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Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate
  1. Kevin Damman1,
  2. Dirk J Van Veldhuisen1,
  3. Gerjan Navis2,
  4. Vishal S Vaidya3,
  5. Tom D J Smilde1,
  6. B Daan Westenbrink1,
  7. Joseph V Bonventre3,
  8. Adriaan A Voors1,
  9. Hans L Hillege1,4
  1. 1Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  2. 2Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  3. 3Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  4. 4Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  1. Correspondence to Dr Hans L Hillege, Department of Cardiology and Epidemiology, Hanzeplein 1, PO 30001, 9700 RB Groningen, The Netherlands; h.hillege{at}


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 ([125I]iothalamate and [131I]hippuran clearances). The tubular markers neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-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 m2. Urinary NGAL (175 (70–346) μg/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.

  • Chronic heart failure
  • renal failure
  • prognosis
  • tubular damage
  • renal disease
  • cardiomyopathy dilated
  • renin-angiotensin system

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  • Funding KD is supported by the Netherlands Heart Foundation (grant 2006B157). AAV and DJvV are clinical established investigators of the Netherlands Heart Foundation (grants 2006T37 and D97-017, respectively). JVB is supported by the National Institute of Health (grants DK39773 and DK74099). Other Funders: NIH.

  • Competing interests JVB is co-inventor on KIM-1 patents.

  • Ethics approval This study was conducted with the approval of the local medical ethics committee of the University Medical Center Groningen.

  • Provenance and peer review Not commissioned; externally peer reviewed.