Cardiorenal syndrome: Prognosis and treatment

INTRODUCTION — Acute or chronic dysfunction of the heart or kidneys can induce acute or chronic dysfunction in the other organ. In addition, both heart and kidney function can be impaired by an acute or chronic systemic disorder. The term "cardiorenal syndrome" (CRS) has been applied to these interactions.

The prognosis and treatment of type 1 and 2 CRS will be reviewed here. Issues related to the prevalence of a reduced glomerular filtration rate in patients with heart failure (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 baseline glomerular filtration rate (GFR) is generally associated with a worse prognosis in patients with heart failure (HF). However, the prognostic significance of worsening renal function (WRF) likely depends upon its cause. (See 'Change in glomerular filtration rate during therapy for heart failure' below.)

An analysis of the PROTECT trial identified multiple different trajectories in renal function during hospitalization for acute heart failure [1]. The most common trajectories were in-hospital transient rise in serum creatinine (19 percent), sustained increase (17.6 percent), and decrease (14.5 percent). After multivariable adjustment, no trajectory of change was associated with significantly better or worse outcomes, questioning the prognostic importance of changes in renal function during acute HF.

Reduced baseline glomerular filtration rate — The prevalence of moderate to severe reductions in GFR (less than 60 mL/min per 1.73 m²) in patients with HF has ranged from 30 to 60 percent in large clinical studies [2,3]. This observation is important clinically because the baseline GFR is a predictor of mortality in both acute and chronic HF [2-9].

The following observations illustrate the range of findings:

●A systematic review of 16 studies included more than 80,000 patients with HF [2]. 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 [10]. (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 [HR] 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 [4]. All-cause mortality increased significantly when the baseline eGFR was below 75 mL/min per 1.73 m² (adjusted HR 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 HR increased from 1.20 at an eGFR of 60 to 75 mL/min per 1.73 m² to 2.92 at an 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 HR 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 <30 mL/min compared with those with eGFR ≥60 mL/min [11]. The major reduction in survival occurred within the first three months after LVAD implantation.

Change in glomerular filtration rate during therapy for heart failure — Worsening or improving GFR is associated with increased mortality risk in some patient populations but the cause of worsening GFR influences its prognostic significance [5,12-21]. Most of the data on the relationship between change in GFR and outcomes were obtained from patients hospitalized for worsening HF.

The prevalence of WRF in patients with HF was illustrated by a study of 3,570,865 United States veterans with an eGFR ≥60 mL/min/1.73 m² of which 156,743 were diagnosed with HF [22]. Incident chronic kidney disease (CKD) was 69.0/1000 patient-years in patients with HF versus 14.5/1000 patient-years in those without. Twenty-two percent of HF patients compared with 8.5 percent of patients without HF experienced a rapid decline in eGFR. HF patients had greater than two times the risk of incident CKD, a composite of incident CKD or mortality, as well as rapid eGFR decline.

Association between change and prognosis — The association between worsening renal function and mortality are illustrated by a meta-analysis of eight studies with more than 18,000 patients with HF [15]. 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 with 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 [19]. Compared with 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 with patients with stable renal function [20]. This finding was largely restricted to patients who developed recurrent renal dysfunction post-discharge.

Importance of cause of worsening renal function — 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 [21]. 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 [23,24]. An analysis of data from the Heart failure End point evaluation of Angiotensin II Antagonist Losartan (HEAAL) trial found that 150 mg losartan compared with 50 mg was associated with increased risk of acute rise in serum creatinine as well as with greater long-term reductions in eGFR, but that despite these effects, high-dose losartan retained its net clinical benefit and was associated with reduced risk of death or HF hospitalization [25]. 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.)

In an analysis of the ESCAPE trial, in-hospital WRF was not associated with increased risk of mortality among patients who were successfully decongested at discharge [26]. Transient increases (bumps) in serum creatinine during decongestion may be predominantly functional or hemodynamic in nature. Increases in creatinine observed during aggressive decongestion may thus be clinically benign events, not signifying true injury nor associated with subsequent adverse outcomes [27]. In an analysis of the Renal Optimization Strategies Evaluation – Acute Heart Failure (ROSE-AHF) trial, 283 patients with baseline and 72-hour urine tubular injury biomarkers were analyzed [28]. There was no correlation between change in tubular injury biomarkers and metrics of diuresis and decongestion. Changes in renal filtration markers, serum creatinine, and cystatin C during aggressive diuresis were not associated with changes in markers of renal tubular injury, KIM-1, NGAL, and NAG. Thus, transient increases in serum creatinine most likely reflect temporary changes in renal filtration rather than acute kidney injury [28]. Other investigations have similarly found a lack of association between serum and urinary NGAL and subsequent WRF defined by rising serum creatinine [29,30].

In contrast, in the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial, intensive volume removal resulted in worsening creatinine in about half of the patients, and was associated with a rise in tubular injury biomarkers [31]. Decongestion and renal functional recovery at 60 days, however, were superior in patients with increased tubular injury markers, suggesting the primary importance of adequate decongestion over transient changes in renal function during therapy.

The importance of mechanism of WRF as reflected by change is systemic blood pressure is discussed separately. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Reduced systemic blood pressure'.)

Blood urea nitrogen — An elevation in blood urea nitrogen (BUN) or blood urea is also associated with increased mortality in patients with HF [18,32-34], an effect that may be independent of the serum creatinine and GFR [32,33]. A probable contributing factor is that a disproportionate increase in BUN is often seen with a reduction in renal perfusion (ie, prerenal azotemia). (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology".)

Other prognostic indicators — Microalbuminuria is associated with increased event rates among ambulatory patients with HF with reduced ejection fraction [35]. In patients with advanced HF, baseline proteinuria prior to surgery has similarly been associated with an increased risk of requiring renal replacement therapy, as well as increased mortality following LVAD implantation [36,37]. Baseline proteinuria added increment risk of poor outcome independent of a high versus low baseline estimated GFR.

However, modest increases in urine albumin-to-creatinine ratio (UACR) observed shortly after initiating angiotensin receptor-neprilysin inhibitor therapy is not associated with adverse events. It is suspected that that modest increase in UACR associated with sacubitril/valsartan use reflects an acute intrarenal hemodynamic effect, likely due to the actions of natriuretic peptides [38].

Hypochloremia has also been recognized to independently predict adverse outcomes in HF patients [39].

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 "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Definition and classification' 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 [11]. 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 [40].

●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 (30 to 59 mL/min) [41,42]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.)

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".)

A post hoc analysis compared the decongestive efficacy of urine-output guided diuretic adjustment with standard therapy for the management of cardiorenal dysfunction in acute decompensated HF [43]. Patient data from subjects randomized to the stepwise pharmacologic care algorithm in the CARRESS-HF trial and those who developed worsening renal function in the DOSE-AHF and ROSE-AHFs trials were included. Compared with standard therapy, the stepwise pharmacologic care algorithm resulted in greater weight change and more net fluid loss after 24 hours with slight improvement in renal function.

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 [44]. (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 dilation 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 [45]. 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 [HR] 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 [46]. Despite this association, every 5 percent increase in in-hospital hematocrit change was associated with a decreased risk of all-cause mortality (HR 0.81, 95% CI 0.70-0.95).

Another analysis from the EVEREST trial evaluated the association between eGFR, markers of volume overload, and changes in hemoconcentration [47]. While a decline in eGFR was associated with high risk of both death and the composite outcome, this did not hold true if there was evidence of decongestion (defined as a decline in B-type natriuretic peptide [BNP], N-terminal pro-BNP, or weight, or an increase in hematocrit, albumin, or total protein). Thus, worsening eGFR was not associated with a higher risk of adverse outcomes if markers of decongestion were improving.

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 with no hemoconcentration [48]. 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 [49]. 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".)

Renin-angiotensin system antagonists

General effects — Angiotensin inhibition with an angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor-neprilysin inhibitor (ARNI), or an angiotensin II receptor blocker (ARB) is a standard part of the therapy of HF with reduced ejection fraction, being associated with symptomatic improvement, reduced hospitalization for HF, and enhanced survival. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.)

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. Additionally, there is a dose effect. Compared with low-dose ARB therapy in chronic HF, high-dose losartan is associated with sustained reductions in eGFR. Despite this effect, high-dose losartan is associated with improved long-term clinical outcomes [25]. The supportive data and management are presented separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Sacubitril-valsartan, ACE inhibitor, or ARB'.)

An analysis of the SOLVD trials showed that chronic eGFR decline over median three-year follow-up was not significantly different between the enalapril and placebo arms [50]. These findings may encourage clinicians that ACE inhibitors will not only promote survival but also have no detrimental, albeit also no beneficial, longer-term effect on kidney function among patients with HFrEF.

Determining a threshold of eGFR decline that can still be tolerated after initiating ACE inhibitor therapy among patients with HFrEF remains a challenging question. An analysis from the SOLVD trials incorporated assumptions regarding the varying degrees of hemodynamic medication-related decline and found that in most models, up to a 15 percent eGFR decline after enalapril initiation was still associated with significant mortality benefit, and up to 40 percent eGFR decline with enalapril was still associated with significant protection against hospitalizations for heart failure [51]. These results give reassurance to clinicians that, at least among stable HFrEF outpatients without advanced chronic kidney disease (CKD; patients with creatinine >2.5 mg/dL were excluded), there should be compelling reason beyond a moderate eGFR decline to withdraw this beneficial class of medications.

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 CKD as well as cohort studies have demonstrated that the beneficial effect of RAAS antagonism on clinical outcomes is not mitigated by concomitant CKD [23,52-54]. 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 [23,24,52,54-56]. 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 [49].

ARNI — An analysis of data from the PARADIGM-HF trial found that a decrease in eGFR during follow-up was less with ARNI therapy compared with treatment with an ACE inhibitor, despite a greater increase in the urine albumin-to-creatinine ratio (UACR) in ARNI-treated patients [35]. Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in eGFR; eGFR decreased by 10.2 mL/min/1.73m² (95% CI 12.1-8.3 mL/min/1.73m²) in patients assigned to enalapril and by 7.8 mL/min/1.73m² (95% CI 9.6-9.6 mL/min/1.73m²) in those assigned to sacubitril/valsartan between screening and end of follow-up [35]. The clinical benefit (on cardiovascular death and HF hospitalization) of sacubitril/valsartan compared with enalapril was consistent in patients with and without CKD and across stages of CKD, including stage 3B.

In a CKD population with baseline mean eGFR of 34 mL/min/17.3 m², sacubitril-valsartan was well tolerated, with similar rates of adverse events when compared with irbesartan [57]. Given the prevalence of concomitant CKD among patients with HF, these data provide some reassurance regarding tolerability of ARNI therapy in this high-risk population.

The indications for ARNI therapy in patients with HFrEF and HFpEF are discussed elsewhere. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy' and "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Secondary therapies'.)

Sodium-glucose co-transporter 2 inhibitors — In patients with HFrEF, but not in patients with HFpEF, sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of cardiovascular and kidney outcomes:

●In a meta-analysis of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and Reduced Ejection Fraction (EMPEROR-Reduced) and Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction (DAPA-HF) trials, the combined renal endpoint was reduced among patients randomized to SGLT2 inhibitor therapy compared with placebo (HR 0.62, 95% CI 0.43-0.010; p = 0.013) [58].

●In another meta-analysis comprised of 14,113 patients with HFrEF who were enrolled among seven trials, SGLT2 inhibitor treatment was associated with a lower incidence of a significant decrease in renal function when compared with placebo [59].

●In patients with HFpEF, treatment with empagliflozin was not found to improve renal outcomes [60].

The indications for SGLT2 inhibitor treatment are discussed elsewhere. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Sodium-glucose co-transporter 2 inhibitors' and "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Sodium-glucose co-transporter 2 inhibitors'.)

Vasodilators — Intravenous vasodilators used in the treatment of acute decompensated HF include nitroglycerin and nitroprusside. (See "Treatment of acute decompensated heart failure: Specific therapies", section on 'Vasodilator 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) [61]. 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.

Inotropic drugs — Intravenous administration of inotropic (calcitropic) drugs, such as dobutamine, dopamine, and milrinone, has a role in the treatment of cardiogenic shock in a subset of 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. The supporting data and management are discussed in detail elsewhere. (See "Inotropic agents in heart failure with reduced ejection fraction", section on 'Summary and recommendations' and "Treatment of acute decompensated heart failure in acute coronary syndromes" and "Treatment of acute decompensated heart failure: Specific therapies", section on 'Inotropic agents' and "Prognosis and treatment of cardiogenic shock complicating acute myocardial infarction", section on 'Vasopressors and inotropes'.)

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 [62,63]. Dopamine increased renal blood flow at doses of 2 to 10 mcg/kg/min in such patients [62,64]. This effect appears to be due to dilation of both large conductance and small resistance renal blood vessels [64]. 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) [65].

•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 with placebo (n = 119) among patients hospitalized with HF and concomitant renal disease [66]. 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 "Management of refractory heart failure with reduced ejection fraction", section on 'Ultrafiltration'.)

Three randomized trials (UNLOAD, RAPID-CHF, and CARESS-HF) compared ultrafiltration with diuretic therapy in patients with acute decompensated HF [67-69]. The mean baseline serum creatinine levels were 1.5, 1.7, and 2.0 mg/dL (133, 150, and 177 micromol/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 with 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 [69]. 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 "Management of refractory heart failure with reduced ejection fraction", 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 acute decompensated HF or as an effective therapy for CRS. The 2013 American Heart Association/American College of Cardiology guidelines note that ultrafiltration is reasonable for patients with refractory congestion not responding to medical therapy [49].

Vasopressin receptor antagonists — 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 [70]. (See "Predictors of survival in heart failure with reduced ejection fraction", 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. Tolvaptan is approved only for the treatment of hyponatremia in patients with HF. (See "Hyponatremia in patients with heart failure", section on 'Vasopressin receptor antagonists'.)

The effects of tolvaptan therapy on clinical outcomes in patients with HF were evaluated in the following randomized trials:

●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 compared with placebo [71]. 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).

●In a study of 250 patients with acute HF selected for greater potential benefit from vasopressin receptor inhibition based on evidence of CKD, hyponatremia, or diuretic resistance, tolvaptan administration was not associated with greater early improvement in dyspnea compared with placebo [72]. However, the tolvaptan group showed greater early and sustained weight loss, associated with progressively greater improvement in dyspnea scores, reaching a maximum at three days.

●A separate study of 257 patients with acute HF randomized within 24 hours of presentation demonstrated similar findings whereby tolvaptan administration did not result in a higher early response rate (defined as greater dyspnea relief without the need for rescue therapy or death) despite evidence of greater weight loss and a trend toward greater dyspnea scores over three days [73].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults".)

SUMMARY

●Reduced GFR and prognosis – 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.)

●Change in GFR during HF therapy – A fall in GFR during treatment of HF has often been associated with increased mortality in clinical studies in which the risk of mortality 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 glomerular filtration rate during therapy for heart failure' above.)

●Management – 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.)

•Diuretics – 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.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marvin Konstam, MD, who contributed to earlier versions of this topic review.