Background: In decompensated heart failure (HF), reversible renal dysfunction (RD) is more frequently observed in patients with mild liver dysfunction likely due to the shared pathophysiologic factors involved. The objective of this study was to determine if these findings also apply to stable HF outpatients. Methods: Patients in the Beta-Blocker Evaluation of Survival Trial (BEST) were studied. Improvement in renal function (IRF) was defined as a 20% improvement in the estimated glomerular filtration rate from baseline to 3 months. Results: Elevated bilirubin (BIL), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were significantly associated with signs of congestion or poor perfusion. IRF occurred in 12.0% of all patients and was more common in those with elevated BIL (OR = 1.5, p = 0.003), ALT (OR = 1.4, p = 0.01), and AST (OR = 1.4, p = 0.01). In a model containing all 3 liver parameters and baseline characteristics, including markers of congestion/poor perfusion, BIL (OR = 1.6, p = 0.001) and ALT (OR = 1.7, p < 0.001) were independently associated with IRF. Conclusions: Biochemical evidence of mild liver dysfunction is significantly associated with IRF in stable HF outpatients. Given the widespread availability and low cost of these markers, additional research is necessary to determine the utility of these parameters in identifying patients with reversible RD who may benefit from cardiorenal interventions.

Renal dysfunction (RD) is highly prevalent in patients with heart failure (HF) [1,2]. In addition to identifying patients at high risk for mortality, RD often presents an obstacle to the optimal use of neurohormonal antagonists and the maintenance of euvolemia [3]. As such, identifying patients with potentially reversible HF-induced RD is important. Unfortunately, methodology proven to differentiate reversible HF-induced RD from irreversible chronic kidney disease is not currently available.

Similar pathophysiologic factors such as venous congestion and reduced perfusion are thought to underlie both HF-induced liver dysfunction and RD [3,4,5,6,7]. Since these organs share a common venous system and are perfused by the same heart, factors such as venous congestion and the consequences of reduced cardiac output would be expected to affect both organs similarly and simultaneously. Unlike HF-induced RD, HF-induced liver dysfunction produces a relatively characteristic pattern of laboratory abnormalities [7]. To that end, we have recently demonstrated that in the setting of acute decompensated HF (ADHF), evidence of mild liver dysfunction is strongly associated with reversible RD. The purpose of this study was to determine if evidence of mild liver dysfunction may also identify stable HF outpatients with the potential for improvement in renal function (IRF).

The Beta-Blocker Evaluation of Survival Trial (BEST) was a National Heart, Lung and Blood Institute (NHLBI)-sponsored randomized, placebo-controlled trial investigating the impact of bucindolol on all-cause mortality in compensated chronic HF patients. The design and primary results have been previously published [8]. Briefly, 2,708 patients with New York Heart Association (NYHA) functional class III or IV HF, a left ventricular ejection fraction of ≤35%, and use of an angiotensin-converting enzyme inhibitor for ≥1 month (unless contraindicated) were randomized to bucindolol or placebo. Exclusion criteria were reversible HF, uncorrected primary valvular disease, decompensated HF, life expectancy of <3 years, a serum creatinine level of ≥3.0 mg/dl, active liver disease, or the use of a beta blocker within 30 days of baseline. This paper was prepared using BEST research materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of the BEST study investigators or the NHLBI. Elevated levels of bilirubin (BIL; ≥1.0 mg/dl), alkaline phosphatase (AP; ≥113 U/l), aspartate aminotransferase (AST; ≥30 U/l), and alanine aminotransferase (ALT; ≥31 U/l) were defined as a value in the upper quartile for analyses of this dataset. Estimated glomerular filtration rate (eGFR) was calculated using the Modified Diet and Renal Disease equation [9]. IRF was defined as a ≥20% increase in eGFR, consistent with our prior work on the subject [10,11,12,13,14]. This study was determined to be exempt from institutional review board review by the Institutional Review Boards of Yale and Medical University of South Carolina.

Statistical Methods

The primary analyses in this study focused on the associations between laboratory markers of liver dysfunction and subsequent IRF. Values reported are the mean ± standard deviation, median (quartile 1 to quartile 4), and percentile. Independent Student's t test or the Mann-Whitney U test was used to compare continuous parameters. Pearson's χ2 was used to evaluate categorical variables. The independent association between AST, ALT, AP, and BIL and IRF was determined using logistic regression. Candidate covariates were obtained by screening clinical characteristics for a univariate association with IRF at p < 0.2. Covariates that had a p > 0.2 but a theoretical basis for potential confounding were retained in the final model. Covariates were removed using backward elimination (likelihood ratio test), and variables with a p < 0.2 were retained [15]. Significance was defined as two-tailed p < 0.05 for all analyses. Statistical analysis was performed with PASW Statistics version 19 (SPSS Inc., Chicago, Ill., USA).

In total, 2,490 patients in the BEST study had data available on RF both at baseline and at 3 months after randomization. The baseline characteristics of these patients are presented in table 1. Similar to previous reports, elevated BIL, AST, ALT, and AP were associated with multiple markers of congestion and/or poor perfusion (table 2). BIL was strongly associated with all metrics of congestion, in addition to having the strongest association with hypotension and a low proportional pulse pressure. AP generally demonstrated stronger associations with measures of congestion than did AST or ALT but was similarly associated with markers of poor perfusion. AST, but not ALT, was associated with several markers of congestion. ALT was only associated with a low proportional pulse pressure. RV ejection fraction (available in n = 1,999) was lower in patients with higher BIL (30.2 ± 12.7 vs. 36.6 ± 13.4%, p < 0.001), AP (31.36 ± 12.7 vs. 36.0 ± 13.6%, p < 0.001), AST (32.2 ± 13.5 vs. 35.7 ± 13.5%, p < 0.001), and ALT (33.5 ± 14.0 vs. 35.3 ± 13.3%, p = 0.014) levels.

Table 1

Baseline characteristics stratified by IRF

Baseline characteristics stratified by IRF
Baseline characteristics stratified by IRF
Table 2

Association between liver dysfunction laboratory values and physical examination findings in HF outpatients

Association between liver dysfunction laboratory values and physical examination findings in HF outpatients
Association between liver dysfunction laboratory values and physical examination findings in HF outpatients

Overall, the incidence of IRF at 3 months was 12.0%, and the average improvement in eGFR amongst those experiencing IRF was 37.2 ± 18.8%. Table 1 describes the characteristics of patients with and without IRF. Similar to our findings in the setting of ADHF, baseline values of BIL, AST, and ALT were higher in patients who experienced IRF, while AP levels were similar between groups. Patients with laboratory values in the top quartile of BIL, ALT, and AST were significantly more likely to experience IRF than patients not in the top quartile (table 3). There was no difference with respect to elevated AP levels (table 3). Notably, changes in liver laboratory values between baseline and 3 months were also associated with IRF such that those patients with the greatest improvements in AST and ALT demonstrated a significantly increased incidence of IRF at 3 months (table 3). In a multivariable model including all 4 elevated liver dysfunction-related parameters (BIL, AP, ALT, and AST), only BIL in the top quartile (OR = 1.6, p = 0.001) and ALT in the top quartile (OR = 1.4, p = 0.019) were independently associated with IRF. Interestingly, the individual metrics of congestion and poor perfusion that were associated with markers of mild liver dysfunction were not directly associated with IRF (table 1). Both an elevated BIL (OR = 1.6, p = 0.001) and an elevated ALT (OR = 1.4, p = 0.018) remained significantly associated with IRF after adjusting for metrics of congestion and poor perfusion (edema, rales, S3 gallop, hepatomegaly, jugular venous distention, hypotension, and low proportional pulse pressure). Following the addition of baseline characteristics (eGFR, blood urea nitrogen, race, sex, coronary disease, blood pressure, heart rate, randomization to bucindolol, serum sodium, uric acid, glucose, and left ventricular ejection fraction) to the above model, both BIL (OR = 1.6, p = 0.001) and ALT (OR = 1.7, p < 0.001) remained independently associated with IRF. The odds for IRF were particularly high when comparing patients with elevated BIL and ALT versus normal parameters (adjusted OR = 2.9, p < 0.001)

Table 3

Association between liver dysfunction laboratory values and IRF

Association between liver dysfunction laboratory values and IRF
Association between liver dysfunction laboratory values and IRF

The principal finding of this analysis is that the significant and independent association between laboratory evidence of mild liver dysfunction and subsequent IRF is detectable in stable HF outpatients. Similar to our previously reported findings in ADHF, elevated levels of BIL, ALT, and AST were significantly more common in patients who subsequently experienced IRF. Additionally, improvements in laboratory evidence of liver dysfunction, particularly AST and ALT, were associated with improvements in RF over the course of 3 months, further supporting the potential use of observed HF-induced dysfunction in one organ to infer HF-induced dysfunction in another.

The relationship between liver dysfunction and RD in patients with HF rests on the fact that these two organs share a common venous system and are perfused by the same heart. As such, the sequelae of HF should affect these organs similarly and simultaneously. Potential mechanisms reportedly involved in both HF-induced RD and hepatic dysfunction may thereby explain these relationships and include increased neurohormonal activation, decreased perfusion, and venous congestion [3,4,5,6,7]. As a result, the strong association between elevated BIL (a marker of hepatic congestion) and elevated transaminases (a marker of decreased perfusion and ischemic hepatitis) with IRF may implicate the aforementioned mechanistic pathways [16]. Interestingly, these parameters of mild liver dysfunction appeared to provide unique information above and beyond traditional markers of congestion and poor perfusion. This was evidenced by the inability of signs of congestion/poor perfusion to directly predict IRF and the unchanged association between liver dysfunction and IRF after adjusting for these parameters. These data taken collectively provide further evidence that reversible RD may be a discernible entity in patients with HF.

The pathophysiology underlying ‘cardiorenal syndrome' is complex and incompletely understood. Our limited understanding has been highlighted by the recent high-profile failure of several ‘cardiorenal' interventions. Despite strong preclinical data, approaches such as the natriuretic peptides, adenosine antagonists, low-dose dopamine, loop diuretic infusions, and ultrafiltration have failed to provide meaningful benefit [17,18,19,20,21]. Although it is possible that the problem lies in that all of these agents are ineffective, an equally likely possibility is that patient selection is driving the lack of observed effectiveness. Importantly, RD in the setting of HF is not a single disease but rather a prognostically and mechanistically diverse group of overlapping disorders [10,22,23,24]. Much in the way that we would not expect vitamin B12 supplementation to show efficacy in a trial of unselected anemic patients with diverse etiologies for the anemia, better patient selection in cardiorenal clinical trials is likely also important. Additional research will be necessary to determine if markers such as BIL and ALT will provide sufficient discrimination of patients with RD that will be useful in future clinical trials.

Qualitatively, the observations in this study were very similar to those previously reported in the setting of ADHF [25]. Notably, BIL and ALT demonstrated the strongest associations with IRF, and AP was unrelated to IRF. However, there were quantitative differences. Notably, the incidence of IRF in this population of stable outpatients (12% in the current study) was substantially lower than the rate of IRF occurring in patients with ADHF (30-50%) [13,26]. Similarly, the strength of the association between markers of liver dysfunction and subsequent IRF was also lower than that observed in ADHF. However, this is not surprising since, by definition, there is a clear treatment target present at the time of ADHF presentation. As such, it follows that in a population with decompensated HF, IRF will often accompany the return to compensation. However, in stable HF outpatients, overt opportunities for improving patients' overall HF status are less common, and targeted therapies to improve RF are currently not available. Although this may represent a limitation of the current study design, the fact that the signals were detectable in spite of this limitation is very encouraging, showing that with the application of new cardiorenal treatments (i.e., renal sympathetic denervation), the rate of IRF in these subgroups may substantially increase.

Limitations

Given the post hoc and observational nature of this study, the limitations inherent to retrospective analyses apply, and uncontrolled confounding cannot be excluded. Although large and multicenter, the BEST study population may have dissimilarities to more contemporary HF populations given that enrollment ended in 1998, prior to the widespread use of aldosterone antagonists. Additionally, the exclusion of patients with active liver disease from the BEST study, potentially excluding patients with overt HF-induced liver dysfunction, is a limitation. The occurrence of liver dysfunction unrelated to HF was not accounted for in this analysis likely decreasing the effect size of the associations. Furthermore, alcohol use in those included in the trial was not further assessed, preventing adjustment for the degree of alcohol consumption. Given that clinicians were not blinded to the laboratory results, treatment may have been modified in response. However, the current lack of consensus regarding the methods to improve RF in HF patients limits the impact of this possibility. Since IRF is assumed to occur as a result of improvement in volume overload and/or hemodynamics, appropriate treatment or spontaneous improvement in HF must occur. As a result, patients with HF-induced RD with no change in therapy or no improvement in HF would not be detected by IRF.

In the setting of chronic stable HF, patients with laboratory evidence of mild liver dysfunction have a significantly higher prevalence of reversible RD. Although in need of further replication, these findings indicate that biochemical evidence of mild liver dysfunction may provide a widely accessible, inexpensive method by which patients with potentially reversible HF-induced RD can be identified. Additional research will be necessary to determine if these findings can be applied toward improved patient selection for cardiorenal interventions.

The study was funded by NIH grant 1K23HL114868.

The authors declare that there are no conflicts of interest to disclose.

1.
Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran JR, Wynne J; ASA Committee and Investigators: High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail 2007;13:422-430.
2.
McAlister FA, Ezekowitz J, Tarantini L, Squire I, Komajda M, Bayes-Genis A, Gotsman I, Whalley G, Earle N, Poppe KK, Doughty RN: Renal dysfunction in patients with heart failure with preserved versus reduced ejection fraction: impact of the new Chronic Kidney Disease-Epidemiology Collaboration Group formula. Circ Heart Fail 2012;5:309-314.
3.
Bock JS, Gottlieb SS: Cardiorenal syndrome: new perspectives. Circulation 2010;121:2592-2600.
4.
Giallourakis CC, Rosenberg PM, Friedman LS: The liver in heart failure. Clin Liver Dis 2002;6:947-967, viii-ix.
5.
Richman SM, Delman AJ, Grob D: Alterations in indices of liver function in congestive heart failure with particular reference to serum enzymes. Am J Med 1961;30:211-225.
6.
Sherlock S: The liver in heart failure; relation of anatomical, functional, and circulatory changes. Br Heart J 1951;13:273-293.
7.
van Deursen V, Damman K, Hillege H, van Beek A, van Veldhuisen D, Voors A: Abnormal liver function in relation to hemodynamic profile in heart failure patients. J Card Fail 2010;16:84-90.
8.
Beta-Blocker Evaluation of Survival Trial Investigators: A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659-1667.
9.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F; Chronic Kidney Disease Epidemiology Collaboration: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247-254.
10.
Brisco MA, Coca SG, Chen J, Owens AT, McCauley BD, Kimmel SE, Testani JM: Blood urea nitrogen/creatinine ratio identifies a high-risk but potentially reversible form of renal dysfunction in patients with decompensated heart failure. Circ Heart Fail 2013;6:233-239.
11.
Testani JM, Brisco M, Kimmel S, Coca S, Owens A: Randomization to digoxin is associated with improvement in renal function and reduction in death or hospitalization in patients with chronic heart failure: insights from the digitalis intervention group trial limited dataset. J Am Coll Cardiol 2012;59:E1041.
12.
Brisco MA, Jessup M, Coca S, Kimmel S, Testani JM: Biochemical evidence of liver dysfunction identifies patients likely to have improvement in renal function with mechanical circulatory support: insights from intermacs. J Card Fail 2012;18:S38-S39.
13.
Testani JM, McCauley BD, Chen J, Coca SG, Cappola TP, Kimmel SE: Clinical characteristics and outcomes of patients with improvement in renal function during the treatment of decompensated heart failure. J Card Fail 2011;17:993-1000.
14.
Testani JM, Chen M, McCauley BD, Shannon RP, Shen YT: The role of right ventricular dysfunction/venous congestion in cardiac-renal interactions. Circulation 2011;124:A8958.
15.
Mickey RM, Greenland S: The impact of confounder selection criteria on effect estimation. Am J Epidemiol 1989;129:125-137.
16.
Seeto RK, Fenn B, Rockey DC: Ischemic hepatitis: clinical presentation and pathogenesis. Am J Med 2000;109:109-113.
17.
Bart BA, Goldsmith SR, Lee KL, Givertz MM, O'Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, LeWinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E: Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296-2304.
18.
O'Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, Heizer GM, Komajda M, Massie BM, McMurray JJ, Nieminen MS, Reist CJ, Rouleau JL, Swedberg K, Adams KF Jr, Anker SD, Atar D, Battler A, Botero R, Bohidar NR, Butler J, Clausell N, Corbalan R, Costanzo MR, Dahlstrom U, Deckelbaum LI, Diaz R, Dunlap ME, Ezekowitz JA, Feldman D, Felker GM, Fonarow GC, Gennevois D, Gottlieb SS, Hill JA, Hollander JE, Howlett JG, Hudson MP, Kociol RD, Krum H, Laucevicius A, Levy WC, Mendez GF, Metra M, Mittal S, Oh BH, Pereira NL, Ponikowski P, Wilson WH, Tanomsup S, Teerlink JR, Triposkiadis F, Troughton RW, Voors AA, Whellan DJ, Zannad F, Califf RM: Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32-43.
19.
Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O'Connor CM: Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364:797-805.
20.
Massie BM, O'Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, Weatherley BD, Cleland JG, Givertz MM, Voors A, DeLucca P, Mansoor GA, Salerno CM, Bloomfield DM, Dittrich HC: Rolofylline, an adenosine a1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363:1419-1428.
21.
Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, Semigran MJ, Goldsmith SR, Bart BA, Bull DA, Stehlik J, LeWinter MM, Konstam MA, Huggins GS, Rouleau JL, O'Meara E, Tang WH, Starling RC, Butler J, Deswal A, Felker GM, O'Connor CM, Bonita RE, Margulies KB, Cappola TP, Ofili EO, Mann DL, Davila-Roman VG, McNulty SE, Borlaug BA, Velazquez EJ, Lee KL, Shah MR, Hernandez AF, Braunwald E, Redfield MM: Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013;310:2533-2543.
22.
Testani JM, Coca SG, McCauley BD, Shannon RP, Kimmel SE: Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes. Eur J Heart Fail 2011;13:877-884.
23.
Testani JM, Coca SG, Shannon RP, Kimmel SE, Cappola TP: Influence of renal dysfunction phenotype on mortality in the setting of cardiac dysfunction: analysis of three randomized controlled trials. Eur J Heart Fail 2011;13:1224-1230.
24.
Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP: Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation 2010;122:265-272.
25.
Brisco MA, McCauley BD, Chen J, Parikh CR, Testani JM: Biochemical evidence of mild hepatic dysfunction identifies decompensated heart failure patients with reversible renal dysfunction. J Card Fail 2013;19:739-745.
26.
Testani JM, McCauley BD, Kimmel SE, Shannon RP: Characteristics of patients with improvement or worsening in renal function during treatment of acute decompensated heart failure. Am J Cardiol 2010;106:1763-1769.

Drs. Brisco and Cheng contributed equally to this work and are co-first authors of this paper.

Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.