Disclosures: Michael S Kiernan, MD Nothing to disclose. James E Udelson, MD, FACC Grant/Research/Clinical Trial Support: NHLBI [Imaging]. Consultant/Advisory Boards: Lantheus Medical Imaging [Cardiac imaging (Flupiridaz)]. Mark Sarnak, MD Nothing to disclose. Marvin Konstam, MD Grant/Research/Clinical Trial Support: Otsuka [Heart failure (Tolvaptan)]. Merck; Novartis; Arbor; Amgen; Johnson & Johnson; Takeda [Heart failure and thrombosis (Losartan, Bidil, and Nesiritide)]. Stephen S Gottlieb, MD Grant/Research/Clinical Trial Support: Pfizer [amyloidosis (tafamidis)]; Novartis [heart failure (seralaxin)]; Resmed [sleep apnea (CPAP)]; Respircardia [sleep apnea (remede)]; Amgen [heart failure (omecamtiv mecarbil)]. Consultant/Advisory Boards: Novartis [heart failure (seralaxin)]; BMS [heart failure]; Relypsa [hyperkameia (patiromer)]. Susan B Yeon, MD, JD, FACC Nothing to disclose.
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.
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 . 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 . (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 :
●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 . 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 . (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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 .
●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 . (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 . 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 . 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 . 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 . 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 .
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 "Nesiritide in the treatment of acute decompensated heart failure", section on 'Effect on renal function' and "Treatment of acute decompensated heart failure: Components of therapy".)
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) . 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) . 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 . (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 "Inotropic agents in heart failure due to systolic dysfunction", section on 'Summary' and "Treatment of acute decompensated heart failure in acute coronary syndromes" and "Treatment of acute decompensated heart failure: Components of therapy".)
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 . 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) .
•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 . 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".)
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 . 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".)
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 .
Investigational therapies — Two other classes of drugs have been evaluated in the treatment of HF, with no proven effect on kidney function: antagonists of the vasopressin receptors, 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 . (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 . 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 vasopressin receptor antagonists for the management of the CRS are ongoing. (See "Hyponatremia in patients with 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 . Thus, selective adenosine A1 receptor antagonism can increase GFR and promote a diuresis , 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 . 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).
●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.)
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