Skip to main content
Top
Published in: Pediatric Nephrology 6/2006

01-06-2006 | Original Article

Kidney NGAL is a novel early marker of acute injury following transplantation

Authors: Jaya Mishra, Qing Ma, Caitlin Kelly, Mark Mitsnefes, Kiyoshi Mori, Jonathan Barasch, Prasad Devarajan

Published in: Pediatric Nephrology | Issue 6/2006

Login to get access

Abstract

Acute kidney injury secondary to ischemia–reperfusion in renal allografts often results in delayed graft function. We tested the hypothesis that expression of neutrophil gelatinase-associated lipocalin (NGAL) is an early marker of acute kidney injury following transplantation. Sections from paraffin-embedded protocol biopsy specimens obtained at approximately one hour of reperfusion after transplantation of 13 cadaveric (CAD) and 12 living-related (LRD) renal allografts were examined by immunohistochemistry for expression of NGAL. The staining intensity was correlated with cold ischemia time, peak post-operative serum creatinine, and dialysis requirement. There were no differences between the LRD and CAD groups in age, gender or preoperative serum creatinine. Using a scoring system of 0 (no staining) to 3 (most intense staining), NGAL expression was significantly increased in CAD specimens (2.3±0.8 versus 0.8±0.7 in LRD, p<0.001). There was a strong correlation between NGAL staining intensity and cold ischemia time (R=0.87, p<0.001). Importantly, NGAL staining in these early CAD biopsies was strongly correlated with peak postoperative serum creatinine, which occurred days later (R=0.86, p<0.001). Four patients developed delayed graft function requiring dialysis during the first week posttransplantation; all of these patients displayed the most intense NGAL staining in their first protocol biopsies. We conclude that NGAL staining intensity in early protocol biopsies represents a novel predictive biomarker of acute kidney injury following transplantation.
Literature
1.
go back to reference Star RA (1998) Treatment of acute renal failure. Kidney Int 54:1817–1831PubMed Star RA (1998) Treatment of acute renal failure. Kidney Int 54:1817–1831PubMed
2.
go back to reference Schrier RW, Wang W, Poole B, Mitra A (2004) Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 114:5–14PubMedPubMedCentral Schrier RW, Wang W, Poole B, Mitra A (2004) Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 114:5–14PubMedPubMedCentral
3.
go back to reference Lamiere N, Van Biesen W, Vanholder R (2005) Acute renal failure. Lancet 365:417–430 Lamiere N, Van Biesen W, Vanholder R (2005) Acute renal failure. Lancet 365:417–430
4.
go back to reference Molitoris BA (2003) Transitioning to therapy in ischemic acute renal failure. J Am Soc Nephrol 14:265–267PubMed Molitoris BA (2003) Transitioning to therapy in ischemic acute renal failure. J Am Soc Nephrol 14:265–267PubMed
5.
go back to reference Bonventre JV, Weinberg JM (2003) Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol 14:2199–2210PubMed Bonventre JV, Weinberg JM (2003) Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol 14:2199–2210PubMed
6.
go back to reference Siegel NJ, Shah SV (2003) Acute renal failure: directions for the next decade. J Am Soc Nephrol 14:2176–2177PubMed Siegel NJ, Shah SV (2003) Acute renal failure: directions for the next decade. J Am Soc Nephrol 14:2176–2177PubMed
7.
go back to reference Devarajan P (2005) Cellular and molecular derangements in acute tubular necrosis. Curr Opin Pediatr 17:193–199PubMed Devarajan P (2005) Cellular and molecular derangements in acute tubular necrosis. Curr Opin Pediatr 17:193–199PubMed
8.
go back to reference Schrier RW (2004) Need to intervene in established acute renal failure. J Am Soc Nephrol 15:2756–2758PubMed Schrier RW (2004) Need to intervene in established acute renal failure. J Am Soc Nephrol 15:2756–2758PubMed
9.
go back to reference Hewitt SM, Dear J, Star RA (2004) Discovery of protein biomarkers for renal diseases. J Am Soc Nephrol 15:1677–1689PubMed Hewitt SM, Dear J, Star RA (2004) Discovery of protein biomarkers for renal diseases. J Am Soc Nephrol 15:1677–1689PubMed
10.
go back to reference Herget-Rosenthal S, Marggraf G, Hüsing J, Goring F, Pietruck F, Janssen O, Phillip T, Kribben A (2004) Early detection of acute renal failure by serum cystatin C. Kidney Int 66:1115–1122PubMed Herget-Rosenthal S, Marggraf G, Hüsing J, Goring F, Pietruck F, Janssen O, Phillip T, Kribben A (2004) Early detection of acute renal failure by serum cystatin C. Kidney Int 66:1115–1122PubMed
11.
go back to reference Rabb H (2003) Novel urinary markers for early diagnosis of ARF. Am J Kidney Dis 42:599–600PubMed Rabb H (2003) Novel urinary markers for early diagnosis of ARF. Am J Kidney Dis 42:599–600PubMed
12.
go back to reference Bellomo R, Kellum JA, Ronco C (2004) Defining acute renal failure: physiological principles. Intensive Care Med 30:33–37PubMed Bellomo R, Kellum JA, Ronco C (2004) Defining acute renal failure: physiological principles. Intensive Care Med 30:33–37PubMed
13.
go back to reference Perico N, Cattaneo D, Sayegh MH, Remuzzi G (2004) Delayed graft function in kidney transplantation. Lancet 364:1814–1827PubMed Perico N, Cattaneo D, Sayegh MH, Remuzzi G (2004) Delayed graft function in kidney transplantation. Lancet 364:1814–1827PubMed
14.
go back to reference Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL (1997) Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63:968–974PubMed Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL (1997) Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63:968–974PubMed
15.
go back to reference Koning OH, Ploeg RJ, van Bockel H, Groenewegen M, van der Woude FJ, Persijn GG, Hermans J (1997) Risk factors for delayed graft function in cadaveric kidney transplantation: a prospective study of renal function and graft survival after preservation with University of Wisconsin solution in multi-organ donors. Transplantation 63:1620–1628PubMed Koning OH, Ploeg RJ, van Bockel H, Groenewegen M, van der Woude FJ, Persijn GG, Hermans J (1997) Risk factors for delayed graft function in cadaveric kidney transplantation: a prospective study of renal function and graft survival after preservation with University of Wisconsin solution in multi-organ donors. Transplantation 63:1620–1628PubMed
16.
go back to reference Jacobs SC, Cho E, Foster C, Liao P, Bartlett ST (2004) Laparoscopic donor nephrectomy: the University of Maryland 6-year experience. J Urol 171:47–51PubMed Jacobs SC, Cho E, Foster C, Liao P, Bartlett ST (2004) Laparoscopic donor nephrectomy: the University of Maryland 6-year experience. J Urol 171:47–51PubMed
17.
go back to reference Lu CY, Penfield JG, Kielar ML, Vasquez MA, Jeyarajah DR (1999) Hypothesis: is renal allograft rejection initiated by the response to injury sustained during the transplant process? Kidney Int 55:2157–2168PubMed Lu CY, Penfield JG, Kielar ML, Vasquez MA, Jeyarajah DR (1999) Hypothesis: is renal allograft rejection initiated by the response to injury sustained during the transplant process? Kidney Int 55:2157–2168PubMed
18.
go back to reference Sayegh MH (1999) Why do we reject a graft? Role of indirect allorecognition in graft rejection. Kidney Int 65:1967–1979 Sayegh MH (1999) Why do we reject a graft? Role of indirect allorecognition in graft rejection. Kidney Int 65:1967–1979
19.
go back to reference Boom H, Mallat MJ, de Fijter JW, Zwinderman AH, Paul LC (2000) Delayed graft function influences renal function, but not survival. Kidney Int 58:859–866PubMed Boom H, Mallat MJ, de Fijter JW, Zwinderman AH, Paul LC (2000) Delayed graft function influences renal function, but not survival. Kidney Int 58:859–866PubMed
20.
go back to reference Giral-Classe M, Hourmant M, Cantarovich D, Dantal J, Blancho G, Daguin P, Ancelet D, Soulillou JP (1998) Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneys. Kidney Int 54:972–978PubMed Giral-Classe M, Hourmant M, Cantarovich D, Dantal J, Blancho G, Daguin P, Ancelet D, Soulillou JP (1998) Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneys. Kidney Int 54:972–978PubMed
21.
go back to reference Shoskes DA, Cecka M (1998) Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection. Transplantation 66:1697–1701PubMed Shoskes DA, Cecka M (1998) Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection. Transplantation 66:1697–1701PubMed
22.
go back to reference Troppman C, Gruessner AC, Gillingham KJ, Sutherland DE, Matas AJ, Gruessner RW (1999) Impact of delayed graft function on long-term graft survival after solid organ transplantation. Transplant Proc 31:1290–1292 Troppman C, Gruessner AC, Gillingham KJ, Sutherland DE, Matas AJ, Gruessner RW (1999) Impact of delayed graft function on long-term graft survival after solid organ transplantation. Transplant Proc 31:1290–1292
23.
go back to reference Woo YM, Jardine AG, Clark AF, MacGregor MS, Bowman AW, Macpherson SG, Briggs JD, Junor BJ, McMillan MA, Rodger RS (1999) Early graft function and patient survival following cadaveric renal transplantation. Kidney Int 55:692–699PubMed Woo YM, Jardine AG, Clark AF, MacGregor MS, Bowman AW, Macpherson SG, Briggs JD, Junor BJ, McMillan MA, Rodger RS (1999) Early graft function and patient survival following cadaveric renal transplantation. Kidney Int 55:692–699PubMed
24.
go back to reference Tejani AH, Sullivan EK, Alexander SR, Fine RN, Harmon WE, Kohaut EC (1999) Predictive factors for delayed graft function (DGF) and its impact on renal graft survival in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 3:293–300PubMed Tejani AH, Sullivan EK, Alexander SR, Fine RN, Harmon WE, Kohaut EC (1999) Predictive factors for delayed graft function (DGF) and its impact on renal graft survival in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 3:293–300PubMed
25.
go back to reference Prommool S, Jhangri GS, Cockfield SM, Halloran PF (2000) Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 11:565–573PubMed Prommool S, Jhangri GS, Cockfield SM, Halloran PF (2000) Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 11:565–573PubMed
26.
go back to reference Halloran PF, Hunsicker LG (2001) Delayed graft function: state of the art, Nov 10–11, 2000. Summit meeting, Scottsdale, Arizona, USA. Am J Transplant 1:115–120PubMed Halloran PF, Hunsicker LG (2001) Delayed graft function: state of the art, Nov 10–11, 2000. Summit meeting, Scottsdale, Arizona, USA. Am J Transplant 1:115–120PubMed
27.
go back to reference Salahudeen AK, Haider N, May W (2004) Cold ischemia and the reduced long-term survival of cadaveric renal allografts. Kidney Int 65:713–718PubMed Salahudeen AK, Haider N, May W (2004) Cold ischemia and the reduced long-term survival of cadaveric renal allografts. Kidney Int 65:713–718PubMed
28.
go back to reference Irish WD, McCollum DA, Tesi RJ, Owen AB, Brennan DC, Bailly JE, Schnitzler MA (2003) Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients. J Am Soc Nephrol 14:2967–2974PubMed Irish WD, McCollum DA, Tesi RJ, Owen AB, Brennan DC, Bailly JE, Schnitzler MA (2003) Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients. J Am Soc Nephrol 14:2967–2974PubMed
29.
go back to reference Brier ME, Ray PC, Klein JB (2003) Prediction of delayed renal allograft function using an artificial neural network. Nephrol Dial Transplant 18:2655–2659PubMed Brier ME, Ray PC, Klein JB (2003) Prediction of delayed renal allograft function using an artificial neural network. Nephrol Dial Transplant 18:2655–2659PubMed
30.
go back to reference Supavekin S, Zhang W, Kucherlapati R, Kaskel FJ, Moore LC, Devarajan P (2003) Differential gene expression following early renal ischemia–reperfusion. Kidney Int 63:1714–1724PubMed Supavekin S, Zhang W, Kucherlapati R, Kaskel FJ, Moore LC, Devarajan P (2003) Differential gene expression following early renal ischemia–reperfusion. Kidney Int 63:1714–1724PubMed
31.
go back to reference Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P (2003) Identification of NGAL as a novel urinary biomarker for ischemic injury. J Am Soc Nephrol 4:2534–2543 Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P (2003) Identification of NGAL as a novel urinary biomarker for ischemic injury. J Am Soc Nephrol 4:2534–2543
32.
go back to reference Devarajan P, Mishra J, Supavekin S, Patterson LT, Potter SS (2003) Gene expression in early ischemic renal injury: clues towards pathogenesis, biomarker discovery and novel therapeutics. Mol Genet Metab 80:365–376PubMed Devarajan P, Mishra J, Supavekin S, Patterson LT, Potter SS (2003) Gene expression in early ischemic renal injury: clues towards pathogenesis, biomarker discovery and novel therapeutics. Mol Genet Metab 80:365–376PubMed
33.
go back to reference Oberbauer R, Rohrmoser M, Regele H, Mulhbacher F, Mayer G (1999) Apoptosis of tubular epithelial cells in donor kidney biopsies predicts early renal allograft function. J Am Soc Nephrol 10:2006–2013PubMed Oberbauer R, Rohrmoser M, Regele H, Mulhbacher F, Mayer G (1999) Apoptosis of tubular epithelial cells in donor kidney biopsies predicts early renal allograft function. J Am Soc Nephrol 10:2006–2013PubMed
34.
go back to reference Castaneda MP, Swiatecka-Urban A, Mitsnefes MM, Feuerstein D, Kaskel FJ, Tellis V, Devarajan P (2003) Activation of mitochondrial apoptotic pathways in human allografts after ischemia–reperfusion injury. Transplantation 76:50–54PubMed Castaneda MP, Swiatecka-Urban A, Mitsnefes MM, Feuerstein D, Kaskel FJ, Tellis V, Devarajan P (2003) Activation of mitochondrial apoptotic pathways in human allografts after ischemia–reperfusion injury. Transplantation 76:50–54PubMed
35.
go back to reference Schwarz C, Regele H, Steininger R, Hansmann C, Mayer G, Oberbauer R (2001) The contribution of adhesion molecule expression in donor kidney biopsies to early allograft dysfunction. Transplantation 71:1666–1670PubMed Schwarz C, Regele H, Steininger R, Hansmann C, Mayer G, Oberbauer R (2001) The contribution of adhesion molecule expression in donor kidney biopsies to early allograft dysfunction. Transplantation 71:1666–1670PubMed
36.
go back to reference Yang J, Goetz D, Li J-Y, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J (2002) An iron delivery pathway mediated by a lipocalin. Mol Cell 10:1045–1056PubMed Yang J, Goetz D, Li J-Y, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J (2002) An iron delivery pathway mediated by a lipocalin. Mol Cell 10:1045–1056PubMed
37.
go back to reference Gwira JA, Wei F, Ishibe S, Ueland JM, Barasch J, Cantley LG (2005) Expression of NGAL regulates epithelial morphogenesis in vitro. J Biol Chem 280:7875–7882PubMed Gwira JA, Wei F, Ishibe S, Ueland JM, Barasch J, Cantley LG (2005) Expression of NGAL regulates epithelial morphogenesis in vitro. J Biol Chem 280:7875–7882PubMed
38.
go back to reference Mishra J, Mori K, Ma Q, Kelly C, Yang J, Mitsnefes M, Barasch J, Devarajan P (2004) Amelioration of ischemic acute renal injury by NGAL. J Am Soc Nephrol 15:3073–3082PubMed Mishra J, Mori K, Ma Q, Kelly C, Yang J, Mitsnefes M, Barasch J, Devarajan P (2004) Amelioration of ischemic acute renal injury by NGAL. J Am Soc Nephrol 15:3073–3082PubMed
39.
go back to reference Mori K, Lee HT, Rapoport D, Drexler I, Foster K, Yang J, Schmidt-Ott, Chen X, Li JY, Weiss S, Mishra J, Cheema FH, Markowitz G, Suganami T, Sawai K, Mukoyama M, Kunis C, D’Agati V, Devarajan P, Barasch J (2005) Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia. J Clin Invest 115:610–621PubMedPubMedCentral Mori K, Lee HT, Rapoport D, Drexler I, Foster K, Yang J, Schmidt-Ott, Chen X, Li JY, Weiss S, Mishra J, Cheema FH, Markowitz G, Suganami T, Sawai K, Mukoyama M, Kunis C, D’Agati V, Devarajan P, Barasch J (2005) Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia. J Clin Invest 115:610–621PubMedPubMedCentral
40.
go back to reference Salmela K, Wramner L, Ekberg H, Hauser I, Bentdal O, Lins LE, Isoniemi H, Backman L, Persson N, Neumayer HH, Jorgensen PF, Spieker C, Hendry B, Nicholls A, Kirste G, Hasche G (1999) A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimobab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group. Transplantation 67:729–736PubMed Salmela K, Wramner L, Ekberg H, Hauser I, Bentdal O, Lins LE, Isoniemi H, Backman L, Persson N, Neumayer HH, Jorgensen PF, Spieker C, Hendry B, Nicholls A, Kirste G, Hasche G (1999) A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimobab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group. Transplantation 67:729–736PubMed
41.
go back to reference Acker CG, Flick R, Shapiro R, Shapiro R, Scantlebury VP, Jordan ML, Vivas C, Greenberg A, Johnson JP (2002) Thyroid hormone in the treatment of post-transplant acute tubular necrosis (ATN). Am J Transplant 2:57–61PubMed Acker CG, Flick R, Shapiro R, Shapiro R, Scantlebury VP, Jordan ML, Vivas C, Greenberg A, Johnson JP (2002) Thyroid hormone in the treatment of post-transplant acute tubular necrosis (ATN). Am J Transplant 2:57–61PubMed
42.
go back to reference Hladunewich MA, Corrigan G, Derby GC, Ramaswamy D, Kambham N, Scandling JD, Myers BD (2003) A randomized, placebo-controlled trial of IGF-1 for delayed graft function: a human model to study postischemic ARF. Kidney Int 64:593–602PubMed Hladunewich MA, Corrigan G, Derby GC, Ramaswamy D, Kambham N, Scandling JD, Myers BD (2003) A randomized, placebo-controlled trial of IGF-1 for delayed graft function: a human model to study postischemic ARF. Kidney Int 64:593–602PubMed
43.
go back to reference Schwarz A, Gwinner W, Hiss M, Radermacher J, Mengel M, Haller H (2005) Safety and adequacy of renal transplant protocol biopsies. Am J Transplant 5:1992–1996PubMed Schwarz A, Gwinner W, Hiss M, Radermacher J, Mengel M, Haller H (2005) Safety and adequacy of renal transplant protocol biopsies. Am J Transplant 5:1992–1996PubMed
44.
go back to reference Heilman RL, Mazur MJ, Reddy KS, Moss A, Post D, Mulligan D (2005) Steroid avoidance immunosuppression in low-risk kidney transplant. Transplant Proc 37:1785–1788PubMed Heilman RL, Mazur MJ, Reddy KS, Moss A, Post D, Mulligan D (2005) Steroid avoidance immunosuppression in low-risk kidney transplant. Transplant Proc 37:1785–1788PubMed
45.
go back to reference Sakai K, Miyagi Y, Hasegawa T, Itabashi Y, Muramatsu M, Sugiyama K, Kawamura T, Arai K, Aikawa A, Ohara T, Mizuiri S, Hasegawa A (2005) The pathologic impact of tacrolimus on protocol biopsy in renal transplant patients with basiliximab-based immunosuppression. Transplant Proc 37:1757–1759PubMed Sakai K, Miyagi Y, Hasegawa T, Itabashi Y, Muramatsu M, Sugiyama K, Kawamura T, Arai K, Aikawa A, Ohara T, Mizuiri S, Hasegawa A (2005) The pathologic impact of tacrolimus on protocol biopsy in renal transplant patients with basiliximab-based immunosuppression. Transplant Proc 37:1757–1759PubMed
46.
go back to reference Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P (2005) Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury following cardiac surgery. Lancet 365:1231–1238PubMed Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P (2005) Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury following cardiac surgery. Lancet 365:1231–1238PubMed
47.
go back to reference Morrow DA, Braunwald E (2003) Future of biomarkers in acute coronary syndrome: Moving toward a multimarker strategy. Circulation 108:250–252PubMed Morrow DA, Braunwald E (2003) Future of biomarkers in acute coronary syndrome: Moving toward a multimarker strategy. Circulation 108:250–252PubMed
48.
go back to reference Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P (2004) Neutrophil gelatinase-associated lipocalin (NGAL): a novel urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 24:307–315PubMed Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P (2004) Neutrophil gelatinase-associated lipocalin (NGAL): a novel urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 24:307–315PubMed
Metadata
Title
Kidney NGAL is a novel early marker of acute injury following transplantation
Authors
Jaya Mishra
Qing Ma
Caitlin Kelly
Mark Mitsnefes
Kiyoshi Mori
Jonathan Barasch
Prasad Devarajan
Publication date
01-06-2006
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Nephrology / Issue 6/2006
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-006-0055-0

Other articles of this Issue 6/2006

Pediatric Nephrology 6/2006 Go to the issue