Urinary NGAL Ratio Is Not a Sensitive Biomarker for Monitoring Acute Tubular Injury in Kidney Transplant Patients: NGAL and ATI in Renal Transplant Patients
Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is known to predict the prolonged delayed graft function after kidney transplantation. We examined the relation of uNGAL with histological findings of acute tubular injury (ATI). Analyses were made in biopsies taken at 6 weeks, 3 months, and 6 months after kidney transplantation. uNGAL was measured in the spot urines, normalized to urinary creatinine excretion, and correlated to biopsy findings and clinical, laboratory, and demographic variables. Controls included healthy individuals, individuals after kidney donation and ICU patients with acute kidney failure. Renal transplant recipients without ATI did not display elevated uNGAL levels compared to the healthy controls. Transplant patients with ATI had a higher uNGAL excretion at 6 weeks than patients without ATI (27,435 versus 13,605？ng/g; ). This increase in uNGAL was minor compared to ICU patients with acute renal failure ( ？ng/g). Patients with repeated findings of ATI or severe ATI did not have higher urinary NGAL levels compared to those with only one ATI finding or moderate ATI. Female recipient gender and urinary tract infection were identified as potential confounders. uNGAL has a relation with histological signs of acute tubular injury. The usability of this biomarker in renal allograft recipients is limited because of the low sensitivity. 1. Introduction Acute kidney injury early after transplantation may arise from the donor’s condition, prolonged cold ischemia time, and early posttransplant injuries like rejection and drug toxicity. Immediate clinical correlates of this injury may be delayed graft function or a less-than-optimal glomerular filtration rate. However, acute kidney injury carries adverse long-term consequences as patients with acute tubular injury early posttransplantation have an inferior long-term allograft function [1]. Therefore, markers, which facilitate early diagnosis of acute kidney injury or even provide prognostic information, would be helpful in the posttransplant care of these patients. Traditionally, serum parameters as creatinine and urine output are used to monitor kidney function in transplanted patients. However, a rise in serum creatinine already implies a significant amount of kidney damage, which limits its ability to detect impaired graft function at early stages. Recently, novel biomarkers such as Kim-1, IL-18, and neutrophil gelatinase-associated lipocalin (NGAL) have been proven useful in detecting nontransplant acute kidney damage [2]. NGAL, a 25-kDa protein, is a member of the lipocalin
References
[1]
W. Gwinner, K. Hinzmann, U. Erdbruegger et al., “Acute tubular injury in protocol biopsies of renal grafts: prevalence, associated factors and effect on long-term function,” American Journal of Transplantation, vol. 8, no. 8, pp. 1684–1693, 2008.
[2]
P. Devarajan, “Emerging biomarkers of acute kidney injury,” Contributions to Nephrology, vol. 156, pp. 203–212, 2007.
[3]
J. Mishra, C. Dent, R. Tarabishi et al., “Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery,” The Lancet, vol. 365, no. 9466, pp. 1231–1238, 2005.
[4]
C. R. Parikh, A. Jani, J. Mishra et al., “Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation,” American Journal of Transplantation, vol. 6, no. 7, pp. 1639–1645, 2006.
[5]
J. Mishra, Q. Ma, C. Kelly et al., “Kidney NGAL is a novel early marker of acute injury following transplantation,” Pediatric Nephrology, vol. 21, no. 6, pp. 856–863, 2006.
[6]
I. E. Hall, S. G. Yarlagadda, S. G. Coca et al., “IL-18 and urinary NGAL predict dialysis and graft recovery after kidney transplantation,” Journal of the American Society of Nephrology, vol. 21, no. 1, pp. 189–197, 2010.
[7]
L. C. Racusen, P. F. Halloran, and K. Solez, “Banff 2003 meeting report: new diagnostic insights and standards,” American Journal of Transplantation, vol. 4, no. 10, pp. 1562–1566, 2004.
[8]
L. Cai, J. Rubin, W. Han, P. Venge, and S. Xu, “The origin of multiple molecular forms in urine of HNL/NGAL,” Clinical Journal of the American Society of Nephrology, vol. 5, no. 12, pp. 2229–2235, 2010.
[9]
N. Paragas, A. Qiu, Q. Zhang et al., “The Ngal reporter mouse detects the response of the kidney to injury in real time,” Nature Medicine, vol. 17, no. 2, pp. 216–223, 2011.
[10]
K. Mori and K. Nakao, “Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage,” Kidney International, vol. 71, no. 10, pp. 967–970, 2007.
[11]
S. Supavekin, W. Zhang, R. Kucherlapati, F. J. Kaskel, L. C. Moore, and P. Devarajan, “Differential gene expression following early renal ischemia/reperfusion,” Kidney International, vol. 63, no. 5, pp. 1714–1724, 2003.
[12]
J. Mishra, M. A. Qing, A. Prada et al., “Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury,” Journal of the American Society of Nephrology, vol. 14, no. 10, pp. 2534–2543, 2003.
[13]
P. Devarajan, J. Mishra, S. Supavekin, L. T. Patterson, and S. S. Potter, “Gene expression in early ischemic renal injury: clues towards pathogenesis, biomarker discovery, and novel therapeutics,” Molecular Genetics and Metabolism, vol. 80, no. 4, pp. 365–376, 2003.
[14]
H. Ding, Y. He, K. Li et al., “Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy,” Clinical Immunology, vol. 123, no. 2, pp. 227–234, 2007.
[15]
M. E. Hollmen, L. E. Kyll？nen, K. A. Inkinen, M. L. T. Lalla, and K. T. Salmela, “Urine neutrophil gelatinase-associated lipocalin is a marker of graft recovery after kidney transplantation,” Kidney International, vol. 79, no. 1, pp. 89–98, 2011.
[16]
M. Kusaka, Y. Kuroyanagi, T. Mori et al., “Serum neutrophil gelatinase-associated lipocalin as a predictor of organ recovery from delayed graft function after kidney transplantation from donors after cardiac death,” Cell Transplantation, vol. 17, no. 1-2, pp. 129–134, 2008.
[17]
S. Schaub, M. Mayr, G. H？nger et al., “Detection of subclinical tubular injury after renal transplantation: comparison of urine protein analysis with allograft histopathology,” Transplantation, vol. 84, no. 1, pp. 104–112, 2007.
[18]
F. Gaspari, P. Cravedi, M. Mandalà et al., “Predicting cisplatin-induced acute kidney injury by urinary neutrophil gelatinase-associated lipocalin excretion: a pilot prospective case-control study,” Nephron—Clinical Practice, vol. 115, no. 2, pp. c154–c160, 2010.
[19]
J. Malyszko, H. Bachorzewska-Gajewska, J. S. Malyszko, K. Pawlak, and S. Dobrzycki, “Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in hypertensive and normotensive patients with coronary artery disease,” Nephrology, vol. 13, no. 2, pp. 153–156, 2008.
[20]
D. N. Grigoryev, M. Liu, H. T. Hassoun, C. Cheadle, K. C. Barnes, and H. Rabb, “The local and systemic inflammatory transcriptome after acute kidney injury,” Journal of the American Society of Nephrology, vol. 19, no. 3, pp. 547–558, 2008.
[21]
M. Haase, R. Bellomo, P. Devarajan, P. Schlattmann, and A. Haase-Fielitz, “Accuracy of Neutrophil Gelatinase-Associated Lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and Meta-analysis,” American Journal of Kidney Diseases, vol. 54, no. 6, pp. 1012–1024, 2009.
[22]
A. S. C. Decavele, L. Dhondt, M. L. De Buyzere, and J. R. Delanghe, “Increased urinary neutrophil gelatinase associated lipocalin in urinary tract infections and leukocyturia,” Clinical Chemistry and Laboratory Medicine, vol. 49, no. 6, pp. 999–1003, 2011.
[23]
E. Singer, A. Elger, S. Elitok et al., “Urinary neutrophil gelatinase-associated lipocalin distinguishes pre-renal from intrinsic renal failure and predicts outcomes,” Kidney International, vol. 80, pp. 405–414, 2011.
