Cardiorenal Syndrome: The Nephrologist’s Perspective

renal dysfunction is a common and often progressive complication of heart failure (Figure 1). Renal function is—to use a descriptive term—“twitchy” in the patient with heart failure. It can change relating to patient volume status, concomitant medications, and adequacy of pump function, with all factors influenced by the background level of renal function. When corrective measures are taken in patients who experience a “bump” in serum creatinine levels, and renal function returns to baseline, all is well from a nephrologist’s perspective—at least for the moment. Patients who experience transient deterioration in function would be viewed as having a moment of poor cardiac and renal crosstalk, but not necessarily cardiorenal syndrome (CRS).

Figure 1
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A recent classification of CRS into categories, although arbitrary, provides needed perspective for the nephrologist on the sorting of the sometimes puzzling bidirectional nature of kidney–heart interactions (Figure 1). Five subtypes of CRS have been proposed that reflect the temporal nature of organ interactions as well as the primary and secondary pathology of kidney-heart crosstalk.

Type 1 CRS (acute cardiorenal syndrome) is an abrupt worsening of cardiac function, such as acute decompensated heart failure, leading to acute kidney injury. Type 2 CRS (chronic cardiorenal syndrome) comprises chronic abnormalities in cardiac function, such as chronic advanced stage heart failure causing progressive and permanent chronic kidney disease. Type 3 CRS (acute renocardiac syndrome) is an abrupt worsening of renal function, such as nephrotic syndrome, provoking an acute cardiac disorder, such as heart failure or coronary ischemia. Type 4 CRS (chronic renocardiac syndrome) comprises chronic kidney disease of any origin contributing to structural and functional cardiac abnormalities and a heightened risk of cardiovascular events. Type 5 CRS (secondary cardiorenal syndrome) is a systemic condition, such as sepsis, causing both cardiac and renal dysfunction (1).

Nephrologists who treat patients with CRS should assume that cardiac function has been optimized with available medication and device therapies. If these corrective measures do not result in any meaningful improvement in renal function and electrolyte status, the nephrologist enters into the fray in a more defined way. Mindful of the diverse ways in which the kidney may be affected by cardiac dysfunction, the nephrologist should adopt a systematic treatment approach that optimizes diuretic therapy, corrects electrolyte abnormalities, stabilizes blood pressure, and manages anemia (Table 1). Of these treatment considerations, optimizing diuretic therapy and stabilizing renal function are by far the most important and are where the nephrologist best fits in.

Most patients with CRS are significantly volume overloaded and are typically viewed as being diuretic refractory or diuretic resistant (2). In heart failure patients who respond poorly to conventional doses of a loop diuretic, high-dose therapy may prove effective. In one study, daily doses of 500 to 2000 mg of intravenous furosemide were administered to a series of patients with heart failure and refractory edema. With this regimen, a diuretic response was elicited, body weight was reduced, and heart failure class was improved. Similar studies have reported improved furosemide efficacy in refractory heart failure when high doses of oral furosemide are administered (3). Administering a loop diuretic as an infusion, rather than as bolus therapy, is another treatment stratagy that can improve the diuretic response in the heart failure patient with diuretic resistance. A significantly greater diuresis/natriuresis is observed frequently when a continuous loop diuretic infusion is given compared with intermittent bolus administration; this differential benefit is accomplished at lower peak loop diuretic concentrations. When continuously infused, this method of loop diuretic delivery results in a more efficient delivery of the drug to its site of action in the nephron (4).

Diuretic combinations can also be used in heart failure patients who are otherwise refractory to loop diuretics alone. The process of combining diuretics that work at different nephron segments is called sequential nephron blockade. Because of structural adaptation occurring in the distal nephron with prolonged loop diuretic therapy, the combination of a distal-acting diuretic and a loop diuretic is particularly effective in such patients.

Numerous reports have demonstrated significant diuresis accompanied by clinical improvement with the addition of metolazone to a loop diuretic (usually furosemide) in heart failure patients previously resistant to loop diuretic therapy alone. Metolazone is particularly effective because its duration of action is quite prolonged, it is lipophilic with a large volume of distribution, and it remains effective in advanced stage renal failure (5). Spironolactone has also been used in combination with loop diuretics and thiazide-type diuretics and has improved the diuretic response in diuretic refractory heart failure patients; however, the risk of hyperkalemia is greater in the cardiorenal patient, and spironolactone should be given cautiously if at all.

Recent clinical studies of intravenous dopamine, natriuretic peptide infusion, or oral adenosine or vasopressin antagonists have all been ineffective in reliably improving the response to diuretic therapy in patients with evolving CRS. A final issue with volume control in the CRS patient is that of isolated ultrafiltration, which can be performed by a nephrologist in a dialysis unit setting (although this procedure has recently become commonplace in heart failure units in a nephrologist-independent manner).

The ultrafiltration device used in heart failure units is 0.12 m2 and can be used with either peripheral or central access in that the required blood flow is 10 to 40 mL/min (total filter set volume of 33 mL). Up to 500 mL of isotonic fluid can be removed hourly, and the filters last for one to two days on average. Several recent clinical trials have demonstrated the safety and feasibility of ultrafiltration in the management of acute decompensated heart failure. Ultrafiltration may be more effective at removing fluid than standard diuretic therapy, and it has been associated with some beneficial long-term results (6). However, it remains to be determined whether ultrafiltration is truly nephroprotective, what its actual safety profile is, and what its real cost-effectiveness is. An additional issue with isolated ultrafiltration is the extent to which dialysis unit staff should provide support for non–dialysis unit procedures occurring elsewhere in the hospital.

Because renal impairment in the setting of CRS is a very important indicator of adverse outcome, every effort should be made to prevent any significant (>25 percent of basal value) rise in serum creatinine levels consequent to diuretic unloading therapy. Unfortunately, this proves quite difficult, and diuretic therapy is often stopped because of the degree to which serum creatinine “bumps” with even modest unloading. Renal function can deteriorate suddenly when renin–angiotensin–aldosterone system inhibitor therapy is first begun. In addition, it can acutely change in patients receiving chronic therapy, particularly patients with systolic heart failure who have a low pretreatment mean arterial pressure value as well as some pre-existing level of renal failure.

In most patients who experience worsening renal function with renin–angiotensin–aldosterone system inhibitor therapy, one or more of three main mechanisms can be implicated (7). First and most importantly, if the mean arterial pressure falls to levels that are insufficient to sustain renal perfusion or that provoke substantial reflex renal sympathetic nerve activity, renal function will worsen. Angiotensin-converting enzyme inhibitor–related hypotension is generally more common with long-acting agents or in situations in which the pharmacologic half-life of an angiotensin-converting enzyme (ACE) inhibitor is inordinately prolonged, as occurs when the degree of renal insufficiency is underestimated and an ACE inhibitor cleared predominantly by renal pathways is given. Second, ACE inhibitors or angiotensin receptor blockers (ARBs) are more likely to cause acute kidney injury in the patient with heart failure who becomes volume depleted, whether it be from overly aggressive diuresis or an intercurrent volume-depleting illness. Third, ACE inhibitors or ARBs may induce acute kidney injury in patients with high-grade bilateral renal artery stenosis or stenosis of a dominant or a single kidney renal artery; in patients with extensive atherosclerotic disease in smaller preglomerular vessels; or in patients with significant luminal narrowing of afferent arterioles, as occurs with poorly treated hypertension or chronic calcineurin inhibitor use. More often than not, the complex nature of renal function changes in the CRS patient requires that ACE inhibitor or ARB therapy be temporarily stopped.

Many CRS patients are on the cusp of needing dialysis as their disease moves forward in what is sometimes an almost inexorable fashion; therefore, it must be determined whether a patient’s clinical status has deteriorated enough that dialysis will be soon needed and, if so, which form of central access should be used for temporary dialysis. Once dialysis starts and a patient is brought to a euvolemic state and electrolyte abnormalities are corrected, a determination can be made as to whether dialytic intervention was merely a bridge therapy until improvement or whether long-term dialysis plans need to be initiated. The prevailing blood pressure often dictates the form of long-term dialysis that is considered. Maintenance hemodialysis can prove challenging in CRS patients with significant hypotension, and in such patients peritoneal dialysis may be the better dialytic modality (8). Of note, once end stage renal failure is determined to be present, it is not uncommon to have a role reversal in which the nephrologist becomes the primary health care provider and the cardiologist offers learned consultation.

Sica,Domenic Sica, MD, is professor of medicine and pharmacology and chairman of the section of clinical pharmacology and hypertension, division of nephrology, at the Virginia Commonwealth University Health System.

References

1.

Ronco C, et al. Cardiorenal syndrome. J Am Coll Cardiol 2008; 52:1527–1539.

2.

Sarraf M, Masoumi A, Schrier RW. Cardiorenal syndrome in acute decompensated heart failure. Clin J Am Soc Nephrol 2009; 4:2013–2026.

3.

Gerlag PG, van Meijel JJ. High-dose furosemide in the treatment of refractory congestive heart failure. Arch Intern Med 148:286, 1988.

4.

Thomson MR, et al. Continuous versus intermittent infusion of furosemide in acute decompensated heart failure. J Card Fail 2010; 16:188–193.

5.

Sica DA, Gehr TW. Diuretic combinations in refractory oedema states:pharmacokinetic-pharmacodynamic relationships. Clin Pharmacokinet 1996 30:229–249.

6.

Costanzo MR, et al. Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) Investigators. Ultrafiltration is associated with fewer rehospitalizations than continuous diuretic infusion in patients with decompensated heart failure: results from UNLOAD. J Card Fail 2010; 16:277–284.

7.

Schoolwerth A, et al. Considerations in angiotensin converting enzyme inhibitor therapy. Circulation 2001; 104:1985–1991.

8.

Krishnan A, Oreopoulos DG. Peritoneal dialysis in congestive heart failure. Adv Perit Dial 2007; 23:82–89.

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Table 1

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