Cardio renal syndrome

Table I.

Nephrotoxic Agent	Possible Effects on the Kidneys and the Heart
Nonsteroidal anti-inflammatory drugs (NSAIDs)/COX-2 inhibitors	These two classes of drugs have the same safety zone for patients with renal insufficiency. Both of them can cause hypertension, edema, heart failure, and acute or chronic renal failure. Side effects are dose-dependent and usually reversible, although patients with advanced renal failure can become permanently dependent on dialysis. Suitable alternatives should be sought wherever practical. Acetaminophen is by far the safest analgesic for patients with renal failure.Previously, the combinations of acetaminophen and other analgesics were thought to be responsible for analgesic nephropathy, but acetaminophen alone in recommended doses is rarely nephrotoxic (except when combined with alcohol). For example, in episodic gout with renal failure, colchicine (dose-adjusted for renal impairment), joint injection, and brief courses of systemic corticosteroids are better tolerated than NSAIDs.If an NSAID is required, use the lowest dose necessary for controlling inflammation for the shortest period possible and monitor patients closely for hypertension, edema, CHF, and renal function.
Cyclosporine	Cyclosporine use can lead to glomerular capillary thrombosis that may progress to graft failure. The pathologic changes that can happen resemble those seen in the hemolytic-uremic syndrome and include thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function.
Metformin	Metformin now has been used by many physicians, but it could pose a problem if the patient has kidney dysfunction because it is excreted through the kidneys.A healthy kidney will improve the outcome with metformin. Kidney function should be assessed before starting metformin and rechecked at least once a year while taking it. The physician should consider stopping it if the creatinine level is >1.4 mg/dl.The interesting thing is that about 3 of every 100,000 people who take metformin will develop a medical emergency called “lactic acidosis.” Lactic acid is a metabolic byproduct that can become toxic if it builds up faster than it is neutralized. Lactic acidosis is most likely to occur in people who have diabetes, kidney or liver disease, those on multiple medications, and those with dehydration or severe chronic stress.
Antibiotics	Renal failure can be a result of different mechanisms, which include direct toxicity to the renal tubules, allergic interstitial nephritis, and crystallization of the drug within the renal tubules.Aminoglycosides, which are very common antibiotics, can be nephrotoxic and doses must be adjusted for patients with renal impairment. Even so, proper dose adjustment is no guarantee of avoidance of kidney injury. Aminoglycosides are excreted solely in the urine and are directly toxic to proximal tubular cells.Once-daily dosing with aminoglycosides is convenient and can be considered less toxic for patients with normal renal function, but no data support once-daily dosing for patients with impaired renal function even if the dosage is adjusted. The physician should avoid aminoglycosides completely in patients with renal insufficiency. If no suitable alternative is available for patients suspected of having life-threatening Gram-negative bacteremia, a single 1.5-mg/kg dose of an aminoglycoside would be considered safe and would allow time to consult an infectious disease expert.Allergic interstitial nephritis, which is an allergic and an idiosyncratic reaction, can be a side effect of many drugs. Antibiotics are by far the most common culprits. The physician cannot prevent interstitial nephritis; he or she can only recognize the syndrome promptly and discontinue the offending agent. Symptoms including fever, rash, progressive renal failure, and eosinophilia during prolonged antibiotic therapy should suggest interstitial nephritis, which can be confirmed by renal biopsy. Although penicillins and cephalosporins are well-recognized causative agents, almost any antibiotic can be the cause. The fluoroquinolone ciprofloxacin is now a well-recognized cause of allergic interstitial nephritis.Crystallization of antibiotics in the renal tubules can lead to acute oliguric renal failure and has been reported with sulfa drugs, acyclovir, and indinavir (used to treat HIV infection). Although adequate hydration can prevent it, risk is increased substantially in the low-glomerular-filtration-rate state of chronic renal insufficiency. Adjusting the dose of sulfa drugs for patients with renal insufficiency is recommended but does not guarantee safety and prevention of worsening of kidney failure. Although renal function can be restored after discontinuation of sulfa, some patients are rendered permanently dependent on dialysis. Therefore, it is best to avoid sulfa drugs in patients with renal insufficiency. Trimethoprim alone is as effective as combination therapy with trimethoprim-sulfamethoxazole for uncomplicated urinary tract infections.
Intravenous Iodinated Contrast	High-molecular-weight or ionic contrast dye can cause severe vasospasm in the afferent arteriole and acute renal failure in susceptible patients.Risk factors include diabetes, myeloma, chronic renal failure, dehydration, diuretic therapy, and heart failure. Vasospasm is less common with newer lower-molecular-weight or nonionic contrast dye. Hydration with intravenous saline or sodium bicarbonate is the simplest way to reduce the risk of contrast-induced AKI, provided a urine flow rate of >150 ml/hr is achieved in the first six hours after the procedure. It remains unclear whether these measures can prevent acute tubular necrosis in extremely high-risk patients with advanced renal failure. The best way to prevent contrast-induced AKI is to avoid contrast dye altogether by using ultrasound, magnetic resonance imaging (gadolinium enhancement is not nephrotoxic), or unenhanced computed tomography scans for high-risk patients.

The RIFLE criteria for acute kidney injury are listed in Figure 6.

Figure 6.

3. Diagnosis

Diagnostic criteria and tests

There is considerable interest in blood and urine biomarkers to detect CRS. For decades, the rise in serum creatinine and the decrease in the GFR have been the only detectable sign of a reduction in glomerular filtration. Creatinine has had the disadvantage of being linked to creatine and the overall body muscle mass, hence, differing according to body size in addition to the rate of renal elimination. Furthermore, the kidney both filters and secretes creatinine.

The assays used to measure creatinine have not been standardized across laboratories; therefore, studies reporting values from multiple centers have inherent variation in values attributed to differences in measurement technique.

There is a clear need for better laboratory markers of renal filtration. An ideal marker would be independent of muscle mass, would reflect actual renal filtration at the time it was measured, and would be sensitive to changes in actual GFR in order to alert clinicians to a meaningful change shortly after it occurs.

Unlike cardiac biomarkers indicating myocardial injury and overload (troponin, creatine kinase myocardial band, and natriuretic peptides), the field of nephrology has been devoid of approved blood or urine markers of AKI. The current paradigm is that renal injury occurs. Clinicians must wait to observe a reduction in GFR before AKI is inferred. The concept of measuring makers of the acute injury process is crucial to the early upstream identification of AKI before there is serious loss of organ function.

Below is a summary of relatively novel renal markers and what is known about them in acute cardiac and renal injury. Their use in the years to come will undoubtedly influence the epidemiology of CRS. However, there are pitfalls to the widespread use of novel biomarkers, including inappropriate conclusions along all lines of clinical decision making. Thus, considerable data are needed before any new marker enters the clinical arena.

1. Neutrophil Gelatinase-Associated Lipocalin (NGAL)

Siderocalin, or NGAL, was originally identified as a 25-kDa protein that is a natural siderophore working to scavenge cellular and pericellular labile iron, thus reducing its availability for bacterial growth. By reducing the availability of poorly liganded Fe(II) and Fe(III), which are needed to catalyze the Haber-Weiss and Fenton equations in the generation of reactive oxygen species, NGAL appears to have an important role in limiting oxidative damage in both acute and chronic diseases.

NGAL seems to be one of the earliest kidney markers of ischemic or nephrotoxic injury in animal models and it may be detected in the blood and urine of humans soon after AKI. Several studies have confirmed these findings; in intensive care adult patients with AKI secondary to sepsis, ischemia, or nephrotoxins, NGAL levels are significantly increased in the plasma and urine when compared to normal controls.

The NGAL test is currently approved for diagnosis of AKI in Europe, but not in the U.S.

2. Cystatin C

Cystatin C is a cysteine protease inhibitor that is synthesized and released into the blood at a relatively constant rate by all nucleated cells. It is freely filtered by the glomerulus, completely reabsorbed by the proximal tubule, and not secreted into urine. Its blood levels are not affected by age, gender, race, or muscle mass; thus, it appears to be a better predictor of glomerular function than serum creatinine in patients with CKD.

In AKI, urinary excretion of cystatin C has been shown to predict the requirement for renal replacement therapy earlier than creatinine. Finally, cystatin C has consistently outperformed serum creatinine and eGFR in the risk prediction for events in patients with CVD.

Cystatin C is currently approved in the U.S. for the diagnosis of AKI.

3. N-acetyl-β-(D)glucosaminidase (NAG)

Recognized over 30 years ago, NAG is a lysosomal brush border enzyme found in proximal tubular cells. It is a large protein (>130 kD) and is therefore not filtered through the glomerular membrane. NAG has been shown to function as a marker of AKI, reflecting particularly the degree of tubular damage. It is found not only in elevated urinary concentrations in AKI and CKD, but also in diabetic patients and patients with essential hypertension and heart failure.

Normal lab values

1. Creatinine level: 0.6-1.2 mg/dl

2. Hemoglobin level: male (14-17 g/dl), female (12-16 g/dl)

3. NGAL: urine and plasma <131.7 ng/dl; in one study it increased 15-fold 2 hours after cardiopulmonary bypass and by 25-fold 4-6 hours after that.

4. Cystatin C level: male (0.56-0.98 mg/l with a mean of 0.77 mg/l), female (0.52-0.90 mg/l with a mean of 0.71 mg/l)

How do I know this is what the patient has?

There is strong association between both acute and chronic dysfunction of the heart and kidneys with respect to morbidity and mortality. Both cardiac and renal diseases commonly present in the same patient and have been associated with increased cost of care, complications, and mortality.

The plural term “cardiorenal syndromes” suggests several subtypes denoted by the principal organ dysfunction by temporal sequence (cardiac versus renal or simultaneous) as well as relative acuity of each illness.

Both organs must have or develop evidence of pathological changes to fulfill the criteria for definition, so we can define it as a “disorder” of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other.

Recently the World Congress of Nephrology emphasized the bidirectional nature of the heart-kidney interaction and the vast interrelated derangement that can take place in cardiorenal syndrome. They hence proposed that the recent CRS definition be modified into categories whose labels reflect the likely primary and secondary pathology and time frame. (See the pathophysiology section for the five possible types).

Useful diagnostic tests include ECG and chest x-ray to detect previous heart attacks, arrhythmia, heart enlargement, and fluid in and around the lungs. Perhaps the single most useful diagnostic test is the echocardiogram, in which ultrasound is used to image the heart muscle, valve structures, and blood flow patterns. The echocardiogram is very helpful in diagnosing heart muscle weakness. In addition, the test can suggest possible causes for the heart muscle weakness (for example, prior heart attacks and severe valve abnormalities).

Another helpful diagnostic test is a blood test called brain natriuretic peptide level (BNP). This level can vary with age and gender but is typically elevated from heart failure. It can aid in the diagnosis and can also be useful in following the response to treatment of congestive heart failure.

Other possible diagnoses

The most important mimic of acute kidney injury is a functional change in serum Cr based on reduced renal blood flow or normal tubuloglomerular feedback. The term “prerenal azotemia” has been used to describe an elevated Cr in the setting of intravascular volume depletion, with proof being a normalization of Cr when IV fluids are given.

It is recognized that a systemic insult, particularly in a younger patient with no prior heart or kidney disease, can lead to simultaneous organ dysfunction. This is almost always in the setting of critical illness such as sepsis, multiple trauma, or burns and can be thought of being part of multi-organ system failure.

There are limited data on the incidence and determinants of CRS in part because of confounders such as hypotension, respiratory failure, liver failure, and other organ injury beyond the cardiac and renal systems, which create a difficult human model for investigation.

Interstitial nephritis is a condition recognized by urine and peripheral eosinophilia and cutaneous manifestations of allergic reaction, and it often occurs in the context of a new or recognized drug that has been implicated in this condition. This problem has been described with drugs that block the RAAS as well as diuretics, making the diagnosis difficult when these agents are so commonly used. The eosinophilia and rash should be a clue that interstitial nephritis is present. Withdrawal of the offending agent and supportive care are indicated. Steroids and misoprostol have been used in this scenario without proven benefit.

Sepsis as a precipitator of CRS is common and its incidence is increasing, with a mortality estimated at 20-60%. Approximately 11-64% of septic patients develop AKI that is associated with a higher morbidity and mortality. Abnormalities in cardiac function are also common in sepsis, including wall motion abnormalities and transient reductions in left ventricular ejection fraction.

Observational data have found approximately 30-80% of individuals with sepsis have measurable blood troponin I or T that elevates above the 99th detection limits. These elevated cardiac biomarkers have been associated with reduced left ventricular function and higher mortality even in patients without known coronary disease. Importantly, volume overload as a result of aggressive fluid resuscitation appears to be a significant determinant of CRS.

Among the 3,147 patients enrolled in the Sepsis Occurrence in Acutely Ill Patients (SOAP), there was a 36% incidence of AKI, and volume overload was the strongest predictor of mortality. Iatrogenic volume overload appears to play an important additional role, possibly along the lines described for CRS type 1 and passive venous congestion of the kidney, in the pathogenesis of AKI.

At the same time, volume overload increases left ventricular wall tension and likely contributes to cardiac decompensation in those predisposed to both systolic and diastolic HF. In summary, both AKI and markers of cardiac injury followed by volume overload are common in sepsis, with each being associated with increased mortality. However, there is a current lack of integrative information on the incidence of bidirectional organ failure and its pathophysiological correlates in a variety of acute care settings.

Specific confirmatory tests

CRS is an interdependent involvement of both the heart and the kidney in a spiral fashion leading to volume overload, diuretic resistance, and further involvement of all systems in which the patient’s clinical condition will likely worsen before it gets better.

For decades, the rise in serum creatinine and the decline in GFR were the landmarks for decreased kidney function and renal failure. Regarding the heart, in addition to markers to suspect its involvement like troponin in acute coronary syndrome, plus BNP in heart failure, we do have blood and urine biomarkers to detect CRS. These are novel biomarkers and considerable data are needed before any new marker enters the clinical arena. They are NGAL, cystatin C, and NAG.

An ECG is a noninvasive test used to measure electrical activity in the heart. Electrical sensors called leads are attached to predetermined positions on the arms, legs, and chest to record electrical activity and help assess heart function as well as prior heart attacks or arrhythmias.

Echocardiogram (cardiac echo) is an ultrasound examination of the heart that produces detailed images of the organ. It can be used to detect abnormalities in the structure of the heart and to measure the ejection fraction and other measures of diastolic function.

Chest x-ray demonstrates the degree of pulmonary congestion and gives an estimate of cardiac size.

4. Specific Treatment

1. Diuretics

Diuretics always have been considered to be an initial and essential part of the management of CRS patients. Loop, thiazide, and potassium-sparing diuretics provide diuresis and natriuresis as quickly as 20 minutes after administration. Moreover, they provide effective short-term symptomatic relief. Despite limited clinical trial data suggesting a beneficial role, physicians still prefer to use them.

However, diuretics are not free from side effects, such as long-term cardiovascular effects. Diuretics exacerbate neurohormonal activity, increase systemic vascular resistance, and worsen left ventricular function, thus increasing the risk of mortality. They also affect renal dysfunction as measured by an increase in serum creatinine and decreasing GFR.

Furosemide can cause fibrosis by its known stimulation of the renin-angiotensin-aldosterone axis. Several studies regarding this medication found that higher doses of diuretics were independently associated with death, sudden death, and pump failure. And unfortunately this relationship persists after controlling for other confounding variables. However, it is unclear if this is related to diuretic use per se or to higher diuretic doses being used in sicker patients, so it is still difficult to draw a conclusion.

2. Adding salt-poor albumin to intravenous furosemide

Sometimes while treating these patients with diuretics, the physician will notice resistance to these medications, especially in patients with low serum albumin levels. Studies suggest that these patients might respond to furosemide if salt-poor albumin is added to the infusion. The resulting furosemide-albumin complex is believed to deliver more diuretic to the kidney, primarily by staying in the vascular space, and a better response will be achieved.

3. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

Inhibition of the RAAS is the cornerstone of the management of patients with left ventricular systolic dysfunction. That inhibition can also prevent further kidney dysfunction in diabetic nephropathy and other forms of chronic kidney disease. It was also observed that discontinuation of ACE inhibitors because of kidney dysfunction identified a patient group with heart failure who had a high mortality risk.

However, ACE inhibitors should be used cautiously in patients with renal insufficiency. To reduce the incidence of renal dysfunction, ACE inhibitors should be started at a lower dose while monitoring the patient’s hydration status. The concomitant use of NSAIDs should be avoided.

We can refrain from administering ACE inhibitors or ARBs if the serum creatinine concentration is approximately 6 mg/dl or the estimated GFR is <15 ml/min. ACE inhibitors or ARBs can be continued as long as kidney function does not steadily deteriorate and severe hyperkalemia does not develop.

4. Inotropes

If the low cardiac output and decreased renal perfusion is the main factor regarding worsening renal function, a trial of inotropic therapy with dobutamine or milrinone may be considered. However, these agents should be given only for low cardiac output states for a short term in a monitored setting as they may increase the risk of arrhythmias.

5. Vasodilators and natriuretic peptide

The Food and Drug Administration has approved nesiritide for the treatment of acute decompensated heart failure. Nesiritide is a recombinant form of BNP peptide. Administration of nesiritide results in venous, arterial, and coronary vasodilations, reducing cardiac preload and afterload, which increases cardiac output without direct inotropic effects.

6. Ultrafiltration

Another potential therapy in patients with diuretic resistance is to use ultrafiltration to alleviate volume overload. Renal replacement therapy (ultrafiltration or dialysis) improves renal responsiveness and cardiac hemodynamics, but is usually used for palliation in the end stages of CRS and does not provide a long-term solution. These patients often continue to retain fluid, and giving them larger doses of diuretics poses the clinical dilemma of potentially improving symptoms at the cost of further worsening the already compromised renal function. Ultrafiltration may, however, be more beneficial if used earlier.

7. Arginine vasopressin receptor antagonists

The pituitary gland secrets arginine vasopressin (AVP) and its effects are mediated by three types of receptors: V1A, V1B, and V2. V2 receptors are located in the renal distal tubules and the collecting duct. As soon as the AVP binds to the V2 receptors, intracellular levels of cyclic adenosine monophosphate increase; this molecule acts as a second messenger in the translocation of vesicles containing the water channel aquaporin-2 and in increasing the transcription of aquaporin-2.

AVP-regulated aquaporin-2 activity determines the water permeability of the collecting duct and is associated with decreased diuresis. In heart failure, secretion of AVP may be increased because of low blood pressure or diminished arterial volume. Excess AVP can also lead to hyponatremia, which is a reason why V2 receptor antagonists are indicated.

V2 receptor antagonists (“vaptans,” e.g., conivaptan and tolvaptan) result in an aquaresis and retention of electrolytes. These agents are currently under investigation.

Five subtypes of cardiorenal syndrome

Specifically, we can divide the treatment according to the five subtypes of cardiorenal syndrome:

CRS type 1

Physicians should pay attention to patients with low cardiac output state, a marked increase in venous pressure, or both, which leads to kidney congestion, and should take the necessary diagnostic steps to either confirm or exclude the diagnosis. Diuretic responsiveness may be impaired in these patients. In contrast, diuretics often represent the main cause of worsening renal function. Accordingly, diuretics may best be given in acute heart failure patients with evidence of systemic fluid overload with the goal of achieving a gradual diuresis.

Furosemide can be titrated according to renal function, systolic BP, and history of chronic diuretic use. A continuous diuretic infusion might be helpful, although we suggest having it guided by techniques for fluid status assessment such as bioimpedance vector analysis (BIVA) and B-type natriuretic peptide (BNP) monitoring. In parallel, measurement of cardiac output and venous pressure may also help ensure continued and targeted diuretic therapy.

Cardiac output can be easily estimated by means of arterial pressure monitoring combined with pulse contour analysis or by Doppler ultrasound. If diuretic-resistant fluid overload exists despite an optimized cardiac output, isotonic fluid can be removed by ultrafiltration. The presence of AKI with or without concomitant hyperkalemia may also affect patient outcome by inhibiting the prescription of ACE inhibitors and aldosterone inhibitors. This is unfortunate because, provided there is close monitoring of renal function and potassium levels, the potential benefits of these interventions will likely outweigh their risks even in these patients.

ACE inhibitors and B-blockers are generally used together in these patients. However, in the setting of type I CRS, such combination therapy should be done with caution when trying to optimize and stabilize the patient’s clinical status. In some patients, stroke volume cannot be increased and relative or absolute tachycardia sustains the adequacy of cardiac output. Blockade of such compensatory tachycardia and sympathetic system-dependent inotropic compensation can precipitate cardiogenic shock and can be lethal. Particular concern applies to beta-blockers excreted by the kidney, such as atenolol or sotalol, especially if combined with calcium antagonists.

These considerations should not inhibit the slow, careful, and titrated introduction of appropriate treatment with B-blockers once patients are hemodynamically stable. This aspect of treatment is particularly relevant in patients with CRS in which undertreatment after myocardial infarction is common. Attention should be paid to preserving renal function, perhaps as much attention as is paid to preserving myocardial muscle.

Worsening renal function or type 1 CRS during admission for ST-elevation MI is a powerful and independent predictor of in-hospital and 1-year mortality. In this context, creatinine rise is not simply a marker of illness severity; rather, it represents a causative factor for cardiovascular injury acceleration through the activation of hormonal, immunological, inflammatory, and oxidative processes.

CRS type 2

Patients with type 2 CRS are more likely to receive loop diuretics and vasodilators at higher doses than patients with stable renal function, and such treatment may precipitate the development of further renal injury. Regardless of the cause, reductions in renal function in the context of heart failure are associated with increased risk for adverse outcomes.

Of patients with CKD stage IV and V, less than 50% are on the combination of aspirin, B-blocker, ACE inhibitors, and statins. This failure to treat is not just limited to most severe CKD stages. Patients at lower stages of CKD are also less likely to receive adequate risk-modifying medications following MI. This therapeutic failure is likely due to concerns about worsening of renal function, therapy-related toxic effects, or both due to low clearance rates.

However, several studies have shown that when appropriately titrated and monitored, cardiovascular medications used in the general population can be safely administered to those with renal impairment and with similar benefits. Renal effects of new approaches for the treatment of cardiac failure, such as cardiac resynchronization therapy (CRT), have not yet been studied. Vasopressin V2-receptor blockers have been reported to decrease body weight and edema in patients with CHF, but their effects in patients with CRS have not been systematically studied, and a recent large, randomized controlled trial showed no evidence of a survival benefit with these agents.

CRS type 3

The development of AKI, especially in the setting of CKD, can affect the use of medications that normally would maintain clinical stability in patients with CHF, exposing the patient to the risk of undertreatment. If AKI is severe and renal replacement therapy is necessary, cardiovascular instability generated by rapid fluid and electrolyte shifts secondary to conventional dialysis can induce hypotension, arrhythmias, and myocardial ischemia. Continuous techniques of renal replacement possibly guided by bioimpedance, BNP levels, and blood volume measurement appear physiologically safer and more effective in achieving adequate volume management.

CRS type 4

The logical practical implication of the plethora of data linking CKD with cardiovascular disease is that more attention needs to be paid to reducing risk factors and optimizing medications in these patients, and that undertreatment due to concerns about pharmacodynamics in this setting may have lethal consequences at the individual level and huge potential adverse consequences at public health levels.

In patients with advanced CKD, the initiation or increased dosage of ACE inhibitors can precipitate clinically significant worsening of renal function or marked hyperkalemia. The latter may be dangerously exacerbated by the use of aldosterone antagonists. Such patients, if aggressively treated, become exposed to a significant risk of developing dialysis dependence or life-threatening hyperkalemic arrhythmias. If treated too cautiously, they may develop equally life-threatening cardiovascular complications. In these patients, the judicious use of all options while taking into account patient preferences, social circumstances, and other comorbidities, and applying a multidisciplinary approach to care seems the best approach.

CRS type 5

Supportive care with a judicious intravenous fluid approach and the use of pressor agents as needed to avoid hypotension are reasonable but cannot be expected to avoid AKI or cardiac damage.

Drugs and dosages

1. Diuretics

Furosemide (Lasix):

LASIX® is a diuretic that is an anthranilic acid derivative. LASIX tablets for oral administration contain furosemide as the active ingredient and the following inactive ingredients: lactose monohydrate NF, magnesium stearate NF, starch NF, talc USP, and colloidal silicon dioxide NF. Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid. LASIX is available as white tablets for oral administration in dosage strengths of 20, 40, and 80 mg as tolerated.

Regarding the intravenous form, start with 20-40 mg IV, and the dose can be increased as tolerated.

Metolazone (Zaroxolyn):

Suitable initial dosages will usually fall in the ranges given.

Edema of cardiac failure: ZAROXOLYN 5 to 20 mg once daily.

Edema of renal disease: ZAROXOLYN 5 to 20 mg once daily.

Bumetanide (Bumex):

The usual total daily dosage of Bumex is 0.5-2 mg and in most patients is given as a single dose. If the diuretic response to an initial dose of Bumex is not adequate, in view of its rapid onset and short duration of action, a second or third dose may be given at 4- to 5-hour intervals up to a maximum daily dose of 10 mg. An intermittent dose schedule, whereby Bumex is given on alternate days or for 3 to 4 days with rest periods of 1 to 2 days in between, is recommended as the safest and most effective method for the continued control of edema. In patients with hepatic failure, the dosage should be kept to a minimum and, if necessary, dosage increased very carefully.

2. ACE inhibitors

In patients with heart failure who have hyponatremia (serum sodium < 130 mEq/L) or moderate to severe renal impairment (creatinine clearance ≤ 30 ml/min or serum creatinine > 3 mg/dl), therapy with lisinopril should be initiated at a dose of 2.5 mg once a day under close medical supervision and increased as tolerated.

3. Angiotensin receptor blockers

The usual starting dose of ARBs such as losartan for adults is 50 mg daily. The maximum dose is 100 mg daily. The total daily dose may be divided and administered twice daily. Losartan may be given with or without food.

4. Dobutamine

The recommendation is to start at 5 mcg/kg/min, max is 20 mcg/kg/min, and it is indicated when the cardiac output is low and AKI is believed to be due to low forward output. Dobutamine at doses < 5 mcg/kg/min should not be used given the selective vasodilation that occurs without a rise in cardiac output, which can result in systemic hypotension.

5. Milrinone (Primacor)

Loading dose of 50 mcg/kg over 10 minutes, then maintenance dose of 0.375-0.75 mcg/kg/min continuous infusion, indicated again if a low cardiac output is contributing to CRS. Excretion of milrinone is via the urine (85% as unchanged drug) within 24 hours; active tubular secretion is a major elimination pathway for milrinone. The following is a suggested dosing schedule for milrinone based on CrCl:

CrCl 50 mL/minute: Administer 0.43 mcg/kg/minute

CrCl 40 mL/minute: Administer 0.38 mcg/kg/minute

CrCl 30 mL/minute: Administer 0.33 mcg/kg/minute

CrCl 20 mL/minute: Administer 0.28 mcg/kg/minute

CrCl 10 mL/minute: Administer 0.23 mcg/kg/minute

CrCl 5 mL/minute: Administer 0.2 mcg/kg/minute

6. Dopamine

Dopamine is a sympathomimetic drug that stimulates splanchnic dopamine receptors, causing vasodilation in these vessels. A dopamine drip rate may also be calculated without a chart or table, by using drip set, to determine the amount to be infused and time for administration. The recommendation is to start at a dose of 1-3 mcg/kg/min and if used to increase renal perfusion, not to exceed 5 mcg/kg/min.

7. Nesiritide (Natrecor)

The recommended dose of Natrecor is an IV bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min. Natrecor should not be initiated at a dose that is above the recommended dose.

Refractory cases

Diuretic resistance:

In the management of acute decompensated heart failure, the lack of a response to diuretic therapy is commonly observed. Because diuretic therapy can worsen renal function, and worsening renal function is associated with poor outcome, diuretic resistance can be considered to be another indicator of poor prognosis in patient with CHF. However, in the absence of definitive data, patients with volume overload should not be restricted from receiving loop or thiazide diuretics as necessary to alleviate symptoms.

Because the lack of response to diuretic is a common scenario, overcoming this problem is an important part of CRS management. The braking phenomenon or short-term tolerance means that the response to a diuretic is reduced after the first dose has been administrated. Escalating the bolus dose or starting a continuous infusion has been associated with worsening CRS. If the patient can take 5 mg or 10 mg of metolazone orally, this treatment may enhance the response to loop diuretics, but it requires careful monitoring of the sodium and potassium losses.

Other important issues about diuretics are that a single effective dose should be determined. It is important to remember that diuretics do not have a smooth dose-response curve; hence, no natriuresis occurs until a threshold rate of drug excretion is attained. A patient who does not respond to 20 mg of furosemide may not exceed this threshold, and the dose should be increased to 40 mg rather than giving the same dose twice a day. The dose should be given intravenously and slowly over 30 to 60 minutes to avoid the risk of ototoxicity.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Renal function may remain stable at a diminished level in heart failure patients; however, in many it can lead to worsening end-organ damage, frequent hospitalizations, exacerbations of symptoms, resistance to standard therapy, inability to maintain a good quality of life, and, eventually, death.

Medical management of patients with concomitant renal and heart failure remains a challenge. The burden is exacerbated because most of the evidence for treating heart failure comes from clinical trials that excluded patients with significant renal impairment.

ACE inhibitors are known to increase the survival rate in patients with heart failure. However, these drugs should be used cautiously in patients with renal insufficiency. Many trials that confirmed the benefits of ACE inhibitors, such as SOLVD, excluded patients with serum creatinine concentrations > 2.0 mg/dl.

The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) included patients with renal impairment, but only if their serum creatinine concentrations were <=3.4 mg/dl. Although only a minority of patients in CONSENSUS had creatinine levels >2.0 mg/dL, this subgroup showed evidence of improved outcomes when treated with an ACE inhibitor.

CONSENSUS also showed that patients with the most severe heart failure had a substantial increase in creatinine (>30%) when an ACE inhibitor was added to their regimen, independent of their baseline renal function, and few patients needed to stop therapy. In most of the patients in whom the ACE inhibitor was stopped, the creatinine level returned to baseline. To reduce the incidence of renal dysfunction, patients should be started on the lowest dose of an ACE inhibitor when they are judged not to be dehydrated.

NSAIDs should be avoided. However, ACE inhibitor therapy in patients with baseline renal insufficiency is associated with significant long-term benefits, and unless contraindicated, should be routinely used. Most patients who are already on an ACE inhibitor who develop renal insufficiency during hospitalization for heart failure decompensation should not have their ACE inhibitor stopped. ACE inhibitors are not associated with worsening renal function in these patients in general. However, clinical judgment needs to be exercised for extreme clinical situations (e.g., patients in cardiogenic shock or acute renal failure).

The role of diuretic therapy in CRS is controversial. Several studies found that higher doses of diuretics were independently associated with pump failure, death, and sudden death. Although this relationship persists after controlling for other confounding variables, it is still difficult to judge whether it is related to diuretic use per se or to higher diuretic doses being used in sicker patients. Inadequate response to oral diuretics is often reversible once the acute volume overload is resolved, and many patients can return to oral therapy.

In general, a patient who is resistant to oral furosemide is not likely to respond to a similar dose of another loop diuretic.

Some patients with low serum albumin levels may be resistant to diuretic therapy. Data suggest that these patients might respond to furosemide if salt-poor albumin is added to the infusion. The resulting furosemide-albumin complex is believed to deliver more diuretic to the kidney, primarily by staying in the vascular space.

Nesiritide, a synthetic BNP, has been used in heart failure to reduce preload and afterload, to cause natriuresis and diuresis, and to suppress norepinephrine, endothelin-1, and aldosterone. The Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial assessed the impact of early nesiritide infusion on symptoms and pulmonary pressures in patients with decompensated heart failure. A total of 489 patients with renal insufficiency received either nesiritide or nitroglycerin. At 24 hours, 83% of the patients with renal insufficiency and 91% of patients without renal insufficiency who were treated with nesiritide reported improvements in dyspnea.

Incorrect diagnosis

If the patient is unresponsive to therapy, reconsider the diagnosis of CRS.

Interstitial nephritis, which is most commonly caused by a hypersensitivity reaction to a medication, may falsely lead a clinician to a diagnosis of CRS in a patient who simultaneously has underlying heart failure. Drug-induced acute interstitial nephritis may manifest as fever, pruritus, rash, and eosinophilia; however, these features may be absent, particularly in acute interstitial nephritis, due to use of NSAIDs and proton pump inhibitors.

Urinalysis findings in patients with acute interstitial nephritis may include leukocyte casts, eosinophils, and a urine protein-creatinine ratio usually <2.5 mg/mg. Kidney biopsy is often required to establish a definitive diagnosis because of the lack of sensitivity and specificity of eosinophiluria or gallium scanning.

In patients with suspected drug-induced acute interstitial nephritis, discontinuing the inciting agent and monitoring for improvement in kidney function over the next 2 to 3 weeks are often sufficient. Indications for biopsy generally include diagnostic uncertainty, advanced kidney failure, consideration of potentially toxic treatment, or lack of spontaneous recovery following cessation of drug therapy.

Follow-up

The patient should be followed in the clinic within a week. A thorough physical exam along with a repeated creatinine level should be obtained. The patient should have a follow-up BNP level checked within 6-8 weeks after discharge from the hospital.

The most effective yet least used general measure in patients with heart failure is close observation and follow-up. Nonadherence with diet and medications can profoundly affect the clinical status of patients. Increases in body weight and minor changes in symptoms commonly precede by several days the occurrence of major clinical episodes requiring emergency care or hospitalization.

Patient education and close supervision, which includes surveillance by the patient and his or her family, can reduce the likelihood of nonadherence and lead to the detection of changes in body weight or clinical status early enough to allow the patient or a healthcare provider to implement treatments that can prevent clinical deterioration. Supervision need not be performed by a physician and may ideally be accomplished by a physician assistant or nurse with special training in the care of patients with heart failure. This approach has been reported to have significant clinical benefits.

Recommendations for the Hospitalized Patient 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults

1. The diagnosis of HF is primarily based on signs and symptoms derived from a thorough history and physical examination.

Clinicians should determine the following:

a. adequacy of systemic perfusion;

b. volume status;

c. the contribution of precipitating factors and/or comorbidities;

d. if the heart failure is new onset or an exacerbation of chronic disease; and

e. whether it is associated with preserved ejection fraction.

Chest radiographs, electrocardiogram, and echocardiography are key tests in this assessment. (Level of Evidence: C)

2. Concentrations of B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) should be measured in patients being evaluated for dyspnea in which the contribution of HF is not known. Final diagnosis requires interpreting these results in the context of all available clinical data and ought not to be considered a stand-alone test. (Level of Evidence: A)

3. Acute coronary syndrome precipitating heart failure hospitalization should be promptly identified by electrocardiogram and cardiac troponin testing, and treated, as appropriate, to the overall condition and prognosis of the patient. (Level of Evidence: C)

4. It is recommended that the following common potential precipitating factors for acute HF be identified, as recognition of these comorbidities is critical to guide therapy:

— acute coronary syndromes/coronary ischemia;

— severe hypertension;

— atrial and ventricular arrhythmias;

— infections;

— pulmonary emboli;

— renal failure; and

— medical or dietary noncompliance. (Level of Evidence: C)

5. Oxygen therapy should be administered to relieve symptoms related to hypoxemia. (Level of Evidence: C) New recommendation.

6. Whether the diagnosis of heart failure is new or chronic, patients who present with rapid decompensation and hypoperfusion associated with decreasing urine output and other manifestations of shock are critically ill and rapid intervention should be used to improve systemic perfusion. (Level of Evidence: C)

7. Patients admitted with heart failure and with evidence of significant fluid overload should be treated with intravenous loop diuretics. Therapy should begin in the emergency department or outpatient clinic without delay, as early intervention may be associated with better outcomes for patients hospitalized with decompensated heart failure. (Level of Evidence: B) If patients are already receiving loop diuretic therapy, the initial intravenous dose should equal or exceed their chronic oral daily dose. Urine output and signs and symptoms of congestion should be serially assessed, and diuretic dose should be titrated accordingly to relieve symptoms and to reduce extracellular fluid volume excess. (Level of Evidence: C)

8. Effect of heart failure treatment should be monitored with careful measurement of fluid intake and output; vital signs; body weight, determined at the same time each day; clinical signs (supine and standing) and symptoms of systemic perfusion and congestion. Daily serum electrolytes, urea nitrogen, and creatinine concentrations should be measured during the use of IV diuretics or active titration of HF medications. (Level of Evidence: C)

9. When diuresis is inadequate to relieve congestion, as evidenced by clinical evaluation, the diuretic regimen should be intensified using either:

a. higher doses of loop diuretics;

b. addition of a second diuretic (such as metolazone, spironolactone or intravenous chlorothiazide); or

c. continuous infusion of a loop diuretic. (Level of Evidence: C)

10. In patients with clinical evidence of hypotension associated with hypoperfusion and obvious evidence of elevated cardiac filling pressures (e.g., elevated jugular venous pressure; elevated pulmonary artery wedge pressure), intravenous inotropic or vasopressor drugs should be administered to maintain systemic perfusion and preserve end-organ performance while more definitive therapy is considered. (Level of Evidence: C)

11. Invasive hemodynamic monitoring should be performed to guide therapy in patients who are in respiratory distress or with clinical evidence of impaired perfusion in whom the adequacy or excess of intracardiac filling pressures cannot be determined from clinical assessment. (Level of Evidence: C)

12. Medications should be reconciled in every patient and adjusted as appropriate on admission to and discharge from the hospital. (Level of Evidence: C)

13. In patients with reduced ejection fraction experiencing a symptomatic exacerbation of hear failure requiring hospitalization during chronic maintenance treatment with oral therapies known to improve outcomes, particularly ACE inhibitors or ARBs and beta-blocker therapy, it is recommended that these therapies be continued in most patients in the absence of hemodynamic instability or contraindications. (Level of Evidence: C)

14. In patients hospitalized with heart failure with reduced ejection fraction not treated with oral therapies known to improve outcomes, particularly ACE inhibitors or ARBs and beta-blocker therapy, initiation of these therapies is recommended in stable patients prior to hospital discharge. (Level of Evidence: B)

15. Initiation of beta-blocker therapy is recommended after optimization of volume status and successful discontinuation of intravenous diuretics, vasodilators, and inotropic agents. Beta-blocker therapy should be initiated at a low dose and only in stable patients. Particular caution should be used when initiating beta blockers in patients who have required inotropes during their hospital course. (Level of Evidence: B)

16. In all patients hospitalized with HF, both with preserved and low EF, transition should be made from intravenous to oral diuretic therapy with careful attention to oral diuretic dosing and monitoring of electrolytes. With all medication changes, the patient should be monitored for supine and upright hypotension, worsening renal function, and HF signs/symptoms. (Level of Evidence: C)

17. Comprehensive written discharge instructions for all patients with hospitalization for HF and their caregivers is strongly recommended, with special emphasis on the following 6 aspects of care: low-sodium diet; discharge medications, with a special focus on adherence, persistence, and uptitration to recommended doses of ACE inhibitor/ARB and beta-blocker medication; activity level; follow-up appointments; daily weight monitoring; and what to do if heart failure symptoms worsen. (Level of Evidence: C)

18. Post-discharge systems of care, if available, should be used to facilitate the transition to effective outpatient care for patients hospitalized with heart failure. (Level of Evidence: B)

Class IIa

1. When patients present with acute heart failure and known or suspected acute myocardial ischemia due to occlusive coronary disease, especially when there are signs and symptoms of inadequate systemic perfusion, urgent cardiac catheterization and revascularization is reasonable where it is likely to prolong meaningful survival. (Level of Evidence: C)

2. In patients with evidence of severely symptomatic fluid overload in the absence of systemic hypotension, vasodilators such as intravenous nitroglycerin, nitroprusside, or nesiritide can be beneficial when added to diuretics and/or in those who do not respond to diuretics alone. (Level of Evidence: C)

3. Invasive hemodynamic monitoring can be useful for carefully selected patients with acute heart failure who have persistent symptoms despite empiric adjustment of standard therapies, and

a. whose fluid status, perfusion, or systemic or pulmonary vascular resistances are uncertain,

b. whose systolic pressure remains low, or is associated with symptoms, despite initial therapy,

c. whose renal function is worsening with therapy,

d. who require parenteral vasoactive agents or

e. who may need consideration for advanced device therapy or transplantation. (Level of Evidence: C)

4. Ultrafiltration is reasonable for patients with refractory congestion not responding to medical therapy. (Level of Evidence: B)

Class IIb

1. Intravenous inotropic drugs such as dopamine, dobutamine, or milrinone, might be reasonable for those patients presenting with documented severe systolic dysfunction, low blood pressure, and evidence of low cardiac output, with or without congestion, to maintain systemic perfusion and preserve end-organ performance. (Level of Evidence: C)

Class III

1. Use of parenteral inotropes in normotensive patients with acute decompensated heart failure without evidence of decreased organ perfusion is not recommended. (Level of Evidence: B)

2. Routine use of invasive hemodynamic monitoring in normotensive patients with acute decompensated heart failure and congestion with symptomatic response to diuretics and vasodilators is not recommended. (Level of Evidence: B)

Pathophysiology

The pathophysiology of renal dysfunction is much more complex than simply reduced cardiac output. Vascular factors such as nitric oxide, prostaglandin, natriuretic peptides, and endothelin may mediate renal perfusion independently of cardiac hemodynamics.

The heart, kidneys, renin-angiotensin system, sympathetic nervous system, immune system, and endothelium often interact through intricate feedback loops. An imbalance in this complex system will often cause deterioration in both cardiac and renal function.

If cardiac output and mean arterial pressure fall, so does renal blood flow, activating the renin-angiotensin system, reducing nitric oxide in the endothelium, activating the sympathetic nervous system, and inducing inflammatory mediators, all of which, in a vicious circle, cause structural and functional damage to the kidneys and heart. Recently, researchers have been focusing on the role of inflammatory markers as links between cardiovascular and kidney disease.

For example, C-reactive protein (CRP), an acute-phase reactant that is believed to play a vital role in the pathophysiology of atherosclerosis, is found in high levels during end-stage renal failure. It is likely that CRP and many other inflammatory mediators play a synergistic role in progression of both renal and cardiovascular disease.

CRS type 1 (acute)

Type 1 CRS is characterized by an acute worsening of cardiac function leading to AKI (Fig. 1). Heart failure can be divided into four main subtypes: hypertensive pulmonary edema with preserved left ventricular systolic function, acute decompensated chronic heart failure (CHF), cardiogenic shock and predominant right ventricular failure. Type 1 CRS is common as it represents an abrupt worsening of renal function secondary to all above-mentioned clinical manifestations of heart failure.

Among patients with acute decompensated heart failure or de novo acute heart failure, premorbid chronic renal dysfunction is common and predisposes to AKI. The mechanisms by which the onset to acute or acute decompensated heart failure leads to AKI are multiple and complex and are summarized in Figure 1. The clinical importance of each of these mechanisms is likely to vary from patient to patient (e.g. acute cardiogenic shock vs. hypertensive pulmonary edema) and situation to situation (acute heart failure secondary to perforation of a mitral valve leaflet from acute bacterial endocarditis versus worsening of right heart failure secondary to noncompliance with diuretic therapy).

In acute heart failure, AKI seems to be more severe in patients with impaired left ventricular ejection fraction (LVEF) compared with those with preserved LVEF. Its incidence is >70% in patients with cardiogenic shock. Furthermore, impaired renal function is consistently found as an independent risk factor for one-year mortality in acute heart failure patients, including patients with ST-elevation MI. A plausible reason for this independent effect might be that an acute decline in renal function does not only act as a marker of illness severity but also carries an associated acceleration in cardiovascular pathobiology, leading to a higher rate of cardiovascular events both acutely and chronically, possibly through the activation of inflammatory pathways.

The onset of AKI in the setting of acute or acute decompensated heart failure implies inadequate renal perfusion until proven otherwise. Attention should be paid to preserving renal function, perhaps as much attention as is paid to preserving myocardial muscle. Worsening renal function during admission for ST-elevation MI is a powerful and independent predictor of in-hospital and 1-year mortality. In this context, the creatinine rise is not simply a marker of illness severity but rather represents a causative factor for cardiovascular injury acceleration through the activation of hormonal, immunological, and inflammatory pathways.

CRS type 2 (chronic)

Type 2 CRS or chronic CRS is characterized by chronic abnormalities in cardiac function (e.g., chronic congestive heart failure) causing progressive impairment of kidney function (Fig. 2). This is associated with significantly increased adverse outcomes and prolonged hospitalizations.

Independent predictors of worsening rental function include hypertension, diabetes mellitus, old age, and acute coronary syndromes. CHF is characterized by a relatively stable long-term situation of probably reduced renal perfusion, often predisposed by both micro- and macrovascular disease in the context of the same vascular risk factors associated with cardiovascular disease.

However, although a greater proportion of patients with eGFR have a worse New York Heart Association (NYHA) class, no evidence of association between LVEF and estimated GFR can be consistently demonstrated. Thus, patients with CHF and preserved LVEF appear to have similar eGFR than patients with impaired LVEF (<45%).

Neurohormonal abnormalities are present with excessive production of vasoconstrictive mediators (epinephrine, angiotensin, and endothelin) and altered sensitivity, release of endogenous vasodilatory factors (natriuretic peptides and nitric oxide) or both, as summarized in Figure 2.

CRS type 3 (acute renocardiac syndrome)

Type 3 CRS is characterized by an abrupt worsening of renal function causing or contributing to acute cardiac dysfunction (Fig. 3). This is considered less common than type 1 CRS because the development of AKI as a primary event leading to cardiac dysfunction has not been adequately studied so far. AKI can affect the heart through several pathways. Hyperkalemia can contribute to arrhythmias and may cause cardiac arrest.

Fluid retention can contribute to unstable heart function and to the development of pulmonary edema. Untreated uremia affects myocardial contractility through the accumulation of myocardial depressant factors and can cause pericarditis. Partially corrected or uncorrected acidemia produces pulmonary vasoconstriction, which, in some patients, can significantly contribute to right-sided heart failure.

Acidemia appears to have a negative inotropic effect and may, together with electrolyte imbalances, contribute to an increased risk of arrhythmias. Finally, as discussed above, renal ischemia itself may precipitate activation of inflammation and apoptosis at the cardiac level. The development of AKI, especially in the setting of CKD, can affect the use of medications that normally would maintain clinical stability in patients with CHF, exposing the patient to the risk of undertreatment.

If AKI is severe and renal replacement therapy is necessary, cardiovascular instability generated by rapid fluid and electrolyte shifts secondary to conventional dialysis can induce hypotension, arrhythmias, and myocardial ischemia.

CRS type 4 (chronic renocardiac syndrome)

Type 4 CRS is characterized by a status of CKD inducing decreased cardiac function, ventricular hypertrophy, diastolic dysfunction, increased risk of adverse cardiovascular events, or all as summarized in Figure 4.

Individuals with CKD, particularly those receiving renal replacement therapies, are at high risk for cardiovascular events. Less severe forms of CKD also appear to be associated with significant cardiovascular risk, although the association between reduced renal function and cardiovascular risk appears to consistently occur at eGFR levels <60 ml/min/1.73 m².

In patients with advanced CKD, the initiation or increased dosage of ACE inhibitors can precipitate clinically significant worsening of renal function or marked hyperkalemia. The latter may be dangerously exacerbated by the use of aldosterone antagonists. Such patients, if aggressively treated, become exposed to a significant risk of developing dialysis dependence or life-threatening hyperkalemic arrhythmias. If too cautiously treated, they may develop equally life-threatening cardiovascular complications.

CRS type 5 (secondary cardiorenal syndrome)

Type 5 CRS is characterized by the presence of combined cardiac and renal dysfunction due to acute or chronic systemic disorders, as summarized in Figure 5. There is limited systematic information on type 5 CRS, in which both kidneys and heart are affected by other systemic processes. Although there is an appreciation that, as more organs fail, mortality increases in critical illness, there is limited insight into how combined renal and cardiovascular failure may differently affect such outcome compared with, for example, combined pulmonary and renal failure.

It is clear that several acute and chronic diseases can affect both organs simultaneously, and that the disease induced in one can affect the other and vice versa. Several chronic conditions, such as diabetes and hypertension, are discussed as part of type 2 and type 4 CRS.

In the acute setting, severe sepsis represents the most common and serious condition that can affect both organs. It can induce AKI while leading to profound myocardial depression. The mechanisms responsible for such changes are poorly understood but may involve the effects of circulating factors such as tumor necrosis factor (TNF) on both organs.

The onset of myocardial functional depression and a state of inadequate cardiac output can further decrease renal function, as discussed in type 1 CRS, and the development of AKI can affect cardiac function, as described in type 3 CRS. Renal ischemia may then induce further myocardial injury in a vicious cycle, which is injurious to both organs.

Epidemiology

Prevalence of renal disease in patients with heart failure

In the Acute Decompensated Heart Failure National Registry (ADHERE) of 105,000 individuals admitted for acute decompensated heart failure, 21% had serum creatinine concentrations >2.0 mg/dl, 30% had a history of renal insufficiency, and 9% had creatinine concentrations >3.0 mg/dl. McAlister et al. found that only 17% of 754 outpatients with heart failure had creatinine clearances >90 ml/min.

In their cohort, 39% with NYHA class IV symptoms and 31% with NYHA class III symptoms had creatinine clearance <30 ml/min. These numbers are remarkable when one considers the complexity of treating volume overload in those with coexistent renal disease and that there are millions of hospitalizations for decompensated heart failure in the United States annually.

Impact of renal disease on clinical outcomes in patients with heart failure

Renal dysfunction is one of the most important independent risk factors for poor outcomes and all-cause mortality in patients with heart failure. Baseline GFR appears to be a stronger predictor of mortality in patients with heart failure than LVEF or NYHA functional class. Both elevated serum creatinine on admission and worsening creatinine during hospitalization predict prolonged hospitalization, rehospitalization, and death. Even small changes in creatinine >=0.3 mg/dl are common and have been linked with prolonged hospitalization and increased mortality.

Heart failure outcomes in patients with renal disease

On the basis of estimates provided by the Third National Health and Nutrition Examination Survey (NHANES III), almost 8 million individuals living in the United States have a GFR <60 ml/min. Patients with chronic renal insufficiency are at remarkably higher risk for MI, heart failure with systolic dysfunction, heart failure with preserved LVEF, and death resulting from cardiac causes compared with individuals with normal GFR.

A recent meta-analysis suggests that individuals with primary renal disease are more likely to eventually die of cardiovascular causes than renal failure itself. This is not just secondary to atherosclerotic disease; in a multicenter cohort study of 432 patients, 31% planning to initiate hemodialysis had heart failure symptoms, and 33% of such patients had an estimated LVEF of <40%.

Patients with heart failure and new hemodialysis had a median survival of only 36 months compared with 62 months in patients without heart failure. Furthermore, 25% who did not have heart failure symptoms on initiation of dialysis developed these symptoms after a median follow-up of 15 months. Conversely, reversal of renal dysfunction can improve cardiac function.

In a study of 103 hemodialysis patients with heart failure and LVEF <40%, the mean ejection fraction increased from 32% to 52% after renal transplantation, and 70% had normalization of cardiac function.

Hypertensive heart disease and heart failure with a normal ejection fraction are common among individuals with advanced and end-stage renal disease. One study showed that there is echocardiographic evidence of left ventricular hypertrophy in 45% of individuals with creatinine clearance of 24 mL/min and in 70% of those planning to initiate hemodialysis.

Accelerated rates of coronary events and markers of uremia are more prevalent in renal patients with left ventricular hypertrophy compared with those with normal left ventricular mass, and a high proportion of these individuals develop clinical heart failure.

Prognosis

In heart failure, as the heart gets worse, often so do the kidneys, complicating the treatment of heart failure and worsening the prognosis. The question is: “What determines prognosis?” Although renal function may remain stable at a diminished level in heart failure patients, in many it eventually leads to worsening end-organ damage, resistance to standard therapy, frequent hospitalizations, exacerbation of symptoms, inability to maintain a good quality of life, and, eventually, death.

In ambulatory heart failure patients, the presence of concomitant renal dysfunction consistently has been one of the strongest risk factors for mortality. This risk becomes evident even at serum creatinine clearance levels >1.3 mg/d; and estimated creatinine clearance values 60-70 mL/min. Furthermore, renal function is at least as powerful an adverse prognostic factor as most clinical variables, including ejection fraction and NYHA class. Although renal dysfunction predicts all-cause mortality, it is most predictive of death from progressive heart failure, which suggests that it is a manifestation of and/or exacerbating factor for left ventricular dysfunction.

In the setting of hospitalization for decompensated heart failure, worsening renal function is even more important than baseline renal function for predicting adverse outcomes. Although any increase in creatinine is associated with poorer survival rates, longer hospitalization, and more frequent readmission, several studies have used a threshold of a >=0.3-mg/dl (26.5-mmol/l) rise in serum creatinine over baseline to define this phenomenon (AKIN Definition).

Changes of this magnitude generally occur in 25-45% of patients admitted for heart failure (dependent primarily on whether the cutpoint is defined as >0.3 versus >=0.3). Such patients are more likely to require management in an intensive care unit and aggressive treatment with intravenous vasodilators or positive inotropic agents.

Patients with this syndrome experience high rates of morbidity and mortality, and clinicians frequently become frustrated by their inability to improve the patient’s clinical status.

In one multicenter cohort study, a creatinine increase of 0.3 mg/dL had a sensitivity of 65% and specificity of 81% for predicting in-hospital mortality. Other studies have reported this degree of worsening renal function to be associated with a 2.3-day longer length of stay, a 67% increased risk of death within 6 months after discharge, and a 33% increased risk for hospital readmission.

Among heart failure patients, several clinical features are more common in those who develop worsening renal function. On average, they are older and have a greater prevalence of prior heart failure, renal dysfunction, diabetes, and hypertension. Somewhat surprisingly, they are not more likely to have systolic dysfunction; in fact, 37-55% have a LVEF of 40%.

In addition, worsening renal function does not appear to be characterized by a “low-output state” because a greater proportion of these patients present with elevated blood pressure (39% with systolic pressure 160 mmHg versus 30% without worsening renal function) and fewer complained of fatigue (21% versus 28%). In contrast, the findings that accompany worsening renal function have been those of fluid retention (tachypnea, rales, and elevated jugular venous pressure).

Special considerations for nursing and allied health professionals.

N/A

What's the evidence?

Description of the problem

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Emergency management

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Ricci, Z, Cruz, D, Ronco, C. “The RIFLE criteria and mortality in acute kidney injury: A systematic review. RIFLE criteria and mortality in AKI”. Kidney International. vol. 73. 2008. pp. 538-46.

Diagnosis

Myers, GL, Miller, WG, Coresh, J, Fleming, J, Greenberg, N. “Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program”. Clin Chem. vol. 52. 2006 Jan. pp. 5-18..

Stevens, LA, Stoycheff, N. “Standardization of serum creatinine and estimated GFR in the Kidney Early Evaluation Program (KEEP)”. Am J Kidney Dis. vol. 51. 2008 Apr. pp. S77-82.

Soni, SS, Ronco, C, Katz, N, Cruz, DN. “Early diagnosis of acute kidney injury: the promise of novel biomarkers”. Blood Purif. vol. 28. 2009. pp. 165-74.

Mori, K, Nakao, K. “Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage”. Kidney Int. vol. 71. 2007. pp. 967-97.

McMurray, MD, Trivax, JE, McCullough, PA. “Serum cystatin C, renal filtration function, and left ventricular remodeling”. Circ Heart Fail. vol. 2. 2009 Mar. pp. 86-9.

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McCullough, PA. “Why is chronic kidney disease the "spoiler" for cardiovascular outcomes?”. J Am Coll Cardiol. vol. 41. 2003 Mar 5. pp. 725-8.

Sarnak, MJ, Levey, AS, Schoolwerth, AC, Coresh, J, Culleton, B. “American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention”. Circulation. vol. 108. 2003 Oct 28. pp. 2154-69.

Ronco, C, McCullough, P, Anker, SD, Anand, I, Aspromonte, N. “Cardio-renal syndromes: report from the consensus conference of the Acute Dialysis Quality Initiative”. Eur Heart J. 2009 Dec 25.

Angus, DC, Linde-Zwirble, WT, Lidicker, J, Clermont, G, Carcillo, J. “Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care”. Crit Care Med. vol. 29. 2001. pp. 1303-10..

Martin, GS, Mannino, DM, Eaton, S, Moss, M. “The epidemiology of sepsis in the United States from 1979 through 2000”. N Engl J Med. vol. 348. 2003. pp. 1546-54.

Bagshaw, SM, Lapinsky, S, Dial, S, Arabi, Y, Dodek, P. “Acute kidney injury in septic shock: clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy”. Intensive Care Med.

Lopes, JA, Jorge, S, Resina, C, Santos, C, Pereira, A, Neves, J, Antunes, F, Prata, MM. “Acute renal failure in patients with sepsis”. Crit Care. vol. 11. 2007. pp. 411

Zanotti-Cavazzoni, SL, Hollenberg, SM. “Cardiac dysfunction in severe sepsis and septic shock”. Curr Opin Crit Care. vol. 15. 2009 Oct. pp. 392-7.

Favory, R, Neviere, R. “Significance and interpretation of elevated troponin in septic patients”. Crit Care. vol. 10. 2006. pp. 224

Ammann, P, Maggiorini, M, Bertel, O, Haenseler, E, Joller-Jemelka, HI. “Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes”. J Am Coll Cardiol. vol. 41. 2003. pp. 2004-2009..

Mehta, NJ, Khan, IA, Gupta, V, Jani, K, Gowda, RM. “Cardiac troponin I predicts myocardial dysfunction and adverse outcome in septic shock”. Int J Cardiol. vol. 95. 2004 May. pp. 13-7..

Vincent, JL, Sakr, Y, Sprung, CL, Ranieri, VM, Reinhart, K. “Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: results of the SOAP study”. Crit Care Med. vol. 34. 2006 Feb. pp. 344-53..

Chinnaiyan, KM, Alexander, D, Maddens, M, McCullough, PA. “Curriculum in cardiology: integrated diagnosis and management of diastolic heart failure”. Am Heart J. vol. 153. 2007 Feb. pp. 189-200.

Myers, GL, Miller, WG, Coresh, J, Fleming, J, Greenberg, N. “Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program”. Clin Chem. vol. 52. 2006 Jan. pp. 5-18..

Stevens, LA, Stoycheff, N. “Standardization of serum creatinine and estimated GFR in the Kidney Early Evaluation Program (KEEP)”. Am J Kidney Dis. vol. 51. 2008 Apr. pp. S77-82.

Soni, SS, Ronco, C, Katz, N, Cruz, DN. “Early diagnosis of acute kidney injury: the promise of novel biomarkers”. Blood Purif. vol. 28. 2009. pp. 165-74.

Treatment

Weinfeld, MS, Chertow, GM, Stevenson, LW. “Aggravated renal dysfunction during intensive therapy for advanced chronic renal failure”. Am Heart J. vol. 138. 1999. pp. 285-90,.

Costanzo, MR, Henwood, JT, DeMarco, T. “Impact of renal insufficiency and chronic diuretic therapy on outcome and resource utilization in patients with acute decompensated heart failure [abstract]”. J Am coll Cardiol. vol. 43. 2004. pp. A180

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Fliser, D, Zurbruggen, I, Mutschler, E. “Coadministration of albumin and furosemide in patients with the nephroptic syndrome”. Kidney Int. vol. 55. 1999. pp. 629-34..

Leier, CV. “Renal roadblock in managing low output heart failure”. Crit Care Med. vol. 32. 2004. pp. 1228-9.

Jaski, BE, Ha, J, Denys, BG, Lamba, S, Trupp, RJ. “Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients”. J Cardiac Failure. vol. 9. 2003. pp. 227-31..

Schenarts, PJ, Sagraves, SG, Brad, MR. “Low-dose dopamine: A physiologically based review”. Curr Surg. vol. 63. 2006. pp. 219-25.

Geisberg, C, Butler, J. “Addressing the challenges of cardiorenal syndrome”. Cleveland Clinic J Med. vol. 73. 2006. pp. 5

Butler, J, Emerman, C, Peacock, WF, Mathur, VS, Young, JB. “The efficacy and safety of B-type natriuretic peptide (nesiritide) in patients with renal insufficiency and acutely decompensated congestive heart failure”. Nephrol Dial Transplant. vol. 19. 2004. pp. 391-9..

Tahara, A, Tomura, Y, Wada, K. “Effect of YM087, a potent nonpeptide vasopressin antagonist, on vasopressin-induced protein synthesis in neonatal rat cardiomyocyte”. Cardiovasc Res. vol. 38. 1998. pp. 198-205..

Almeshari, K, Ahlstrom, NG, Capraro, FE. “A volume independent component to post diuretic sodium retention in humans”. J Am Soc Nephrol. vol. 102. 1993. pp. 450-8..

Howard, PA, Dunn, MI. “Aggressive diuresis for severe heart failure in the elderly”. Chest. vol. 119. 2001. pp. 807-10.

Opdam, H, Wan, L, Bellomo, R. “A pilot assessment of the FloTrac cardiac output monitoring system”. Intensive Care Med. vol. 133. 2007. pp. 344-9.

Mayer, J, Boldt, J, Wolf, MW. “Cardiac output derived from arterial pressure waveform analysis in patients undergoing cardiac surgery. Validity of a second generation device”. Anesth Analg. vol. 106. 2008. pp. 867-72..

Wan, L, Naka, T, Uchino, S, Bellomo, R. “A pilot study of pulse contour cardiac output monitoring in patients with septic shock”. Crit Care Resusc. vol. 7. 2005. pp. 165–-9.

Nguyen, BH, Losey, T, Rasmussen, BA. “Inter-rater reliability of cardiac output measurements by transcutaneous Doppler ultrasound: implications for noninvasive hemodynamic monitoring in the ED”. Am J Emerg Med. vol. 24. 2006. pp. 828-35..

Costanzo, MR, Guglin, ME, Saltzberg, MT. “Ultrafiltration versus diuretics for patients hospitalized for acute decompensated heart failure”. J Am Coll Cardiol. vol. 49. 2007. pp. 675-83..

Chen, ZM, Pan, HC, Chen, YP. “Early intravenous then oral metoprolol in 45 852 patients with acute myocardial infarction: a randomized placebo-controlled trial”. Lancet. vol. 366. 2005. pp. 1622-32..

Yorgun, H, Deniz, A, Aytemir, K. “Cardiogenic shock secondary to combination of diltiazem and sotalol”. Intern Med J. vol. 38. 2008. pp. 221-2.

Butler, J, Forman, DE, Abraham, WT. “Relationship between heart failure treatment and development of worsening renal function among hospitalized patients”. Am Heart J. vol. 147. 2004. pp. 331-9..

McCullough, PA. “Cardiorenal risk: an important clinical intersection”. Rev Cardiovasc Med. vol. 3. 2002. pp. 71-6.

French, WJ, Wright, RS. “Renal insufficiency and worsened prognosis with STEMI: a call for action”. J Am Coll Cardiol. vol. 42. 2003. pp. 1544-6.

Levin, A, Foley, RN. “Cardiovascular disease in chronic renal insufficiency”. Am J Kidney Dis. vol. 36. 2000. pp. S24-S30.

Ruggenenti, P, Perna, A, Remuzzi, G. “ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy”. J Am Soc Nephrol. vol. 12. 2001. pp. 2832-7.

Uchino, S, Bellomo, R, Goldsmith, D, Bates, S. “An assessment of the RIFLE criteria for ARF in hospitalized patients”. Crit Care Med. vol. 34. 2006. pp. 1913-7.

Ricci, Z, Cruz, D, Ronco, C. “The RIFLE criteria and mortality in acute kidney injury: A systematic review”. Kidney Int. vol. 73. 2008. pp. 538-46.

Cunningham, PN, Dyanov, HM, Park, P. “Acute renal failure in endotoxemia is caused by TNF acting directly on TNF-1 receptors in kidney”. J Immunol. vol. 168. 2007. pp. 5817-23..

Refractory cases

Geisberg, C, Butler, J. “Addressing the challenges of cardiorenal syndrome”. Clev Clin J Med. vol. 73. 2006. pp. 485-91.

Francis, G. “Acute decompensated heart failure. The cardiorenal syndrome”. Clev Clin J Med. vol. 73. 2006. pp. S8-13.

Weinfeld, MS, Chertow, GM, Stevenson, LW. “Aggravated renal dysfunction during intensive therapy for advanced chronic renal failure”. Am Heart. vol. 138. J1999. pp. 285-90.

Costanzo, MR, Heywood, JT, DeMarco, T. “Impact of renal insufficiency and chronic diuretic therapy on outcome and resource utilization in patients with acute decompensated heart failure”. J Am Coll Cardiol. vol. 43. 2004. pp. A180

Disease monitoring, follow-up and disposition

“Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure”. N Engl J Med. vol. 325. 1992. pp. 293-302..

Ljungman, S, Kjekshus, J, Swedberg, K. “Renal function in severe congestive heart failure during treatment with enalapril (the Cooperative North Scandinavian Enalapril Survival Study Trial)”. Am J Cardiol. vol. 70. 1992. pp. 479-87.

Shlipak, MG. “Pharmacotherapy for heart failure in patients with renal insufficiency”. Ann Intern Med. vol. 138. 2003. pp. 917-23.

Hou, FF, Zhang, X, Zhang, GH. “Efficacy and safety of benazepril for advanced chronic renal insuficiency”. N Engl J Med. vol. 354. 2006. pp. 131-40..

Butler, J, Forman, DE, Abraham, WT. “Relationship between heart failure treatment and development of worsening renal function among hospitalized patients”. Am Heart J. vol. 147. 2004. pp. 331-8..

Neuberg, GW, Miller, AB, O’Connor, CM. “Diuretic resistance predicts mortality in patients with advanced heart failure (Prospective Randomized Amlodipine Survival Evaluation)”. Am Heart J. vol. 144. 2002. pp. 31-8..

“Intravenous nesiritide vs. nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial”. JAMA. vol. 287. 2002. pp. 1531-40..

Butler, J, Emerman, C, Peacock, WF, Mathur, VS, Young, JB. “The efficacy and safety of B-type natriuretic peptide (nesiritide) in patients with renal insufficiency and acutely decompensated congestive heart failure”. Nephrol Dialy Transplant. vol. 19. 2004. pp. 391-9..

Rich, MW, Beckham, V, Wittenberg, C. “A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure”. N Engl J Med. vol. 333. 1995. pp. 1190-5..

Shah, NB, Der, E, Ruggerio, C. “Prevention of hospitalizations for heart failure with an interactive home monitoring program”. Am Heart J. vol. 135. 1998. pp. 373-8..

Fonarow, GC, Stevenson, LW, Walden, JA. “Impact of a comprehensive heart failure management program on hospital readmission and functional status of patients with advanced heart failure”. J Am Coll Cardiol. vol. 30. 1997. pp. 725-32..

Philbin, EF. “Comprehensive multidisciplinary programs for the management of patients with congestive heart failure”. J Gen Intern Med. vol. 14. 1999. pp. 130-5.

Jessup, M, Abraham, WT, Casey, DE, Feldman, AM, Francis, GS. “2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation”. Circulation. vol. 119. 2009 Apr 14. pp. 1977-2016.

Maisel, AS, Krishnaswamy, P, Nowak, RM. “Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure”. N Engl J Med.. vol. 347. 2002. pp. 161-7..

Moe, GW, Howlett, J, Januzzi, JL. “N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study”. Circulation. vol. 115. 2007. pp. 3103-10..

Silvers, SM, Howell, JM, Kosowsky, JM. “Clinical policy: Critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes”. Ann Emerg Med. vol. 49. 2007. pp. 627-69.

Mebazaa, A, Gheorghiade, M, Pina, IL. “Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes”. Crit Care Med. vol. 36. 2008. pp. S129-39..

Costanzo, MR, Johannes, RS, Pine, M. “The safety of intravenous diuretics alone versus diuretics plus parenteral vasoactive therapies in hospitalized patients with acutely decompensated heart failure: a propensity score and instrumental variable analysis using the Acutely Decompensated Heart Failure National Registry (ADHERE) database”. Am Heart J. vol. 154. 2007. pp. 267-77..

Metra, M, Torp-Pedersen, C, Cleland, JG. “Should beta-blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET”. Eur J Heart Fail. vol. 9. 2007. pp. 901-9.

Fonarow, GC, Abraham, WT, Albert, NM. “Influence of beta-blocker continuation or withdrawal on outcomes in patients hospitalized with heart failure: findings from the OPTIMIZE-HF program”. J Am Coll Cardiol. vol. 52. 2008. pp. 190-9..

McAlister, FA, Stewart, S, Ferrua, S. “Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials”. J Am Coll Cardiol. vol. 44. 2004. pp. 810-9..

Costanzo, MR, Guglin, ME, Saltzberg, MT. “Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure”. J Am Coll Cardiol. vol. 49. 2007. pp. 675-83..

Cuffe, MS, Califf, RM, Adams, KF. “Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial”. JAMA. vol. 287. 2002. pp. 1541-7..

Binanay, C, Califf, RM, Hasselblad, V. “Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial”. JAMA. vol. 294. 2005. pp. 1625-33..

Pathophysiology

Forman, DE, Bulter, J, Wang, Y. “Incidence, predicators at admission and impact of worsening renal function among patients hospitalized with heart failure”. J Am Coll Cardiol. vol. 43. 2004. pp. 62-7..

Bongartz, LG, Cramer, MJ, Braam, B. “The cardiorenal connection”. Hypertension. vol. 43. 2004. pp. e14

Arici, M, Walls, J. “End-stage renal disease, atherosclerosis, and cardiovascular mortality: is C-reactive protein the missing link?”. Kidney Int. vol. 59. 2001. pp. 407-10.

Mebazaa, A, Gheorghiade, M, Pina, IL. “Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes”. Crit Care Med. vol. 36. 2008. pp. S129-S139..

Bellomo, R, Ronco, C, Kellum, JA. “Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the ADQI Group”. Crit Care. vol. 8. 2004. pp. R204-12..

Adams, KF, Fonarow, GC, Emerman, CL. “Characteristics and outcome of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100 000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE)”. Am Heart J. vol. 149. 2005. pp. 209-16..

Fonarow, GC, Gattis Stough, W, Abraham, WT. “Characteristics, treatments and outcomes of patients with preserved systolic function hospitalized for heart failure”. J Am Coll Cardiol. vol. 50. 2007. pp. 768-77..

Jose, P, Skali, H, Anavekar, N. “Increase in creatinine and cardiovascular risk in patients with systolic dysfunction after myocardial infarction”. J Am Soc Nephrol. vol. 17. 2006. pp. 2886-91..

Goldberg, A, Hammerman, H, Petcherski, S. “In-hospital and 1-year mortality of patients who develop worsening renal function following acute ST-elevation myocardial infarction”. Am Heart J. vol. 150. 2005. pp. 330-7..

Tokuyama, H, Kelly, DJ, Zhang, Y. “Macrophage infiltration and cellular proliferation in the nonischemic kidney and heart following prolonged unilateral renal ischemia”. Nephron Physiol. vol. 106. 2007. pp. 54-62..

Opdam, H, Wan, L, Bellomo, R. “A pilot assessment of the FloTrac cardiac output monitoring system”. Intensive Care Med. vol. 133. 2007. pp. 344-9.

Mayer, J, Boldt, J, Wolf, MW. “Cardiac output derived from arterial pressure waveform analysis in patients undergoing cardiac surgery. Validity of a second generation device”. Anesth Analg. vol. 106. 2008. pp. 867-72..

Wan, L, Naka, T, Uchino, S, Bellomo, R. “A pilot study of pulse contour cardiac output monitoring in patients with septic shock”. Crit Care Resusc. vol. 7. 2005. pp. 165-169.

Bhatia, RS, Tu, JV, Lee, DS. “Outcome of heart failure with preserved ejection fraction in a population-based study”. N Engl J Med. vol. 355. 2006. pp. 260-9..

Blake, P, Hasegawa, Y, Khosla, MC. “Isolation of myocardial depressant factor(s) from the ultrafiltrate of heart failure patients with acute renal failure”. ASAIO J. vol. 42. 1996. pp. M911-5..

Meyer, TW, Hostetter, TH. Uremia N Engl J Med. vol. 357. 2007. pp. 1316-25.

Figueras, J, Stein, L, Diez, V. “Relationship between pulmonary hemodynamics and arterial pH and carbon dioxide tension in critically ill patients”. Chest. vol. 70. 1976. pp. 466-72..

Brady, JP, Hasbargen, JA. “A review of the effects of acidosis on nutrition in dialysis patients”. Semin Dial. vol. 13. 2000. pp. 252-5.

McCullough, PA, Sandberg, KR. “Chronic kidney disease and sudden death: strategies for prevention”. Blood Purif. vol. 22. 2004. pp. 136-42.

Selby, NM, McIntyre, CW. “The acute cardiac effects of dialysis”. Semin Dial. vol. 20. 2007. pp. 220-8.

Chertow, GM, Normand, SL, Silva, LR, McNeil, BJ. “Survival after acute myocardial infarction in patients with end-stage renal disease: results from the cooperative cardiovascular project”. Am J Kidney Dis. vol. 35. 2000. pp. 1044-51.

Cunningham, PN, Dyanov, HM, Park, P. “Acute renal failure in endotoxemia is caused by TNF acting directly on TNF-1 receptors in kidney”. J Immunol. vol. 168. 2007. pp. 5817-23..

Kumar, A, Paladugu, B, Mensing, J. “Nitric oxide-dependent and independent mechanisms are involved in TNF-alpha induced depression of cardiac myocyte contractility”. Am J Physiol Regul Integr Comp Physiol. vol. 292. 2007. pp. R1900-6..

Ronco, C, Haapio, M, House, AA. “Cardiorenal syndrome”. J Am Coll Cardiol. vol. 52. 2008. pp. 1527-39..

Epidemiology

Adams, KF, Fonarow, GC, Emerman, CL, LeJemtel, TH, Costanzo, MR. “Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE)”. Am Heart J. vol. 149. 2005. pp. 209-16..

McAlister, FA, Ezekowtiz, J, Tonelli, M, Armstrong, PW. “Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study”. Circulation. vol. 109. 2003. pp. 1004-9.

Hillege, HL, Girbes, AR, de Kam, PJ, Boomsma, F, de Zeeuw, D. “Renal function, neurohormonal activation, and survival in patients with chronic heart failure”. Circulation. vol. 102. 2000. pp. 203-10..

Forman, DE, Butler, J, Wang, Y, Abraham, WT, O’Connor, CM. “Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure”. J Am Coll Cardiol. vol. 43. 2004. pp. 61-7..

Gottlieb, SS, Abraham, WT, Butler, J, Forman, DE, Loh, E. “The prognostic importance of different definitions of worsening renal function in congestive heart failure”. J Card Fail. vol. 8. 2002. pp. 136-41..

Coresh, J, Astor, BC, Greene, T, Eknoyan, G, Levey, AS. “Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey”. Am J Kidney Dis. vol. 41. 2003. pp. 1-12.

Foley, RN, Parfrey, PS, Sarnak, MJ. “Epidemiology of cardiovascular disease in chronic renal disease”. J Am Soc Nephrol. vol. 9. 1998. pp. S16-S23.

Tonelli, M, Wiebe, N, Culleton, House, A, Rabbat, C, Fok, M, McAlister, F, Garg, AX. “Chronic kidney disease and mortality risk: a systemic review”. J Am Soc Nephrol. vol. 17. 2006. pp. 2034-47.

Harnett, JD, Foley, RN, Kent, GM, Barre, PE, Murray, D. “Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors”. Kidney Int. vol. 47. 1995. pp. 884-90..

Wali, RK, Wang, GS, Gottlieb, SS, Bellumkonda, L, Hansalia, R. “Effect of kidney transplantation on left ventricular systolic function and congestive heart failure in patients with end-stage renal disease”. J Am Coll Cardiol. vol. 45. 2005. pp. 1051-1060.

Levin, A, Singer, J, Thompson, CR, Ross, H, Lewis, M. “Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention”. Am J Kidney Dis. vol. 27. 1996. pp. 347-54.

Parfrey, PS, Foley, RN, Harnett, JD, Kent, GM, Murray, DC. “Outcome and risk factors for left ventricular disorders in chronic uraemia”. Nephrol Dial Transplant. vol. 11. 1996. pp. 1277-85..

Prognosis

Gottlieb, SS, Abraham, W, Butler, J. “The prognostic importance of different definitions of worsening renal function in congestive heart failure”. J Card Fail. vol. 8. 2002. pp. 136-41..

Harnett, JD, Foley, RN, Kent, GM. “Congestive heart failure in dialysis patients: Prevalence, incidence, prognosis and risk factors”. Kidney Int. vol. 47. 1995. pp. 884-90..

Fonarow, GC, Adams, KF, Abraham, WT. “Risk stratification for in-hospital mortality in acutely decompensated heart failure: Classification and regression tree analysis”. JAMA. vol. 293. 2005. pp. 572-80..

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