Albuminuria and impaired GFR were independent, additive risk factors for mortality among older adults with diabetes. GFR estimated using serum cystatin C was more strongly associated with mortality than GFR estimated using serum creatinine. These findings support current recommendations to regularly assess both albuminuria and GFR in the clinical care of patients with diabetes (4
) with a sharp focus on interventions to prevent or treat CVD in the presence of albuminuria, impaired GFR, or both and further consideration of cystatin C use in clinical care.
The additive prognostic utilities of albuminuria and impaired GFR are consistent with prior studies in populations without diabetes or with low diabetes prevalence (8
). Demonstration of this relationship in a diabetic population is particularly useful, because this population has a high cardiovascular risk and is well suited for regular health screening. Our results are similar and complementary to those from a Hong Kong cohort in which associations of albuminuria and estimated GFR with incident cardiovascular events were assessed (3
). In contrast, an Italian study of type 2 diabetes observed albuminuria to be the primary renal risk factor for mortality, with estimated GFR being an independent risk factor only at levels <30 ml/min per 1.73 m2
). Our results may differ from results for the Italian study owing to older participant age or to use of serum cystatin C to estimate GFR.
In our study, 53% of participants with impaired GFR (eGFRCYS
<60 ml/min per 1.73 m2
) had urine ACR <30 mg/g. This proportion is higher than that observed in NHANES III, (21
) possibly because of 1
) the added effects of diabetes and advanced age on GFR and 2
) more sensitive detection of impaired GFR using serum cystatin C. This large proportion of participants with impaired GFR but normal urine ACR is similar to that observed in the UK Prospective Diabetes Study (22
), and, when combined with the independent and additive associations of each kidney disease measure with mortality, supports the general concept that albuminuria and impaired GFR are separate but overlapping, complementary manifestations of diabetic kidney disease. This concept has recently emerged as an alternative to an earlier paradigm describing albuminuria and impaired GFR as serial manifestations of diabetic kidney disease along a single, linear disease pathway (23
Thus, albuminuria and impaired GFR may reflect different pathways of kidney damage. Albuminuria may reflect widespread vascular damage and endothelial dysfunction, thus identifying susceptibility to disease in nonrenal vascular beds (25
). Impaired GFR may reflect loss of nephrons and parenchymal fibrosis that leads to CVD through accumulation of uremic toxins, impaired volume and blood pressure regulation, and multiple metabolic abnormalities. Whether albuminuria and impaired GFR lead to CVD through distinct mechanisms, thus requiring distinct interventions, has not been established.
The association of cystatin C–estimated GFR with mortality was modestly stronger than that for GFR estimated from serum creatinine. This finding is consistent with prior studies using the full CHS population (6
). These studies demonstrated 1
) that cystatin C–estimated GFR was linearly associated with mortality risk, whereas MDRD-estimated GFR demonstrated a U-shaped association with mortality, and 2
) that elevated serum cystatin C was associated with mortality when MDRD-estimated GFR was in the “normal” range. It is possible that cystatin C estimates true GFR more precisely in the near-normal range or that cystatin C is less susceptible to confounding by body size among older adults. We evaluated only one formula estimating GFR from cystatin C, which was developed among individuals with impaired kidney function, and other cystatin C–based formulas may perform differently.
In our study, a change in cystatin C–estimated GFR within individuals over time was not associated with mortality more strongly than a single baseline cystatin C measurement. This result may be explained in part by the relatively high correlation of cystatin C concentration within individuals over time and suggests that single cystatin C measurements carry important prognostic information on their own, even without prior context. However, the value of longitudinal measurements may be increased when more measurements per individual are available.
Limitations of this study include the availability of only a single urine ACR measurement and lack of data assessing current glycemic control. Notably, however, we were able to account for diabetes duration and the use of hypoglycemic medications, which reflect cumulative exposure to hyperglycemia and disease severity and have been associated with mortality in CHS (14
). In addition, our findings may not extrapolate to younger diabetic populations. Study strengths include the diverse, community-based diabetic population, multiple measurements of kidney disease, long-term follow-up for mortality and adjudicated CVD events, and large numbers of events to facilitate study of kidney disease interactions.