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European Journal of Heart Failure 2005 7(4):468-474; doi:10.1016/j.ejheart.2004.09.018
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© 2005 European Society of Cardiology

Uric acid renal excretion and renal insufficiency in decompensated severe heart failure

Marcelo E. Ochiai, Antonio C.P. Barretto*, Múcio T. Oliveira, Jr., Robinson T. Munhoz, Paulo C. Morgado and José A.F. Ramires

Cotoxó Hospital, Prevention and Rehabilitation Service, Heart Institute (InCor), University of São Paulo Medical School Av. Dr. Enéas de Carvalho Aguiar, 44-CEP 05403-900, São Paulo-SP, Brazil

* Corresponding author. Tel./Fax: +55 11 3069 5417. E-mail address: pereira.barretto{at}incor.usp.br


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Objective: To evaluate uric acid renal excretion, hyperuricemia, renal dysfunction, and prognosis in patients with decompensated severe heart failure, as there are few data available.

Methods: One hundred and twenty-two patients, hospitalized for heart failure decompensation, in NYHA class IV, were classified into 3 groups as follows. Pilot group [ejection fraction (EF)≤0.45, n=16], group 1 (EF≤0.45, n=90), and group 2 (EF>0.45 and valvular dysfunction, n=16). The patients in groups 1 and 2 underwent assessment of creatinine and uric acid clearance before and after pyrazinamide, to estimate uric acid tubular secretion. Uric acid clearance <6.8 mL/min and secretion <170 µg/min were considered reduced. In groups 1 and pilot (n=106), mortality was analyzed by Cox regression model, and the prognostic value of hyperuricemia was assessed by ROC curve.

Results: In groups 1 and 2, respectively, serum uric acid was 511.7 and 422.5 mol/L, and creatinine clearance was 46.7 and 61.4 mL/min. Uric acid clearance (3.2 vs. 3.9 mL/min) and tubular secretion (116 vs. 128 µg/min) were not different, but lower than normal values. In groups 1 and pilot, the 12-month mortality was 46.4% (CI 95%: 36.7%–56.0%). At end of follow-up, mortality was associated with impaired creatinine clearance (p<0.001), but not with hyperuricemia (p=0.236).

Conclusions: In patients with decompensated severe heart failure, the tubular secretion and the clearance of uric acid were reduced. Renal dysfunction was associated with mortality, but hyperuricemia was not.

Key Words: Congestive heart failure • Uric acid • Kidney insufficiency

Received November 7, 2003; Revised July 16, 2004; Accepted September 16, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The medical literature has described the presence of hyperuricemia in patients with heart failure [1,2], however, this information has been not widely disseminated. An increase in uric acid production, caused by tissue hypoxia, could explain this increase in serum level [3]. The role of urinary excretion, however, remains little studied, and the prognostic value of uric acid has been evaluated in few studies. Recently, Anker et al. [4] described hyperuricemia as an independent marker of impaired prognosis in heart failure; their study showed an annual mortality rate in moderate heart failure of 15% to 24%. However, the cause and the meaning of hyperuricemia in severe heart failure, mainly in acute decompensation, remains unclear.

In patients with decompensated severe heart failure, renal function influences clinical management. The use of drug therapy, including diuretics, angiotensin-converting enzyme inhibitors, cardiac glycosides, and spironolactone, should consider the renal function. The prognostic value of renal dysfunction in heart failure, however, has been studied only in retrospective studies [5].

This raises some questions. In decompensated severe heart failure, is there an impaired renal excretion of uric acid that contributes to hyperuricemia? Are hyperuricemia and renal function associated with greater mortality in patients with decompensated severe heart failure?

The purpose of this study was to evaluate, in patients with decompensated severe heart failure, the role of renal excretion of uric acid in hyperuricemia, and the association of hyperuricemia and renal dysfunction with mortality.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Design
This study was divided into 2 parts: a cross-sectional study to compare variables between groups with (group 1) and without (group 2) reduced left ventricular ejection fraction, and an inception cohort to evaluate mortality in the group with reduced left ventricular ejection fraction (groups 1 and pilot).

2.2. Endpoints and sample size
We defined 2 primary endpoints for this study to determine the sample size. The cross-sectional study endpoints were creatinine clearance and serum uric acid levels, which were compared between groups 1 and 2. In groups 1 and 2, respectively, the creatinine clearance estimate was 50 mL/min and 75 mL/min, and the serum uric acid estimate was 535.5 µmol/L (9.0 mg/dL) and 416.5 µmol/L (7.0 mg/dL). To detect a difference between the groups, the sample size was calculated as 16 patients in each group.

For the cohort study, the endpoint was mortality in group 1, and we needed 20 events to assess the prognostic value of creatinine clearance and serum uric acid, i.e., 10 events for each variable. The estimated mortality from heart failure, ejection fraction ≤0.45, and class IV patients (group 1) is 60% per year [6]. Thus, we needed 67 patients in group 1. Therefore, taking into consideration the loss of patients during follow-up, the sample size calculated was 90 patients in group 1 and 16 patients in group 2, with a power of 80% to detect a difference. To improve the power of the cohort study, we included the 16 patients from the pilot study, with similar characteristics to group 1, but without uric acid tubular secretion data.

2.3. Patients
We selected patients from the Cotoxó Hospital, Heart Institute (InCor), São Paulo Medical School University, Brazil. We included consecutive patients hospitalized for acute heart failure decompensation and New York Heart Association class IV, in order to select patients with advanced stage and at high risk of death. We excluded patients with the following conditions: anuresis or being in a dialysis program, aortic stenosis, acute coronary syndrome within the previous 2 months, and hepatic dysfunction defined as aspartate transaminase, alanine transaminase, or bilirubin plasma levels greater than twice normal values.

The 16 patients in the pilot study were enrolled between September 1998 and December 1998. In the period between December 2000 and August 2002, 1556 patients were hospitalized in our service, of these 178 suitable patients were initially identified, of these, 8 patients refused to participate, and 64 patients were excluded because of hepatic dysfunction.

The 106 patients enrolled in the study and 16 patients from the pilot study were divided according to left ventricular ejection fraction assessed by echocardiography during the previous 6 months. The ejection fraction was obtained by Teichholz's method in the presence of a diffuse contractile deficit or Simpson's method in the presence of a segmental contractile deficit [7].

The patients with ejection fraction ≤0.45 were in group 1(n=90) and pilot group (n=16), and those with ejection fraction >0.45 and heart failure caused by valvular dysfunction (n=16) were in group 2. The whole sample was 122 patients.

In groups 1 and pilot, the predominant cause of ventricular dysfunction was hypertension in 24 patients (22.6%), myocardial ischemia in 27 patients (25.6%), both in 6 patients (5.7%), Chagas' disease in 24 patients (22.6%), alcohol in 3 patients (2.8%), idiopathic in 16 patients (15.1%), hypertension and Chagas' disease in 4 patients (3.8%), aortic insufficiency and Chagas' disease in 1 patient (0.9%), and myocardial ischemia and Chagas' disease in 1 patient (0.9%). The mean period from the beginning of heart failure symptoms to the beginning of the study was 44±55 months.

In group 2, the valvopathy was mitral stenosis in 11 patients (69%), mitral insufficiency in 3 patients (19%), both in 1 patient (6%), and aortic insufficiency in 1 patient (6%). The mean period from the beginning of heart failure symptoms to the beginning of the study was 41±26 months.

Cardiovascular medications and their dosages were recorded for each patient during the study period. The diuretics used were furosemide, spironolactone, and thiazides, and the patients were classified according to the number of diuretic types. A daily dose of captopril ≤75 mg or enalapril ≤20 mg, was classified as low-dose ACE inhibitor therapy. The patients who were discharged from hospital were followed-up at least every 3 months. Each patient's cardiologist was responsible for clinical management.

The study was approved by the hospital's ethics committee and performed in accordance with the Declaration of Helsinki. All participants gave written informed consent before the beginning of the study.

2.4. Interventional procedures
To assess the relationship between hyperuricemia, urinary excretion of uric acid, and renal function, we assessed creatinine clearance, uric acid clearance, and the estimation of tubular secretion of uric acid using the pyrazinamide suppression technique [8].

After the initial stabilization of heart failure, all patients underwent 24-h urinary collection, begun and completed at 6:00 a.m. The urinary volume was measured, and creatinine and uric acid concentrations were determined. A blood sample was collected at 7:00 a.m., for measurement of creatinine, urea, sodium, potassium, uric acid, erythrocyte sedimentation rate, mucoprotein, leukocyte and platelet count, and gamma globulin. At 8:00 a.m., the patients received 3 g of pyrazinamide to inhibit uric acid tubular secretion. Additional urine was collected between 10:00 a.m. and 2:00 p.m., and the laboratory determinations were repeated. At 2:00 p.m., another blood sample was collected and creatinine, urea, uric acid, sodium, and potassium determinations were made.

We used the following formulas for calculations:

  1. Creatinine clearance=urinary creatinine/serum creatinine multiplied by urinary flow, adjusted by body surface area (BSA), multiplied by the correcting factor (1.73/BSA).
  2. Uric acid clearance=urinary uric acid/serum uric acid multiplied by urinary flow; multiplied by the correcting factor (1.73/BSA).
  3. Uric acid excretion fraction=urinary uric acid/serum uric acid multiplied by urinary creatinine/serum creatinine.
  4. Uric acid filtration rate=serum uric acid multiplied by creatinine clearance.
  5. Tubular secretion of uric acid=urinary excretion rate minus post-PZA urinary excretion rate.

Hyperuricemia was considered present when serum uric acid was above the normal values, 416.5 µmol/L in men and 357.0 µmol/L in women. We considered reduced renal excretion of uric acid, for values of tubular secretion of uric acid lower than 170 µg/min, and uric acid clearance lower than 6.8 mL/min per 1.73 m2. These values have been reported as the lowest levels in normal subjects [8].

2.5. Statistical analysis
The continuous variables were expressed as mean and standard deviation and the difference between the groups was assessed by Student t test. The correlation between continuous variables was performed by using Pearson's coefficient (r). The comparison of variables between groups and before and after pyrazinamide was made by analysis of variance with repeated measures. The categorical variables were expressed by proportion and compared between the groups by {chi}2 test or Fisher's Exact Test.

The variables with a p value <0.10 associated with the occurrence of death by univariate analysis or those with clinical interest were selected for multivariate analysis by Cox stepwise regression model [9], performed by SAS software (SAS Institute, Cary, N.C.). Relative risks and 95% confidence interval were calculated.

The survival curves were constructed by the Kaplan–Meier model [10], according to creatinine clearance and serum uric acid. For groups pilot and 1, the patients were divided according to the creatinine clearance, and the Receiver Operator Characteristics (ROC) curve determined the best cut-off value. For serum uric acid, the ROC curve determined sensitivity and specificity of diagnosing death at 6th month, at 12th month, and within total follow-up. Survival rates were compared with the log–rank test.

The 2-tailed p value <0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
The baseline characteristics of study patients are shown in Table 1. The patients in groups 1 and pilot were older and the majority were men compared with those in group 2. During hospitalization, dobutamine was necessary in 48 patients (45%), all in groups 1 and pilot.


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  		Table 1 Baseline characteristics

 
3.1. Uric acid and renal function
The Student's t test showed that serum uric acid was higher in group 1 than in group 2 patients (511.7±154.7 vs. 422.5±95.2 µmol/L; p=0.005); however, 24-h urinary uric acid was similar (350±202 vs. 362±210 mg/1.73 m2; p= 0.843). The uric acid clearance (3.2±2.4 vs. 3.9±2.6 mL/min; p=0.695) and excretion fraction (6.6±3.8 vs. 7.3±6.4%; p=0.683) were not different between both groups, however values were smaller than in normal subjects.

The uric acid tubular secretion was 116±190 and 128±169 µg/min, respectively, in groups 1 and 2, which was not statistically different. However, there was a reduction in secretion rate, compared with normal values.

In the entire population, uric acid clearance was lower after pyrazinamide (3.1±2.3 vs. 1.4±1.6 mL/min, before and after pyrazinamide, respectively, p<0.001), and this response, attributed to tubular secretion and assessed by variance analysis, was not different in groups 1 and 2 (p=0.785). Similarly, the uric acid excretion fraction was reduced by inhibition of tubular secretion by pyrazinamide (7.0±4.3 vs. 2.4±2.6%, p<0.001); however, no difference existed between groups 1 and 2 (p=0.264).

Despite the predominance of males in group 1 (66% vs. 25%), sex did not influence serum uric acid. In group 1, serum uric acid values in men and women were not different (505.8±136.9 vs. 523.6±178.5 µmol/L; p=0.577), this was similar in group 2 (440.3±53.6 vs. 416.5±113.1 µmol/L, p=0.597). Eighty-four patients (79%) had hyperuricemia, 73 (81%) in group 1 and 11(69%) in group 2. Hyperuricemia was associated with thiazides (p=0.013) and spironolactone (p=0.041), but not with furosemide (p=0.115). The use of two or more diuretics was associated with hyperuricemia (p<0.001). Only 10 patients had a history of gout.

The 24-h urinary uric acid had a correlation with creatinine clearance (r=0.60; p<0.001), 24-h urinary volume (r=0.44; p<0.001), and no correlation with serum uric acid levels (r=–0.17, p=0.742).

The creatinine clearance was lower in patients in group 1 than in group 2 (46.7±24.3 vs. 61.4±21.3 mL/min; p=0.021), as was the serum creatinine (132.6±53.0 vs. 97.2±26.5 µmol/L; p<0.001), and urea (15.0±6.8 vs. 9.1±4.7 mmol/L; p<0.001). In contrast, the 24-h urinary volume was not different between groups 1 and 2 (1383±575 vs. 1279±526 mL; p=0.483).

3.2. Clinical outcomes
In groups 1 and pilot, at the end of follow-up, 59 patients had died. The 6-month mortality was 33.5% (CI 95%: 24.4%–42.6%) and the 12-month mortality was 46.4% (CI 95%: 36.7%–56.0%). Table 2 shows the univariate analysis according to mortality. The multivariate analysis showed that low serum sodium, reduction in creatinine clearance, low-dose ACE inhibitor, dobutamine use, and no use of beta-blocker (Table 3) were independently associated with mortality. The relative risk of impaired creatinine clearance was 1.03, which means that for each 1 mL/min reduction, we observed a 3% increase in mortality.


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  		Table 2 Variables associated with mortality by univariate analysis

 


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  		Table 3 Variables associated with mortality by multivariate analysis (Cox regression)

 
The best cut-off of creatinine clearance was 42 mL/min. The survival curves (<42 vs. ≥42 mL/min) were statistically different (Fig. 1). The ROC curve analysis showed serum uric acid was not associated with mortality at 6 months (p=0.318), at 12 months (p=0.582), and total mortality (p=0.236). Fig. 2 shows the ROC curve for 12-month mortality.


Figure 1
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  		Fig. 1 Survival curve according to creatinine clearance, adjusted by 1.73 m2 of body surface area.

 


Figure 2
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  		Fig. 2 ROC curve for serum acid uric and 12-month mortality; the best cut-off was 571.2 µmol/L (9.6 mg/dL), to sensitivity=62.3% and specificity=33.3%. Area under the curve=0.527 (CI 95%: 0.415–0.639).

 
3.3. Safety of pyrazinamide intake
The control determinations of transaminases and bilirubin were measured a mean of 3.1 days after pyrazinamide intake. Five patients showed increases in transaminases or bilirubin levels, all were transitory and with spontaneous normalization. None of the patients required specific therapy.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
We found higher serum uric acid and reduced uric acid urinary excretion in decompensated severe heart failure due to systolic dysfunction. Several studies have demonstrated that patients with heart failure have high serum uric acid [1,2]. The most common explanation has been an overproduction of uric acid; however, only Dosman et al. [11] has demonstrated, through a radioisotopic method, an increased turnover in uric acid after myocardial infarction. An elevation in serum uric acid has related to inflammatory markers [12], leg vascular resistance [13], maximal oxygen uptake, NYHA class [3], and diastolic dysfunction [14], but urinary excretion has been little studied.

One small study [15] detected an impairment in urinary excretion of uric acid in children with low cardiac output. Our findings suggest that the hyperuricemia may be caused, in part, by a reduction in urinary excretion of uric acid. In our study the uric acid clearance was not different between groups 1 and 2, but the value was below normal ranges. In subjects without heart failure, urinary excretion of uric acid increases with serum levels [8]. We did not find an increase in urinary excretion of uric acid in patients with high serum uric acid; however, we did find a correlation between 24-h urinary uric acid and creatinine clearance. This fact suggests that both, urinary excretion and creatinine clearance are reduced as a consequence of low renal blood flow.

In severe heart failure, the low cardiac output and consequently low renal blood flow may contribute to reduced creatinine clearance. The possibility of the reduction in uric acid filtration causing the urinary retention of uric acid may be unlikely because uric acid filtration contributes to only 10% of total urinary excretion. The low renal blood flow can limit the oxygen supply and consequently the active uric acid tubular secretion. In our study, the uric acid secretion was similar between patients with a higher serum uric acid (group 1) and patients with near normal serum uric acid (group 2), which is compatible with the above theory. The number of diuretics used was similar between both groups, and this did not influence the differences in serum uric acid. On the other hand, in the entire population, the use of two or more diuretics was associated with hyperuricemia. Nevertheless, it is unlikely that diuretics alone caused the reduction of uric acid urinary excretion in heart failure. However, other factors like angiotensin II, catecholamines [16], and reduced distal load of sodium may also reduce the urinary excretion of uric acid and interfere with the prognosis.

The high mortality in our study may be explained by the admission criteria in our hospital, i.e., acutely decompensated heart failure with intravenous use of inotropic drugs or no response to diuretic therapy in emergency room. The patients admitted were in the advanced stages of heart failure and had a high risk of death. Previous studies from our group confirm the very high mortality rates (63% in 12 months) [6]. In our sample, the variables associated with mortality were renal dysfunction, hyponatremia, dobutamine use, low dose of angiotensin converting enzyme inhibitor, and no use of beta-blocker. Moreover, classical prognostic factors, like age and left ventricular ejection fraction, did not predict the mortality. Interestingly, the first three variables could be related with low cardiac output.

Age influences mortality in heart failure, mainly due to the higher prevalence of concomitant disease, e.g., diabetes mellitus, cerebrovascular disease and chronic obstructive pulmonary disease. In acutely decompensated heart failure, the importance of hemodynamic status increases over the other classical prognostic factors. In fact, we found a prognostic value in variables related to low cardiac output. Although medical therapy improves cardiac output during hospitalization, allowing discharge, the low-output continues to determine the prognosis, mainly in severe heart failure.

Few studies have looked for and found serum uric acid elevation as a prognostic factor in heart failure. Bettencourt et al. [17] studied the prognosis in mild and moderate heart failure and after multivariate analysis did not identify hyperuricemia among the predictors. Batin et al. [18] studied patients with heart failure, the majority in New York Heart Association class II and III, and serum uric acid was a predictor of mortality. Serum uric acid elevation has been described as a predictor of cardiac death in patients with stroke, but this association was based on only 19 cardiac deaths, and the comorbidity and heart disease were not described [19]. Another recently published study [4], has demonstrated that hyperuricemia predicts mortality in patients, around 60 years old, with heart failure, in majority New York Heart Association class II or III. The authors found an increased mortality according to the uric acid level, with a relative risk of 1.76, 6.27, and 18.53, respectively, for 401 to 600 µmol/L, 601 to 800 µmol/L, and >800 µmol/L. However, the 12-month mortality (15% and 24%) was lower than the mortality of our patients.

We did not find an association between hyperuricemia and worse outcome. With 59 deaths, our sample had sufficient power; therefore, the lack of association can be considered real, and not a type II error. In patients with more severe heart failure, it is possible that hyperuricemia loses its prognostic value, like other variables, such as age and ejection fraction [20]. Nevertheless, hyperuricemia may be similar to anaemia, i.e., loses the prognostic value only in decompensation [21], however this does not happen systematically [22]. Whether hyperuricemia recovers its prognostic value after recompensation is a question that our study cannot answer.

In our study, the creatinine clearance of patients of group 1 was significantly smaller than those in group 2, and an impaired clearance had an association with a worse outcome in groups 1 and pilot. Parker et al. [23] found similar creatinine clearance values in patients with severe heart failure (ejection <0.30 and New York Heart Association class IV). We did not use the estimation based on the Cockcroft–Gault formula, in contrast with other studies, and this could make our results stronger. Cardiorenal syndrome has been described and associated not only with low cardiac output but also with an altered balance in vasodilating and vasoconstricting hormones.

The SOLVD group [24] analyzed, retrospectively, the prognostic value of moderate renal insufficiency in patients with heart failure in NYHA class I to III and found a relative risk of 1.41 to mortality. Hillege et al. [25] studied the patients from PRIME II study, mainly NYHA class III and reported that patients with creatinine clearance below 44 mL/min had a relative risk of 2.85 for mortality. Recently, Mahon et al. [26] analyzed the prognostic value of creatinine clearance in patients in the DIG trial, with a mean ejection fraction of 0.35 and NYHA class II and III. The hazard ratio of the more depressed creatinine clearance group was 2.1 for mortality. Krumholz et al. [27] described, in elderly patients with heart failure, the association between 6-month mortality and worsening renal function, defined as an increase in serum creatinine of 0.3 mg/dL from admission, with an adjusted odds ratio of 1.56. Weinfeld et al. [28] retrospectively studied 48 patients with heart failure in NYHA class III and IV, and after 7 deaths, found a relative risk of mortality of 5.3 for the presence of renal insufficiency. Our study, prospectively and with a greater number of deaths, shows that reduced creatinine clearance is an independent factor associated with mortality. The magnitude of association may be considered great, because for each 1 mL/min reduction in creatinine clearance, the mortality increases 3%. This finding was independent of classical prognostic factors like serum sodium, hospital dobutamine use, ACE inhibitor dosage, and beta-blocker use.

The reasons for renal insufficiency increases mortality, moreover the relationship with low output, may be volemic and electrolyte disturbances, a greater possibility of the influence of digitalis intoxication, and a reduced response to ACE inhibitors, spironolactone, and angiotensin receptor blockers. Nevertheless, as shown by Cox regression, renal dysfunction was associated with a higher mortality, independently of drug therapy.

The use of dobutamine during hospitalization was associated with a worse prognosis even in patients who were discharged. This variable is probably a marker of more severe disease and of a high risk of death, because it is unlikely that dobutamine could increase middle and long-term mortality. However, the use of dobutamine almost doubles the risk of death. In our study, drug therapy without beta-blockers and with low-dose ACE inhibitors was associated with a worse prognosis. These findings can be explained by the well-known beneficial effects of these drugs. On the other hand, the severity of heart failure can limit beta-blocker use, as can the high dosage of ACE inhibitors. Consequently, patients with less severe heart failure were more likely to receive beta-blockers and higher dosages of ACE inhibitors.

4.1. Limitations
We studied a very selected population with severe heart failure, during hospitalization due to acute decompensation; therefore, our conclusions may not be applicable to patients with mild disease. Frequently, in acute decompensation, renal function has a great variation. Although we looked for relatively stable patients, this fact may have interfered with our results. We chose the control group (group 2) with preserved left ventricular ejection fraction to verify the influence of this variable on renal function and hyperuricemia. However, these patients had heart failure caused by valvar dysfunction and thus could suffer neurohumoral interference with renal function and uric acid metabolism.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
In decompensated severe heart failure, the tubular secretion and the clearance of uric acid were reduced. Impaired creatinine clearance was associated with mortality, in contrast with serum uric acid elevation.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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