Skip Navigation

European Journal of Heart Failure 2008 10(10):997-1000; doi:10.1016/j.ejheart.2008.07.001
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (4)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Damman, K.
Right arrow Articles by Hillege, H. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Damman, K.
Right arrow Articles by Hillege, H. L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2008 European Society of Cardiology

Urinary neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage, is increased in patients with chronic heart failure

Kevin Dammana, Dirk J. van Veldhuisena, Gerjan Navisb, Adriaan A. Voorsa and Hans L. Hillegea,c,*

a Department of Cardiology, University Medical Center Groningen, University of Groningen Groningen, The Netherlands
b Department of Nephrology, University Medical Center Groningen, University of Groningen Groningen, The Netherlands
c Department of Epidemiology, University Medical Center Groningen, University of Groningen Groningen, The Netherlands

* Corresponding author. Department of Cardiology and Epidemiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO 30001, 9700 RB Groningen, The Netherlands. Tel.: +31503618066; fax: +31503618062. E-mail address: h.hillege{at}tcc.umcg.nl (H.L. Hillege).


   Abstract
Top
 Abstract
1. Background
 2. Aim
 3. Methods
 4. Results
 5. Conclusion
 References
 
Renal impairment, as measured by reduced glomerular filtration rate (GFR) and increased urinary albumin excretion (UAE), is prevalent in patients with chronic heart failure (CHF) and is associated with reduced survival. The prevalence of structural tubular damage in CHF is unknown. We investigated 90 CHF patients and 20 age and sex matched healthy controls, and determined estimated GFR, UAE, N terminal-pro brain natriuretic peptide (NT-proBNP) and urinary neutrophil gelatinase associated lipocalin (NGAL) as a marker for tubular damage. CHF patients had significantly lower averaged estimated GFR (64 ± 17 vs 90 ± 12 mL/min/1.73 m2, P<0.0001), but higher NT-proBNP and UAE levels (both P<0.0001). Median urinary NGAL levels were markedly increased in CHF patients compared to controls (175 (70–346) vs 37 (6–58) µg/gCr, P<0.0001). Both serum creatinine (r=0.26, P=0.006) and eGFR (r=–0.29, P=0.002) were significantly associated with urinary NGAL levels as were NT-proBNP and UAE but to a lesser extent. In conclusion, renal impairment in CHF patients is not only characterised by decreased eGFR and increased UAE, but also by the presence of tubular damage, as measured by increased urinary NGAL concentrations.

Key Words: Chronic heart failure • Renal function • Albuminuria • Tubular damage • NGAL • Neutrophil gelatinase associated lipocalin

Received December 28, 2007; Revised April 17, 2008; Accepted July 1, 2008


   1. Background
Top
 Abstract
 1. Background
2. Aim
 3. Methods
 4. Results
 5. Conclusion
 References
 
Renal dysfunction, as measured by decreased glomerular filtration rate (GFR), is common in chronic systolic heart failure (CHF) and is associated with severely increased mortality and morbidity, which is apparent even in the early stages of borderline renal dysfunction [1-3]. Even if GFR is only mildly impaired, increased urinary albumin excretion (UAE) levels, as a marker of early renal damage, are commonly observed in patients with CHF [4]. In primary renal disease, renal impairment is not only associated with decreased GFR and increased UAE, but also with the presence of structural tubular damage, as measured by increased urinary concentrations of specific tubular marker proteins [5-7]. One of these markers is neutrophil gelatinase associated lipocalin (NGAL), which has been shown to be highly increased in patients with acute and chronic renal injury in different clinical stages [5,8].


   2. Aim
Top
 Abstract
 1. Background
 2. Aim
3. Methods
 4. Results
 5. Conclusion
 References
 
In the present study, we aimed to 1) investigate the prevalence of structural tubular damage as measured by urinary NGAL concentrations, 2) establish the relationship between urinary NGAL levels and estimated GFR, and 3) investigate the relationship between urinary NGAL levels and UAE, in patients with CHF.


   3. Methods
Top
 Abstract
 1. Background
 2. Aim
 3. Methods
4. Results
 5. Conclusion
 References
 
Ninety clinically stable CHF outpatients, aged ≥18 years, with a left ventricular ejection fraction (LVEF) <45%, were asked to participate. All patients were on angiotensin converting enzyme inhibitors and/or angiotensin II receptor blockers, and all medication had been stable for at least 1 month. In addition, 20 healthy, age and sex matched controls were studied. All subjects gave informed consent to participate in the study, which was approved by the ethics review committee of the study centre.

Baseline measurements included standard weight, height, systolic and diastolic blood pressure, serum creatinine, haemoglobin levels, N terminal-pro brain natriuretic peptide (NT-proBNP) and assessment of NYHA functional class. LVEF was determined by nuclear ventriculography. All patients and controls performed 24-hour urine collections, and urinary albumin excretion (UAE) was determined. Urinary creatinine was determined to correct for concentration of urine. Urinary NGAL was determined by means of a commercially available ELISA test kit from Antibody Shop (Gentofte, Denmark) and was expressed per gram of urinary creatinine (µg/gCr). In brief, a monoclonal antibody against human NGAL, and biotinylated antibody against bound NGAL was used to detect NGAL in the urine samples. Horseradish peroxidase conjugated streptavidin was added, followed by colour-forming peroxidase substrate containing tetramethylbenzidine. The colour was then measured at 450 nm by a microtiter plate reader and compared with a standard curve. NGAL levels below the detection level were scored as 0.1 µg/gCr. Estimated GFR was calculated using the simplified modification of diet in renal disease formula (186.3xserum creatinine–1.154xage–0.203 (x0.742 if female) (x1.212 if black)) as validated in CHF patients [9].

3.1. Statistical analysis
Data are presented as mean±standard deviation when normally distributed, and as median and interquartile range for skewed data. Differences between patients and controls were tested using Mann-Whitney U or Student's T testing where appropriate. Correlations were performed using Spearman's correlation coefficients. Multivariate regression analysis was used to correct for eGFR when comparing patients with controls. All reported probability values are 2-tailed, and a P-value<0.05 was considered statistically significant. Statistical analyses were performed using SPSS, Chicago version 12.0.


   4. Results
Top
 Abstract
 1. Background
 2. Aim
 3. Methods
 4. Results
5. Conclusion
 References
 
Clinical characteristics of patients and controls are summarized in Table 1. Urinary NGAL levels were highly elevated in patients with CHF (175 (70-346) µg/gCr) compared to healthy controls (37 (6-58) µg/gCr, P<0.0001) (Fig. 1). Combining findings in CHF patients and controls, urinary NGAL levels were significantly related to eGFR (r=–0.29, P=0.002) (Fig. 2), serum creatinine (r=0.26, P=0.006), UAE levels (r=0.33, P=0.001) and NT-proBNP (r=0.26, P=0.007) (Fig. 3). When adjusted for eGFR in multivariate analysis, CHF patients still had significantly higher urinary NGAL levels (P=0.0004). Urinary NGAL levels were similar among different aetiologies of heart failure, NYHA class and haemoglobin levels.


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline characteristics of CHF patients and controls

 


Figure 01
View larger version (15K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Urinary NGAL and UAE levels in CHF patients vs controls. Box plots for urinary NGAL and UAE levels are shown. Boxes display median (horizontal bars), interquartile ranges (lower and upper limits of boxes) and 5th and 95th percentiles (error bars). Abbreviations: CHF: chronic heart failure, NGAL: neutrophil gelatinase associated lipocalin, UAE: urinary albumin excretion.

 


Figure 02
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Relationship between eGFR and urinary NGAL levels. Abbreviations: CHF: chronic heart failure, eGFR: estimated glomerular filtration rate, NGAL: neutrophil gelatinase associated lipocalin.

 


Figure 03
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Relationship between plasma NT-proBNP and urinary NGAL levels. Abbreviations: CHF: chronic heart failure, NGAL: neutrophil gelatinase associated lipocalin, NT-proBNP: N terminal-pro brain natriuretic peptide.

 

   5. Conclusion
Top
 Abstract
 1. Background
 2. Aim
 3. Methods
 4. Results
 5. Conclusion
References
 
In the present study we show for the first time that structural tubular damage, as measured by increased urinary concentrations of NGAL, is highly prevalent in patients with CHF. Furthermore, across the spectrum of heart failure and healthy controls, urinary NGAL levels are not only associated with different indices of renal dysfunction, but also positively associated with increased levels of NT-proBNP.

NGAL is a 21 kDa protein of the lipocalin family and is normally secreted in low amounts in lung, kidney, trachea, stomach and colon tissue [10]. NGAL levels are elevated in various pathological states, and possess bacteriostatic effects, by inhibition of iron-binding molecules that are important to specific bacteria. In renal failure, both serum and urinary concentrations rise massively, and therefore (urinary) NGAL is thought to be a marker of tubular injury, an effect independent of its bacteriostatic properties [10].

NGAL has been shown to be associated with morphological changes and albuminuria in patients with primary renal disease, but never in patients with heart failure [5]. In CHF, reduced GFR is mainly dependent of reduced renal perfusion, which may serve as a hypoxic trigger for tubular damage [11,12]. In the chronic setting, patients with renal insufficiency due to IgA nephropathy had higher urinary NGAL levels compared to controls, and the urinary NGAL concentration also correlated strongly with the extent of tubulointerstitial injury [5].

Chronic renal hypoxia has not only been proposed as the final common pathway to end stage renal disease [12], but may also be the initiating trigger for a vicious circle between tubulointerstitial injury and chronic renal insufficiency [13]. This hypothesis may be one of the pathways by which chronic renal insufficiency may develop in patients with CHF.

Recently we hypothesized that venous congestion might also be a determinant of renal damage [14]. Plasma NT-proBNP levels were indeed correlated to NGAL levels, fitting this hypothesis, but may also be an expression of impaired cardiac systolic function leading to renal impairment.

NGAL has mainly been studied in the setting of acute renal failure. During cardiopulmonary bypass operation, patients who experienced acute renal dysfunction showed a marked increase in urinary NGAL levels, which preceded the increase in serum creatinine by a day [15,16]. In a single case of acute tubular necrosis due to heart failure induced hypotension, NGAL tubular expression was reported to be strongly increased [8].

Hence, measurements of NGAL may serve as a very early marker of worsening renal function. Urinary (or plasma) NGAL levels could therefore be used to adjust therapy, to anticipate and possibly prevent expected renal injury, even before a peak in serum creatinine occurs. This potential of NGAL needs to be explored further in future studies.

In conclusion, patients with CHF frequently suffer from a combination of reduced GFR, increased UAE and structural tubular damage. NGAL may serve as a novel non-invasive marker for (worsening) renal function in heart failure.


   Acknowledgements
 
K. Damman is supported by The Netherlands Heart Foundation (grant 2006B157). A.A. Voors and D.J. van Veldhuisen are Clinical Established Investigators of The Netherlands Heart Foundation (grants 2006T37 and D97-017, respectively).


   References
Top
 Abstract
 1. Background
 2. Aim
 3. Methods
 4. Results
 5. Conclusion
 References
 

  1. Hillege H.L., Nitsch D., Pfeffer M.A., et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation (2006) 113:671–678.[Abstract/Free Full Text]
  2. Ruilope L.M., van Veldhuisen D.J., Ritz E., Luscher T.F. Renal function: the cinderella of cardiovascular risk profile. J Am Coll Cardiol (2001) 38:1782–1787.[Abstract/Free Full Text]
  3. Hillege H.L., van Gilst W.H., van Veldhuisen D.J., et al. Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition: the CATS randomized trial. Eur Heart J (2003) 24:412–420.[Abstract/Free Full Text]
  4. van de Wal R.M., Asselbergs F.W., Plokker H.W., et al. High prevalence of microalbuminuria in chronic heart failure patients. J Card Fail (2005) 11:602–606.[CrossRef][Web of Science][Medline]
  5. Ding H., He Y., Li K., et al. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy. Clin Immunol (2007) 123:227–234.[CrossRef][Web of Science][Medline]
  6. Liangos O., Perianayagam M.C., Vaidya V.S., et al. Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol (2007) 18:904–912.[Abstract/Free Full Text]
  7. Trachtman H., Christen E., Cnaan A., et al. Urinary neutrophil gelatinase-associated lipocalcin in D+HUS: a novel marker of renal injury. Pediatr Nephrol (2006) 21:989–994.[CrossRef][Web of Science][Medline]
  8. Mori K., Lee H.T., Rapoport D., et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest (2005) 115:610–621.[CrossRef][Web of Science][Medline]
  9. Smilde T.D., van Veldhuisen D.J., Navis G., Voors A.A., Hillege H.L. Drawbacks and prognostic value of formulas estimating renal function in patients with chronic heart failure and systolic dysfunction. Circulation (2006) 114:1572–1580.[Abstract/Free Full Text]
  10. Schmidt-Ott K.M., Mori K., Li J.Y., et al. Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol (2007) 18:407–413.[Abstract/Free Full Text]
  11. Ljungman S., Laragh J.H., Cody R.J. Role of the kidney in congestive heart-failure— relationship of cardiac index to kidney-function. Drugs (1990) 39:10–21.[CrossRef][Web of Science][Medline]
  12. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol (2006) 17:17–25.[Abstract/Free Full Text]
  13. Norman J.T., Fine L.G. Intrarenal oxygenation in chronic renal failure. Clin Exp Pharmacol Physiol (2006) 33:989–996.[CrossRef][Web of Science][Medline]
  14. Damman K., Navis G., Smilde T.D., et al. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail (2007) 9:872–878.[Abstract/Free Full Text]
  15. Mishra J., Dent C., Tarabishi R., et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet (2005) 365:1231–1238.[CrossRef][Web of Science][Medline]
  16. Wagener G., Jan M., Kim M., et al. Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology (2006) 105:485–491.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (4)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Damman, K.
Right arrow Articles by Hillege, H. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Damman, K.
Right arrow Articles by Hillege, H. L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?