Cardiorenal Syndrome: Definition, Prevalence, Diagnosis, and Pa Tho Physiology

Cardiorenal syndrome: Denition, prevalence, diagnosis, and ...
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Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology

Authors Michael S Kiernan, MD James E Udelson, MD, FACC Mark Sarnak, MD Marvin Konstam, MD Disclosures Last literature review version 19.3: Setembro 2011 | This topic last updated: Outubro 6, 2010 DEFINITION AND CLASSIFICATION There are a number of important interactions between heart disease and kidney disease. The interaction is bidirectional as acute or chronic dysfunction of the heart or kidneys can induce acute or chronic dysfunction in the other organ. The clinical importance of such relationships is illustrated by the following observations: Mortality is increased in patients with heart failure (HF) who have a reduced glomerular filtration rate (GFR). (See "Cardiorenal syndrome: Prognosis and treatment", section on 'Reduced GFR and prognosis'.) Patients with chronic kidney disease have an increased risk of both atherosclerotic cardiovascular disease and heart failure, and cardiovascular disease is responsible for up to 50 percent of deaths in patients with renal failure [1,2]. (See "Chronic kidney disease and coronary heart disease", section on 'Introduction'.) Acute or chronic systemic disorders can cause both cardiac and renal dysfunction. The term cardiorenal syndrome (CRS) has been applied to these interactions, but the definition and classification have not been clear. A 2004 report from the National Heart, Lung, and Blood Institute defined CRS as a condition in which therapy to relieve congestive symptoms of HF is limited by a decline in renal function as manifested by a reduction in GFR [3]. The reduction in GFR was initially thought to result from a reduction in renal blood flow. However, various studies have demonstrated that cardiorenal interactions occur in both directions and in a variety of clinical settings [4]. (See 'Pathophysiology' below.) The different interactions that can occur led to the following classification of CRS that was proposed by Ronco and colleagues [5]: Type 1 (acute) Acute HF results in acute kidney injury (AKI, previously called acute renal failure) Type 2 Chronic cardiac dysfunction (eg, chronic HF) causes progressive chronic Section Editor Stephen S Gottlieb, MD Deputy Editor Susan B Yeon, MD, JD, FACC
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kidney disease (CKD, previously called chronic renal failure) Type 3 Abrupt and primary worsening of kidney function due, for example, to renal ischemia or glomerulonephritis causes acute cardiac dysfunction, which may be manifested by HF Type 4 Primary CKD contributes to cardiac dysfunction, which may be manifested by coronary disease, HF, or arrhythmia Type 5 (secondary) Acute or chronic systemic disorders (eg, sepsis or diabetes mellitus) that cause both cardiac and renal dysfunction. The prevalence of impaired renal function in patients with HF, the diagnosis of CRS, and the mechanisms by which acute HF leads to worsening kidney function (type 1 CRS) will be reviewed here. However, it may be difficult to distinguish between type 1 and type 2 CRS (chronic HF), and similar mechanisms may apply to type 2. Issues related to the prognosis and treatment of type 1 or 2 CRS are presented separately. (See "Cardiorenal syndrome: Prognosis and treatment".) PREVALENCE Heart failure (HF) is frequently accompanied by a reduction in glomerular filtration rate (GFR) via mechanisms that will be described below. (See 'Pathophysiology' below.) The prevalence of moderate to severe kidney impairment (defined as a GFR less than 60 mL/min per 1.73 m2; normal more than 90 mL/min per 1.73 m2) is approximately 30 to 60 percent in patients with HF [6-10]. The following observations are illustrative: In a systematic review of 16 studies of more than 80,000 hospitalized and nonhospitalized patients with HF, moderate to severe kidney impairment (defined as an estimated GFR less than 53 mL/minute, a serum creatinine of 1.5 mg/dL [132 micromol/L] or higher, or a serum cystatin C of 1.56 mg/dL or higher) was present in 29 percent of patients [6]. The Acute Decompensated Heart Failure National Registry (ADHERE) database reported data on over 100,000 patients with HF requiring hospitalization [9]. Approximately 30 percent had a diagnosis of chronic kidney disease (defined as a serum creatinine greater than 2.0 mg/dL [177 micromol/L]). The mean estimated GFR was 55 mL/min per m2, and only 9 percent had a normal estimated GFR (defined as greater than 90 mL/min per 1.73m2) [10]. In addition to these baseline observations, patients undergoing treatment for acute or chronic HF frequently develop an increase in serum creatinine, which fulfills criteria for type 1 or type 2 CRS [11-20]. In different series, approximately 20 to 30 percent of patients developed an increase in serum creatinine of more than 0.3 mg/dL (27 micromol/L) [11,12,14,16,18], and, in one report, 24 percent had an increase of 0.5 mg/dL (44 micromol/L) or more [14]. Risk factors for worsening kidney function during admission for HF include a prior history of HF or diabetes, an admission serum creatinine of 1.5 mg/dL (133 micromol/L) or higher, and uncontrolled hypertension [12,13,21]. The rise in serum creatinine usually occurs in the first three to five days of hospitalization [12]. DIAGNOSIS Impaired kidney function in patients with heart failure (HF) is defined as a reduction in glomerular filtration rate (GFR). The most common test used to estimate GFR is the serum creatinine concentration. However, older and sicker patients often have a
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reduction in muscle mass and therefore in creatinine production. Thus, the GFR may be substantially reduced in patients who have a serum creatinine that is in the normal range or only mildly elevated. Estimation equations are available that provide a better estimate of GFR than the serum creatinine alone by including known variables that affect the serum creatinine independent of GFR (eg, age, weight, sex). Another alternative to serum creatinine is measurement of serum cystatin C, which is an endogenous proteinase inhibitor synthesized and released into plasma at a constant rate by all nucleated cells. All of these tests require that the serum creatinine or cystatin C concentration be stable; they cannot be used to estimate GFR in a patient who has a rising serum creatinine. These issues are discussed in detail elsewhere. (See "Assessment of kidney function: Serum creatinine; BUN; and GFR", section on 'Requirement for stable kidney function'.) Among patients with HF 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 the cardiorenal syndrome (CRS). This distinction may be difficult and some patients have both underlying chronic kidney disease and CRS. Findings suggestive of underlying kidney disease include significant proteinuria (usually more than 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. (See "Diagnostic approach to the patient with acute or chronic kidney disease", section on 'Urinary findings'.) Measurement of the urine sodium concentration also may be helpful. A urine sodium concentration below 25 meq/L would be expected with HF, since renal perfusion is reduced with associated activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, both of which promote sodium retention. However, higher values may be seen with concurrent diuretic therapy if the measurement is made while the diuretic is still acting. (See "Diagnostic approach to the patient with acute or chronic kidney disease", section on 'Urine sodium excretion'.) PATHOPHYSIOLOGY A variety of factors can contribute to a reduction in glomerular filtration rate (GFR) in patients with heart failure (HF) [4,16,22,23] (figure 1). The major mechanisms that have been evaluated include neurohumoral adaptations, reduced renal perfusion, increased renal venous pressure, and right ventricular dysfunction. Neurohumoral adaptations Impaired left ventricular function leads to a number of hemodynamic derangements, including reduced stroke volume and cardiac output, arterial underfilling, elevated atrial pressures and venous congestion [24]. These hemodynamic derangements trigger a variety of compensatory neurohormonal adaptations including activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system and increases in the release of vasopressin (antidiuretic hormone), and endothelin-1 which promote salt and water retention and systemic vasoconstriction. These adaptations overwhelm the vasodilatory and natriuretic effects of natriuretic peptides, nitric oxide, prostaglandins, and bradykinin [20,22,25]. Neurohumoral adaptations can contribute to preservation of perfusion to vital organs (the brain and heart) by maintenance of systemic pressure via arterial vasoconstriction in other circulations, including the renal circulation, and by increasing myocardial contractility and heart rate. However, systemic vasoconstriction increases cardiac afterload, which reduces cardiac output, which can further reduce renal perfusion. The maladaptive nature of these
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adaptations is evidenced by the slowing of disease progression and reduction in mortality with the administration of angiotensin inhibitors and beta blockers in patients with HF due to systolic dysfunction. These issues are discussed in detail elsewhere. (See "Pathophysiology of heart failure: Neurohumoral adaptations" and "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use" and "Angiotensin II receptor blockers in heart failure due to systolic dysfunction: Therapeutic use" and "Use of beta blockers in heart failure due to systolic dysfunction".) Reduced renal perfusion As mentioned above, an original definition described the cardiorenal syndrome (CRS) as a disorder in which therapy to relieve congestive symptoms of HF (eg, loop diuretics) is limited by a reduction in glomerular filtration rate (GFR); the fall in GFR was thought to result from a decline in cardiac output of as much as 20 percent due to the reduction in ventricular preload [3,26]. A similar reduction in renal perfusion may be induced by acute decompensated HF prior to treatment. However, some patients initially have little or no reduction in cardiac output with loop diuretic therapy because they are on the flat part of the Frank-Starling curve in which changes in left ventricular end-diastolic pressure have little or no effect on cardiac performance (figure 2), while others have an increase in GFR following diuretic therapy that may be mediated by a reduction in renal venous pressure and/or right ventricular dilatation. (See "Pathophysiology of heart failure: Left ventricular pressure-volume relationships", section on 'Pressure-volume relationships in heart failure' and 'Increased renal venous pressure' below and 'Right ventricular dilatation and dysfunction' below.) However, worsening kidney function in patients with HF is not solely due to reduced renal perfusion induced by a low cardiac output, as illustrated by the following observations: The ESCAPE trial evaluated the effectiveness of pulmonary artery catheterization in 433 patients with acute decompensated HF [27]. There was no correlation between the cardiac index and either the baseline GFR or worsening kidney function, and increasing the cardiac index did not improve renal function after discharge. Similar findings were noted in another report in which HF patients with worsening kidney function did not have lower cardiac outputs or filling pressures than those without worsening kidney function [15]. It has been suggested that, although reductions in cardiac index lead to a reduction in renal blood flow, the GFR is initially maintained by an increase in the fraction of renal plasma flow that is filtered (ie, the filtration fraction) [28]. In this study, the GFR was similar in patients with a cardiac index of more than 2.0 and 1.5 to 2.0 L/min per m2 (respective filtration fractions 24 and 35 percent) but substantially reduced in patients with a cardiac index below 1.5 L/min per m2 (38 versus 62 and 67 mL/min per 1.73 m2). In addition, hypotension, which can reduce the GFR independent of renal blood flow, is an uncommon finding in patients hospitalized for acute decompensated HF. In the ADHERE registry of over 100,000 such patients, 50 percent had a systolic blood pressure of 140 mmHg or higher, while less than 2 percent had a systolic blood pressure below 90 mm/Hg [9]. Increased renal venous pressure Both animal and human studies have shown that increasing intraabdominal or central venous pressure, which should also increase renal venous pressure, reduce the glomerular filtration rate (GFR) [4,29]. In an initial study in 17 normal adults, for example, raising the intraabdominal venous pressure to about 20
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mmHg led to average reductions in renal plasma flow and GFR of 24 and 28 percent, respectively [30]. An adverse impact of venous congestion on kidney function has also been described in animal models as manifested by a reduction in GFR [31-34] and sodium retention [31,35,36]. Subsequent studies in patients with HF demonstrated an inverse relationship between venous pressure and GFR when the central venous pressure was measured directly [37-39] or elevated jugular venous pressure was diagnosed on physical examination [40]: In one report, 58 of 145 patients (40 percent) hospitalized for acute decompensated HF developed worsening kidney function, defined as an increase in serum creatinine of at least 0.3 mg/dL (27 micromol/L) [37]. These patients had a significantly higher central venous pressure (CVP) than those with stable renal function (18 versus 12 mmHg) and the frequency of worsening kidney function was lowest in patients with a CVP less than 8 mmHg. The predictive value of CVP was independent of systemic blood pressure, pulmonary capillary wedge pressure, cardiac index, and estimated GFR. In contrast to the importance of CVP, the cardiac index on admission and an improvement in cardiac index with therapy had a limited impact on the frequency of worsening kidney function. Similar findings were noted in another study in which a higher CVP was also associated with a significant increase in mortality at a median follow-up of more than 10 years (hazard ratio 1.03 per 1 mmHg increase in CVP) [38]. In a series of 40 consecutive patients with acute decompensated HF, 24 had an elevation in intraabdominal venous pressure (IAVP) which was defined as 8 mmHg or higher [39]. At baseline, these patients, compared with those with a normal IAVP, had a significantly higher serum creatinine (mean 2.3 versus 1.5 mg/dL [203 versus 133 micromol/L]) and a significantly lower estimated GFR (mean 40 versus 63 mL/min). In addition, there was a strong correlation between the degree of reduction in IAVP with therapy and improvement in GFR that did not correlate with any other hemodynamic variable (graph 1). Increases in renal venous pressure may also contribute to the association between the degree of tricuspid regurgitation (TR) and worsening kidney function. In a review of 196 patients with TR, those with at least moderate TR had a lower estimated GFR [41]. In addition, there was a linear relationship between the severity of TR and the magnitude of impairment in GFR. The mechanisms by which increased renal venous pressure might lead to a reduction in GFR are not well understood [16,29]. Right ventricular dilatation and dysfunction Right ventricular (RV) dilatation and dysfunction may adversely affect kidney function through at least two mechanisms: The associated elevation in central venous pressure elevation can lower the GFR as discussed in the preceding section. RV dilatation impairs left ventricular (LV) filling, and therefore forward output, via a ventricular interdependent effect (also known as the reverse Bernheim phenomenon) [42]. Increased pressure within a distended right ventricle increases LV extramural pressure, reducing LV transmural pressure for any given intracavitary LV pressure and inducing leftward interventricular septal bowing, thereby diminishing LV preload
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and distensibility and reducing forward flow [43,44]. An intact pericardium plays a role in ventricular interaction, but experimental observations suggest that the pericardium is not critical to the interaction [45]. Thus, a reduction in RV filling pressure during treatment of HF may lead to an increase in GFR, both by reducing renal venous pressure and by diminishing ventricular interdependent impairment of left ventricular filling [46]. SUMMARY 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. In type 1 CRS, acute heart failure (HF) leads to worsening kidney function. In type 2 CRS, chronic HF causes progressive chronic kidney disease. (See 'Definition and classification' above.) The prevalence of moderate to severe kidney impairment (defined as a glomerular filtration rate [GFR] less than 60 mL/min per 1.73 m2) is approximately 30 to 40 percent in patients with HF. In addition to these baseline observations, patients undergoing treatment for acute or chronic HF frequently develop an increase in serum creatinine, which fulfills criteria for type 1 or type 2 CRS. (See 'Prevalence' above.) Among patients with HF 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 the CRS. (See 'Diagnosis' above.) A variety of factors can contribute to a reduction in GFR in patients with HF. The major mechanisms that have been evaluated include neurohumoral adaptations, reduced renal perfusion, increased renal venous pressure, and right ventricular dysfunction. (See 'Pathophysiology' above.)
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GRAPHICS
Pathophysiology of cardiorenal syndrome
ACEI: angiotensin converting enzyme inhbitor; ARBs: angiotensin II receptor blockers; CO: cardiac output; CVP: central venous pressure; LVEDP: left ventricular end-diastolic pressure; ETs: endothelins; NO: nitric oxide; NP: natriuretic peptides; NSAIDs: nonsteroidal antiinflammatory drugs; RAAS: renal angiotenin aldosterone system; SNS: sympathetic nervous system; SV: stroke volume.
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Frank-Starling curves in HF
Idealized family of Frank-Starling curves produced by worsening ventricular function in heart failure. In ventricles with normal cardiac performance, there is a steep and positive relationship between increased cardiac filling pressures (as estimated from the left ventricular end- diastolic or pulmonary capillary wedge pressure) and increased stroke volume or cardiac output (top curve). In comparison, during progression from mild to severe myocardial dysfunction, this relationship is right-shifted (ie, a higher filling pressure is required to achieve the same cardiac output) and flattened so that continued increases in left heart filling pressures lead to minimal increases in cardiac output at the possible expense of pulmonary edema. The onset of mild heart failure results in an initial reduction in cardiac function (point B), a change that can be normalized, at least at rest, by raising the LVEDP via fluid retention (point C). In comparison, normalization of stroke volume is not attainable in severe heart failure (bottom curve).
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Change in serum creatinine versus change in intraabdominal pressure
Adapted from: Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 2008; 51:300, courtesy of the authors.
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Official reprint from UpToDate www.uptodate.com 2011 UpToDate