Our study found subnormal eGFR but not high normal ACR to be a powerful predictor of major CV events in T2DM patients with normoalbuminuria. Low eGFR was significantly associated with incidental major CV events both in older and younger patients with T2DM, the association being more obvious in younger patients.
In a pooled analysis of 4 studies (the Atherosclerosis Risk in Communities, Cardiovascular Health, Framingham Heart, and Framingham Offspring studies),32 it was found that CKD was a risk factor for all-cause mortality in the general population. Another meta-analysis study33 found that diabetic patients with low eGFR (<60 mL/min) and normoalbuminuria had significantly higher all-cause mortality but not CV mortality than those with normal eGFR (≥60 mL/min) and normoalbuminuria. One large study34 of 1,102,581 individuals (75% Asians, 21% Whites, and 4% Blacks) found that low eGFR was independently associated with an increased risk of all-cause mortality and CV mortality in the three major races. However, the National Health and Nutrition Examination Survey (NHANES) I study35 reported that moderate renal insufficiency was not associated with all-cause mortality and CV mortality after adjustment for traditional CV risk factors. The Framingham Heart Study36 did not find baseline kidney disease to be associated with CV mortality in multivariable analyses. Our study also did not find there to be an association between low eGFR and all-cause mortality or CV mortality, although there was a trend toward increased all-cause mortality as the eGFR decreased. Although the first three studies 32–34 were very large and had sufficient statistical power to investigate the relationship between CKD and CV and all-cause mortality, they each had their own definition of normal eGFR as the reference category in the meta-analysis studies. These differences in the definition may have influenced their results. One of them33 evaluated the association between low eGFR and mortality in patients with diabetes, and this meta-analysis concluded that the patient numbers investigating the association between low eGFR and mortality were small. Our study found that eGFR was significantly associated with major CV events but not with CV mortality and all-cause mortality. Therefore, eGFR may be a specific predictor of major CV events but not an unspecific marker of health status.
The traditional definition of microalbuminuria, based on the level of urinary albumin excretion in patients with diabetes, predicts the development of clinical diabetic nephropathy. Although microalbuninuria has been known to be a predictor of CV morbidities and mortality,1–4 it was not until it was discovered that there was an association between low-grade albuminuria and CV events that much attention was paid to it. Gerstein et al1 found any degree of albuminuria, starting well below the microalbuminuria cutoff, to be a risk factor for CV events in individuals with or without diabetes. Klausen et al6,37 reported urinary albumin excretion >4.8 μg/min to be a strong and independent determinant of coronary artery disease and death in the general population and hypertensive subjects. Recently, Huang et al38 found an association between low grade albuminuria, which is below the current cutoff point of microalbuminuria, and carotid intima-media thickness (IMT) in Chinese T2DM. Our current study, however, did not find an association between high normal ACR and incidental major CV events or death in Chinese with normoalbuminuria. The difference between 2 of the previous studies and our current one might be explained by the fact that the subjects of previous studies6,37 came from the general population or were hypertensive subjects with a low prevalence of diabetes. The other study38 focused on the association between albuminuria and carotid IMT, but was not designed to follow progression. Our study evaluated the effect of multiple factorial interventions in a 5-year cohort of normoalbuminuric T2DM patients. Therefore, the difference in our results and those of others may be related in differences in study populations and design. We did not find an association between high normal ACR and risk for major CV events or mortality in normoalbuminuric T2DM Chinese.
A reduced eGFR may be associated with retention of urotoxins and an increased occurrence of nontraditional risk factors of CV events, including chronic inflammation, hyperhomocysteinemia, and increased oxidative stress, all of which could lead to atherosclerosis.39,40 Albuminuria can indicate damage to glomerular basement membranes and may reflect endothelial dysfunction.41 Recently, Drury et al21 reported reduced eGFR and albuminuria to be independent risk factors for CV events and mortality in patients with T2DM. One collaborative meta-analysis42 has also concluded that low eGFR and high ACR were independent predictors of mortality in the general population. Our prospective cohort has clearly demonstrated an inverse relationship between eGFR and major CV events in diabetic patients with normoalbuminuria. This association was obvious even in subjects with eGFR between 61 and 90 mL/min. On the other hand, we found no association between high normal ACR and major CV events. It is likely that reduced eGFR and albuminuria are markers of different pathologic processes. Our findings are in agreement with the ADA recommendation5 that albuminuria and renal function, as estimated by eGFR, be used to assess CV risk in diabetic patients.
This study has several limitations. First, we have not examined the contribution of nontraditional risk factors, which are complex and not routinely measured in daily clinical practice. Nontraditional risk factors such as oxidant stress, elevated inflammatory markers, and homocystine are associated with atherosclerosis and may be additional contributors to high risk of CV events in CKD.43,44 Second, we did not find an association between ACR and adverse outcomes. This could be due to several possible reasons. One possibility is that there is a threshold effect at or near the ACR decision point of 30 mg/g. Another is that the correlations between ACR and adverse outcomes are small and continuous. The inability to show that small changes in ACR within the reference interval are predictive of an adverse outcome could be due to the small size of our sample and the short follow-up time. A third limitation is that we did not demonstrate a relationship between eGFR and CV mortality or all-cause mortality, possibly also due to the small number of CV mortalities and all-cause mortalities. A large cohort study with a longer follow-up time may be necessary to clarify the association between eGFR and mortality. The strengths of the present study should be acknowledged as well. First, this is the first study to evaluate whether subnormal eGFR and high normal ACR are independently associated with CV events and mortality in T2DM with normoalbuminuria under multifactorial intervention. Second, eGFR was calculated by both MDRD and CKD-EPI equations in this study. Third, our study clarifies the important role of renal function, as estimated by eGFR, showing it can be used in the assessment of CV risk in diabetic patients with normoalbuminuria. Although the ADA recommends that albuminuria and renal function, as estimated by eGFR, to be used to assess CV risk in diabetic patients,5 the awareness of CKD by general practitioners is low in diabetic population.45 One study also reported the low rates of CKD detection at a large hospital.46 Furthermore, some studies reported that eGFR was not a strong predictor of CV events in the absence of microalbuminuria. It is reasonable to hypothesize that unawareness of CKD is common especially in diabetic patients with normoalbuminuria in the real world practice.
In conclusion, this study found subnormal eGFR to be a strong predictor of major CV events in diabetic patients with normoalbuminuria. Renal function, as estimated by eGFR, can be used to assess CV risk in diabetic patients with normoalbuminuria. Normoalbuminuric diabetic patients with subnormal eGFR are at higher risk of CV events and may need intensive CV risk factor intervention to prevent and treat CV events.
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