albuminuria y ECV

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Albuminuria in chronic heart failure: prevalence and

prognostic importanceColette 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

SummaryBackground Increased excretion of albumin in urine might be a marker of the various pathophysiological changesthat arise in patients with heart failure. Therefore our aim was to assess the prevalence and prognostic value of a spoturinary 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 micro albuminuriaand macroalbuminuria, and the predictive value of UACR for the primary composite outcome of each CHARMstudyie, death from cardiovascular causes or admission to hospital with worsening heart failureand death from

any cause were assessed.

Findings 1349 (58%) patients had a normal UACR, 704 (30%) had microalbuminuria, and 257 (11%) hadmacroalbuminuria. The prevalence of increased UACR was similar in patients with reduced and preserved leftventricular 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 renaldysfunction. Elevated UACR was associated with increased risk of the composite outcome and death even afteradjustment for other prognostic variables including renal function, diabetes, and haemoglobin A 1c. The adjustedhazard ratio (HR) for the composite outcome in patients with microalbuminuria versus normoalbuminuria was143 (95% CI 121169; p


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intolerance. Within each of the component trials, patientswere randomly allocated to candesartan (up to 32 mgonce a day) or matching placebo. Median follow-up of theentire cohort was 377 months.

The primary outcome of the entire programme wasdeath from any cause and the primary composite outcomefor the three component trials was death from acardiovascular cause or admission for worsening heartfailure. Other prespecified outcomes were death from anycause or admission for heart failure; death from a cardio-vascular cause, admission for worsening heart failure,non-fatal myocardial infarction, or non-fatal stroke; and

death from a cardiovascular cause, admission for worsen-ing heart failure, non-fatal myocardial infarction, non-fatal stroke, or a coronary revascularisation procedure.

All endpoints were independently adjudicated. Thecause of death was considered to be cardiovascular unlessanother clear cause was apparent. Treatment in hospitalfor worsening heart failure was defined as an unplannedadmission that was necessitated by heart failure andrequired intravenous diuretics.

By design, all patients enrolled in Canada and the USA(n=2743) had blood chemistry and haematology measuredin 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 ofserum creatinine were measured spectrophotometrically

with the Olympus Chemistry Analyzer (OlympusAmerica, Center Valley, PA, USA), urinary albumin witha competitive radioimmunoassay Immulite (DiagnosticProducts, Los Angeles, CA, USA), and urine creatininewith a colourimetric kinetic Jaffe method on the CobasIntegra Instrument (Roche Diagnostic Systems,Branchburg, NJ, USA).7

Statistical analysisThese analyses were restricted to the North Americanparticipants for whom UACRs were available. Macro-albuminuria was defined as UACR greater than25 mg/mmol in men and women, and micro albuminuriaas UACR 25250 mg/mmol in men and

35250 mg/mmol in women.22

Cox proportionalhazards models were used to analyse the prospectiveassociation between UACR and death from acardiovascular cause or admission for worsening heartfailure, all-cause death, and admission to hospital forworsening heart failure. The association between UACRand these outcomes was adjusted for 33 baseline variablesas described previously:19,20 randomly assigned treatment(candesartan vs placebo), sex (men vs women), NYHAclass (III/IV vs II), smoking habit (current vs none orpast), age, LVEF, body-mass index, systolic blood pressure,diastolic blood pressure, heart rate, history (admission forheart failure, myocardial infarction, angina pectoris,stroke, hypertension, diabetes mellitus, atrial fibrillation,

cancer, coronary artery bypass surgery, percutaneouscoronary revascularisation, implanted cardioverterdefibrillator, or pacemaker), and baseline treatment(diuretic, digitalis, blocker, angiotensin-converting enzyme inhibitor, calcium-channel blocker,other vasodilator, antiarrhythmic drug, lipid-loweringdrug, anticoagulant, aspirin, and other antiplatelet).UACR was added to this model, as a categorical andcontinuous variable (34-variable model). Concentrationsof serum creatinine and haemoglobin A 1c (HbA1c) werethen added simultaneously to the model with UACR(36-variable model) to assess risk associated with increasedUACR, independently of renal dysfunction and

Normoalbuminuria(n=1349)

Microalbuminuria(n=704)

Macroalbuminuria(n=257)

p value

Demographic characteristics

Age (years) 65 (114) 68 (114) 68 (104)


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dysglycaemia.23,24 An alternative 36-variable model wasalso run with an estimated glomerular filtration rate(eGFR) with the four-variable equation for modificationof diet in renal disease instead of concentration of serumcreatinine.25

Role of the funding sourceThe collection and analysis of urine samples for albuminexcretion was a preplanned and investigator-originatedsubstudy. The measurement of urinary albuminconcentrations was paid for by the sponsor and done atMcMaster University and Hamilton Health Sciences,Hamilton, ON, Canada. The statistical analyses weredone by SZ who is an employee of the sponsor.

Results

UACR was measured in 2310 (84%) of 2743 NorthAmerican patients in CHARM. Table 1 shows thebaseline characteristics of the three groups: 58% had anormal UACR, 30% had microalbuminuria, and 11%had macroalbuminuria. Patients with an increasedUACR were older, had a higher systolic blood pressure,and were more likely to have a history of hypertensionand diabetes (especially those with macroalbuminuria)than were those with normal UACR. A history of stroke,coronary heart disease, and atrial fibrillation was alsomore common in patients with an elevated UACR. HbA1clevel was higher in patients with an elevated UACR (evenin those without diabetes), and renal dysfunction(defined as eGFR


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212 (28%) had microalbuminuria and 43 (6%) hadmacroalbuminuria.

372 (27%) of 1375 patients with an eGFR greater thanor equal to 60 mL/min/173m had microalbuminuriaand 108 (8%) had macroalbuminuria. Of 638 patientswith renal impairment (eGFR 40%), 281 (29%) had microalbumin-uria and 119 (12%) had macroalbuminuria.

405 (31%) of 1319 patients who were not taking anangiotensin-converting enzyme inhibitor at baselinehad microalbuminuria and 150 (11%) had macro-albuminuria. 299 (30%) of 991 patients taking anangiotensin-converting enzyme inhibitor at baselinehad microalbuminuria and 107 (11%) had macro-albuminuria.

The unadjusted risk of adverse cardiovascularoutcomes was increased in patients with an elevatedUACR (table 2). Fewer patients with a normal UACRhad the primary composite outcome of death from acardiovascular cause or admission for heart failure thandid those with microalbuminuria or macroalbuminuria

(figure 1; table 2). Elevated UACR was associated withan increased risk of each of the components of thisoutcome. This increased risk was also noted for theexpanded secondary cardiovascular outcomes thatincluded myocardial infarction, stroke, and coronaryrevascularisation (table 2). Notably, the proportions ofpatients admitted to hospital with heart failure wereincreased substantially in the elevated UACRcategorieswith the highest increase in patients withmacroalbuminuria (table 2). The proportion of patientswho died from any cause also increased with increase inUACR (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 addedto the Cox regression analysis with 33 baselinedemographic and clinical factors as covariates (table 3).For each of these outcomes, patients with microalbumin-uria or macroalbuminuria had a 4080% increase inadjusted risk. UACR was also an independent predictorof outcome when analysed as a continuous variable. Anincrease in UACR of 100 mg/mmol was associated withabout a 10% increase in adjusted risk for all threeoutcomes.

Creatinine was a significant independent predictor ofall three outcomes whereas the predictive value of HbA1cwas not always significant for the primary outcome inthe multivariable analysis that included UACR, HbA1c,

and creatinine (table 4). However, UACR remained anindependent predictor when both creatinine and HbA1cwere added to the model, with little reduction in thehazard ratios (HRs) related to microalbuminuria andmacroalbuminuria for any of the three outcomes (table 4).Similar results were obtained when this 36-covariatemodel was re-run with eGFR instead of creatinine (datanot shown).

The risk associated with excretion of albumin in urine,assessed as a continuous or categorical variable, wassimilar in patients with low LVEF and in those withpreserved LVEF. HR for the primary composite outcomein the categorical analysis was 184 (95% CI 139243)

NormoalbuminuriaMicroalbuminuria

Macroalbuminuria

Number at risk

Number at risk

1346703256

1246592209

1168547174

1099487153

1013434136

817326100

411148

45

NormoalbuminuriaMicroalbuminuria

Macroalbuminuria

1348704256

1312657242

1270632229

1234589211

1170542195

964421150

492192

64

07

06

05

04

03

Estimatedcumulativedistributionfunction

Estimatedcumulativedistributionfunction

02

01

0

035

040

045

030

025

020

015

010

005

0

0 05 10 15 20Time (years)

25 30

A

B

Macroalbuminuria

MicroalbuminuriaNormoalbuminuria

Figure 1: Cardiovascular death or admission for chronic heart failure (A), and all-cause mortality (B), stratifiedby albuminuria status


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for macroalbuminuria versus normoalbuminuria and161 (134195) for microalbuminuria versus normo-albuminuria in patients with a low LVEF compared with203 (145285) for macroalbuminuria versus normo-albuminuria, and 131 (099174) for microalbumin-uria versus normoalbuminuria in those with a preservedLVEF (p=01566 for interaction between LVEF andmacroalbuminuria, and p=08280 for interactionbetween LVEF and microalbuminuria). HR per unitUACR (100 mg/mmol) was 110 (099121) in patientswith low LVEF and 112 (104121) in those with

preserved LVEF (p=06283 for interaction).The risk related to excretion of albumin in urine wasalso evident in the subset of patients with a normalUACR at baseline (and of at least the same magnitude asin the overall patient population; figure 2). HR for theprimary outcome for each unit increase in UACR was115 (95% CI 100132; p=00565). Urine samples werenot obtained at follow-up in a large proportion of patients(table 5). There was no evidence to suggest that treatmentwith candesartan prevented the development or reducedthe excessive excretion of albumin in urine.

DiscussionThe prevalence of elevated UACR in patients with heart

failure was high and was associated with a substantiallyincreased risk of adverse clinical outcomes, includingdeath. Even after adjustment for other risk factors in amultivariable model, microalbuminuria or macro-albuminuria remained strong independent predictors,with a 6080% adjusted increase in the risk of death anda 3070% increase in the adjusted risk of admission forheart failure.

Little is known about excretion of albumin in urine inpatients with heart failure and nothing is known aboutits prognostic importance. Few data are available for theprevalence of increased excretion of albumin in theurine of patients with heart failure. Most patients in the

Studies of Left Ventricular Dysfunction (SOLVD) had aurine dipstick test for protein at baseline.26 Of 5487 (81%of total) tested, 177 (3%) had proteinuria. These patientshad a higher blood pressure and a higher prevalence ofdiabetes mellitus, and also greater left ventricularsystolic dysfunction and more symptomatic heartfailure than did those without proteinuria. The resultsof dipstick urine testing for proteinuria were alsoreported 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

150 (128175)


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with left ventricular systolic dysfunction after myocardialinfarction who were enrolled in the Survival andVentricular Enlargement trial (SAVE).27 15% of this

subset had a trace of proteinuria and 6% had greaterthan trace proteinuria. Patients with proteinuria had ahigher baseline creatinine and Killip class than didthose without proteinuria. They also had a lower LVEFbut had a similar prevalence of diabetes to those withoutproteinuria.

By contrast with these two studies,26,27 UACR wasmeasured in one other study in which 29 (30%) of 96outpatients (mean age 69 years; 22% women) withpredominantly NYHA class III heart failure had micro-albuminuria, and 5 (5%) had macroalbuminuria.15Although differences between patients with and withoutmicroalbuminuria were noted, they were not significant,probably because there were few patients in each group(and patients with macroalbuminuria were not describedfurther).

In our study, microalbuminuria was much morecommon than was macroalbuminuria. Patients with anincreased UACR were older and had more cardiovascularproblems, dysglycaemia, and renal impairment, and alsohad worse symptoms of heart failure than did thosewithout increased UACR. LVEF did not differ betweenthose with and without an increased UACR, and thecorollary was also trueie, the prevalence of an increasedUACR was similar in patients with reduced andpreserved LVEF heart failure. However, a third of patientswithout diabetes had microalbuminuria or macro-albuminuria, and more than a third of those withouthypertension or renal impairment also had an elevatedUACR. Consequently, increased excretion of albumin in

urine in patients with heart failure cannot be whollyexplained by concomitant diabetes, hypertension, orrenal dysfunction. Notably, the prevalence of micro-albuminuria in patients without diabetes was three-foldgreater than that in age-matched individuals in thegeneral population; the prevalence of microalbuminuriain Dutch individuals aged 6074 years was 104%(95% CI 98110).15

The mechanism underlying albuminuria in patientswithout these conditions is not known. Renal venouscongestion caused proteinuria in dogs, and urinaryalbumin excretion was inversely related to renal bloodflow in patients with heart failure.2830 Increased albuminexcretion might therefore have a haemodynamic basis in

heart failure, particularly when renal venous congestionis associated with reduced renal blood flow. All of theserenal changes are associated with worse outcomes inpatients with heart failure.2830

Even after the differences between those with andwithout an elevated UACR are accounted for in themultivariable analyses, increased UACR remained asignificant independent predictor of the primarycomposite outcome of cardiovascular death or admissionfor worsening heart failure, and all-cause mortality. Ofnote, increased urinary albumin excretion was also anindependent predictor of the disease-specific non-fataloutcome of admission for worsening heart failure. The

Hazard ratio(95% CI)

p value

Cardiovascular death or admission for heart failure

UACR categorical*

Microalbuminuria vs normoalbuminuria 143 (121169)


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small proportion of patients with dipstick proteinuria inSOLVD also had an increased risk of death and ofadmission for heart failure.26 Dipstick proteinuria wasalso a significant independent predictor of mortality inSAVE.27

The hazard related to increased urinary albumin excre-tion was independent of renal dysfunction, as assessedby both serum creatinine concentration and eGFR, andalso dysglycaemia, with adjustment for history ofdiabetes and HbA1c. The risk related to increasedalbumin excretion in urine was apparent in patientswith low LVEF and also those with preserved LVEFheart failure.

Another important finding, lending support to recentfindings in patients with stable atherosclerotic disease,is that even an increasing UACR within the normo-

albuminuric range was associated with an increasedhazard of adverse clinical outcomes, showing thaturinary albumin excretion represents a continuousmeasure of risk.8

Candesartan did not reduce excessive albuminexcretion or prevent its development although theinterpretation of this analysis is uncertain with the highproportion of missing follow-up urine samples and isprobably too soon to conclude that angiotensin-receptorblockers definitely have no effect on urinary albuminexcretion in patients with heart failure. These drugsreduce albumin excretion in patients with type 2 diabetesmellitus, hypertension, substantial renal impairment,and marked proteinuria. Whether the pathogenesis of

increased albumin excretion in heart failure is the sameand whether an angiotensin-receptor blocker shouldreduce albumin excretion in patients with heart failureare not known.

One limitation of our study is that patients wereselected from those enrolled in a clinical trial, and,particularly, those with severe renal dysfunction werenot included. However, the proportions of patients withmicroalbuminuria and macroalbuminuria in our studywere similar to those reported in the only other studydone in patients with heart failure.15 Newer methods formeasurement of renal function, such as levels ofcystatin C, and other important prognostic markers suchas 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, itmight be of value in risk stratification of patients withheart failure. However, whether UACR adds incrementalprognostic information to other new prognosticbiomarkers, particularly natriuretic peptides, which arealso increasingly and widely used in clinical practice,needs to be assessed. Of potential interest to physiciansand patientsis whether therapeutic reduction in albuminexcretion, which did not occur with candesartan, mightbe useful in the prediction of improvement in clinicaloutcomes.

Contributors

MAP, KS, CBG, JJVM, SY, BO, and ELM designed the CHARMProgramme and substudies. HCG and SDS also contributed to the

design and interpretation of the present study. SZ and BO did thestatistical analyses. All authors contributed to the interpretation of thedata. CEJ and JJVM wrote the draft of the report, and all authorscontributed to its revision. JJVM takes responsibility for the report.

Conflicts of interest

MAP, KS, HCG, CBG, JJVM, SDS, and SY have received researchfunding, and lecture and consulting fees from AstraZeneca. ELM, BO,and SZ are employees of AstraZeneca. CEJ declares that she has noconflicts of interest.

Acknowledgments

The CHARM Programme was funded by AstraZeneca.

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