Cardiorenal Syndrome Type 1

22  Cardiorenal Syndrome Type 1 David L. Brown

OUTLINE Definition and Classification, 216 Prevalence, 216 Prognosis, 216 Risk Factors, 218 Diagnosis, 218

Pathophysiology, 218 Prevention, 220 Management, 221 Summary, 222

Various organ systems within the body are intimately connected to each other and communicate via organ crosstalk, the complex biologic communication and feedback between organ systems mediated by soluble and cellular messengers. In the normal state, this crosstalk helps to maintain homeostasis and optimal function of the body and all its component systems. However, during disease, this crosstalk can transfer signals from the diseased organ that initiate and perpetuate dysfunction in other organs.1,2

emergent dialysis, in which case the diagnosis would be CRS type 3. In the cardiac intensive care unit (CICU) environment, the most commonly encountered CRS is type 1, which will be the focus of this chapter. CRS type 1 is characterized by an acute deterioration in cardiac function that then leads to a reduction in glomerular filtration rate (GFR) and AKI (Fig. 22.1). The most common precipitants of acute cardiac dysfunction in the CICU that result in AKI are cardiogenic shock, ADHF, acute myocardial infarction (MI), acute mitral or aortic regurgitation, pericardial tamponade, constrictive pericarditis, or prolonged arrhythmias with associated hypotension or cardiogenic shock. For any given patient, there are four patterns of CRS type 1: (1) de novo cardiac injury leading to de novo kidney injury; (2) de novo cardiac injury leading to acute-on-chronic kidney injury; (3) acute on chronic cardiac decompensation leading to de novo kidney injury; and (4) acute-on-chronic cardiac decompensation leading to acuteon-chronic kidney injury.4

DEFINITION AND CLASSIFICATION Combined disorders of the heart and kidney are referred to as cardiorenal syndromes (CRSs) and have been defined as “a complex pathophysiological disorder of the heart and the kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ.”3 The CRSs are classified into four subtypes based on the primary organ that is dysfunctional, either “cardiorenal” syndromes (types 1 or 2) or “renocardiac” syndromes (types 3 or 4) and whether the organ dysfunction is acute (types 1 and 3) or chronic (types 2 and 4). A fifth subtype is characterized by simultaneous cardiac and renal dysfunction in the setting of a systemic illness. The five subtypes are summarized in Table 22.1.3 The temporal sequence of the organ dysfunction and which problem predominates can also be used to distinguish types 1 or 2 (cardiac first) from types 3 or 4 (renal first).4 Furthermore, the classification is not static, as patients may transition between different CRS subtypes both in and out of the hospital.5 For example, a patient with chronic congestive heart failure (CHF) and chronic kidney disease (CKD) who is considered to have CRS type 2 may develop acute decompensated heart failure (ADHF) requiring hospitalization complicated by acute kidney injury (AKI); the patient would then be diagnosed with CRS type 1. Successful treatment of the ADHF with resolution of the AKI will return the patient to CRS type 2. Likewise, the same patient could progress to end-stage renal disease and develop acute pulmonary edema requiring

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PREVALENCE CRS type 1 has been described in 27% to 45% of hospitalized patients with ADHF6–12 and in 9% to 54% of patients with acute coronary syndromes (ACS).13–19 Of patients with preexisting CKD who present with ADHF, approximately 60% will develop AKI.4 AKI can be present on admission or can develop after admission. Approximately 20% to 30% of heart failure patients develop an increase in serum creatinine of more than 0.3 mg/dL9,20–23 following admission. The rise in serum creatinine usually occurs in the first 3 to 5 days of hospitalization for ADHF.24

PROGNOSIS The development of CRS type 1 is associated with worse clinical outcomes, more rehospitalizations, and greater health care expenditures.11,12,15,25 The mortality risk associated with CRS type



Keywords Cardiorenal syndrome acute decompensated heart failure heart failure acute kidney injury chronic heart failure chronic kidney disease hemodialysis continuous renal replacement treatment

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CHAPTER 22  Cardiorenal Syndrome Type 1



217

TABLE 22.1  Classification of the Cardiorenal Syndromes Class

Type

Description

Examples

1

Acute cardiorenal syndrome

Acute worsening of cardiac function resulting in AKI

2

Chronic cardiorenal syndrome

3

Acute renocardiac syndrome

Chronic abnormalities of cardiac function leading to CKD Abrupt worsening of renal function leading to acute cardiac dysfunction

4 5

Chronic renocardiac syndrome Secondary cardiorenal syndrome

ADHF Cardiac surgery Acute coronary syndromes CIN Hypertension CHF Acute pulmonary edema in AKI Arrhythmia due to acidosis or electrolyte abnormalities or volume overload CIN leading to CHF Left ventricular hypertrophy in CKD Sepsis Systemic lupus erythematosus Diabetes

CKD leading to chronic cardiac dysfunction Systemic disorders causing cardiac and renal dysfunction

ADHF, acute decompensated heart failure; AKI, acute kidney injury; CHF, congestive heart failure; CIN, contrast-induced nephropathy; CKD, chronic kidney disease. Modified from Cruz DN. Cardiorenal syndrome in critical care: the acute cardiorenal and renocardiac syndromes. Adv Chronic Kidney Dis. 2013; 20:56–66. Reduced renal autoregulation

Increased susceptibility

Vasoconstriction Relative decrease in cardiac output

Arterial underfilling Sympathetic nervous system RAAS Arginine vasopressin Endothelin

Decreased perfusion pressure

ADHF

Increased preload

Functional (pre-renal)

Ineffective natriuretic peptides Kinin-kallikrein system Prostaglandins Endothelial relaxin factor

Venous congestion

Glomerularinterstitial damage

AKI

Parenchymal damage

Sclerosis Fibrosis

Increased venous pressure Related episodes of AKI Uremic milieu

CKD

Fig. 22.1  Pathogenesis of CRS type 1. Acute decompensated heart failure (ADHF) via arterial underfilling and venous congestion sets off a series of changes in neurohormonal and hemodynamic factors that culminate in acute kidney injury (AKI). CKD, Chronic kidney disease; CRS, cardiorenal syndrome; RAAS, renin-angiotensin-aldosterone system. (Modified from Ronco C, Cicoira M, McCullough PA. Cardiorenal syndrome type 1. Pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acute decompensated heart failure. J Am Coll Cardiol. 2012;60:1031–1042.)

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1 is most pronounced early25 but an increased risk of death has been observed 10 years after the index hospitalization for acute MI patients who develop AKI.18 Furthermore, a biologic gradient has been observed between the severity of CRS type 1 and mortality risk.17,25 In ADHF, any reduction in GFR is generally associated with a worse prognosis, whether it is present at baseline or develops during treatment. A systematic review of 16 studies including more than 80,000 patients with heart failure20 categorized renal function as normal (estimated GFR [eGFR] 90 mL/min or higher), mildly impaired (eGFR 53 to 89 mL/min), or moderately to severely impaired (eGFR <53 mL/min). The mortality rate at a follow-up of 1 year or more was 24% in those with a normal eGFR compared with 38% and 51% in patients with mild and moderate to severe reductions in eGFR, respectively (adjusted hazard ratios, 1.6 and 2.3, respectively). It is estimated that mortality increases by approximately 15% for every 10 mL/min reduction in eGFR. However, the relationship between change in GFR and prognosis is complex. Patients with improving renal function may also experience worse outcomes. Fluctuating renal function may reflect a sicker cohort of patients with significantly worse survival than those with stable renal function. An analysis of 401 patients enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial found that patients with an improvement or a decline in estimated GFR during treatment of ADHF had similar outcomes.26 Compared to patients with a stable GFR, those with either an improvement or a decline in GFR were significantly more likely to have a reduced cardiac index and to require intravenous inotrope and vasodilator therapy. These patients also experienced a significantly higher rate of all-cause mortality. Additionally, the mechanism of worsening renal function in heart failure impacts its prognostic significance. An analysis of 6337 subjects enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) trial showed that early worsening of renal function was associated with increased mortality in the overall population.27 However, in the enalapril group, early worsening of renal function was not associated with increased mortality, while in the placebo group, the association with mortality was significant. 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 (ACE) inhibitor administration, it is a manifestation of the agent’s pharmacologic properties, which exert a favorable effect on long-term outcome.

RISK FACTORS Several predisposing risk factors for CRS type 1 have been identified. Nonmodifiable risk factors include a history of diabetes, prior admissions for ADHF or MI, and more severe cardiac dysfunction at the time of presentation (pulmonary edema, tachyarrhythmias, worse Killip class or lower ejection fraction).10,13,14,28 Impaired kidney function on admission has consistently been associated with higher risk for CRS type 1. Modifiable risk factors include

high doses of diuretics (e.g., daily furosemide dose >100 mg/day or in-hospital use of thiazides) and/or vasodilator therapy as well as higher contrast volumes (e.g., contrast media volume-to-creatinine clearance ratio [V/CrCl] >3.7) during cardiac catheterization and intervention.6,7,10,12,24,29,30

DIAGNOSIS Among patients with heart failure who have an elevated serum creatinine and/or a reduced estimated GFR, it is important to distinguish between underlying kidney disease and impaired kidney function due to CRS type 1.31 This distinction may be difficult since many patients have both. Findings suggestive of underlying kidney disease include significant proteinuria (usually >1000 mg/day), an active urine sediment with hematuria with or without pyuria or cellular casts, and/or small kidneys on radiologic evaluation. However, a normal urinalysis, which is typically present in CRS without underlying kidney disease, can also be seen in variety of renal diseases, including nephrosclerosis and obstructive nephropathy.31 Ultimately, the diagnosis of CRS type 1 is made retrospectively after treatment to improve cardiac performance results in improvement in renal function.

PATHOPHYSIOLOGY ADHF may reduce GFR by several mechanisms, including neurohumoral adaptations, reduced renal perfusion, increased renal venous pressure, and right ventricular (RV) dysfunction32–35 (see Fig. 22.1). In addition, exposure to nephrotoxins may precipitate CRS type 1. The pathophysiology of CRS type 1 may vary at different time points during a single hospitalization. For example, early in a CICU admission, AKI may be related to a low cardiac output state and/or marked increase in central venous pressure (CVP). However, later in the hospital course, exposure to nephrotoxins—such as contrast media or medications that impair renal perfusion, including nonsteroidal antiinflammatory drugs (NSAIDs) or ACE inhibitors—may contribute to the development of CRS type 1. Iatrogenic causes of CRS type 1 are presented in Fig. 22.2. Impaired LV function leads to several hemodynamic derangements, including reduced stroke volume and cardiac output, arterial underfilling, elevated atrial pressures, and venous congestion.36 These hemodynamic derangements trigger a variety of compensatory neurohormonal adaptations, including activation of the sympathetic nervous system and the renin-angiotensinaldosterone system and increases in the release of vasopressin and endothelin-1, which promote salt and water retention as well as systemic vasoconstriction. These pathways lead to the disproportionate reabsorption of urea compared with that of creatinine.37–39 In the setting of ADHF, blood urea nitrogen therefore represents a surrogate marker of neurohormonal activation.40,41 These adaptations overwhelm the vasodilatory and natriuretic effects of natriuretic peptides, nitric oxide, prostaglandins, and bradykinin.11,34,42 In the short term, neurohumoral adaptations contribute to preservation of perfusion to vital organs (the brain and heart) by maintenance of systemic pressure via arterial vasoconstriction

CHAPTER 22  Cardiorenal Syndrome Type 1

Drug accumulation ↓ contractility

Chemotherapy

Urate precipitation interstitial damage

Accumulation

Antibiotics NSAIDs

Toxic damage

Imaging

Contrast media

Transient ischemia Oxidative stress

Heart failure

↓ Afterload ↑ Contractility

↑ Afterload arrhythmias V1/V2 imbalance

Overhydration dehydration

Lactic acidosis interstitial damage

Metformin

Tumor lysis, urate-mediated dysfunction

ACEi - ARB

Aldosterone receptor blockers AVP receptor blockers

Diuretics

219

Acute kidney injury

↓ Filtration fraction ↓ Tubuloglomerular feedback ↓ Na reabsorption Hyperkalemia Polyuria

↑ Diuresis Hypovolemia

Fig. 22.2  Iatrogenic causes of CRS type 1. Multiple sources of iatrogenic injury, some of which may be unavoidable, can result in either cardiac, renal, or cardiorenal impairment and kidney damage in patients with acutely decompensated heart failure (ADHF). ACEi, Angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AVP, arginine vasopressin; NSAIDs, nonsteroidal antiinflammatory drugs. (Modified from Ronco C, Cicoira M, McCullough PA. Cardiorenal syndrome type 1. Pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acute decompensated heart failure. J Am Coll Cardiol. 2012;60:1031–1042.)

in other circulations, including the renal circulation, and by increasing myocardial contractility and heart rate. However, over the long term, systemic vasoconstriction increases cardiac afterload and reduces cardiac output, which can further reduce renal perfusion. The maladaptive nature of these adaptations is evidenced by the slowing of disease progression and reduction in mortality with the administration of ACE inhibitors and β-blockers in patients with heart failure and reduced ejection fraction. In the absence of shock, impaired renal perfusion is an uncommon cause of CRS type 1 in ADHF. Hypotension is an uncommon finding in patients hospitalized for ADHF. In the Acute Decompensated Heart Failure National Registry (ADHERE) of over 100,000 patients, 50% had a systolic blood pressure of 140 mm Hg or higher, while less than 2% had a systolic blood pressure below 90 mm Hg.22 ADHF patients with reduced ejection fraction have little or no reduction in cardiac output with loop

diuretic therapy because they are on the flat part of the FrankStarling curve, where changes in left ventricular end-diastolic pressure (LVEDP) have little or no effect on cardiac performance. Furthermore, the ESCAPE trial of 433 patients with ADHF6 found no correlation between the cardiac index and either the baseline GFR or worsening kidney function. Increasing the cardiac index did not improve renal function after discharge. In contrast, patients with ADHF and preserved systolic function are on a steep Starling curve such that, for every unit reduction in LVEDP induced by diuresis, there is a significant fall in stroke volume. These patients are more sensitive to diuresis; excessive diuresis can reduce preload and cardiac output, leading to hypotension, a reduction in renal perfusion, and CRS type 1 (Fig. 22.3). Increased intraabdominal or central venous pressure, which increases renal venous pressure, reduces GFR.32,43 Raising the intraabdominal venous pressure to about 20 mm Hg reduces renal plasma flow and GFR of 24% and 28%, respectively, in

220

PART IV  Noncoronary Diseases: Diagnosis and Management Dehydration

Fluid balance

Overhydration

Diuretics ultrafiltration

Liberal intake positive balance

Risk of cardiorenal syndrome

Hypotension Tachycardia Shock Organ hypoperfusion Oliguria

At-risk kidneys

Diseased heart

Management window

Normal heart

Volume depletion arterial underfilling Low

Hypertension Peripheral edema Impaired oxygenation Organ congestion

Normal kidneys

Optimal status Blood pressure

Acute decompensation High

Fig. 22.3  Volume and blood pressure management window. Patients at risk for cardiorenal syndrome type 1 have a narrow window for management of both blood pressure and volume; extremes in either parameter can be associated with worsened renal function. (Modified from Ronco C, Cicoira M, McCullough PA. Cardiorenal syndrome type 1. Pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acute decompensated heart failure. J Am Coll Cardiol. 2012;60:1031–1042.)

normal adults.44 Studies in heart failure patients demonstrate an inverse relationship between venous pressure and GFR when the central venous pressure was measured directly45–47 or elevated jugular venous pressure was diagnosed on physical examination.48 RV dilation and dysfunction may adversely affect kidney function through at least two mechanisms31: (1) the associated elevation in CVP elevation can lower the GFR; and (2) RV dilation impairs LV filling and, therefore, forward output, via ventricular interdependence (the reverse Bernheim phenomenon).49 Increased pressure within a distended RV increases LV extramural pressure, reducing LV transmural pressure for any given intracavitary LV pressure and inducing leftward interventricular septal bowing, thereby diminishing LV preload and distensibility and reducing stroke volume and forward flow.50,51 An intact pericardium plays a role in ventricular interdependence but is not critical to the interaction.52 Thus, a reduction in RV filling pressure during treatment of ADHF may lead to an increase in GFR, both by reducing renal venous pressure and by diminishing the impairment of LV filling.53 Some drugs commonly prescribed for the treatment of ADHF can also contribute to development of AKI by disturbing systemic and renal hemodynamics (see Fig. 22.2). Diuretics are recommended in ADHF to reduce dyspnea and edema, but their overuse may result in excessive intravascular volume depletion and further compromise kidney perfusion (see Fig. 22.3).54,55 Diuretic resistance may also complicate the clinical picture of CRS type 1 by acutely or chronically increasing sodium retention.56 ACE inhibitors, angiotensin receptor blockers (ARBs), and aldosterone receptor antagonists are guideline-directed therapies for heart

failure57 because these drugs have been shown to significantly improve survival of these patients.58–64 However, they affect renal hemodynamics, and their use must be carefully monitored to avoid the development of AKI in decompensated patients. Another important iatrogenic nephrotoxin in ADHF and ACS is iodinated contrast media commonly used for vascular imaging procedures (see Fig. 22.2). These agents induce intense and prolonged vasoconstriction at the corticomedullary junction of the kidney and directly impair the autoregulatory capacity of the kidney through a reduction in nitric oxide synthesis.65,66 These effects, coupled with direct tubular toxicity of iodinated radiocontrast, can lead to overt acute tubular necrosis and AKI.

PREVENTION CRS type 1 is a result of the interaction between complex pathogenic factors; once it becomes clinically apparent, it is difficult to abort and is often irreversible. Most important, CRS type 1 is associated with adverse outcomes, even if the AKI resolves.11,15 Thus, prevention of CRS is paramount in clinical practice with an aim to identify and avoid precipitating factors as well as to use measures to maintain optimal functioning of the heart and kidneys. This may involve multimodality and multidisciplinary preventive strategies, working via diverse therapeutic targets. Although evidence-based guidelines currently exist for management of ADHF,67,68 ACS,69–71 and AKI,72 there are no clear recommendations for the management of CRS type 1.73 The multitude of pathophysiologic interactions and their complexity render the management of CRS challenging.

CHAPTER 22  Cardiorenal Syndrome Type 1



BOX 22.1  Renoprotective Strategies in the

Cardiac Intensive Care Unit

• Regular monitoring of fluid intake/output, urine output, renal function, blood pressure • Accurate and frequent monitoring of volume status • Hold ACE inhibitors/ARBs in patients with worsening renal function • Optimize volume status • Adjust diuretic doses based on volume status • Pharmacovigilance (drug monitoring, avoid nephrotoxins, attention to drug interactions) • Initial use of vasodilators (nitrates, hydralazine) in ADHF if blood pressure is adequate • Avoid unnecessary use of iodinated contrast agents • Optimize volume status before use of iodinated contrast agents • Minimize volume of iodinated contrast agents ACE, Angiotensin-converting enzyme; ADHF, acute decompensated heart failure; ARBs, angiotensin receptor blockers. Modified from Cruz DN. Cardiorenal syndrome in critical care: the acute cardiorenal and renocardiac syndromes. Adv Chronic Kidney Dis. 2013;20:56–66.

Improving the natural history of heart failure and avoiding acute decompensation are the cornerstones of prevention of CRS type 1.74 Strategies for prevention in these patients should follow those recommended by the American College of Cardiology/ American Heart Association (ACC/AHA) for stage A and stage B heart failure.75 These include coronary artery disease risk factor modification and avoidance of medications that may precipitate salt and water retention, including NSAIDs and thiazolidinediones. More important, use of renin-angiotensin-aldosterone system antagonists and β-blockers should be optimized. In patients with CKD, efforts must be made to cautiously introduce these cardioprotective agents with close monitoring of kidney function. Another mainstay of prevention is to recognize patients at risk for CRS. Patients who develop CRS type 1 are generally older, have a history of previous hospitalizations for heart failure or MI, and often have baseline kidney dysfunction and hypertension. Risk prediction scores for AKI have been published for ADHF24 for contrast-induced AKI after percutaneous coronary intervention,76 after cardiac surgery,77 and in hospitalized patients.78 Such scoring systems can be used to recognize preemptively the patients at a high intrinsic risk of developing AKI. Renoprotective measures can then be selectively instituted in high-risk patients to reduce the risk of acute CRS79 (Box 22.1).

MANAGEMENT No medical therapies directly increase the GFR (manifested clinically by a decline in serum creatinine) in patients with heart failure. On the other hand, improving cardiac function can result in increases in GFR, indicating that CRS type 1 has substantial reversible components.80 AKI induced by primary cardiac dysfunction implies inadequate renal perfusion until proven otherwise.81 Inadequate perfusion may be a consequence of a low cardiac output state, increased CVP leading to renal congestion, or both. Elevated CVP leading to renal venous hypertension is a product of right

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heart function, blood volume, and venous capacitance—all of which are heavily influenced by neurohormonal systems.4 A careful history and physical examination can usually differentiate a volume-depleted patient from one who is severely volume overloaded. Diuretics, typically beginning with a loop diuretic, are first-line therapy for managing volume overload in patients with ADHF as manifested by peripheral and/or pulmonary edema. In patients with heart failure, an elevated BUN/creatinine ratio should not deter diuretic therapy if clinical evidence of congestion is present.80 That aggressive diuresis improves outcomes is suggested in two studies, ESCAPE82 and Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST),83 in which hemoconcentration, an indicator of aggressive diuresis, was found to be associated with worsening of renal function in the hospital but an improvement in survival after discharge. These findings provide support for the recommendation included in the 2013 ACC/AHA heart failure 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.84 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. The optimal diuretic regimen has not been determined in randomized controlled trials. Continuous intravenous infusion of diuretics has traditionally been considered more effective than bolus in severe ADHF.85,86 However, in the recent Diuretic Optimization Strategies Evaluation (DOSE) randomized trial, there were no significant differences in patients’ symptoms or in the change in kidney function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose (2.5 times the previous outpatient oral dose) as compared with a low dose (equivalent to the previous oral dose).87 The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of kidney function (23% vs. 14% in low dose, P = .04). It is frequently overlooked that the median hourly dose of furosemide by continuous infusion in the DOSE trial was only 5 mg in the low-dose arm and 10.7 mg in the high-dose arm. These doses are significantly below the 20- to 40 mg/h doses frequently required in CRS type 1 patients. In addition, ADHF patients with serum creatinine greater than 3 mg/dL were excluded from the DOSE trial. Those patients are more likely to need higher doses of furosemide and are more susceptible to develop CRS type 1 during hospitalization for ADHF. Intravenous administration of inotropic drugs—such as dobutamine, dopamine, and milrinone—has a role in the treatment of patients who develop cardiogenic shock. However, both routine use of short-term intravenous therapy in patients with ADHF and prolonged therapy with oral inotropic drugs other than digoxin has 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 role of inotropes in patients with CRS is uncertain and the routine use of inotropes is not recommended given their lack of proven efficacy and their association with adverse events when used in patients other than

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those with cardiogenic shock or ADHF who are deteriorating toward cardiogenic shock.80 Ultrafiltration is an alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening kidney function. The Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial randomized 200 ADHF patients to ultrafiltration or intravenous diuretics and found that ultrafiltration safely produced greater weight loss and fluid removal than intravenous diuretics and reduced readmissions for heart failure.88 However, in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial,89 the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. Thus, although ultrafiltration may be helpful for fluid removal in ADHF in patients unresponsive to diuretic therapy, the available evidence does not establish ultrafiltration as first-line therapy for ADHF or as an effective therapy for CRS type 1. The 2009 ACC/AHA guidelines state that ultrafiltration is reasonable for patients with refractory congestion not responding to medical therapy.68

Intravenous vasodilators used in the treatment of ADHF include nitroglycerin, nitroprusside, and nesiritide. In the ADHERE database of almost 100,000 patients, worsening of renal function was significantly more common when intravenous diuretics were given with nitroglycerin or nesiritide compared with intravenous diuretics alone (relative risk, 1.20 and 1.44, respectively).90 However, a causal effect could not be distinguished from patients requiring combination therapy because they had worse heart failure. There are no randomized trials of nitroglycerin or nitroprusside. Randomized trials have yielded conflicting results on the effect of nesiritide therapy on renal function in the treatment of ADHF. The largest trial, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), nesiritide was not associated with a worsening of renal function but was associated with increased rates of hypotension.91 Similarly, the Renal Optimization Strategies Evaluation (ROSE) trial found that low-dose nesiritide did not enhance decongestion or alter renal function when added to diuretic therapy.92 Overall, nesiritide has not been found to be of benefit in ADHF and it is not currently recommended for the prevention of AKI.72

SUMMARY In summary, CRS type 1 is a complex and multidimensional entity that is commonly encountered in the CICU and has a significant effect on morbidity and mortality. Preventive strategies in general for all patients at risk for CRS type 1 will help decrease the incidence of AKI. The management of CRS type 1 is

The full reference list for this chapter is available at ExpertConsult.com.

challenging because of the many complex pathophysiologic interactions between the heart and kidney. Although evidencebased guidelines currently exist for management of ADHF, ACS, and AKI, at present there are no clear recommendations for the management of CRS type 1.



CHAPTER 22  Cardiorenal Syndrome Type 1

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CHAPTER 22  Cardiorenal Syndrome Type 1

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