Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts
2011; Elsevier BV; Volume: 80; Issue: 1 Linguagem: Inglês
10.1038/ki.2010.531
ISSN1523-1755
AutoresRon T. Gansevoort, Kunihiro Matsushita, Marije van der Velde, Brad C. Astor, Mark Woodward, Andrew S. Levey, Paul E. de Jong, Josef Coresh,
Tópico(s)Acute Kidney Injury Research
ResumoBoth a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m2 but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors. Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m2 but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors. This is the third in a series of four manuscripts to report the results of collaborative meta-analyses of estimated GFR (eGFR) and albuminuria on outcomes of chronic kidney disease (CKD) undertaken by the CKD Prognosis Consortium. These analyses were undertaken in conjunction with the 2009 Controversies Conference sponsored by Kidney Disease Improving Global Outcomes (KDIGO) to evaluate the current definition and classification of CKD and proposed alternatives.1.Eckardt K.U. Berns J.S. Rocco M.V. et al.Definition and classification of CKD: the debate should be about patient prognosis–a position statement from KDOQI and KDIGO.Am J Kidney Dis. 2009; 53: 915-920Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar The report of the Consensus Conference is included in this issue of Kidney International.2.Levey A.S. de Jong P.E. Coresh J. et al.Chronic kidney disease - definition, classification and prognosis: a KDIGO controversies conference reaches a consensus.Kidney Int. 2010; 375: 2073-2081Google Scholar Widespread implementation of the definition and classification of CKD, as proposed by Kidney Disease Outcomes Quality Initiative (KDOQI) in 2002 and subsequently endorsed by KDIGO in 2004, has promoted increased attention to CKD in clinical practice, research, and public health.3.National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-266Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 4.Levey A.S. Coresh J. Balk E. et al.NKF practice guidelines for CKD: evaluation, classification and stratification.Arch Int Med. 2003; 139: 137-147Google Scholar, 5.Levey A.S. Eckardt K.U. Tsukamoto Y. et al.Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2005; 67: 2089-2100Abstract Full Text Full Text PDF PubMed Scopus (2202) Google Scholar, 6.Levey A.S. Atkins R. Coresh J. et al.Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.Kidney Int. 2007; 72: 247-259Abstract Full Text Full Text PDF PubMed Scopus (947) Google Scholar It has also generated substantial debate about the appropriateness of recommending the same GFR thresholds for people of all ages, the optimal level of albuminuria for diagnosing kidney damage, and about the value of the 5-stage classification system based on eGFR without consideration of albuminuria.7.Gansevoort R.T. de Jong P.E. The case for using albuminuria in staging chronic kidney disease.J Am Soc Nephrol. 2009; 20: 465-468Crossref PubMed Scopus (83) Google Scholar, 8.Glassock R.J. Winearls C. An epidemic of chronic kidney disease: fact or fiction?.Nephrol Dial Transpl. 2008; 23: 1117-1123Crossref PubMed Scopus (169) Google Scholar, 9.Ikizler T.A. CKD classification: time to move beyond KDOQI.J Am Soc Nephrol. 2009; 20: 929-930Crossref PubMed Scopus (26) Google Scholar, 10.Wetzels J.F. Willems H.L. den Heijer M. Age- and gender-specific reference values of estimated glomerular filtration rate in a Caucasian population: results of the Nijmegen Biomedical Study.Kidney Int. 2008; 73: 657-658Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 11.Winearls C.G. Glassock R.J. Dissecting and refining the staging of chronic kidney disease.Kidney Int. 2009; 75: 1009-1014Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar It was the position of KDOQI and KDIGO that a comprehensive analysis of mortality and kidney outcomes according to eGFR and albuminuria was needed to answer key questions underlying the debate.1.Eckardt K.U. Berns J.S. Rocco M.V. et al.Definition and classification of CKD: the debate should be about patient prognosis–a position statement from KDOQI and KDIGO.Am J Kidney Dis. 2009; 53: 915-920Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 2.Levey A.S. de Jong P.E. Coresh J. et al.Chronic kidney disease - definition, classification and prognosis: a KDIGO controversies conference reaches a consensus.Kidney Int. 2010; 375: 2073-2081Google Scholar Until recently, most of the data on kidney outcomes were from studies of patients with later stages of CKD rather than from general population cohorts or cohorts at increased risk for CKD.12.Ruggenenti P. Perna A. Mosconi L. et al.Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. ‘Gruppo Italiano di Studi Epidemiologici in Nefrologia’ (GISEN).Kidney Int. 1998; 53: 1209-1216Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 13.Keane W.F. Zhang Z. Lyle P.A. Brenner B.M. RENAAL Study Investigators et al.Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: the RENAAL study.Clin J Am Soc Nephrol. 2006; 1: 761-767Crossref PubMed Scopus (145) Google Scholar, 14.Jafar T.H. Stark P.C. Schmid C.H. Levey A.S. AIPRD Study Group et al.Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis.Ann Intern Med. 2003; 139: 244-252Crossref PubMed Scopus (897) Google Scholar Reports from the general population and high-risk cohorts focused mainly on all-cause and cardiovascular mortality,15.Wen C.P. Cheng T.Y. Tsai M.K. et al.All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462 293 adults in Taiwan.Lancet. 2008; 371: 2173-2182Abstract Full Text Full Text PDF PubMed Scopus (655) Google Scholar, 16.Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8250) Google Scholar, 17.Hallan S. Astor B. Romundstad S. et al.Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: the HUNT II Study.Arch Intern Med. 2007; 167: 2490-2496Crossref PubMed Scopus (213) Google Scholar, 18.Astor B.C. Hallan S.I. Miller III, E.R. et al.Glomerular filtration rate, albuminuria, and risk of cardiovascular and all-cause mortality in the US population.Am J Epidemiol. 2008; 167: 1226-1234Crossref PubMed Scopus (259) Google Scholar, 19.Brantsma A.H. Bakker S.J. Hillege H.L. Gansevoort R.T. PREVEND Study Group et al.Cardiovascular and renal outcome in subjects with K/DOQI stage 1–3 chronic kidney disease: the importance of urinary albumin excretion.Nephrol Dial Transplant. 2008; 23: 3851-3858Crossref PubMed Scopus (135) Google Scholar, 20.Hemmelgarn B.R. Manns B.J. Lloyd A. et al.Relation between kidney function, proteinuria, and adverse outcomes.JAMA. 2010; 303: 423-429Crossref PubMed Scopus (752) Google Scholar with fewer data available on kidney outcomes.19.Brantsma A.H. Bakker S.J. Hillege H.L. Gansevoort R.T. PREVEND Study Group et al.Cardiovascular and renal outcome in subjects with K/DOQI stage 1–3 chronic kidney disease: the importance of urinary albumin excretion.Nephrol Dial Transplant. 2008; 23: 3851-3858Crossref PubMed Scopus (135) Google Scholar, 20.Hemmelgarn B.R. Manns B.J. Lloyd A. et al.Relation between kidney function, proteinuria, and adverse outcomes.JAMA. 2010; 303: 423-429Crossref PubMed Scopus (752) Google Scholar, 21.van der Velde M. Halbesma N. de Charro F.T. et al.Screening for albuminuria identifies individuals at increased renal risk.J Am Soc Nephrol. 2009; 20: 852-862Crossref PubMed Scopus (111) Google Scholar, 22.Hallan S.I. Ritz E. Lydersen S. et al.Combining GFR and albuminuria to classify CKD improves prediction of ESRD.J Am Soc Nephrol. 2009; 20: 1069-1077Crossref PubMed Scopus (233) Google Scholar In this manuscript, we describe a collaborative meta-analysis of nine general population and eight high-risk cohorts. The outcomes reported in this manuscript include kidney failure treated by dialysis or transplantation (end-stage renal disease (ESRD)) or coded on the death certificate. In addition, we also included acute kidney injury, because it is increasingly recognized as a major cause for23.Coca S.G. Long-term outcomes of acute kidney injury.Curr Opin Nephrol Hypertens. 2010; 19: 266-272Crossref PubMed Scopus (35) Google Scholar and consequence of CKD,24.Goldberg R. Dennen P. Long-term outcomes of acute kidney injury.Adv Chronic Kidney Dis. 2008; 15: 297-307Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar and kidney disease progression, based on fast eGFR decline (progressive CKD), because of its clinical importance and potential to lead to ESRD or other complications. Other papers in this series deal with all-cause and cardiovascular mortality in general population cohorts and high-risk cohorts.25.The Chronic Kidney Disease Prognosis Consortium Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality: a collaborative meta-analysis of general population cohorts.Lancet. 2010; 375: 2073-2081Abstract Full Text Full Text PDF PubMed Scopus (2460) Google Scholar, 26The Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality: a collaborative meta-analysis of high risk cohorts. Kidney Int. (submitted).Google Scholar This report describes the kidney outcomes from these cohorts. A fourth manuscript reports mortality and kidney outcomes in CKD cohorts.27The Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with mortality and end-stage renal disease: a collaborative meta-analysis of kidney disease cohorts. Kidney Int.. (submitted).Google Scholar A priori we hypothesized that both eGFR and albuminuria would be associated with these outcomes, independent of traditional cardiovascular risk factors and independent of each other, and despite inclusion of diverse study populations. Of the nine general population cohorts (845,125 subjects), five had data on albumin-to-creatinine ratio and four on dipstick. Of the eight high-risk cohorts (173,892 subjects), five had data on albumin-to-creatinine ratio and three on dipstick (Table 1). Acronyms and abbreviations for studies included in the current report are given in Supplementary Web appendix Table S1 online. Subjects in the high-risk cohorts were more often male, and these cohorts had a higher prevalence of cardiovascular risk factors than did the general population cohorts. Moreover, the high-risk cohorts generally had a lower eGFR and higher albumin-to-creatinine ratio. Not all cohorts had data on all kidney outcomes. There were a total of 2179, 4939, and 11,144 participants who developed ESRD, acute kidney injury, and progressive CKD, respectively. The incidence rates for the kidney outcomes were two- to sixfold higher in the high-risk cohorts compared with the general population cohorts (1.83 versus 0.31 for ESRD, 4.88 versus 2.21 for acute kidney injury, and 18.44 versus 7.55 events per 1000 person-years for progressive CKD, respectively) (Supplementary Web appendix Tables S1–4 online, respectively). A total of 13.7% of the subjects of general population cohorts with albumin-to-creatinine ratio data had CKD according to the current definition (eGFR <60 ml/min per 1.73 m2 or albumin-to-creatinine ratio ≥30 mg/g) (Supplementary Web appendix Table S5 online). This subgroup accounted for 88.6% of ESRD events (Supplementary Web appendix Table S6 online), 61.5% of acute kidney injury events (Supplementary Web appendix Table S7 online), and 76.7% of subjects with progressive CKD (Supplementary Web appendix Table S8 online).Table 1Characteristics of included studiesNAge, yearMale, %Black, %CVD, %HT, %HC, %DM, %Smoking, %eGFR, ml/min per 1.73 m2ACR, mg/gFU, YearESRD, nAKI, npCKD, nGeneral population cohorts with ACR data147427173 ARIC11,40862.844.222.28.647.634.516.714.982.53.78.092363— AusDiab11,24051.544.908.332.770.68.415.578.94.95.0——72 CHS323078.040.215.929.350.131.014.77.679.48.87.6—64— HUNT2952562.044.8022.582.561.317.619.783.87.510.555—— MESA672862.247.227.50.044.89.012.613.081.25.34.7—101General population cohorts with dipstick data71334384624 AKDN UDIP690,68047.445.1NA1.820.2NA6.1NA80.9—2.347834384475 Beaver Dam492662.043.9014.850.553.910.319.776.2—11.6——149 Okinawa 83665951.939.5NANANANA3.8NA73.9—16.861—— Okinawa 9393,23454.643.6NANANANA4.7NA77.3—6.9174——High-risk cohorts with ACR data74010744935 ADVANCE11,14065.857.5NA32.282.233.010015.178.215.94.859—822 AKDN ACR67,40655.556.8NA5.046.8NA49.0NA76.811.12.319110131572 ONTARGET25,62066.473.32.592NA*NA*37.512.673.652.24.5162611914 Pima634126.445.40NA12.94.220.427.814411.913.5328—273 TRANSCEND592666.9571.892.5NA*NA*35.79.871.725.34.6——354High-risk cohorts with dipstick data579—1412 CARE409858.687.23.210082.979.014.216.171.9—4.8——124 Hawaii40,21059.050.4NA17.0NANA48.013.671.5—2.4331—1288 MRFIT12,85146.210031.30.062.357.13.163.779.7—21.6248——Abbreviations: ACR, albumin-to-creatinine ratio; AKI, acute kidney injury; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; FU, duration of follow-up; HC, hypercholesterolemia; HT, hypertension; NA, not available; pCKD, progressive chronic kidney disease.NA* in ONTARGET and TRANSCEND, respectively, a history of hypertension was reported by 69 and 76%, and statin use by 62 and 55%. Open table in a new tab Download .doc (.93 MB) Help with doc files Supplementary Information Abbreviations: ACR, albumin-to-creatinine ratio; AKI, acute kidney injury; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; FU, duration of follow-up; HC, hypercholesterolemia; HT, hypertension; NA, not available; pCKD, progressive chronic kidney disease. NA* in ONTARGET and TRANSCEND, respectively, a history of hypertension was reported by 69 and 76%, and statin use by 62 and 55%. Pooled hazard ratios of ESRD according to eGFR and albuminuria adjusted for each other and covariates in the general population cohorts and the high-risk cohorts are shown in Figure 1. ESRD risk was relatively constant between an eGFR of 75 and 120 ml/min per 1.73 m2, and was exponentially greater at lower eGFR. In the general population cohorts, eGFR risk association with ESRD showed hazard ratios at eGFR 60, 45, and 15 ml/min per 1.73 m2 of 3.69 (2.36–5.76), 29.3 (19.5–44.1), and 454.9 (112.4–1840.2), respectively. The relationship of albumin-to-creatinine ratio to the relative risk of ESRD was monotonic on the log–log scale, without threshold effects. As compared with albumin-to-creatinine ratio 5 mg/g, hazard ratios for ESRD at albumin-to-creatinine ratios of 30, 300 and 1000 mg/g were 4.87 (2.30–10.3), 13.4 (5.49–32.7), and 28.4 (14.9–54.2), respectively. These patterns for ESRD in the high-risk cohorts were similar to the general population cohorts (Figure 1). The patterns for acute kidney injury and progressive CKD were generally similar to the patterns for ESRD, although less steep (Supplementary Web appendix Figures S1, S2 online). The multiplicative interaction between eGFR and albuminuria was significant for ESRD in only 1 out of 8 cohorts, for acute kidney injury in 3 out of 5 cohorts, and for progressive CKD in 4 out of 11 cohorts (Supplementary Web appendix Table S9 online). Significant interaction between eGFR and age was found for ESRD in only 1 out of 9 cohorts, for acute kidney injury in 3 out 5 cohorts, and for progressive CKD in 4 out of 11 cohorts (Supplementary Web appendix Table S9 online). Age interactions tended to show lower hazard ratios at older age, but a similar pattern of the associations of eGFR and albumin-to-creatinine ratio with the various kidney outcomes (Supplementary Web appendix Tables S10–12 online). The eGFR × albumin-to-creatinine ratio interaction can be visually assessed in graph 2. At low eGFR, the hazard ratio of higher albumin-to-creatinine ratio tended to be less than at high eGFR for ESRD as well as for acute kidney injury, but not for progressive CKD. As the albumin-to-creatinine ratio and the dipstick cohorts showed similar relationships between eGFR and albuminuria with ESRD, these two type of cohorts were combined to increase power for investigation of the joint associations of eGFR and albuminuria with kidney outcomes, both in general population and in high-risk cohorts (Supplementary Web appendix Figure S3 online). Table 2 shows unadjusted incidence rates of the three kidney outcomes for general population cohorts. Pooled hazard ratios/odds ratios for ESRD, acute kidney injury, and progressive CKD of the 21 categories of eGFR and albuminuria for the general population cohorts are shown in Tables 3 and 4. Low eGFR showed a similar association with risk across all levels of albuminuria, and high albuminuria showed a similar association with risk across all levels of eGFR, indicating multiplicative independent risk for kidney outcomes. At severely reduced eGFR values (15–29 ml/min per 1.73 m2), the risk associated with higher albuminuria was attenuated. The patterns were much steeper (that is, risk increased more rapidly with increasing albuminuria) for ESRD than for acute kidney injury and progressive CKD (Tables 3 and 4). Figure 2 shows the continuous analyses (allowing interaction) of the hazard ratios/odds ratios of eGFR and albuminuria for ESRD, acute kidney injury, and progressive CKD, respectively.Table 2General population cohorts Open table in a new tab Table 3General population cohortsView Large Image Figure ViewerDownload (PPT) Open table in a new tab Table 4General population cohortsView Large Image Figure ViewerDownload (PPT) Open table in a new tab Figure 2Pooled adjusted hazard ratios or odds ratios (95% confidence interval) for ESRD (upper panels), acute kidney injury (middle panels), and progressive chronic kidney disease (lower panels) according to eGFR and albuminuria based on continuous models with eGFR (splines), albuminuria (log-linear albumin-to-creatinine ratio or categorical dipstick), and their interaction terms. Hazard ratios are adjusted for age, sex, and cardiovascular risk factors. Reference category is eGFR 95 ml/min per 1.73 m2 plus albumin-to-creatinine ratio 5 mg/g or dipstick negative or trace. Left panels shows results for general population cohorts, and right panels for high-risk cohorts. Dots represent statistical significance, triangles represent non-significance, and shaded areas are 95% confidence interval. In this figure, albuminuria is treated categorically. Black lines and blue shading represent an albumin-to-creatinine ratio <30 mg/g or dipstick negative or trace, green lines and green shading an albumin-to-creatinine ratio 30–299 mg/g or dipstick 1+, and red lines and red shading an albumin-to-creatinine ratio ≥300 mg/g or dipstick ≥2+. AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GP cohorts, general population cohorts; HR, hazard ratio; HR cohorts, high-risk cohorts; OR, odds ratio; pCKD, progressive chronic kidney disease.View Large Image Figure ViewerDownload (PPT) Similar data are given for cohorts at high risk for CKD (Tables 5, 6 and 7). The patterns for ESRD were less steep in the high-risk cohorts (Table 6) compared with the general population cohorts (Table 3), whereas the patterns for acute kidney injury and progressive CKD were similar in the general population cohorts and high-risk cohorts.Table 5High-risk cohorts Open table in a new tab Table 6High-risk cohortsView Large Image Figure ViewerDownload (PPT) Open table in a new tab Table 7High-risk cohortsView Large Image Figure ViewerDownload (PPT) Open table in a new tab The overall incidence rates for the kidney outcomes were three- to ninefold higher in the subgroup of subjects with age ≥65 years compared with the subgroup with age <65 years (Supplementary Web appendix Tables S2–4 online, respectively). Pooled hazard ratios for ESRD of the 21 categories of eGFR and albuminuria according to age group are shown in Table 4 for the general population cohorts and in Table 5 for the high-risk cohorts. The general pattern of higher risk for a lower eGFR independent of albuminuria level and of a higher albuminuria independent of eGFR level was observed in both age groups. However, in general, relative hazards were smaller among participants ≥65 years of age than among participants <65 years of age (Supplementary Web appendix Table S10 online). Similar findings were obtained for acute kidney injury (Supplementary Web appendix Table S11 online) and progressive CKD (Supplementary Web appendix Table S12 online). eGFR × albumin-to-creatinine ratio categories with significant heterogeneity are shown in the Supplementary Web appendix Table S10–12 online. Quantitative heterogeneity, rather than qualitative heterogeneity, was observed in several categories, reflecting numerical differences in the hazard ratios between cohorts, but the direction of the risk was similar in all cohorts (increased risk with lower eGFR categories and with higher albuminuria categories). However, in all cohorts, the direction of the risk was similar (increased risk with lower eGFR categories and with higher albuminuria categories). Moreover, significant heterogeneity was limited to the lowest eGFR and the highest albuminuria categories. There was no significant heterogeneity in the groups with eGFR of 45–60 ml/min per 1.73 m2 and in the groups with microalbuminuria (albumin-to-creatinine ratio 30–299 mg/g or dipstick 1+), either in the general population or in the high-risk population. Meta-regression analysis was performed to test whether the association between eGFR and albumin-to-creatinine ratio with outcomes differed by the proportion of diabetic participants within each high-risk cohort. The proportion of diabetic participants was not significantly associated with the hazard ratio for ESRD associated with eGFR (45 versus 95 ml/min per 1.73 m2; P=0.58) or albumin-to-creatinine ratio (30 versus 5 mg/g; P=0.31). Likewise, the proportion of diabetic participants was not significantly associated with the hazard ratio for progressive CKD associated with eGFR (P=0.57) or albumin-to-creatinine ratio (P=0.96). There were too few cohorts with sufficient events to allow similar meta-regression models for acute kidney injury. In this collaborative meta-analysis of nine general population and eight high-risk cohorts, including a total of more than 1 million subjects, we found that lower eGFR and higher albuminuria were associated with a higher risk for ESRD, independent of each other and independent of traditional CVD risk factors. A similar association of eGFR and albuminuria was found with the risk for acute kidney injury and for progressive CKD, although the relative hazards were higher for ESRD. The risk for ESRD based on eGFR and albuminuria have been reported in a limited number of follow-up studies from general population cohorts.20.Hemmelgarn B.R. Manns B.J. Lloyd A. et al.Relation between kidney function, proteinuria, and adverse outcomes.JAMA. 2010; 303: 423-429Crossref PubMed Scopus (752) Google Scholar, 22.Hallan S.I. Ritz E. Lydersen S. et al.Combining GFR and albuminuria to classify CKD improves prediction of ESRD.J Am Soc Nephrol. 2009; 20: 1069-1077Crossref PubMed Scopus (233) Google Scholar, 28.Iseki K. Kinjo K. Iseki C. et al.Relationship between predicted creatinine clearance and proteinuria and the risk of developing ESRD in Okinawa, Japan.Am J Kidney Dis. 2004; 44: 806-814Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 29.Ishani A. Grandits G.A. Grimm R.H. et al.Association of single measurements of dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25-year incidence of end-stage renal disease in the multiple risk factor intervention trial.J Am Soc Nephrol. 2006; 17: 1444-1452Crossref PubMed Scopus (212) Google Scholar, 30.Imai E. Horio M. Yamagata K. et al.Slower decline of glomerular filtration rate in the Japanese general population: a longitudinal 10-year follow-up study.Hypertens Res. 2008; 31: 433-441Crossref PubMed Scopus (209) Google Scholar The current meta-analysis confirms these studies and extends the generalizability of these data to other populations worldwide. Furthermore, our collaborative meta-analysis includes 2201 ESRD outcomes, substantially more than the number of events in reports of individual studies, thereby allowing evaluation of the independent and joint associations of eGFR and albuminuria with this outcome. In addition, we included data on acute kidney injury and progressive CKD, other kidney disease outcomes of clinical and epidemiologic interest. We found similar patterns in studies that had data on albumin-to-creatinine ratio and in the studies that only had semiquantitative information available on dipstick proteinuria. These findings suggest that measurement of dipstick proteinuria is useful for risk stratification, despite being a less precise measure of albuminuria. This is of importance considering the lower cost of dipstick compared with albumin-to-creatinine ratio measurement. However, studies directly comparing dipstick testing with more accurate albuminuria measurements are needed to investigate sensitivity, specificity, and negative and positive predictive value to make definite recommendations for screening. Also, it is important to bear in mind that most studies had measured albuminuria only once, thus raising questions regarding reproducibility and chronicity of albuminuria. However, the finding that a single urine test has significant prognostic implication strengthens the conclusion that albuminuria is an important risk factor. In addition, a single test may underestimate rather than overestimate the risk associated wi
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