Nephrology Hypertension

Acute Kidney Injury: Cardiorenal Syndromes (acute decompensated heart failure and worsening renal function)

Does this patient have acute decompensated heart failure and worsening renal function?

The co-existence of cardiac and renal impairment has been called "Cardiorenal Syndrome (CRS)." Initial attempts at defining CRS described it as a state in which therapy to relieve heart failure symptoms was limited by worsening renal function. However, the bidirectional interplay between these two pathological states was not reflected accurately by this working consensus. Therefore, Ronco et al developed a more complete definition, which defines CRS as "a pathophysiological disorder of the heart and kidneys, whereby acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of the other."

CRS was accordingly subdivided into five categories:

  • Acute cardiorenal syndrome (CRS type 1) - acute deterioration in cardiac function leading to worsening renal function

  • Chronic cardiorenal syndrome (CRS type 2) - chronic cardiac dysfunction leading to worsening renal function

  • Acute renocardiac syndrome (CRS type 3) - acute renal dysfunction leading to cardiac dysfunction

  • Chronic renocardiac syndrome (CRS type 4) - chronic kidney disease leading to cardiac disease

  • Secondary cardiorenal syndromes - systemic conditions that cause both renal and cardiac dysfunction

This review will focus on the management of CRS type 1, since renal issues caused by acute decompensated heart failure are the most common presentation in the hospitalized setting.

What are the common presenting symptoms of cardiorenal syndrome type 1?

Patients with acute cardiorenal syndrome predominantly present with signs and synptoms of acute decompensated heart failure. The most common presenting symptom is shortness of breath (dyspnea). Dyspnea can be graded in severity according to the New York Heart Association classification, which has important prognostic implications.

The combination of dyspnea, orthopnea, and paroxysmal nocturnal dyspnea constitutes the cardinal symptoms of left ventricular impairment. The symptoms of right ventricular impairment are much less specific - symmetrical lower extremity edema is perhaps the most common, as it frequently causes discomfort and may become apparent to the patient due to poorly fitting shoes or clothes. All of the above complaints reflect elevation in either pulmonary of systemic venous pressures, caused by a failing left and right heart respectively.

Some other important symptoms to enquire about include chest pain ( as up to one-third of presentations of acute heart failure are caused by myocardial ischemia), palpitations, syncope, claudication, fatigue, weight loss or gain, anorexia, and fever.

The differential diagnosis for acute heart failure should include lower respiratory tract infections, chronic obstructive pulmonary disease (COPD) exacerbations, pneumothorax, musculoskeletal disorders, esophageal disorders, peptic ulcer disease, pancreatitis, gallstone disease, and even psychological diagnoses, including panic attacks.

In contrast, the symptoms of worsening renal function are non-specific and vary widely depending on acuity. It is important to broaden the differential beyond so called "pre-renal" or hypo-perfusion related diagnoses. History taking should enquire about urinary obstructive symptoms (hesitancy, poor stream, post-micturition dribbling, double voiding, frequency, nocturia), dysuria and flank pain (possibly reflecting infections or renal stone disease), gross hematuria (reflecting glomerular or non-glomerular bleeding), urine frothiness ( reflecting proteinuria) and urine volume. Oliguria (<400mLs per day) and anuria (<100mLs/day) may reflect obstruction, severe volume depletion, or intrinsic renal parenchymal disease.

Acute anuria is quite rare in CRS type 1. If present, it may reflect acute obstruction, renal arterial thrombosis or massive ischemic kidney injury from shock. The"extra-renal" effects of kidney impairment (hypertension, anemia, volume overload, electrolyte and acid-base abnormalities) more often result in patients seeking medical attention. Other non-specific features of chronic renal failure include anorexia, altered taste sensation, vomiting, pruritis, hiccups, peripheral neuropathy, and altered sleep patterns.

What are the important points to focus on in the medication history?

Taking an accurate medication and allergy history in the current era of polypharmacy is vital, particularly in light of the ever-expanding availability of prescription and non-prescription drugs, herbal remedies and supplements. Timing of medication changes, introduction of new medications, and follow-up laboratory checks after dose changes are extremely important.

Diuretics

Loop diuretics are the mainstay of treatment for acute decompensated heart failure (ADHF). They are associated with worsening renal function, as measured by serum creatinine, in around 21-27% of hospitalized cases of ADHF. Even small rises in creatinine of 0.3mg/dL have been associated with increased mortality and readmissions to hospital in this population.

The nature of this association is unclear, and recent evidence suggests that changes in creatinine may not be universally harmful, at least when they occur in the setting of an effective diuresis. A recent study, for example, showed that the presence of hemoconcentration (a surrogate for aggressive diuresis) was associated with worsening renal function, but simultaneously associated with improved survival. Further research is needed to better understand the meaning of these observations.

The use of aldosterone antagonists, such as spironolactone or eplerenone, have been associated with improved survival in individuals with heart failure. The use of these, or other potassium sparing diuretics, such as triamterene and amiloride, should be closely monitored for development of hyperkalemia, especially when used in combination with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs).

ACEI/ARBS

These medications have a proven mortality benefit in patients with systolic heart failure. They attenuate the vasoconstrictor effects of angiotensin II on the efferent arteriole, leading to decreased intra-glomerular pressure and subsequent reduction in proteinuria. In the setting of acute cardiac decompensation, this property may predispose to further reductions in filtration pressure, leading to worsening renal function.

There is debate on whether or not these medications should be held in the setting of CRS type 1; however, it is well recognized that worsening renal function is associated with under-prescribing of these medications in clinical contexts with a known mortality benefit. Therefore, every effort should be made to reinstitute ACE inhibitors or ARBs before discharge, starting at a low dose and giving consideration to stopping the medication if the serum creatinine increases by more than 30% form baseline within 5-7 days of initiation.

Beta blockers

This class of medication has proven mortality benefits in the post-myocardial infarction and systolic heart failure settings. Beta blockers are also useful in the treatment of tachyarrhythmias. In patients with ADHF, beta blockers should not be initiated acutely, as they could potentially lead to a profound low-output state and cardiogenic shock. Atenolol, nadolol, and sotalol are renally cleared and require dose adjustment (or avoidance) in individuals with renal failure.

Aspirin/Clopidogrel/Anti-coagulants

At low doses, aspirin does not appear to have clinically apparent effects of renal function. Clopidogrel has been associated with a thrombotic microangiopathy–type picture, an important consideration in a patient who presents with AKI and is taking this drug.

Low molecular weight heparins are largely renally cleared and must be dose-adjusted in AKI and CKD to avoid predisposition to major bleeding events. The widespread use of anti-coagulants and their prolonged half-life in individuals with renal disease can have important consequences for patients who require procedures, eg, placement of a dialysis catheter or performance of a renal biopsy.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Prostaglandin-dependent afferent arterioar vasodilation may be critical to the maintenance of GFR in individuals with heart failure and low effective circulating volume. Inhibition of prostaglandins by NSAIDs can lead to afferent arteriole vasoconstriction, decreased GFR, sodium retention, and hyperkalemia. NSAIDs are also associated with the development of acute interstitial nephritis and minimal change disease, important differentials to keep in mind as part of your workup.

Statins/Fibrates

Monotherapy with MHGCoA reductase inhibitors can, in rare cases, cause rhabdomyolysis - the estimated event risk from a recent systematic review was 3 per 100,000 person-years. The combination of fibrates and statins warrants even closer monitoring, as the incidence of rhabdomyolysis was estimated to be approximately tenfold higher with combination therapy. Development of AKI can predispose to worsening cardiac decompensation, whilst heart failure patients may be at higher risk of developing AKI in the setting of rhabdomyolysis, as aggressive volume supplementation is often contraindicated.

Immunosuppressants

Patients with cardiac transplants, other solid organ transplants, or auto-immune disease may be taking a variety of immunosuppressive agents. Nephrotoxic side effects are common with calcineurin inhibitors (cyclosporine and tacrolimus, which can cause progressive CKD, hypertension, hyperkalemia and development of post-transplant diabetes. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, may also lead to development of new or worsening proteinuria. All are associated with dyslipidemia.

Other important points in history taking

Family history

A history of ischemic heart disease in a first-degree relative is significant, particularly if they were under 60 years old at diagnosis. Diabetes is a classical systemic disease that leads to both cardiovascular and renal compromise, often with dire consequences.

Certain familial conditions can affect both the the heart and kidneys. with autosomal dominant polycystic kidney disease (ADPKD) and Fabry's disease being notable examples.

ADPKD can lead to progressive renal failure, which is an independent risk factor for cardiovascular disease. It is also associated with mitral valve prolapse, which may lead to the development of valvular heart disease over the long term.

Fabry's disease is an X-linked lysosomal storage disorder characterized by the intracellular accumulation of globotriaosylceramide. This affects multiple organ systems and is associated with the development of left ventricular hypertrophy, increased risk of stroke, neuropathy, and proteinuric kidney disease.

Social history

Excess alcohol use, smoking, and illicit drug use can underlie ADHF, as they increase the risk for ischemic heart disease and stroke. Cocaine and amphetamines can cause chronic as well as malignant hypertension, ischemia and arrhythmias, whilst development of malignant hyperthermia with these substances has the potential to lead to rhabdomyolysis. Cocaine has also been associated with the development of ischemic nephropathy and a thrombotic microangiopathic–type disease.

What are the physical findings?

General appearance

Hyperventilation, best seen from the end of the bed, may indicate an underlying metabolic acidosis. Presence of hiccups, myoclonic jerks, and altered mental status may indicate underlying severe uremia. Rarely the presence of uremic fetor, described as a musty smell (possible due to the breakdown of urea into ammonia in saliva), may be noted.

Vitals

Detection of relative hypo- or hypertension, especially the presence of postural hypotension, is important in the assessment of volume status and hemodynamic stability. Tachycardia may indicate volume depletion, but may not be present in patients on rate-controlling agents. Elevated temperature can be associated with underlying infection or inflammatory conditions, for instance. The resting respiratory rate is an important clue to the severity of pulmonary edema.

Hands

Palmar crease pallor may indicate underlying anemia. Uremic frost - purportedly caused by precipitation of urea from sweat in patients with severe azotemia - is an important clue to the presence of severe renal failure, but is rarely observed in modern times. Asterixis may indicate underlying uremic encephalopathy and can be seen with less severe azotemia.

Finally, the arms and legs should be examined for the presence of arteriovenous fistulae, which may have been placed in anticipation of future commencement of hemodialysis. In individuals with limited cardiac reserve, ADHF may be precipitated by the rapid increase in blood flow through a recently placed fistula.

Head and neck

The jugular venous pressure (JVP) should initially be examined with the patient lying at 45 degrees and from the patient's right side. JVP is a surrgate for right atrial pressure, not necessarily increased volume. Differential causes of a raised JVP include volume overload, right ventricular hypertrophy with a stiff ventricle, pulmonary hypertension, pulmonary of tricuspid valve pathology, pericaridal constriction/effusion, and superior vena caval obstruction (the latter does not have a dynamic waveform).

If the JVP is not seen, it may be excessively high, in which case you need to sit the patient more upright; or too low, in which case the patient needs to be lowered below 45 degrees. Suboptimal examination conditions and inter-observer variability limit the usefulness of JVP as an isolated test.

Chest

A displaced point of maximal impulse (apex beat) is associated with cardiac dilation and may signify underlying cardiomyopathy. A third heart sound is indicative of left ventricular failure, whilst a fourth heart sound signals a stiff ventricle, often from chronic systemic hypertension. A pericardial rub may be associated with underlying uremia. This finding on its own is an indication to begin renal replacement therapy. Auscultation of the lung bases can detect pleural effusions and crackles, suggestive of pulmonary edema.

Abdomen and lower extremities

Hepatomegaly and a pulsatile liver are asociated with right ventricular failure and tricuspid regurgitation respectively. Ascites may develop in advanced right heart failure and should be examined for with patients in the supine position. Palpation may reveal an obstructed bladder in the lower midline. Auscultation for renal bruits may signify underlying renal artery stenosis, which can occasionally cause ADHF.

Pitting edema in heart failure is usually symmetrical and the extent should be recorded and examined for on a daily basis (with daily weights) to assess treatment efficacy.

What tests to perform?

Initial tests

Blood urea nitrogen (BUN)/Creatinine

Serum creatinine, despite its imperfections, remains the standard measurement in clinical practice for the determination of renal function. Various staging systems have been devised to classify the severity of acute kidney injury, based on acute changes in serum creatinine, including the RIFLE and AKIN staging systems. There has been limited validation of these systems in the acute heart failure setting.

Even small changes in creatinine, of as little as 0.3mg/dL, have been associated with increased mortality in a generalized hospital sample, whilst changes of 0.5mg/dL have been associated with increased mortality in patients undergoing percutaneous coronary interventions. Changes in BUN have also been associated with poor outcome in in patients hospitalized with ADHF. Changes in BUN reflect not only underlying GFR, but may be altered in the setting of "pre-renal" physiology, upper gastrointestinal hemorrhage, high dose steroid use and severe sepsis. Despite the intrinsic limitations, assessment of renal function with BUN and creatinine should be performed daily in individuals with CRS type 1.

Cardiac biomarkers

The interpretation of cardiac biomarkers in patients with CKD and ESRD is difficult, and the role of biomarkers in AKI has been understudied to date. Overall, it would appear that cardiac troponin I is more sensitive in detecting acute coronary syndromes in patients with chronic kidney disease and ESRD than other cardiac biomarkers. Elevated baseline cardiac troponins have also been reported as markers of poor prognosis in patietns with advanced CKD. Biomarkers of ischemic cardiac injury should be evaluated upon admission and as part of serial data collection, as up to one third of heart failure admissions may be associated with acute cardiac ischemia.

Brain natriuretic peptide (BNP) is released from the atial and ventricular walls in response to increased wall stretch. BNP concentration is inversely related to GFR, making its interpretation as a marker of cardiac failure difficult in patients with CKD. A low value, however, is useful in ruling out the diagnosis of cardiac failure. N-terminal BNP is an inactive cleavage product , released in stoichiometrically similar amounts to BNP - it too is cleared by the kidneys, making elevated levels of controversial diagnostic utility in patients with acute or chronic decline in GFR.

Chest X-ray

A simple chest film can provide useful diagnostic information and help to rule out alternative causes of acute dyspnea; Plain chest X-rays should be included in the initial evaluation of patients with suspected heart failure. The presence of interstitial infiltrates, blunted costophrenic angles and Kerley B lines are consistent with pulmonary oedema. The presence of cardiomegaly supports the diagnosis of a dilated heart of systolic failure. Follow-up X-rays should be performed after several days to assess response to therapy and to determine resolution of congestion or parenchymal disease.

Renal ultrasound

A renal ultrasound is a simple, non-invasive, and reliable method of ruling out urinary tract obstruction and assessing the renal parenchyma. Attention should be paid to kidney length, echotexture and cortical thickness. In adults, the average length is 10-12cm. Smaller kidneys and cortical thinning suggest a chronic disease process, whilst larger kidneys have an alternative differential - including infiltrative disease, early diabetic nephropathy, polycystic kidney disease and tumors. In selected cases, doppler ultrasound can be used to examine the patency of the renal arteries and veins - renal artery stenosis can cause "flash" pulmonary edema and is a potentially fixable condition.

Ultrasound (or alternative imaging) evaluation should be performed when acute kidney injury has developed, as it is imperative to rule out obstruction. - an easily treatable cause of AKI.

Electrocardiogram

Routine electrocardiograms (EKGs) should be performed upon presentation of a patient with ADHF and inspected for ishemic changes. Tracings should be compared with baseline EKGs for interval changes. Ischemic changes may be masked by left ventricular hypertrophy, present in up to 75% of individuals with stage 5 CKD.

Electrolyte derangements may be present in individuals with CRS, with hyperkalemia being the most noted and feared. The typical changes of hyperkalemia include peaked T waves, widening of the QRS complex, flattening of the P waves and progression to a sinusoidal pattern.

An EKG should be performed upon admission and as part of serial data collection when ischemia is suspected. Furthermore, it provides vital information on the cardiac effects of electrolyte abnormalities, allowing prioritization of treatment of potentially life-threatening emergencies.

Echocardiogram

Quantification of ejection fraction, chamber size and valvular function can lend important diagnostic information. It is estimated that 40-50% of heart failure cases have preserved left ventricular function - so called "diastolic heart failure." This diagnostic category has a paucity of evidence-based treatment algorithms and can be challenging to treat. The pericardium may be evaluated and the presence of hemodynamically significant pericardial effusions can be ascertained. Evaluation of inferior vena cava respiratory variation as a measure of intravascular volume status may be useful.

Other tests

Blood chemistries

Hyponatremia is an important independent risk factor for increased mortality in patients with heart failure. Non-osmotic release of vasopressin in the setting of effective arterial underfilling promotes the retention of water in the renal collecting ducts, leading to a dilutional hyponatremia. Additionally, thiazide diuretics and other medications can cause a drug-induced hyponatremia.

Serum bicarbonate concentration may give important clues to the presence of an underlying acid-base disturbance. Excessive diuresis may be signified by a rise in serum bicarbonate and development of metabolic alkalosis. This value should be interpreted in conjunction with pH and arterial blood gases.

Complete blood count (CBC)

Anemia is common in patients with heart failure, CKD and coexistent disease states, and has been associated with poorer outcomes. Nevertheless, recent clinical trials have demonstrated an association between higher hemoglobin values and increased mortality in CKD patients receiving erythropoietin and suggest a more limited role for its use. Similarly, the role of transfusion in patients who are potential cardiac or renal transplant candidates is limited, due to the potential for "sensitizing" these patients, via production of antibodies against antigens on foreign blood products.

Iron studies should be evaluated in anemic patients - there is some evidence that correction of iron is beneficial in patients with heart failure, even beyond its effects on raising the hemoglobin.

No guidelines exist for anemia management in individuals with AKI. The acuity of the anemia and current patient hemodynamic parameters need to be taken into consideration when deciding the appropriateness of transfusion.

Urinalysis/Urine microscopy/Urine sodium

Every patient with AKI should have a urinalysis and microscopy performed by an experienced operator. New persistent proteinuria, hematuria with dysmorphic red cells, presence of urinary casts or significant leukocyturia all suggest the possibility of underlying glomerular or interstitial disease, rather than classical CRS type 1.

Isolated proteinuria is an independent risk factor for cardiovascular disease and is becoming recognized as a risk factor for AKI. The presence of proteinuria should also be quantified by a first morning spot urine micro-albumin/creatinine ratio or urine protein/creatinine ratio.

The urine sodium can sometuimes be helpful - in situations of effective arterial underfilling, it is likely to be <25mmol/L on a spot urine sample. Values above this may suggest underlying tubular injury. It's improtant to remember that the urine sodium cannot be interpreted in the setting of diuretic use and bicarbonaturia from a metabolic alkalosis, as both conditions will increase the urinary excretion of sodium.

Urine biomarkers of AKI

Serum creatinine is a relatively late marker of kidney injury and reflects changes in GFR, rather than actual tubular damage. In the future, urine biomarkers that can specifically detect tubular injury may help in risk stratification and management. Some small studies have shown that urine biomarkers such as kidney inury molecule 1 (KIM1), N-acetyl-beta-D-glucosaminidase (NAG) and neutrophil gelatinse-associated lipocain (NGAL) become elevated in patients with CRS type 1 and predict worsening renal function, increased mortality, and increased frequency of hospitalization.

Serology/Complements/Serum protein electrophoresis/Serum free light chain assay

It is important to keep a broad differential in mind, and avoid falling into the trap of ascribing all renal impairment in the setting of ADHF to hypoperfusion-related disease. Systemic disease can occasionally cause simultaneous or overlaping cardiac and renal dysfunction, eg, diabetes, amyloid, lupus, and infective endocarditis with an immune complex mediated glomerulonephritis. Blood cultures, serum complement levels, serum free light chains, anti-nuclear antibodies (ANA), hepatitis serology, anti-neutrophil cytoplasmic antibodies (ANCA), and anti- glomerular basement membrane (anti-GBM) titers may be considered in the proper clinical context.

Cardiac catheterization

Formal angiography and right-sided cardiac catheterization are invasive procedures, but generally yield the most accurate information regarding the actual hemodynamic parameters under which the heart is operating. The ability to evaluate and intervene on the coronary vasculature is an obvious benefit of left-sided catheterization, allowing definitive treatment for ischemic lesions and restoration of blood flow to compromised tissue. A randomized trial of pulmonary artery versus clinical assessment guided treatment of CHF found an increased frequency of adverse events in the intervention group and no significant improvement in mortality or hospitalizations.

Before the use of intravenous iodinated contrast material, any patient with CKD or AKI should have appropriate prophylaxis for kidney protection. The first ideal step in prevention is obviously avoidance. If contrast must be given, then patients should be appropriately volume replete pre-contrast administration, as their hemodynamic status allows.

Differing pre-hydration fluid regimens have been proposed, but may not be feasible in patients with ADHF - temporarily holding diuretics may be the best alternative. Contrast should be iso-osmolar or low osmolar and a minimum quantity used; consideration can ge given to pre-contrast administration of n-acetylcysteine.

Percutaneous interventions may also cause disruption of mural plaque, resulting in cholesterol crystal embolization and resultant acute kidney injury.

Given the increasing availability of magnetic resonance imaging scans, the use if gadolinium-based contrast agents has become an important issue. Gadolinium is now contraindicated in patients with advanced CKD adn ESRD due to a strong association with the development of nephrogenic systemic fibrosis (NSF). There is little evidence to guide us in the setting of AKI. If gadolinium must be used in patients with ESRD, the current recommendation is for them to be dialyzed immediately aftewards.

How should patients with cardiorenal syndrome type 1 be managed?

The major treatment strategies in the treatment of acute cardiorenal syndrome focus on the cardiac presentation, as renal impairment generally results from the underlying cardiac pathophysiology, or the instituted treatment. Management can therefore be broadly categorized into relieving congestion, controlling volume status and optimizing end-organ perfusion.

Volume overload and venous congestion

The vast majority of patients with ADHF present with shortness of breath due to pulmonary congestion from elevated left ventricular pressure. However, dyspnea can also develop in the absence of overt pulmonary edema. Isolated right heart failure tends to present more non-specifically, but patients may note dependent edema, abdominal distention and fatigue.

Initial treatment is aimed at relieving congestion and off-loading the left and right ventricles. It has been increasingly recognized that elevated systemic pressure may play a role in the development of worsening renal function in ADHF. For example, in the ESCAPE study sample, the only hemodynamic variable to correlate significantly with baseline creatinine was right atrial pressure. Similarly, other studies found that the severity of tricuspid regurgitation, a surrogate for higher systemic venous pressure, was a significant independent predictor of lower estimated GFR.

Loop diuretics/Vasodilators

Loop diuretics have been used to relieve congestion for many years, but have a limited randomized controlled trial evidence base. Diuretics are often used intravenously in the acute settingb to ensure adequate bioavailability; dosing can be titrated to the minimal dose required to cause a brisk diuresis. Once this threshold has been determined, changes in dosing frequency may be more effective than changes in actual dose.

The starting intravenous dose in ADHF should be generally at least the same as the patient's chronic home oral dose. A recently published randomized controlled trial found no significant difference in either patient symptoms or changes in renal function between low dose versus high dose, or boluses versus continuous infusions of furosemide.

Physical exam, monitoring of hemodynamic paramters, ins and outs and daily weights should be used to monitor the response to therapy. If the rate of volume loss from the intravascular space exceeds the rate of refill from the extravascular compartments, then hypotension may develop. Diuretics can cause electrolyte deficiencies - in particular, hypokalemia and hypomagnesemia should be anticipated, monitored and treated appropriately, especially in patients taking digoxin.

Conflicting evidence exists on outcomes associated with high dose diuretic use in ADHF. A reduction in intravascular volume may lead to renal hypoperfusion and subsequent development of worsening renal function. Furthermore, high dose loop diuretics may activate various neurohormonal pathways, including the renin-angiotensin-aldosterone system and sympathetic nervous system, which may mitigate potential benefits from any additional improvement in congestion

Nitrates

Short-term, low dose notroglycerin causes venodilation, reduced venous return and reduced preload on the struggling heart; higher doses cause systemic vasodilation and afterload reduction. Nitroglycerin administration should generally be avoided in patients who have recently taken phospodiesterase inhibitors for erectile dysfunction.

Nitroprusside

Sodium nitroprusside causes venous and arterial vasodilation, leading to reductions in preload and afterload. Reflex tachycardia may develop. Extreme caution should be exercised in patients with AKI or advanced CKD due to the potential accumulation of thiocyanate. Vasodilator therapies are limited by hypotension, which can further impair renal perfusion leading to worsening of renal function.

Nesiritide

Nesiritide is a recombinant formation of human BNP. It cna be given intravenously in an attempt to inrcrease cardiac output, by reducing preload and afterload. It promotes natriuresis, thereby reducing vascular congestion. A meta-analysis of randomized controlled trials has suggested it may lead to worsening of renal function. The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial (ASCEND-HF) will hopefully lead to a more definitve conclusion of it's efficacy and safety.

Sodium and fluid restriction

A fluid restriction of less than 2 liters per day should be implemented in any patient with ADHF. In patients with hyponatremia of less than 130mmol/L, a stricter regimen may need to be enforced.

Sodium restriction of <2g per day should also be considered. However, there is some emerging evidence that patients who become "diuretic-resistant" may benefit from short-term, small volumes of hypertonic saline, which appear to promote vascular refilling and reduce neurohormonal activation.

Dialysis/Ultrafiltration

Often seen as the therapy of last resort, isolated ultrafiltration and dialysis play an imprtant role in the treatment of refractory voume overload and acute cardiorenal syndrome. In the ADHF setting, acute dialysis can be considered for refractory volume overload refractory hyperkalemia, refractory acidosis. and uremia. For the presence of refractory volume overload, isolated ultrafiltration is an alternative.

Various studies have compared isolated ultrafiltration to standard care (diuretics), with the belief that less diuretic use would reduce heurohormonal activation, leading to reduced incidence of AKI and reduced mortality. Unfortunately, the studies performed to date have reached differing conclusions - the RAPID-CHF study achieved greater negatiove fluid balance with ultrafiltration, but did not examine hard outcomes; the UNLOAD study also achieved greater fluid removal with ultrafiltration and noted fewer re-hospitalizations, but had no mortality benefit nor difference in renal outcomes, as assessed by delta creatinine. One further study found no difference in measured renal hemodynamic parameters between ultrafiltration versus furosemide.

In some individuals, despite maximal medical care, frequent episodes of ADHF and significant CKD or CRS persist - in these scenarios, chronic renal replacement therapy in the form of hemodialysis or peritoneal dalysis may be a reasonable alternative to further attempts at medical therapy. Although there are obvious tradeoffs, chronic dialysis is not limited by the need to maintain endogenous renal function (although more is beneficial), and it may offer better control of congestive symptoms, relief of cardiac cachexia, and a better quality of life than the continued use of high-dose diuretics and recurrent decompensations.

Vasporessin antagonists

The relatively recent availability of medications that can block the V2 receptor in the kidney has lead to the term "aquaresis" to desrcibe the predominant water excretion that this causes. The EVEREST trial evaluated the use of tolvaptan in hospitalized patients with ADHF and serum sodium <134mmol/L. While it' use resulted in increased serum sodium, there were no benefits in terms of improved renal function, mortality or heart failure related morbidity. These medications may find use in treatment of symptomatic hyponatremia, but great care must be exercised to avoid overly rapid correction of sodium, due to the concern of osmotic demyelination syndrome.

Noninvasive positive pressure ventilation

Positive inspiratory pressure is thought to help relieve pulmonary congestion and improve gaseous exchange - however, it has not been associated with improved survival in ADHF to date, when compared to standard oxygen therapy.

Low-flow state and relative hypotension

In times past, the traditional view of the failing heart leading to renal impairment was that of systolic dysfunction leading to poor forward flow, relative hypotension and subsequent renal hypoperfusion.This view has been challenged by the recognition of diastolic heart failure and the importance of systemic venous hypertension, as discussed earlier. However, there is still a place for institution of inotropic agents, such as dobutamine and milrinone, in certain situations where systolic failure and cardiogenic shock play a role in end-organ hypoperfusion.

Inotropic agents

Dobutamine and milrinone are potent cardiac inotropes. Their use has been associated with mixed results in ADHF. Milrinone increased the frequency of hypotensive episodes and atrial arrhythmias compared to standard therapy and did not improve mortality outcomes. This study excluded patients with serum creatinine >3mg/dL at baseline and no difference in renal outcomes was reported. In a retrospective comparison of dobutamine to milrinone, no significant difference was observed in the percentage of cases of AKI requring dialysis, nor the in-hospital mortality rates, in ADHF patients.

Dopamine has not been shown to afford any particular renal protective effects and should not be prescribed for this purpose.

Fenoldopam is a dopamine-1 receptor agonist that has shown some interesting potential in preventing AKI in various clinical settings (predominantly cardiac surgery). However, trials have been relatively small and suffer from a lack of consistent definitions and outcomes examined. Fonoldopam has not been formally evaluated in the ADHF setting.

Renin-angiotensin-aldosterone axis and the sysmpathetic nervous system

ACE inhibitors and ARBs

As described earlier, this axis can be activated by effective arterial underfilling, relative hypotension, and diuretic-induced changes in intravascular volume. Angiotensin II up-regulates many pro-inflammatory cytokines and is known to promote sodium reabsorption in the proximal tubule.

While the use of ACE inhibitors and ARBs has proven efficacy in other settings, their use in CRS type 1 does not have a strong evidence base. Cautious administration of short-acting formulations, taking great care to avoid relative hypotension, hyperkalemia and elevations in serum creatinine >30% from baseline, is probably reasonable in stabilized patients. For patients with low systemic vascular resistance or concurrent volume depletion, these medications may need to be avoided, held or have dose reductions in order to preserve GFR.

Aldosterone blockade

Aldosterone blockade, with agents such as spironolactone or eplerenone, has been associated with a reduced mortality in patients with chronic systolic heart failure. Again, there is a lack of strong evidence in the acute heart failure setting, with particular concern relating to its use in patients with concomitant renal insufficiency. These concerns relate in part to the possibility of additional diuresis, leading to effective volume depletion, but also to the increased potential for hyperkalemia, particularly in combination with ACE inhibitors or ARBs.

Beta blockade

Sustained increases in sympathetic activity can lead to reduced density of B1 receptors in the cardiac ventricles. Relative hypotension can promote renal sympathetic activation, leading to local renin release and direct and indirect stimulation of proximal tubular sodium reabsoprtion. Beta blockers also have an important role in the treatment of chronic heart failure - however, they must be used with extreme caution in ADHF, as acute administration may lead to an acute deterioration in cardiac output and cardiogenic shock.

If the patient is on chronic home beta blocker therapy, and is not displaying signs of relative hypotenson or hypoperfusion, then the drug can be maintained at the home dose, with close in-hospital supervision.

For those with moderate or greater decompensation, it is recommended to hold beta blockers untuil the patient has been stabilized and perfusion is restored.

For those who are not on chronic home beta blocker medications, it is not recommended to start during the acute decompensated setting of heart failure.

What happens to patients with cardiorenal syndrome type 1?

Whilst acute decompensated heart failure has been relatively well defined, the lack of a consistent and accepted definition of AKI in the literature has hampered accurate determination of the epidemiology of CRS type 1. Even the definition of an acute decline in renal function is confusing and has been referred to by various names, such as acute renal failure, acute decline in GFR, acute kidney injury and worsening renal function, to name but a few. Furthermore, the criteria to qualify for these diagnoses have differed from study to study - eg, absolute increases or percentage increases in serum creatinine versus decline in estimated or measured GFR.

Taking these varying definitions into account, the frequency of an acute decline in renal function in the setting of ADHF is estimated to be between 24 - 45%. Around 50% of AKI appears to develop within the first 3 days of hospitalization with ADHF, and 90% within the first week. However, the timing of procedures such as cardiac catheterization must be accounted for and may play a role in later presentation of AKI in these patients.

Impaired baseline renal function appears to predict a greater likelihood of developing AKI in the setting of ADHF. Those who have a persistent impairment in renal function following an episode of decompensated heart failure have higher subsequent 6-month mortality than those whose renal function returned to baseline. Even small rises in creatinine of 0.3-0.5mg/dL in the setting of ADHF have been shown to associate with increased hospital stay, readmission, and mortality.

How to utilize team care?

Specialty consultations

In situations where a patient with ADHF is under a medicine service, early consultation with cardiology is recommended.

Nephrology

Nephrology should be invloved sooner rather than later. Expert advice in volume management, drug dosing, timing of renal replacement therapy to ultrafiltration is readily available. An approach from a different viewpoint often ensures that a broader differential of AKI is considered.

Pharmacy

Pharmacists play a major role in helping with medication choice, dosing, timing and highlighting potential drug-drug interactions. These issues become all the more important and complex in the patients with AKI and CKD.

Nutrition

Nutrition sevice input is being increasingly recognized as being paramount in both acute and chronic care of heart failure patients and patients with CKD. These patients often have to grapple with multiple medical conditions, each with its own particular associated dietary restrictions.

Physical Therapy

Advanced heart failure can lead to cardiac and skeletal muscle deconditioning. Aerobic training has been shown to increase left ventricular ejection fraction, VO2max, 6-minute walk distance and to reduce mortality in patients with heart failure. Therefore, close involvement of a physical therapist can be of enormous benefit.

Are there clinical practice guidelines to inform decision making?

There are currently four major national and international sets of guidelines regarding the treatment of heart failure. These guidelines are based on varying strengths of medical evidence and, where such evidence is absent, on expert opinion. Some make reference to the scenario of worsening renal function in ADHF.

There are no guidelines available, as yet, to advise on the appropriate evidence-based management of acute kidney injury nor cardiorenal syndrome per se.

The heart failure management guidelines are listed below:

The American College of Cardiology/American Heart Association

The European Society of Cardiology

The Canadian Cardiovascular Society

The Heart Failure Society of America

What is the evidence?

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