New Directions for Treating Cardio-Renal Syndrome

September 12, 2010

New answers are emerging to help shed light on the complex relationship between renal function and heart failure.

The reduced cardiac output associated with heart failure sets off reflexes that, while intended to preserve the volume and pressure of the arteries, can also result in volume retention, hyponatremia, and worsening renal function, according to data presented at the Heart Failure Society of America’s 14th Annual Scientific Sessions.

At the satellite symposium, entitled “Cardio-Renal Connections in Heart Failure: from Pathophysiology to Therapy,” four experts discussed findings from studies providing new insight into the pathophysiology, clinical significance, and treatment options for both hyponatremia and worsening renal function in HF patients.

John C. Burnett, Jr., Marriott Family Professor of Cardiovascular Research at the Mayo Clinic College of Medicine in Rochester, MN, focused his talk on the pathophysiology of cardio-renal syndrome (CRS), a clinical entity that is “manifested by a decreasing glomerular filtration rate (GFR) accompanied by more avid sodium and water retention with resistance to diuretics.”

Burnett believes there may be two separate entities of CRS, the first of which is driven by myocardial dysfunction with impaired renal perfusion pressure secondary to both reduced cardiac output and pressure from the arteries, together with elevated venous pressure. This process then impairs glomerular and tubular function—even in a health kidney—and there may be excessive renal degradation of nitric oxide. This entity, however, is reversible, and restoring myocardial function often restores renal function.

“The kidney is the more regenerative organ in the body,” he said during the presentation. “It has a fantastic ability to repair itself.”

The second entity, according to Burnett, presents where there is pre-existing renal disease and renal structural remodeling. In patients with worsening HF and pre-existing renal disease, the kidney may be unable to repair or regenerate itself. In the absence of renal repair, regenerative pathways may be insufficient and there may be more effective pathways within the kidney, which contributes to renal fibrosis, more renal restructuring, and accelerate chronic kidney disease (CKD), which in turn can further accelerate HF.

Burnett believes that future research is warranted on this topic to develop an improved understanding of the heart-kidney connection in heart failure, and better biomarkers to detect renal injury in CHF and the impact of therapy. There is also a need for “novel therapeutics that target neurohumoral mechanisms.

In the second presentation, James E. Udelson, Chief, Division of Cardiology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, reviewed recent data on the clinical significance and treatment of hyponatremia in HF. Hyponatremia has been consistently identified as a prognostic sign in patients with heart failure, and is a “clear predictor of poor outcome and mortality in HF patients. In fact, he pointed out, even in cases of mild hyponatremia, the 60-day survival rates indicate an “unfavorable outcome.”

The goal in treating the condition is to normalize the patient’s sodium level and relieve the volume overload; but although loop diuretics are used is some patients, this therapy can lead to little change or can even worsen hyponatremia in those with heart failure. Hypertonic saline is not always successfully, and another method, fluid restriction, is difficult to maintain in this patient population, said Udelson.

So what can clinicians to do treat this “relatively common problem” in heart failure patients? According to Udelson, one of the key advances of the past decade has been the development of vasopressin receptor 2 antagonists such as tolvaptan, which “interrupt the biological pathway that is causing hyponatremia,” and not just treating the underlying condition.

James L. Januzzi, Director, Cardiac Intensive Care Unit, at Massachusetts General Hospital, Boston, MA, spoke about emerging biomarkers in heart failure management. “Worsening renal failure is a thorny issue in acutely decompensated heart failure (ADHF) patients,” he said, pointing out that 75-80% of cases occur within the first five days of admission.

“It may have little to do with reductions in cardiac output,” said Januzzi. “We know it is far more complex, and we know that venous congestion plays very important role in worsening renal failure in ADHF patients.”

Renal failure is associated with negative outcomes in patients, including prolonged hospitalization and increased mortality rates. One factor that can provide some answers in more effectively identifying patients at risk for CRD is the emergence of biomarkers beyond the standard measures of creatinine, blood urea nitrogren, and estimated glomerular filtration rate (GFR) in predicting renal failure.

According to Januzzi, Cystatin C has demonstrated “prognostic meaning” in a number of different populations, while beta trace protein “promises to add complementary, it not added value to Cystatin C. These biomarkers add incremental value to traditional serum sodium and creatinine,” he said, equating them to “creatinine on steroids.”

Finally, he identified tubular injury markers, including kidney injury molecule and NGAL (neturophil gelatinase-associated lipcalin), that have also “shown to be effective predictors.”

In the final presentation, John R. Teerlink, Director, Heart Failure Program and Clinical Echocardiography, San Francisco Veterans Affairs Medical Center, San Francisco, CA, addressed treatment options for heart failure patients with CRS.

Worsening renal function is “clearly a negative marker,” said Teerlink, in both chronic and acute heart failure patients, with in-hospital mortality rates as high as 19.8%.

He reviewed several classes of treatment for acute HF and CRS, including inotropic agents, which improved cardiac function but not renal function; vasodilators, which “actually showed an increase in renal failure and renal impairment; low-dose furosimide, which resulted in increased mortality (although it may not have been clinically significant); vasopressin antagonists, which resulted in increased weight loss with less diuretic use; and ultrafiltration, which resulted in significantly greater weight loss, but did not necessarily improve serum creatinine.

Further research, he noted, is needed to determine the effectiveness of markers in worsening renal function in ADHF patients.