Published online before print November 19, 2007, doi: 10.1161/CIRCULATIONAHA.107.723270
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(Circulation. 2007;116:2687-2693.)
© 2007 American Heart Association, Inc.
Coronary Heart Disease |
Influence of Albuminuria on Cardiovascular Risk in Patients With Stable Coronary Artery Disease
From the Divisions of Cardiovascular Medicine, Renal Medicine, and General Medicine, Brigham and Women’s Hospital (S.D.S., J.L., C.G.S., E.B., M.A.P.), Boston, Mass; George Washington University Biostatistics Center (K.A.J., M.M.R., J.H.), Rockville, Md; University of Minnesota Medical Center (M.S.), Minneapolis, Minn; National Heart, Lung, and Blood Institute (M.D.), Bethesda, Md; Mayo Clinic College of Medicine (B.J.G.), Rochester, Minn; London Health Sciences Centre, (J.M.O.A.), London, Ontario, Canada; and University of Montreal (J.R.), Montreal, Quebec, Canada.
Correspondence to Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail ssolomon{at}rics.bwh.harvard.edu
Received June 22, 2007; accepted September 27, 2007.
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Abstract |
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Background— Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and the risks for death and cardiovascular events among patients with stable coronary disease.
Methods and Results— We studied patients enrolled in the Prevention of Events with an ACE inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed up for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate and outcomes. The majority of patients (73%) had a baseline ACR within the normal range (<17 µg/mg for men and <25 µg/mg for women). Independent of the estimated glomerular filtration rate and other baseline covariates, a higher ACR, even within the normal range, was associated with increased risks for all-cause mortality (P<0.001) and cardiovascular death (P=0.01). The effect of trandolapril therapy on outcomes was not modified significantly by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 versus 14.6 µg/mg, P=0.0002), after adjustment for baseline ACR, time between collections, and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (hazard ratio per log ACR 1.74, 95% CI 1.08 to 2.82).
Conclusions— Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.
Key Words: cardiovascular diseases • kidney • albuminuria
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Introduction |
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Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality.1–4 Albuminuria, considered a marker for both renal and systemic vascular disease, is a significant predictor of risk for cardiovascular disease in nondiabetic and diabetic patients,5 independent of estimated glomerular filtration rate (eGFR).6,7 Microalbuminuria, traditionally defined as a urinary albumin excretion rate (AER) of 20 to 200 µg/min or 30 to 300 mg per 24 hours, is likewise a well-recognized predictor of cardiovascular risk in both low-risk community-based populations8 and high-risk populations.5,9 Limited data indicate that albumin excretion below the traditional microalbuminuric range may also be predictive of cardiovascular risk, but this is less well studied. In addition, the extent to which albuminuria is a significant predictor of cardiovascular events independent of other measures of renal function or other comorbidities remains unclear.
Clinical Perspective p 2693
We have previously reported that patients enrolled in the Prevention of Events with an ACE inhibitor (PEACE) trial10 who had reduced eGFR were at increased risk for cardiovascular events and that these patients were more likely to have benefited from ACE inhibitor therapy than patients with normal renal function.11 We have also previously observed that patients with systolic dysfunction after myocardial infarction with trace or greater proteinuria derived the greatest benefit from ACE inhibitor therapy.12 We therefore used data from the PEACE trial to assess the risk for cardiovascular events associated with a range of albuminuria and to determine whether the presence of albuminuria influenced the efficacy of ACE inhibitor therapy.
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Methods |
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Patient Population
The design and main results of the PEACE trial have been described previously.10 In brief, 8290 patients aged
50 years with documented coronary artery disease and left ventricular ejection fraction >40% were randomized to the ACE inhibitor trandolapril or placebo and followed up for a median of 4.8 years. Patients who had been hospitalized for unstable angina in the preceding 2 months or who had coronary revascularization within the prior 3 months, planned elective coronary revascularization, or serum creatinine >2.0 mg/dL (177 µmol/L) were excluded. All patients who provided both baseline serum and urine samples were included in the present substudy.
Baseline Measures
During the baseline visit with clinic research staff, patients reported their cigarette smoking status, medication use, and history of hypertension, diabetes mellitus, angina, intermittent claudication, transient ischemic attack, stroke, myocardial infarction, and coronary revascularization. Prior myocardial infarction, coronary revascularizations, recent ventricular function, and pharmacotherapy were also assessed. The clinic research staff measured height, weight, and blood pressure using standard procedures.
Blood and Urine Sampling Procedures and Biochemical Assays
As part of the study protocol, serum and spot urine samples were obtained at baseline; results of both measures were available in 2977 subjects. Follow-up samples, collected between 6 and 76 months (mean 34 months) after baseline, were available in 1339 of these subjects. Samples were frozen and stored at –70°C or colder until thawed for biochemical assays. The PEACE central laboratory at the University of Minnesota measured serum creatinine and urinary creatinine on a Hitachi 911 analyzer (Hitachi, Tokyo, Japan) with a rate-blanked Jaffe assay standardized to a method by isotope dilution mass spectrometry. Urinary albumin was assayed with a Dade Behring ProSpec (Dade Behring, Deerfield, Ill) by a nephelometric immunoassay. The lowest threshold for detection for urinary albumin concentration was 2 mg/L. The coefficients of variation for urinary albumin, urinary creatinine, and serum creatinine were all 
5%.
All testing was performed by personnel masked as to clinical outcomes and treatment allocation. The 4-component Modification of Diet in Renal Disease equation (which uses serum creatinine, age, sex, and race) was used to estimate the glomerular filtration rate (in mL · min–1 · 1.73 m–2).13 Urinary albumin and creatinine concentrations were used to calculate the albumin-to-creatinine ratio (ACR; µg/mg).
End Points
The present analysis focused on the end points of all-cause mortality, cardiovascular death, and the PEACE primary composite outcome (cardiovascular death, nonfatal myocardial infarction, and coronary revascularization). All patient-reported outcomes were classified after a review of the patients’ medical records by an events adjudication committee blinded as to intervention.
Statistical Analysis
We used Cox proportional hazards models to examine the association between the ACR and mortality and cardiovascular end points. Cox models were also used to assess potentially confounding factors, ie, baseline factors associated with both the ACR and mortality or cardiovascular end points. The baseline covariates, chosen a priori, included assigned treatment group, age, sex, history of myocardial infarction, diabetes mellitus, hypertension, left ventricular ejection fraction <50% (versus 50%), current smoking, eGFR, and body mass index (in kg/m2).
We used sex-specific cut points for ACR of 25 to 354 µg/mg in women and 17 to 250 µg/mg in men to define microalbuminuria; these values correspond to an AER of 20 to 200 µg/min.14–16 To assess risk within the normal range, we divided the normoalbuminuria range into sex-specific tertiles. Categories were as follows for the ACR (in µg/mg): lowest normal (<5.0), low normal (5.0 to 7.7 in women and 5.0 to 6.6 in men), medium normal (7.7 to 11.5 in women and 6.6 to 9.5 in men), and high normal (11.5 to 25.0 in women and 9.5 to 17.0 in men). Because frank albuminuria was uncommon, we divided patients who had albumin excretion in the microalbuminuria range or higher at the sex-specific median level: low to medium (25.0 to 177.00 µg/mg in women and 17.0 to 125.0 µg/mg in men) and high microalbuminuria to macroalbuminuria (>177.00 µg/mg in women and >125.00 µg/mg in men). We tested for an interaction between eGFR and the ACR. To assess whether effects of trandolapril varied with the level of albumin excretion, we also tested for interaction between assigned treatment group and the ACR.
In the subset of patients with both baseline and follow-up values, we used Cox proportional hazards models to examine the association between change in the ACR and mortality and cardiovascular end points. Change was defined as the log of the follow-up value minus the log of the baseline value and was assessed as a continuous time-varying independent variable. Analyses were adjusted for the same baseline covariates listed above. We also tested for interaction between assigned treatment group and change in the ACR. To determine whether assigned treatment group may have influenced the follow-up ACR, we used a least-squared-means general linear model to estimate adjusted follow-up ACR means by treatment group. These means were adjusted for the baseline log ACR and time between the baseline and follow-up sample collections.
Residual analysis was used to assess model fit. The negative log-survival (cumulative hazard) function was used to test the proportional hazard assumption. The collinearity index was used to check for intercorrelations among covariates. The SAS analysis system version 8.2 was used for all analyses (SAS Institute, Inc, Cary, NC).
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Results |
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The patients who had urine collected were similar to those without urine collection with respect to baseline characteristics, with statistically significant but clinically unimportant differences in a minority of baseline characteristics. Among patients with baseline urine and blood samples, higher baseline ACR was associated with older age, male sex, nonwhite race, history of angina, diabetes mellitus, hypertension, cigarette smoking, elevated blood pressure, prior PTCA or CABG, lower eGFR, and less use of calcium channel blockers and aspirin (Table 1).
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Higher ACR at baseline was associated with increases in the rate of all-cause mortality (Figure 1) and cardiovascular death (Table 2) in both treatment groups. Compared with low-normal levels of albuminuria, albuminuria within the medium-normal and high-normal ranges was associated with significantly greater risks for mortality after adjustment for baseline covariates (Table 3). Presence of diabetes mellitus (hazard ratio [HR] 1.62, 95% CI 1.19 to 2.19, P=0.002), current smoking (HR 2.16, 95% CI 1.56 to 2.98, P<0.001), and eGFR <60 mL · min–1 · 1.73 m–2 (HR 1.64, 95% CI 1.17 to 2.29, P=0.004) were also independently associated with mortality in the fully adjusted Cox model, whereas body mass index (per increase in kg/m2) was not (HR 0.99, 95% CI 0.96 to 1.02, P=0.55). We observed a weak inverse relationship between eGFR and ACR (r=–0.07, P<0.0001; Figure 2). Nevertheless, patients at both ends of the eGFR spectrum demonstrated a wide range of albuminuria, and a higher ACR was associated with increased rates of mortality in patients with normal and reduced eGFR (Figure 3). Lower eGFR and greater albuminuria were independently associated with increased mortality; there was no significant interaction between these variables. Moreover, the effect of trandolapril on cardiovascular outcomes did not vary significantly with baseline levels of albuminuria.
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Follow-Up Urine Albuminuria
Among the 1339 patients who also had follow-up urine samples available, the mean time to follow-up was 34±13 months, and there were no significant differences between the groups with and without follow-up urine samples. Trandolapril therapy was associated with a significantly lower adjusted mean follow-up ACR (mean 12.5 µg/mg [95% CI 11.7 to 13.2 µg/mg] versus mean 14.6 µg/mg [95% CI 13.8 to 15.6 µg/mg], P=0.0002), after adjustment for baseline ACR, time between collections, and other covariates. A baseline-adjusted increase per unit log ACR was associated with increased risk of cardiovascular death (HR 1.74, 95% CI 1.08 to 2.82), after adjustment for baseline ACR and other covariates, including age, sex, history of diabetes mellitus, hypertension, myocardial infarction, smoking, left ventricular ejection fraction, body mass index, and eGFR.
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Discussion |
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We found in a relatively healthy cohort of patients with stable coronary disease that urinary ACR, even within the "normal" range, was associated with increased risk for all-cause mortality and cardiovascular death. This elevated risk was independent of eGFR and other baseline covariates. The magnitude of adjusted mortality risk conferred by the presence of a medium-normal range of albuminuria or greater (AER
10 mg/24 hours; Table 3) is comparable to those between diabetes mellitus (HR 1.62, 95% CI 1.19 to 2.19, P=0.002), current smoking (HR 2.16, 95% CI 1.56 to 2.98), or eGFR <60 mL · min–1 · 1.73 m–2 (HR 1.64, 95% CI 1.17 to 2.29, P=0.004) and all-cause mortality. Although a similar graded increase in hazards across ACR categories and cardiovascular death was noted (P for trend 0.01), associations between ACR in the normal range and cardiovascular death were not statistically significant, likely because of the wide 95% CIs that reflected a low number of outcomes (Table 3). ACE inhibitor therapy reduced progression of albuminuria, and those patients with the greatest increase in ACR at an average follow-up of 34 months were at the greatest risk for cardiovascular death. Therefore, progression of albuminuria appears to be independently associated with worse outcome.
Microalbuminuria may represent an early marker of diffuse vascular endothelial dysfunction in patients with diabetes mellitus,17 as well as in those without diabetes or overt kidney disease. For example, the Losartan Intervention For End point reduction (LIFE) study,18 which included 8206 hypertensive adults with left ventricular hypertrophy, and the Heart Outcomes Prevention Evaluation (HOPE) study,19 a clinical trial of >9000 adults with a history of cardiovascular disease or diabetes mellitus, demonstrated an increased risk for cardiovascular events among patients with higher levels of albuminuria, irrespective of diabetes status. In the present study, we also observed that participants who had clinically evident vascular disease at baseline (such as those with angina, prior PTCA, stroke, or transient ischemic attack) were more likely to have higher levels of albuminuria.
The present findings that low levels of urinary albumin excretion are associated with total mortality are consistent with previous reports. The LIFE study analysis of nondiabetic patients with hypertension randomized to losartan or atenolol reported that higher urinary ACR conferred a continuous increased risk for all-cause mortality without specific thresholds. Likewise, in the population-based Prevention of REnal and Vascular ENd stage Disease (PREVEND) study,8 a urinary albumin concentration of 10 to 20 mg/L, considered in the submicroalbuminuria range, was associated with significantly elevated mortality.
In contrast to these previous reports, however, the present analysis used rigorous sex-specific ACR definitions that have been correlated to the "gold standard" definition of an AER and adjusted not only for baseline covariates but also for eGFR. Moreover, the prognostic independence of albuminuria and eGFR suggests that both measures should be considered in assessment of a patient’s risk and that different mechanisms contribute to adverse outcomes.
The observation that mortality was increased within the medium-normal range of albuminuria, the lower threshold of which is equivalent to an AER of 
10 mg/24 hours (well below the 30 to 300 mg/24-hour excretion rate traditionally considered to be a prognostically relevant microalbuminuria) has important clinical implications. Because urinary albumin dipstick testing would not detect urinary ACR in this range, a quantitative urine ACR is needed for more accurate risk stratification. Spot urinary ACR is easily obtained in contrast to cumbersome 24-hour urine collections and has an excellent correlation with 24-hour urine collections for microalbuminuria (Spearman r=0.92).20 Spot urine ACRs have reported a sensitivity of >90% and a specificity of >88% to predict microalbuminuria compared with 24-hour urine AER.21
We have previously observed a significant interaction between eGFR and treatment effect in patients in the PEACE study: Those with eGFR <60 mL · min–1 · 1.73 m–2 had a 27% reduction in risk of death with trandolapril treatment.11 We also observed a similar interaction between ACE inhibitor therapy and overt proteinuria in the Survival And Ventricular Enlargement (SAVE) trial of patients with left ventricular dysfunction after myocardial infarction. Patients with trace or higher proteinuria were those most likely to derive benefit from ACE inhibitor treatment.6 In contrast, we did not observe an interaction between albuminuria and treatment effect in PEACE, which may reflect the low number of individuals in the present cohort who had levels of albuminuria that would have been detected with a dipstick test. Nevertheless, we observed an increased risk of cardiovascular death associated with progression of albuminuria, findings similar to those observed with an angiotensin receptor blocker in the RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study.22 Therefore, because reduction of albuminuria even within the "normal" range over time was associated with better outcomes, clinicians should consider serial quantification of ACR as a marker of risk, because its reduction may be a metric of treatment efficacy.
A number of limitations of the present analysis should be noted. PEACE represented a relatively healthy population of well-treated patients with chronic stable coronary disease who experienced relatively low event rates, thus limiting its power to assess the relationships between albuminuria and outcomes. Moreover, the absolute risk increase attributable to albuminuria in this population is low. Because very few study participants met the definition of macroalbuminuria, we chose to combine those in the upper range of microalbuminuria (equivalent to an AER >150 mg per 24 hours) with those with frank macroalbuminuria for the present analyses, which potentially limited our ability to assess the relationship between albuminuria and outcomes in this range. We also do not have more detailed information on noncardiovascular causes of death in the present cohort. Finally, because the collection of follow-up urine samples was highly variable, we are limited in our ability to assess the time course of changes in albuminuria with ACE inhibitor therapy. In summary, we showed in a population of patients with stable coronary disease that albuminuria, even within the "normal" range, and the progression of albuminuria over time confer increased risk for adverse events, independent of eGFR and important baseline covariates.
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Acknowledgments |
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The authors gratefully acknowledge the efforts of the PEACE investigators, research coordinators, and committee members. A list of these individuals has been published previously10 and can be found at http://www.bsc.gwu.edu/peace/.
Sources of Funding
The PEACE trial was supported by a contract from the National Heart, Lung, and Blood Institute (N01HC65149) and by Knoll Pharmaceuticals and Abbott Laboratories, which also provided the study medication. Drs Jablonski and Rice are supported in part by National Institutes of Health/National Heart, Lung, and Blood Institute grant N01 HC065149 and a supplement from Knoll Pharmaceuticals and Abbott Laboratories.
Disclosures
None.
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References |
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8. Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, Gans RO, Janssen WM, Grobbee DE, de Jong PE; Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002; 106: 1777–1782.
9. de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004; 65: 2309–2320.[CrossRef][Medline] [Order article via Infotrieve]
10. Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA, Rice MM, Rosenberg YD, Rouleau JL; PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004; 351: 2058–2068.
11. Solomon SD, Rice MM, A Jablonski K, Jose P, Domanski M, Sabatine M, Gersh BJ, Rouleau J, Pfeffer MA, Braunwald E; Prevention of Events with ACE inhibition (PEACE) Investigators. Renal function and effectiveness of angiotensin-converting enzyme inhibitor therapy in patients with chronic stable coronary disease in the Prevention of Events with ACE inhibition (PEACE) trial. Circulation. 2006; 114: 26–31.
12. Jose P, Tomson C, Skali H, Rouleau J, Braunwald E, Arnold JM, Cuddy T, Sussex B, Bernstein V, Pfeffer M, Solomon S. Influence of proteinuria on cardiovascular risk and response to angiotensin-converting enzyme inhibition after myocardial infarction. J Am Coll Cardiol. 2006; 47: 1725–1727.
13. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function– measured and estimated glomerular filtration rate. N Engl J Med. 2006; 354: 2473–2483.
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19. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S; HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001; 286: 421–426.
20. Zelmanovitz T, Gross JL, Oliveira JR, Paggi A, Tatsch M, Azevedo MJ. The receiver operating characteristics curve in the evaluation of a random urine specimen as a screening test for diabetic nephropathy. Diabetes Care. 1997; 20: 516–519.[Abstract]
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22. de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation. 2004; 110: 921–927.
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Footnotes |
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*Drs Solomon and Lin contributed equally to this article.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000558.
Guest Editor for this article was Daniel W. Jones, MD.
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