Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology

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

The prevalence of impaired renal function in patients with heart failure (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 2 CRS (caused by 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".)

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 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 HF, 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 (previously called acute renal failure).

●Type 2 – Chronic cardiac dysfunction (eg, chronic HF) causes progressive chronic 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.

PREVALENCE — 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 1.73 m²) [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 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 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). These equations require that the serum creatinine 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".)

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.

The blood urea nitrogen/creatinine ratio (BUN/Cr) is frequently used to aid in the differentiation of prerenal renal failure from intrinsic renal disease. An elevated BUN/Cr ratio is typically suggestive of a prerenal etiology, as long as other causes of a high ratio (eg, increased urea production) are not present (see "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults", section on 'Blood urea nitrogen/serum creatinine ratio'). HF is a cause of prerenal azotemia, although evidence suggests that worsening renal function due to HF is not solely related to reduced cardiac output and frequently occurs in the setting of volume overload [22,23] (see 'Pathophysiology' below):

In HF, an elevated BUN/Cr should not deter decongestive or diuretic therapies if evidence of clinical congestion is present. (See 'Pathophysiology' below and "Cardiorenal syndrome: Prognosis and treatment".)

Measurement of the urine sodium concentration (UNa) may also be helpful. UNa is easily measurable and readily available. A UNa 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 UNa values may be seen with concurrent diuretic therapy if the measurement is made while the diuretic is still acting. (See "Evaluation of acute kidney injury among hospitalized adult patients", section on 'Urine sodium excretion'.)

There is a mounting evidence suggesting that UNa profiling can predict short-term responsiveness to IV loop diuretics in patients with acute HF [24,25]. Low UNa concentration from spot and continuous urine collection samples are associated with diminished diuretic response, as well as increased risk of HF readmission and cardiovascular mortality [25-30]. Natriuretic response from a single dose of loop diuretic can be predicted rapidly from a spot urine sample collected one to two hours after dose of loop diuretic is administered [25]. Spot urinary sodium may thus allow clinicians to more rapidly interpret diuretic responsiveness, providing an opportunity to intervene if sodium content is low, prompting aggressive diuretic titration [24,31]. A position statement on use of diuretics in HF from the European Society of Cardiology (ESC) proposes a spot urine sodium content of <50 to 70 mEq/L after two hours, or an hourly urine output <100 to 150mL during the first six hours to identify a patient with insufficient diuretic response [31].

PATHOPHYSIOLOGY — The pathogenesis of rising serum creatinine in setting of acute HF and aggressive diuresis remains incompletely understood. The cardiorenal syndrome is most likely a diverse group of pathophysiologically distinct processes with worsening renal function embodying a common pathway of these mechanistically distinct pathways [32]. Thus, the prognosis associated with worsening renal function (WRF) is likely dependent on the mechanism behind a rising creatinine, which may not accurately reflect pathologic renal injury [33]. Worsening renal function is not synonymous with acute kidney injury.

A variety of factors can contribute to a reduction in glomerular filtration rate (GFR) in patients with HF (figure 1) [4,16,34,35]. 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 [36]. 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 pathways lead to the disproportionate reabsorption of urea compared with that of creatinine [22,37,38]. In the setting of HF, blood urea nitrogen therefore represents a surrogate marker of neurohormonal activation [39,40]. These adaptations overwhelm the vasodilatory and natriuretic effects of natriuretic peptides, nitric oxide, prostaglandins, and bradykinin [20,34,41].

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 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 with reduced ejection fraction. These issues are discussed in detail elsewhere. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction" and "Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action".)

Chloride handling — In patients with HF, chloride plays an important role in fluid homeostasis, neurohormonal activation, and diuretic resistance [42]. Chloride is a primary modulator of tubuloglomerular feedback and has a unique role in homeostasis that is distinct from that of sodium [43].

Hypochloremia, which commonly occurs during acute HF therapy, interferes with the kidney’s regulator role in electrolyte homeostasis and diuresis, and evidence suggests that a change in serum chloride is a primary determinant of changes in plasma volume and in activation of the renin-angiotensin-aldosterone system [44]. In patients with HF who are receiving diuresis, hypochloremia is frequently accompanied by a metabolic alkalosis (chloride depletion alkalosis). Despite clinical evidence of persistent volume overload, alkalosis in this setting is frequently and inappropriately attributed to intravascular volume depletion (ie, "contraction alkalosis"), which may lead to premature deescalation of decongestive therapies. If the patient has evidence of hypervolemia, metabolic alkalosis in this setting is more likely attributable to abnormal electrolyte homeostasis that results in chloride depletion alkalosis, which is characterized by elevated urine chloride levels [45].

Coadministration of acetazolamide with loop diuretics can reduce chloride loss, though the clinical efficacy of acetazolamide administration is uncertain.

Hemodynamic factors

Reduced systemic blood pressure — The importance of differing mechanisms of WRF and their associations with subsequent outcomes was demonstrated by an analysis of 386 patients enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial [32]. In this subgroup analysis, reduction in systolic blood pressure was greater in patients who experienced worsening renal function (odds ratio 1.3 per 10 mmHg reduction). Among patients with reduced systolic blood pressure (SBP), WRF was not associated with worsened survival; however, in patients without SBP reduction, WRF was strongly associated with increased mortality (adjusted hazard ratio 5.3). Similar findings have been reported elsewhere [46]. Compared with changes in SBP, changes in cardiac output have not been associated with WRF [32,46]. Collectively, these findings suggest that regulation of renal blood flow and glomerular filtration are more dependent on pressure rather than flow, and that blood pressure rather than cardiac output or congestion is more closely associated to changes in renal function during acute HF hospitalization.

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 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 [3,47]. 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 dilation. (See 'Increased renal venous pressure' below and 'Right ventricular dilation and dysfunction' below.)

The following observations suggest that reduced cardiac index is not the primary driver for renal dysfunction in patients hospitalized for HF:

●The ESCAPE trial evaluated the effectiveness of pulmonary artery catheterization in 433 patients with acute decompensated HF [48]. 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].

●Among 575 patients undergoing pulmonary artery catheterization in the randomized or registry portions of the ESCAPE trial, there was a weak but significant inverse correlation between cardiac index and estimated GFR (eGFR), such that higher cardiac index was paradoxically associated with worse eGFR [49]. Cardiac index was not associated with either BUN or the BUN/Cr ratio.

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) [50]. In a study of patients with chronic HF, 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 intra-abdominal or central venous pressure, which should also increase renal venous pressure, reduces the GFR [4,51]. In an initial study in 17 normal adults, for example, raising the intra-abdominal venous pressure to approximately 20 mmHg led to average reductions in renal plasma flow and GFR of 24 and 28 percent, respectively [52]. An adverse impact of venous congestion on kidney function has also been described in animal models as manifested by a reduction in GFR [53-56] and sodium retention [53,57,58].

Subsequent studies in patients with HF demonstrated an inverse relationship between venous pressure and GFR when the central venous pressure was measured directly [59-61] or elevated jugular venous pressure was diagnosed on physical examination [62]:

●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) [59]. 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) [60].

●In a series of 40 consecutive patients with acute decompensated HF, 24 had an elevation in intra-abdominal venous pressure (IAVP) which was defined as 8 mmHg or higher [61]. 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. Changes in IAVP and GFR did not correlate with any other hemodynamic variable (figure 3).

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 [63]. 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 [16,51].

Right ventricular dilation and dysfunction — Right ventricular (RV) dilation 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 dilation impairs left ventricular (LV) filling, and therefore forward output, via a ventricular interdependent effect (also known as the reverse Bernheim phenomenon) [64]. 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 forward flow [65,66]. An intact pericardium plays a role in ventricular interaction, but experimental observations suggest that the pericardium is not critical to the interaction [67].

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 [68].

Associations with heart failure with preserved ejection fraction — Renal dysfunction is frequently seen in patients with HF with preserved ejection fraction (HFpEF) [69] (as well as those with reduced ejection fraction). Endothelial dysfunction and a proinflammatory state have emerged as important mediators of cardiorenal interactions. Renal dysfunction can lead to metabolic derangements resulting in systemic inflammation and microvascular dysfunction, which can cause cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis [69].

In a study of patients with acute decompensated HFpEF, 38 (36 percent) of 104 subjects developed worsening renal function (WRF; increase in serum creatinine of ≥0.3 mg/dL) within 72 hours of hospitalization [70]. While linear and volumetric measures of right atrial and right ventricular (RV) chamber size did not differ significantly between those patients with versus those without WRF, those with WRF had significantly reduced RV function and increased RV free wall thickness. Again, these associations do not prove causality between renal dysfunction and adverse RV remodeling and dysfunction. Many of these observations are similar to those seen in HFrEF and is not clear which, if any, of these findings are unique to patients with preserved versus reduced EF.

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

SUMMARY

●Definition and classifications – 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.)

●Prevalence – 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 60 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.)

●Diagnosis – 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.)

●Pathophysiology – 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.)

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