Acute cardiorenal syndrome: Mechanisms and clinical implications

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Fluid removal with diuresis or ultrafiltration is the cornerstone of treatment. Other treatments such as inotropes are reserved for patients with resistant disease.


The goal of therapy in acute cardiorenal syndrome is to achieve aggressive diuresis, typically using intravenous diuretics. Loop diuretics are the most potent class of diuretics and are the first-line drugs for this purpose. Other classes of diuretics can be used in conjunction with loop diuretics; however, using them by themselves is neither effective nor recommended.

Resistance to diuretics at usual doses is common in patients with acute cardiorenal syndrome. Several mechanisms contribute to diuretic resistance in these patients.21

Oral bioavailability of diuretics may be reduced due to intestinal edema.

Diuretic pharmacokinetics are significantly deranged in cardiorenal syndrome. All diuretics except mineralocorticoid antagonists (ie, spironolactone and eplerenone) act on targets on the luminal side of renal tubules, but are highly protein-bound and are hence not filtered at the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter,22 whereas epithelial sodium channel inhibitors (amiloride and triamterene) are secreted via the organic cation transporter 2.23 In renal dysfunction, various uremic toxins accumulate in the body and compete with diuretics for secretion into the proximal convoluted tubule via these transporters.24

Finally, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, thereby also blunting the diuretic response.

Diuretic dosage. In patients whose creatinine clearance is less than 15 mL/min, only 10% to 20% as much loop diuretic is secreted into the renal tubule as in normal individuals.25 This effect warrants dose adjustment of diuretics during uremia.

Recommended dosing of diuretics in renal insufficiency
For example, the ceiling dose of an intravenous bolus of furosemide in patients with severe renal insufficiency is 160 to 200 mg, in contrast to patients with preserved renal function, in whom it is 40 to 80 mg. When thiazides are used in conjunction with loop diuretics, similar dose adjustments are warranted. The recommended dose of hydrochlorothiazide if the creatinine clearance is less than 20 mL/min is 100 to 200 mg per day.25 Dose adjustments in renal insufficiency for other diuretics have not been clearly established; however, the higher end of the usual dose range should be used (Table 2).

Continuous infusion or bolus? Continuous infusion of loop diuretics is another strategy to optimize drug delivery. Compared with bolus therapy, continuous infusion provides 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 vs bolus furosemide therapy in 308 patients admitted with acute decompensated heart failure.26 There was no difference in symptom control or net fluid loss at 72 hours in either group. Other studies have shown more diuresis with continuous infusion than with a similarly dosed bolus regimen.27 However, definitive clinical evidence is lacking at this point to support routine use of continuous loop diuretic therapy.

Combination diuretic therapy. Sequential nephron blockade with combination diuretic therapy is an important therapeutic strategy against diuretic resistance. Notably, urine output-guided diuretic therapy has been shown to be superior to standard diuretic therapy.28 Such therapeutic protocols may employ combination diuretic therapy as a next step when the desired diuretic response is not obtained with high doses of loop diuretic monotherapy.

The desired diuretic response depends on the clinical situation. For example, in patients with severe congestion, we would like the net fluid output to be at least 2 to 3 L more than the fluid intake after the first 24 hours. Sometimes, patients in the intensive care unit are on several essential drug infusions, so that their net intake amounts to 1 to 2 L. In these patients, the desired urine output would be even more than in patients not on these drug infusions.

Loop diuretics block sodium reabsorption at the thick ascending loop of Henle. This disrupts the countercurrent exchange mechanism and reduces renal medullary interstitial osmolarity; these effects prevent water reabsorption. However, the unresorbed sodium can be taken up by the sodium-chloride cotransporter and the epithelial sodium channel in the distal nephron, thereby blunting the diuretic effect. This is the rationale for combining 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 then reabsorbed distally. Hence, the combination of a loop diuretic and acetazolamide can also have a synergistic diuretic effect.

The most popular combination is a loop diuretic plus a thiazide, although no large-scale placebo-controlled trials have been performed.29 Metolazone (a thiazidelike diuretic) is typically used due to its low cost and availability.30 Metolazone has also been shown to block sodium reabsorption at the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a faster onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.31

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, a recent study showed that adding acetazolamide to bumetanide led to significantly increased natriuresis.32

In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial, adding spironolactone in high doses to usual therapy was not found to cause any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.33

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Hemodynamically, the kidney is at the heart of cardiorenal syndrome

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