Loop diuretics have been used as a heart failure (HF) management strategy for years but it still remains unknown whether they are of benefit to the patient. However, new research has found that diuretic therapy can positively affect renal and tubular function by decreasing congestion and that diuretic withdrawal and reinstitution can be markers of tubular dysfunction in stable HF patients, according to study results published in the May 25 issue of the Journal of the American College of Cardiology.

However, in an accompanying JACC editorial, Stephen S. Gottlieb, MD, of the University of Maryland in Baltimore, offered that the current study does not answer whether or not diuretics are either harmful or beneficial and called the study’s inconsistencies “worrisome.”

During the study, Kevin Damman, MD, PhD, of the University Medical Center Groningen, in Groningen, the Netherlands, and colleagues enrolled 30 patients from Heart Failure Services at City and Sandwell Hospitals in Birmingham, England, to evaluate what effect modulating diuretics had on renal function.

All patients had a left ventricular ejection fraction (LVEF) of less than 40 percent and were symptomatic but stable on chronic oral furosemide dosing (40 mg to 80 mg daily). All patients were on either ACE inhibitor or ARB therapy and coronary artery disease was the main cause of systolic HF in two-thirds of patients. The majority of patients were male and had mean age of 70 years.

The patients were taken off loop diuretics at the beginning of the study. After 72 hours, the furosemide regimen was reinstated and followed-up with three days later. For each patient, the researchers measured serum creatinine, atrial and B-type natriuretic peptide, urinary kidney injury molecule (KIM)-1, urinary N-acetyl-beta-D-glucosaminidase (NAG) and serum and urinary neutrophil gelatinase-associated lipocalin (NGAL).

After diuretics were discontinued, Damman et al reported that increases in atrial and B-type natruiretic peptides occurred but serum creatinine was unaffected. Additionally, it was reported that both urinary KIM-1 and NAG levels increased after the diuretic was withdrawn but serum and urinary NGAL were not significantly affected. When the furosemide regimen was reinstated urinary KIM-1 and NAG concentrations returned to baseline and NGAL values were unaffected.

Sixty-seven percent of patients showed an increase in KIM-1 at day four and 57 percent of patients experienced an increase in NAG at day four. Patients who showed increases in urinary KIM-1 and NAG levels at day four also had higher levels of serum creatinine, but significantly lower levels of hemoglobin levels and mean arterial pressure.

“In our present study, we found that during withdrawal of diuretics, there was a subtle increase in both ANP and BNP, as well as a nonsignificant increase in weight, which may suggest a small increment in CVP [central venous pressure],” the authors wrote. “However, the accompanied change in serum creatinine was negligible.”

The researchers noted that individual patients react differently to changes in CVP. “Some patients may be characterized by an asymptomatic intravascular dehydratic state, whereas others may be euvolemic or even volume-expanded, all without overt decompensation or symptoms,” the authors wrote. However, the authors noted that creatinine may not be the most accurate measurement for changes in renal function because the full effect of serum creatinine may only occur hours or days after the on-set of renal damage.

Damman et al also noted that tubular markers could detect changes in renal function earlier than serum creatinine.

The authors found that patients with compromised kidney function, lower hemoglobin levels and lower blood pressures at baseline were more at risk for experiencing deteriorating tubular function and may be more susceptible to volume/diuretic changes that can alter renal perfusion and oxygen delivery.

“Our results suggest that loop diuretic therapy may favorably affect markers of tubular function in HF patients with a presumed euvolemic state,” the researchers wrote. “Whether this is due to changes in volume status or a more direct effect is unclear.

“Our results further underline the need for individualized medicine and the need for more research on the interaction between diuretics, volume status and renal function in patients with HF,” the authors concluded. “Diuretic therapy may favorably affect tubular function by decreasing congestion or a direct pharmacological effect. Withdrawal of diuretic therapy in stable patients may be associated with recordable rises in biomarkers of renal injury.”

"Are diuretics the culprit of mortality and morbidity or the means of preventing adverse consequences? Are these agents remnants of treatment from unenlightened times or the epitome of treatment that improves symptoms and outcomes?" asked Gottlieb in the editorial.

While Gottlieb said that “there is no question that diuretics improve symptoms,” he said that recent studies have shown that patients receiving higher doses could experience worse outcomes. “Yes, higher doses of diuretics are clearly associated with worse outcomes, but patients receiving higher doses are sicker and expected to have worse outcomes,” Gottlieb offered.

“The study emphasizes that our ideas about diuretics are not equivalent to their reality. Only increasing knowledge will permit us to better use these commonly prescribed, and frequently disparaged, agents,” Gottlieb concluded.