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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2016  |  Volume : 27  |  Issue : 4  |  Page : 659-664
Comparison of serum creatinine, cystatin C, and neutrophil gelatinase-associated lipocalin for acute kidney injury occurrence according to risk, injury, failure, loss, and end-stage criteria classification system in early after living kidney donation


Department of Nephrology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

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Date of Web Publication5-Jul-2016
 

   Abstract 

To evaluate the kidney function after living kidney donation, we measured serum creatinine (SCr), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) of 42 living donors before uninephrectomy and in three immediate days after it. We also evaluated the prevalence of the occurrence of the different stages of acute kidney injury (AKI) classified according to risk, injury, failure, loss, and end-stage (RIFLE) criteria, and accuracy of each of these three biomarkers for predicting them were evaluated. Significant serum NGAL (s-NGAL) changes were limited to the 1 st day after donation, whereas SCr and cystatin C changes continued to the third day after donation. s-NGAL level in the 1 st day and serum cystatin C in the 3 rd day after donation, respectively, had the largest area under curve and best sensitivity and specificity for Stage 1 (risk) AKI prediction. During the immediate three days after donation, about half of patients suffered from AKI; mostly Stage 1 (injury). The sequence of the emergence of s-NGAL and s-cystatin C in the 1 st and 3 rd days as biomarkers with highest accuracy and power for RIFLE criteria defined AKI stage discrimination in our study was comparable to previous studies. We conclude that our study suggests that AKI was best detected in the 1 st day after uninephrectomy by the s-NGAL levels, whereas cystatin C was the best in the 3 rd day after donation for detection of AKI.

How to cite this article:
Hekmat R, Mohebi M. Comparison of serum creatinine, cystatin C, and neutrophil gelatinase-associated lipocalin for acute kidney injury occurrence according to risk, injury, failure, loss, and end-stage criteria classification system in early after living kidney donation. Saudi J Kidney Dis Transpl 2016;27:659-64

How to cite this URL:
Hekmat R, Mohebi M. Comparison of serum creatinine, cystatin C, and neutrophil gelatinase-associated lipocalin for acute kidney injury occurrence according to risk, injury, failure, loss, and end-stage criteria classification system in early after living kidney donation. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2021 Oct 18];27:659-64. Available from: https://www.sjkdt.org/text.asp?2016/27/4/659/185220

   Introduction Top


Several issues related to living kidney donation remain unresolved such as the short-and long-term medical consequences. [1],[2],[3] Living-related donor transplants comprise about 40% of all transplants performed in the USA, whereas their proportion is much less (10-15%) in Europe and Australia. [1] Iran performs most of the kidney transplants in the Middle East, and 77% of them are from living unrelated donors. [2] Since living donors in Iran are selected from healthy young individuals with normal kidney function and no medical problem, evaluation of kidney function in them provides a unique opportunity for assessing the impact of donation on kidney function biomarkers. Furthermore, the impact of acute loss of at least 50% of the glomerular filtration rate (GFR) on kidney function biomarkers can be compared with each other. The most evaluated parameters of kidney function include serum creatinine (SCr), serum cystatin C, and serum neutrophil gelatinase-associated lipocalin (s-NGAL) that have good prediction ability for the occurrence of different levels of kidney injury in the donor according to the Riffle criteria.

Finding the optimal biomarker requires prospective studies in patients with different causes of AKI has recently gained momentum. [4]

We aimed in this study to evaluate the impact of donation on the different risk, injury, failure, loss, and end-stage (RIFLE) criteria for occurrence of acute kidney injury (AKI) in living donors during the first three days after donation using the three parameters SCr, cystatin C, and NGAL to evaluate the kidney function to find the optimal biomarker among them.


   Materials and Methods Top


We studied 42 living unrelated kidney donors with a mean age of 30.3±4.18 years in Qaem and Imam-Reza Hospitals, Mashhad, Iran from June 2010 to April 2011. The research protocol was approved by the Ethical Committee of Mashhad University of Medical Sciences (No. 89066).There were no exclusion criteria of the study individuals.

We collected 164 blood samples; four samples from each donor: one before nephrectomy and three other samples on days 1, 2, and 3 after the operation. Serum was centrifuged and then stored at −20°C. For measuring serum cystatin C and NGAL, we used commercially available kits from BioVendor Medical Laboratory; Czech Republic. The creatinine kit was a picric acid-base qualitative one, made by Pars Azmoon Company, Iran.

The Cockcroft-Gault and modification of diet in renal disease (MDRD) formulas were used for the estimation of GFR in our study. Cystatin-based estimated GFR was performed using five different formulas. For classifying different stages of AKI in donors, the RIFLE classification system was used. [5] In this system, R = risk for renal dysfunction is defined as an increase in serum creatinine ≥1.5× baseline or decrease in GFR ≥25% or urine output <0.5 mL/kg/h for 6 h; I = injury to the kidney is defined as an increase in serum creatinine ≥2.0× baseline or decrease in GFR ≥50% or urine output <0.5 mL/kg/h for 12 h; F = failure of kidney function is defined as an increase in serum creatinine ≥3.0× baseline OR serum creatinine ≥4.0 mg/dL in the setting of an acute rise (0.5 mg/dL) or a decrease in GFR ≥75%, or urine output <0.3 mL/kg/h for 24 h or anuria for 12 h. L = loss of kidney function is defined as a persistent failure >4 weeks. E = end-stage renal disease is defined as a persistent kidney failure >3 months.


   Statistical analysis Top


In this study, paired sample t-test and Mann-Whiney U-test were performed for comparing the paired quantitative variables. Changes in serum levels of biomarkers before and after nephrectomy were compared using repeated measurement and receiver operating curves (ROCs) of the three biomarker variables to define the most accurate for the evaluation of the different stages of AKI. The data were analyzed using International Business Machines (IBM) SPSS version 19.0, software, CA, USA.


   Results Top


Significant changes of SCr and cystatin C levels continued to the 3 rd day after uninephrectomy. However, significant s-NGAL changes were limited to the 1 st day after donation [Table 1]. Percentile increase of the NGAL levels was significantly more in the 1 st day after donation than the percentile increase of SCr and cystatin C in the same day (P =0.013 and 0.007, respectively). Of note was the wide range and standard deviation (SD) of the obtained values, especially for NGAL, perhaps due to AKI causes such as ischemia, reperfusion injury rather than simple loss of GFR because of uninephrectomy.
Table 1: Comparison of s-creatinine-cystatin C and serum neutrophil gelatinase-associated lipocalin before (day 0) and after nephrectomy in days 1, 2, and 3.

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About 50% of donors experienced RIFLE Stage 1 or 2 (risk or injury) in the first two days after donation. However, none of the three biomarkers serum levels before donation could predict the occurrence of AKI.

s-NGAL levels in the 1st day after donation had the largest area under curve and best sensitivity and specificity for RIFLE Stage 1 (risk) prediction as estimated by the increase in SCr ≥1.5× baseline or decrease of more than 25% decrease in GFR (calculate by MDRD or GC formulas) [Table 2] and [Figure 1].
Figure 1: Comparison of receiver operating curve curves area under curve, sensitivity and specificity of serum-neutrophil gelatinase-associated lipocalin, serum-creatinine and serum-cystatin C for predicting risk, injury, failure, loss, end-stage Stage 1 (risk) in the 1st day after nephrectomy.

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Table 2: Area under curve, P-value, best cut off level, sensitivity and specificity of serum-neutrophil gelatinase-associated lipocalin, serum creatinine and serum cystatin C for predicting risk, injury, failure, loss, end-stage Stage 1 (risk) acute kidney injury in first 3 days after kidney donation as obtained by receiver operative curve characteristics.

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In the 3 rd day after donation, it was cystatin C that emerged as the best marker for prediction of injury stage [Table 2], this shows at least a 24h interval between the beginning of emergence of s-NGAL in the 1 st day and s-cystatin C in the 3 rd day after donation as the best predictors for the occurrence of AKI Stage 1.

In the 2 nd day after uninephrectomy, none of the three biomarkers was an estimator of RIFLE Stage 1 AKI described as increase in serum creatinine ≥1.5× baseline. Using GFR-based definitions of RIFLE criteria as state variables and s-NGAL, SCr, or s-cystatin C as test variables, respectively, for ROC curve depiction, again the results for all three markers was unacceptable (all P >0.05). None of three biomarkers had acceptable sensitivity and specificity for detecting Stage 2 or 3 (injury and failure) RIFLE criteria for AKI in the first three days after donation.

Using MedCalc statistics software, MedCalc Software private limited liability company, Ostend, Belgium, the area under curves of ROC curves for s-NGAL in the 1 st day and s-cystatin C in the 3 rd day after uninephrectomy were identical whether using more than 1.5fold increases in baseline s-SCr or decrease in GFR ≥25% as estimated by MDRD or GC formulas for defining Stage 1 AKI (P >0.05).


   Discussion Top


In our study, we could obtain the results of the SCr, s-cystatin C, and s-NGAL in living donors in the early three days after donation. In Germany, 10 living-related kidney donors were studied comparing their SCr and cystatin C daily before donation and for four days after it. That study showed superiority and accuracy of s-cystatin C for early detection of the rapid GFR decrease in comparison with SCr. [6]

Our results suggested the superiority of NGAL for detecting early AKI Stage 1 (risk) compared with SCr and s-cystatin C. Other studies showed similar findings such as the study of Bachorzewska-Gajewska et al who found that NGAL could represent an early biomarker of contrast-induced nephropathy in patients with normal SCr levels undergoing percutaneous coronary interventions. Significant increase in s-NGAL levels occurred 2, 4, and 8 h after the procedure, whereas cystatin C levels increased significantly 24 h after the procedure. [7]

Malyszko et al found that NGAL in non-diabetic hypertensive patients and in normotensive patients with coronary artery disease can be a useful early marker for kidney injury, especially in patients with another risk factor for kidney damage, namely coronary artery disease. [8] The same authors in another study found that NGAL in adult chronic kidney disease (CKD) patients and in kidney transplant recipients can represent a new, sensitive marker of kidney function. [9] Poniatowski et al. in chronic heart failure patients normal serum creatinine demonstrated that NGAL has the potential of detecting kidney injury earlier than SCr. [10] In a prospective cohort study conducted in 120 children undergoing CPB, Dent et al demonstrated that diagnosis of AKI defined as a 50% or greater increase in SCr was delayed by two to three days after operation, whereas plasma NGAL levels increased threefold within 2 h of CPB and significantly remained elevated for 24 h after it. [11]

Bolignano et al in Italy confirmed that in CKD patients s-NGAL, urinary NGAL (u-NGAL) were significantly increased as compared to controls. Furthermore, correlation between s-NGAL and u-NGAL was notably more than serum creatinine and residual GFR. [12] Tuladhar et al also were able to show a significant predictive value of s-NGAL in the 1 st h after CPB for subsequent kidney injury. [13]

In our study, the s-cystatin C changes showed the best sensitivity and specificity for detecting Stage 1 AKI according to RIFLE criteria on the 3 rd day after uninephrectomy is compatible with others results. In a four-year follow-up study, Perkins et al have shown the usefulness of serial s-cystatin C measurement for accurately detecting renal function decline in diabetes. [14] In patients with mild to moderate CKD, serum cystatin C had a higher diagnostic accuracy of than SCr in evaluating impaired kidney function as reported in Hojs et al study. [15] Furthermore, two studies [16],[17] of stable renal transplant recipients compared GFR estimation using cystatin C-based and standard creatinine-based equations and showed superiority of the cystatin C over creatinine for patients classification into the correct CKD stage. Furthermore, cystatin C was found to be a more accurate serum marker than serum creatinine for discriminating type 2 diabetic patients with reduced GFR from those with normal GFR. [18] Others have found cystatin C estimated GFR to detect ARF as defined by RIFLE classification one to two days earlier than creatinine estimated GFR. [19]

The wide range and SD of the percentile increment of the three biomarkers in our study, especially for NGAL, may point to AKI occurrence due to causes such as ischemia, reperfusion injury rather than simple loss of GFR because of simple uninephrectomy in some patients, but this is only an assumption that needs further study.

Our study has some limitations; among them is the restriction of biomarkers evaluation to the first three day after donation then we were able to detect superiority of NGAL in the first (and cystatin C in the 3 rd day after nephrectomy for detecting FIRLE Stage 1 (injury) AKI occurrence. Perhaps by continuing the study for one to two more days, we would have witnessed emergence of creatinine as the best marker. Moreover, we were not able to use a more precise method such as radioisotope scanning as the gold standard for comparing GFR changes against biomarker's fluctuations.


   Conclusion Top


We conclude that our study suggests that s-NGAL has the best sensitivity and specificity for detecting Stage 1 (risk) AKI according to RIFLE criteria in the 1 st day after uninephrectomy, Whereas s-cystatin C was the best marker for detecting AKI Stage 1 in the 3 rd day after kidney donation. [20]

Conflict of interest: None declared.

 
   References Top

1.
Chan LL, Wiseman A, Wang W, Jani A, Kam I. Outcomes and complications of renal transplantation. In: Schrier RW, ed. Diseases of the Kidney & Urinary Tract. 8th ed., Vol. 2.  Back to cited text no. 1
    
2.
Philadelphia: Lippincott Williams & Wilkins; 2007. p. 2563.  Back to cited text no. 2
    
3.
Rafique MM. Renal transplantation in developing countries. In: Morris PJ, Knechtle SJ, eds. Kidney Transplantation: Principles and Practice. 6th ed. Philadelphia: Saunders Elsevier Press; 2008. p. 638.  Back to cited text no. 3
    
4.
Magee CC. Evaluation of donors and recipients. In: Himmelfarb J, Sayegh MH, eds. Chronic Kidney Disease, Dialysis, and Transplantation. 3rd ed. Philadelphia: Saunders, Elsevier Press; 2010. p. 491-4.  Back to cited text no. 4
    
5.
Edelstein CL, Faubel S. Biomarkers in acute kidney injury. In: Edelstein CL, ed. Biomarkers in Kidney Disease. 1st ed. Amsterdam: Elsevier Press; 2011. p. 211.  Back to cited text no. 5
    
6.
Edelstein CL, Faubel S. Biomarkers in acute kidney injury. In: Edelstein CL, ed. Biomarkers in Kidney Disease. 1st ed. Amsterdam: Elsevier Press; 2011. p. 179-81, 186-90, 197-201.  Back to cited text no. 6
    
7.
Herget-Rosenthal S, Pietruck F, Volbracht L, Philipp T, Kribben A. Serum cystatin C - A superior marker of rapidly reduced glomerular filtration after uninephrectomy in kidney donors compared to creatinine. Clin Nephrol 2005;64:41-6.  Back to cited text no. 7
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8.
Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, et al. Could neutrophilgelatinase-associated lipocalin and cystatin C predict the development of contrast-induced nephropathy after percutaneous coronary interventions in patients with stable angina and normal serum creatinine values? Kidney Blood Press Res 2007;30:408-15.  Back to cited text no. 8
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9.
Malyszko J, Bachorzewska-Gajewska H, Malyszko JS, Pawlak K, Dobrzycki S. Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in hypertensive and normotensive patients with coronary artery disease. Nephrology (Carlton) 2008;13:153-6.  Back to cited text no. 9
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10.
Malyszko J, Malyszko JS, Bachorzewska-Gajewska H, Poniatowski B, Dobrzycki S, Mysliwiec M. Neutrophil gelatinase-associated lipocalin is a new and sensitive marker of kidney function in chronic kidney disease patients and renal allograft recipients. Transplant Proc 2009;41:158-61.  Back to cited text no. 10
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11.
Poniatowski B, Malyszko J, Bachorzewska-Gajewska H, Malyszko JS, Dobrzycki S. Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in patients with chronic heart failure and coronary artery disease. Kidney Blood Press Res 2009;32:77-80.  Back to cited text no. 11
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12.
Dent CL, Ma Q, Dastrala S, et al. Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: A prospective uncontrolled cohort study. Crit Care 2007;11:R127.  Back to cited text no. 12
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13.
Bolignano D, Lacquaniti A, Coppolino G, Campo S, Arena A, Buemi M. Neutrophil gelatinase-associated lipocalin reflects the severity of renal impairment in subjects affected by chronic kidney disease. Kidney Blood Press Res 2008;31:255-8.  Back to cited text no. 13
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14.
Tuladhar SM, Püntmann VO, Soni M, Punjabi PP, Bogle RG. Rapid detection of acute kidney injury by plasma and urinary neutrophil gelatinase-associated lipocalin after cardiopulmonary bypass. J Cardiovasc Pharmacol 2009;53:261-6.  Back to cited text no. 14
    
15.
Perkins BA, Nelson RG, Ostrander BE, et al. Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: Results of a 4-year follow-up study. J Am Soc Nephrol 2005;16:1404-12.  Back to cited text no. 15
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16.
Hojs R, Bevc S, Ekart R, Gorenjak M, Puklavec L. Serum cystatin C as an endogenous marker of renal function in patients with mild to moderate impairment of kidney function. Nephrol Dial Transplant 2006;21:1855-62.  Back to cited text no. 16
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17.
White C, Akbari A, Hussain N, et al. Chronic kidney disease stage in renal transplantation classification using cystatin C and creatinine-based equations. Nephrol Dial Transplant 2007;22:3013-20.  Back to cited text no. 17
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18.
Maillard N, Mariat C, Bonneau C, et al. Cystatin C-based equations in renal transplantation: Moving toward a better glomerular filtration rate prediction? Transplantation 2008;85:1855-8.  Back to cited text no. 18
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19.
Mussap M, Dalla Vestra M, Fioretto P, et al. Cystatin C is a more sensitive marker than creatinine for the estimation of GFR in type 2 diabetic patients. Kidney Int 2002;61:1453-61.  Back to cited text no. 19
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20.
Herget-Rosenthal S, Marggraf G, Hüsing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004;66:1115-22.  Back to cited text no. 20
    

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Correspondence Address:
Reza Hekmat
Department of Nephrology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad
Iran
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DOI: 10.4103/1319-2442.185220

PMID: 27424680

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