Microalbuminuria is an independent prognostic marker in patients with chronic heart failure

Abstracts

FUNDAMENTO: A microalbuminúria tem sido descrita como um fator de risco para doenças cardiovasculares e renais progressivas. Pouco se sabe sobre seu valor prognóstico em pacientes (pts) com Insuficiência Cardíaca (IC) estabelecida. OBJETIVO: Avaliar o papel da microalbuminúria como um marcador de prognóstico em pacientes com IC crônica recebendo medicação padrão. MÉTODOS: De janeiro de 2008 até setembro de 2009, 92 pacientes com IC crônica foram prospectivamente incluídos. A idade média foi de 63,7 ± 12,2 e 37 (40,7%) eram do sexo masculino. A média de fração de ejeção do ventrículo esquerdo (FEVE) foi de 52,5 ± 17,5%. Pacientes em diálise foram excluídos. A Concentração de Albumina Urinária (CAU) foi determinada em primeira amostra de urina da manhã. O tempo decorrido até o primeiro evento (internação por IC, consulta no departamento de emergência por IC ou morte cardiovascular) foi definido como endpoint. O seguimento médio foi de 11 ± 6,1 meses. RESULTADOS: No momento da inclusão no estudo, 38 (41,3%) pacientes tinham microalbuminúria e nenhum paciente teve albuminúria evidente. Pacientes com microalbuminúria apresentaram menor fração de ejeção ventricular esquerda do que o restante dos indivíduos (47,9 ± 18,5 vs. 54,5 ± 17,7%, p = 0,08). A CAU apresentou-se maior em pacientes com eventos (mediana 59,8 vs. 18 mg/L, p = 0,0005). Sobrevida livre de eventos foi menor nos pacientes com microalbuminúria quando comparados com albuminúria normal (p < 0,0001). As variáveis independentes relacionadas a eventos cardíacos foram CAU (taxa de risco p < 0,0001 = 1,02, 95% CI = 1,01-1,03 por 1-U aumento da CAU), e histórico de infarto do miocárdio (p = 0,025, IC = 3,11, 95% IC = 1,15-8,41). CONCLUSÃO: A microalbuminúria é um marcador prognóstico independente em pacientes com IC crônica. Pacientes com microalbuminúria tinham tendência para FEVE inferior.

Albuminúria; insuficiência cardíaca; doenças renais; prognóstico

FUNDAMENTO: La microalbuminuria ha sido descripta como un factor de riesgo para enfermedades cardiovasculares y renales progresivas. Poco se sabe sobre su valor pronóstico en pacientes (pts) con Insuficiencia Cardíaca (IC) establecida. OBJETIVOS: Evaluar el papel de la microalbuminuria como un marcador de pronóstico en pacientes con IC crónica recibiendo medicación estándar. MÉTODOS: De enero de 2008 hasta setiembre de 2009, 92 pacientes con IC crónica fueron prospectivamente incluidos. La edad media fue de 63,7 ± 12,2 y 37 (40,7%) eran del sexo masculino. La media de fracción de eyección del ventrículo izquierdo (FEVI) fue de 52,5 ± 17,5%. Pacientes en diálisis fueron excluidos. La Concentración de Albúmina Urinaria (CAU) fue determinada en primera muestra de orina de la mañana. El tiempo transcurrido hasta el primer evento (internación por IC, consulta en el departamento de emergencia por IC o muerte cardiovascular) fue definido como endpoint. El seguimiento medio fue de 11 ± 6,1 meses. RESULTADOS: En el momento de la inclusión en el estudio, 38 (41,3%) pacientes tenían microalbuminuria y ningún paciente tuvo albuminuria evidente. Pacientes con microalbuminuria presentaron menor fracción de eyección ventricular izquierda que el resto de los individuos (47,9 ± 18,5 vs. 54,5 ± 17,7%, p = 0,08). La CAU presentó mayor en pacientes con eventos (mediana 59,8 vs. 18 mg/L, p = 0,0005). La sobrevida libre de eventos fue menor en los pacientes con microalbuminuria cuando fueron comparados con albuminuria normal (p < 0,0001). Las variables independientes relacionadas a eventos cardíacos fueron CAU (tasa de riesgo p < 0,0001 = 1,02, 95% CI = 1,01-1,03 por 1-U aumento de la CAU), e historia de infarto de miocardio (p = 0,025, IC = 3,11, 95% IC = 1,15-8,41). CONCLUSIÓN: La microalbuminuria es un marcador pronóstico independiente en pacientes con IC crónica. Pacientes con microalbuminuria tenían tendencia a FEVI inferior.

Albuminuria; insuficiencia cardíaca; enfermedades renales; pronóstico

Microalbuminuria is an independent prognostic marker in patients with chronic heart failure

Humberto Villacorta; Paula de Vilhena Ferradaes; Evandro Tinoco Mesquita; Antônio Cláudio Lucas da Nóbrega

Universidade Federal Fluminense - Curso de Pós-Graduação em Ciências Cardiovasculares, Niterói, RJ, Brazil

Mailing Address

ABSTRACT

BACKGROUND: Microalbuminuria has been described as a risk factor for progressive cardiovascular and renal diseases. Little is known about its prognostic value in patients (pts) with established heart failure (HF).

OBJECTIVE: To assess the role of microalbuminuria as a prognostic marker in patients with chronic HF receiving standard medication.

METHODS: From January 2008 through September 2009, 92 pts with chronic HF, were prospectively included. Mean age was 63.7±12.2 and 37 (40.7%) were male. Mean left ventricular ejection fraction (LVEF) was 52.5±17.5%. Pts under dialysis were excluded. Urinary albumin concentration (UAC) was determined in first morning spot sample of urine. Time to first event (HF hospitalization, emergency department visit for HF or cardiovascular death) was defined as endpoint. Mean follow-up was 11±6.1 months.

RESULTS: At the time of inclusion in the study, 38 (41.3%) pts had microalbuminuria and no patient had overt albuminuria. Pts with microalbuminuria had lower left ventricular ejection fraction than the rest of the individuals (47.9±18.5 vs 54.5±17.7%, p=0.08). UAC was higher in patients with events (median 59.8 vs 18 mg/L, p=0.0005). Event-free survival was lower in pts with microalbuminuria as compared with normoalbuminuria (p<0.0001). Independent variables related to cardiac events were UAC (p<0.0001, hazard ratio=1.02, 95% CI=1.01 to 1.03 per 1-U increase of UAC), and previous myocardial infarction (p=0.025, HR=3.11, 95% CI=1.15 to 8.41).

CONCLUSION: Microalbuminuria is an independent prognostic marker in pts with chronic HF. Pts with microalbuminuria had a trend for lower LVEF.

Keywords: Albuminuria, heart failure, kidney diseases, prognosis.

Introduction

Urinary albumin concentration (UAC) has been described as a risk factor for progressive cardiovascular and renal diseases^1-4. The prevalence of microalbuminuria in patients with hypertension and diabetes is 10% to 15% and 15% to 20%, respectively, which is higher than the prevalence in individuals from the general population in whom values of 6% to 8% have been described^1,2. Increased albumin excretion may be a marker of diffuse vascular injury, systemic inflammation, activation of the renin-angiotensin system, or early renal failure. Many of these abnormalities also occur in heart failure (HF). UAC has been associated with increased mortality not only in patients with diabetes and hypertension^5-9, but also in the general population^3,4. However, little is known about the prognostic value of microalbuminuria in patients with established heart failure. Therefore, in this study, we assessed the prevalence and prognostic value of microalbuminuria in patients with stable chronic HF.

Methods

From January 2008 through September 2009, 92 patients with chronic HF, New York Heart Association (NYHA) functional class II to IV, were prospectively included. Patients were recruited from the Heart Failure Clinic of our Medical School Hospital. The diagnosis of HF was made on the basis of medical history, ongoing symptoms, and physical examination. In cases where the clinical diagnosis of HF was uncertain, B-type natriuretic peptide (BNP) was measured (Triage, Biosite Inc., San Diego, USA). Patients had been clinically stable for at least three months before the study and were on stable dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), and a betablocker, unless contraindicated. In all off the patients, left ventricular ejection fraction (LVEF) was assessed by echocardiography using the Sympson method. Mean LVEF of the entire population was 52.5±17.5%. Patients with LVEF <50% were considered as having HF with reduced ejection fraction (HFREF) whereas patients with LVEF >50% were classified as HF with normal ejection fraction (HFNEF). Patients under dialysis were excluded. The study was approved by the ethics committee of our hospital and written informed consent was obtained from all patients.

Venous blood samples were taken and analysed at the local laboratory. Serum creatinine was measured using standard techniques. Serum creatinine, age, race, and gender were used to calculate glomerular filtration rate (GFRc) using the Modification of Diet in Renal Disease (MDRD) Study equation. First morning spot sample of urine was taken with the patient in the upright position and transported immediately to the laboratory. UAC was determined using a turbidimetric assay (Bioclin, Quibasa Química Básica, Belo Horizonte, Brazil) and microalbuminuria was defined as UAC 25-200 mg/L, according to the manufacturer's instructions. UAC was determined at baseline and after 6 months.

Patients were followed-up at our HF clinic, with visits every three months. Mean follow-up was 11±6.1 months. The primary endpoint of the study was a composite outcome of death from a cardiovascular cause, admission for HF, emergency department visit for HF requiring intravenous diuretics. All endpoints were independently adjudicated.

Values are expressed as mean values ± SD or absolute number and percentage. Differences between group were investigated using unpaired t-test for independent samples or the chi-square test, when appropriate. Variables without Gaussian distribution are expressed as median and interquartil range and were analysed using Mann-Whitney test. Kaplan-Meyer event-free survival curves were constructed and compared using the log-rank test. Cox proportional hazards models were used to investigate the prospective association between UAC and events during follow-up.

Results

Mean age of the entire population was 63.6±12.2 years and 36 (39.1%) were male. Fifty eight (63%) patients were in NYHA functional class II, 26 (28.3%) in class III, and 8 (8.7%) in class IV. Median UAC was 21 mg/dL (interquartil range 9.72-50.95). Thirty eight (41.3%) patients had microalbuminuria and no patient had macroalbuminuria. Baseline characteristics of patients with and without microalbuminuria are shown in table 1. There were no differences regarding baseline characteristics between groups, except that patients with microalbuminuria had a trend for lower LVEF. However, median values of UAC were not different in patients with LVEF <50% as compared with LVEF >50%, as shown in figure 1. There was no correlation between UAC and serum creatinine (r = 0.06; p = 0.82). Likewise, no correlation was found between UAC and GFRc (r = -0.04; p = 0.84).

Twenty seven (29.3%) patients experienced an event during follow-up. Baseline UAC was higher in these patients, as shown in figure 2. However, no significant change in UAC overtime was observed in patients with or without events. Patients with events were also more likely to have a reduced LVEF. Univariate comparison of patients with and without events is shown in table 2. Event-free survival was lower in patients with microalbuminuria as compared with normoalbuminuria, as shown in figure 3. Using Cox proportional hazards models, only microalbuminuria (continuous variable) and previous myocardial infarction were independent predictors of events (table 3).

Discussion

In this study, we found that patients with HF who evolve with microalbuminuria have a worse prognosis, in spite of optimized treatment. This is an important finding, since 40% of the patients with chronic HF in our study were shown to have microalbuminuria. Interestingly, no differences regarding baseline characteristics were observed between patients with and without microalbuminuria suggesting that increased UAC was related to HF itself and not to comorbidities. Of note, UAC did not change significantly over time in either event or non event groups.

In this study, microalbuminuria was prevalent even in patients without hypertension or diabetes, suggesting that these abnormalities are not the cause of increased albumin excretion.

Although microalbuminuria has been for a long time described as a risk factor for developing HF and for cardiovascular mortality in hypertensive^5,9 and diabetic patients⁷, and also in the general population^3,4, only recently it has been studied in patients with established HF. Dipstick urine testing for proteinuria was performed at baseline in a subset of patients in the Studies of Left Ventricular Dysfunction (SOLVD)¹⁰ and in the Survival and Ventricular Enlargement (SAVE)¹¹ trials. The prevalence of proteinuria in these studies was 3% and 15%, respectively. By contrast, van de Wal et al¹², using urinary albumin to creatinine ratio, found higher prevalence, reporting that 32% of their patients had microalbuminuria. No significant differences were observed between patients with or without microalbuminuria, but a small number of patients were included. In this study, however, no data on outcomes were reported.

Only two recent studies assessed the prognostic value of microalbuminuria in patients with established HF. In the CHARM Study¹³, a clinical trial where candesartan was assessed in patients with HF, microalbuminuria was found in 30% of the patients whereas macroalbuminuria was observed in 11%. Albuminuria (either as a categorical or continuous variable) was an independent predictor of all-cause mortality and admission for HF when added to the Cox regression analysis with 33 baseline characteristics as covariates. Candesartan did not reduce or prevent urinary albumin excretion. In another clinical trial, retrospective data on microalbuminuria was also reported. In the GISSI-HF, the prevalence of micro and macroalbuminuria was 20% and 5.4%, respectively¹⁴. There was a progressive, significant increase in the adjusted rate of mortality in the study population and in the subgroup of patients without diabetes or hypertension (hazard ratio, 1.12; 95% CI, 1.05 to 1.18 per 1-U increase of log urinary albumin-to-creatinine ratio). Randomized treatments (n-3 polyunsaturated fatty acids or rosuvastatin) had no major impact on albumin excretion.

We found that microalbuminuria was an independent predictor of events when assessed as a continuous variable. This finding suggests that even an increasing UAC within the "normal" range is associated with increased risk of hospitalisation or death. The same finding was observed in the CHARM and in the GISSI-HF trials. Similar results have been described in patients with stable coronary artery disease¹⁵.

In this study, microalbuminuria was prevalent even in patients without hypertension or diabetes, suggesting that these abnormalities are not the cause of increased albumin excretion. Likewise, no correlation was observed between UAC and creatinine or between UAC and GFRc. Additionally, UAC was a predictor of events regardless of renal function, as assessed by creatinine or GFRc, and LVEF.

The mechanisms underlying albuminuria in HF patients are not known. Renal abnormalities have been observed in patients with increased UAC^16,17 and microalbuminuria has been suggested as a marker of early renal damage. Although microalbuminuria has been observed in the presence of normal renal function as assessed by traditional tools, such as creatinine and estimated GFR¹², it is possible that renal abnormalities may be evident when using more sensitive markers of renal function. As a matter of fact, in one study, in diabetic patients with normal renal function (GFR>60 mL/min/1.73 m²) UAC was significantly correlated with cystatin C, a sensitive marker of renal failure, both in patients with normoalbuminuria or microalbuminuria. On the other hand, it was not correlated either with serum creatinine or calculated creatinine clearance¹⁸. In another study, urinary neuthrophile gelatinase-associated lipocalin (NGAL), another early marker of tubular damage, was shown to be high in patients with HF and paralleled the increases in UAC¹⁹. The relationship of UAC with these markers of renal failure needs to be defined in prospective follow-up studies.

Another possible hypothesis is that microalbuminuria may be related to subclinical congestion. In chronic HF, venous congestion may be absent even in the presence of high filling pressures²⁰. Patients with HF frequently are readmitted to the hospital after an index hospitalization and unrecognized congestion has been implicated²¹. As a matter of fact, central venous pressure was found to be more important than cardiac index as a predictor of death in a broad population of patients with cardiovascular disease, including HF²². Venous congestion has also been related to renal failure in patients with HF^22,23. Therefore, microalbuminuria may be a marker of early renal failure and preclinical congestion.

Generalized endothelial dysfunction has also been implicated in the genesis of albuminuria^12,24,25. Patients with HF have abnormal endothelial function and this may explain, at least in part, the high prevalence of microalbuminuria in HF.

Some limitations of this study must be addressed. First, this is a small, single center study. Therefore, our data need to be validated in larger prospective studies. Secondly, we did not measure important biomarkers of renal function, such as cystatin C and NGAL. BNP was measured in a small subgroup of patients, which limited statistical analysis.

Despite these limitations, this was a prospective longitudinal study with relevant information regarding prognosis in stable HF patients, using a simple and cheap method that can be easily used in daily clinical practice. Studies in a large population addressing the natural course of microalbuminuria in chronic HF and the potential for treatment target are warranted.

Conclusion

We found that microalbuminuria is common in pts with chronic HF despite optimal treatment and is independently related to prognosis. Pts with microalbuminuria in this setting have a trend for lower LVEF.

References

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Publication Dates

• Publication in this collection
  13 Dec 2011
• Date of issue
  Jan 2012

History

• Received
  15 Mar 2011
• Accepted
  22 June 2011
• Reviewed
  13 June 2011