Understanding Acute Cardiorenal Syndrome: Interdependence of Cardiac and Renal Functions

Acute cardiorenal syndrome is called the acute exacerbation of heart failure that leads to acute kidney injury, which leads to admission to the Intensive Care Unit (ICU).

 Cardiorenal syndromes are a group of disorders related to the heart and kidneys and are classified as acute or chronic and, primary, if the problem is in the heart (cardiorenal syndrome) or kidneys (renocardiac syndrome), or secondary, when it affects to another organ (secondary cardiorenal syndrome). This classification is still evolving.

> Two types of acute cardiac dysfunction

Although these definitions provide a good overview, there is a need for more detail that takes into account the nature of the organ dysfunction. Acute kidney dysfunction can be defined unambiguously using the AKIN ( Acute Kidney Injury Network ) and RIFLE ( risk, injury, failure, loss of kidney function, and end-stage kidney disease) classifications. failure, loss of kidney function and end-stage kidney disease).

On the other hand, acute cardiac dysfunction is an ambiguous term that encompasses 2 clinically and pathophysiologically distinct conditions: cardiogenic shock and acute heart failure.

Cardiogenic shock is characterized by a catastrophic compromise of cardiac pump function leading to severe global hypoperfusion, sufficient to cause systemic organ damage. The cardiac index at which organs begin to fail varies in different cases, but in general, a value <1.8 l/min/m2 is used to define cardiogenic shock.

Acute heart failure , in turn, is defined by signs corresponding to a gradual or rapid worsening and by symptoms of congestive heart failure, caused by worsening pulmonary or systemic congestion.

The hallmark of acute heart failure is hypervolemia , while patients with cardiogenic shock may be hypervolemic, normovolemic, or hypovolemic . Although in some cases of acute heart failure, cardiac output may be slightly reduced, systemic perfusion may be sufficient to maintain organ function.

The main hemodynamic mechanism of kidney injury in patients with acute heart failure is reduced renal perfusion due to venous congestion of the kidney.

These two conditions cause kidney damage by different mechanisms and have completely different therapeutic consequences. It is currently believed that the main hemodynamic mechanism of renal injury in patients with acute heart failure is reduced renal perfusion due to venous congestion of the kidney.

Furthermore, in cardiogenic shock, renal perfusion is reduced due to a critical decrease in cardiac pump function.

The definition of acute cardiorenal syndrome must describe a distinctive pathophysiology of the syndrome and offer different therapeutic options to counteract it. On this basis, the authors propose that kidney injury caused by cardiogenic shock should not be included in the definition.

This approach has also been adopted in some of the recent reviews. In this article, the authors only discuss acute cardiorenal syndrome in relation to kidney injury caused by acute heart failure.

The mechanisms involved in the pathophysiology of cardiorenal syndrome are multiple.

Sympathetic overactivity is the effect of a compensatory mechanism of heart failure and may be aggravated if cardiac output is further reduced. Its effects include constriction of afferent and efferent arterioles, resulting in reduced renal perfusion and increased reabsorption of sodium and water in the renal tubule.

> Venous hypertension without reduction in cardiac output causes kidney injury

The classic view was that, in acute heart failure, renal dysfunction is caused by reduced renal blood flow due to a failure in cardiac pump function. Cardiac output may be reduced in cases of acute heart failure for various reasons, such as atrial fibrillation, myocardial infarction, or other processes, but in the pathogenesis of kidney injury in the setting of acute heart failure, reduced cardiac output has a minimal paper, if you have it.

As evidence of this, acute heart failure is not always associated with reduced cardiac output. Even if the cardiac index (cardiac output divided by body surface area) is slightly reduced, renal blood flow is largely unaffected thanks to effective renal autoregulatory mechanisms.

When mean arterial pressure falls below 70 mm Hg , these mechanisms fail and renal blood flow begins to decrease. Therefore, unless cardiac performance is compromised enough to cause cardiogenic shock, renal blood flow generally does not change significantly, with cardiac output reduced.

Hanberg et al. performed a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) study, in which 525 patients with advanced heart failure They underwent pulmonary artery catheterization to measure cardiac index. The authors found no association between cardiac index and renal function.

> How does venous congestion affect the kidney?

In light of current clinical evidence, the focus has shifted to renal venous congestion. According to Poiseuille’s law, blood flow in the kidneys depends on the pressure gradient ? elevated blood pressure on the arterial side and low on the venous side.

The increase in renal venous pressure causes a decrease in renal perfusion pressure, therefore affecting renal perfusion. This is now recognized as an important hemodynamic mechanism of acute heart failure syndrome.

Renal congestion can also affect kidney function through indirect mechanisms. For example, it can cause renal interstitial edema which can then cause increased intratubular pressure thereby reducing the transglomerular pressure gradient.

Other important manifestations of systemic congestion are splanchnic and intestinal congestion, which can cause splanchnic and intestinal edema and sometimes ascites. This leads to increased intra-abdominal pressure, which can further compromise kidney function by compressing the veins and ureters. Systemic decongestion and paracentesis can help alleviate these manifestations.

Firth et al, in animal experiments, found that increasing renal venous pressure >18.75 mm Hg significantly reduces the glomerular filtration rate, which is completely resolved when renal venous pressure returns to baseline levels.

In a study of 145 patients hospitalized for acute heart failure, Mullens et al reported that 58 (40%) developed acute kidney injury. Pulmonary artery catheterization revealed that the primary hemodynamic factor driving renal dysfunction is elevated central venous congestion rather than reduced cardiac output.

Patients with acute cardiorenal syndrome present with clinical features of systemic or pulmonary congestion (or both) and acute kidney injury.

Usually, elevated pressures are on the left side, but they are not always associated with elevated pressures on the right side. In a study of 1,000 patients with advanced heart failure, pulmonary capillary wedge pressure =22 mm Hg had a positive predictive value of 88% for right atrial pressure =10 mm Hg. Therefore, the clinical presentation may vary, depending on the location (pulmonary, systemic, or both) and the degree of congestion.

Symptoms of pulmonary congestion are worsening dyspnea on exertion and orthopnea; auscultation of bilateral crackles (if pulmonary edema is present).

Systemic congestion can cause significant peripheral edema and weight gain. Jugular venous distention may be observed. The presence of oliguria is due to renal dysfunction, and maintenance diuretic therapy is often ineffective.

> Signs of acute heart failure

In a meta-analysis of 22 studies, Wang et al. They concluded that the characteristics that most strongly suggest acute heart failure are:

• History of paroxysmal nocturnal dyspnea

• Presence of a third heart sound

• Evidence of pulmonary venous congestion on chest x-ray

• Radiographic evidence of cardiomegaly.

Patients may not present with some of these classic clinical features and the diagnosis of acute heart failure may be difficult. For example, even if left-sided pressures are very high, pulmonary edema may be absent due to pulmonary vascular remodeling that occurs in chronic heart failure.

Pulmonary artery catheterization reveals elevated cardiac filling pressures and may serve as a therapeutic guide, but clinical evidence argues against its routine use.

Urinary electrolytes ( sodium excretion fraction <1% and urea excretion fraction <35%) usually suggest a prerenal form of acute kidney injury, since hemodynamic derangements in acute cardiorenal syndrome reduce renal perfusion.

Biomarkers of cell cycle arrest, such as urinary pseudoinsulin growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2, have recently been shown to identify patients with acute heart failure at risk of developing cardiorenal syndrome. sharp.

Misdiagnosis of acute cardiorenal syndrome, such as hypovolemia-induced acute kidney injury, can be catastrophic

The main differential diagnosis of acute cardiorenal syndrome is kidney injury due to hypovolemia. Patients with initially stable heart failure usually have mild hypervolemia, but may become hypovolemic due to very aggressive diuretic treatment, severe diarrhea, or other causes.

Although the fluid status of patients suffering from these 2 conditions is opposite, they can be difficult to distinguish. In both conditions, urinary electrolytes suggest prerenal acute kidney injury .

A history of recent fluid loss or excessive use of diuretics may help identify hypovolemia. To make the correct diagnosis it may be of great importance to analyze the recent evolution of the patient’s body weight, if available.

Misdiagnosis of acute cardiorenal syndrome, such as hypovolemia-induced acute kidney injury, can be catastrophic. If the cause of acute kidney injury is mistakenly interpreted as hypovolemia, fluid administration may further worsen cardiac and renal function, which may perpetuate the vicious cycle already in play. Lack of kidney recovery may prompt administration of more fluids.

> Treatment

The cornerstone of treatment is the elimination of fluid through diuresis or ultrafiltration. Other treatments, such as inotropes, are reserved for patients with resistant disease.

> Diuretics
The goal of treatment for acute cardiorenal syndrome is to achieve aggressive diuresis, using intravenous diuretics. Loop diuretics are the most potent class of diuretics, and the first-line medications for this purpose. Other classes of diuretics can be used along with loop diuretics since their isolated use is neither effective nor recommended.

Resistance to diuretics at their usual doses is common in patients with acute heart failure syndrome. In these patients, several mechanisms contribute to diuretic resistance. The oral bioavailability of diuretics may be reduced by intestinal edema. In cardiorenal syndrome, diuretic pharmacokinetics is significantly altered.

All diuretics except the mineralocorticoid antagonists (spironolactone and eplerenone) act in the lumen of the renal tubules, but are highly protein bound, and therefore are not filtered in the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter, while epithelial sodium channel inhibitors (amiloride and triamtyrene) are secreted via the organic cation transporter.

In renal dysfunction, several uremic toxins accumulate in the body and compete with diuretics to be secreted into the proximal convoluted tubule through these transporters.

Finally, activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, which also attenuates the response to diuretics.

> Diuretic dose. In patients whose creatinine clearance is <15 mL/min, only 10% to 20% of loop diuretics are secreted into the renal tubule, as in normal individuals. This effect warrants adjustment of the dose of diuretics during uremia.

For example, the maximum intravenous dose of a bolus of furosemide, in patients with severe renal failure, is 160 to 200 mg, in contrast to patients who have preserved renal function, for whom the dose is 40 to 200 mg. 80 mg.

When thiazides are used along with loop diuretics, dosage adjustments are similar and safe. If creatinine clearance is < 20 ml/min, the recommended dose of hydrochlorothiazide is 100 to 200 mg/day. Dose adjustments of other diuretics in renal failure, when creatinine clearance is <20 ml/min, have not been clearly established, but the maximum dose of the usual dosage range should be used.

> Continuous or bolus infusion? Another strategy to optimize drug delivery is loop diuretic infusion: Compared to bolus therapy, continuous infusion provides a more sustained and uniform drug delivery and prevents postdiuretic sodium retention.

The Diuretic Optimization Strategies Evaluation (DOSE) trial compared the efficacy and safety of continuous or bolus infusion of furosemide in 308 patients hospitalized for decompensated heart failure.

At 72 hours, there was no difference between the groups in symptom control or net fluid loss. Other studies show greater diuresis with continuous infusion than with a bolus regimen, dosed similarly. However, at this point, definitive clinical evidence is lacking to support the continued use of loop diuretic therapy.

> Combined diuretic therapy. Sequential nephron blockade by combined diuretic treatment is an important therapeutic strategy against diuretic resistance. The demonstration that treatment guided by urine production is superior to standard diuretic treatment is highlighted. The protocol suggests that, when the desired diuretic response has not been obtained with high doses of loop diuretics in monotherapy, the next step is to resort to combined diuretic treatment.

The desired diuretic response depends on the clinical situation. For example, the authors state that, in patients with severe congestion, they would desire a net fluid excretion that exceeds the fluid ingested by 2 to 3 liters after the first 24 hours.

Sometimes ICU patients receive multiple infusions of essential medications, so their net intake is 1 to 2 liters. In these patients, the desired urine output would be even more than in patients who do not receive these drug infusions.

Loop diuretics block sodium reabsorption in the thick ascending loop of Henle, disrupting the countercurrent exchange mechanism and reducing renal medullary interstitium osmolarity; These effects prevent water reabsorption. However, non-reabsorbed sodium can be taken up by the sodium chloride cotransporter and the epithelial sodium channel in the distal nephron, thus attenuating the diuretic effect.

This is the reason to combine loop diuretics with thiazides or potassium-sparing diuretics. Similarly, carbonic anhydrase inhibitors (eg, acetazolamide) reduce sodium reabsorption from the proximal convoluted tubule, but most of this sodium is reabsorbed distally. Therefore, the combination of a loop diuretic and acetazolamide may also have a synergistic diuretic effect.

The most popular combination is a loop diuretic with a thiazide, although large-scale placebo-controlled trials have not been performed. Metolazone (a thiazide-like diuretic) is commonly used due to its low cost and availability.

It has also been shown to block sodium reabsorption in the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a more rapid onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.

The potential benefit of combining a loop diuretic with acetazolamide is a lower tendency to develop metabolic alkalosis, a potential side effect of loop diuretics and thiazides. Although data are limited, according to a recent study, the addition of acetazolamide to bumetanide significantly increased natriuresis.

In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) study , adding high doses of aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure to usual therapy did not achieve any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.

> Ultrafiltration

Venous ultrafiltration (or aquapheresis) uses an extracorporeal circuit, similar to that used in hemodialysis, that removes iso-osmolar fluid at a fixed rate. Newer ultrafiltration systems are more portable, can be used with peripheral venous access, and require minimal nursing supervision.

Although ultrafiltration appears to be an attractive alternative to diuresis in acute heart failure, studies have been inconclusive. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) compared ultrafiltration and diuresis in 188 patients with acute heart failure and acute cardiorenal syndrome.

Diuresis, achieved according to an algorithm, was found to be superior to ultrafiltration in terms of a bivariate end point of change in weight and change in creatininemia level at 96 hours.

However, a more accurate indicator of kidney function is thought to be the cystatin C level, but the change in cystatin C level from baseline was not different between the two treatment groups. On the other hand, the ultrafiltration rate was 200 ml/hour (discussed by some), and may have been excessive and caused intravascular depletion.

Although the ideal rate of fluid removal is unknown, it should be individualized and adjusted based on the patient’s renal function, volume status, and hemodynamic status.

The initial rate depends on the degree of fluid overload and the anticipated rate of plasma exchange of the interstitial fluid. For example, a malnourished patient may have a low serum oncotic pressure level and therefore have poor plasma exchange during ultrafiltration.

Disturbance of this delicate balance between ultrafiltration rates and plasma exchange can lead to intravascular volume contraction.

In summary , although in resistant cases ultrafiltration is a valuable alternative to diuretics, in view of current data its use cannot be recommended as primary decongestive therapy.

> Inotropes

Inotropes such as dobutamine and milrinone are often used in cases of cardiogenic shock to maintain organ perfusion. There is also a physiological rationale for its use in acute cardiorenal syndrome, especially when the aforementioned strategies do not overcome diuretic resistance.

Inotropes increase cardiac output, improve renal blood flow and right ventricular output, and thus relieve systemic congestion. These hemodynamic effects may improve renal perfusion and response to diuretics. However, clinical evidence supporting this concept is lacking.

The Renal Optimization Strategies Evaluation (ROSE) trial enrolled 360 patients with acute heart failure and kidney dysfunction. Adding low-dose dopamine (2 µg/kg/min) to diuretic therapy had no significant effect on 72-hour cumulative urine output or renal function as measured by cystatin C levels.

However, in this trial, acute kidney injury was not identifiable and the kidney function of many of these patients may have been at baseline when they were admitted. In other words, the authors say, this work does not necessarily include patients with acute kidney injury associated with acute heart failure.

Therefore, it does not necessarily include patients with acute heart failure syndrome. However, inotropic support and temporary mechanical circulatory support should be reserved as a last resort.

> Vasodilators

Reduction in blood pressure during treatment of acute heart failure is an independent risk factor for worsening renal function.

Vasodilators such as nitroglycerin, sodium nitroprusside, and hydralazine are commonly used in patients with acute heart failure, although clinical evidence supporting their use is weak.

Physiologically, arterial dilation reduces afterload and may help relieve pulmonary congestion, while venous dilation increases capacitance and reduces preload.

Theoretically, in patients with acute heart failure syndrome, venodilators such as nitroglycerin can relieve renal venous congestion and therefore improve renal perfusion. However, the use of vasodilators is usually limited by their adverse effects , the most important being hypotension.

This is especially relevant in light of recent data identifying blood pressure reduction during treatment of acute heart failure as an independent risk factor for worsening renal function.

It is important to note that, in these studies, changes in cardiac index did not affect the propensity for worsening kidney function. The precise mechanism of this finding is unclear, but it is possible that systemic vasodilation redistributes cardiac output to nonrenal tissues, thereby overriding renal autoregulatory mechanisms that normally mediate low-performance states.

> Preventive strategies

Several strategies can be used to prevent cardiorenal syndrome. In an outpatient patient, it is very important to apply an optimal diuretic regimen, aimed at avoiding hypervolemia. Patients with advanced congestive heart failure should be followed closely in specialized heart failure clinics until their diuretic regimen is optimized.

It is recommended that patients monitor their weight regularly and consult their doctor if they notice weight gain or a reduction in urine output.

• There is no rigorous clinical definition of cardiorenal syndrome. Therefore, recognition of this condition can be difficult.

• Volume overload is fundamental in its pathogenesis, and accurate evaluation of the state of circulatory volume is important.

• Renal venous congestion is the primary mechanism of cardiorenal syndrome type 1.

• Misdiagnosis can have devastating consequences as it can lead to an opposite therapeutic approach.

• The mainstay of treatment is the elimination of fluids through various strategies.

• Temporary inotropic support should be reserved as a last resort.