communication between these two organs occurs at multiple levels including the sympathetic nervous system ( sns ) , the renin - angiotensin - aldosterone system ( raas ) , the antidiuretic hormone , endothelin , or the natriuretic peptides . the dysfunction of one of them contributes to the dysfunction of the other ; renal dysfunction impairs cardiac performance , which again leads to further impairment of renal function . the term  cardiorenal syndrome  ( crs ) was coined to define this situation , but a consensus of the diagnostic criteria has not been reached yet . initially , it was characterized as a state in which therapy to relieve congestive heart failure ( hf ) symptoms was limited by further worsening renal function . although this definition does not accurately describe the complexity of its nature , it portrays a common situation in daily clinical practise . a broader definition of the crs was developed by the acute dialysis quality initiative . the crs was classified into five categories , according to the underlying etiologies and the nature of concomitant cardiac and renal dysfunction ( table 1 ) . heart failure seems to be the primary failing organ in two of the five described features . crs type 1 occurs when acute decompensated heart failure ( adhf ) leads to acute kidney injury . crs type 2 refers to the development of a progressive worsening of renal function ( wrf ) in the setting of chronic heart failure ( chf ) . both , acute and progressive development of renal dysfunction in patients with heart failure , have been associated with independently worse outcomes compared with preserved renal function [ 313 ] . therefore , a precise understanding of the pathophysiology of this syndrome is needed to provide the rationale for management strategies . the pathophysiology of the cardiorenal syndrome remains unclear but can be attributed to three main factors : low - cardiac output , elevation of both intra - abdominal and central venous pressures , and neurohormonal and inflammatory activation [ 14 , 15 ] . the terms  backward failure  and  forward failure  have been historically used to classify hf syndrome . although not commonly used nowadays , this classification allows an intuitive approach to understand the underlying mechanisms of these forms of crs . this appears to be one of the cornerstones in the development of crs , but not the only one . multiple studies support this conclusion : the evaluation study of congestive heart failure and pulmonary catheterization effectiveness ( escape ) trial associated baseline kidney dysfunction ( estimated glomerular filtration rate , -gfr- , < 60  ml / min ) at admission and at discharge with an increased risk of death and rehospitalization . patients randomized to the group , in which therapy was guided by clinical assessment and a pulmonary artery catheter ( pac ) , presented significantly less deterioration of kidney function , compared with a therapy based on clinical assessment alone , but this did not imply an improvement in clinical outcomes in patients with baseline ckd . incidence of wrf during hospitalization ( serum creatinine > 0.3  mg / dl ) was similar in both arms , and was not associated to increased outcomes of death or rehospitalization . among hemodynamic parameters measured in the pac arm , only right atrial pressure correlated weakly with baseline serum creatinine ( r = 0.165 , p = .03 ) . they studied 145 patients admitted with adhf and treated with intensive medical therapy guided by pulmonary artery catheter . patients who developed wrf did not have a lower cardiac index on admission or at discharge when compared with those without wrf . the mean baseline cardiac index was significantly greater in subjects who developed wrf versus those who did not ( 2.00  0.8  l / min / m versus 1.8  0.4  l / min / m , p = .008 ) . at follow - up , the mean cardiac index and the central venous pressure remained superior ( 2.7  0.7  l / min / m versus 2.4  0.5  l / min / m , p = .01 and 11  8  mm  hg versus 8  5  mm  hg , p = .04 , resp . ) in subjects who developed wrf . these findings support the hypothesis that there must be another mechanism that contributes to renal impairment in heart failure . rising renal venous pressure limits urine formation and renal flow . backward failure implies that systemic venous congestion also affects renal venous pressure and function ( congestive kidney failure ) , by direct hypoxic damage or through raas / sns stimulation way . a substudy of the studies of left ventricular dysfunction ( solvd ) established the prognostic implication of jugular venous pressure on patients with chf . patients with increased venous pressure had a significantly higher serum creatinine level ( 115  27 versus 106  27 interestingly , mullens et al . also described that patients who developed wrf had greater central venous pressure on admission ( 18  7  mm  hg versus 12  6  mm  hg , p = .001 ) and after intensive medical therapy ( 11  8  mm  hg versus 8  5  mm  hg , p = .04 ) . the development of wrf occurred less frequently in patients who achieved a central venous pressure < 8  mm  hg . evaluated right atrial pressure and cardiac index by right heart catheterisation , in 51 patients with cardiac dysfunction , secondary to pulmonary hypertension . in a multivariate analysis , low renal blood flow and high right atrial pressure were independently associated with lower gfr . intra - abdominal pressure has been considered an alternative pathway to explain how decompensated hf may lead to wrf . increased abdominal pressure may lead to renal impairment by a  compressing effect  in renal parenchyma . hence , elevated intra - abdominal pressure ( defined as > 8  mm  hg ) has been associated with significantly lower gfr compared with those with normal iap in patients with advanced decompensated hf ( mean lvef 19% ) . these authors also studied the effect of mechanical fluid removal to reduce iap in patients with adhf , showing a strong correlation ( r = 0.77 , p < .001 ) was observed between improved renal function in patients reduction in iap and with baseline elevated iap . in any case interventions focused on the interactions of the networks which link both systems ( raas , imbalance between reactive oxygen species and nitric oxide , sympathetic nervous system and inflammation processes ) might help to control the progression of the crs . despite its common pathophysiology , each crs 's type embraces a broad spectrum of clinical features . therefore , therapies should be adapted to each single patient 's own situation ( table 2 ) . although their use is widespread , there is little evidence of their influence in managing crs . their use may be associated with electrolyte abnormalities , further neurohormonal activation and worsening renal function . in addition , they may increase the risk to develop adverse effects of concomitant medications , such as angiotensin converting enzyme inhibitors ( acei ) , angiotensin ii receptor blockers ( arb ) , or spironolactone . hence , the first problem to deal with is to strike a balance between removing volume to relieve congestion without stimulating adverse effects . there is lack of evidence in the literature about this topic , not only in ahf , but also in ckd patients , as they are systematically excluded from randomized trials . high - dose administration of intravenous loop diuretics has been associated with worse outcomes in hf patients [ 24 , 25 ] . results of the dose optimization strategy evaluation ( dose ) trial , recently presented at the american college of cardiology ( acc ) 2010 scientific sessions , may highlight this matter . it included acute heart - failure patients with a prior diagnosis of chronic heart failure ( chf ) and daily outpatient use of oral loop diuretics ( 80  mg to 240  mg ) for at least one month . patients with serum creatinine > 3  mg / dl were excluded . patients were randomized to either high dose ( 2.5  their daily chronic oral furosemide dose given iv ) or low dose ( their daily chronic oral furosemide dose given iv ) and were also randomized to dosing via intravenous bolus or continuous infusion . the primary endpoints were symptom resolution and change in serum creatinine from admission to 72 hours . there were no significant differences among the different dosing strategies for any of the two endpoints . the high - dose strategy showed greater symptom improvement , ( p = .06 ) , but was also associated with mild increases in creatinine levels , defined as a > 0.3  mg / dl rise in creatinine . there were no differences among groups for death or rehospitalization outcomes . results of this trial suggest that , apparently , an overaggressive use of loop diuretic is as safe as a conservative treatment . if the response to loop diuretics is inadequate , a thiazide should be added in a dose determined according to the patient 's renal function . these patients should , therefore , be followed closely to prevent volume , magnesium , and potassium depletion . again , this empirical management , which results to be effective in daily practise , has not been tested . vasodilators , such as intravenous nitroglycerin , are recommended at an early stage for ahf patients without hypotension or serious obstructive valvular disease . the reduction in venous pressure may improve transrenal blood flow while protecting renal function , but doses that decrease blood pressure may cause a decline in renal perfusion and further activation of the raas . although it has been published that isosorbide dinitrate should have a beneficial effect in patients with ahf , no randomized controlled studies have been carried out to evaluate its role neither in cardiorenal syndrome nor even in ahf . the ascend trial ( a study testing the effectiveness of nesiritide in patients with acute decompensated heart failure ) enrolled 7,141 patients with severe hf , to determine whether nesiritide was superior to placebo in reducing the hf related hospitalization rate or all cause mortality at 30-days and improvement in dyspnea at six or 24 hours . patients were randomly assigned to continuous intravenous nesiritide or placebo plus standard treatment for 30 days . compared with placebo , nesiritide was not associated with a reduction in 30 day death or hf rehospitalization ( 10.1% versus 9.4% ; p = .31 ) . vasopressin antagonists selectively inhibit the v2 receptor of renal distal tubules and collecting duct , increasing aquaresis and serum sodium in those who are hyponatremic . safety and efficacy of these agents have been tested in several trials in patients with ahf during the acute phase . although they have not proven long - term benefit on clinical outcomes , they could have a favorable effect on renal hemodynamics . adenosine a1 receptor antagonists improve renal blood flow and increase sodium excretion , by enhancing natriuresis , with preserving gfr , in combination with furosemide . an ongoing trial ( a study of the selective a1 adenosine receptor antagonist kw-3902 for patients hospitalized with acute hf and volume overload to assess treatment effect on congestion and renal function , protect-2 study ) is evaluating its application in adhf patients . the ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated congestive heart failure ( unload ) trial demonstrated a greater weight loss in ultrafiltration group , as well as lower rehospitalization rates and emergency department visits , compared to a diuretic - based strategy . inotropic agents should be considered in patients with low - output states in the presence of signs of hypoperfusion or congestion despite the use of vasodilators and/or diuretics . dobutamine has been associated to an increase in renal blood flow , proportional to the increase in cardiac index . low - dose dopamine has also been associated with a theoretical effect on renal blood flow . although it has been proposed that an improvement in cardiac output might lead to preserving renal function , this widespread empirical therapy has not been tested in randomized trials . only milrinone and levosimendan have been evaluated in this situation , and none of them have demonstrated an improvement in renal function [ 15 , 31 ] . mechanisms which lead to a progressive renal impairment in patients with chf are still unclear . several factors may contribute to this situation , including hemodynamic changes , diuretic 's side effects , or a microvascular damage secondary to a concomitant illness ( such as hypertension or diabetes ) . although many pharmacological and no pharmacological therapies have proven to be an advantage on survival in hf , their prescription is often limited by the fear to develop complications attributable to wrf . the results of the registry to improve the use of evidence - based heart failure therapies in the outpatient setting ( improve hf ) have been recently published . the aim of this prospective study was to evaluate the adherence to aha / acc guidelines recommendations in the management of chronic heart failure ( aceis / arb , -blockers , aldosterone antagonists , cardiac resynchronization therapy , implantable cardioverter defibrillator , anticoagulation if atrial fibrillation / flutter , and patient education ) and to determine the influence of renal dysfunction in applying these therapies . about 52% of the patients had a gfr < 60  ml / min/1.73  m. the use of acei / arb ( 87.4% in patients with gfr > 90  ml / min/1.73  m versus 57.9% in patients with gfr < 29  ml / min/1.73  m , p < .001 ) , -blockers ( 90.4% in patients with gfr > 90  ml / min/1.73  m versus 86.2% in patients with gfr < 29  ml / min/1.73 m ) , and aldosterone antagonists was significantly lower in patients with a higher stage of ckd . multivariate analysis showed that the severity of ckd was an independent predictor of adherence to acei / arb ( hr 0.94 ; ci 95% 0.880.99 ; p = .018 ) , but not in the other recommended interventions . treatment with acei improves ventricular function ( as evidenced by an increased ejection fraction and decreased ventricular size ) and patient well - being , reduces hospital admission for worsening hf , and increases survival . this therapy should be used in all patients with symptomatic hf and a lvef < 40% . as it is common to observe a significant increase in the serum creatinine concentration ( > 0.3  mg / dl ) within the initiation of treatment with acei , renal function should be closely monitored . esc guidelines of management of hf accept a 50% increase in creatinine serum level from baseline or an absolute concentration of 3  mg / dl , whichever is lower . if creatinine rises between 33.5  mg / dl , esc guidelines recommend to halve dose of acei . treatment with acei must be interrupted if creatinine serum concentration rises above 3.5 mg / dl . the influence on cardiorenal protection of raas dual blockade , when an arb is used in conjunction with an acei , has also been analyzed in several trials . among patients with hf , an aldosterone antagonist should be added to treatment in symptomatic patients with hf and an lvef < 35% . 5.5 mmol / l ) , esc guidelines suggest to halve the spironolactone or eplerenone doses . when serum creatinine is > 3  mg / dl ( or potassium > the canadian cardiovascular society includes among its recommendations some options of management for these patients . thus , renal function must be checked daily in patients with heart failure and increasing serum creatinine more than 30% from baseline , and acei , arb , and aldosterone dose should be reduced until renal function stabilizes . in oliguric hf patients treatment with diuretics , acei , arb , or aldosterone should be reviewed daily . routine use of ace inhibitors , arbs or spironolactone in the setting of severe renal dysfunction ( serum creatinine levels greater than 250  mol / l or an increase of more than 50% from baseline ) is not routinely recommended . despite these recommendations , it is important to emphasize that serum creatinine concentration is not an accurate measure of gfr . creatinine serum levels vary according to gender , person 's size , and muscle mass , and this must be taken into account . the most common formula for calculating the gfr has not been validated in acute renal failure , but there is on increasing interest in new renal biomarkers for the diagnosis and classification of crs , such as cystatin c or the neutrophil gelatinase - associated lipocalin . neither acc / aha nor esc guidelines establish the correction of anemia as a systematic target in patients with hf , although it has been associated with poor clinical outcomes . even though there is actually no definitive evidence to the optimum approach for the management of anemia in patients with chf which develop a progressive renal dysfunction ( cardiorenal syndrome type 2 ) , a pragmatical strategy for anemia correction , based on ckd guidelines and hf trials , has been proposed . because of the adverse cardiovascular effects of higher hematocrit in ckd trials , authors suggest a target hemoglobin of 1012  g / dl at clinical practise . if hb drops below 10  g / dl , iron deficiency should be excluded before starting therapy with erythropoiesis stimulating agents . nonetheless , patients with hf might benefit from more aggressive anemia correction in view of the results of several cardiology trials [ 3639 ] . the appropriate strategy to take care of these patients remains unclear , both in acute and chronic clinical situations . in accordance with the most plausible underlying pathophysiological mechanisms , treatment targets should be oriented toward an adequate intravascular volume management and to ensure a proper renal perfusion . although there are encouraging advances around this unsolved clinical problem , further investigation should consider the progressive inclusion of patients with advanced renal impairment to allow a better understanding of cardiorenal syndrome .
the clinical relevance of the bidirectional cross - talk between heart and kidney is increasingly recognized . 
 however , the optimal approach to the management of kidney dysfunction in heart failure remains unclear . 
 the purpose of this article is to outline the most plausible pathophysiologic theories that attempt to explain the renal impairment in acute and chronic heart failure , and to review the current treatment strategies for these situations .