Elsevier

The Lancet

Volume 375, Issue 9731, 12–18 June 2010, Pages 2073-2081
The Lancet

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Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis

https://doi.org/10.1016/S0140-6736(10)60674-5Get rights and content

Summary

Background

Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality.

Methods

In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders.

Findings

The analysis included 105 872 participants (730 577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1 128 310 participants (4 732 110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1·73 m2 and 105 mL/min/1·73 m2 and increased at lower eGFRs. Compared with eGFR 95 mL/min/1·73 m2, adjusted HRs for all-cause mortality were 1·18 (95% CI 1·05–1·32) for eGFR 60 mL/min/1·73 m2, 1·57 (1·39–1·78) for 45 mL/min/1·73 m2, and 3·14 (2·39–4·13) for 15 mL/min/1·73 m2. ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0·6 mg/mmol, adjusted HRs for all-cause mortality were 1·20 (1·15–1·26) for ACR 1·1 mg/mmol, 1·63 (1·50–1·77) for 3·4 mg/mmol, and 2·22 (1·97–2·51) for 33·9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements.

Interpretation

eGFR less than 60 mL/min/1·73 m2 and ACR 1·1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease.

Funding

Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation.

Introduction

Chronic kidney disease is recognised as a major global public health problem.1, 2 The disease affects 10–16% of the adult population in Asia, Australia, Europe, and the USA,3, 4, 5, 6 and increases the risk of all-cause mortality, cardiovascular disease, and progression to kidney failure, even after accounting for traditional risk factors such as hypertension and diabetes mellitus.1, 7

The 2002 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines2 define chronic kidney disease as persistent kidney damage, usually marked by albuminuria or reduced glomerular filtration rate (GFR), and assign disease stages on the basis of GFR. The KDOQI guidelines have encouraged research into the prognostic effect of chronic kidney disease and have contributed to increased awareness of it.8, 9 However, substantial controversy surrounds the use of GFR and albuminuria to define and assign stages to chronic kidney disease. Some investigators have proposed a lower GFR threshold (eg, GFR <45 mL/min/1·73 m2 vs <60 mL/min/1·73 m2) or age-specific or sex-specific GFR thresholds to define chronic kidney disease, use of higher urine albumin-to-creatinine ratio (ACR) as a marker of kidney damage (ACR ≥33·9 mg/mmol [≥300 mg/g] vs ≥3·4 mg/mmol [≥30 mg/g]), combining chronic kidney disease stages 1 and 2 (GFR 60 mL/min/1·73 m2 or more), or adding albuminuria within each stage determined by GFR.2, 8, 9, 10, 11

Several studies have reported the association between estimated GFR (eGFR) or albuminuria and clinical outcomes in the general population. However, most of these studies investigated only one measure at a time, did not investigate age-specific associations, and analysed broad eGFR categories (eg, <60 mL/min/1·73 m2 or ≥60 mL/min/1·73 m2). A few studies have dealt with some, but not all, of these issues.3, 12, 13, 14, 15, 16 Thus, there is a need for a comprehensive examination that adjusts for each measure, tests for their interactions on risk with narrow categories, and examines the association separately in younger and older individuals.

Kidney Disease: Improving Global Outcomes (KDIGO)17 has taken the lead in establishing the Chronic Kidney Disease Prognosis Consortium. The Consortium is tasked with compiling and meta-analysing the best available data to provide a more comprehensive assessment of the independent and combined associations of eGFR and albuminuria with mortality and kidney outcomes. The results of these assessments will have clear implications for improving the definition and staging of chronic kidney disease. The Consortium currently consists of 45 cohorts, which arise from general, high-risk, or chronic kidney disease populations. Separate reports will describe mortality and kidney outcomes by population type. This report describes the findings from a collaborative meta-analysis of the 21 general population cohorts for all-cause and cardiovascular mortality.

Section snippets

Search strategy and selection criteria

We searched PubMed on Aug 6, 2009, for studies published between 1966 and July, 2009, using the following combination of terms: (eGFR OR GFR OR glomerular filtration rate OR kidney function OR renal function) AND (albuminuria OR albumin to creatinine ratio OR ACR OR urinary albumin concentration OR UAC OR dipstick) AND (mortality OR ESRD OR end stage renal disease OR progressive chronic kidney disease OR acute kidney injury) AND (adult[MeSH]) AND (Humans[MeSH]). No language restrictions were

Results

Figure 1 shows the flow diagram of study selection for the analysis. Of the 21 studies included in the analysis, nine were from North America, six from Europe, five from Asia, and one from Australia. Characteristics of included studies are shown in table 1. Median follow-up time was 7·9 years (range 2·1–11·6). Overall, 1 234 182 participants (ACR studies, 105 872 participants; dipstick studies, 1 128 310 participants) were followed up for 5 462 687 person-years (ACR studies, 730 577

Discussion

This meta-analysis, which included more than 100 000 individuals with ACR measurements and 1·1 million participants with dipstick measurements from 21 general population cohorts, showed that eGFR and albuminuria were associated with all-cause mortality and cardiovascular mortality independently of each other and traditional cardiovascular risk factors. The consistency in both continuous and categorical models for eGFR and ACR shows that our findings are robust. With 21 studies from 14 countries

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