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Summary
Background Increased excretion of albumin in urine might be a marker of the various pathophysiological changes Lancet 2009; 374: 543–50
that arise in patients with heart failure. Therefore our aim was to assess the prevalence and prognostic value of a spot See Editorial page 501
urinary albumin to creatinine ratio (UACR) in patients with heart failure. See Comment page 506
British Heart Foundation
Methods UACR was measured at baseline and during follow-up of 2310 patients in the Candesartan in Heart failure: Glasgow Cardiovascular
Research Centre, University of
Assessment of Reduction in Mortality and morbidity (CHARM) Programme. The prevalence of microalbuminuria
Glasgow, Glasgow, UK
and macroalbuminuria, and the predictive value of UACR for the primary composite outcome of each CHARM (C E Jackson MB ChB,
study—ie, death from cardiovascular causes or admission to hospital with worsening heart failure—and death from Prof J J V McMurray MD);
any cause were assessed. Brigham and Women’s
Hospital, Boston, MA, USA
(S D Solomon MD,
Findings 1349 (58%) patients had a normal UACR, 704 (30%) had microalbuminuria, and 257 (11%) had Prof M A Pfeffer MD);
macroalbuminuria. The prevalence of increased UACR was similar in patients with reduced and preserved left Department of Medicine and
ventricular ejection fractions. Patients with an increased UACR were older, had more cardiovascular comorbidity, Population Health Research
Institute, McMaster University
worse renal function, and a higher prevalence of diabetes mellitus than did those with normoalbuminuria. However,
and Hamilton Health Sciences,
a high prevalence of increased UACR was still noted among patients without diabetes, hypertension, or renal Hamilton, ON, Canada
dysfunction. Elevated UACR was associated with increased risk of the composite outcome and death even after (Prof H C Gerstein MD,
adjustment for other prognostic variables including renal function, diabetes, and haemoglobin A1c. The adjusted Prof S Yusuf DPhil); AstraZeneca
Research and Development,
hazard ratio (HR) for the composite outcome in patients with microalbuminuria versus normoalbuminuria was Mölndal, Sweden
1·43 (95% CI 1·21–1·69; p<0·0001) and for macroalbuminuria versus normoalbuminuria was 1·75 (1·39–2·20; (S Zetterstrand PhD,
p<0·0001). The adjusted values for death were 1·62 (1·32–1·99; p<0·0001) for microalbuminuria versus normo- B Olofsson PhD); AstraZeneca,
albuminuria, and 1·76 (1·32–2·35; p=0·0001) for macroalbuminuria versus normoalbuminuria. Treatment with Wilmington, DE, USA
(Prof E L Michelson MD); Duke
candesartan did not reduce or prevent the development of excessive excretion of urinary albumin. University Medical Center,
Durham, NC, USA
Interpretation Increased UACR is a powerful and independent predictor of prognosis in heart failure. (Prof C B Granger MD); and
Department of Emergency and
Cardiovascular Medicine,
Funding AstraZeneca. Sahlgrenska Academy,
University of Gothenburg,
Introduction Programme.19,20 We assessed the prevalence of an Gothenburg, Sweden
Increased excretion of albumin in urine is an established increased UACR in these patients at baseline, the (Prof K Swedberg MD)
risk factor for mortality, cardiovascular events, and characteristics of patients with an increased UACR, and Correspondence to:
Prof John J V McMurray, British
adverse renal outcomes in the general population1,2 and the association between an increased UACR at baseline Heart Foundation Cardiovascular
in patients with diabetes,3,4 hypertension,5,6 and other and subsequent clinical outcomes. Research Centre, University of
types of cardiovascular disease.7–9 Screening for increased Glasgow, 126 University Place,
albumin excretion is recommended in patients with Methods Glasgow G12 8TA, UK
j.mcmurray@bio.gla.ac.uk
diabetes and hypertension to help with risk stratification Study design
and target treatment.10,11 Increased excretion might be a The design and results of the CHARM trials are described
marker of diffuse vascular injury, systemic inflammation, elsewhere.19,21 Briefly, we studied 7599 patients with New
activation of the renin-angiotensin system, altered York Heart Association (NYHA) class II to IV heart
glomerular haemodynamics, or abnormal tubular failure with concentrations of serum creatinine of less
function.12–14 Many, if not all, of these pathophysiological than 265 μmol/L (30 mg/L), and serum potassium of less
abnormalities also occur in heart failure.15,16 Measurement than 5·5 mmol/L, who were not taking an
of the urinary albumin to creatinine ratio (UACR) in a angiotensin-receptor blocker, and who had no critical
random urine specimen is a convenient method for aortic or mitral stenosis, or recent myocardial infarction,
detection of increased albumin excretion.17,18 The stroke, or heart surgery. They were divided according to
prevalence and prognostic importance of elevated UACR whether they had left ventricular ejection fraction (LVEF)
in heart failure, however, are not known.15 greater than 40%; LVEF less than or equal to 40% and
We measured UACR in a large subset of patients taking an angiotensin-converting enzyme inhibitor; and
enrolled in the Candesartan in Heart failure: Assessment LVEF less than or equal to 40% and not taking an
of Reduction in Mortality and morbidity (CHARM) angiotensin-converting enzyme inhibitor because of
Data are mean (SD) or number (%). BMI=body-mass index. NYHA=New York Heart Association. LVEF=left ventricular
Results ejection fraction. HR=heart rate. SBP=systolic blood pressure. DBP=diastolic blood pressure. PCI=percutaneous
UACR was measured in 2310 (84%) of 2743 North coronary intervention. CABG=coronary artery bypass grafting. eGFR=estimated glomerular filtration rate.
American patients in CHARM. Table 1 shows the HbA1c=haemoglobin A1c. ACE=angiotensin-converting enzyme.
baseline characteristics of the three groups: 58% had a Table 1: Characteristics of patients with and without an elevated urinary albumin to creatinine ratio
normal UACR, 30% had microalbuminuria, and 11%
had macroalbuminuria. Patients with an increased
UACR were older, had a higher systolic blood pressure, calcium-channel blockers was more common in those
and were more likely to have a history of hypertension with macroalbuminuria (table 1).
and diabetes (especially those with macroalbuminuria) Of 1447 patients without diabetes, 397 (27%) had micro-
than were those with normal UACR. A history of stroke, albuminuria and 88 (6%) had macroalbuminuria.
coronary heart disease, and atrial fibrillation was also 307 (36%) of 863 with diabetes had microalbuminuria
more common in patients with an elevated UACR. HbA1c and 169 (20%) had macroalbuminuria.
level was higher in patients with an elevated UACR (even Among 1714 patients with a systolic blood pressure of
in those without diabetes), and renal dysfunction 140 mm Hg or less, or a diastolic blood pressure of
(defined as eGFR <60 mL/min/1·73 m²) was more 90 mm Hg or less, 508 (30%) had microalbuminuria and
common in these patients than in those with normal 146 (9%) had macroalbuminuria. Of 596 patients with a
UACR. Patients with an increased UACR were also more systolic blood pressure of more than 140 mm Hg or a
likely to have been admitted for heart failure, and a diastolic blood pressure of more than 90 mm Hg,
higher proportion had NYHA functional class III or IV 196 (33%) had microalbuminuria and 111 (19%) had
symptoms at the time of randomisation. The use of macroalbuminuria.
angiotensin-converting enzyme inhibitors, β blockers, Of 796 patients without a history of hypertension,
and digoxin was similar in all three UACR groups 223 (28%) had microalbuminuria and 47 (6%) had
although the proportion of patients being treated with macroalbuminuria. In 1514 patients with a history of
spironolactone was smallest in the group with macro- hypertension, 481 (32%) had microalbuminuria and
albuminuria. Nitrates were used more commonly in 210 (14%) had macroalbuminuria. Of 755 patients
patients with an elevated UACR, and use of without either diabetes or a history of hypertension,
Data are number (%); percentages are Kaplan-Meier failure rates at 3 years. *Unadjusted hazard ratio (compared with normoalbuminuria). †Any occurrence of these outcomes.
40
30
20
10
0
1 2 3 4 5 6 7 8 9 10
Decile of UACR
0–0·40 0·40–0·66 0·66–0·94 0·94–1·32 1·32–1·94 1·94–3·01 3·01–5·04 5·04–10·56 10·56–29·53 >29·53
(n=231) (n=231) (n=231) (n=231) (n=231) (n=232) (n=230) (n=231) (n=231) (n=231)
Figure 2: Clinical outcomes according to decile of urinary albumin to creatinine ratio (UACR)
for macroalbuminuria versus normoalbuminuria and Studies of Left Ventricular Dysfunction (SOLVD) had a
1·61 (1·34–1·95) for microalbuminuria versus normo- urine dipstick test for protein at baseline.26 Of 5487 (81%
albuminuria in patients with a low LVEF compared with of total) tested, 177 (3%) had proteinuria. These patients
2·03 (1·45–2·85) for macroalbuminuria versus normo- had a higher blood pressure and a higher prevalence of
albuminuria, and 1·31 (0·99–1·74) for microalbumin- diabetes mellitus, and also greater left ventricular
uria versus normoalbuminuria in those with a preserved systolic dysfunction and more symptomatic heart
LVEF (p=0·1566 for interaction between LVEF and failure than did those without proteinuria. The results
macroalbuminuria, and p=0·8280 for interaction of dipstick urine testing for proteinuria were also
between LVEF and microalbuminuria). HR per unit reported in a Canadian subset (n=583) of 2231 patients
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). Hazard ratio p value
(95% CI)
The risk related to excretion of albumin in urine was
also evident in the subset of patients with a normal Cardiovascular death or admission for heart failure
UACR at baseline (and of at least the same magnitude as Albuminuria category*
in the overall patient population; figure 2). HR for the Microalbuminuria vs 1·50 (1·28–1·75) <0·0001
primary outcome for each unit increase in UACR was normoalbuminuria
1·15 (95% CI 1·00–1·32; p=0·0565). Urine samples were Macroalbuminuria vs 1·88 (1·53–2·33) <0·0001
normoalbuminuria
not obtained at follow-up in a large proportion of patients
UACR continuous (100 mg/mmol)† 1·10 (1·04–1·17) 0·0016
(table 5). There was no evidence to suggest that treatment
All-cause mortality
with candesartan prevented the development or reduced
Albuminuria category*
the excessive excretion of albumin in urine.
Microalbuminuria vs 1·63 (1·35–1·97) <0·0001
normoalbuminuria
Discussion Macroalbuminuria vs 1·77 (1·36–2·31) <0·0001
The prevalence of elevated UACR in patients with heart normoalbuminuria
failure was high and was associated with a substantially UACR continuous (100 mg/mmol)† 1·10 (1·02–1·19) 0·0153
increased risk of adverse clinical outcomes, including Admission for heart failure
death. Even after adjustment for other risk factors in a Albuminuria category*
multivariable model, microalbuminuria or macro- Microalbuminuria vs 1·41 (1·17–1·69) 0·0003
albuminuria remained strong independent predictors, normoalbuminuria
with a 60–80% adjusted increase in the risk of death and Macroalbuminuria vs 1·88 (1·47–2·40) <0·0001
a 30–70% increase in the adjusted risk of admission for normoalbuminuria
heart failure. UACR continuous (100 mg/mmol)† 1·11 (1·04–1·19) 0·0024
Little is known about excretion of albumin in urine in *UACR analysed as a categorical variable (microalbuminuria or macroalbuminuria
patients with heart failure and nothing is known about vs normoalbuminuria). †UACR analysed as a continuous variable.
its prognostic importance. Few data are available for the
Table 3: Multivariable analysis of urinary albumin to creatinine ratio
prevalence of increased excretion of albumin in the
(UACR) added to 33 baseline covariates by endpoint
urine of patients with heart failure. Most patients in the
with left ventricular systolic dysfunction after myocardial subset had a trace of proteinuria and 6% had greater
infarction who were enrolled in the Survival and than trace proteinuria. Patients with proteinuria had a
Ventricular Enlargement trial (SAVE).27 15% of this higher baseline creatinine and Killip class than did
those without proteinuria. They also had a lower LVEF
Hazard ratio p value but had a similar prevalence of diabetes to those without
(95% CI)
proteinuria.
Cardiovascular death or admission for heart failure By contrast with these two studies,26,27 UACR was
UACR categorical* measured in one other study in which 29 (30%) of 96
Microalbuminuria vs normoalbuminuria 1·43 (1·21–1·69) <0·0001 outpatients (mean age 69 years; 22% women) with
Macroalbuminuria vs normoalbuminuria 1·75 (1·39–2·20) <0·0001 predominantly NYHA class III heart failure had micro-
Creatinine (10 μmol/L) 1·04 (1·02–1·06) <0·0001 albuminuria, and 5 (5%) had macroalbuminuria.15
HbA1c (%) 1·04 (0·99–1·11) 0·1466 Although differences between patients with and without
UACR continuous† microalbuminuria were noted, they were not significant,
UACR (100 mg/mmol) 1·07 (1·00–1·14) 0·0414 probably because there were few patients in each group
Creatinine (10 μmol/L) 1·05 (1·03–1·07) <0·0001 (and patients with macroalbuminuria were not described
HbA1c (%) 1·06 (1·00–1·12) 0·0441 further).
All-cause mortality In our study, microalbuminuria was much more
UACR categorical* common than was macroalbuminuria. Patients with an
Microalbuminuria vs normoalbuminuria 1·62 (1·32–1·99) <0·0001 increased UACR were older and had more cardiovascular
Macroalbuminuria vs normoalbuminuria 1·76 (1·32–2·35) 0·0001 problems, dysglycaemia, and renal impairment, and also
Creatinine (10 μmol/L) 1·03 (1·01–1·05) 0·0171 had worse symptoms of heart failure than did those
HbA1c (%) 1·03 (0·96–1·11) 0·4429 without increased UACR. LVEF did not differ between
UACR continuous† those with and without an increased UACR, and the
UACR (100 mg/mmol) 1·08 (1·00–1·17) 0·0598
corollary was also true—ie, the prevalence of an increased
Creatinine (10 μmol/L) 1·04 (1·01–1·06) 0·0025
UACR was similar in patients with reduced and
HbA1c (%) 1·05 (0·98–1·13) 0·1821
preserved LVEF heart failure. However, a third of patients
without diabetes had microalbuminuria or macro-
Admission for heart failure
albuminuria, and more than a third of those without
UACR categorical*
hypertension or renal impairment also had an elevated
Microalbuminuria vs normoalbuminuria 1·31 (1·07–1·59) 0·0077
UACR. Consequently, increased excretion of albumin in
Macroalbuminuria vs normoalbuminuria 1·67 (1·28–2·17) 0·0002
urine in patients with heart failure cannot be wholly
Creatinine (10 μmol/L) 1·06 (1·03–1·08) <0·0001
explained by concomitant diabetes, hypertension, or
HbA1c (%) 1·04 (0·98–1·11) 0·2223
renal dysfunction. Notably, the prevalence of micro-
UACR continuous†
albuminuria in patients without diabetes was three-fold
UACR (100 mg/mmol) 1·07 (0·99–1·15) 0·0753
greater than that in age-matched individuals in the
Creatinine (10 μmol/L) 1·06 (1·04–1·09) <0·0001
general population; the prevalence of microalbuminuria
HbA1c (%) 1·06 (0·99–1·13) 0·0998
in Dutch individuals aged 60–74 years was 10·4%
HbA1c=haemoglobin A1c. *UACR analysed as a categorical variable (95% CI 9·8–11·0).15
(microalbuminuria or macroalbuminuria vs normoalbuminuria). †UACR analysed The mechanism underlying albuminuria in patients
as a continuous variable.
without these conditions is not known. Renal venous
Table 4: Multivariable analysis of urinary albumin to creatinine ratio congestion caused proteinuria in dogs, and urinary
(UACR), serum creatinine concentration, and haemoglobin A1c added to albumin excretion was inversely related to renal blood
33 baseline covariates by endpoint flow in patients with heart failure.28–30 Increased albumin
excretion might therefore have a haemodynamic basis in
Normoalbuminuria Microalbuminuria Macroalbuminuria Missing heart failure, particularly when renal venous congestion
Placebo at baseline (n=1142)
is associated with reduced renal blood flow. All of these
Normoalbuminuria (n=656) 264 (40%) 88 (13%) 9 (1%) 295 (45%)
renal changes are associated with worse outcomes in
Microalbuminuria (n=355) 57 (16%) 118 (33%) 25 (7%) 155 (44%)
patients with heart failure.28–30
Macroalbuminuria (n=131) 4 (3%) 27 (21%) 44 (34%) 56 (43%)
Even after the differences between those with and
without an elevated UACR are accounted for in the
Candesartan at baseline (n=1168)
multivariable analyses, increased UACR remained a
Normoalbuminuria (n=693) 278 (40%) 72 (10%) 8 (1%) 335 (48%)
significant independent predictor of the primary
Microalbuminuria (n=349) 88 (25%) 116 (33%) 18 (5%) 127 (36%)
composite outcome of cardiovascular death or admission
Macroalbuminuria (n=126) 5 (4%) 28 (22%) 38 (30%) 55 (44%)
for worsening heart failure, and all-cause mortality. Of
Data are number (%). note, increased urinary albumin excretion was also an
independent predictor of the disease-specific non-fatal
Table 5: Urinary albumin to creatinine ratio shifts between baseline and study follow-up visit at 14 months
outcome of admission for worsening heart failure. The
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