In the largest single population-based study of eGFR and CHD to our knowledge thus far, we have shown that there are no strong associations between lower-than-average eGFR and CHD risk in apparently healthy adults over most of the range in renal function. A moderate association may, however, exist among individuals with very low eGFR, i.e., those with eGFR near or less than 60 ml/min/1.73 m2
of body surface area. This cut point coincides with the definition of CKD suggested by the American National Kidney Foundation [25
]. Such an association implies a nonlinear effect of low eGFR on CHD risk, a possibility that requires evaluation in larger numbers. Moderate associations among individuals with eGFR near or less than 60 ml/min/1.73 m2
of body surface area were consistently observed with CHD risk in many clinically relevant subgroups, such as in women and men and at different levels of established risk factors and other characteristics (e.g., blood glucose levels and haematocrit). Our updated meta-analysis reinforces the validity and generalisability of the new data from the Reykjavik study; examination of several study characteristics in our review did not identify important sources of heterogeneity. Finally, our data demonstrate that the decade-to-decade consistency in renal function in apparently healthy adults is similar to that for blood pressure or total blood cholesterol, although larger assessments will be required to assess whether this variability differs importantly at different levels of renal function.
These findings from the Reykjavik study may have several implications. First, the apparent lack of any association of renal function in the normal range with CHD risk implies that strategies which aim to shift the population distribution of renal function may not be optimum for the purposes of CHD prevention [30
]. By contrast, suggestions of associations of lower-than-normal eGFR with CHD risk encourage further investigation of targeting existing cardioprotective interventions (such as lipid- and blood pressure-lowering agents [6
]) in the 5%–10% of the general western adult population who fulfil the criteria for CKD [34
]. Second, highly significant associations of low eGFR with tissue plasminogen activator antigen that have been observed stimulate interest in the potential relevance of haemostasis to renal function [35
], whereas there were no strong cross-sectional associations of low eGFR with C-reactive protein, interleukin 6, and lipoprotein(a) [36
]. Third, our data highlight the need for studies that can determine whether eGFR is primarily a risk factor for CHD or mainly a marker of subclinical cardiovascular diseases (i.e., reflecting the extent and severity of atherosclerosis in renal and other vascular beds such as the coronary circulation [10
]). The former possibility has been highlighted in previous reports of significant correlations between coronary and renal arteriosclerosis in the absence of any overt clinical CKD or CHD [39
]. The latter possibility is suggested by the modest residual association observed between low eGFR and CHD risk after adjustment for measured levels of established risk factors, as adjustment for the full impact of these risk factors might have reduced the association still further (or even abolished it).
The strengths and potential limitations of the present study merit careful consideration. Our report involves new data on eGFR levels and incident CHD that almost double the available evidence on major CHD outcomes in population-based studies and avoids the potentially misleading analysis of heterogeneous cardiovascular disease outcomes used in some studies. We identified participants in population registers, had high response and follow-up rates, used robust methods to ascertain CHD outcomes, and minimized potential biases by exclusion of participants with prevalent diabetes, CHD, and stroke. Concomitant measurements of several established risk factors and emerging markers in the same participants enabled adjustment for a range of possible confounding factors. Although our assays produced creatinine values comparable with those in earlier studies (), eGFR might not be optimal for use in general populations, because standard prediction equations used to calculate it have been developed in patients with kidney disease [21
]. Furthermore, serum creatinine is, of course, an imperfect indicator of GFR because it is influenced by creatinine generation and tubular secretion, but the eGFR equations employed in the current analyses are in widespread use and take into account age, sex, and weight (the latter only in the Cockcroft-Gault equation). Future studies may improve on eGFR methods by recalibration of serum creatinine assays to the isotope-dilution mass spectrometry standard [43
] and by measurement of potentially more sensitive markers such as serum cystatin C [45
] or symmetric and asymmetric dimethylarginine (SDMA and ADMA) [46
]. The current analyses do not address low eGFR and CHD risk among ethnic groups who may be particularly susceptible to the effects of impaired renal function [48
Our new large-scale data in apparently healthy Western adults—reinforced by a meta-analysis of previous relevant studies in similar populations (i.e., Western European, North American, or Australian)—suggest that levels of eGFR compatible with the definition of CKD are associated with about a 40% increased risk in subsequent CHD. These findings could have implications for further understanding the pathogenesis of CHD and targeting existing cardioprotective interventions.