Cardiorenal Syndrome and the Role of Ultrafiltration in Heart Failure

Acute decompensated heart failure (ADHF) with associated volume overload is the most common cause of hospitalization in heart failure patients. When accompanied by worsening renal function, it is described as a cardiorenal syndrome and is a therapeutic challenge. Initial treatment commonly encompasses intravenous diuretics however, suboptimal results and high rehospitalization rates have led experts to search for alternative therapeutic strategies. Recent technological advances in extracorporeal therapies have made ultrafiltration a feasible option for treatment of hypervolemia in ADHF. Recent large randomized trials have compared the efficacy and safety of ultrafiltration with diuretics. Additionally, the benefits of novel pharmacologic approaches, including combining hypertonic saline with diuretics, have recently been studied. The aim of this review is to discuss the developments in both pharmacologic and extracorporeal methods for treating hypervolemia in ADHF and acute cardiorenal syndrome.     

Pharmacologic management of the cardiorenal syndrome in heart failure

Cardiorenal syndrome describes the impairment of renal function and associated diuretic resistance in patients with heart failure and clinically manifest volume overload. The pathophysiology of this syndrome is poorly understood, but appears to be caused by impairment of tubuloglomerular feedback, neurohormonal activation, and other factors and therapies used in the management of heart failure. Early diagnosis of the cardiorenal syndrome by way of markers of renal injury and function is critical for timely interventions that may attenuate progression. Many novel therapies have been evaluated in the cardiorenal syndrome setting, including agents that block key local factors (eg, adenosine A_I receptor antagonists), improve diuresis, aquaresis, and natriuresis, and augment natural vasodilator mechanisms to improve renal perfusion. Furthermore, device-based approaches such as ultrafiltration may also play an important therapeutic role.     

The cardiorenal syndrome: lessons from the ADHERE database and treatment options

Significant renal dysfunction is common in patients hospitalized for heart failure and carries a grim prognosis. Patients with heart failure who have or develop renal dysfunction while being treated for heart failure are said to have the cardiorenal syndrome. The Acute Decompensated Heart Failure National Registry (ADHERE) database, which enrolled nonselected patients admitted to the hospital for acute decompensated heart failure (ADHF), was used to determine the causes for this renal dysfunction and whether treatment can optimize outcomes. Results show that the average patient admitted for ADHF is older than those typically enrolled in clinical trials and has at least moderate kidney damage, with significantly impaired glomerular filtration rates. Renal dysfunction in patients with heart failure is complex and often multifactorial in origin, but the syndrome may be reversible in some patients. Reduction of angiotensin II levels with angiotensin-converting enzyme (ACE) inhibitors may prevent glomerular hyperfiltration and ultimately preserve renal function; however, patients who are volume-depleted may be especially sensitive to ACE inhibitor-induced efferent arteriolar dilation, so ACE inhibitor therapy in patients with renal dysfunction should be initiated when the patient is volume replete. In conclusion, impaired renal function is common in heart failure patients and may be a key cause of the cascade involving fluid retention, decompensation, and eventual hospital admission. Future pharmacologic research should focus on therapies aimed at maintaining or improving renal function in heart failure patients to reduce the high mortality associated with the cardiorenal syndrome.     

The Cardiorenal Syndrome: Lessons from the ADHERE Database and Treatment Options

Significant renal dysfunction is common in patients hospitalized for heart failure and carries a grim prognosis. Patients with heart failure who have or develop renal dysfunction while being treated for heart failure are said to have the cardiorenal syndrome. The Acute Decompensated Heart Failure National Registry (ADHERE®) database, which enrolled nonselected patients admitted to the hospital for acute decompensated heart failure (ADHF), was used to determine the causes for this renal dysfunction and whether treatment can optimize outcomes. Results show that the average patient admitted for ADHF is older than those typically enrolled in clinical trials and has at least moderate kidney damage, with significantly impaired glomerular filtration rates. Renal dysfunction in patients with heart failure is complex and often multifactorial in origin, but the syndrome may be reversible in some patients. Reduction of angiotensin II levels with angiotensin-converting enzyme (ACE) inhibitors may prevent glomerular hyperfiltration and ultimately preserve renal function; however, patients who are volume-depleted may be especially sensitive to ACE inhibitor–induced efferent arteriolar dilation, so ACE inhibitor therapy in patients with renal dysfunction should be initiated when the patient is volume replete. In conclusion, impaired renal function is common in heart failure patients and may be a key cause of the cascade involving fluid retention, decompensation, and eventual hospital admission. Future pharmacologic research should focus on therapies aimed at maintaining or improving renal function in heart failure patients to reduce the high mortality associated with the cardiorenal syndrome.Supported by an unrestricted educational grant from Scios Inc.     

Managing acute renal failure in patients with acute decompensated heart failure: The cardiorenal syndrome

In patients with acute decompensated heart failure, worsening renal function during conventional decongestive therapy (cardiorenal syndrome) affects prognosis and the initiation of therapies with known benefit in chronic heart failure. Potential strategies for decongestion in patients who develop cardiorenal syndrome include invasive hemodynamic monitoring to guide therapy, use of continuous diuretic infusions, ultrafiltration, or novel therapy with adenosine or vasopressin receptor antagonists. Clinical trials by the National Heart, Lung, and Blood Institute’s Heart Failure Network are currently underway to validate such therapies in patients with acute decompensated heart failure with worsening renal function and to establish novel biomarkers for the early identification of patients who develop cardiorenal syndrome.     

Can we prevent or treat renal dysfunction in acute heart failure?

Most patients with heart failure (HF) already have or develop renal dysfunction; this might contribute to their poor outcome. Current treatment for HF can also contribute to worsen renal function. High furosemide doses are traditionally associated with worsening renal function (WRF), but patients with fluid overload may benefit of aggressive fluid removal. Unfortunately, promising therapies like vasopressin antagonists and adenosine antagonists have not been demonstrated to improve outcomes. Likewise, correction of low renal blood flow through dopamine, inotropic agents, or vasodilators does not seem to be associated with a clear benefit. However, transient WRF associated with acute HF treatment may not necessarily portend a poor prognosis. In this review, we focus on the strategies to detect renal dysfunction in acute HF, the underlying pathophysiological mechanisms, and the potential treatments.     

The Effects of Adenosine A1 Receptor Antagonism in Patients With Acute Decompensated Heart Failure and Worsening Renal Function: The REACH UP Study

BackgroundWorsening renal function (WRF) portends a poor prognosis, and recent deterioration in creatinine might identify patients with elevated intrarenal adenosine in whom adenosine A₁ antagonism may improve renal hemodynamics and function. The purpose of this pilot study was to assess whether rolofylline, an adenosine A₁ antagonist (A₁RA), would facilitate diuresis while maintaining renal function in patients with acutely decompensated heart failure (ADHF) and recent WRF.Methods and ResultsSeventy-six patients with ADHF, volume overload, and recent renal deterioration received rolofylline (30 mg, n = 36) or placebo (n = 40) for 3 days. Rolofylline did not demonstrate a beneficial effect on the primary end points of worsening heart failure or renal function after admission or death or readmission within 30 days. Similar proportions of patients receiving rolofylline (33%) and placebo (30%) were treatment failures within 30 days. However, persistent renal impairment (through Day 14) tended to be less common with rolofylline (6%) than placebo (18%). At Day 14, 11 patients receiving placebo and 13 patients receiving rolofylline had a decrease in creatinine ≥0.3 mg/dL. There were fewer heart failure readmissions with rolofylline (n = 2) than with placebo (n = 7) through Day 60.ConclusionsThe Placebo-Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (ie, REACH UP) study did not demonstrate any clear benefit of rolofylline in patients with ADHF and worsening renal function. However, beneficial trends raise the possibility that A₁RAs might prevent renal dysfunction in these high risk patients. To test this hypothesis, further larger studies need to evaluate the effects of adenosine A₁ antagonists in patients with progressive renal dysfunction in the face of active heart failure therapy.     

Changes in Renal Function in Congestive Heart Failure

Both cardiovascular and renal diseases are common and frequently coexist in the same patient. Indeed, renal dysfunction has been shown to be a more powerful independent predictor of poor outcomes in heart failure (HF) than left ventricular ejection fraction or functional class. Furthermore, acute kidney injury is a frequent therapeutic concern in heart failure. Consequently, there has been much interest in developing new renoprotective treatments and novel biomarkers to monitor renal function. Additionally, given the crucial cardiorenal interaction and interdependence, the concept of a cardiorenal syndrome with five different subtypes has been advanced to better categorize patients and facilitate research.     

The progressive cardiorenal syndrome in heart failure: Mechanisms and therapeutic insights

The cardiorenal syndrome refers to the interdependence of cardiocirculatory aberrations and renal dysfunction that signify a worsening in heart failure outcome. Biochemically, it appears covertly as an abnormality in renal function and when progressive, is manifested by symptom exacerbation and worsening renal impairment during application of therapy to ameliorate such symptoms. The pathways leading to these distinct impairments involve not only hemodynamic deterioration but also neurohormonal, inflammatory, and intrinsic renal mechanisms that produce this syndrome. Traditional therapy with diuretics typically worsens the cardiorenal syndrome, and vasodilator or inotropic therapy has not been shown to help either. New therapeutic avenues involving vasopressin antagonists, adenosine antagonists, and ultrafiltration are being investigated. In the absence of underlying primary renal parenchymal disease, mechanical ventricular assist devices or cardiac transplantation achieve reversal of the progressive cardiorenal syndrome, indicating the sentinel role of interrupting the cardiocirculatory aberrations that accompany this clinical manifestation.     

Dialyse- und Ultrafiltrationsverfahren bei kardiorenalem Syndrom

Renal failure is common in patients with severe heart failure and this complex pathophysiological interaction is classified as cardiorenal syndrome. In these patients hydropic decompensation is the main reason for hospitalization. In patients with refractory heart failure characterized by diuretic resistance and congestion due to volume overload, ultrafiltration has to be considered. In cases of acute decompensated heart failure with deterioration of renal function, extracorporeal ultrafiltration is the preferred treatment modality. On the other hand, patients suffering from chronic decompensated heart failure, particularly patients with ascites, will profit from the treatment-specific advantages of peritoneal ultrafiltration. A prerequisite for an optimized care of patients with cardiorenal syndrome is the close collaboration between intensive care physicians, cardiologists and nephrologists.     

Cardiorenal rescue study in acute decompensated heart failure: rationale and design of CARRESS-HF, for the Heart Failure Clinical Research Network

BackgroundWorsening renal function is common among patients hospitalized for acute decompensated heart failure (ADHF). When this occurs, subsequent management decisions often pit the desire for effective decongestion against concerns about further worsening renal function. There are no evidence-based treatments or guidelines to assist in these difficult management decisions. Ultrafiltration is a potentially attractive alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening renal function.Methods and ResultsThe National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network designed a clinical trial to determine if ultrafiltration results in improved renal function and relief of congestion compared with stepped pharmacologic care when assessed 96 hours after randomization in patients with ADHF and cardiorenal syndrome. Enrollment began in June 2008. This paper describes the rationale and design of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF).ConclusionsTreating the signs and symptoms of congestion in ADHF is often complicated by worsening renal function. CARRESS-HF compares treatment strategies (ultrafiltration vs stepped pharmacologic care) for the management of worsening renal function in patients with ADHF. The results of the CARRESS-HF trial are expected to provide information and evidence as to the most appropriate approaches for treating this challenging patient population.     

The cardiorenal syndrome in heart failure: cardiac? renal? syndrome?

There has been increasing interest on the so-called cardiorenal syndrome (CRS), defined as a complex pathophysiological disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other. In this review, we contend that there is lack of evidence warranting the adoption of a specific clinical construct such as the CRS within the heart failure (HF) syndrome by demonstrating that: (a) the approaches and tools regarding the definition of kidney involvement in HF are suboptimal; (b) development of renal failure in HF is often confounded by age, hypertension, and diabetes; (c) worsening of renal function (WRF) in HF may be largely independent of alterations in cardiac function; (d) the bidirectional association between HF and renal failure is not unique and represents one of the several such associations encountered in HF; and (e) inflammation is a common denominator for HF and associated noncardiac morbidities. Based on these arguments, we believe that dissecting one of the multiple bidirectional associations in HF and constructing the so-called cardiorenal syndrome is not justified pathophysiologically. Fully understanding of all morbid associations and not only the cardiorenal is of great significance for the clinician who is caring for the patient with HF.     

The cardiorenal connection in heart failure

Heart failure (HF) and renal dysfunction frequently coexist; this combination is commonly referred to as the “cardiorenal syndrome.” The intersection of cardiac and renal dysfunction has important therapeutic and prognostic implications in patients with HF. Approximately 60% to 80% of patients hospitalized for HF have at least stage III renal dysfunction; this comorbid renal insufficiency (RI) is associated with significantly increased morbidity and mortality risk. Comorbid RI can result from intrinsic renal disease and inadequate renal perfusion. HF and RI stimulate neurohormonal activation, increasing preload and afterload and reducing cardiac output. Inotropic agents augment this neurohormonal activation. Managing cardiorenal patients requires successful negotiation of the delicate balance between adequate volume reduction and adequate renal function. There is a compelling need for additional studies in this patient population.     

Evolving Treatment Strategies for Management of Cardiorenal Syndrome

The treatment of acute decompensated heart failure in the presence of progressive renal dysfunction is a commonly encountered dilemma in clinical practice. Also known as cardiorenal syndrome, this complex disease state has forced researchers and clinicians to develop new treatment strategies to relieve the symptomatic congestion of heart failure while preserving renal function. Loop diuretics remain the standard of pharmacologic treatment of acute heart failure, but their effects on renal function have been called into question. The DOSE trial set out to determine optimal diuretic dosing strategies but no clear regimen was firmly established. Initial studies with vasopressin antagonists showed promise in their ability to increase urine output, provide short-term symptom relief, and correct hyponatremia while maintaining renal function. Unfortunately, the EVEREST trial did not demonstrate any benefit on long-term clinical outcomes. Adenosine antagonists also appeared to be an emerging therapeutic option, but the recently completed PROTECT trial failed to establish their role in the treatment of cardiorenal syndrome. Both nesiritide and low-dose dopamine have endured years of trials with mixed results. Most recently, findings from the ASCEND-HF trial showed that nesiritide was safe with no adverse effects on renal function or mortality and was associated with a modest improvement in dyspnea. The ongoing ROSE study, sponsored by the National Institutes of Health Heart Failure Research Network, will attempt to confirm the safety and efficacy profiles of low-dose nesiritide and dopamine, as well as clarify their roles within acute heart failure management. Despite its inherent complexities, ultrafiltration has demonstrated potential benefit in several clinical outcomes compared to traditional pharmacotherapy. The results of the CARRESS-HF trial will reveal how the use of ultrafiltration specifically applies to patients with cardiorenal syndrome. The most exciting aspects about our evolving understanding of the cardiorenal system are the innovative treatments that have emerged as a result. The creation of chimeric natriuretic peptides, targeted intra-renal pharmacotherapy, the novel use of phosphodiesterase inhibitors, and combination treatment strategies demonstrate that despite our varied success in treating cardiorenal syndrome in the past, there are highly encouraging translational therapies rapidly developing in the pipeline.     

Clinical benefit of tolvaptan in patients with acute decompensated heart failure and chronic kidney disease

Tolvaptan, a vasopressin type 2 receptor antagonist, has an aquaretic effect without affecting renal function. The effects of long-term tolvaptan administration in heart failure patients with renal dysfunction have not been clarified. Here, we assessed the clinical benefit of tolvaptan during a 6-month follow-up in acute decompensated heart failure (ADHF) patients with severe chronic kidney disease (CKD; estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m²). We compared 33 patients with ADHF and severe CKD who were administered tolvaptan in addition to loop diuretics (TLV group), with 36 patients with ADHF and severe CKD who were administered high-dose loop diuretics (≥40 mg) alone (LD group). Alterations in serum creatinine and eGFR levels from the time of hospital discharge to 6-month follow-up were significantly different between the groups, with those in the TLV group being more favorable. Furthermore, Kaplan–Meier analysis revealed that rehospitalization for heart failure (HF) was significantly lower in the TLV group compared with the LD group. In ADHF patients with severe CKD, tolvaptan use for 6 months reduced worsening of renal function and rehospitalization rates for HF when compared with conventional diuretic therapy. In conclusion, tolvaptan could be a safe and effective agent for long-term management of HF and CKD.     

Targeting Hyponatremia and Hemodynamics in Acute Decompensated Heart Failure: Is There a Role for Vasopressin Antagonists?

Current treatment of acute decompensated heart failure (ADHF) has not reduced the significant morbidity or mortality associated with this disease, and has promoted drug development aimed at neurohormonal targets. Hypervolemic hyponatremia, which is linked to the nonosmotic release of arginine vasopressin, is associated with a poor prognosis in patients with heart failure (HF). Vasopressin acts on V₂ and V_1a receptors to cause water retention and vasoconstriction, respectively. Clinical trials have demonstrated that vasopressin receptor antagonists (VRAs) are effective in treating hypervolemic hyponatremia in ADHF without a negative impact on renal function. The small hemodynamic benefit seen with VRA use appeared to result from V₂-receptor antagonist–induced increase in urine output rather than from a vasodilatory drug effect. VRA use in ADHF trials was associated with minimal symptomatic improvement and no impact on morbidity or mortality. At present, clinical trial evidence does not support the routine use of VRAs in ADHF. Given the favorable renal profile of VRAs, studies on the possible benefit of VRAs in ADHF patients with renal insufficiency and diuretic resistance appear warranted.     

Volume control in treatment-resistant congestive heart failure: role for peritoneal dialysis

Chronic congestive heart failure (HF) has a rising prevalence and increasing impact on health care systems. Current treatment consists of diuretics, renin–angiotensin–aldosterone system blockers, and restriction of salt and fluids. This strategy is often hampered by a drop in effective circulating volume and hence renal perfusion and function, triggering harmful counter regulatory mechanisms. Slow ultrafiltration by peritoneal dialysis (PD) might be an effective treatment strategy to relieve fluid overload without compromising cardiac output and thereby renal function. In this review, we discuss the (patho)physiological mechanisms of the cardiorenal interaction and the current literature on PD strategies in congestive HF.     

Novel strategies: challenge loop diuretics and sodium management in heart failure--Part I

This is the first of a 2-part series. This article reviews the relationships among diuretics, neurohormonal activation, renal function, fluid and Na management, the cardiorenal syndrome, and heart failure. Part II will describe novel therapies based on these relationships, focusing particularly on vasopressin antagonists and treatment using hypertonic saline solution with high-dose loop diuretics. Heart failure (HF) is a complex hemodynamic disorder characterized by chronic and progressive pump failure and fluid accumulation. Diuretics are a vital component of symptomatic management, and enhancing diuretic response in the setting of diuretic resistance is therefore pivotal. In HF patients treated with diuretics, compensatory pathophysiologic mechanisms to maintain vascular resistance, such as nonosmotic stimulation of vasopressin secretion and activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, promote renal Na and water reabsorption. Thus, there remains a need to develop novel therapies for HF patients who are refractory to conventional medical treatment. The conflicting results of diuretic treatments in HF and the importance of Na management in the context of the cardiorenal syndrome and neurohormonal activation have suggested novel and counterintuitive strategies, focusing primarily on the use of vasopressin antagonists and hypertonic saline solution with high doses of loop diuretics and neurohormonal interference. The authors review the current evidence for these therapies and suggest hypothetical bases for their efficacy.     

Acute Heart Failure: Acute Cardiorenal Syndrome and Role of Aggressive Decongestion

Congestion and acute renal dysfunction are at the center of acute heart failure (HF) syndromes. Acute cardiorenal syndrome, which refers to worsening of renal function in a patient with acute HF syndrome, is partly related to venous congestion and high renal afterload. Aggressive decongestion improves renal and myocardial flow and ventricular loading conditions, potentially resulting in reduced HF progression, rehospitalization, and mortality. High‐dose diuretic therapy remains the mainstay therapy. Ultrafiltration and inotropic therapy are useful in the subgroup of patients with a low‐output state and diuretic resistance.