The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.

Disclosures: Michael S Kiernan, MD Nothing to disclose. James E Udelson, MD, FACC Grant/Research/Clinical Trial Support: NHLBI (ED imaging). Consultant/Advisory Boards: Lantheus Medical Imaging [SPECT imaging (Flurpiridaz)]. Mark Sarnak, MD Nothing to disclose. Marvin Konstam, MD Grant/Research/Clinical Trial Support: Merck; Otsuka (Heart failure [Tolvaptan]). Consultant/Advisory Boards: Johnson and Johnson; Amgen; Novartis; Pfizer; Ono (Heart failure [ACE inhibitors, ARBs, and Nesiritide]). Stephen S Gottlieb, MD Grant/Research/Clinical Trial Support: Pfizer [amyloidosis (tafamidis)]; Novartis [heart failure (seralaxin)]; Bayer [heart failure (BAY 94-8862)]; Resmed [sleep apnea]; Respircardia [sleep apnea]; Cardioxyl [heart failure (CXL-1427)]; Amgen [heart failure (omecamtiv mecarbil)]. Consultant/Advisory Boards: Novartis [heart failure (seralaxin)]; Pfizer [amyloidosis (tafamidis)]; BMS [heart failure]; GE [heart failure (iobenguane I-123)]. Susan B Yeon, MD, JD, FACC Employee of UpToDate, Inc.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2014. | This topic last updated: Feb 24, 2014.

DEFINITION AND CLASSIFICATION — There are a number of important interactions between heart disease and kidney disease. The interaction is bidirectional as acute or chronic dysfunction of the heart or kidneys can induce acute or chronic dysfunction in the other organ. The clinical importance of such relationships is illustrated by the following observations:

Mortality is increased in patients with heart failure (HF) who have a reduced glomerular filtration rate (GFR). (See 'Reduced GFR and prognosis' below.)

Patients with chronic kidney disease (CKD) have an increased risk of both atherosclerotic cardiovascular disease and heart failure, and cardiovascular disease is responsible for up to 50 percent of deaths in patients with renal failure [1,2]. (See "Chronic kidney disease and coronary heart disease", section on 'Introduction'.)

Acute or chronic systemic disorders can cause both cardiac and renal dysfunction.

The term “cardiorenal syndrome” (CRS) has been applied to these interactions, but the definition and classification have not been clear. A 2004 report from the National Heart, Lung, and Blood Institute defined CRS as a condition in which therapy to relieve congestive symptoms of HF is limited by a decline in renal function as manifested by a reduction in GFR [3]. The reduction in GFR was initially thought to result from a reduction in renal blood flow. However, various studies have demonstrated that cardiorenal interactions occur in both directions and by a variety of mechanisms [4]. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Pathophysiology'.)

The different interactions that can occur led to the following classification of CRS that was proposed by Ronco and colleagues [5]:

Type 1 (acute) – Acute HF results in acute kidney injury (previously called acute renal failure).

Type 2 – Chronic cardiac dysfunction (eg, chronic HF) causes progressive CKD (previously called chronic renal failure).

Type 3 – Abrupt and primary worsening of kidney function due, for example, to renal ischemia or glomerulonephritis causes acute cardiac dysfunction, which may be manifested by HF.

Type 4 – Primary CKD contributes to cardiac dysfunction, which may be manifested by coronary disease, HF, or arrhythmia.

Type 5 (secondary) – Acute or chronic systemic disorders (eg, sepsis or diabetes mellitus) that cause both cardiac and renal dysfunction.

The prognosis and treatment of type 1 and type 2 CRS will be reviewed here. Issues related to the prevalence of a reduced GFR in patients with HF, the diagnosis of type 1 and 2 CRS, and the mechanisms by which acute and chronic HF lead to worsening renal function are discussed separately. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology".)

REDUCED GFR AND PROGNOSIS — A reduced glomerular filtration rate (GFR) is generally associated with a worse prognosis in patients with heart failure (HF), whether present at baseline or developing during therapy for HF. A possible exception may be seen with diuretic therapy in patients with decompensated HF in whom diuretic therapy may improve survival despite a fall in GFR. (See 'Diuretics' below.)  

Reduced baseline GFR — The prevalence of moderate to severe reductions in glomerular filtration rate (GFR less than 60 mL/min per 1.73m2) in patients with HF has ranged from 30 to 60 percent in large clinical studies [6,7]. This observation is important clinically because the baseline GFR is a predictor of mortality in both acute and chronic HF [6-13].

The following observations illustrate the range of findings:

A systematic review of 16 studies included more than 80,000 patients with HF [6]. The patients were categorized as having normal renal function (estimated GFR [eGFR] 90 mL/min or higher), mildly impaired renal function (eGFR 53 to 89 mL/min, serum creatinine greater than 1.0 mg/dL [88.4 micromol/L], or serum cystatin C greater than 1.03 to 1.55 mg/dL), or moderately to severely impaired renal function (eGFR less than 53 mL/min, serum creatinine of 1.5 mg/dL [133 micromol/L] or higher, or serum cystatin C of 1.56 mg/dL or higher). Serum cystatin C may be a better marker of GFR than serum creatinine under certain circumstances because unlike creatinine production, cystatin C production is less dependent upon muscle mass and therefore less influenced by nutritional status [14]. (See "Assessment of kidney function".)

The mortality rate at a follow-up of one year or more was 24 percent in those with a normal eGFR compared with 38 and 51 percent in patients with mild and moderate to severe reductions in eGFR, respectively (adjusted hazard ratio 1.6 and 2.3). It was estimated that mortality increased by approximately 15 percent for every 10 mL/min reduction in eGFR.

Similar findings were noted in a report of 2680 patients with chronic HF in the CHARM program who were followed for a median of almost three years [8]. All-cause mortality increased significantly when the baseline eGFR was below 75 mL/min per 1.73 m2 (adjusted hazard ratio 1.09, 95% CI 1.06-1.14 for every 10 mL/min per 1.73 m2 decrease in eGFR below 75 mL/min per 1.73 m2). The adjusted hazard ratio increased from 1.20 at an eGFR of 60 to 75 mL/min per 1.73m2 to 2.92 at a eGFR below 45 mL/min. This effect was independent of the left ventricular ejection fraction (LVEF), but all-cause mortality increased continuously with reductions in LVEF below 45 percent (adjusted hazard ratio 1.18, 95% CI 1.13-1.23 per 5 percent decrease in LVEF).

Among 4917 patients with a continuous-flow LV assist device (LVAD), worse preimplant renal dysfunction correlated with lower survival rate with an approximately 20 percent lower two-year survival in patients with eGFR >60 mL/min compared to those with eGFR <30 mL/min [15]. The major reduction in survival occurred within the first three months after LVAD implantation.

Change in GFR during therapy for HF — The preceding observations of increased mortality risk in HF patients with reduced GFR were largely based upon baseline estimates of GFR. The relationship between change in GFR and prognosis is more complex. Worsening or improving GFR is associated with increased mortality risk in some patient populations but the cause of worsening GFR influences it prognostic significance [9,16-25]. Most of the data on the relationship between change in GFR and outcomes were obtained from patients hospitalized for worsening HF.

The best data on the association between worsening renal function and mortality come from a meta-analysis of eight studies with more than 18,000 patients with HF [19]. Five studies involved hospitalized patients and three involved outpatients. The following findings were noted:

Worsening renal function, defined as an elevation in serum creatinine of 0.3 mg/dL (27 micromol/L) or more, occurred in 26 percent of patients.

All-cause mortality was significantly higher in the patients with worsening renal function compared to those with a serum creatinine that was unchanged or increased by less than 0.2 mg/dL (18 micromol/L): 43 versus 36 percent. The findings were the same in hospitalized and nonhospitalized patients.

The mortality risk increased progressively with the degree of worsening renal function. The respective odds ratios were:

1.03 (not significant) when the serum creatinine rose by 0.2 to 0.3 mg/dL (18 to 27 micromol/L) or the eGFR declined by less than 5 to 10 mL/min per 1.73 m2.

1.48 when the serum creatinine rose by 0.3 to 0.5 mg/dL (27 to 44 micromol/L) or the eGFR declined by 11 to 15 mL/min per 1.73 m2.

3.22 when the serum creatinine rose by more than 0.5 mg/dL (44 micromol/L) or the eGFR declined by more than 15 mL/min per 1.73 m2.

However, other evidence suggests that patients with improving or worsening renal function may have worse outcomes. Fluctuating renal function may occur in a sicker cohort of patients with significantly worse survival than patients with stable renal function, as illustrated by the following studies:

An analysis of data on 401 patients enrolled in the ESCAPE trial found that patients with an improvement or a decline in estimated GFR during treatment of acute decompensated HF had similar outcomes [23]. Compared to patients with a stable GFR, those with either an improvement or a decline in GFR were significantly more likely to have a reduced cardiac index and to require intravenous inotrope and vasodilator therapy, and had a significantly higher rate of all-cause mortality.

Similarly, an observation study of 903 patients found that those with improved GFR during hospitalization for HF had worsened survival compared to patients with stable renal function [24]. This finding was largely restricted to patients who developed recurrent renal dysfunction post-discharge.

Additionally, the mechanism of worsening renal function in HF is important in determining its prognostic significance. An analysis of data on 6337 subjects enrolled in the Studies Of Left Ventricular Dysfunction (SOLVD) showed that early worsening renal function was associated with increased mortality in the overall population [25]. However, in the enalapril group, early worsening renal function was not associated with increased mortality, while in the placebo group, the association with mortality was strengthened. A significant survival benefit from enalapril therapy was observed in patients who continued enalapril despite early worsening renal function. These findings suggest that worsening renal function is not always a marker of adverse clinical outcome. On the contrary, in the case of angiotensin converting enzyme inhibitor administration, it is a manifestation of the agent’s pharmacologic properties, which exert a favorable effect on long-term outcome.

Other studies of renin-angiotensin-aldosterone system (RAAS) inhibition have similarly demonstrated beneficial effects on long-term outcomes despite an initial early decline in renal function [26,27]. Early decline in GFR in the setting of initiation of RAAS antagonists may reflect antagonism of angiotensin II-mediated efferent arteriolar constriction.

In addition, as noted below, treatment of decompensated HF with diuretics may improve survival despite worsening renal function. (See 'Diuretics' below.)

Blood urea nitrogen — An elevation in blood urea nitrogen (BUN) or blood urea is also associated with increased mortality in patients with HF [22,28-30], an effect that may be independent of the serum creatinine and GFR [28,29]. A probable contributing factor is that a disproportionate increase in BUN is often seen with a reduction in renal perfusion (ie, prerenal azotemia). (See "Assessment of kidney function", section on 'BUN and GFR' and "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology".)

MANAGEMENT — Given the limitations imposed by impaired renal function on the ability to correct volume overload and the frequent association between impaired or worsening renal function and mortality in patients with heart failure (HF), it is possible that effective treatment of the cardiorenal syndrome (CRS) could improve patient outcomes. On the other hand, the worse prognosis in patients with HF and impaired renal function could primarily reflect a reduced glomerular filtration rate (GFR) being a marker of more severe cardiac disease. In this setting, improving renal function alone would not necessarily improve patient outcomes. (See 'Reduced GFR and prognosis' above.)

There are no medical therapies that have been shown to directly increase the GFR (manifested clinically by a decline in serum creatinine) in patients with HF. On the other hand, improving cardiac function can produce increases in GFR, indicating that types 1 and 2 CRS have substantial reversible components. (See 'Definition and classification' above and "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Pathophysiology'.)

Improvement in cardiac function — Evidence suggesting that improvement in cardiac function is associated with improved renal function in patients with types 1 and 2 CRS comes from studies of left ventricular assist devices (LVADs) and cardiac resynchronization therapy:

A study of 4917 patients with continuous-flow LVADs enrolled in the INTERMACS registry demonstrated improvements in serum creatinine and reductions in blood urea nitrogen (BUN) among patients with baseline moderate or severe renal dysfunction. Improvements in estimated GFR (eGFR) were noted within one month of LVAD implantation and persisted over a two-year period of follow-up [15]. However, a separate analysis of data from the INTERMACS registry found that early improvements in eGFR with LVAD use were transient and typically only sustained for a period of weeks to months [31].

Analysis of data from an observational study and from the MIRACLE trial found that cardiac resynchronization therapy improved the LV ejection fraction and the eGFR in selected patients with HF and moderately reduced baseline eGFR (eGFR 30 to 59 mL/min) [32,33]. (See "Rationale for and mechanisms of benefit of cardiac resynchronization therapy".)

Diuretics — Diuretics, typically beginning with a loop diuretic, are first-line therapy for managing volume overload in patients with HF as manifested by peripheral and/or pulmonary edema. In patients with HF, an elevated BUN/creatinine ratio should not deter diuretic therapy if clinical evidence of congestion is present. Issues related to diuretic dosing, the time course of the diuresis, the side effects of diuretic therapy, and the management of refractory edema in these patients are discussed elsewhere. (See "Use of diuretics in patients with heart failure".)

The effect of diuretic-induced fluid removal on the glomerular filtration rate (usually estimated from the serum creatinine) is variable in patients with HF:

Some patients have an increase in serum creatinine that is presumed to be mediated at least in part by a reduction in renal perfusion due to a decline in cardiac output induced by the fall in cardiac filling pressures [34]. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Reduced renal perfusion'.)

Some patients have no change in serum creatinine that may reflect maintenance of cardiac output perhaps because they are on the flat part of the Frank-Starling curve where changes in LV end-diastolic pressure have little or no effect on cardiac performance (figure 1).

Some patients have a reduction in serum creatinine mediated perhaps in part by one or both of the following mechanisms:

Reductions in intraabdominal and renal venous pressures. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Increased renal venous pressure'.)

Reduction in right ventricular dilatation, which may improve LV filling and function via ventricular interdependence (alleviation of the reverse Bernheim phenomenon). (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Right ventricular dilatation and dysfunction'.)

Among patients with decompensated HF, the best outcomes may occur with aggressive fluid removal even if associated with mild to moderate worsening of renal function. Support for aggressive fluid removal comes from the following studies:

A study of 336 patients with decompensated HF in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial found that hemoconcentration was associated with worsening renal function as well as a lower mortality rate [35]. Hemoconcentration was defined as baseline-to-discharge increases in the top one-third of the group in at least two of the following: hematocrit, serum albumin, and serum total protein. Patients with hemoconcentration were treated with higher doses of loop diuretics and more fluid loss, lost more weight, and had greater reductions in intracardiac filling pressures compared with patients without hemoconcentration. Hemoconcentration was strongly associated with worsening renal function (odds ratio 5.3), but also was associated with a significantly lower 180 day mortality rate (adjusted hazard ratio, 0.16, 95% CI 0.02-0.44). Although the total number of deaths was small (n = 29), this study suggests that aggressive decongestion in the face of worsening renal function may favorably affect survival.

An analysis of data from the EVEREST (Efficacy of Vasopressin Antagonism in heart Failure Outcome Study with Tolvaptan) trial demonstrated that hemoconcentration was associated with greater risk of in hospital worsening renal function, though renal parameters generally returned to baseline within four weeks of discharge [36]. Despite this association, every 5 percent increase in-hospital hematocrit change was associated with a decreased risk of all-cause mortality (hazard ratio 0.81, 95% CI: 0.70-0.95).

Additionally, the timing of hemoconcentration may be important, as a study of 845 consecutive inpatients with HF found that hemoconcentration achieved late during the hospitalization was associated with improved survival while early hemoconcentration was not associated with improved survival compared to no hemoconcentration [37]. Late hemoconcentration was associated with higher average daily loop diuretic doses and greater weight loss than early hemoconcentration.

These findings provide support for the recommendation included in the 2013 American College of Cardiology/American Heart Association HF guidelines that the goal of diuretic therapy is to eliminate clinical evidence of fluid retention such as an elevated jugular venous pressure and peripheral edema [38]. The rapidity of diuresis can be slowed if the patient develops hypotension or worsening renal function. However, the goal of diuretic therapy is to eliminate fluid retention even if this leads to asymptomatic mild to moderate reductions in blood pressure or renal function. (See "Use of diuretics in patients with heart failure", section on 'Goals of therapy'.)

Renin-angiotensin-aldosterone-system antagonism — Angiotensin inhibition with an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) is a standard part of the therapy of HF with systolic dysfunction, being associated with symptomatic improvement, reduced hospitalization for HF, and enhanced survival. (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use" and "Angiotensin II receptor blocker and neprilysin inhibitor therapy in heart failure due to systolic dysfunction".)

Despite the above benefits, ACE inhibitor or ARB therapy for HF is not generally associated with an improvement in renal function. Although a minority of patients have an increase in GFR after initiation of ACE inhibitor or ARB therapy, most have a moderate reduction in GFR that can often be ameliorated by reducing the intensity of diuretic therapy. The supportive data and management are presented elsewhere. (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use", section on 'Effect on GFR'.)

While clinical trials of renin-angiotensin-aldosterone system (RAAS) antagonists in HF have not specifically focused on patients with the CRS, subgroup analyses of patients with and without chronic kidney disease (CKD) as well as cohort studies have demonstrated that the beneficial effect of RAAS antagonism on clinical outcomes is not mitigated by concomitant CKD [26,39-41]. While RAAS antagonists retain their clinical benefit in HF among patients with CKD, the risk of adverse events including hyperkalemia and worsening renal function is higher than in patients without CKD [26,27,39,41-43]. Patients with CKD should be monitored closely during periods of drug initiation and titration and should receive periodic monitoring of electrolytes and creatinine throughout the duration of therapy [38].

Vasodilators — Intravenous vasodilators used in the treatment of acute decompensated HF include nitrates (eg, nitroglycerin and nitroprusside) and nesiritide, which is recombinant human brain natriuretic peptide. (See "Treatment of acute decompensated heart failure: Components of therapy", section on 'Vasodilator therapy' and "Nesiritide in the treatment of acute decompensated heart failure", section on 'Effect on renal function'.)

With respect to effects on the CRS, the Acutely Decompensated Heart Failure National Registry (ADHERE) database of almost 100,000 patients defined worsening renal function as a rise in serum creatinine between admission and discharge of more than 0.5 mg/dL (44 micromol/L) or more than 0.3 mg/dL (27 micromol/L) with a serum creatinine more than 1.5 mg/dL (133 micromol/L) [44]. The rate of worsening renal function was significantly higher when intravenous diuretics were given with nitroglycerin or nesiritide compared with intravenous diuretics alone (relative risk 1.20 and 1.44, respectively). However, a causal effect could not be distinguished from patients requiring combination therapy having more severe HF.

Randomized trials have yielded conflicting results on the effect of nesiritide therapy on renal function in the treatment of acute decompensated HF. The largest trial, ASCEND-HF, found no change in risk of worsening renal function with nesiritide therapy (continuous infusion at 0.01 microg/kg per min with an optional initial loading dose of 2 microg/kg) [45]. Similarly, the Renal Optimization Strategies Evaluation (ROSE) trial found that low-dose nesiritide (0.005 mcg/kg/min without bolus for 72 h) did not enhance decongestion or alter renal function when added to diuretic therapy [46]. (See "Nesiritide in the treatment of acute decompensated heart failure", section on 'Effect on renal function'.)

Inotropic drugs — Intravenous administration of inotropic drugs, such as dobutamine, dopamine, and milrinone, has a role in the treatment of cardiogenic shock and in selected patients with acute decompensated HF. However, both routine use of short-term intravenous therapy in patients with acute decompensated HF and prolonged therapy with oral inotropic drugs other than digoxin have been associated with an increase in mortality. As a result, the main role of inotropic drugs other than digoxin is in the management of cardiogenic shock or acute decompensated HF. The supporting data and management are discussed in detail elsewhere. (See "Prognosis and treatment of cardiogenic shock complicating acute myocardial infarction", section on 'Vasopressors and inotropes' and "Treatment of acute decompensated heart failure: Components of therapy", section on 'Inotropic agents' and "Inotropic agents in heart failure due to systolic dysfunction", section on 'Summary' and "Treatment of acute decompensated heart failure in acute coronary syndromes".)

The role of inotropes in patients with CRS is uncertain and the routine use of inotropes cannot be recommended given their lack of proven efficacy and their association with adverse events when used outside of selected patients with cardiogenic shock or acute decompensated HF.

Although it has been proposed that inotropic agents might improve renal function in patients with severe HF by increasing renal blood flow and possibly by reducing renal venous pressure, data supporting such a potential benefit are limited as illustrated by the following observations regarding use of dopamine:

A potential role for dopamine in improving or preserving renal function in HF was suggested by small series indicating that dopamine can significantly increase the GFR in patients with moderate or severe HF [47,48]. Dopamine increased renal blood flow at doses of 2 to 10 mcg/kg/min in such patients [47,49]. This effect appears to be due to dilation of both large conductance and small resistance renal blood vessels [49]. Dopamine also caused significant increases in cardiac output at doses in the range of 5 to 10 mcg/kg/min, but the proportionate increase in renal blood flow was greater than the increase in cardiac output.

The clinical efficacy and safety of dopamine for preservation of renal function in patients with HF has not been established.

A report from the DAD-HF trial of 60 patients with acute decompensated HF found that the combination of dopamine 5 mcg/kg/min plus low-dose furosemide (5mg/h continuous infusion) produced similar urine output as high-dose furosemide (20 mg/h) with reduced risk of worsening renal function (defined as rise in serum creatinine of >0.3 mg/dL from baseline to 24 hours; 7 versus 30 percent) [50].

The Renal Optimization Strategies Evaluation (ROSE) trial also tested the hypothesis of whether low-dose dopamine (2mcg/kg/min) (n = 122) would improve urine output and renal function compared to placebo (n = 119) among patients hospitalized with HF and concomitant renal disease [46]. Low-dose dopamine did not enhance decongestion or improve renal function when added to diuretic therapy.  

Ultrafiltration — Ultrafiltration refers to the removal of isotonic fluid from the venous compartment via filtration of plasma across a semipermeable membrane. In HF patients, ultrafiltration is most often considered in patients with acute decompensated HF and diuretic resistance and/or impaired renal function. By removing isotonic fluid, ultrafiltration tends to maintain physiologic electrolyte balance, in contrast to diuretic therapy. (See "Treatment of acute decompensated heart failure: Components of therapy", section on 'Ultrafiltration'.)

Three randomized trials (UNLOAD, RAPID-CHF, and CARESS-HF) compared ultrafiltration to diuretic therapy in patients with acute decompensated HF [51-53]. The mean baseline serum creatinine levels were 1.5, 1.7, and 2.0 mg/dL (133, 150, and 177 μmol/L), respectively. In UNLOAD and RAPID-CHF, ultrafiltration was associated with a significantly greater rate of fluid loss than diuretic therapy but no difference in serum creatinine. In CARESS-HF, ultrafiltration was compared to stepped pharmacologic therapy (including bolus plus high doses of continuous infusion loop diuretics, addition of thiazide diuretic [metolazone], and selected intravenous inotrope and/or vasodilator therapy) in patients with worsening renal function and persistent congestion [53]. Although weight loss was similar in ultrafiltration and stepped pharmacologic therapy groups, ultrafiltration therapy caused an increase in serum creatinine and a higher rate of adverse events. (See "Treatment of acute decompensated heart failure: Components of therapy", section on 'Ultrafiltration'.)

Thus, although ultrafiltration may be helpful for fluid removal in acute decompensated HF in patients unresponsive to diuretic therapy, the available evidence does not establish ultrafiltration as first line therapy for AHDF or as an effective therapy for CRS. The 2009 American Heart Association/American College of Cardiology guidelines state that ultrafiltration is reasonable for patients with refractory congestion not responding to medical therapy [54].

Investigational therapies — Two other classes of drugs have been evaluated in the treatment of HF, with no proven effect on kidney function: antagonists of vasopressin receptor 2, which mediate the antidiuretic response, and antagonists of the adenosine A1 receptor.

Neurohormonal activation in patients with HF results in the nonosmotic release of antidiuretic hormone (arginine vasopressin), which leads to free water retention and hyponatremia that parallels the severity of the HF [55]. (See "Predictors of survival in heart failure due to systolic dysfunction", section on 'Neurohumoral activation and heart rate' and "Hyponatremia in patients with heart failure", section on 'Predictor of adverse prognosis'.)

Tolvaptan is a selective vasopressin 2 receptor antagonist that produces a water diuresis, not a salt diuresis as induced by conventional diuretics. The effect of tolvaptan on cardiovascular outcomes and decongestion in patients with acute HF was evaluated in the EVEREST Outcome trial [56]. Tolvaptan had no effect on the co-primary end points of all-cause mortality, mortality or HF hospitalization, or seven-day patient global assessment. However, there were significant benefits in a number of secondary end points including an increase in urine output, resulting in reduced dyspnea and edema and an increase in serum sodium. There was also a statistically significant, but not clinically significant, greater increase in serum creatinine with tolvaptan (0.08 versus 0.03 mg/dL [7.1 versus 2.7 micromol/L] with placebo). Tolvaptan is approved only for the treatment of hyponatremia in patients with HF. Further trials evaluating the role of tolvaptan for the management of the CRS are ongoing. (See "Possibly effective emerging therapies for heart failure", section on 'Vasopressin receptor antagonists'.)

Adenosine, acting on the adenosine-1 receptor, constricts the afferent glomerular arteriole, thereby reducing the GFR, and increases tubular sodium reabsorption [57]. Thus, selective adenosine A1 receptor antagonism can increase GFR and promote a diuresis [58], potentially acting synergistically with loop diuretics.

In the PROTECT trial, 2033 patients hospitalized with HF and impaired renal function (mean creatinine clearance 51 mL/min) were randomly assigned to the experimental selective A1 adenosine antagonist rolofylline or to placebo [59]. During the study period, there was no difference between the groups in cardiovascular outcomes or in the rate of persistent worsening of renal function, which was defined as an increase in serum creatinine of 0.3 mg/dL (27 micromol/L). In addition, rolofylline therapy was associated with a higher rate of neurologic events (seizure and stroke).

SUMMARY

Reduced glomerular filtration rates (GFR) are common in patients presenting with heart failure (HF) and are associated with increased mortality. A systematic review found that mortality increased by approximately 15 percent for every 10 mL/min reduction in estimated GFR. (See 'Reduced GFR and prognosis' above.)  

A fall in GFR during treatment of HF has often been associated with increased mortality in clinical studies in which the mortality risk increased progressively with the degree of worsening renal function. However, other evidence suggests that patient outcomes may be improved with aggressive fluid removal even if accompanied by a rise in serum creatinine. (See 'Change in GFR during therapy for HF' above.)

Given the limitations imposed by impaired renal function on the ability to correct volume overload and the strong association between impaired or worsening renal function and adverse clinical outcomes in patients with HF, it is possible that effective treatment of the cardiorenal syndrome (CRS) would improve patient outcomes. On the other hand, the worse prognosis associated with CRS could primarily reflect a reduced GFR being a marker of more severe cardiac disease. In this setting, improving renal function alone would not necessarily improve patient outcomes. (See 'Management' above.)

There are no medical therapies that have been shown to directly increase GFR in patients with the CRS. On the other hand, improving cardiac function can produce increases in GFR, indicating that types 1 and 2 CRS have substantial reversible components. (See 'Management' above.)

The effect of diuretic-induced fluid removal on the GFR is variable in patients with HF. Although fluid removal may result in increases in serum creatinine and rising serum creatinine is associated with worse prognosis in patients with HF, aggressive decongestion leading to worsening renal function may be associated with improved survival. (See 'Diuretics' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

  1. United States Renal Data System: Excerpts from the USRDS 2007 annual data report: atlas of end-stage renal disease in the United States. Minneapolis, MN 2007.
  2. Coresh J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003; 41:1.
  3. http://www.nhlbi.nih.gov/meetings/workshops/cardiorenal-hf-hd.htm (Accessed on September 01, 2010).
  4. Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation 2010; 121:2592.
  5. Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol 2008; 52:1527.
  6. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol 2006; 47:1987.
  7. Heywood JT, Fonarow GC, Costanzo MR, et al. 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.
  8. Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006; 113:671.
  9. Forman DE, Butler J, Wang Y, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 2004; 43:61.
  10. Dries DL, Exner DV, Domanski MJ, et al. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol 2000; 35:681.
  11. McAlister FA, Ezekowitz J, Tonelli M, Armstrong PW. Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation 2004; 109:1004.
  12. Shlipak MG, Smith GL, Rathore SS, et al. Renal function, digoxin therapy, and heart failure outcomes: evidence from the digoxin intervention group trial. J Am Soc Nephrol 2004; 15:2195.
  13. de Silva R, Nikitin NP, Witte KK, et al. Incidence of renal dysfunction over 6 months in patients with chronic heart failure due to left ventricular systolic dysfunction: contributing factors and relationship to prognosis. Eur Heart J 2006; 27:569.
  14. Lassus J, Harjola VP, Sund R, et al. Prognostic value of cystatin C in acute heart failure in relation to other markers of renal function and NT-proBNP. Eur Heart J 2007; 28:1841.
  15. Kirklin JK, Naftel DC, Kormos RL, et al. Quantifying the effect of cardiorenal syndrome on mortality after left ventricular assist device implant. J Heart Lung Transplant 2013; 32:1205.
  16. Smith GL, Vaccarino V, Kosiborod M, et al. Worsening renal function: what is a clinically meaningful change in creatinine during hospitalization with heart failure? J Card Fail 2003; 9:13.
  17. Akhter MW, Aronson D, Bitar F, et al. Effect of elevated admission serum creatinine and its worsening on outcome in hospitalized patients with decompensated heart failure. Am J Cardiol 2004; 94:957.
  18. Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 2004; 147:331.
  19. Damman K, Navis G, Voors AA, et al. Worsening renal function and prognosis in heart failure: systematic review and meta-analysis. J Card Fail 2007; 13:599.
  20. Gottlieb SS, Abraham W, Butler J, et al. The prognostic importance of different definitions of worsening renal function in congestive heart failure. J Card Fail 2002; 8:136.
  21. Logeart D, Tabet JY, Hittinger L, et al. Transient worsening of renal function during hospitalization for acute heart failure alters outcome. Int J Cardiol 2008; 127:228.
  22. Klein L, Massie BM, Leimberger JD, et al. Admission or changes in renal function during hospitalization for worsening heart failure predict postdischarge survival: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF). Circ Heart Fail 2008; 1:25.
  23. 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.
  24. Testani JM, McCauley BD, Chen J, et al. Clinical characteristics and outcomes of patients with improvement in renal function during the treatment of decompensated heart failure. J Card Fail 2011; 17:993.
  25. Testani JM, Kimmel SE, Dries DL, Coca SG. Prognostic importance of early worsening renal function after initiation of angiotensin-converting enzyme inhibitor therapy in patients with cardiac dysfunction. Circ Heart Fail 2011; 4:685.
  26. Anand IS, Bishu K, Rector TS, et al. Proteinuria, chronic kidney disease, and the effect of an angiotensin receptor blocker in addition to an angiotensin-converting enzyme inhibitor in patients with moderate to severe heart failure. Circulation 2009; 120:1577.
  27. Rossignol P, Cleland JG, Bhandari S, et al. Determinants and consequences of renal function variations with aldosterone blocker therapy in heart failure patients after myocardial infarction: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study. Circulation 2012; 125:271.
  28. Aronson D, Mittleman MA, Burger AJ. Elevated blood urea nitrogen level as a predictor of mortality in patients admitted for decompensated heart failure. Am J Med 2004; 116:466.
  29. Filippatos G, Rossi J, Lloyd-Jones DM, et al. Prognostic value of blood urea nitrogen in patients hospitalized with worsening heart failure: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) study. J Card Fail 2007; 13:360.
  30. Fonarow GC, Adams KF Jr, Abraham WT, et al. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA 2005; 293:572.
  31. Brisco MA, Kimmel SE, Coca SG, et al. Prevalence and prognostic importance of changes in renal function after mechanical circulatory support. Circ Heart Fail 2014; 7:68.
  32. Adelstein EC, Shalaby A, Saba S. Response to cardiac resynchronization therapy in patients with heart failure and renal insufficiency. Pacing Clin Electrophysiol 2010; 33:850.
  33. Boerrigter G, Costello-Boerrigter LC, Abraham WT, et al. Cardiac resynchronization therapy improves renal function in human heart failure with reduced glomerular filtration rate. J Card Fail 2008; 14:539.
  34. Stampfer M, Epstein SE, Beiser GD, Braunwald E. Hemodynamic effects of diuresis at rest and during intense upright exercise in patients with impaired cardiac function. Circulation 1968; 37:900.
  35. Testani JM, Chen J, McCauley BD, et al. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation 2010; 122:265.
  36. Greene SJ, Gheorghiade M, Vaduganathan M, et al. Haemoconcentration, renal function, and post-discharge outcomes among patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial. Eur J Heart Fail 2013; 15:1401.
  37. Testani JM, Brisco MA, Chen J, et al. Timing of hemoconcentration during treatment of acute decompensated heart failure and subsequent survival: importance of sustained decongestion. J Am Coll Cardiol 2013; 62:516.
  38. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128:1810.
  39. Eschalier R, McMurray JJ, Swedberg K, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). J Am Coll Cardiol 2013; 62:1585.
  40. Lesogor A, Cohn JN, Latini R, et al. Interaction between baseline and early worsening of renal function and efficacy of renin-angiotensin-aldosterone system blockade in patients with heart failure: insights from the Val-HeFT study. Eur J Heart Fail 2013; 15:1236.
  41. Tokmakova MP, Skali H, Kenchaiah S, et al. Chronic kidney disease, cardiovascular risk, and response to angiotensin-converting enzyme inhibition after myocardial infarction: the Survival And Ventricular Enlargement (SAVE) study. Circulation 2004; 110:3667.
  42. Kiernan MS, Wentworth D, Francis G, et al. Predicting adverse events during angiotensin receptor blocker treatment in heart failure: results from the HEAAL trial. Eur J Heart Fail 2012; 14:1401.
  43. Vardeny O, Wu DH, Desai A, et al. Influence of baseline and worsening renal function on efficacy of spironolactone in patients With severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study). J Am Coll Cardiol 2012; 60:2082.
  44. Costanzo MR, Johannes RS, Pine M, et al. The safety of intravenous diuretics alone versus diuretics plus parenteral vasoactive therapies in hospitalized patients with acutely decompensated heart failure: a propensity score and instrumental variable analysis using the Acutely Decompensated Heart Failure National Registry (ADHERE) database. Am Heart J 2007; 154:267.
  45. O'Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011; 365:32.
  46. Chen HH, Anstrom KJ, Givertz MM, et al. 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.
  47. Ungar A, Fumagalli S, Marini M, et al. Renal, but not systemic, hemodynamic effects of dopamine are influenced by the severity of congestive heart failure. Crit Care Med 2004; 32:1125.
  48. Varriale P, Mossavi A. The benefit of low-dose dopamine during vigorous diuresis for congestive heart failure associated with renal insufficiency: does it protect renal function? Clin Cardiol 1997; 20:627.
  49. Elkayam U, Ng TM, Hatamizadeh P, et al. Renal Vasodilatory Action of Dopamine in Patients With Heart Failure: Magnitude of Effect and Site of Action. Circulation 2008; 117:200.
  50. Giamouzis G, Butler J, Starling RC, et al. Impact of dopamine infusion on renal function in hospitalized heart failure patients: results of the Dopamine in Acute Decompensated Heart Failure (DAD-HF) Trial. J Card Fail 2010; 16:922.
  51. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007; 49:675.
  52. Bart BA, Boyle A, Bank AJ, et al. Ultrafiltration versus usual care for hospitalized patients with heart failure: the Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial. J Am Coll Cardiol 2005; 46:2043.
  53. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296.
  54. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119:1977.
  55. Finley JJ 4th, Konstam MA, Udelson JE. Arginine vasopressin antagonists for the treatment of heart failure and hyponatremia. Circulation 2008; 118:410.
  56. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007; 297:1319.
  57. Vallon V, Mühlbauer B, Osswald H. Adenosine and kidney function. Physiol Rev 2006; 86:901.
  58. Dohadwala MM, Givertz MM. Role of adenosine antagonism in the cardiorenal syndrome. Cardiovasc Ther 2008; 26:276.
  59. Massie BM, O'Connor CM, Metra M, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010; 363:1419.
Topic 15619 Version 11.0

All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.