Cardiorenal Syndrome: The Cardiologist’s Viewpoint

most cardiologists consider the coexistence of heart failure and chronic kidney disease (CKD) (1) or worsening of renal function (WRF) defined as an increase in serum creatinine >0.3 mg/dL (2) during treatment of acute decompensated heart failure (ADHF) as a reasonable working definition of cardiorenal syndrome (CRS). Others consider the presence of diuretic refractoriness despite persistent hypervolemia, inability to handle sodium load, and inability to use adequate doses of heart failure medications as important components of CRS. However, these variables have never been included in the definition because they are difficult to study. This brief review limits discussion to patients with type 1 (acute) and type 2 (chronic) CRS as proposed in a recent classification of CRS (3).

Prevalence and prognosis of cardiorenal syndrome

The prevalence of CKD (type 2 CRS) has been reported in the range of 32–50 percent in the large chronic heart failure trials (49). Population-based surveys in North America have found a similar prevalence of 38–56 percent (1012). Gottlieb et al. found that the sensitivity and specificity for the prediction of poor outcomes with WRF, defined as a rise in serum creatinine of 0.3 mg/dL during ADHF (type 1 CRS), were 81 percent and 62 percent, respectively (2). Using that definition, the prevalence of type 1 CRS is reported in the range of 27–45 percent in previous studies (1315). However, in the ADHERE registry, the prevalence of CKD (GFR < 60 mL/min/1.73 m2) was as high as 65 percent (16).

The presence of CKD or the development of WRF are significant independent predictors of mortality and morbidity in patients with ADHF and chronic heart failure (412, 1617). In the ADHERE registry, the in-hospital mortality increased from 1.9 percent for patients with normal renal function to 7.6 percent for patients with severe renal dysfunction (p < 0.0001) (16).

Predictors of cardiorenal syndrome

Several factors are associated with the presence of CRS in patients with chronic heart failure. In the Val-HeFT trial, the independent predictors for the presence of CRS were age, male gender, diabetes, ischemic etiology of heart failure, low blood pressures, worse neurohormonal and proinflammatory profile, presence of edema, and use of higher doses of diuretics (9).

Left ventricular ejection fraction did not predict the presence of CRS. Indeed, the presence of CRS was similar in patients with preserved (34 percent) or depressed (33 percent) left ventricular function in the CHARM trial, which studied the effects of the angiotensin receptor blocker candesartan in patients with depressed and preserved ejection fraction (6). The pathogenetic mechanisms responsible for the development of WRF during ADHF are not clear. Published studies have reported that baseline serum creatinine, coronary artery disease, hypertension, history of diabetes mellitus, use of calcium channel blockers, pulmonary edema, and high doses of diuretics are associated with its development (14,1820). However, it is unclear whether the development of WRF is related to a pre-renal, intravascular volume depleted state, induced by intensive diuresis during the management of ADHF, or the result of a complex interaction involving heart failure treatment in the setting of intrinsic kidney disease. Other factors considered important in the pathogenesis of CRS are poor renal perfusion owing to low cardiac output, high venous pressure, and systemic and renal vasoconstriction (21,22).

Classical studies have taught us that low cardiac output activates catecholamine and the renin-angiotensin system, causing an increase in systemic and renovascular resistance, leading to a decrease in renal blood flow and GFR and to retention of salt and water (21). However, several hemodynamic studies in patients with ADHF have found that cardiac output is not necessarily low in these patients, although none of these studies directly assessed renal hemodynamics. In a study of 48 patients with ADHF, Weinfeld et al. did not find low cardiac output or estimated renal perfusion pressure (mean arterial minus CVP) in patients who developed CRS during heart failure treatment (23). In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization (ESCAPE) trial, cardiac output, pulmonary capillary wedge pressure, and systolic blood pressure did not correlate with renal function. Only right atrial pressure correlated weakly with baseline serum creatinine (r = 0.165, p = 0.03) (17).

Role of increased venous pressure in cardiorenal syndrome

Over 60 years ago Bradley and Bradley (24) showed that an increase in intra-abdominal pressure (IAP) to ∼80 mm Hg obtained by applying a tight abdominal binder in normal volunteers caused an immediate decrease in effective renal plasma flow (ERPF), GFR, and urine output. Removal of the abdominal binders rapidly normalized the ERPF, GFR, and urine output. It is unclear whether raising the abdominal pressure caused an increase in renal venous pressure. However, in a series of elegant studies on isolated perfused kidney, Firth et al. (22) provided evidence that when arterial pressure is kept constant, an increase in renal venous pressure leads to a decrease in GFR.

In patients with ADHF, there is a potential for ascites and visceral edema that might increase the IAP. Intra-abdominal hypertension (IAH) (IAP >8 mm Hg) is associated with intra-abdominal organ dysfunction. The role of IAP in the pathogenesis of ADHF was recently investigated by Mullens et al. (25) in 40 patients with ADHF (LVEF 19 ± 9 percent, serum creatinine 2.0 ± 0.9 mg/dL), 60 percent of whom had elevated IAH. Elevated IAP was associated with worse renal function (p = 0.009). Intensive medical therapy resulted in improvement in both hemodynamic measurements and IAP. A strong correlation (r = 0.77, p < 0.001) was observed between reduction in IAP and improvement in renal function. However, changes in IAP or renal function did not correlate with changes in any hemodynamic variables (Figure 1). It appears, therefore, that elevated IAP is prevalent in a large number of patients with ADHF and is associated with impaired renal function. However, it is unclear whether high IAP is related to raised venous pressure.

Figure 1

Intra-abdominal pressure (IAP) is increased in a significant number of patients with ADHF. The left half of the graph shows that elevated IAP is associated with worse renal function. Note a strong correlation between reduction in IAP and improved renal function in patients with baseline elevated IAP (Redrawn from Mullens et al. J Am Coll Cardiol 2008; 51:300–6).


To determine whether increased venous pressure rather than impairment of cardiac output is primarily associated with the development of WRF in patients with ADHF, the same inveatigators (26) studied 145 consecutive patients admitted with ADHF (age 57 ± 14 years, cardiac index 1.9 ± 0.6 L/min/m2, LVEF 20 ± 8 percent, serum creatinine 1.7 ± 0.9 mg/dL). WRF developed in 40 percent of these patients. Patients who developed WRF had a higher central venous pressure (CVP) on admission (18 ± 7 mm Hg versus 12 ± 6 mm Hg, p < 0.001) after intensive medical therapy (11 ± 8 mm Hg versus 8 ± 5 mm Hg, p = 0.04). High venous pressure was the most important hemodynamic factor driving WRF in ADHF.

Is cardiorenal syndrome reversible?

In low cardiac output states, auto-regulatory mechanisms help to maintain coronary and cerebral perfusion at the expense of other major organs including the kidneys, liver, and skeletal muscles. The resulting poor renal perfusion contributes to renal dysfunction and has been considered important in the pathogenesis of CRS (21,22). However, studies in patients with chronic heart failure or ADHF have failed to show significant correlation between hemodynamic alterations and renal dysfunction apart from high venous pressure. These findings raise the question of whether intrinsic kidney disease plays a more important role in the pathogenesis of CRS and whether CRS reverses when hemodynamics improve.

Butler and colleagues (27) assessed the relationship between renal function in 220 patients who underwent left ventricular assist device placement. Creatinine clearance (CrCl) increased significantly within a week of left ventricular assist device placement suggesting that renal dysfunction is reversible even in patients with severe end stage heart failure (Figure 2).

Figure 2

Renal function (creatinine clearance) improved substantially and rapidly in post-LVAD survivors (from Butler J, et al. Ann Thorac Surg; 81:1745–1751).


Further support for the reversible nature of CRS comes from studies in patients with chronic constrictive pericarditis. The body fluid compartments, neurohormones, renal function, and hemodynamics were measured in 15 patients with CRS and constrictive pericarditis before and eight weeks after pericardiectomy. Pericardiectomy rapidly normalized the hemodynamics, neurohormones, body fluid compartments, and renal dysfunction. The cardiac index increased from 2.0 ± 0.2 to 3.6 ± 0.3 L/min/m2, right atrial pressure fell from 22.1 ± 1.2 mm Hg to 5.3 ± 0.7 mm Hg, ERPF increased from 243 ± 21 to 382 ± 34 L/min/1.73 m2, and serum creatinine fell from 1.5 to 1.0 mg/dL (28). Taken together these data underscore the importance of hemodynamics in the pathogenesis of CRS and demonstrate that in many patients renal dysfunction is reversible if the hemodynamics can be improved.


CRS is very common in patients with ADHF or chronic heart failure and is an independent predictor of poor clinical outcomes. The exact prevalence of structural kidney disease in CRS is unknown but is likely to be high because of the common association of atherosclerotic CV disease, diabetes, and hypertension with heart failure. Although low cardiac output-induced neurohormonal activation in heart failure reduces renal blood flow and is probably an important factor contributing to renal dysfunction, the exact role of hemodynamic mechanisms is not entirely clear.

Increasing data suggest that elevated venous pressure may contribute to renal dysfunction in heart failure. In many patients, renal dysfunction does normalize when the pump function improves. In others, the underlying structural renal disease may contribute to permanent renal dysfunction. Further studies are required to improve our understanding of the complex interactions between heart failure and renal dysfunction to enable us to devise better therapies for CRS.


[1] Inder S. Anand, MD, DPhil, is professor of medicine, University of Minnesota Medical School, and director of the heart failure program at the VA Medical Center in Minneapolis, MN.



K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39:S1–266.


Gottlieb SS, Abraham W, Butler J, et al. The prognostic importance of different definitions of worsening renal function in congestive heart failure. J Card Fail 2002; 8:136–141.


Ronco C, McCullough P, Anker SD, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 2010; 31:703–711.


Dries DL, Exner DV, Domanski MJ, et al. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol 2000; 35:681–689.


Shlipak MG, Smith GL, Rathore SS, et al. Renal function, digoxin therapy, and heart failure outcomes: evidence from the digoxin intervention group trial. J Am Soc Nephrol 2004; 15:2195–2203.


Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006; 113:671–678.


Khan NA, Ma I, Thompson CR, et al. Kidney function and mortality among patients with left ventricular systolic dysfunction. J Am Soc Nephrol 2006; 17:244–253.


Ahmed A, Rich MW, Sanders PW, et al. Chronic kidney disease associated mortality in diastolic versus systolic heart failure: a propensity matched study. Am J Cardiol 2007; 99:393–398.


Anand IS, Bishu K, Rector TS, et al. Proteinuria, chronic kidney disease, and the effect of an angiotensin receptor blocker in addition to an angiotensin-converting enzyme inhibitor in patients with moderate to severe heart failure. Circulation 2009; 120:1577–1584.


McAlister FA, Ezekowitz J, Tonelli M, Armstrong PW. Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation 2004; 109:1004–1009.


Ezekowitz J, McAlister FA, Humphries KH, et al. The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol 2004; 44:1587–1592.


McClellan WM, Flanders WD, Langston RD, et al. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol 2002; 13:1928–1936.


Smith 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.


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; 43:61–67.


Cowie MR, Komajda M, Murray-Thomas T, et al. Prevalence and impact of worsening renal function in patients hospitalized with decompensated heart failure: results of the prospective outcomes study in heart failure (POSH). Eur Heart J 2006; 27:1216–1222.


Heywood JT, Fonarow GC, Costanzo MR, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail 2007; 13:422–430.


Nohria A, Hasselblad V, Stebbins A, et al. Cardiorenal interactions: insights from the ESCAPE trial. J Am Coll Cardiol 2008; 51:1268–1274.


Akhter MW, Aronson D, Bitar F, et al. Effect of elevated admission serum creatinine and its worsening on outcome in hospitalized patients with decompensated heart failure. Am J Cardiol 2004; 94:957–960.


Chittineni H, Miyawaki N, Gulipelli S, Fishbane S. Risk for acute renal failure in patients hospitalized for decompensated congestive heart failure. Am J Nephrol 2007; 27:55–62.


Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 2004; 147:331–338.


Anand IS, Ferrari R, Kalra GS, et al. Edema of cardiac origin. Studies of body water and sodium, renal function, hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Circulation 1989; 80:299–305.


Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet 1988; 331:1033–1035.


Weinfeld MS, Chertow GM, Stevenson LW. Aggravated renal dysfunction during intensive therapy for advanced chronic heart failure. Am Heart J 1999; 138:285–290.


Bradley SE, Bradley GP. The effect of increased intra-abdominal pressure on renal function in man. J Clin Invest 1947; 26:1010–1022.


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; 51:300–306.


Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53:589–596.


Butler J, Geisberg C, Howser R, et al. Relationship between renal function and left ventricular assist device use. Ann Thorac Surg 2006; 81:1745–1751.


Anand IS, Ferrari R, Kalra GS, et al. Pathogenesis of edema in constrictive pericarditis. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones before and after pericardiectomy. Circulation 1991; 83:1880–1887.