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Albuminuria in chronic heart failure: prevalence and prognostic importance
Articles
Albuminuria in chronic heart failure: prevalence and prognostic importance Colette E Jackson, Scott D Solomon, Hertzel C Gerstein, Sofia Zetterstrand, Bertil Olofsson, Eric L Michelson, Christopher B Granger, Karl Swedberg, Marc A Pfeffer, Salim Yusuf, John J V McMurray for the CHARM Investigators and Committees
Summary Background Increased excretion of albumin in urine might be a marker of the various pathophysiological changes that arise in patients with heart failure. Therefore our aim was to assess the prevalence and prognostic value of a spot urinary albumin to creatinine ratio (UACR) in patients with heart failure. Methods UACR was measured at baseline and during follow-up of 2310 patients in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Programme. The prevalence of microalbuminuria and macroalbuminuria, and the predictive value of UACR for the primary composite outcome of each CHARM study—ie, death from cardiovascular causes or admission to hospital with worsening heart failure—and death from any cause were assessed. Findings 1349 (58%) patients had a normal UACR, 704 (30%) had microalbuminuria, and 257 (11%) had macroalbuminuria. The prevalence of increased UACR was similar in patients with reduced and preserved left ventricular ejection fractions. Patients with an increased UACR were older, had more cardiovascular comorbidity, worse renal function, and a higher prevalence of diabetes mellitus than did those with normoalbuminuria. However, a high prevalence of increased UACR was still noted among patients without diabetes, hypertension, or renal dysfunction. Elevated UACR was associated with increased risk of the composite outcome and death even after adjustment for other prognostic variables including renal function, diabetes, and haemoglobin A1c. The adjusted hazard ratio (HR) for the composite outcome in patients with microalbuminuria versus normoalbuminuria was 1·43 (95% CI 1·21–1·69; p<0·0001) and for macroalbuminuria versus normoalbuminuria was 1·75 (1·39–2·20; p<0·0001). The adjusted values for death were 1·62 (1·32–1·99; p<0·0001) for microalbuminuria versus normoalbuminuria, and 1·76 (1·32–2·35; p=0·0001) for macroalbuminuria versus normoalbuminuria. Treatment with candesartan did not reduce or prevent the development of excessive excretion of urinary albumin. Interpretation Increased UACR is a powerful and independent predictor of prognosis in heart failure. Funding AstraZeneca.
Introduction Increased excretion of albumin in urine is an established risk factor for mortality, cardiovascular events, and adverse renal outcomes in the general population1,2 and in patients with diabetes,3,4 hypertension,5,6 and other types of cardiovascular disease.7–9 Screening for increased albumin excretion is recommended in patients with diabetes and hypertension to help with risk stratification and target treatment.10,11 Increased excretion might be a marker of diffuse vascular injury, systemic inflammation, activation of the renin-angiotensin system, altered glomerular haemodynamics, or abnormal tubular function.12–14 Many, if not all, of these pathophysiological abnormalities also occur in heart failure.15,16 Measurement of the urinary albumin to creatinine ratio (UACR) in a random urine specimen is a convenient method for detection of increased albumin excretion.17,18 The prevalence and prognostic importance of elevated UACR in heart failure, however, are not known.15 We measured UACR in a large subset of patients enrolled in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) www.thelancet.com Vol 374 August 15, 2009
Programme.19,20 We assessed the prevalence of an increased UACR in these patients at baseline, the characteristics of patients with an increased UACR, and the association between an increased UACR at baseline and subsequent clinical outcomes.
Methods Study design
Lancet 2009; 374: 543–50 See Editorial page 501 See Comment page 506 British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK (C E Jackson MB ChB, Prof J J V McMurray MD); Brigham and Women’s Hospital, Boston, MA, USA (S D Solomon MD, Prof M A Pfeffer MD); Department of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada (Prof H C Gerstein MD, Prof S Yusuf DPhil); AstraZeneca Research and Development, Mölndal, Sweden (S Zetterstrand PhD, B Olofsson PhD); AstraZeneca, Wilmington, DE, USA (Prof E L Michelson MD); Duke University Medical Center, Durham, NC, USA (Prof C B Granger MD); and Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (Prof K Swedberg MD) Correspondence to: Prof John J V McMurray, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK [email protected]
The design and results of the CHARM trials are described elsewhere.19,21 Briefly, we studied 7599 patients with New York Heart Association (NYHA) class II to IV heart failure with concentrations of serum creatinine of less than 265 μmol/L (30 mg/L), and serum potassium of less than 5·5 mmol/L, who were not taking an angiotensin-receptor blocker, and who had no critical aortic or mitral stenosis, or recent myocardial infarction, stroke, or heart surgery. They were divided according to whether they had left ventricular ejection fraction (LVEF) greater than 40%; LVEF less than or equal to 40% and taking an angiotensin-converting enzyme inhibitor; and LVEF less than or equal to 40% and not taking an angiotensin-converting enzyme inhibitor because of 543
Articles
Normoalbuminuria (n=1349)
Microalbuminuria (n=704)
Macroalbuminuria (n=257)
p value
Demographic characteristics Age (years)
65 (11·4)
68 (11·4)
68 (10·4)
<0·0001
Male sex
870 (64%)
505 (72%)
163 (63%)
0·0596
Current smoker
183 (14%)
101 (14%)
32 (12%)
0·3727
30 (6·3)
29 (6·4)
30 (6·3)
0·0902
II
531 (39%)
254 (36%)
80 (31%)
··
III
788 (58%)
428 (61%)
169 (66%)
··
IV
30 (2%)
22 (3%)
8 (3%)
39 (15·5)
39 (16·4)
41 (15·8)
0·1088
782 (58%)
423 (60%)
138 (54%)
0·8213
BMI (kg/m²) Heart failure status NYHA class
LVEF (%) LVEF ≤40%
0·0055
··
Physiological measurements HR (beats per min)
death from a cardiovascular cause, admission for worsening heart failure, non-fatal myocardial infarction, nonfatal stroke, or a coronary revascularisation procedure. All endpoints were independently adjudicated. The cause of death was considered to be cardiovascular unless another clear cause was apparent. Treatment in hospital for worsening heart failure was defined as an unplanned admission that was necessitated by heart failure and required intravenous diuretics. By design, all patients enrolled in Canada and the USA (n=2743) had blood chemistry and haematology measured in a central laboratory at baseline, 6 weeks, 14 months, and every year thereafter. Urine was collected, stored, and analysed in a central laboratory at baseline, 14 months, 38 months, and the closing study visit. Concentrations of serum creatinine were measured spectrophotometrically with the Olympus Chemistry Analyzer (Olympus America, Center Valley, PA, USA), urinary albumin with a competitive radioimmunoassay Immulite (Diagnostic Products, Los Angeles, CA, USA), and urine creatinine with a colourimetric kinetic Jaffe method on the Cobas Integra Instrument (Roche Diagnostic Systems, Branchburg, NJ, USA).7
72 (12)
72 (12)
74 (13)
0·1235
SBP (mm Hg)
127 (18)
130 (19)
140 (20)
<0·0001
DBP (mm Hg)
74 (11)
74 (11)
76 (11)
0·1484
Admission for heart failure
879 (65%)
501 (71%)
183 (71%)
0·0095
Previous myocardial infarction
692 (51%)
369 (52%)
138 (54%)
0·4500
Angina pectoris
822 (61%)
421 (60%)
152 (59%)
0·5097
PCI
242 (18%)
136 (19%)
47 (18%)
0·5685
Statistical analysis
CABG
371 (28%)
239 (34%)
97 (38%)
0·0001
Pacemaker
134 (10%)
81 (12%)
25 (10%)
0·5219
These analyses were restricted to the North American participants for whom UACRs were available. Macroalbuminuria was defined as UACR greater than 25 mg/mmol in men and women, and microalbuminuria as UACR 2·5–25·0 mg/mmol in men and 3·5–25·0 mg/mmol in women.22 Cox proportional hazards models were used to analyse the prospective association between UACR and death from a cardiovascular cause or admission for worsening heart failure, all-cause death, and admission to hospital for worsening heart failure. The association between UACR and these outcomes was adjusted for 33 baseline variables as described previously:19,20 randomly assigned treatment (candesartan vs placebo), sex (men vs women), NYHA class (III/IV vs II), smoking habit (current vs none or past), age, LVEF, body-mass index, systolic blood pressure, diastolic blood pressure, heart rate, history (admission for heart failure, myocardial infarction, angina pectoris, stroke, hypertension, diabetes mellitus, atrial fibrillation, cancer, coronary artery bypass surgery, percutaneous coronary revascularisation, implanted cardioverter defibrillator, or pacemaker), and baseline treatment (diuretic, digitalis, β blocker, angiotensinconverting enzyme inhibitor, calcium-channel blocker, other vasodilator, antiarrhythmic drug, lipid-lowering drug, anticoagulant, aspirin, and other antiplatelet). UACR was added to this model, as a categorical and continuous variable (34-variable model). Concentrations of serum creatinine and haemoglobin A1c (HbA1c) were then added simultaneously to the model with UACR (36-variable model) to assess risk associated with increased UACR, independently of renal dysfunction and
Medical history
Diabetes mellitus
387 (29%)
307 (44%)
169 (66%)
<0·0001
Hypertension
823 (61%)
481 (68%)
210 (82%)
<0·0001
Atrial fibrillation
353 (26%)
258 (37%)
87 (34%)
<0·0001
Stroke
125 (9%)
76 (11%)
43 (17%)
0·0031
111 (39·4)
123 (47·2)
<0·0001
Laboratory measurements Serum creatinine (μmol/L)
97 (33·3)
eGFR (mL/min/1·73m²)
81·2 (29·3)
70·6 (28·9)
65·1 (31·8)
<0·0001
<60
275 (20%)
244 (35%)
119 (46%)
<0·0001
<30
17 (1%)
20 (3%)
19 (7%)
<0·0001
Potassium (mmol/L)
4·4 (0·4)
4·4 (0·5)
4·5 (0·5)
Haemoglobin (mg/L)
85 (9)
84 (11)
82 (11)
Haematocrit (%)
41 (4·4)
41 (5·2)
40 (5·5)
HbA1c (%)
6·8 (1·3)
7·4 (1·7)
0·0901 0·0001
7·9 (1·8)
0·0027 <0·0001
History of diabetes
8·0 (1·6)
8·5 (1·7)
8·6 (1·8)
<0·0001
No history of diabetes
6·2 (0·7)
6·4 (0·8)
6·6 (0·7)
<0·0001
(Continues on next page)
intolerance. Within each of the component trials, patients were randomly allocated to candesartan (up to 32 mg once a day) or matching placebo. Median follow-up of the entire cohort was 37·7 months. The primary outcome of the entire programme was death from any cause and the primary composite outcome for the three component trials was death from a cardiovascular cause or admission for worsening heart failure. Other prespecified outcomes were death from any cause or admission for heart failure; death from a cardiovascular cause, admission for worsening heart failure, non-fatal myocardial infarction, or non-fatal stroke; and 544
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dysglycaemia.23,24 An alternative 36-variable model was also run with an estimated glomerular filtration rate (eGFR) with the four-variable equation for modification of diet in renal disease instead of concentration of serum creatinine.25
Normoalbuminuria (n=1349)
Microalbuminuria (n=704)
Macroalbuminuria (n=257)
p value
(Continued from previous page) Drugs at randomisation ACE inhibitor
585 (43%)
299 (42%)
107 (42%)
Role of the funding source
β blocker
725 (54%)
366 (52%)
138 (54%)
0·6248
The collection and analysis of urine samples for albumin excretion was a preplanned and investigator-originated substudy. The measurement of urinary albumin concentrations was paid for by the sponsor and done at McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. The statistical analyses were done by SZ who is an employee of the sponsor.
Diuretic
1124 (83%)
626 (89%)
234 (91%)
<0·0001
Nitrate
384 (28%)
243 (35%)
88 (34%)
0·0031
Spironolactone
202 (15%)
108 (15%)
25 (10%)
0·2098
Digoxin
700 (52%)
385 (55%)
133 (52%)
0·4600
Calcium-channel blocker
326 (24%)
180 (26%)
100 (39%)
0·0003
Lipid-lowering drug
620 (46%)
337 (48%)
134 (52%)
0·0925
Oral anticoagulant
396 (29%)
245 (35%)
79 (31%)
0·0594
Results UACR was measured in 2310 (84%) of 2743 North American patients in CHARM. Table 1 shows the baseline characteristics of the three groups: 58% had a normal UACR, 30% had microalbuminuria, and 11% had macroalbuminuria. Patients with an increased UACR were older, had a higher systolic blood pressure, and were more likely to have a history of hypertension and diabetes (especially those with macroalbuminuria) than were those with normal UACR. A history of stroke, coronary heart disease, and atrial fibrillation was also more common in patients with an elevated UACR. HbA1c level was higher in patients with an elevated UACR (even in those without diabetes), and renal dysfunction (defined as eGFR <60 mL/min/1·73 m²) was more common in these patients than in those with normal UACR. Patients with an increased UACR were also more likely to have been admitted for heart failure, and a higher proportion had NYHA functional class III or IV symptoms at the time of randomisation. The use of angiotensin-converting enzyme inhibitors, β blockers, and digoxin was similar in all three UACR groups although the proportion of patients being treated with spironolactone was smallest in the group with macroalbuminuria. Nitrates were used more commonly in patients with an elevated UACR, and use of
Cardiovascular death or admission for heart failure
0·5657
Data are mean (SD) or number (%). BMI=body-mass index. NYHA=New York Heart Association. LVEF=left ventricular ejection fraction. HR=heart rate. SBP=systolic blood pressure. DBP=diastolic blood pressure. PCI=percutaneous coronary intervention. CABG=coronary artery bypass grafting. eGFR=estimated glomerular filtration rate. HbA1c=haemoglobin A1c. ACE=angiotensin-converting enzyme.
Table 1: Characteristics of patients with and without an elevated urinary albumin to creatinine ratio
calcium-channel blockers was more common in those with macroalbuminuria (table 1). Of 1447 patients without diabetes, 397 (27%) had microalbuminuria and 88 (6%) had macroalbuminuria. 307 (36%) of 863 with diabetes had microalbuminuria and 169 (20%) had macroalbuminuria. Among 1714 patients with a systolic blood pressure of 140 mm Hg or less, or a diastolic blood pressure of 90 mm Hg or less, 508 (30%) had microalbuminuria and 146 (9%) had macroalbuminuria. Of 596 patients with a systolic blood pressure of more than 140 mm Hg or a diastolic blood pressure of more than 90 mm Hg, 196 (33%) had microalbuminuria and 111 (19%) had macroalbuminuria. Of 796 patients without a history of hypertension, 223 (28%) had microalbuminuria and 47 (6%) had macroalbuminuria. In 1514 patients with a history of hypertension, 481 (32%) had microalbuminuria and 210 (14%) had macroalbuminuria. Of 755 patients without either diabetes or a history of hypertension,
Normoalbuminuria Microalbuminuria (n=1349) (n=704)
Hazard ratio* (95% CI)
Macroalbuminuria (n=257)
Hazard ratio* (95% CI)
135 (52%)
2·36 (1·94–2·86)
397 (28%)
306 (43%)
1·74 (1·50–2·02)
Cardiovascular death†
196 (13%)
188 (27%)
··
65 (26%)
··
Admission for heart failure†
292 (22%)
213 (32%)
··
102 (41%)
··
All-cause mortality or admission for heart failure
437 (31%)
332 (46%)
1·71 (1·48–1·97)
146 (55%)
2·32 (1·92–2·79)
Cardiovascular death or admission for heart failure, non-fatal myocardial infarction, or non-fatal stroke
440 (31%)
328 (46%)
1·69 (1·47–1·95)
146 (56%)
2·35 (1·95–2·84)
Cardiovascular death, admission for heart failure, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularisation procedure
488 (35%)
345 (48%)
1·59 (1·38–1·82)
153 (59%)
2·22 (1·85–2·66)
All-cause mortality
249 (17%)
231 (31%)
1·97 (1·65–2·36)
87 (33%)
2·07 (1·63–2·65)
Data are number (%); percentages are Kaplan-Meier failure rates at 3 years. *Unadjusted hazard ratio (compared with normoalbuminuria). †Any occurrence of these outcomes.
Table 2: Clinical outcomes according to baseline urinary albumin to creatinine ratio
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A
Estimated cumulative distribution function
0·7
Macroalbuminuria Microalbuminuria Normoalbuminuria
0·6 0·5 0·4 0·3 0·2 0·1 0
Number at risk Normoalbuminuria 1346 Microalbuminuria 703 Macroalbuminuria 256
1246 592 209
1168 547 174
1099 487 153
1013 434 136
817 326 100
411 148 45
0·5
1·0
1·5 Time (years)
2·0
2·5
3·0
1312 657 242
1270 632 229
1234 589 211
1170 542 195
964 421 150
492 192 64
B 0·45
Estimated cumulative distribution function
0·40 0·35 0·30 0·25 0·20 0·15 0·10 0·05 0 0 Number at risk Normoalbuminuria 1348 Microalbuminuria 704 Macroalbuminuria 256
Figure 1: Cardiovascular death or admission for chronic heart failure (A), and all-cause mortality (B), stratified by albuminuria status
212 (28%) had microalbuminuria and 43 (6%) had macroalbuminuria. 372 (27%) of 1375 patients with an eGFR greater than or equal to 60 mL/min/1·73m² had microalbuminuria and 108 (8%) had macroalbuminuria. Of 638 patients with renal impairment (eGFR <60 mL/min/1·73m²), 244 (38%) had microalbuminuria and 119 (19%) had macroalbuminuria. 423 (31%) of 1343 patients with heart failure and a low LVEF (≤40%) had microalbuminuria and 138 (10%) had 546
macroalbuminuria. In 967 patients with heart failure and a preserved LVEF (>40%), 281 (29%) had microalbuminuria and 119 (12%) had macroalbuminuria. 405 (31%) of 1319 patients who were not taking an angiotensin-converting enzyme inhibitor at baseline had microalbuminuria and 150 (11%) had macroalbuminuria. 299 (30%) of 991 patients taking an angiotensin-converting enzyme inhibitor at baseline had microalbuminuria and 107 (11%) had macroalbuminuria. The unadjusted risk of adverse cardiovascular outcomes was increased in patients with an elevated UACR (table 2). Fewer patients with a normal UACR had the primary composite outcome of death from a cardiovascular cause or admission for heart failure than did those with microalbuminuria or macroalbuminuria (figure 1; table 2). Elevated UACR was associated with an increased risk of each of the components of this outcome. This increased risk was also noted for the expanded secondary cardiovascular outcomes that included myocardial infarction, stroke, and coronary revascularisation (table 2). Notably, the proportions of patients admitted to hospital with heart failure were increased substantially in the elevated UACR categories—with the highest increase in patients with macroalbuminuria (table 2). The proportion of patients who died from any cause also increased with increase in UACR (figure 2; table 2). The albuminuria category was an independent, significant, predictor of the primary outcome, all-cause mortality, and admission for heart failure when added to the Cox regression analysis with 33 baseline demographic and clinical factors as covariates (table 3). For each of these outcomes, patients with microalbuminuria or macroalbuminuria had a 40–80% increase in adjusted risk. UACR was also an independent predictor of outcome when analysed as a continuous variable. An increase in UACR of 100 mg/mmol was associated with about a 10% increase in adjusted risk for all three outcomes. Creatinine was a significant independent predictor of all three outcomes whereas the predictive value of HbA1c was not always significant for the primary outcome in the multivariable analysis that included UACR, HbA1c, and creatinine (table 4). However, UACR remained an independent predictor when both creatinine and HbA1c were added to the model, with little reduction in the hazard ratios (HRs) related to microalbuminuria and macroalbuminuria for any of the three outcomes (table 4). Similar results were obtained when this 36-covariate model was re-run with eGFR instead of creatinine (data not shown). The risk associated with excretion of albumin in urine, assessed as a continuous or categorical variable, was similar in patients with low LVEF and in those with preserved LVEF. HR for the primary composite outcome in the categorical analysis was 1·84 (95% CI 1·39–2·43) www.thelancet.com Vol 374 August 15, 2009
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60
Cardiovascular death or admission for heart failure Death from any cause
Clinical outcomes (%)
50 40 30 20 10 0 1
2
3
4
5
6
7
8
9
10
1·94–3·01 (n=232)
3·01–5·04 (n=230)
5·04–10·56 (n=231)
10·56–29·53 (n=231)
>29·53 (n=231)
Decile of UACR 0–0·40 (n=231)
0·40–0·66 (n=231)
0·66–0·94 (n=231)
0·94–1·32 (n=231)
1·32–1·94 (n=231)
Figure 2: Clinical outcomes according to decile of urinary albumin to creatinine ratio (UACR)
for macroalbuminuria versus normoalbuminuria and 1·61 (1·34–1·95) for microalbuminuria versus normoalbuminuria in patients with a low LVEF compared with 2·03 (1·45–2·85) for macroalbuminuria versus normoalbuminuria, and 1·31 (0·99–1·74) for microalbuminuria versus normoalbuminuria in those with a preserved LVEF (p=0·1566 for interaction between LVEF and macroalbuminuria, and p=0·8280 for interaction between LVEF and microalbuminuria). HR per unit UACR (100 mg/mmol) was 1·10 (0·99–1·21) in patients with low LVEF and 1·12 (1·04–1·21) in those with preserved LVEF (p=0·6283 for interaction). The risk related to excretion of albumin in urine was also evident in the subset of patients with a normal UACR at baseline (and of at least the same magnitude as in the overall patient population; figure 2). HR for the primary outcome for each unit increase in UACR was 1·15 (95% CI 1·00–1·32; p=0·0565). Urine samples were not obtained at follow-up in a large proportion of patients (table 5). There was no evidence to suggest that treatment with candesartan prevented the development or reduced the excessive excretion of albumin in urine.
Discussion The prevalence of elevated UACR in patients with heart failure was high and was associated with a substantially increased risk of adverse clinical outcomes, including death. Even after adjustment for other risk factors in a multivariable model, microalbuminuria or macroalbuminuria remained strong independent predictors, with a 60–80% adjusted increase in the risk of death and a 30–70% increase in the adjusted risk of admission for heart failure. Little is known about excretion of albumin in urine in patients with heart failure and nothing is known about its prognostic importance. Few data are available for the prevalence of increased excretion of albumin in the urine of patients with heart failure. Most patients in the www.thelancet.com Vol 374 August 15, 2009
Studies of Left Ventricular Dysfunction (SOLVD) had a urine dipstick test for protein at baseline.26 Of 5487 (81% of total) tested, 177 (3%) had proteinuria. These patients had a higher blood pressure and a higher prevalence of diabetes mellitus, and also greater left ventricular systolic dysfunction and more symptomatic heart failure than did those without proteinuria. The results of dipstick urine testing for proteinuria were also reported in a Canadian subset (n=583) of 2231 patients
Hazard ratio (95% CI)
p value
Cardiovascular death or admission for heart failure Albuminuria category* Microalbuminuria vs normoalbuminuria
1·50 (1·28–1·75) <0·0001
Macroalbuminuria vs normoalbuminuria
1·88 (1·53–2·33) <0·0001
UACR continuous (100 mg/mmol)†
1·10 (1·04–1·17)
0·0016
All-cause mortality Albuminuria category* Microalbuminuria vs normoalbuminuria
1·63 (1·35–1·97) <0·0001
Macroalbuminuria vs normoalbuminuria
1·77 (1·36–2·31)
<0·0001
1·10 (1·02–1·19)
0·0153
Microalbuminuria vs normoalbuminuria
1·41 (1·17–1·69)
0·0003
Macroalbuminuria vs normoalbuminuria
1·88 (1·47–2·40) <0·0001
UACR continuous (100 mg/mmol)† Admission for heart failure Albuminuria category*
UACR continuous (100 mg/mmol)†
1·11 (1·04–1·19)
0·0024
*UACR analysed as a categorical variable (microalbuminuria or macroalbuminuria vs normoalbuminuria). †UACR analysed as a continuous variable.
Table 3: Multivariable analysis of urinary albumin to creatinine ratio (UACR) added to 33 baseline covariates by endpoint
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with left ventricular systolic dysfunction after myocardial infarction who were enrolled in the Survival and Ventricular Enlargement trial (SAVE).27 15% of this Hazard ratio (95% CI)
p value
Cardiovascular death or admission for heart failure UACR categorical* 1·43 (1·21–1·69)
<0·0001
Macroalbuminuria vs normoalbuminuria 1·75 (1·39–2·20)
<0·0001
Creatinine (10 μmol/L)
1·04 (1·02–1·06)
<0·0001
HbA1c (%)
1·04 (0·99–1·11)
0·1466
Microalbuminuria vs normoalbuminuria
UACR continuous† UACR (100 mg/mmol)
1·07 (1·00–1·14)
0·0414
Creatinine (10 μmol/L)
1·05 (1·03–1·07)
<0·0001
HbA1c (%)
1·06 (1·00–1·12)
0·0441
1·62 (1·32–1·99)
<0·0001
Macroalbuminuria vs normoalbuminuria 1·76 (1·32–2·35)
0·0001
All-cause mortality UACR categorical* Microalbuminuria vs normoalbuminuria Creatinine (10 μmol/L)
1·03 (1·01–1·05)
0·0171
HbA1c (%)
1·03 (0·96–1·11)
0·4429
UACR (100 mg/mmol)
1·08 (1·00–1·17)
0·0598
Creatinine (10 μmol/L)
1·04 (1·01–1·06)
0·0025
HbA1c (%)
1·05 (0·98–1·13)
0·1821
UACR continuous†
Admission for heart failure UACR categorical* 1·31 (1·07–1·59)
0·0077
Macroalbuminuria vs normoalbuminuria 1·67 (1·28–2·17)
0·0002
Microalbuminuria vs normoalbuminuria Creatinine (10 μmol/L)
1·06 (1·03–1·08)
<0·0001
HbA1c (%)
1·04 (0·98–1·11)
0·2223
UACR continuous† UACR (100 mg/mmol)
1·07 (0·99–1·15)
0·0753
Creatinine (10 μmol/L)
1·06 (1·04–1·09)
<0·0001
HbA1c (%)
1·06 (0·99–1·13)
0·0998
HbA1c=haemoglobin A1c. *UACR analysed as a categorical variable (microalbuminuria or macroalbuminuria vs normoalbuminuria). †UACR analysed as a continuous variable.
Table 4: Multivariable analysis of urinary albumin to creatinine ratio (UACR), serum creatinine concentration, and haemoglobin A1c added to 33 baseline covariates by endpoint
Normoalbuminuria Microalbuminuria
Macroalbuminuria Missing
Placebo at baseline (n=1142) Normoalbuminuria (n=656)
264 (40%)
88 (13%)
9 (1%)
295 (45%)
Microalbuminuria (n=355)
57 (16%)
118 (33%)
25 (7%)
155 (44%)
Macroalbuminuria (n=131)
4 (3%)
27 (21%)
44 (34%)
56 (43%)
Candesartan at baseline (n=1168) Normoalbuminuria (n=693)
278 (40%)
72 (10%)
8 (1%)
335 (48%)
Microalbuminuria (n=349)
88 (25%)
116 (33%)
18 (5%)
127 (36%)
Macroalbuminuria (n=126)
5 (4%)
28 (22%)
38 (30%)
55 (44%)
Data are number (%).
Table 5: Urinary albumin to creatinine ratio shifts between baseline and study follow-up visit at 14 months
548
subset had a trace of proteinuria and 6% had greater than trace proteinuria. Patients with proteinuria had a higher baseline creatinine and Killip class than did those without proteinuria. They also had a lower LVEF but had a similar prevalence of diabetes to those without proteinuria. By contrast with these two studies,26,27 UACR was measured in one other study in which 29 (30%) of 96 outpatients (mean age 69 years; 22% women) with predominantly NYHA class III heart failure had microalbuminuria, and 5 (5%) had macroalbuminuria.15 Although differences between patients with and without microalbuminuria were noted, they were not significant, probably because there were few patients in each group (and patients with macroalbuminuria were not described further). In our study, microalbuminuria was much more common than was macroalbuminuria. Patients with an increased UACR were older and had more cardiovascular problems, dysglycaemia, and renal impairment, and also had worse symptoms of heart failure than did those without increased UACR. LVEF did not differ between those with and without an increased UACR, and the corollary was also true—ie, the prevalence of an increased UACR was similar in patients with reduced and preserved LVEF heart failure. However, a third of patients without diabetes had microalbuminuria or macroalbuminuria, and more than a third of those without hypertension or renal impairment also had an elevated UACR. Consequently, increased excretion of albumin in urine in patients with heart failure cannot be wholly explained by concomitant diabetes, hypertension, or renal dysfunction. Notably, the prevalence of microalbuminuria in patients without diabetes was three-fold greater than that in age-matched individuals in the general population; the prevalence of microalbuminuria in Dutch individuals aged 60–74 years was 10·4% (95% CI 9·8–11·0).15 The mechanism underlying albuminuria in patients without these conditions is not known. Renal venous congestion caused proteinuria in dogs, and urinary albumin excretion was inversely related to renal blood flow in patients with heart failure.28–30 Increased albumin excretion might therefore have a haemodynamic basis in heart failure, particularly when renal venous congestion is associated with reduced renal blood flow. All of these renal changes are associated with worse outcomes in patients with heart failure.28–30 Even after the differences between those with and without an elevated UACR are accounted for in the multivariable analyses, increased UACR remained a significant independent predictor of the primary composite outcome of cardiovascular death or admission for worsening heart failure, and all-cause mortality. Of note, increased urinary albumin excretion was also an independent predictor of the disease-specific non-fatal outcome of admission for worsening heart failure. The www.thelancet.com Vol 374 August 15, 2009
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small proportion of patients with dipstick proteinuria in SOLVD also had an increased risk of death and of admission for heart failure.26 Dipstick proteinuria was also a significant independent predictor of mortality in SAVE.27 The hazard related to increased urinary albumin excretion was independent of renal dysfunction, as assessed by both serum creatinine concentration and eGFR, and also dysglycaemia, with adjustment for history of diabetes and HbA1c. The risk related to increased albumin excretion in urine was apparent in patients with low LVEF and also those with preserved LVEF heart failure. Another important finding, lending support to recent findings in patients with stable atherosclerotic disease, is that even an increasing UACR within the normoalbuminuric range was associated with an increased hazard of adverse clinical outcomes, showing that urinary albumin excretion represents a continuous measure of risk.8 Candesartan did not reduce excessive albumin excretion or prevent its development although the interpretation of this analysis is uncertain with the high proportion of missing follow-up urine samples and is probably too soon to conclude that angiotensin-receptor blockers definitely have no effect on urinary albumin excretion in patients with heart failure. These drugs reduce albumin excretion in patients with type 2 diabetes mellitus, hypertension, substantial renal impairment, and marked proteinuria. Whether the pathogenesis of increased albumin excretion in heart failure is the same and whether an angiotensin-receptor blocker should reduce albumin excretion in patients with heart failure are not known. One limitation of our study is that patients were selected from those enrolled in a clinical trial, and, particularly, those with severe renal dysfunction were not included. However, the proportions of patients with microalbuminuria and macroalbuminuria in our study were similar to those reported in the only other study done in patients with heart failure.15 Newer methods for measurement of renal function, such as levels of cystatin C, and other important prognostic markers such as natriuretic peptides and troponin were not measured in CHARM. Because UACR is a simple, readily available clinical test that is widely used in primary and secondary care, it might be of value in risk stratification of patients with heart failure. However, whether UACR adds incremental prognostic information to other new prognostic biomarkers, particularly natriuretic peptides, which are also increasingly and widely used in clinical practice, needs to be assessed. Of potential interest to physicians and patients is whether therapeutic reduction in albumin excretion, which did not occur with candesartan, might be useful in the prediction of improvement in clinical outcomes. www.thelancet.com Vol 374 August 15, 2009
Contributors MAP, KS, CBG, JJVM, SY, BO, and ELM designed the CHARM Programme and substudies. HCG and SDS also contributed to the design and interpretation of the present study. SZ and BO did the statistical analyses. All authors contributed to the interpretation of the data. CEJ and JJVM wrote the draft of the report, and all authors contributed to its revision. JJVM takes responsibility for the report. Conflicts of interest MAP, KS, HCG, CBG, JJVM, SDS, and SY have received research funding, and lecture and consulting fees from AstraZeneca. ELM, BO, and SZ are employees of AstraZeneca. CEJ declares that she has no conflicts of interest. Acknowledgments The CHARM Programme was funded by AstraZeneca. References 1 Arnlöv J, Evans JC, Meigs JB, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation 2005; 112: 969–75. 2 Diercks GF, van Boven AJ, Hillege HL, et al. Microalbuminuria is independently associated with ischaemic electrocardiographic abnormalities in a large non-diabetic population. The PREVEND (Prevention of REnal and Vascular ENdstage Disease) study. Eur Heart J 2000; 21: 1922–27. 3 Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 1984; 310: 356–60. 4 Deckert T, Yokoyama H, Mathiesen E, et al. Cohort study of predictive value of urinary albumin excretion for atherosclerotic vascular disease in patients with insulin dependent diabetes. BMJ 1996; 312: 871–74. 5 Agewall S, Wikstrand J, Ljungman S, Fagerberg B. Usefulness of microalbuminuria in predicting cardiovascular mortality in treated hypertensive men with and without diabetes mellitus. Risk Factor Intervention Study Group. Am J Cardiol 1997; 80: 164–69. 6 Wachtell K, Ibsen H, Olsen MH, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med 2003; 139: 901–06. 7 Gerstein HC, Mann JF, Yi Q, et al; HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001; 286: 421–26. 8 Solomon SD, Lin J, Solomon CG, et al. Influence of albuminuria on cardiovascular risk in patients with stable coronary artery disease. Circulation 2007; 116: 2687–93. 9 Brantsma AH, Bakker SJ, Hillege HL, 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: 3851–58. 10 Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105–87. 11 American Diabetes Association. Standards of medical care in diabetes–2008. Diabetes Care 2008; 31 (suppl 1): S12–54. 12 Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, et al. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 1989; 32: 219–26. 13 Chugh A, Bakris GL. Microalbuminuria: what is it? Why is it important? What should be done about it? An update. J Clin Hypertens (Greenwich) 2007; 9: 196–200. 14 Weir MR. Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007; 2: 581–90. 15 van de Wal RM, Asselbergs FW, Plokker HW, et al. High prevalence of microalbuminuria in chronic heart failure patients. J Card Fail 2005; 11: 602–06. 16 Silverberg D, Wexler D, Blum M, et al. The association between congestive heart failure and chronic renal disease. Curr Opin Nephrol Hypertens 2004; 13: 163–70. 17 Jensen JS, Clausen P, Borch-Johnsen K, et al. Detecting microalbuminuria by urinary albumin/creatinine concentration ratio. Nephrol Dial Transplant 1997; 12 (suppl 2): 6–9.
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Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): a position paper of the National Kidney Foundation. Am J Kidney Dis 1999; 33: 1004–10. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362: 759–66. Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J 2006; 27: 65–75. Swedberg K, Pfeffer M, Granger C, et al. Candesartan in heart failure--assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Programme Investigators. J Card Fail 1999; 5: 276–82. IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes: recommendations for standard, comprehensive, and minimal care. Diabet Med 2006; 23: 579–93. Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006; 113: 671–78. Gerstein HC, Swedberg K, Carlsson J, et al. The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program. Arch Intern Med 2008; 168: 1699–704.
25
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Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–70. Capes SE, Gerstein HC, Negassa A, Yusuf S. Enalapril prevents clinical proteinuria in diabetic patients with low ejection fraction. Diabetes Care 2000; 23: 377–80. Jose P, Tomson C, Skali H, et al. Influence of proteinuria on cardiovascular risk and response to angiotensin-converting enzyme inhibition after myocardial infarction. J Am Coll Cardiol 2006; 47: 1725–27. Wegria R, Capeci NE, Blumenthal MR, et al. The pathogenesis of proteinuria in the acutely congested kidney. J Clin Invest 1955; 34: 737–43. Smilde TD, Damman K, van der Harst P, et al. Differential associations between renal function and “modifiable” risk factors in patients with chronic heart failure. Clin Res Cardiol 2009; 98: 121–29. Damman K, van Deursen VM, Navis G, et al. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53: 582–88.
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Albuminuria in chronic heart failure: prevalence and prognostic importance Colette E Jackson, Scott D Solomon, Hertzel C Gerstein, Sofia Zetterstrand, Bertil Olofsson, Eric L Michelson, Christopher B Granger, Karl Swedberg, Marc A Pfeffer, Salim Yusuf, John J V McMurray for the CHARM Investigators and Committees
Summary Background Increased excretion of albumin in urine might be a marker of the various pathophysiological changes that arise in patients with heart failure. Therefore our aim was to assess the prevalence and prognostic value of a spot urinary albumin to creatinine ratio (UACR) in patients with heart failure. Methods UACR was measured at baseline and during follow-up of 2310 patients in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Programme. The prevalence of microalbuminuria and macroalbuminuria, and the predictive value of UACR for the primary composite outcome of each CHARM study—ie, death from cardiovascular causes or admission to hospital with worsening heart failure—and death from any cause were assessed. Findings 1349 (58%) patients had a normal UACR, 704 (30%) had microalbuminuria, and 257 (11%) had macroalbuminuria. The prevalence of increased UACR was similar in patients with reduced and preserved left ventricular ejection fractions. Patients with an increased UACR were older, had more cardiovascular comorbidity, worse renal function, and a higher prevalence of diabetes mellitus than did those with normoalbuminuria. However, a high prevalence of increased UACR was still noted among patients without diabetes, hypertension, or renal dysfunction. Elevated UACR was associated with increased risk of the composite outcome and death even after adjustment for other prognostic variables including renal function, diabetes, and haemoglobin A1c. The adjusted hazard ratio (HR) for the composite outcome in patients with microalbuminuria versus normoalbuminuria was 1·43 (95% CI 1·21–1·69; p<0·0001) and for macroalbuminuria versus normoalbuminuria was 1·75 (1·39–2·20; p<0·0001). The adjusted values for death were 1·62 (1·32–1·99; p<0·0001) for microalbuminuria versus normoalbuminuria, and 1·76 (1·32–2·35; p=0·0001) for macroalbuminuria versus normoalbuminuria. Treatment with candesartan did not reduce or prevent the development of excessive excretion of urinary albumin. Interpretation Increased UACR is a powerful and independent predictor of prognosis in heart failure. Funding AstraZeneca.
Introduction Increased excretion of albumin in urine is an established risk factor for mortality, cardiovascular events, and adverse renal outcomes in the general population1,2 and in patients with diabetes,3,4 hypertension,5,6 and other types of cardiovascular disease.7–9 Screening for increased albumin excretion is recommended in patients with diabetes and hypertension to help with risk stratification and target treatment.10,11 Increased excretion might be a marker of diffuse vascular injury, systemic inflammation, activation of the renin-angiotensin system, altered glomerular haemodynamics, or abnormal tubular function.12–14 Many, if not all, of these pathophysiological abnormalities also occur in heart failure.15,16 Measurement of the urinary albumin to creatinine ratio (UACR) in a random urine specimen is a convenient method for detection of increased albumin excretion.17,18 The prevalence and prognostic importance of elevated UACR in heart failure, however, are not known.15 We measured UACR in a large subset of patients enrolled in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) www.thelancet.com Vol 374 August 15, 2009
Programme.19,20 We assessed the prevalence of an increased UACR in these patients at baseline, the characteristics of patients with an increased UACR, and the association between an increased UACR at baseline and subsequent clinical outcomes.
Methods Study design
Lancet 2009; 374: 543–50 See Editorial page 501 See Comment page 506 British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK (C E Jackson MB ChB, Prof J J V McMurray MD); Brigham and Women’s Hospital, Boston, MA, USA (S D Solomon MD, Prof M A Pfeffer MD); Department of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada (Prof H C Gerstein MD, Prof S Yusuf DPhil); AstraZeneca Research and Development, Mölndal, Sweden (S Zetterstrand PhD, B Olofsson PhD); AstraZeneca, Wilmington, DE, USA (Prof E L Michelson MD); Duke University Medical Center, Durham, NC, USA (Prof C B Granger MD); and Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (Prof K Swedberg MD) Correspondence to: Prof John J V McMurray, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK [email protected]
The design and results of the CHARM trials are described elsewhere.19,21 Briefly, we studied 7599 patients with New York Heart Association (NYHA) class II to IV heart failure with concentrations of serum creatinine of less than 265 μmol/L (30 mg/L), and serum potassium of less than 5·5 mmol/L, who were not taking an angiotensin-receptor blocker, and who had no critical aortic or mitral stenosis, or recent myocardial infarction, stroke, or heart surgery. They were divided according to whether they had left ventricular ejection fraction (LVEF) greater than 40%; LVEF less than or equal to 40% and taking an angiotensin-converting enzyme inhibitor; and LVEF less than or equal to 40% and not taking an angiotensin-converting enzyme inhibitor because of 543
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Normoalbuminuria (n=1349)
Microalbuminuria (n=704)
Macroalbuminuria (n=257)
p value
Demographic characteristics Age (years)
65 (11·4)
68 (11·4)
68 (10·4)
<0·0001
Male sex
870 (64%)
505 (72%)
163 (63%)
0·0596
Current smoker
183 (14%)
101 (14%)
32 (12%)
0·3727
30 (6·3)
29 (6·4)
30 (6·3)
0·0902
II
531 (39%)
254 (36%)
80 (31%)
··
III
788 (58%)
428 (61%)
169 (66%)
··
IV
30 (2%)
22 (3%)
8 (3%)
39 (15·5)
39 (16·4)
41 (15·8)
0·1088
782 (58%)
423 (60%)
138 (54%)
0·8213
BMI (kg/m²) Heart failure status NYHA class
LVEF (%) LVEF ≤40%
0·0055
··
Physiological measurements HR (beats per min)
death from a cardiovascular cause, admission for worsening heart failure, non-fatal myocardial infarction, nonfatal stroke, or a coronary revascularisation procedure. All endpoints were independently adjudicated. The cause of death was considered to be cardiovascular unless another clear cause was apparent. Treatment in hospital for worsening heart failure was defined as an unplanned admission that was necessitated by heart failure and required intravenous diuretics. By design, all patients enrolled in Canada and the USA (n=2743) had blood chemistry and haematology measured in a central laboratory at baseline, 6 weeks, 14 months, and every year thereafter. Urine was collected, stored, and analysed in a central laboratory at baseline, 14 months, 38 months, and the closing study visit. Concentrations of serum creatinine were measured spectrophotometrically with the Olympus Chemistry Analyzer (Olympus America, Center Valley, PA, USA), urinary albumin with a competitive radioimmunoassay Immulite (Diagnostic Products, Los Angeles, CA, USA), and urine creatinine with a colourimetric kinetic Jaffe method on the Cobas Integra Instrument (Roche Diagnostic Systems, Branchburg, NJ, USA).7
72 (12)
72 (12)
74 (13)
0·1235
SBP (mm Hg)
127 (18)
130 (19)
140 (20)
<0·0001
DBP (mm Hg)
74 (11)
74 (11)
76 (11)
0·1484
Admission for heart failure
879 (65%)
501 (71%)
183 (71%)
0·0095
Previous myocardial infarction
692 (51%)
369 (52%)
138 (54%)
0·4500
Angina pectoris
822 (61%)
421 (60%)
152 (59%)
0·5097
PCI
242 (18%)
136 (19%)
47 (18%)
0·5685
Statistical analysis
CABG
371 (28%)
239 (34%)
97 (38%)
0·0001
Pacemaker
134 (10%)
81 (12%)
25 (10%)
0·5219
These analyses were restricted to the North American participants for whom UACRs were available. Macroalbuminuria was defined as UACR greater than 25 mg/mmol in men and women, and microalbuminuria as UACR 2·5–25·0 mg/mmol in men and 3·5–25·0 mg/mmol in women.22 Cox proportional hazards models were used to analyse the prospective association between UACR and death from a cardiovascular cause or admission for worsening heart failure, all-cause death, and admission to hospital for worsening heart failure. The association between UACR and these outcomes was adjusted for 33 baseline variables as described previously:19,20 randomly assigned treatment (candesartan vs placebo), sex (men vs women), NYHA class (III/IV vs II), smoking habit (current vs none or past), age, LVEF, body-mass index, systolic blood pressure, diastolic blood pressure, heart rate, history (admission for heart failure, myocardial infarction, angina pectoris, stroke, hypertension, diabetes mellitus, atrial fibrillation, cancer, coronary artery bypass surgery, percutaneous coronary revascularisation, implanted cardioverter defibrillator, or pacemaker), and baseline treatment (diuretic, digitalis, β blocker, angiotensinconverting enzyme inhibitor, calcium-channel blocker, other vasodilator, antiarrhythmic drug, lipid-lowering drug, anticoagulant, aspirin, and other antiplatelet). UACR was added to this model, as a categorical and continuous variable (34-variable model). Concentrations of serum creatinine and haemoglobin A1c (HbA1c) were then added simultaneously to the model with UACR (36-variable model) to assess risk associated with increased UACR, independently of renal dysfunction and
Medical history
Diabetes mellitus
387 (29%)
307 (44%)
169 (66%)
<0·0001
Hypertension
823 (61%)
481 (68%)
210 (82%)
<0·0001
Atrial fibrillation
353 (26%)
258 (37%)
87 (34%)
<0·0001
Stroke
125 (9%)
76 (11%)
43 (17%)
0·0031
111 (39·4)
123 (47·2)
<0·0001
Laboratory measurements Serum creatinine (μmol/L)
97 (33·3)
eGFR (mL/min/1·73m²)
81·2 (29·3)
70·6 (28·9)
65·1 (31·8)
<0·0001
<60
275 (20%)
244 (35%)
119 (46%)
<0·0001
<30
17 (1%)
20 (3%)
19 (7%)
<0·0001
Potassium (mmol/L)
4·4 (0·4)
4·4 (0·5)
4·5 (0·5)
Haemoglobin (mg/L)
85 (9)
84 (11)
82 (11)
Haematocrit (%)
41 (4·4)
41 (5·2)
40 (5·5)
HbA1c (%)
6·8 (1·3)
7·4 (1·7)
0·0901 0·0001
7·9 (1·8)
0·0027 <0·0001
History of diabetes
8·0 (1·6)
8·5 (1·7)
8·6 (1·8)
<0·0001
No history of diabetes
6·2 (0·7)
6·4 (0·8)
6·6 (0·7)
<0·0001
(Continues on next page)
intolerance. Within each of the component trials, patients were randomly allocated to candesartan (up to 32 mg once a day) or matching placebo. Median follow-up of the entire cohort was 37·7 months. The primary outcome of the entire programme was death from any cause and the primary composite outcome for the three component trials was death from a cardiovascular cause or admission for worsening heart failure. Other prespecified outcomes were death from any cause or admission for heart failure; death from a cardiovascular cause, admission for worsening heart failure, non-fatal myocardial infarction, or non-fatal stroke; and 544
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dysglycaemia.23,24 An alternative 36-variable model was also run with an estimated glomerular filtration rate (eGFR) with the four-variable equation for modification of diet in renal disease instead of concentration of serum creatinine.25
Normoalbuminuria (n=1349)
Microalbuminuria (n=704)
Macroalbuminuria (n=257)
p value
(Continued from previous page) Drugs at randomisation ACE inhibitor
585 (43%)
299 (42%)
107 (42%)
Role of the funding source
β blocker
725 (54%)
366 (52%)
138 (54%)
0·6248
The collection and analysis of urine samples for albumin excretion was a preplanned and investigator-originated substudy. The measurement of urinary albumin concentrations was paid for by the sponsor and done at McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. The statistical analyses were done by SZ who is an employee of the sponsor.
Diuretic
1124 (83%)
626 (89%)
234 (91%)
<0·0001
Nitrate
384 (28%)
243 (35%)
88 (34%)
0·0031
Spironolactone
202 (15%)
108 (15%)
25 (10%)
0·2098
Digoxin
700 (52%)
385 (55%)
133 (52%)
0·4600
Calcium-channel blocker
326 (24%)
180 (26%)
100 (39%)
0·0003
Lipid-lowering drug
620 (46%)
337 (48%)
134 (52%)
0·0925
Oral anticoagulant
396 (29%)
245 (35%)
79 (31%)
0·0594
Results UACR was measured in 2310 (84%) of 2743 North American patients in CHARM. Table 1 shows the baseline characteristics of the three groups: 58% had a normal UACR, 30% had microalbuminuria, and 11% had macroalbuminuria. Patients with an increased UACR were older, had a higher systolic blood pressure, and were more likely to have a history of hypertension and diabetes (especially those with macroalbuminuria) than were those with normal UACR. A history of stroke, coronary heart disease, and atrial fibrillation was also more common in patients with an elevated UACR. HbA1c level was higher in patients with an elevated UACR (even in those without diabetes), and renal dysfunction (defined as eGFR <60 mL/min/1·73 m²) was more common in these patients than in those with normal UACR. Patients with an increased UACR were also more likely to have been admitted for heart failure, and a higher proportion had NYHA functional class III or IV symptoms at the time of randomisation. The use of angiotensin-converting enzyme inhibitors, β blockers, and digoxin was similar in all three UACR groups although the proportion of patients being treated with spironolactone was smallest in the group with macroalbuminuria. Nitrates were used more commonly in patients with an elevated UACR, and use of
Cardiovascular death or admission for heart failure
0·5657
Data are mean (SD) or number (%). BMI=body-mass index. NYHA=New York Heart Association. LVEF=left ventricular ejection fraction. HR=heart rate. SBP=systolic blood pressure. DBP=diastolic blood pressure. PCI=percutaneous coronary intervention. CABG=coronary artery bypass grafting. eGFR=estimated glomerular filtration rate. HbA1c=haemoglobin A1c. ACE=angiotensin-converting enzyme.
Table 1: Characteristics of patients with and without an elevated urinary albumin to creatinine ratio
calcium-channel blockers was more common in those with macroalbuminuria (table 1). Of 1447 patients without diabetes, 397 (27%) had microalbuminuria and 88 (6%) had macroalbuminuria. 307 (36%) of 863 with diabetes had microalbuminuria and 169 (20%) had macroalbuminuria. Among 1714 patients with a systolic blood pressure of 140 mm Hg or less, or a diastolic blood pressure of 90 mm Hg or less, 508 (30%) had microalbuminuria and 146 (9%) had macroalbuminuria. Of 596 patients with a systolic blood pressure of more than 140 mm Hg or a diastolic blood pressure of more than 90 mm Hg, 196 (33%) had microalbuminuria and 111 (19%) had macroalbuminuria. Of 796 patients without a history of hypertension, 223 (28%) had microalbuminuria and 47 (6%) had macroalbuminuria. In 1514 patients with a history of hypertension, 481 (32%) had microalbuminuria and 210 (14%) had macroalbuminuria. Of 755 patients without either diabetes or a history of hypertension,
Normoalbuminuria Microalbuminuria (n=1349) (n=704)
Hazard ratio* (95% CI)
Macroalbuminuria (n=257)
Hazard ratio* (95% CI)
135 (52%)
2·36 (1·94–2·86)
397 (28%)
306 (43%)
1·74 (1·50–2·02)
Cardiovascular death†
196 (13%)
188 (27%)
··
65 (26%)
··
Admission for heart failure†
292 (22%)
213 (32%)
··
102 (41%)
··
All-cause mortality or admission for heart failure
437 (31%)
332 (46%)
1·71 (1·48–1·97)
146 (55%)
2·32 (1·92–2·79)
Cardiovascular death or admission for heart failure, non-fatal myocardial infarction, or non-fatal stroke
440 (31%)
328 (46%)
1·69 (1·47–1·95)
146 (56%)
2·35 (1·95–2·84)
Cardiovascular death, admission for heart failure, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularisation procedure
488 (35%)
345 (48%)
1·59 (1·38–1·82)
153 (59%)
2·22 (1·85–2·66)
All-cause mortality
249 (17%)
231 (31%)
1·97 (1·65–2·36)
87 (33%)
2·07 (1·63–2·65)
Data are number (%); percentages are Kaplan-Meier failure rates at 3 years. *Unadjusted hazard ratio (compared with normoalbuminuria). †Any occurrence of these outcomes.
Table 2: Clinical outcomes according to baseline urinary albumin to creatinine ratio
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A
Estimated cumulative distribution function
0·7
Macroalbuminuria Microalbuminuria Normoalbuminuria
0·6 0·5 0·4 0·3 0·2 0·1 0
Number at risk Normoalbuminuria 1346 Microalbuminuria 703 Macroalbuminuria 256
1246 592 209
1168 547 174
1099 487 153
1013 434 136
817 326 100
411 148 45
0·5
1·0
1·5 Time (years)
2·0
2·5
3·0
1312 657 242
1270 632 229
1234 589 211
1170 542 195
964 421 150
492 192 64
B 0·45
Estimated cumulative distribution function
0·40 0·35 0·30 0·25 0·20 0·15 0·10 0·05 0 0 Number at risk Normoalbuminuria 1348 Microalbuminuria 704 Macroalbuminuria 256
Figure 1: Cardiovascular death or admission for chronic heart failure (A), and all-cause mortality (B), stratified by albuminuria status
212 (28%) had microalbuminuria and 43 (6%) had macroalbuminuria. 372 (27%) of 1375 patients with an eGFR greater than or equal to 60 mL/min/1·73m² had microalbuminuria and 108 (8%) had macroalbuminuria. Of 638 patients with renal impairment (eGFR <60 mL/min/1·73m²), 244 (38%) had microalbuminuria and 119 (19%) had macroalbuminuria. 423 (31%) of 1343 patients with heart failure and a low LVEF (≤40%) had microalbuminuria and 138 (10%) had 546
macroalbuminuria. In 967 patients with heart failure and a preserved LVEF (>40%), 281 (29%) had microalbuminuria and 119 (12%) had macroalbuminuria. 405 (31%) of 1319 patients who were not taking an angiotensin-converting enzyme inhibitor at baseline had microalbuminuria and 150 (11%) had macroalbuminuria. 299 (30%) of 991 patients taking an angiotensin-converting enzyme inhibitor at baseline had microalbuminuria and 107 (11%) had macroalbuminuria. The unadjusted risk of adverse cardiovascular outcomes was increased in patients with an elevated UACR (table 2). Fewer patients with a normal UACR had the primary composite outcome of death from a cardiovascular cause or admission for heart failure than did those with microalbuminuria or macroalbuminuria (figure 1; table 2). Elevated UACR was associated with an increased risk of each of the components of this outcome. This increased risk was also noted for the expanded secondary cardiovascular outcomes that included myocardial infarction, stroke, and coronary revascularisation (table 2). Notably, the proportions of patients admitted to hospital with heart failure were increased substantially in the elevated UACR categories—with the highest increase in patients with macroalbuminuria (table 2). The proportion of patients who died from any cause also increased with increase in UACR (figure 2; table 2). The albuminuria category was an independent, significant, predictor of the primary outcome, all-cause mortality, and admission for heart failure when added to the Cox regression analysis with 33 baseline demographic and clinical factors as covariates (table 3). For each of these outcomes, patients with microalbuminuria or macroalbuminuria had a 40–80% increase in adjusted risk. UACR was also an independent predictor of outcome when analysed as a continuous variable. An increase in UACR of 100 mg/mmol was associated with about a 10% increase in adjusted risk for all three outcomes. Creatinine was a significant independent predictor of all three outcomes whereas the predictive value of HbA1c was not always significant for the primary outcome in the multivariable analysis that included UACR, HbA1c, and creatinine (table 4). However, UACR remained an independent predictor when both creatinine and HbA1c were added to the model, with little reduction in the hazard ratios (HRs) related to microalbuminuria and macroalbuminuria for any of the three outcomes (table 4). Similar results were obtained when this 36-covariate model was re-run with eGFR instead of creatinine (data not shown). The risk associated with excretion of albumin in urine, assessed as a continuous or categorical variable, was similar in patients with low LVEF and in those with preserved LVEF. HR for the primary composite outcome in the categorical analysis was 1·84 (95% CI 1·39–2·43) www.thelancet.com Vol 374 August 15, 2009
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60
Cardiovascular death or admission for heart failure Death from any cause
Clinical outcomes (%)
50 40 30 20 10 0 1
2
3
4
5
6
7
8
9
10
1·94–3·01 (n=232)
3·01–5·04 (n=230)
5·04–10·56 (n=231)
10·56–29·53 (n=231)
>29·53 (n=231)
Decile of UACR 0–0·40 (n=231)
0·40–0·66 (n=231)
0·66–0·94 (n=231)
0·94–1·32 (n=231)
1·32–1·94 (n=231)
Figure 2: Clinical outcomes according to decile of urinary albumin to creatinine ratio (UACR)
for macroalbuminuria versus normoalbuminuria and 1·61 (1·34–1·95) for microalbuminuria versus normoalbuminuria in patients with a low LVEF compared with 2·03 (1·45–2·85) for macroalbuminuria versus normoalbuminuria, and 1·31 (0·99–1·74) for microalbuminuria versus normoalbuminuria in those with a preserved LVEF (p=0·1566 for interaction between LVEF and macroalbuminuria, and p=0·8280 for interaction between LVEF and microalbuminuria). HR per unit UACR (100 mg/mmol) was 1·10 (0·99–1·21) in patients with low LVEF and 1·12 (1·04–1·21) in those with preserved LVEF (p=0·6283 for interaction). The risk related to excretion of albumin in urine was also evident in the subset of patients with a normal UACR at baseline (and of at least the same magnitude as in the overall patient population; figure 2). HR for the primary outcome for each unit increase in UACR was 1·15 (95% CI 1·00–1·32; p=0·0565). Urine samples were not obtained at follow-up in a large proportion of patients (table 5). There was no evidence to suggest that treatment with candesartan prevented the development or reduced the excessive excretion of albumin in urine.
Discussion The prevalence of elevated UACR in patients with heart failure was high and was associated with a substantially increased risk of adverse clinical outcomes, including death. Even after adjustment for other risk factors in a multivariable model, microalbuminuria or macroalbuminuria remained strong independent predictors, with a 60–80% adjusted increase in the risk of death and a 30–70% increase in the adjusted risk of admission for heart failure. Little is known about excretion of albumin in urine in patients with heart failure and nothing is known about its prognostic importance. Few data are available for the prevalence of increased excretion of albumin in the urine of patients with heart failure. Most patients in the www.thelancet.com Vol 374 August 15, 2009
Studies of Left Ventricular Dysfunction (SOLVD) had a urine dipstick test for protein at baseline.26 Of 5487 (81% of total) tested, 177 (3%) had proteinuria. These patients had a higher blood pressure and a higher prevalence of diabetes mellitus, and also greater left ventricular systolic dysfunction and more symptomatic heart failure than did those without proteinuria. The results of dipstick urine testing for proteinuria were also reported in a Canadian subset (n=583) of 2231 patients
Hazard ratio (95% CI)
p value
Cardiovascular death or admission for heart failure Albuminuria category* Microalbuminuria vs normoalbuminuria
1·50 (1·28–1·75) <0·0001
Macroalbuminuria vs normoalbuminuria
1·88 (1·53–2·33) <0·0001
UACR continuous (100 mg/mmol)†
1·10 (1·04–1·17)
0·0016
All-cause mortality Albuminuria category* Microalbuminuria vs normoalbuminuria
1·63 (1·35–1·97) <0·0001
Macroalbuminuria vs normoalbuminuria
1·77 (1·36–2·31)
<0·0001
1·10 (1·02–1·19)
0·0153
Microalbuminuria vs normoalbuminuria
1·41 (1·17–1·69)
0·0003
Macroalbuminuria vs normoalbuminuria
1·88 (1·47–2·40) <0·0001
UACR continuous (100 mg/mmol)† Admission for heart failure Albuminuria category*
UACR continuous (100 mg/mmol)†
1·11 (1·04–1·19)
0·0024
*UACR analysed as a categorical variable (microalbuminuria or macroalbuminuria vs normoalbuminuria). †UACR analysed as a continuous variable.
Table 3: Multivariable analysis of urinary albumin to creatinine ratio (UACR) added to 33 baseline covariates by endpoint
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with left ventricular systolic dysfunction after myocardial infarction who were enrolled in the Survival and Ventricular Enlargement trial (SAVE).27 15% of this Hazard ratio (95% CI)
p value
Cardiovascular death or admission for heart failure UACR categorical* 1·43 (1·21–1·69)
<0·0001
Macroalbuminuria vs normoalbuminuria 1·75 (1·39–2·20)
<0·0001
Creatinine (10 μmol/L)
1·04 (1·02–1·06)
<0·0001
HbA1c (%)
1·04 (0·99–1·11)
0·1466
Microalbuminuria vs normoalbuminuria
UACR continuous† UACR (100 mg/mmol)
1·07 (1·00–1·14)
0·0414
Creatinine (10 μmol/L)
1·05 (1·03–1·07)
<0·0001
HbA1c (%)
1·06 (1·00–1·12)
0·0441
1·62 (1·32–1·99)
<0·0001
Macroalbuminuria vs normoalbuminuria 1·76 (1·32–2·35)
0·0001
All-cause mortality UACR categorical* Microalbuminuria vs normoalbuminuria Creatinine (10 μmol/L)
1·03 (1·01–1·05)
0·0171
HbA1c (%)
1·03 (0·96–1·11)
0·4429
UACR (100 mg/mmol)
1·08 (1·00–1·17)
0·0598
Creatinine (10 μmol/L)
1·04 (1·01–1·06)
0·0025
HbA1c (%)
1·05 (0·98–1·13)
0·1821
UACR continuous†
Admission for heart failure UACR categorical* 1·31 (1·07–1·59)
0·0077
Macroalbuminuria vs normoalbuminuria 1·67 (1·28–2·17)
0·0002
Microalbuminuria vs normoalbuminuria Creatinine (10 μmol/L)
1·06 (1·03–1·08)
<0·0001
HbA1c (%)
1·04 (0·98–1·11)
0·2223
UACR continuous† UACR (100 mg/mmol)
1·07 (0·99–1·15)
0·0753
Creatinine (10 μmol/L)
1·06 (1·04–1·09)
<0·0001
HbA1c (%)
1·06 (0·99–1·13)
0·0998
HbA1c=haemoglobin A1c. *UACR analysed as a categorical variable (microalbuminuria or macroalbuminuria vs normoalbuminuria). †UACR analysed as a continuous variable.
Table 4: Multivariable analysis of urinary albumin to creatinine ratio (UACR), serum creatinine concentration, and haemoglobin A1c added to 33 baseline covariates by endpoint
Normoalbuminuria Microalbuminuria
Macroalbuminuria Missing
Placebo at baseline (n=1142) Normoalbuminuria (n=656)
264 (40%)
88 (13%)
9 (1%)
295 (45%)
Microalbuminuria (n=355)
57 (16%)
118 (33%)
25 (7%)
155 (44%)
Macroalbuminuria (n=131)
4 (3%)
27 (21%)
44 (34%)
56 (43%)
Candesartan at baseline (n=1168) Normoalbuminuria (n=693)
278 (40%)
72 (10%)
8 (1%)
335 (48%)
Microalbuminuria (n=349)
88 (25%)
116 (33%)
18 (5%)
127 (36%)
Macroalbuminuria (n=126)
5 (4%)
28 (22%)
38 (30%)
55 (44%)
Data are number (%).
Table 5: Urinary albumin to creatinine ratio shifts between baseline and study follow-up visit at 14 months
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subset had a trace of proteinuria and 6% had greater than trace proteinuria. Patients with proteinuria had a higher baseline creatinine and Killip class than did those without proteinuria. They also had a lower LVEF but had a similar prevalence of diabetes to those without proteinuria. By contrast with these two studies,26,27 UACR was measured in one other study in which 29 (30%) of 96 outpatients (mean age 69 years; 22% women) with predominantly NYHA class III heart failure had microalbuminuria, and 5 (5%) had macroalbuminuria.15 Although differences between patients with and without microalbuminuria were noted, they were not significant, probably because there were few patients in each group (and patients with macroalbuminuria were not described further). In our study, microalbuminuria was much more common than was macroalbuminuria. Patients with an increased UACR were older and had more cardiovascular problems, dysglycaemia, and renal impairment, and also had worse symptoms of heart failure than did those without increased UACR. LVEF did not differ between those with and without an increased UACR, and the corollary was also true—ie, the prevalence of an increased UACR was similar in patients with reduced and preserved LVEF heart failure. However, a third of patients without diabetes had microalbuminuria or macroalbuminuria, and more than a third of those without hypertension or renal impairment also had an elevated UACR. Consequently, increased excretion of albumin in urine in patients with heart failure cannot be wholly explained by concomitant diabetes, hypertension, or renal dysfunction. Notably, the prevalence of microalbuminuria in patients without diabetes was three-fold greater than that in age-matched individuals in the general population; the prevalence of microalbuminuria in Dutch individuals aged 60–74 years was 10·4% (95% CI 9·8–11·0).15 The mechanism underlying albuminuria in patients without these conditions is not known. Renal venous congestion caused proteinuria in dogs, and urinary albumin excretion was inversely related to renal blood flow in patients with heart failure.28–30 Increased albumin excretion might therefore have a haemodynamic basis in heart failure, particularly when renal venous congestion is associated with reduced renal blood flow. All of these renal changes are associated with worse outcomes in patients with heart failure.28–30 Even after the differences between those with and without an elevated UACR are accounted for in the multivariable analyses, increased UACR remained a significant independent predictor of the primary composite outcome of cardiovascular death or admission for worsening heart failure, and all-cause mortality. Of note, increased urinary albumin excretion was also an independent predictor of the disease-specific non-fatal outcome of admission for worsening heart failure. The www.thelancet.com Vol 374 August 15, 2009
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small proportion of patients with dipstick proteinuria in SOLVD also had an increased risk of death and of admission for heart failure.26 Dipstick proteinuria was also a significant independent predictor of mortality in SAVE.27 The hazard related to increased urinary albumin excretion was independent of renal dysfunction, as assessed by both serum creatinine concentration and eGFR, and also dysglycaemia, with adjustment for history of diabetes and HbA1c. The risk related to increased albumin excretion in urine was apparent in patients with low LVEF and also those with preserved LVEF heart failure. Another important finding, lending support to recent findings in patients with stable atherosclerotic disease, is that even an increasing UACR within the normoalbuminuric range was associated with an increased hazard of adverse clinical outcomes, showing that urinary albumin excretion represents a continuous measure of risk.8 Candesartan did not reduce excessive albumin excretion or prevent its development although the interpretation of this analysis is uncertain with the high proportion of missing follow-up urine samples and is probably too soon to conclude that angiotensin-receptor blockers definitely have no effect on urinary albumin excretion in patients with heart failure. These drugs reduce albumin excretion in patients with type 2 diabetes mellitus, hypertension, substantial renal impairment, and marked proteinuria. Whether the pathogenesis of increased albumin excretion in heart failure is the same and whether an angiotensin-receptor blocker should reduce albumin excretion in patients with heart failure are not known. One limitation of our study is that patients were selected from those enrolled in a clinical trial, and, particularly, those with severe renal dysfunction were not included. However, the proportions of patients with microalbuminuria and macroalbuminuria in our study were similar to those reported in the only other study done in patients with heart failure.15 Newer methods for measurement of renal function, such as levels of cystatin C, and other important prognostic markers such as natriuretic peptides and troponin were not measured in CHARM. Because UACR is a simple, readily available clinical test that is widely used in primary and secondary care, it might be of value in risk stratification of patients with heart failure. However, whether UACR adds incremental prognostic information to other new prognostic biomarkers, particularly natriuretic peptides, which are also increasingly and widely used in clinical practice, needs to be assessed. Of potential interest to physicians and patients is whether therapeutic reduction in albumin excretion, which did not occur with candesartan, might be useful in the prediction of improvement in clinical outcomes. www.thelancet.com Vol 374 August 15, 2009
Contributors MAP, KS, CBG, JJVM, SY, BO, and ELM designed the CHARM Programme and substudies. HCG and SDS also contributed to the design and interpretation of the present study. SZ and BO did the statistical analyses. All authors contributed to the interpretation of the data. CEJ and JJVM wrote the draft of the report, and all authors contributed to its revision. JJVM takes responsibility for the report. Conflicts of interest MAP, KS, HCG, CBG, JJVM, SDS, and SY have received research funding, and lecture and consulting fees from AstraZeneca. ELM, BO, and SZ are employees of AstraZeneca. CEJ declares that she has no conflicts of interest. Acknowledgments The CHARM Programme was funded by AstraZeneca. References 1 Arnlöv J, Evans JC, Meigs JB, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation 2005; 112: 969–75. 2 Diercks GF, van Boven AJ, Hillege HL, et al. Microalbuminuria is independently associated with ischaemic electrocardiographic abnormalities in a large non-diabetic population. The PREVEND (Prevention of REnal and Vascular ENdstage Disease) study. Eur Heart J 2000; 21: 1922–27. 3 Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 1984; 310: 356–60. 4 Deckert T, Yokoyama H, Mathiesen E, et al. Cohort study of predictive value of urinary albumin excretion for atherosclerotic vascular disease in patients with insulin dependent diabetes. BMJ 1996; 312: 871–74. 5 Agewall S, Wikstrand J, Ljungman S, Fagerberg B. Usefulness of microalbuminuria in predicting cardiovascular mortality in treated hypertensive men with and without diabetes mellitus. Risk Factor Intervention Study Group. Am J Cardiol 1997; 80: 164–69. 6 Wachtell K, Ibsen H, Olsen MH, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med 2003; 139: 901–06. 7 Gerstein HC, Mann JF, Yi Q, et al; HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001; 286: 421–26. 8 Solomon SD, Lin J, Solomon CG, et al. Influence of albuminuria on cardiovascular risk in patients with stable coronary artery disease. Circulation 2007; 116: 2687–93. 9 Brantsma AH, Bakker SJ, Hillege HL, 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: 3851–58. 10 Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105–87. 11 American Diabetes Association. Standards of medical care in diabetes–2008. Diabetes Care 2008; 31 (suppl 1): S12–54. 12 Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, et al. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 1989; 32: 219–26. 13 Chugh A, Bakris GL. Microalbuminuria: what is it? Why is it important? What should be done about it? An update. J Clin Hypertens (Greenwich) 2007; 9: 196–200. 14 Weir MR. Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007; 2: 581–90. 15 van de Wal RM, Asselbergs FW, Plokker HW, et al. High prevalence of microalbuminuria in chronic heart failure patients. J Card Fail 2005; 11: 602–06. 16 Silverberg D, Wexler D, Blum M, et al. The association between congestive heart failure and chronic renal disease. Curr Opin Nephrol Hypertens 2004; 13: 163–70. 17 Jensen JS, Clausen P, Borch-Johnsen K, et al. Detecting microalbuminuria by urinary albumin/creatinine concentration ratio. Nephrol Dial Transplant 1997; 12 (suppl 2): 6–9.
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