Merhaut, Shawn RN, MSN, ACNP, BC; Trupp, Robin J. RN, PhD, ACNP, BC
Section Editor(s): Martin, Rhonda K. Symposium Editor
Left ventricular dysfunction and renal dysfunction are common chronic conditions that frequently coexist in the same individual. Importantly, both are associated with significant morbidity and mortality.1,2 Because both the heart and the kidneys are highly vascular organs that work in tandem to regulate blood pressure, vascular tone, tissue perfusion, and intravascular volume, disorders in one generally lead to dysfunction in the other. This bidirectional interaction serves as the pathophysiological basis for cardiorenal syndrome (CRS).
The human body is 60% water by weight, and one-third of that volume is located in the extracellular space. The kidneys maintain relatively constant serum sodium levels across a wide range of sodium ingestion in the setting of normal blood pressure, cardiac output, neurohormonal (NH) status, and renal tubular function. However, heart failure (HF) produces alterations in all of these parameters, making sodium homeostasis, and ultimately volume management, a problem.
Substantial numbers of patients with HF develop some degree of renal dysfunction, primarily from 2 sometimes overlapping pathophysiologies. Estimates are that 20% to 40% of patients hospitalized for decompensated HF, typically manifested by volume overload and symptoms of congestion, have underlying renal dysfunction.3 Intrinsic renal disease, caused by comorbidities commonly seen in HF such as hypertension or diabetes, results from damage to the nephron itself with loss of renal filtering capacity.
Functional, or dynamic, renal disease is associated with low cardiac output states, such as HF, where renal blood flow is decreased. The kidneys' ability to excrete sodium is impaired and may be exacerbated by diuretics. When functional renal disease is prolonged, intrinsic disease may develop as well. Unfortunately, the mainstay of treatment of excess volume, aimed at alleviating the congestion, is diuretics, which are known to worsen renal function.
Until recently, CRS has been neither well defined nor well understood, making its diagnosis and treatment challenging for clinicians. On the basis of the recent Acute Dialysis Quality Initiative consensus conference recommendations, this article discusses the pathophysiology of CRS, therapeutic interventions targeting CRS, and novel therapies for CRS.1
Both left ventricular dysfunction, or HF, and renal dysfunction are worldwide public health problems receiving increased attention due to associated morbidity, mortality, and health care expenditures. Generally speaking, the impact of HF on kidney function is appreciated, whereas the impact of renal insufficiency on cardiac performance is less respected.4 However, in both scenarios, complex NH activation of the primary organ exerts direct and indirect effects on the secondary organ, creating a vicious cycle of bidirectional impairment that is depicted in Figure 1.1
Figure 1:. Bidirecti...Image Tools
Neurohormonal stimulation plays a critical role in HF and is a prominent factor in renal dysfunction as well. Preservation of the integrity of the arterial circulation and maintenance of blood flow to the vital organs are initiated by the renin-angiotensin-aldosterone system and the sympathetic nervous system. These 2 systems are coactivated and coregulated in both health and disease. Their effects in HF include the following: (1) increased ventricular preload (per the Frank-Starling mechanism) via ventricular dilation, peripheral vasoconstriction, and elevated filling pressures; (2) peripheral arterial vasoconstriction to maintain vital organ perfusion; (3) renal sodium and water retention to increase ventricular preload; and (4) sympathetic nervous system stimulation to increase heart rate and cardiac output via catecholamine release. Other important NH mechanisms in HF involve the arginine vasopressin and endothelin levels. Although counterregulatory mechanisms, such as natriuretic peptides, exist to offset the vasoconstrictor systems, they may become overwhelmed, leading to episodes of excess volume or worsening HF.
Chronic renal insufficiency also produces NH stimulation. Altered renal perfusion stimulates the release of catecholamines, angiotensin, and aldosterone.5 As in HF, this NH response is initially compensatory, but if left untreated, it leads to progressive and irreversible kidney injury. Moreover, 25% to 40% of patients hospitalized for decompensated HF experience deteriorations in renal function, with negative outcomes for morbidity, mortality, recidivism, and length of stay.1
Moving from a simplistic view of CRS as kidney dysfunction resulting from reduced cardiac output and subsequent reduced renal perfusion, the Acute Dialysis Quality Initiative panel used a broader definition: “disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other.”1(p704) To further define CRS, the panel members identified 5 specific subtypes (Figure 2), which are as follows:
Figure 2:. Subtypes ...Image Tools
Type 1. Acute cardiorenal syndrome, defined as the “acute worsening of heart function leading to kidney injury and/or dysfunction.”
Type 2. Chronic cardiorenal syndrome, defined as “chronic abnormalities in heart function leading to kidney injury or dysfunction.”
Type 3. Acute renocardiac syndrome, defined as “acute worsening of kidney function leading to heart injury and/or dysfunction.”
Type 4. Chronic renocardiac syndrome, defined as “chronic kidney disease (CKD) leading to heart injury, disease, and/or dysfunction.”
Type 5. Secondary cardiorenal syndromes, defined as “systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney.”1(p704)
These categories are not fixed, and patients may move between subtypes during the course of their disease.
Acute Cardiorenal Syndrome (Type 1)
Whether from decompensated HF, acute coronary syndrome, or cardiogenic shock, in CRS type 1 an abrupt change in myocardial performance produces secondary effects on the kidneys, as evidenced by acute kidney injury (AKI) and a rapid loss of renal function. Among those with HF, nonadherence to dietary or medication regimens is the most common precipitant for decompensation,6 resulting in significant hemodynamic alterations in cardiac output and intracardiac filling pressures as well as peripheral vasoconstriction. In the setting of acute coronary syndrome or cardiogenic shock, the risk for CRS type I is high, despite the use of inotropes, vasopressors, or intra-aortic counterpulsation.7
A large body of evidence exists for this scenario, largely from pharmaceutical clinical trials or post hoc analyses of large databases.1 Most studies have found that renal function begins to decline shortly after presentation to the hospital, implying that this impairment is related to the acute hemodynamic changes of HF. Importantly, renal dysfunction is associated with greater all-cause and cardiovascular mortality, longer lengths of stay, higher recidivism, and higher health care costs.1 In fact, the risk for poorer outcomes from worsening renal function is consistent, regardless of whether the decline is transient or sustained or the amount of change in serum creatinine.8,9
Chronic Cardiorenal Syndrome (Type 2)
As previously stated, chronic heart disease and CKD frequently coexist, often making it difficult to discern which came first. In addition, retrospective review of large databases does not allow a distinction to be made between CRS type 2 and type 4.1 However, it is fair to surmise that long-standing HF leads to progressive kidney disease, possibly through episodes of AKI.7 Preexisting renal dysfunction is evident in 45% to 60% of patients with HF.1,8–13 Both hypertension and hypotension can precipitate this type of CRS, but unfortunately the “optimal” blood pressure in HF has not been identified.7 Moreover, added insults, from nonsteroidal anti-inflammatory agents or contrast media, may induce decompensation and worsening renal function in these vulnerable patients.
Acute Renocardiac Syndrome (Type 3)
CRS type 3 has only recently been identified, and consequently there is little evidence on specific treatment recommendations once this subtype occurs.1 Therefore, the prevention of CRS type 3 is the focus. An initial approach using a careful history of present illness, concentrating on the patient's medication history, is recommended to identify any potential iatrogenic etiologies for CRS. Potentially nephrotoxic agents, such as antibiotics (particularly aminoglycosides and sulfonamide), chemotherapeutic and immunosuppressant medications, and nonsteroidal anti-inflammatory agents, warrant immediate attention, with assessment of the risk-benefit for continuing the medication versus its substitution or cessation. The impact of medications commonly prescribed in cardiovascular disease (CVD)—such as diuretics, angiotensin-converting enzyme (ACE) inhibitors/ angiotensin receptor blockers (ARBs), and antihyperlipidemics—on renal function also must be considered both upon initiation and for long-term use of the therapy.
Chronic Renocardiac Syndrome (Type 4)
CRS type 4 is a common syndrome involving the progression of CKD, often because of diabetes mellitus or hypertension, with accelerated atherosclerosis, progressive left ventricular hypertrophy, and the development of diastolic and systolic dysfunction.1 Most evidence on CRS type 4 comes from observational studies evaluating cardiovascular event rates and outcomes in selected CKD populations.1,7 Mortality rates for CKD patients with CVD are 10 to 20 times higher than those for age- and sex-matched non-CKD populations.1 In fact, patients with CKD are more likely to die of CVD than to progress to dialysis,14 and a very strong association between coronary artery disease, HF, and sudden death has been established.15
Secondary Cardiorenal Syndromes (Type 5)
CRS type 5 occurs in the setting of severe systemic illness, either acute or chronic in nature, which induces both heart and renal dysfunction simultaneously. Examples of inciting systemic illness include diabetes mellitus, systemic lupus erythematous, amyloidosis, sarcoidosis, or sepsis.
Treatment strategies are directed at the specific subtype on presentation and/or at diagnosis. As previously stated, it is important to acknowledge that patients do not necessarily fall permanently within one subtype and may move between subclasses throughout the course of their illness. Paramount is the evaluation of volume status, as it determines the therapy and the subsequent evaluation of efficacy. Although it may appear that hypovolemia and symptomatic hypotension, indicative of low flow states, would be the main drivers of worsening renal function, evidence shows that these features may account for only a small subset of this population.9,10 Rather, hypertension (systolic blood pressure > 160 mm Hg) and hypervolemia are far more common and are stronger predictors for worsening renal function.9,11 Given the complexities of this disease state, managing patients with CRS frequently requires a multidisciplinary approach by cardiac, renal, and critical care practitioners.
Acute Cardiorenal Syndrome (Type 1)
A general and cautionary approach to the treatment of patients with CRS type 1 is to assume that AKI is a direct result of renal hypoperfusion until otherwise identified.2 Evaluation for evidence of low cardiac output and/or increased venous pressure leading to kidney congestion should be performed as part of the decision process upon initiating pharmacologic intervention.2 Although this cohort accounts for only a small percentage of patients, understanding the patient's hemodynamic and volume status will help tailor appropriate therapy and avoid iatrogenic worsening of renal function.
Loop diuretics and vasodilators (nitrates, nesiritide) are the mainstays of treatment.1 Despite a lack of randomized controlled trials supporting their safety and efficacy, loop diuretics continue to play a primary role in alleviating excess volume and symptoms of congestion.3 Diuretics should be used to achieve a gradual diuresis, which should be tailored on the basis of renal function, systolic blood pressure, and history of long-term use.3 A target fluid removal rate of 500 mL/h allows for refilling of the renal vascular beds and prevents overaggressive diuresis that further worsens renal function. In addition, it is important to realize that the use of loop diuretics can lead to significant deleterious effects including electrolyte imbalances, arrhythmias, hypotension, and NH activation.
Diuretic resistance has emerged as a significant barrier in the care of patients with CRS type 1. Concomitant HF and renal insufficiency cause a shift in the diuretic “dose-response curve,” resulting in escalating diuretic doses to produce a diuretic response or a decrease in diuretic responsiveness.3 To address this challenge, current guidelines advocate the use of higher doses of loop diuretics, the addition of a second diuretic that acts on the distal tubule, such as metolazone or a thiazide, or consideration of a continuous loop diuretic infusion strategy.3,16
However, results from the DOSE (Diuretic Optimization Strategies Evaluation in Acute Heart Failure) trial showed no statistically significant difference in symptom relief or change in renal function between furosemide administration strategies (intravenous administration of boluses every 12 hours or continuous infusion) or between dosing strategies (low intensity of 1 times the home oral dose or high intensity of 2.5 times the home oral dose).17 Currently, American College of Cardiology/American Heart Association guidelines support continuous infusion as a class I recommendation for those patients who are refractory to initial diuretic strategies.16
Vasodilators provide hemodynamic benefits by decreasing both preload and afterload, leading to improvements in stroke volume, blood pressure, and cardiac output.3 This class of medications is indicated as an adjunct to diuretic therapy for patients with evidence of volume overload in the presence of adequate blood pressure.11 Furthermore, the addition of nitrates to low-dose diuretics has shown to be increasingly more efficacious than high-dose diuretics alone.3 However, overzealous use of vasodilators can lead to hypotension and reflex sympathetic activation, precipitating further decline in renal function.3 Careful attention to hemodynamics and meticulous volume status are essential to prevent this from occurring.
Chronic Cardiorenal Syndrome (Type 2)
Treatment of patients with CRS type 2 is multifactorial and driven primarily by treatment of the underlying cardiac dysfunction. Despite the high prevalence of renal insufficiency in patients with HF, specific treatment recommendations are sparse, as preexisting renal insufficiency is typically an exclusion criterion in clinical trials in this population. However, opportunities do exist to prevent CRS type 2 from developing by optimally managing volume status via a low-sodium diet and the lowest dose of diuretics necessary to maintain hemodynamics and obviate symptoms.7,18 Therefore, the focus should be on providing evidence-based therapies, including appropriate pharmacologic and device interventions.1 Evidence-based and guideline-supported pharmacologic agents, such as ACE inhibitors, specific β-blockers, ARBs, and aldosterone antagonists, have been shown to significantly reduce mortality and morbidity in patients with HF.16 Hydralazine and nitrates are also viable options for patients intolerant to ACE inhibitors and ARBs.13 Appropriately identifying and treating patients with cardiac resynchronization therapy is also key in this population.16
Acute Renocardiac Syndrome (Type 3)
The main problem in many cases of CRS type 3 is congestion due to sodium and water retention. Therefore, prompt aggressive management of hypervolemia may mitigate the development of cardiac decompensation.7
CRS type 3 is also a common etiology in cardiac patients through contrast-induced nephropathy (CIN) and post-cardiac surgery AKI. Different upstream and periprocedural strategies, including the use of oral N-acetylcysteine (Mucomyst), sodium bicarbonate infusion, low- or iso-osmolar contrast agents, hemofiltration, or dialysis, to prevent CIN have been studied.19 Evidence from trials of these strategies, either alone or in combination, has yielded disappointing results. The use of isotonic fluids alone to avoid dehydration, or in combination with oral N-acetylcysteine, continues to be the most successful approach in preventing CIN.20
Acute kidney injury following cardiovascular surgery also remains problematic because of the massive fluid shifts and difficulties in balancing volume status that may occur before, during, and after surgery. Recently, the NAPA (Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery) trial evaluated the use of nesiritide in patients with left ventricular dysfunction undergoing coronary artery bypass grafting and cardiopulmonary bypass.21 Compared with placebo, patients treated with nesiritide demonstrated statistically significant attenuation of peak rises in serum creatinine, less impairment of glomerular filtration rate, and greater urine output. Shorter hospital stays and lower 180-day mortality rates were also noted. This study demonstrates a potential “renoprotective property” of nesiritide in this population.1
Bilateral renal artery stenosis or unilateral stenosis in patients with a solitary kidney can also precipitate CRS type 3.2 Chronic, accelerating, or malignant hypertension in this setting leads to perpetual activation of vasoconstriction, renin-angiotensin-aldosterone system, and sodium and water retention, resulting in subsequent worsening renal function and left ventricular diastolic dysfunction.2 In this subset of patients, renal revascularization should be considered.22
Chronic Renocardiac Syndrome (Type 4)
Treatment of patients with CRS type 4 involves attenuation of underlying primary chronic kidney disease, a multifactorial problem that is beyond the scope of this discussion. Focus should remain on general cardiovascular risk reduction, given the excessive cardiovascular risk in patients with CKD in combination with the staggering underuse of evidence-based pharmacologic therapies in this population. It has been found that less than 50% of patients with end-stage renal disease receive appropriate therapy with aspirin, β-blockers, and ACE inhibitors following acute myocardial infarction, despite known benefits.23
In addition, dosing of HF medications is an important issue in that worsening kidney function influences the prescription, dose escalation, and tolerability of ACE inhibitors/ARBs and aldosterone antagonists while also reducing diuretic efficacy. Sadly, both overdosing and underdosing HF medications are associated with worsened outcomes. No specific evidence-based guidelines exist that provide optimal renal filtration function equations and drug dosing.7 Additional focus in patients with CRS type 4 should be on preventing hypervolemia, possibly through early renal replacement support and correcting significant anemia.2
For patients undergoing dialysis, “cardioprotective” approaches can reduce hemodynamic fluctuations and achieve optimal volume status to minimize both the risks of ischemia and the development of diastolic and systolic dysfunction.7 An example may be to cool the dialysate, thereby reducing the degree of transient left ventricular dysfunction during the dialysis session.
Secondary Cardiorenal Syndromes (Type 5)
Research specific to the treatment of CRS type 5 is lacking, and to date, there are no positive studies demonstrating an appropriate treatment strategy to prevent or attenuate AKI in the critically ill patient.2 Treatment strategies are patient specific and mimic strategies for type 1 and type 3 CRS, depending on the clinical scenario. Supportive therapies, such as fluid resuscitation and inotropic agents when appropriate, are indicated to maintain adequate stroke volume and cardiac output. Continued evaluation and treatment of the underlying systemic illness, such as sepsis, amyloidosis, diabetes mellitus, sarcoidosis, and systemic lupus erythematous, are key and, if successful, can lead to general improvement in both cardiac and renal function.1
Use of ultrafiltration (UF) is indicated in patients with excessive volume overload that is refractory to conventional therapy and is particularly useful in patients with diuretic resistance.1,12 Unlike diuretics, UF has a number of physiological benefits, including significant changes in heart rate or systolic blood pressure, renal function, electrolytes, or intravascular volume. In addition, UF does not evoke NH activation.24 The UNLOAD (Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure) trial evaluated the safety and efficacy of UF compared to the standard use of diuretics in HF patients hospitalized for decompensation.25 Results showed a statistically significant improvement in weight loss (5.0 kg vs 3.5 kg) and fluid loss (4.6 L vs 3.3 L) at 48 hours in the UF group. Moreover, those receiving UF had significant decreases in rehospitalization days for HF (1.4 vs 3.8 days) and unscheduled HF visits (21% vs 44%).
Vasopressin Receptor Antagonists
Another novel class of renal-sparing agents has emerged: vasopressin receptor antagonists (vaptans). Currently, tolvaptan (Samasca; Otsuka Pharmaceuticals) is the only vaptan approved for use in HF patients by the Food and Drug Administration and is indicated specifically for the treatment of hypervolemia and euvolemic hyponatremia (serum sodium < 125 mEq/L). Tolvaptan targets renal vasopressin (V2) receptors in the distal nephron, preventing binding of arginine vasopressin (AVP) and effectively promoting urinary excretion of electrolyte-free water.24 The benefits in patients with decompensated HF include decreased body weight and volume and increased serum sodium without adverse effects on electrolytes, hemodynamics, or renal function.26
The EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan) trials evaluated the effects of tolvaptan on clinical status, morbidity, and mortality in hospitalized HF patients.27 Although results demonstrated clinical and morbidity benefits, no mortality benefit was shown.20 The ECLIPSE (Effect of Tolvaptan on Hemodynamic Parameters in Subjects With Heart Failure) trial validated the symptomatic benefits demonstrated in the EVEREST trials by evaluating hemodynamic changes using varying doses of tolvaptan (15, 30, and 60 mg) as compared with placebo.28 Statistically significant hemodynamic benefits were noted, including reduced pulmonary capillary wedge pressure, right atrial pressure, and pulmonary artery pressure in subjects receiving tolvaptan at all dosages versus placebo as well as increased urine output without changes in renal function.28
Cardiorenal syndrome results from complex bidirectional interactions between the heart and kidneys. The new classification system for CRS makes the overlap between HF and kidney disease more understandable and recognizable, but further research is necessary on how to interrupt, if not completely reverse, CRS and its adverse outcomes.
1. Ronco C, McCullough P, Anker SD, et al. Cardiorenal syndrome: report from the consensus conference on the Acute Dialysis Quality Initiative. Eur Heart J. 2010; 31:703–711.
2. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008; 52:1527–1539.
3. Rastogi A, Fonarow GC. The cardiorenal connection in heart failure. Curr Cardiol Rep. 2008; 10:190–197.
4. Berl T, Henrich W. Kidney-heart interactions: epidemiology, pathogenesis, and treatment. Clin J Am Soc Nephrol. 2006; 1:8–18.
5. Brewster UC, Setaro JF, Perazella MA. The renin-angiotensin-aldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci. 2003; 326:15–24.
6. Ghali JK, Kadakia S, Cooper R, Ferlinz J. Precipitating factors leading to decompensation of heart failure. Arch Intern Med. 1988; 148:2013–2016.
7. McCullough PA, Haapio M, Mankad S, et al. Prevention of cardiorenal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant. 2010; 25:1777–1784.
8. Latchamsetty R, Fang J, Kline-Rogers E, et al. Prognostic value of transient and sustained increase in in-hospital creatinine on outcomes of patients admitted with acute coronary syndrome. Am J Cardiol. 2007; 99:939–942.
9. Heywood JT, Fonarow GC, Costanzo MR, et al. High prevalence of renal dysfunction and its impact on outcome in 118,645 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail. 2007; 13:422–430.
10. Smit GL, Vaccarino V, Kosiborod M, et al. Worsening renal function: what is a clinically meaningful change in creatinine during hospitalization with heart failure? J Card Fail. 2003; 9:13–25.
11. Forman DE, Butler J, Wang Y, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol. 2004; 43(1):61–67.
12. Wencker D. Acute cardio-renal syndrome: progression from congestive heart failure to congestive kidney failure. Curr Heart Fail Rep. 2007; 4:134–138.
13. Fonarow GC, Heywood JT. The confounding issue of comorbid renal insufficiency. Am J Med. 2006; 119(suppl 1):S17–S25.
14. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004; 164:659–663.
15. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention. Circulation. 2003; 108:2154–2169.
16. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult—summary article. J Am Coll Cardiol. 2005; 46(6):1116–1143.
17. Felker GM on behalf of the NHLBI Heart Failure Clinical Research Network. Diuretic optimization strategies evaluation in acute heart failure. Paper presented at: 2010 American College of Cardiology & i2 Summit; March 2010; Atlanta, GA.
18. Hasselblad V, Gattis Stough W, Shah MR, et al. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial. Eur J Heart Fail. 2007; 9:1064–1069.
19. Maioli M, Toso A, Leoncini M, et al. Sodium bicarbonate versus saline for the prevention of contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. J Am Coll Cardiol. 2008; 52(8):599–604.
20. Fishbane S, Durham J, Marzo K, Rudnick M. N-acetylcysteine in the prevention of radiocontrast-induced nephropathy. J Am Soc Nephrol. 2004; 15:251–260.
21. Mentzer RM, Oz M, Sladen RN, et al. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery. J Am Coll Cardiol. 2007; 49(6):716–726.
22. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on practice guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol. 2006; 47(6):1239–1312.
23. Berger AK, Duval S, Krumholz HM. Aspirin, beta-blocker, and angiotensin-converting enzyme inhibitor therapy in patients with end-stage renal disease and an acute myocardial infarction. J Am Coll Cardiol. 2003; 42(2):201–208.
24. Costanzo MR, Saltzberg M, O'Sullivan J, Sobotka P. Early ultrafiltration in patients with decompensated heart failure and diuretic resistance. J Am Coll Cardiol. 2005; 46(11):2047–2051.
25. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2007; 49(6):675–683.
26. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2
-receptor antagonist, for hyponatremia. N Engl J Med. 2006; 355(20):2099–2112.
27. Gheorghiade M, Konstam MA, Burnett JC. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST clinical status trials. JAMA. 2007; 297(12):1332–1343.
28. Udelson JE, Orlandi C, Ouyang J, et al. Acute hemodynamic effects of tolvaptan, a vasopressin V2
receptor blocker, in patients with symptomatic heart failure and systolic dysfunction. J Am Coll Cardiol. 2008; 52(19):1540–1545.
cardiorenal syndrome; CRS; decompensated heart failure