Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A novel strategy for identifying early acute kidney injury in pediatric hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 54, pages 1453–1461 (2019)Cite this article

Subjects

Abstract

Acute kidney injury (AKI) is a common complication in pediatric hematopoietic stem cell transplantation (HSCT). Serum creatinine is an imprecise biomarker of AKI. We hypothesized that combining creatinine with serum cystatin C (cysC) and urinary neutrophil gelatinase-associated lipocalin (NGAL) more effectively characterizes AKI during the first 28 days of HSCT and better identifies patients at risk of adverse outcomes than creatinine alone. We prospectively assessed the type and severity of AKI in 80 consecutive allogeneic HSCT patients using weekly creatinine, cysC, and NGAL. We combined the biomarkers to define 7 Composite Types of AKI, including All Positive AKI (simultaneously detected creatinine, cysC, and NGAL AKI). Outcomes included renal replacement therapy and transplant-related mortality. In all, 75% of patients had AKI by at least one measure; 33% developed >1 type of AKI. Mild AKI often preceded Severe AKI. Patients with creatinine or NGAL AKI that were Severe or Repeated tended to have worse outcomes. The five patients with All Positive AKI had the highest rates of morbidity and mortality. AKI evaluation with creatinine, cysC, and NGAL provides a comprehensive profile of early AKI and narrowly identifies patients at highest risk of adverse outcomes, providing opportunities for early, impactful intervention.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Didsbury MS, Mackie FE, Kennedy SE. A systematic review of acute kidney injury in pediatric allogeneic hematopoietic stem cell recipients. Pediatr Transplant. 2015;19:460–70.

    Article  Google Scholar 

  2. Laskin BL, Jodele S. Kidney disease in cancer survivors: focus on hematopoietic stem cell transplantation. J Onco-Nephrol. 2017;1:163–9.

    Article  Google Scholar 

  3. Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med. 2016;374:2256–67.

    Article  Google Scholar 

  4. Liu H, Li YF, Liu BC, Ding JH, Chen BA, Xu WL, et al. A multicenter, retrospective study of acute kidney injury in adult patients with nonmyeloablative hematopoietic SCT. Bone Marrow Transplant. 2010;45:153–8.

    Article  CAS  Google Scholar 

  5. Parikh CR, McSweeney P, Schrier RW. Acute renal failure independently predicts mortality after myeloablative allogeneic hematopoietic cell transplant. Kidney Int. 2005;67:1999–2005.

    Article  Google Scholar 

  6. Parikh CR, Sandmaier BM, Storb RF, Blume KG, Sahebi F, Maloney DG, et al. Acute renal failure after nonmyeloablative hematopoietic cell transplantation. J Am Soc Nephrol. 2004;15:1868–76.

    Article  Google Scholar 

  7. Zager RA, O’Quigley J, Zager BK, Alpers CE, Shulman HM, Gamelin LM, et al. Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients. Am J Kidney Dis. 1989;13:210–6.

    Article  CAS  Google Scholar 

  8. Hari P, Bagga A, Mahajan P, Lakshmy R. Effect of malnutrition on serum creatinine and cystatin C levels. Pediatr Nephrol. 2007;22:1757–61.

    Article  Google Scholar 

  9. Lagos-Arevalo P, Palijan A, Vertullo L, Devarajan P, Bennett M, Sabbisetti V, et al. Cystatin C in acute kidney injury diagnosis: early biomarker or alternative to serum creatinine? Pediatr Nephrol. 2015;30:665–76.

    Article  Google Scholar 

  10. Filler G, Lee M. Educational review: measurement of GFR in special populations. Pediatr Nephrol. 2018;33:2037–46.

    Article  Google Scholar 

  11. Laskin BL, Nehus E, Goebel J, Furth S, Davies SM, Jodele S. Estimated versus measured glomerular filtration rate in children before hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014;20:2056–61.

    Article  Google Scholar 

  12. Hazar V, Gungor O, Guven AG, Aydin F, Akbas H, Gungor F, et al. Renal function after hematopoietic stem cell transplantation in children. Pediatr Blood Cancer. 2009;53:197–202.

    Article  Google Scholar 

  13. Laskin BL, Goebel J, Davies SM, Khoury JC, Bleesing JJ, Mehta PA, et al. Early clinical indicators of transplant-associated thrombotic microangiopathy in pediatric neuroblastoma patients undergoing auto-SCT. Bone Marrow Transplant. 2011;46:682–9.

    Article  CAS  Google Scholar 

  14. Filler G, Bokenkamp A, Hofmann W, Le Bricon T, Martinez-Bru C, Grubb A. Cystatin C as a marker of GFR--history, indications, and future research. Clin Biochem. 2005;38:1–8.

    Article  CAS  Google Scholar 

  15. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis. 2002;40:221–6.

    Article  CAS  Google Scholar 

  16. Laskin BL, Nehus E, Goebel J, Khoury JC, Davies SM, Jodele S. Cystatin C-estimated glomerular filtration rate in pediatric autologous hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18:1745–52.

    Article  CAS  Google Scholar 

  17. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005;365:1231–8.

    Article  CAS  Google Scholar 

  18. Mishra J, Ma Q, Kelly C, Mitsnefes M, Mori K, Barasch J, et al. Kidney NGAL is a novel early marker of acute injury following transplantation. Pediatr Nephrol. 2006;21:856–63.

    Article  Google Scholar 

  19. Hirsch R, Dent C, Pfriem H, Allen J, Beekman RH 3rd, Ma Q, et al. NGAL is an early predictive biomarker of contrast-induced nephropathy in children. Pediatr Nephrol. 2007;22:2089–95.

    Article  Google Scholar 

  20. Wheeler DS, Devarajan P, Ma Q, Harmon K, Monaco M, Cvijanovich N, et al. Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury in critically ill children with septic shock. Crit Care Med. 2008;36:1297–303.

    Article  CAS  Google Scholar 

  21. Haase M, Devarajan P, Haase-Fielitz A, Bellomo R, Cruz DN, Wagener G, et al. The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol. 2011;57:1752–61.

    Article  CAS  Google Scholar 

  22. Basu RK, Wong HR, Krawczeski CD, Wheeler DS, Manning PB, Chawla LS, et al. Combining functional and tubular damage biomarkers improves diagnostic precision for acute kidney injury after cardiac surgery. J Am Coll Cardiol. 2014;64:2753–62.

    Article  CAS  Google Scholar 

  23. Larsson A, Malm J, Grubb A, Hansson LO. Calculation of glomerular filtration rate expressed in mL/min from plasma cystatin C values in mg/L. Scand J Clin Lab Invest. 2004;64:25–30.

    Article  CAS  Google Scholar 

  24. Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20:629–37.

    Article  Google Scholar 

  25. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–70.

    Article  CAS  Google Scholar 

  26. Schuh MP, Nehus E, Ma Q, Haffner C, Bennett M, Krawczeski CD, et al. Long-term stability of urinary biomarkers of acute kidney injury in children. Am J Kidney Dis. 2016;67:56–61.

    Article  CAS  Google Scholar 

  27. Kellum JA, Lameire N, Aspelin P, Barsoum RS, Burdmann EA, Goldstein SL, et al. Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1–138.

  28. Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL. Epidemiology of acute kidney injury in critically ill children and young adults. N Engl J Med. 2017;376:11–20.

    Article  Google Scholar 

  29. Bennett M, Nehus E, Haffner C, Ma Q, Devarajan P. Pediatric reference ranges for acute kidney injury biomarkers. Pediatr Nephrol. 2015;30:677–85.

    Article  Google Scholar 

  30. Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A. Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009;54:1012–24.

    Article  CAS  Google Scholar 

  31. McCullough PA, Shaw AD, Haase M, Bouchard J, Waikar SS, Siew ED, et al. Diagnosis of acute kidney injury using functional and injury biomarkers: workgroup statements from the tenth Acute Dialysis Quality Initiative Consensus Conference. Contrib Nephrol. 2013;182:13–29.

    Article  Google Scholar 

  32. Ronco C, Kellum JA, Haase M. Subclinical AKI is still AKI. Crit Care. 2012;16:313.

    Article  Google Scholar 

  33. Nehus E, Kaddourah A, Bennett M, Pyles O, Devarajan P. Subclinical kidney injury in children receiving nonsteroidal anti-inflammatory drugs after cardiac surgery. J Pediatr. 2017;189:175–80.

    Article  CAS  Google Scholar 

  34. Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014;124:645–53.

    Article  CAS  Google Scholar 

  35. Taghizadeh-Ghehi M, Sarayani A, Ashouri A, Ataei S, Moslehi A, Hadjibabaie M. Urine neutrophil gelatinase associated lipocalin as an early marker of acute kidney injury in hematopoietic stem cell transplantation patients. Ren Fail. 2015;37:994–8.

    Article  CAS  Google Scholar 

  36. Deger SM, Erten Y, Suyani E, Aki SZ, Ulusal Okyay G, Pasaoglu OT, et al. Early diagnostic markers for detection of acute kidney injury in allogeneic hematopoietic stem cell transplant recipients. Exp Clin Transplant. 2017.

Download references

Acknowledgements

We acknowledge the support of the Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA for purchasing biomarker assay supplies.

Author information

Authors and Affiliations

  1. Division of Nephrology & Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Stefanie W. Benoit, Stuart L. Goldstein & Michael R. Bennett

  2. Kidney Center at Children’s Hospital Colorado Medical Center, Aurora, CO, USA

    Bradley P. Dixon

  3. Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

    Bradley P. Dixon

  4. University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Stuart L. Goldstein, Michael R. Bennett, Adam Lane & Stella M. Davies

  5. Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Stuart L. Goldstein

  6. Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Adam Lane, Kelly E. Lake, Bridget Litts & Stella M. Davies

  7. Weirton Medical Center, Weirton, WV, USA

    Dana T. Lounder

  8. Department of Pediatric Hematology, Oncology, and Blood and Marrow Transplantation, Cleveland Clinic Foundation, Cleveland, OH, USA

    Seth J. Rotz

  9. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

    Seth J. Rotz

  10. University of California San Diego, Rady Children’s Hospital, San Diego, CA, USA

    Nicholas J. Gloude

Authors
  1. Stefanie W. Benoit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bradley P. Dixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stuart L. Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael R. Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Adam Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dana T. Lounder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seth J. Rotz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nicholas J. Gloude
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kelly E. Lake
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bridget Litts
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stella M. Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefanie W. Benoit.

Ethics declarations

Conflict of interest

SLG consults for and has received grant support from Bioporto, Inc. The other authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Benoit, S.W., Dixon, B.P., Goldstein, S.L. et al. A novel strategy for identifying early acute kidney injury in pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant 54, 1453–1461 (2019). https://doi.org/10.1038/s41409-018-0428-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0428-6

This article is cited by

Search

Advanced search

Quick links