Worsening Renal Function in Patients With Acute Heart Failure Undergoing Aggressive Diuresis Is Not Associated With Tubular Injury

Abstract

Background: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation-Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis.

Methods: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C.

Results: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300-815 mg), which induced a urine output of 8425 mL (interquartile range, 6341-10 528 mL) over the 72-hour intervention period. Levels of N-acetyl-β-d-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P>0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (-8.7 ng/mg; interquartile range, -169 to 35 ng/mg; P<0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin (P=0.21), N-acetyl-β-d-glucosaminidase (P=0.46), or kidney injury molecule 1 (P=0.22). Increases in neutrophil gelatinase-associated lipocalin, N-acetyl-β-d-glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69-0.91; P=0.001).

Conclusions: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury.

Keywords: acute kidney injury; biomarkers; heart failure; renal insufficiency.

Figure 1. CONSORT (Consolidated Standards of Reporting Trials) diagram of patient selection into the study cohort

GFR indicates glomerular filtration rate; KIM-1, kidney injury molecule 1; NAG, N-acetyl-β-D-glucosaminidase; NGAL, neutrophil gelatinase-associated lipocalin; and ROSE-AHF, Renal Optimization Strategies Evaluation.

Figure 2. Absolute or relative changes in kidney function

Change in kidney function assessed from baseline to 72 hours. A, Absolute change in renal function with units of milligrams per deciliter (creatinine) and milligrams per liter (cystatin C). B, Relative change in estimated glomerular filtration rate (eGFR) calculated with either cystatin C or creatinine. Dotted line represents those patients with 20% increase in eGFR.

Figure 3. Scatterplots of changes in kidney tubular injury biomarkers

A, Scatterplots of changes in kidney tubular injury biomarkers by change in cystatin C. Left, The 72-hour changes in cystatin C vs log changes in neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-β-D-glucosaminidase (NAG). The 72-hour changes in cystatin C vs absolute changes in kidney injury molecule 1 (KIM-1) (Bottom). B, Scatterplots of changes in kidney tubular injury biomarkers by change in creatinine. Right, the 72-hour changes in creatinine vs log changes in NGAL and NAG. The 72-hour changes in creatinine vs absolute changes in KIM-1 (Bottom).

Figure 4. Changes in kidney tubular injury biomarkers by decile change

A, Changes in kidney tubular injury biomarkers by decile change in cystatin C. B, Changes in kidney tubular injury biomarkers by decile change in creatinine. (Left to right): Tukey box plots of 72-hour changes in neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D-glucosaminidase (NAG), and kidney injury molecule 1 (KIM-1) across each decile change in cystatin C (top) and creatinine (bottom).

Figure 5. Baseline and 72-hour biomarkers of kidney tubular injury according to cystatin C–based worsening renal function (WRF) status

A (Top to bottom), Box plots (whiskers represent 10th and 90th percentiles) of 72-hour changes in neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D-glucosaminidase (NAG), and kidney injury molecule 1 (KIM-1) between patients with and without WRF. B, Baseline and 72-hour biomarkers of kidney tubular injury according to creatinine-based WRF status. (Top to bottom), Box plots (whiskers represent 10th and 90th percentiles) of 72-hour changes in NGAL, NAG, and KIM-1 between patients with and without WRF, as gauged by creatinine changes.

Figure 6. Associations between kidney tubular injury biomarkers and renal dysfunction with survival

↑ Cys C indicates increase in cystatin C; ↔↓ Cys C, no change or decrease in cystatin C; ↑ Injury biomarkers, change in composite biomarker score >50th percentile; and ↓ Injury biomarkers, change in composite biomarker score <50th percentile. As shown, patients with a decline in kidney function and increase in tubular injury markers had the best outcomes and patients with no change or improvement in kidney function/tubular injury biomarkers had the worst outcomes; P_trend indicates adjusted linear trend increasing from ↔↓ Cys C/↓ Injury biomarkers (high risk) to ↑ Cys C/↑ Injury biomarkers (low risk).