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By Van Selby, MD
Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart Failure Section
Dr. Selby reports no financial relationships relevant to this field of study.
SYNOPSIS: In patients with acute heart failure who receive aggressive diuresis, worsening renal function identified by a rise in serum creatinine or cystatin C is not indicative of kidney tubular injury.
SOURCE: Ahmad T, Jackson K, Rao VS, et al. Worsening renal function in patients with acute heart failure undergoing aggressive diuresis is not associated with tubular injury. Circulation 2018;137:2016-2028.
Diuretics are the primary therapy for acute heart failure (AHF) with congestion. Patients receiving diuretics often experience worsening renal function (WRF), identified by a rise in the serum creatinine level. While WRF causes concern among treating clinicians, it is not clear that WRF is evidence of renal tubular injury.
To investigate the relationship between WRF and markers of renal injury, Ahmad et al analyzed data from the Renal Optimization Strategies Evaluation in Acute Heart Failure trial, which concerned the efficacy of low-dose dopamine and nesiritide in patients hospitalized for AHF. All patients received aggressive intravenous loop diuretics (median 560 mg intravenous furosemide or equivalent over a 72-hour study period). For this secondary analysis, the primary outcome was the change in three validated markers of renal tubular injury: N-acetyl-beta-D-glucosaminidase, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin. WRF was defined as a ≥ 20% decrease in estimated glomerular filtration rate (GFR), calculated using both cystatin C and creatinine.
During the 72-hour study period, WRF occurred in 21.2% of patients. The development of WRF was not associated with an increase in any marker of renal tubular injury (P > 0.2 for the association with all three markers). Also, there was no correlation between changes in markers of kidney injury and the degree of diuresis or decongestion achieved.
In an adjusted analysis, WRF was not associated with worsened 180-day survival (adjusted P = 0.84). Similarly, an increase in markers of renal injury during the study period was not associated with worse survival. In fact, a paradoxical relationship was observed in which patients with evidence of worsening renal tubular injury demonstrated improved survival at 180 days.
The authors concluded that kidney tubular injury is not associated with WRF in patients with AHF who receive aggressive diuresis.
In patients with AHF who are treated with diuretics, so-called “creatinine bumps” are all too common. The standard reaction to a rise in serum creatinine is either reduction or discontinuation of diuretics, with a goal of avoiding permanent kidney damage, even when the patient remains volume overloaded. This results in both prolonged hospitalization and inadequate decongestion at discharge, increasing the likelihood of readmission.
It is important to understand whether these small-to-medium rises in creatinine are markers of true renal injury or more benign fluctuations in glomerular filtration related to the hemodynamic shifts that occur during diuresis.
Ahmad et al provide strong evidence that in AHF patients, there is no significant association between rises in either creatinine or cystatin C and three markers of renal tubular injury. Furthermore, the authors found that when WRF occurs, it does not affect long-term outcomes significantly. Ahmad et al’s findings add to previous studies of diuretic strategies for AHF. For example, the authors of the DOSE trial found that patients randomized to higher-dose loop diuretics were more likely to experience a serum creatinine rise > 0.3 mg/dL, but these elevations were transient and did not increase the risk of renal failure or other adverse outcomes at 60 days.
Although this was a thorough study, several limitations are worth mentioning. First, this was an analysis of a highly controlled clinical trial carried out at large heart failure centers by experienced clinicians. We do not know how medications were adjusted in response to fluctuations in creatinine, nor whether other measures were instituted to improve WRF and mitigate its long-term impact.
Therefore, it is not clear how these findings would translate to other medical centers, providers, or “real-world” patients who may be less clinically stable compared to those enrolled in clinical trials.
Despite these limitations, given the clear lack of an association observed in the present trial, and similar findings reported by other authors, it is reasonable to conclude the association between WRF as measured by creatinine or cystatin C and renal tubular injury is minimal at best.
In AHF with volume overload, achieving adequate diuresis is crucial. Other investigators have found that patients hospitalized for AHF often are discharged without significant decreases in weight, hemoconcentration, or other evidence of fluid loss. Creatinine bumps certainly contribute to this lack of adequate diuresis. Based on the findings from Ahmad et al, it is reasonable to conclude that a mild-to-moderate decrease in the estimated GFR should not automatically prompt cessation or reduction of diuretics.
When the creatinine continues to rise during diuresis, it is important to first make sure the patient remains fluid-overloaded by physical exam and other available markers. Second, treating clinicians should ensure renal perfusion is sufficient, and consider measures to increase it when needed.
Otherwise, when a patient remains fluid-overloaded, it is important to continue diuretics until euvolemia is achieved, with the understanding that mild-to-moderate rises in serum creatinine will resolve without lasting damage.
Financial Disclosure: Clinical Cardiology Alert’s Physician Editor Michael H. Crawford, MD, Peer Reviewer Susan Zhao, MD, Nurse Planner Aurelia Macabasco-O’Connell, PhD, ACNP-BC, RN, PHN, FAHA, Editor Jonathan Springston, Editor Jesse Saffron, and Editorial Group Manager Terrey L. Hatcher report no financial relationships relevant to this field of study.