mortality.