Impaired cardiac function leads to activation of the neurohumoral axis, sodium and water retention, congestion and ultimatelyimpaired kidney function. This sequence of events has been termed the Cardiorenal Syndrome. This is different from theincrease in cardiovascular complications which occur with primary kidney disease, that is, the so-called Renocardiac Syndrome.The present review discusses the pathogenesis of the Cardiorenal Syndrome followed by the benefits and potential deleteriouseffects of pharmacological agents that have been used in this setting. The agents discussed are diuretics, aquaretics, natriureticpeptides, vasodilators, inotropes and adenosine α1 receptor antagonists. The potential role of ultrafiltration is also brieflydiscussed.
1. Introduction
Patients with acute heart failure syndromes (AHFS) areusually admitted because of severe systemic congestion thatfrequently presents with dyspnea. Known as the hallmarkof AHFS, congestion is mainly due to pulmonary venoushypertension (World Health Organization type 2). Thesepatients may also present with low cardiac output and/orsystemic hypotension. This has ranged from <2% [1] to 7.7%[2] to 29% [3] depending on the series. Dyspnea is the mostcommon symptom in these patients that implies an elevatedpulmonary venous pressure that is often accompanied byincreased central venous pressure (CVP) and/or peripheraledema. Therefore, the most reasonable therapeutic targetis systemic congestion. There is substantial evidence thatthe main driver of morbidity, mortality, and readmissionto the hospital is volume overload [1–5]. Moreover, it iswell established that patients who are admitted with AHFSand renal dysfunction have worse outcomes [1, 5–9]. Inthis paper, we discuss the pathophysiology of AHFS and itscontribution to impairment of kidney function. In the end,we approach the current evidence of therapeutic strategies inpatients with cardiorenal syndrome in AHFS.
2. Pathophysiology
As noted above, the hallmark of AHFS is congestion. Theinteraction between the heart and the kidney is modulatedby the cardiorenal axis. The sympathetic nervous system(SNS), renin-angiotensin-aldosterone system (RAAS), andarginine vasopressin (AVP) are the primary neurohormonesthat maintain the integrity of effective arterial blood volume,hence the cardiorenal axis [4, 10–14].
In a nonfailing heart, an increase in left atrial pressurestimulates a feedback system, which decreases the releaseof AVP from posterior pituitary. This reflex is abolishedby vagotomy. Furthermore, the elevated atrial pressuredecreases the renal SNS stimulation. On the other hand,natriuretic peptides are released due to myocardial stretchand dilatation. The interaction of these pathways ultimatelyincreases sodium and water excretion that maintains a steadystate for total blood volume and preserves the integrity of thearterial circulation [4, 13] (Figure 1).
When heart failure develops, this physiologic response isdisrupted and the kidneys continue to retain sodium andwater despite an elevated total blood volume. However, theprimary regulation of body fluid homeostasis is modulated
2 International Journal of Nephrology
↓ SNS
↑ ANP
↓ AVP
↑ RAP
↑ U/O
Figure 1: Physiologic interaction of neurohormones and main-tenance of total blood volume. U/O: Urine output, ↑: increased,RAP: right atrial pressure, ANP: atrial natriuretic peptide, SNS:sympathetic nervous system and AVP: arginine vasopressin.
by the smaller arterial circulation, enabling the systemresponsible for the perfusion of the body’s vital organs torespond to small changes in body fluid volume [4, 10, 11].This portion of blood volume only comprises 15% of thetotal blood volume [10, 11]. Therefore, in a failing heart,despite elevated total sodium and total water and significantengorgement of the venous system, kidneys continue toretain sodium and water due to disrupted maintenance ofbody fluid homeostasis (Figure 2). This applies to patientswith low or high cardiac output [10].
Elevated level of renin secretion is demonstrated in earlystages of heart failure [14]. Renin stimulates angiotensinII (Ang-II) generation. Angiotensin II causes arterial vaso-constriction and therefore, increases cardiac afterload witha resultant decrease in stroke volume. Moreover, Ang-IIstimulates the release of aldosterone and SNS. The activationof RAAS and SNS results in further vasoconstriction of theafferent arterioles of the kidneys [4, 13] that decreases renalblood flow and glomerular filtration rate (GFR). The stim-ulation of RAAS and SNS also increases proximal tubularabsorption of sodium and decreases sodium delivery to thedistal tubules and collecting ducts, which is the site of actionof aldosterone [15]. Therefore, in patients with heart failureescape from the sodium-retaining effect of aldosterone onthe distal nephrons, a phenomenon that normally occurs, isimpaired. The end-result of this combined neurohormonalactivation is continuous reabsorption of sodium and waterwhich leads to congestion.
SNS is activated through increased Ang-II (see above)as well as activation of the baroreceptors in the aorta andaortic arch [11]. SNS has a positive feedback on RAASstimulation that results in further stimulation of aldosterone.Aldosterone and Ang-II both accelerate fibrosis of themyocardium and remodeling of the failing heart [16]. Fur-thermore, neurohormones are strong mediators of oxidativeinjury, inflammation, and cell death that leads to widespreadendothelial dysfunction. Thus, Ang-II exerts many deleteri-ous effects through the activation of NADPH- and NADH-oxidase. These enzymes are activated within vascular smooth
muscle cells, cardiac myocytes, and renal tubular epithelialcells, generating superoxide, a reactive oxygen species withunfavorable effects [17]. More importantly, nitric oxiderelease by endothelium may be disturbed in the presenceof superoxide and reactive oxygen species. This results inendothelial dysfunction, hypertension, and increased cardiacafterload [17]. As many as 50% of patients with AHFSpresent with a systolic blood pressure >140 mm/Hg [1].Elevated blood pressure is present in patients either withsystolic heart failure or heart failure with preserved ejectionfraction [1].
AVP is a hormone that is secreted from the posteriorpituitary and is normally suppressed by hypoosmolality. Inthe failing heart, however, even in the presence of hypona-tremia, and thus hypoosmolality, there is a marked increasein AVP secretion secondary to nonosmotic baroreceptor-mediated release of the hormone. This phenomenon com-monly overrides the osmotic release of AVP [18–20]. AVPactivates the V2 receptor on the basolateral surface ofprincipal cell of the collecting duct. This increases expressionand trafficking of the aquaporin 2 water channel to theapical surface. The resultant increased water permeabilityof the collecting duct allows osmotic water equilibriumwith the hypertonic interstitium and urinary concentration.Also, AVP stimulates the V1a receptors of the vascularsmooth muscle that results in vasoconstriction of the arterialand venous system. Therefore, AVP increases preload andafterload through V2 and V1a receptor activation [4]. Thus,AVP potentially may result in further remodeling of themyocardium by these pathways (Figure 3).
3. Goal of Therapy
It is evident that the neurohormonal storm and worsen-ing kidney function in AHFS ultimately ensue to venouscongestion and elevated central venous pressure (CVP),which results in a vicious cycle. In a prospective cohortof 145 patients from the Cleveland Clinic, CVP was themost important hemodynamic factor causing worseningrenal function in patients with AHFS [21]. In addition, ina retrospective analysis of 2557 patients who underwentcardiac catheterization for hemodynamic assessment, ele-vated CVP remained as the single most important prognosticfactor for worsening renal function and mortality [22]. Thereis growing evidence that hypervolemia, that is, increasedpulmonary capillary wedge pressure, independently corre-lates with mortality [23] and may predict an urgent needfor cardiac transplantation [24]. Furthermore, improvementin cardiac output/index in patients with AHFS has littleimpact on outcome of patients with AHFS [25], even whentherapy for decongestion is modulated carefully by invasivehemodynamic assessment [26]. Furthermore, transmissionof venous pressure to renal venous system impairs renalblood flow and GFR. In 1861, Ludwig observed that asCVP increased above 10 mm/Hg, the urine output startedto fall [27]. In 1931, Winton showed in isolated kidneysfrom dogs, that elevated venous pressure drops the urineoutput, while the arterial side was connected to a perfusing
International Journal of Nephrology 3
High-output cardiacfailure
Low-output cardiacfailure
Systemic arterialvasodilation
Arterialunderfilling
↑ Nonosmotic AVPrelease
↑ Sympatheticnervous system
↑ Renin-angiotensin-aldosterone system
Diminished renal hemodynamics and renalsodium and water excretion
↓ Cardiac output
Figure 2: Pathophysiology of acute decompensated heart failure. (Reproduced with permission from [8].)
Cardiac failure
↑ Nonosmoticvasopressin release
V1a receptor stimulation
V2 receptorstimulation
Water retention
↑ Proteinsynthesis of
cardiacmyocytes
Coronaryconstriction
Systemic arteriolarvasoconstriction
Venoconstriction
Myocardialischemia
↑ Cardiacafterload
↑ Cardiacpreload
↑Wall stress
Left ventricular dilatationand hypertrophy
Figure 3: Vasopressin stimulation of V2 and V1a receptors can contribute to events that worsen cardiac function (with permission from[2].)
pump [28]. More recently, Mullens et al. demonstrated thatintra-abdominal pressure (IAP) correlated with worseningrenal function and lowering IAP improves renal function[29]. Thus, the focus of the clinician should be on reducingthe congestion with as little hemodynamic compromise aspossible. The rate of fluid removal, therefore, should notexceed the interstitial fluid mobilization rate (estimated at 12to 15 mL/min), since it may further activate the RAAS andworsen the neurohormonal storm [25, 30].
4. Treatment of Patients with AHFS
Much of the challenge of the management of patientswith cardiorenal syndrome who present with AHFS lies inthe balance of decongestion and hemodynamic compro-mise. Ideally, one wishes to lower the preload, afterloadand pulmonary capillary wedge pressure without reduc-ing the blood pressure and GFR. Thus, the ideal agentshould reduce left ventricular filling pressure, pulmonary
4 International Journal of Nephrology
Table 1: Pharmacologic agents in the management of patients with AHFS.
Medication Initial dose Dose range comments
Diuretics
Furosemide 20–80 mg IV bolus20–400 mg boluses may
repeat q6–8 HInfusion is recommended at 5 to 40 mg/hr. If >240 mg/hr,
Nitroprusside 0.3–0.5 μg/kg/min 0.3–5 μg/kg/minInfusion rates of >10 μg/kg/min may cause cyanide
toxicity. Also, caution during active myocardial ischemia
Nitroglycerine 10–20 μg/min 20–400 μg/min severe headache, hypotension, closed-angle glaucoma
Nesiritide NO BOLUS 0.005–0.03 μg/kg/minTitration: increase infusion rate by 0.005 μg/kg/min (no
more than every 3 hr, up to a maximum of0.03 μg/kg/min)
Inotropes
Dopamine 2–5 μg/kg/min 2–20 μg/kg/min May increase mortality. Caution for arrhythmia
Dobutamine 1-2 μg/kg/min 1–20 μg/kg/min May increase mortality. Caution for arrhythmia
Milrinone50 μg/kg IV loading dose
over 10 min; then0.25–1.0 μg/kg/min infusion
0.10–0.75 μg/kg/min May increase mortality. Caution for arrhythmia
Other
Levosimendan0.05–0.2 μg/kg/min bolusover 10 min followed by
infusion0.5–2.0 μg/kg/min
May increase mortality. Not approved in the US. Cautionfor hepatic impairment and LV outflow obstruction
congestion, improve renal function, preserve myocardialtissue, reduce neurohormonal levels, and not increase theincidence of arrhythmias. Unfortunately, to date there isno such medical regimen available. Since congestion is thehallmark of heart failure and correlates with morbidity andmortality in short, and long-term studies (see above), theprimary aim of therapy should focus on decongestion withthe goals described above.
5. Pharmacologic Approach
We divide therapy to pharmacologic and nonpharmacologicinterventions with the latest available evidence. For phar-macologic approach, one may utilize diuretics, aquaretics(V2 receptor antagonists), vasodilators, and inotropes. Fornonpharmacologic approach, there is a paucity of well-done randomized control data in patients with AHFS;nevertheless, we will discuss the role of ultrafiltration inpatients with AHFS.
5.1. Diuretics. Heart Failure Society of America guidelinesrecommends loop diuretics as the corner stone of ther-apy in patients with congestive symptoms in the settingof AHFS [31]. More than 88% of patients receive loopdiuretics, mainly intravenously [1]. There are no randomizedcontrolled trials to have evaluated the outcome studies of
loop diuretics, but it is evident that patients with AHFSshould not be left in the congestive state. As stated earlier,congestion correlates with mortality. Loop diuretics relievethe symptoms, even before diuresis [31] and also reducethe wedge pressure and left ventricular filling pressure. Inpatients who have severe congestion and renal dysfunction,diuresis may improve kidney function, possibly throughrelieving the venous and/or abdominal congestion. Thedilemma, however, is the fact that there is no prognosticationas to which patient will improve or worsen with diuretictherapy. In Table 1 are listed the diuretics in clinical practicefor AHFS.
Comprehensive HFSA guideline recommends switchingfrom intravenous to continuous infusion in patients whoseem to be nonresponsive to diuretics [31]. This questionhas been recently investigated in a randomized double-blind,double dummy controlled trial in a 2 × 2 factorial designin Diuretic Optimization Strategies Evaluation (DOSE) trial[30]. In this study, the investigator concluded there was nostatistically significant difference in global symptom relief orchange in renal function at 72 hours (coprimary endpoint)between intermittent versus continuous infusion or low dose(×1 of the oral outpatient dose) versus high dose (×2.5 timesof the oral outpatient dose) [32]. This is the first randomized,controlled exploration of a management strategy in loopdiuretics in AHFS patients. However, the high-dose strategycaused a mild renal dysfunction that was reversible within
Figure 4: The mechanisms of adverse effects of loop diuretics (with permission from [11]).
one week. There was also no evidence for increased risk ofclinical events at 60 days after high-dose therapy or after low-dose, continuous, or intermittent diuretic therapy. On theother hand, patients in the high-dose group, compared withthe low-dose group, showed significant improvements in aseries of secondary end points assessed at 72 hours, includingweight loss, heart-failure biomarkers and dyspnea [32].
Despite all the benefits of loop diuretics in acutesetting there are serious adverse effects associated withthese agents [13]. Loop diuretics frequently develop elec-trolyte abnormalities, mainly hyponatremia, hypokalemiaand hypomagnesemia. The loop diuretics inhibit the mac-ula densa of the nephron. This results in further releaseof renin and stimulation of neurohormones and acutevasoconstriction response after administering loop diuretics(Figure 4) [33]. The vasoconstriction can reduce the GFR byfurther afferent vasoconstriction, which may occur despitesubstantial increase in urine output [34]. However, improvedmyocardial function may develop due to reduction inventricular size and wall stress. This may ultimately diminishmitral regurgitation and improve cardiac output and GFR[13]. Hypotension does not frequently happen when usingdiuretics, but it may occur in the presence of generous dosesof vasodilators.
Another important dilemma in managing these patientsis diuretic resistance. Patients with AHFS have significantneurohormonal activation and may have chronic kidneydysfunction [1]. Using loop diuretics may quickly worsenthe compromised GFR and further enhance neurohormonalstimulation. In addition, there is a potential hypertrophyof the distal tubule in these patients that further limitsthe kidney’s response to diuretics [35, 36]. To overcomediuretic resistance, it is always a reasonable approach to limittotal daily sodium intake to less than 2 gm. HFSA guideline
recommends fluid restriction of 2 liters and if patienthas moderate hyponatremia (<130 mEq/L), more aggressivefluid restriction [31]. The pharmacologic approach to over-come resistance is to add another diuretic that blocks thedistal tubule, such as a thiazide diuretic. Another approachis adding metolazone but consideration of the agent’s longhalf life is very important (∼5 days). Lastly, switching fromintermittent to continuous infusion may be considered,although as stated above, in the randomized control study,the outcome was not different. At the time of writing of thispaper further details of the DOSE trial are not available.
5.1.1. Mineralocorticoid Antagonists. About 50% of patientswith AHFS have heart failure with preserved ejection fraction(HFPEF) [1]. In these patients, the neurohormonal stimula-tion is independent of the cardiac output or ejection fractionof the patient. On the other hand, cirrhotic patients share acommon pathophysiology for sodium and water retention byneurohormonal activation secondary to splanchnic vasodi-lation. As stated earlier, patients with heart failure cannotescape from the sodium-retaining effect of aldosterone.The same is true for cirrhotic patients with ascites. Thus,patients with heart failure have a similar pathophysiology ofcirrhotic patients. Both patient populations have secondaryhyperaldosteronism. The diuretic of choice in cirrhosis ismineralocorticoid antagonists, not a loop diuretic [37]. Theyare used as the mainstay of therapy since they target aprimary underlying pathophysiology of the disease namely,secondary hyperaldosteronism. Loop diuretics are utilizedin cirrhosis as an adjunct. In the Randomized AldactoneEvaluation Study (RALES), spironolactone was used as 25 mgorally once a day [38]. It was shown that this dose did notdecrease sodium retention. The interpretation of the RALES
6 International Journal of Nephrology
study therefore was that the results were due to nongenomic,nonnatriuretic effects of spironolactone on myocardiumby preventing further remodeling and/or reducing fibrosis[38]. There are limited data for using the natriuretic dosesof spironolactone (at least 50 mg orally once a day) inpatients with heart failure. To our knowledge, other thana small report, there are no randomized well-conductedstudies available to evaluate the effect of natriuretic doses ofspironolactone in heart failure patients. In 1965, Braunwaldet al. conducted a small trial of spironolactone in 3 patientswith heart failure (mainly due to valvular disease). The doseof spironolactone utilized in that study was 100 mg orallyonce a day and sodium excretion increased [39]. In a smallprospective study in patients with severe heart failure andconfirmed diuretic resistance, the effect of spironolactonewas investigated [38]. All medications were discontinued.Spironolactone was started at 200 mg orally twice a day,while the patients were taken off supplemental potassium.Over a 4-day period, spironolactone completely abolishedthe urinary sodium retention and atrial natriuretic peptidediminished substantially [40].
Since the publication of RALES study, there has beensome concern regarding the risk of hyperkalemia. Thiscautionary note is mainly based on one epidemiologic studyfrom Canada. In this study, the investigators observed astatistically significant increased risk of hospitalization andhospital mortality in association with hyperkalemia afterpublication of the RALES trial [41]. However, a subanal-ysis of Eplerenone Post-Acute Myocardial Infarction HeartFailure Efficacy and Survival Study (EPHESUS) showed thateplerenone (dose range of 25 to 50 mg/d) in postmyocardialinfarction patients with heart failure and/or LV ejectionfraction (LVEF < 40%) did not significantly increase therisk of hyperkalemia [42]. Furthermore, in another studyfrom Scotland, in a population-based longitudinal analysisin patients with or without heart failure, there has beenno increase in hospitalizations for hyperkalemia between1994 to 2007 [43]. Nevertheless, with the paucity of resultswith natriuretic doses of mineralocorticoid antagonists(>25 mg/day of spironolactone or >50 mg of eplerenone),prospective, randomized studies need to be performed inpatients with AHFS, in the presence of a low-potassiumdiet and a potassium-losing loop diuretic, to block thesodium retaining effect of aldosterone by careful titrating ofspironolactone doses greater than 25 mg/d. If shown to beeffective in treating congestion in AHFS, this could alter thefrequent rehospitalization for congestion and the dischargeof AHFS patients with continued symptoms of congestion(estimated to be ∼50%).
5.2. Vasopressin Antagonists (Aquaretics). The only phar-macologic agent other than loop diuretics that is capableof rapid diuresis in AHFS is vasopressin antagonist. V2receptors are stimulated by AVP and increase the aquaporins(see above) on the distal nephrons and increases permeabilityto water. A profound water diuresis (aquaresis) occurs byblocking the V2 receptors. Unlike any other diuretics, V2antagonists do not affect the urinary excretion of electrolytes.In fact, in patients with hyponatremia, the serum sodium
concentration normalizes while the intravascular volume isdecreasing. Currently, there are 2 vasopressin antagonistsavailable in the U.S., conivaptan and tolvaptan. Conivaptanis a mixed antagonist (V1a and V2 antagonist) and tolvaptanis a selective V2 receptor antagonist. The indication for usefor both agents is the presence of hyponatremia and heartfailure. It is not indicated for hypervolemia in the absence ofhyponatremia [44].
In the Acute and Chronic Therapeutic Impact of aVasopressin antagonist in Congestive Heart Failure (ACTIV)trial, 319 patients with heart failure were randomized in3 different doses of tolvaptan [45]. Tolvaptan produceda significant decrease in body weight throughout hospi-talization and a modest improvement in HF symptomswithout any adverse hemodynamic compromise, electrolytesabnormalities, or renal dysfunction. A post-hoc analysisof this study demonstrated that mortality was reduced inpatients with renal dysfunction or severe systemic congestionin the tolvaptan arm [44]. In a followup study of the Efficacyof Vasopressin Antagonism in Heart Failure Outcome StudyWith Tolvaptan (EVEREST) trial, patients were randomizedto tolvaptan or placebo and followed for short term andlong-term (median follow-up of 9.9 months) outcomes [46].While tolvaptan produced a substantial normalization of theserum sodium concentration and significant weight loss incomparison to placebo, these findings did not translate tobeneficial effect on readmission for heart failure or mortality[46]. EVEREST did show a statistically significant decreasein dyspnea during the first week on congestion. Thus far,there is only one study in AHFS patients with a mixedV1a/V2 antagonist (conivaptan) [47]. In this pilot studywith conivaptan, there was a marked aquaresis in heartfailure patients without any hemodynamic compromise [47].Whether this agent improves outcomes of patients withAHFS remains to be elucidated.
5.3. Natriuretic Peptides. Brain natriuretic peptides (BNP)act upon guanylyl cyclase-linked natriuretic peptide recep-tors A and B. The downstream pathway of stimulation ofthese receptors is increased cyclic GMP production. Natri-uretic peptides reduce the cardiac filling pressure and canimprove symptoms of dyspnea as shown in Vasodilatationin the Management of Acute CHF study (VMAC) [48].Nesiritide, a synthetic natriuretic peptide, was able to reducesignificantly the pulmonary capillary wedge pressure in 15minutes when compared to placebo, but not when comparedto nitroglycerine [48]. Subsequently, significant concern wasraised against nesiritide by a meta-analysis of randomizedcontrolled trials that found a significant increased risk ofworsening renal function [49]. In a retrospective study fromthe Mayo Clinic, Riter et al. demonstrated if these agentsare judiciously used in low doses without an initial bolus(as was the case in the trials), the renal function improves[13, 50]. This approach has not been studied in a randomizedcontrolled trial.
5.4. Vasodilators. Decongestion is the center focus of treat-ment of patients with AHFS with the expectation thatas intravascular volume falls, cardiac filling pressures will
International Journal of Nephrology 7
decline and symptoms improve. Therefore, it is a reasonableapproach to target the systemic vascular resistance. Bydecreasing the vascular resistance, the cardiac filling pres-sures, pulmonary and systemic congestion may be alleviatedand ventricular systolic and diastolic function may improve.
Nitroglycerine (NTG) improves the hemodynamics bydecreasing right atrial pressure, pulmonary capillary wedgepressure, and reducing afterload [13]. These changes havea substantial effect on the congestive state of the patient.Furthermore, by reducing the preload, the myocardialstretch is diminished and the myocardial wall stress declinessubstantially. While all of these changes intuitively maketherapeutic sense, there has never been any study in patientswith AHFS randomized to NTG versus placebo. There is onlyone study of comparison of high-dose NTG and low-dosefurosemide versus low-dose NTG and high-dose furosemidein patients with AHFS that was in favor of high-dose NTGand low-dose furosemide [51]. While NTG may decreaseBNP, there is a concern for renin elevation, most likelydue to hypotension [52]. There is ample evidence thatNTG increases coronary flow, but whether the coronarycirculation changes in AHFS due to elevated LVEDP andreduced coronary perfusion pressure are beneficial is notwell studied. This is particularly important in heart failurepatients with ischemic cardiomyopathy. Judicious use ofNTG in appropriately selected patients seems to be quite safe(Table 1).
Nitroprusside is a very potent balanced venous andarterial vasodilator. It remains the reference vasodilator forsevere acute low-output left-sided heart failure as long as thearterial pressure is reasonable. In patients with congestionand acute myocardial infarction, nitroprusside is the agent ofchoice. In patients who present with acute or chronic heartfailure, it is still a very reasonable option, as long as theclinician is aware of the potential side effects of nitroprusside.The most important side effects is the precipitous fall inblood pressure (that should be avoided in AHFS), possiblecoronary steal, and thiocyanate toxicity, which can be fatal ifnot treated promptly [15].
5.5. Inotropes. In extreme conditions when the cardiacoutput is compromised, there is a clear indication forusing inotropes. Once very well received in intensive careunits, inotropes now are utilized less often except forcondition just described. There is substantial evidence inlarge randomized clinical trials as well as retrospective studiesthat these agents significantly increase mortality despite allthe desirable effects on hemodynamics including increasingcardiac output and reducing systemic vascular resistance.With the exception of dopamine none of the inotropes haveany effects on renal hemodynamics.
Dobutamine is a synthetic catecholamine that acts onβ1 and weakly on β2 receptors. The β1 receptor has avasodilatory effect on the vascular smooth muscle andpositive inotropy on the myocardium. So, by improvingthe contraction of myocardium and reducing afterload thecardiac output improves. Milrinone blocks the phosphodi-esterase inhibitor III that ordinarily deactivates cyclic AMP(cAMP). The increased cytosolic level of cAMP improves
the myocardial function and decreases the vascular tonesimilar to dobutamine, but by a different mechanism. A novelinotrope that is not approved by FDA in the US is levosi-mendan. This agent stabilizes the conformational changeof troponin to calcium and increases contraction. Therewas a randomized study with and without levosimendan inpatients with severe heart failure which demonstrated animprovement in renal function with levosimendan [53].
Dobutamine has improved the symptoms in heart failureup to 30 days [54, 55]. In a large registry of patients withAHFS, however, dobutamine was associated with a markedincrease in mortality when compared to NTG [56]. In theIntravenous Milrinone for Exacerbations of Chronic HeartFailure (OPTIME-CHF), 951 patients without cardiogenicshock were randomized to milrinone versus placebo. Themain outcome of the study was the cumulative days ofhospitalization for cardiovascular cause within 60 daysfollowing randomization. There was no statistically signif-icant difference between the groups. There was a trendtowards higher mortality in milrinone group (P = .19).Patients in milrinone arm had more episodes of hypotensionthat required intervention compared to placebo [57]. Inthe Randomized Multicenter Evaluation of IntravenousLevosimendan Efficacy (REVIVE) II study, the investigatordemonstrated a significant symptomatic improvement of33% in levosimendan arm [58]. But, this finding was negatedby a trend toward increased mortality in patients randomizedto levosimendan [59].
The routine use of inotropes, therefore, is not recom-mended unless the patient’s hemodynamics are severelycompromised. It is evident that all inotropes may causeharm, mainly by increased mortality. In the era of betablockade as one of the main treatments for chronic heartfailure, many patients may present with AHFS while they areon beta blockers. There are no data as to whether it is safeor unsafe to stop the beta blockade, but a recommendationto decrease the dose by 50% and continue with inotropeof choice seems reasonable. It is important to note thatamong all inotropes, dobutamine and dopamine act uponbeta receptors. So, if it is possible to use milrinone that hasa different mechanism of action and there is no need tostop beta blockers unless the patient is in preshock or shockstate that prompts the physician to stop the beta blockersimmediately.
5.6. Adenosine α1 Receptor Antagonists. Adenosine ismarkedly elevated in patients with AHFS. Since adenosinehas a profound vasoconstrictor effect on the glomeruli,it is theoretically attractive to hypothesize that blockadeof adenosine would improve the kidney function andoutcomes. Since adenosine acts upon α1 receptor on theafferent glomerulus, the agent of choice should be a selectiveα1 adenosine receptor blocker. In the Placebo-ControlledRandomized Study of the Selective A1 Adenosine ReceptorAntagonist Rolofylline for Patients Hospitalized with AcuteDecompensated Heart Failure and Volume Overload toAssess Treatment Effect on Congestion and Renal Function(PROTECT) a randomized, double-blind controlledstudy with rolofylline failed to show any difference as
8 International Journal of Nephrology
to the primary composite end point of persistent renalimpairment, hospital readmission, or death in up to 60 daysafter admission [60].
5.7. Ultrafiltration. Theoretically it is very reasonable toapproach to patients with AHFS who present with significantvolume overload. Ultrafiltration bypasses the kidney andthere is virtually no immediate neurohormonal stimula-tion as occurs with loop diuretics blocking the maculadensa. In the Ultrafiltration versus Intravenous Diureticsfor Patients Hospitalized for Acute Decompensated HeartFailure (UNLOAD) trial, there was a marked decrease inbody weight, vasoactive drug requirement as well as hospitalreadmission in 90 days in the ultrafiltration arm [61].However, this was associated with a trend towards higher-serum creatinine level in the first week of therapy in theultrafiltration arm. One critique to this study may be the factthat patients in the diuretic arm were not very aggressivelydiuresed. So, it may be more difficult to demonstrate suchbeneficial effects if compared with diuretic therapy of com-parable negative fluid balance. Nonetheless, it is a reasonableoption in patients who are left in congestive state and makelittle urine despite maximal medical therapy. There is a recentstudy comparing the effects of ultrafiltration versus diureticsin decompensated heart failure. Ultrafiltration showed agreater clinical and hemodynamic improvement, as wellas a decrease in aldosterone and N- terminal pro-B-typenatriuretic peptide [62].
6. Conclusion
Cardiorenal syndrome is frequently present in patients whopresent with AHFS. The main driver of the pathophysiologyand symptomatology of the patients is congestion. The focusof treatment should be relieving the congestion withoutperturbing the hemodynamics of the cardiorenal axis. Asdiscussed in this paper, unfortunately every modality oftreatment has beneficial and detrimental effects on this axis.Loop diuretics relieve congestion but stimulate the neuro-hormones and reduce GFR. Inotropes improve hemodynam-ics but can potentially increase mortality and arrhythmias.Aquaretics have not been proven to decrease mortality ina large randomized control trial, although there are nolarge data on mixed receptor blockers. Natriuretic peptidesmay worsen the kidney function and possibly increasemortality. Vasodilators can cause substantial hypotensionwhile improving the hemodynamics. There is very littledata about the use of natriuretic doses of mineralocorticoidreceptor antagonists in severe heart failure. For these reasons,it is not possible to give one set of hard and fast rules to treatthe AHFS patients who present with cardiorenal syndrome.This is left to the astute clinician to take advantage of everyagent at the appropriately selected patients.
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