Articles
Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data

https://doi.org/10.1016/S2213-8587(15)00040-6Get rights and content

Summary

Background

The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach.

Methods

We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4·2–19·0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both.

Findings

The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0·0139 [95% CI 0·0105–0·0174] for ACR and 0·0065 [0·0042–0·0088] for eGFR) and heart failure (0·0196 [0·0108–0·0284] and 0·0109 [0·0059–0·0159]) than for coronary disease (0·0048 [0·0029–0·0067] and 0·0036 [0·0019–0·0054]) and stroke (0·0105 [0·0058–0·0151] and 0·0036 [0·0004–0·0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0·0227 (0·0158–0·0296) after omission of eGFR and ACR compared with less than 0·007 for any single modifiable traditional predictor.

Interpretation

Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population.

Funding

US National Kidney Foundation, National Institute of Diabetes and Digestive and Kidney Diseases.

Introduction

Individuals with chronic kidney disease (CKD) are at high risk of cardiovascular disease,1 and roughly half die of cardiovascular disease without developing end-stage renal disease.2 Two key kidney measures for definition and staging of CKD—glomerular filtration rate (GFR) and albuminuria—are consistently associated with high cardiovascular risk in a broad range of populations.3 However, previous studies assessing whether these measures of kidney disease improve cardiovascular risk prediction beyond traditional risk factors have shown conflicting results,4, 5, 6, 7, 8, 9 leading to controversy in guidelines for primary prevention as to whether CKD status should be taken into account for classification of cardiovascular risk.10, 11

Significant associations do not necessarily result in improvement of risk prediction,12 and previous studies varied substantially in terms of study population, cardiovascular outcomes or measures of interest for kidney disease (eg, often omitting albuminuria), and statistics to assess prediction improvement,4, 5, 6, 7, 8, 9 making it difficult to resolve the discrepancy between risk association and prediction in this context, and to achieve definitive conclusions.

We used data from the extensive database of the CKD Prognosis Consortium (CKD-PC) to examine the role of GFR and albuminuria in prediction of various cardiovascular outcomes beyond traditional risk factors, using standard definitions and analytic approaches across contributing cohorts. We aimed to assess these issues in primary prevention (ie, individuals without history of cardiovascular disease), in which traditional risk factors are most relevant for cardiovascular risk prediction.5

Research in context

Evidence before this study

We searched PubMed in addition to manual searches of reference lists of previous studies, and identified a few studies specifically assessing the improvement of cardiovascular risk prediction by incorporation of either or both kidney measures (estimated glomerular filtration rate [eGFR] based on serum creatinine, cystatin C, or both) and kidney damage (based on albuminuria or proteinuria), exclusively or predominantly in individuals without history of cardiovascular disease at baseline. However, these studies obtained conflicting results and varied substantially in terms of study population and method, making achievement of definitive conclusions difficult and leading to inconsistent approaches about how to incorporate measures of kidney disease in assessment of cardiovascular risk across different clinical guidelines.

Added value of this study

We meta-analysed individual-level data from 24 cohorts (637 315 participants without a history of cardiovascular disease) and assessed risk prediction improvement with either or both of creatinine-based eGFR and albuminuria (albumin-to-creatinine ratio [ACR] or dipstick proteinuria) for cardiovascular mortality, coronary disease, stroke, and heart failure. Although creatinine-based eGFR and albuminuria independently improved cardiovascular prediction in general, the improvement was particularly evident for cardiovascular mortality and heart failure. ACR outperformed eGFR and most of the modifiable traditional risk factors for these two outcomes, as well as stroke. The discrimination improvement with ACR was especially evident in individuals with diabetes or hypertension but remained significant for cardiovascular mortality and heart failure even in those without either of these disorders. When the analysis was restricted to patients with chronic kidney disease (CKD), the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors, suggesting the value of their simultaneous assessment for cardiovascular risk classification.

Implications of all the available evidence

Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when they are already assessed for clinical purposes (eg, in individuals with chronic kidney disease, diabetes, or hypertension), or when cardiovascular mortality and heart failure are the outcomes of interest (eg, as stated by European guidelines for cardiovascular prevention). ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved cardiovascular risk classification, supporting current guidelines for chronic kidney disease.

Section snippets

Study design and data sources

In this collaborative, individual-level meta-analysis, we used data from cohorts joining the CKD-PC, details of which have been previously described.3, 13 This analysis used data from 24 cohorts (19 general-population cohorts, three high-risk cohorts of individuals with diabetes, and two CKD cohorts exclusively enrolling patients with CKD), all with data about fatal and non-fatal cardiovascular outcomes and median follow-up longer than 4 years. We restricted analyses to individuals aged 18

Results

Our analysis included 637 315 individuals from 24 cohorts with no history of cardiovascular disease, who had a mean age of 47 years (SD 16) and were followed up for a mean of 8·9 years (SD 4·6), equivalent to 6 million person-years after excluding 146 769 individuals because of missing values for eGFR, albuminuria, or traditional risk factors at baseline (table 1; appendix pp 13–15). Almost all black individuals were from four US general-population cohorts, and data for Asian individuals were

Discussion

In this collaborative, individual-level meta-analysis, eGFR and albuminuria independently improved the prediction of incident cardiovascular events beyond traditional risk factors. In the general population, the improvement was greater with ACR than with eGFR or dipstick proteinuria and was more evident for cardiovascular mortality and heart failure than for coronary heart disease and stroke. ACR was better than most of the modifiable traditional risk factors for prediction of cardiovascular

References (33)

  • H Ito et al.

    The effect of including cystatin C or creatinine in a cardiovascular risk model for asymptomatic individuals: the multi-ethnic study of atherosclerosis

    Am J Epidemiol

    (2011)
  • DE Weiner et al.

    Kidney disease, Framingham risk scores, and cardiac and mortality outcomes

    Am J Med

    (2007)
  • CM Clase et al.

    Estimated glomerular filtration rate and albuminuria as predictors of outcomes in patients with high cardiovascular risk: a cohort study

    Ann Intern Med

    (2011)
  • J Perk et al.

    European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts)

    Eur Heart J

    (2012)
  • DC Goff et al.

    2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

    Circulation

    (2014)
  • MS Pepe et al.

    Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker

    Am J Epidemiol

    (2004)
  • Cited by (0)

    View full text