Portal de Periódicos da CAPES

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts

2011; Elsevier BV; Volume: 79; Issue: 12 Linguagem: Inglês

10.1038/ki.2010.550

1523-1755

Brad C. Astor, Kunihiro Matsushita, Ron T. Gansevoort, Marije van der Velde, Mark Woodward, Andrew S. Levey, Paul E. de Jong, Josef Coresh,

Renal Diseases and Glomerulopathies

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m2 lower eGFR below a threshold of 45 ml/min per 1.73 m2 was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD. We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m2 lower eGFR below a threshold of 45 ml/min per 1.73 m2 was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD. This manuscript is the fourth in a series of manuscripts to report the results of collaborative meta-analyses of estimated glomerular filtration rate (eGFR) and albuminuria on outcomes of chronic kidney disease (CKD) undertaken by the CKD Prognosis Consortium. These analyses were conducted in conjunction with the 2009 Controversies Conference, sponsored by Kidney Disease Improving Global Outcomes (KDIGO), which sought to evaluate the current definition and classification of CKD and propose alternatives. The report of the Consensus Conference is included in this issue of Kidney International.1.Levey A.S. de Jong P.E. Coresh J. et al.The definition, classification and prognosis of chronic kidney disease: a KDIGO Controversies Conference report.Kidney Int. 8 December 2010; (e-pub ahead of print)Google Scholar The first three papers in this series dealt with all-cause and cardiovascular mortality and with kidney outcomes in general population cohorts and high-risk cohorts.2.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, 3.van der Velde M. Matsushita K. Coresh J. et al.Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts.Kidney Int. 2011Abstract Full Text Full Text PDF Scopus (546) Google Scholar, 4.Gansevoort R.T. Matsushita K. van der Velde M. et al.Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes in both general and high-risk populations. A collaborative meta-analysis of general and high-risk population cohorts.Kidney Int. 2011Google Scholar This paper reports the results of a collaborative meta-analysis of mortality and end-stage renal disease (ESRD) in 13 CKD cohorts, including predominantly individuals with CKD of diverse clinical diagnoses accompanied by decreased eGFR and elevated levels of albuminuria, corresponding to microalbuminuria or macroalbuminuria. We hypothesized a priori 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 particular relevance to these cohorts is the question of whether the severity of albuminuria provides additional prognostic information among individuals with CKD, over and above eGFR, as the current classification of CKD does not have separate stages by severity of albuminuria.1.Levey A.S. de Jong P.E. Coresh J. et al.The definition, classification and prognosis of chronic kidney disease: a KDIGO Controversies Conference report.Kidney Int. 8 December 2010; (e-pub ahead of print)Google Scholar, 5.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 Previous reports of the associations of eGFR and albuminuria with outcomes in CKD studies did not use uniform analytic approaches, and most reports were not powered to evaluate the independent associations of eGFR and albuminuria with these outcomes.6.Menon V. Wang X. Sarnak M.J. et al.Long-term outcomes in nondiabetic chronic kidney disease.Kidney Int. 2008; 73: 1310-1315Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 7.Wright Jr, J.T. Bakris G. Greene T. et al.Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002; 288: 2421-2431Crossref PubMed Scopus (1526) Google Scholar, 8.Brenner B.M. Cooper M.E. de Z.D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar A total of 21,688 participants from 14 studies are included in at least one analysis, including 6 randomized controlled trials, 4 observational studies of referred patients, and 4 studies of participants identified by laboratory testing (Table 1 and Supplementary Appendix S1 online).6.Menon V. Wang X. Sarnak M.J. et al.Long-term outcomes in nondiabetic chronic kidney disease.Kidney Int. 2008; 73: 1310-1315Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 7.Wright Jr, J.T. Bakris G. Greene T. et al.Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002; 288: 2421-2431Crossref PubMed Scopus (1526) Google Scholar, 8.Brenner B.M. Cooper M.E. de Z.D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar, 9.Levin A. Djurdjev O. Beaulieu M. et al.Variability and risk factors for kidney disease progression and death following attainment of stage 4 CKD in a referred cohort.Am J Kidney Dis. 2008; 52: 661-671Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 10.Landray M.J. Thambyrajah J. McGlynn F.J. et al.Epidemiological evaluation of known and suspected cardiovascular risk factors in chronic renal impairment.Am J Kidney Dis. 2001; 38: 537-546Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 11.Johnson E.S. Thorp M.L. Yang X. et al.Predicting renal replacement therapy and mortality in CKD.Am J Kidney Dis. 2007; 50: 559-565Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 12.Van Zuilen A.D. Wetzels J.F. Bots M.L. et al.MASTERPLAN: study of the role of nurse practitioners in a multifactorial intervention to reduce cardiovascular risk in chronic kidney disease patients.J Nephrol. 2008; 21: 261-267PubMed Google Scholar, 13.Dieplinger B. Mueller T. Kollerits B. et al.Pro-A-type natriuretic peptide and pro-adrenomedullin predict progression of chronic kidney disease: the MMKD Study.Kidney Int. 2009; 75: 408-414Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 14.Moranne O. Froissart M. Rossert J. et al.Timing of onset of CKD-related metabolic complications.J Am Soc Nephrol. 2009; 20: 164-171Crossref PubMed Scopus (276) Google Scholar, 15.Ruggenenti P. Perna A. Remuzzi G. ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy.J Am Soc Nephrol. 2001; 12: 2832-2837PubMed Google Scholar, 16.Ruggenenti P. Perna A. Loriga G. et al.Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial.Lancet. 2005; 365: 939-946Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, 17.Hovind P. Tarnow L. Rossing P. et al.Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study.BMJ. 2004; 328: 1105Crossref PubMed Google Scholar, 18.Clark L.E. Prescott G. Fluck N. et al.Reduced eGFR—does this mean CKD? (abstract).Nephrol Dial Transplant. 2007; 22: ix54-ix62Google Scholar A total of 4374 deaths occurred in the 10 studies from which information on mortality was captured. Of these studies, six had data on albumin-to-creatinine ratio (ACR), three had data on protein-to-creatinine ratio (PCR), and one had data on dipstick proteinuria. The mortality incidence rate varied dramatically from 19.8 to 254.7 per 1000 person-years. A total of 4157 ESRD events occurred in the 12 studies from which such information was captured. Of these studies, six had data on ACR, five had data on PCR and one had data on dipstick proteinuria. The ESRD incidence rate varied markedly from 13.6 to 115.3 per 1000 person-years. The mean eGFR varied from 22.2 to 69.8 ml/min per 1.73 m2. The median ACR varied from 26.5 to 1245.5 mg/g and the median PCR varied from 80.8 to 2337.4 mg/g (Table 2).Table 1Participating studies and incidence of mortality and end-stage renal diseaseStudy designSource/interventionNMortalityEnd-stage renal diseaseFollow-up, yearsNo. of eventsIncidence rateaPer 1000 person-years.Follow-up, yearsNo. of eventsIncidence rateaPer 1000 person-years.Studies with albumin-to-creatinine ratio British Columbia9.Levin A. Djurdjev O. Beaulieu M. et al.Variability and risk factors for kidney disease progression and death following attainment of stage 4 CKD in a referred cohort.Am J Kidney Dis. 2008; 52: 661-671Abstract Full Text Full Text PDF PubMed Scopus (214) Google ScholarObservationalReferred13,0382.8244966.12.5222268.9 CRIB10.Landray M.J. Thambyrajah J. McGlynn F.J. et al.Epidemiological evaluation of known and suspected cardiovascular risk factors in chronic renal impairment.Am J Kidney Dis. 2001; 38: 537-546Abstract Full Text Full Text PDF PubMed Scopus (93) Google ScholarObservationalReferred3086.111561.44.2149115.3 Grampian-ACR23.Clark L.E. Prescott G. Fluck N. et al.Reduced eGFR-does this mean CKD? (abstract).Nephrol Dial Transplant. 2007; 22: ix54-ix62Google ScholarObservationalIdentified by laboratory results2082.794166.0——— MASTERPLAN12.Van Zuilen A.D. Wetzels J.F. Bots M.L. et al.MASTERPLAN: study of the role of nurse practitioners in a multifactorial intervention to reduce cardiovascular risk in chronic kidney disease patients.J Nephrol. 2008; 21: 261-267PubMed Google ScholarClinical trialNurse practitioner- aided care6204.15019.84.16124.8 Nephro Test14.Moranne O. Froissart M. Rossert J. et al.Timing of onset of CKD-related metabolic complications.J Am Soc Nephrol. 2009; 20: 164-171Crossref PubMed Scopus (276) Google ScholarObservationalReferred1021———2.514255.1 RENAAL8.Brenner B.M. Cooper M.E. de Z.D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google ScholarClinical trialLosartan15132.831367.23.434179.3 Steno17.Hovind P. Tarnow L. Rossing P. et al.Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study.BMJ. 2004; 328: 1105Crossref PubMed Google ScholarObservationalClinic3808.911533.97.55418.6 Overall17,088—3136——2969—Studies with protein-to-creatinine ratio AASK7.Wright Jr, J.T. Bakris G. Greene T. et al.Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002; 288: 2421-2431Crossref PubMed Scopus (1526) Google ScholarClinical trial, followed by observational studyAntihypertensives and blood pressure goal10848.725026.47.531138.5 Grampian-PCR23.Clark L.E. Prescott G. Fluck N. et al.Reduced eGFR-does this mean CKD? (abstract).Nephrol Dial Transplant. 2007; 22: ix54-ix62Google ScholarObservationalIdentified by laboratory results1592.394254.7——— MDRD6.Menon V. Wang X. Sarnak M.J. et al.Long-term outcomes in nondiabetic chronic kidney disease.Kidney Int. 2008; 73: 1310-1315Abstract Full Text Full Text PDF PubMed Scopus (63) Google ScholarClinical trial, followed by observational studyDietary protein restriction8399.520826.16.2553105.8 MMKD13.Dieplinger B. Mueller T. Kollerits B. et al.Pro-A-type natriuretic peptide and pro-adrenomedullin predict progression of chronic kidney disease: the MMKD Study.Kidney Int. 2009; 75: 408-414Abstract Full Text Full Text PDF PubMed Scopus (60) Google ScholarObservationalReferred203———4.07389.8 REIN15.Ruggenenti P. Perna A. Remuzzi G. ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy.J Am Soc Nephrol. 2001; 12: 2832-2837PubMed Google ScholarClinical trialRamipril352———2.68188.8 REIN 2 (ref. 16.Ruggenenti P. Perna A. Loriga G. et al.Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial.Lancet. 2005; 365: 939-946Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar)Clinical trialRamipril335———1.972113.0 Overall2972—552——1090—Studies with dipstick proteinuria Kaiser Permanente Northwest11.Johnson E.S. Thorp M.L. Yang X. et al.Predicting renal replacement therapy and mortality in CKD.Am J Kidney Dis. 2007; 50: 559-565Abstract Full Text Full Text PDF PubMed Scopus (50) Google ScholarObservationalIdentified by laboratory results16284.568692.64.49813.6Overall21,688—4374——4157—Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CRIB, Chronic Renal Impairment in Birmingham; MASTERPLAN, Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of a Nurse Practitioner; MDRD, Modification of Diet in Renal Disease; MMKD, Mild to Moderate Kidney Disease Study; REIN, Ramipril Efficacy in Nephropathy; REIN 2, Ramipril Efficacy in Nephropathy 2; RENAAL, Reduction of Endpoints in Non-insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; Steno, Steno Type 1 Diabetes Study.a Per 1000 person-years. Open table in a new tab Download .pdf (.07 MB) Help with pdf files Supplementary InformationTable 2Baseline characteristics of participating study populationsMean age, years (s.d.)Female, %Black, %CVD, %DM, %Smoking, %Hypertension, %Hypercholesterolemia, %Median ACR/PCR, mg/gMean eGFR ml/min per 1.73 m2 (s.d.)Studies with albumin-to-creatinine ratio British Columbia68.5 (13.9)44.80.523.532.45.441.1—94.634.9 (17.9) CRIB61.7 (14.2)34.15.845.517.213.390.6—467.222.2 (10.6) Grampian-ACR73.0 (11.4)56.4024.28.561.659.5—26.534.6 (5.8) MASTERPLAN60.5 (12.4)31.02.730.224.320.295.418119.136.3 (13.2) Nephro Test59.6 (15.0)31.79.616.026.010.088.716.677.641.1 (20.1) RENAAL60.2 (7.4)36.815.235.010018.196.4—1245.539.8 (12.3) Steno42.6 (10.8)38.1010.210051.982.236.9498.069.8 (27.5)Studies with protein-to-creatinine ratio AASK54.6 (10.7)38.8100.051.6029.310055.680.842.5 (13.2) Grampian-PCR73.4 (14.8)61.6017.02.555.452.8—300.934.6 (6.2) MDRD51.7 (12.4)39.57.99.65.116.686.223.0268.532.6 (12.3) MMKD46.4 (12.3)34.0012.3021.789.238.41035.043.4 (26.7) REIN49.5 (13.6)23.60.607.718.286.4—2337.442.9 (18.5) REIN 254.2 (15.0)25.1005.116.173.1—1875.331.0 (16.7)Studies with dipstick proteinuria Kaiser Permanente Northwest71.79 (9.73)56.03.144.838.812.892.926.0—45.7 (10.5)Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CRIB, Chronic Renal Impairment in Birmingham; MASTERPLAN, Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of a Nurse Practitioner; MDRD, Modification of Diet in Renal Disease; MMKD, Mild to Moderate Kidney Disease Study; REIN, Ramipril Efficacy in Nephropathy; REIN 2, Ramipril Efficacy in Nephropathy 2; RENAAL, Reduction of Endpoints in Non-insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; Steno, Steno Type 1 Diabetes Study. Open table in a new tab Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CRIB, Chronic Renal Impairment in Birmingham; MASTERPLAN, Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of a Nurse Practitioner; MDRD, Modification of Diet in Renal Disease; MMKD, Mild to Moderate Kidney Disease Study; REIN, Ramipril Efficacy in Nephropathy; REIN 2, Ramipril Efficacy in Nephropathy 2; RENAAL, Reduction of Endpoints in Non-insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; Steno, Steno Type 1 Diabetes Study. Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CRIB, Chronic Renal Impairment in Birmingham; MASTERPLAN, Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of a Nurse Practitioner; MDRD, Modification of Diet in Renal Disease; MMKD, Mild to Moderate Kidney Disease Study; REIN, Ramipril Efficacy in Nephropathy; REIN 2, Ramipril Efficacy in Nephropathy 2; RENAAL, Reduction of Endpoints in Non-insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; Steno, Steno Type 1 Diabetes Study. The incidence rate of mortality was generally greater in lower eGFR categories, but there was wide variation in the incidence rate across studies at every eGFR category (Figure 1a). After adjustment, all eight of the studies included showed a positive association between lower eGFR category and mortality (Table 3). Four of the eight studies had a significantly higher hazard ratio (HR) for an eGFR of 30–44 ml/min per 1.73 m2 compared with 45–74 ml/min per 1.73 m2, and seven of eight studies had a significantly elevated HR for an eGFR of 15–29 ml/min per 1.73 m2 compared with 45–74 ml/min per 1.73 m2. In continuous analyses, additionally adjusted for category of ACR, PCR, or dipstick proteinuria, below an eGFR of 45 ml/min per 1.73 m2, the association between a 15 ml/min per 1.73 m2 lower eGFR and mortality was statistically significant in five of eight studies, with a pooled HR of 1.47 (95% confidence interval (CI): 1.22, 1.79; Figure 2a). There was significant heterogeneity between studies in the HR estimates (I2=82.7%; P<0.001).Table 3Adjusted hazard ratio (95% confidence interval) for mortality, by estimated glomerular filtration rate categoryaAdjusted for age, sex, race, previous cardiovascular disease, smoking status, diabetes mellitus, systolic blood pressure, and serum total cholesterol concentration.Estimated glomerular filtration rate (ml/min per 1.73 m2)45–7430–4415–29<15Studies with albumin-to-creatinine ratio British ColumbiaReference1.40 (1.20, 1.62)3.06 (2.66, 3.52)4.07 (3.42, 4.84) CRIBReference1.18 (0.14, 9.65)1.93 (0.24, 15.32)3.39 (0.43, 26.88) MASTERPLANReference1.32 (0.54, 3.20)2.62 (1.11, 6.21)4.49 (1.08, 18.66) RENAALReference1.13 (0.84, 1.50)1.95 (1.43, 2.66)— StenoReference1.46 (0.80, 2.68)2.78 (1.48, 5.19)5.90 (2.33, 14.96)Studies with protein-to-creatinine ratio AASKReference1.66 (1.25, 2.20)1.55 (1.10, 2.19)6.28 (0.85, 46.44) MDRDReference1.75 (1.10, 2.77)1.79 (1.13, 2.85)1.68 (0.79, 3.57)Studies with dipstick proteinuria Kaiser Permanente NorthwestReference1.24 (1.05, 1.47)2.41 (1.94, 2.99)—OverallReference1.35 (1.23, 1.49)2.25 (1.81, 2.79)3.74 (2.69, 5.20)Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CRIB, Chronic Renal Impairment in Birmingham; MASTERPLAN, Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of a Nurse Practitioner; MDRD, Modification of Diet in Renal Disease; RENAAL, Reduction of Endpoints in Non-insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; Steno, Steno Type 1 Diabetes Study.a Adjusted for age, sex, race, previous cardiovascular disease, smoking status, diabetes mellitus, systolic blood pressure, and serum total cholesterol concentration. Open table in a new tab Figure 2Forest plot of adjusted hazard ratio for mortality associated a 15 ml/min per 1.73 m2 lower estimated glomerular filtration rate and an eightfold higher albumin-to-creatinine ratio or protein-to-creatinine ratio. Forest plot of adjusted hazard ratio for mortality associated with (a) a 15 ml/min per 1.73 m2 lower estimated glomerular filtration (eGFR) rate (below an eGFR of 45 ml/min per 1.73 m2) and (b) an eightfold higher albumin-to-creatinine ratio or protein-to-creatinine ratio. The models are adjusted for age, sex, race, previous cardiovascular disease, smoking status, diabetes mellitus, systolic blood pressure, serum total cholesterol concentration, and albuminuria (a) or eGFR splines (b). AASK, African American Study of Kidney Disease; CI, confidence interval; CKD, chronic kidney disease; CRIB, Chronic Renal Impairment in Birmingham; Grampian-ACR, Grampian albumin-to-creatinine ratio; Grampian-PCR, Grampian protein-to-creatinine ratio; Kaiser NW, Kaiser Permanente Northwest; MASTERPLAN, Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse Practitioners; MDRD, Modification of Diet in Renal Disease; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; Steno, Steno Type 1 Diabetes Study.View Large Image Figure ViewerDownload (PPT) Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CRIB, Chronic Renal Impairment in Birmingham; MASTERPLAN, Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of a Nurse Practitioner; MDRD, Modification of Diet in Renal Disease; RENAAL, Reduction of Endpoints in Non-insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; Steno, Steno Type 1 Diabetes Study. The incidence rate of mortality also varied within albuminuria categories, with a higher incidence with higher albuminuria categories in most studies (Figure 1b). After adjustment, a higher albuminuria category was also associated with the risk of mortality (Table 4). The third category of albuminuria, compared with the lowest category, had a statistically significant association with mortality risk in two of the five studies with ACR, in two of the three studies with PCR, and in one study with dipstick proteinuria. After additional adjustment for eGFR category, an eightfold higher ACR was significantly associated with mortality risk in four of seven studies, and an eightfold higher PCR was significantly associated with mortality in all three studies (Figure 2b). The pooled HR for ACR studies (1.36; 95% CI: 1.16, 1.59) was very similar to the pooled estimate for PCR studies (1.46; 95% CI: 1.28, 1.66), without evidence of significant heterogeneity overall (I2=39.9%; P=0.10).Table 4Adjusted hazard ratio (95% confidence interval) for mortality, by albuminuria categoryaAdjusted for age, sex, race, previous cardiovascular disease, smoking status, diabetes mellitus, systolic blood pressure, and serum total cholesterol concentration.Albumin-to creatinine ratio (mg/g)<3030–299300–999≥1000British ColumbiaReference1.49 (1.26, 1.77)2.42 (2.09, 2.81)3.01 (2.51, 3.62)CRIBReference1.65 (0.83, 3.27)2.15 (1.05, 4.40)3.56 (1.80, 7.02)Grampian-ACRReference1.14 (0.05, 27.74)14.91 (0.60, 369.78)43.91 (1.90, 1014.98)MASTERPLANReference1.12 (0.58, 2.14)0.53 (0.19, 1.46)1.10 (0.41, 2.90)StenoReference2.39 (0.96, 5.93)1.95 (0.81, 4.69)2.32 (0.94, 5.76)OverallReference1.50 (1.28, 1.75)1.85 (1.08, 3.16)2.73 (1.74, 4.26)Protein-to-creatinine ratio (mg/g)<5050–499500–1499≥1500AASKReference1.82 (1.35, 2.45)1.93 (1.30, 2.87)2.60 (1.54, 4.40)Grampian-PCRReference0.53 (0.22, 1.27)0.99 (0.40, 2.45)0.73 (0.25, 2.14)MDRDReference0.99 (0.52, 1.88)2.17 (1.06, 4.46)1.80 (0.85, 3.80)OverallReference1.08 (0.54, 2.18)1.81 (1.30, 2.53)1.72 (0.90, 3.29)Dipstick category-/±++++++Kaiser Permanente NorthwestReference1.46 (1.16, 1.82)1.58 (1.28, 1.95)1.98 (1.48, 2.64)OverallReference1.46 (1.24, 1.71)1.80 (1.38, 2.35)2.26 (1.68, 3.04)Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CRIB, Chronic Renal Impairment in Birmingham; MASTERPLAN, Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of a Nurse Practitioner; MDRD, Modification of Diet in Renal Disease; Steno, Steno Type 1 Diabetes Study.a Adjusted for age, sex, race, previous cardiovascular disease, smoking status, diabetes mellitus, systolic blood pressure, and serum total cholesterol concentration. Open table in a new tab Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CRIB, Chronic Renal Impairment in Birmingham; MASTERPLAN, Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of a Nurse Practitioner; MDRD, Modification of Diet in Renal Disease; Steno, Steno Type 1 Diabetes Study. The incidence rate of ESRD was markedly greater with lower eGFR categories (Figure 3a). After adjustment, 9 of 11 studies had a significantly higher HR for an eGFR of 30–44 ml/min per 1.73 m2 compared with 45–74 ml/min per 1.73 m2, with a pooled HR of 2.72 (95% CI: 1.29, 3.37; Table 5). All 11 studies had a significantly elevated HR for an eGFR of 15–29 ml/min per 1.73 m2 compared with 45–74 ml/min per 1.73 m2. In continuous analyses, additionally adjusting for ACR, PCR, or dipstick proteinuria category as appropriate, below an eGFR of 45 ml/min per 1.73 m2, the association between a 15 ml/min per 1.73 m2 lower eGFR and ESRD was statistically significant in all 12 studies (Figure 4a). Each 15 ml/min per 1.73 m2 lower eGFR was associated with a 6.24-fold (95% CI: 4.84, 8.05) higher risk of ESRD after adjustment for albuminuria and other covariates. There was significant heterogeneity between studies in the HR estimates (I2=87.9%; P<0.001).Table 5Adjusted hazard ratio (95% confidence interval) for end-stage renal disease, by estimated glomerular filtration rate categoryaAdjusted for age, sex, race, previous cardiovascular disease, smoking status, diabetes mellitus, systolic blood pressure, and serum total cholesterol concentration.Estimated glomerular filtration rate (ml/min per 1.73 m2)45–7430–4415–29<15Studies with albumin-to-creatinine ratio British Columbia1.0 (reference)1.90 (1.54, 2.35)8.34 (6.90, 10.07)25.97 (21.24, 31.75) MASTERPLAN1.0 (reference)2.51 (0.28, 22.51)40.66 (5.57, 296.57)203.60 (25.68, 1614.08) NephroTest1.0 (reference)3.75 (1.41, 9.96)14.67 (5.88, 36.61)75.80 (29.73, 193.26) RENAAL1.0 (reference)2.66 (1.85, 3.82)9.33 (6.50, 13.40)— Steno1.0 (reference)4.17 (1.89, 9.18)13.08 (6.05, 28.28)156.93 (34.44, 715.10)Studies with protein-to-creatinine ratio AASK1.0 (reference)3.49 (2.49, 4.88)12.24 (8.88, 17.02)118.85 (27.53, 513.09) MDRD1.0 (reference)2.68 (1.92, 3.73)6.75 (4.87, 9.34)27.35 (17.85, 41.90) MMKD1.0 (reference)9.34 (2.10, 41.52)21.25 (5.01, 90.05)121.44 (28.12, 524.42) REIN1.0 (reference)3.69 (1.67, 8.14)11.13 (5.27, 23.49)63.43 (20.61, 195.19) REIN 21.0 (reference)1.44 (0.30, 6.91)8.59 (2.06, 35.85)27.37 (6.22, 120.48)Studies with dipstick proteinuria Kaiser Permanente Northwest1.0 (reference)2.14 (1.29, 3.55)15.08 (9.24, 14.60)—Overall1.0 (reference)2.72 (2.19, 3.37)10.21 (8.36, 12.46)51.48 (31.95, 82.97)Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; MASTERPLAN, Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of a Nurse Practitioner; MDRD, Modification of Diet in Renal Disease; MMKD, Mild to Moderate Kidney Disease Study; REIN, Ramipril Efficacy in Nephropathy; REIN 2, Ramipril Efficacy in N