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NGAL (neutrophil gelatinase-associated lipocalin) and cystatin C: Are they good predictors of contrast nephropathy after percutaneous coronary interventions in patients with stable angina and normal serum creatinine?
International Journal of Cardiology 127 (2008) 290 – 291 www.elsevier.com/locate/ijcard
Letter to the Editor
NGAL (neutrophil gelatinase-associated lipocalin) and cystatin C: Are they good predictors of contrast nephropathy after percutaneous coronary interventions in patients with stable angina and normal serum creatinine? H. Bachorzewska-Gajewska a,1 , J. Malyszko a,b,⁎,1 , E. Sitniewska a , J.S. Malyszko a , B. Poniatowski a , K. Pawlak a , S. Dobrzycki a b
a Department of Invasive Cardiology, Medical University, Bialystok, Poland Department of Nephrology and Transplantology, Medical University, 15-540 Bialystok, Zurawia 14, Poland
Received 15 January 2007; accepted 4 April 2007 Available online 13 June 2007
Abstract The aim of the study was to assess whether NGAL and cystatin C could predict contrast-induced nephropathy in non-diabetic patients (n = 60, mean age 60 ± 11 years) with normal serum creatinine undergoing elective PCI. We found a significant rise in serum NGAL after 2, 4 and 8 h, and in urinary NGAL after 4, 8 and 24 h after PCI. Cystatin C rose significantly 8 and 24 h after the procedure. Prevalence of CIN was 10%. We found 90% sensitivity and 74% specificity of serum and 76% sensitivity and 80% specificity of urinary NGAL increase. NGAL may represent a sensitive early biomarkers of renal impairment after PCI. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Contrast nephropathy; NGAL; Cystatin C; Coronary artery disease; PCI
Since interventional cardiologists are being asked more frequently to perform percutaneous coronary interventionPCI on increasing numbers of patients, contrast nephropathy-CIN is its potentially serious complication [1]. Unfortunately, creatinine is an unreliable indicator during acute changes in kidney function [2]. Mishra et al. [3] highlighted value of NGAL (neutrophil gelatinase-associated lipocalin) as a novel marker for early detection of acute renal failureARF. Because of its small molecular size (25 kDa) and resistance to degradation, NGAL is readily excreted and
⁎ Corresponding author. Department of Nephrology and Transplantology, Medical University, 15-540 Bialystok, Zurawia 14, Poland. Tel.: +48 85 7409464; fax: +48 85 7412391. E-mail address: [email protected] (J. Malyszko). 1 H. Bachorzewska-Gajewska and J. Malyszko contributed equally to this paper. 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.04.048
detected in urine as cystatin C. Therefore, the aim of the study was to assess whether NGAL and cystatin C could predict contrast-induced nephropathy in non-diabetic patients (n = 60,mean age 60 ± 11 years) with normal serum creatinine undergoing elective PCI. None of the patients investigated had received nephrotoxic drugs at least 1 week before and during the study period. All the patients were informed about the aim of the study and gave their consent, the protocol was approved by the local Ethics Committee. Serum, urinary NGAL (ANTIBODYSHOP, Gentofte, Denmark), cystatin C (Dade Behring, Germany) were evaluated before, and after 2, 4, 8, 24 and 48 h after PCI using commercially available serum creatinine was assessed before, 24 and 48 h after PCI. ANOVA or Kruskall–Wallis ANOVA for repeated measurements were used in statistical analysis. We found a significant rise in serum NGAL after 2, 4 and 8 h (94.95 ± 41.41 ng/ml, p b 0.05, 125.50 ± 64.47 mg/ml, p b 0.001, 92.38 ± 35.61, p b 0.05 vs 82.03 ± 37.79 ng/ml at baseline), and in urinary
H. Bachorzewska-Gajewska et al. / International Journal of Cardiology 127 (2008) 290–291
NGAL after 4, 8 and 24 h after PCI (10, 5; 0.55–117 ng/ml, p b 0.05, 14.8; 0.5–237 ng/ml, p b 0.01, 13.3; 0.5–251 ng/ml, p b 0.05 vs 1.5; 0–58 ng/ml at baseline). Serum cystatin C increased significantly 8 h, reaching peak 24 h after PCI (3.07 ± 1.69 mg/L, p b 0.05, 3.40 ± 1.73 mg/L, p b 0.01 vs 2.19 ± 1.41 mg/L at baseline) and then decreased after 48 h. Before PCI serum NGAL was related to creatinine (r = 0.45, p b 0.001), urinary NGAL (r = 0.32, p b 0.05), cystatin C (r = 0.52, p b 0.001). Urinary NGAL before PCI correlated with creatinine (r = 0.31, p b 0.05), but not with cystatin C. When contrast nephropathy was defined as an increase in serum creatinine by N25% of the baseline level 48 h after PCI, the prevalence of CIN was 10%. Patients with CIN received significantly more contrast agent (p b 0.01, all received lowosmolal contrast), but duration of PCI was similar. NGAL levels were significantly higher in patients with CIN starting 2 h after PCI (serum NGAL) or 4 h (urinary NGAL). Cystatin C were higher only 8 and 24 h after PCI in patients with CIN. When we defined contrast nephropathy as a 25% increase in cystatin C from baseline values (n = 27), then we calculated sensitivity and specificity of a respective 25% serum and urinary NGAL increase to detect this cystatin C increase. We found 90% sensitivity and 74% specificity of serum and 76% sensitivity and 80% specificity of urinary NGAL increase. In patients with a 25% increase in serum cystatin C, we found a significantly higher serum and urinary NGAL (all p b 0.05), higher cystatin C at baseline (p b 0.05) when compared to patients without 25% increase in serum cystatin C. Our study demonstrated that NGAL could predict CIN in patients undergoing PCI with good sensitivity and specificity, much earlier then serum creatinine and even cystatin C. The reported incidence of CIN varies widely, ranging from 0–50% [4], in our study-10%. This variability results from differences in the presence or absence of risk factors (primarily renal failure), definition of CIN, amount, type of agent administered, prospective or retrospective design, the exact procedure, and whether other causes of ARF unrelated to contrast media were excluded. Mishra et al. [3] reported a rise in serum and urinary NGAL in samples taken after 2 h or at the first available sample after cardiopulmonary bypass-CPB in children who developed ARF. Children without ARF have a small, but significant rise in serum NGAL at the same time. We studied patients with stable angina undergoing PCI. Time of PCI is much shorter than CPB, it does not require extracorporeal circulation. Patients after PCI are typically discharged within 48 h, sometimes even earlier, therefore we could miss patients with ARF which developed after 48 h. They compared data of children with over 50% increase in serum creatinine after 48– 72 h, whereas we used CIN definition as a rise in serum creatinine by 25% over baseline at 48 h after PCI (not later). In a study of Wagener et al. [5] in patients after cardiac surgery, urinary NGAL was higher in 16 subjects developing ARF over to 65 patients without ARF. The pathomechanism of ARF in
291
their study was probably ischemia–reperfusion like in the previous studies [3,6]. An earlier rise in serum NGAL, than in urine, may be due to the fact that NGAL was released into the circulation probably secondary to inflammatory activation of neutrophils initiated by PCI. Moreover, since NGAL is increased in atherosclerotic plaques [7], it might be also released into the circulation during the PCI. Rise in NGAL, despite non-significant changes in creatinine, may be due to renal injury and/or inflammatory component of NGAL. Herget-Rosenthal et al. [8] reported that serum cystatin C is a useful detection marker of ARF and might detect ARF one or two days earlier than creatinine. Rickli et al. [9] observed the rise in cystatin C achieved a maximum at 24 h after the application of the contrast agent. Therefore, in our study we simultaneously assessed NGAL, serum cystatin C, creatinine and confirmed their findings. It should be stressed that NGAL correlated well with both cystatin C, and creatinine. Our findings may have important implications for the clinical management of patients undergoing PCI. The “window of opportunity” is narrow in contrast nephropathy and time is limited to introduce proper treatment after initiating insult, particularly when patients are discharged within 24– 48 h after the procedure. Therefore, NGAL needs to be investigated as a potential early marker for nephrotoxicity, especially in the upcoming setting of short-time hospitalizations for coronary angiographies and interventions. Thus, further studies in patients with renal failure undergoing radiocontrast application are warranted to assess the usefulness of NGAL in respect of an earlier detection of radiocontrast nephrotoxicity. References [1] Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780–5. [2] Bellomo R, Kellum JA, Ronco C. Defining acute renal failure: physiological principles. Intensive Care Med 2004;30:33–7. [3] 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;365:1231–8. [4] Gami AS, Garovic VD. Contrast nephropathy after coronary angiography. Mayo Clin Proc 2004;79:211–9. [5] 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;105:485–91. [6] Parikh CR, Mishra J, Thiessen-Philbrook H, et al. Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 2006;70:199–203. [7] Hemdahl AL, Gabrielsen A, Zhu C, et al. Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction. Arterioscler Thromb Vasc Biol 2006;26:136–42. [8] Herget-Rosenthal S, Marggraf G, Husing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004;66:1115–22. [9] Rickli H, Benou K, Ammann P, et al. Time course of serial cystatin C levels in comparison with serum creatinine after application of radiocontrast media. Clin Nephrol 2004;61:98–102.
Letter to the Editor
NGAL (neutrophil gelatinase-associated lipocalin) and cystatin C: Are they good predictors of contrast nephropathy after percutaneous coronary interventions in patients with stable angina and normal serum creatinine? H. Bachorzewska-Gajewska a,1 , J. Malyszko a,b,⁎,1 , E. Sitniewska a , J.S. Malyszko a , B. Poniatowski a , K. Pawlak a , S. Dobrzycki a b
a Department of Invasive Cardiology, Medical University, Bialystok, Poland Department of Nephrology and Transplantology, Medical University, 15-540 Bialystok, Zurawia 14, Poland
Received 15 January 2007; accepted 4 April 2007 Available online 13 June 2007
Abstract The aim of the study was to assess whether NGAL and cystatin C could predict contrast-induced nephropathy in non-diabetic patients (n = 60, mean age 60 ± 11 years) with normal serum creatinine undergoing elective PCI. We found a significant rise in serum NGAL after 2, 4 and 8 h, and in urinary NGAL after 4, 8 and 24 h after PCI. Cystatin C rose significantly 8 and 24 h after the procedure. Prevalence of CIN was 10%. We found 90% sensitivity and 74% specificity of serum and 76% sensitivity and 80% specificity of urinary NGAL increase. NGAL may represent a sensitive early biomarkers of renal impairment after PCI. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Contrast nephropathy; NGAL; Cystatin C; Coronary artery disease; PCI
Since interventional cardiologists are being asked more frequently to perform percutaneous coronary interventionPCI on increasing numbers of patients, contrast nephropathy-CIN is its potentially serious complication [1]. Unfortunately, creatinine is an unreliable indicator during acute changes in kidney function [2]. Mishra et al. [3] highlighted value of NGAL (neutrophil gelatinase-associated lipocalin) as a novel marker for early detection of acute renal failureARF. Because of its small molecular size (25 kDa) and resistance to degradation, NGAL is readily excreted and
⁎ Corresponding author. Department of Nephrology and Transplantology, Medical University, 15-540 Bialystok, Zurawia 14, Poland. Tel.: +48 85 7409464; fax: +48 85 7412391. E-mail address: [email protected] (J. Malyszko). 1 H. Bachorzewska-Gajewska and J. Malyszko contributed equally to this paper. 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.04.048
detected in urine as cystatin C. Therefore, the aim of the study was to assess whether NGAL and cystatin C could predict contrast-induced nephropathy in non-diabetic patients (n = 60,mean age 60 ± 11 years) with normal serum creatinine undergoing elective PCI. None of the patients investigated had received nephrotoxic drugs at least 1 week before and during the study period. All the patients were informed about the aim of the study and gave their consent, the protocol was approved by the local Ethics Committee. Serum, urinary NGAL (ANTIBODYSHOP, Gentofte, Denmark), cystatin C (Dade Behring, Germany) were evaluated before, and after 2, 4, 8, 24 and 48 h after PCI using commercially available serum creatinine was assessed before, 24 and 48 h after PCI. ANOVA or Kruskall–Wallis ANOVA for repeated measurements were used in statistical analysis. We found a significant rise in serum NGAL after 2, 4 and 8 h (94.95 ± 41.41 ng/ml, p b 0.05, 125.50 ± 64.47 mg/ml, p b 0.001, 92.38 ± 35.61, p b 0.05 vs 82.03 ± 37.79 ng/ml at baseline), and in urinary
H. Bachorzewska-Gajewska et al. / International Journal of Cardiology 127 (2008) 290–291
NGAL after 4, 8 and 24 h after PCI (10, 5; 0.55–117 ng/ml, p b 0.05, 14.8; 0.5–237 ng/ml, p b 0.01, 13.3; 0.5–251 ng/ml, p b 0.05 vs 1.5; 0–58 ng/ml at baseline). Serum cystatin C increased significantly 8 h, reaching peak 24 h after PCI (3.07 ± 1.69 mg/L, p b 0.05, 3.40 ± 1.73 mg/L, p b 0.01 vs 2.19 ± 1.41 mg/L at baseline) and then decreased after 48 h. Before PCI serum NGAL was related to creatinine (r = 0.45, p b 0.001), urinary NGAL (r = 0.32, p b 0.05), cystatin C (r = 0.52, p b 0.001). Urinary NGAL before PCI correlated with creatinine (r = 0.31, p b 0.05), but not with cystatin C. When contrast nephropathy was defined as an increase in serum creatinine by N25% of the baseline level 48 h after PCI, the prevalence of CIN was 10%. Patients with CIN received significantly more contrast agent (p b 0.01, all received lowosmolal contrast), but duration of PCI was similar. NGAL levels were significantly higher in patients with CIN starting 2 h after PCI (serum NGAL) or 4 h (urinary NGAL). Cystatin C were higher only 8 and 24 h after PCI in patients with CIN. When we defined contrast nephropathy as a 25% increase in cystatin C from baseline values (n = 27), then we calculated sensitivity and specificity of a respective 25% serum and urinary NGAL increase to detect this cystatin C increase. We found 90% sensitivity and 74% specificity of serum and 76% sensitivity and 80% specificity of urinary NGAL increase. In patients with a 25% increase in serum cystatin C, we found a significantly higher serum and urinary NGAL (all p b 0.05), higher cystatin C at baseline (p b 0.05) when compared to patients without 25% increase in serum cystatin C. Our study demonstrated that NGAL could predict CIN in patients undergoing PCI with good sensitivity and specificity, much earlier then serum creatinine and even cystatin C. The reported incidence of CIN varies widely, ranging from 0–50% [4], in our study-10%. This variability results from differences in the presence or absence of risk factors (primarily renal failure), definition of CIN, amount, type of agent administered, prospective or retrospective design, the exact procedure, and whether other causes of ARF unrelated to contrast media were excluded. Mishra et al. [3] reported a rise in serum and urinary NGAL in samples taken after 2 h or at the first available sample after cardiopulmonary bypass-CPB in children who developed ARF. Children without ARF have a small, but significant rise in serum NGAL at the same time. We studied patients with stable angina undergoing PCI. Time of PCI is much shorter than CPB, it does not require extracorporeal circulation. Patients after PCI are typically discharged within 48 h, sometimes even earlier, therefore we could miss patients with ARF which developed after 48 h. They compared data of children with over 50% increase in serum creatinine after 48– 72 h, whereas we used CIN definition as a rise in serum creatinine by 25% over baseline at 48 h after PCI (not later). In a study of Wagener et al. [5] in patients after cardiac surgery, urinary NGAL was higher in 16 subjects developing ARF over to 65 patients without ARF. The pathomechanism of ARF in
291
their study was probably ischemia–reperfusion like in the previous studies [3,6]. An earlier rise in serum NGAL, than in urine, may be due to the fact that NGAL was released into the circulation probably secondary to inflammatory activation of neutrophils initiated by PCI. Moreover, since NGAL is increased in atherosclerotic plaques [7], it might be also released into the circulation during the PCI. Rise in NGAL, despite non-significant changes in creatinine, may be due to renal injury and/or inflammatory component of NGAL. Herget-Rosenthal et al. [8] reported that serum cystatin C is a useful detection marker of ARF and might detect ARF one or two days earlier than creatinine. Rickli et al. [9] observed the rise in cystatin C achieved a maximum at 24 h after the application of the contrast agent. Therefore, in our study we simultaneously assessed NGAL, serum cystatin C, creatinine and confirmed their findings. It should be stressed that NGAL correlated well with both cystatin C, and creatinine. Our findings may have important implications for the clinical management of patients undergoing PCI. The “window of opportunity” is narrow in contrast nephropathy and time is limited to introduce proper treatment after initiating insult, particularly when patients are discharged within 24– 48 h after the procedure. Therefore, NGAL needs to be investigated as a potential early marker for nephrotoxicity, especially in the upcoming setting of short-time hospitalizations for coronary angiographies and interventions. Thus, further studies in patients with renal failure undergoing radiocontrast application are warranted to assess the usefulness of NGAL in respect of an earlier detection of radiocontrast nephrotoxicity. References [1] Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780–5. [2] Bellomo R, Kellum JA, Ronco C. Defining acute renal failure: physiological principles. Intensive Care Med 2004;30:33–7. [3] 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;365:1231–8. [4] Gami AS, Garovic VD. Contrast nephropathy after coronary angiography. Mayo Clin Proc 2004;79:211–9. [5] 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;105:485–91. [6] Parikh CR, Mishra J, Thiessen-Philbrook H, et al. Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 2006;70:199–203. [7] Hemdahl AL, Gabrielsen A, Zhu C, et al. Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction. Arterioscler Thromb Vasc Biol 2006;26:136–42. [8] Herget-Rosenthal S, Marggraf G, Husing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004;66:1115–22. [9] Rickli H, Benou K, Ammann P, et al. Time course of serial cystatin C levels in comparison with serum creatinine after application of radiocontrast media. Clin Nephrol 2004;61:98–102.