Combined Association of Creatinine, Albuminuria, and Cystatin C with All-Cause Mortality and Cardiovascular and Kidney Outcomes

, ‡Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland
Clinical Journal of the American Society of Nephrology (Impact Factor: 4.61). 12/2012; 8(3). DOI: 10.2215/CJN.04960512
Source: PubMed


Estimated GFR by serum creatinine (eGFRcreatinine) is a pivotal measure of kidney function in clinical practice but can be affected by several non-GFR determinants, resulting in misclassification. Combining multiple kidney markers to predict risk is an area of substantial interest.

Design, setting, participants, & measurements:
This study followed 9489 adults from visit 4 (1996-1998) of the Atherosclerosis Risk in Communities Study for a median of 11.2 years, and assessed joint association of eGFRcreatinine, eGFRcystatin, and urinary albumin/creatinine ratio (ACR) with mortality, coronary heart disease, heart failure, AKI, and ESRD using Cox proportional hazards models. The predictive ability of ACR and eGFRcystatin beyond eGFRcreatinine was also investigated.

Lower eGFRcreatinine and eGFRcystatin as well as elevated ACR were independently associated with risk for all outcomes. eGFRcreatinine <60 was not associated with risk of mortality, coronary heart disease, or heart failure if eGFRcystatin ≥60 with ACR <30 mg/g compared with those with all three markers above CKD cutoffs (i.e., eGFRcystatin ≥60, eGFRcreatinine ≥60, and ACR<30), whereas risk association with kidney outcomes remained: Hazard ratio (95% confidence interval), 0.96 (0.66, 1.39) for mortality, 0.85 (0.55, 1.31) for coronary heart disease, 0.99 (0.60, 1.63) for heart failure, 1.61 (0.92, 2.82) for AKI, and 3.53 (1.06, 11.68) for ESRD. Adding ACR to the fully adjusted model with eGFRcreatinine or adding eGFRcystatin to both eGFRcreatinine and ACR improved risk classification for all outcomes (P ≤ 0.01).

eGFRcystatin can be a useful confirmatory marker in those with eGFRcreatinine <60 and whose ACR is <30 mg/g. This approach improves risk classification, and provides reassurance to a large group of individuals with eGFRcreatinine <60.

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    ABSTRACT: The application of serum creatinine and cystatin C in patients with CKD has been limited to using estimated glomerular filtration rate (eGFR). Criteria for choosing the best GFR estimating equation are 1) accuracy in estimating measured GFR, 2) optimal discrimination of clinical outcomes, and 3) association with CKD risk factors and outcomes similar to that of measured GFR. Notably, these criteria are often not in agreement; and while the last criterion is the most important, it has been widely overlooked. The primary problem with eGFR is that the non-GFR determinants of serum creatinine and cystatin C, as well as their surrogates (age, sex, and race), associate with CKD risk factors and outcomes. This leads to a distorted understanding of CKD, though eGFR based on serum creatinine appears to be less biased than eGFR based on cystatin C. Because of this problem, the use of eGFR should be limited to settings where knowing actual GFR is relevant and eGFR is more informative about GFR than serum creatinine or cystatin C alone. Such settings include staging CKD severity by GFR and dosing medications cleared by glomerular filtration. Alternatively, the diagnosis of CKD, the longitudinal progression of CKD, and prognostic models for CKD are settings where serum creatinine and cystatin C can be better applied and interpreted without eGFR.
    Preview · Article · May 2013 · Clinical Journal of the American Society of Nephrology
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    ABSTRACT: IMPORTANCE Excess urinary albumin excretion is more common in black than white individuals and is more strongly associated with incident stroke risk in black vs white individuals. Whether similar associations extend to coronary heart disease (CHD) is unclear. OBJECTIVE To determine whether the association of urinary albumin excretion with CHD events differs by race. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of black and white US adults aged 45 years and older who were enrolled within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study between 2003 and 2007 with follow-up through December 31, 2009. We examined race-stratified associations of urinary albumin-to-creatinine ratio (ACR) in 2 groups: (1) incident CHD among 23 273 participants free of CHD at baseline; and (2) first recurrent CHD event among 4934 participants with CHD at baseline. MAIN OUTCOMES AND MEASURES Expert-adjudicated incident and recurrent myocardial infarction and acute CHD death. RESULTS A total of 616 incident CHD events (421 nonfatal MIs and 195 CHD deaths) and 468 recurrent CHD events (279 nonfatal MIs and 189 CHD deaths) were observed over a mean time of 4.4 years of follow-up. Among those free of CHD at baseline, age- and sex-adjusted incidence rates of CHD per 1000 person-years of follow-up increased with increasing categories of ACR in black and white participants, with rates being nearly 1.5-fold greater in the highest category of ACR (>300 mg/g) in black participants (20.59; 95% CI, 14.36-29.51) vs white participants (13.60; 95% CI, 7.60-24.25). In proportional hazards models adjusted for traditional cardiovascular risk factors and medications, higher baseline urinary ACR was associated with greater risk of incident CHD among black participants (hazard ratio [HR] comparing ACR >300 vs <10 mg/g, 3.21 [95% CI, 2.02-5.09]) but not white participants (HR comparing ACR >300 vs <10 mg/g, 1.49 [95% CI, 0.80-2.76]) (P value for interaction = .03). Among those with CHD at baseline, fully adjusted associations of baseline urinary ACR with first recurrent CHD event were similar between black participants (HR comparing ACR >300 vs <10 mg/g, 2.21 [95% CI, 1.22-4.00]) vs white participants (HR comparing ACR >300 vs <10 mg/g, 2.48 [95% CI, 1.61-3.78]) (P value for interaction = .53). CONCLUSIONS AND RELEVANCE Higher urinary ACR was associated with greater risk of incident but not recurrent CHD in black individuals when compared with white individuals. These data confirm that black individuals appear more susceptible to vascular injury.
    No preview · Article · Aug 2013 · JAMA The Journal of the American Medical Association
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