Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate

Abstract

Background: The prognostic impact of reduced glomerular filtration rate (GFR) in chronic heart failure (CHF) is increasingly recognised, but little is known about tubular damage in these patients.

Objective: To investigate the prevalence of tubular damage, and its association with GFR, and prognosis in patients with CHF.

Methods and results: In 90 patients with CHF, GFR and effective renal plasma flow (ERPF) were measured ([(125)I]iothalamate and [(131)I]hippuran clearances). The tubular markers neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1) as well as urinary albumin excretion were determined in 24 h urine collections. Mean GFR was 78+/-26 ml/min/1.73 m(2). Urinary NGAL (175 (70-346) microg/g creatinine (gCr)), NAG (12 (6-17) U/gCr) and KIM-1 (277 (188-537) ng/gCr) levels were increased compared with 20 healthy controls (all p<0.001). Urinary NAG, but not NGAL or KIM-1 correlated with GFR (r=-0.34, p=0.001) and ERPF (r=-0.29, p=0.006). Both NAG (r=0.21, p=0.048) and KIM-1 (r=0.23, p=0.033) correlated with plasma N-terminal pro-brain natriuretic peptide levels. Both urinary KIM-1 (HR=1.15 (95% CI 1.02 to 1.30) per 100 ng/gCr increase, p=0.025) and NAG (HR=1.42 (95% CI 1.02 to 1.94) per 5 U/gCr increase, p=0.039), were associated with an increased risk of death or heart failure hospitalisations, independent of GFR.

Conclusion: Tubular damage, as indicated by increased urinary concentrations of NGAL, NAG and KIM-1 is common in patients with CHF and mildly reduced GFR. Both urinary KIM-1 and NAG showed prognostic information additional to GFR. These findings suggest an important role for tubular damage and tubular markers in cardiorenal interaction in heart failure.

Figure 1

Urinary NGAL, NAG and KIM-1 levels in patients with CHF versus controls. Shown are box plots with median and interquartile ranges (box) and 5—95% ranges (error bars) of urinary NAG, NGAL and KIM-1 levels. * p<0.0001 versus controls. CHF, chronic heart failure; KIM-1, kidney injury molecule 1; NAG, N-acetyl-β-D-glucosaminidase; NGAL, Neutrophil gelatinase-associated lipocalin.

Figure 2

Relationship between CKD and urinary NAG, NGAL and KIM-1. Shown are box plots with median and interquartile ranges (box) and 5—95% ranges(error bars) of urinary NAG, NGAL and KIM-1 levels. *p<0.001 versus controls; † p=0.008 versus no CKD. CHF, chronic heart failure; CKD, chronic kidney disease; KIM-1, kidney injury molecule 1; NAG, N-acetyl-β-D-glucosaminidase; NGAL, Neutrophil gelatinase-associated lipocalin.

Figure 3

Relationship of tubular markers, urinary albumin excretion and GFR with prognosis. GFR is shown as decreasing GFR. GFR, glomerular filtration rate; KIM-1, kidney injury molecule 1; NAG, N-acetyl-β-D-glucosaminidase; NGAL, Neutrophil gelatinase-associated lipocalin.