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.

  • Original Article
  • Published:

Transplant Toxicities

Markers of coagulation activation and acute kidney injury in patients after hematopoietic cell transplantation

Abstract

Acute kidney injury (AKI) is common after hematopoietic cell transplant (HCT). The etiology of AKI is unknown because biopsies are rarely performed. The pathophysiology of injury is inferred from clinical data. Thrombotic microangiopathy (TMA) is often invoked as the cause of renal injury. Patients >2 years old undergoing their first HCT at Fred Hutchinson Cancer Research Center participated in this study. We prospectively measured plasma markers of coagulation activation, (PAI-1 and tPA) and fibrinolyis (D-dimer) weekly in 149 patients during the first 100 days post transplant. Cox proportional hazards modeling was used to determine associations between these markers and AKI (doubling of baseline serum creatinine). Kruskal–Wallis test was used to determine the associations between day 100 urinary albumin to creatinine ratios and these markers. Thirty one percent of patients developed AKI. Though elevations in these markers occurred frequently, neither PAI-1 nor tPA were associated with the development of AKI. D-dimer was associated with a slightly increased risk of AKI (relative risk=1.76; P-value 0.04). None of these markers were associated with micro- or macroalbuminuria at day 100. The lack of an association with AKI suggests that endothelial injury in the form of TMA is not a common cause of AKI early after transplant.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363: 2091–2101.

    Article  CAS  Google Scholar 

  2. Changsirikulchai S, Myerson D, Guthrie KA, McDonald GB, Alpers CE, Hingorani SR . Renal thrombotic microangiopathy after hematopoietic cell transplant: role of GVHD in pathogenesis. Clin J Am Soc Nephrol 2009; 4: 345–353.

    Article  Google Scholar 

  3. Eddy AA . Plasminogen activator inhibitor-1 and the kidney. Am J Physiol Renal Physiol 2002; 283: F209–F220.

    Article  CAS  Google Scholar 

  4. Lemarchant S, Docagne F, Emery E, Vivien D, Ali C, Rubio M . tPA in the injured central nervous system: different scenarios starring the same actor? Neuropharmacology 2012; 62: 749–756.

    Article  CAS  Google Scholar 

  5. Nurnberger W, Michelmann I, Burdach S, Gobel U . Endothelial dysfunction after bone marrow transplantation: increase of soluble thrombomodulin and PAI-1 in patients with multiple transplant-related complications. Ann Hematol 1998; 76: 61–65.

    Article  CAS  Google Scholar 

  6. Anthony MT, Zeigler ZR, Lister J, Raymond JM, Shadduck RK, Kramer RE et al. Plasminogen activator inhibitor (PAI-1) antigen levels in primary TTP and secondary TTP post-bone marrow transplantation. Am J Hematol 1998; 59: 9–14.

    Article  CAS  Google Scholar 

  7. Salat C, Holler E, Reinhardt B, Kolb HJ, Seeber B, Ledderose G et al. Parameters of the fibrinolytic system in patients undergoing BMT: elevation of PAI-1 in veno-occlusive disease. Bone Marrow Transplant 1994; 14: 747–750.

    CAS  PubMed  Google Scholar 

  8. Carella AM, Champlin R, Slavin S, McSweeney P, Storb R . Mini-allografts: ongoing trials in humans. Bone Marrow Transplant 2000; 25: 345–350.

    Article  CAS  Google Scholar 

  9. Doroshow JH, Synold TW . Pharmacologic basis for high-dose chemotherapy. In: Appelbaum FR, Forman SJ, Negrin RS, Blume KG (eds). Thomas' Hematopoietic Cell Transplantation. Wiley-Blackwell: Oxford, UK, 2009; pp 287–315.

    Chapter  Google Scholar 

  10. Leather HL, Wingard JR . Bacterial infections. In: Appelbaum FR, Blume KG, Forman SJ (eds). Thomas' Hematopoietic Cell Transplantation. Wiley-Blackwell: Oxford, UK, 2009; pp 1325–1345.

    Chapter  Google Scholar 

  11. Zaia JA . Cytomegalovirus infection. In: Appelbaum FR, Blume KG, Forman SJ (eds). Thomas' Hematopoietic Cell Transplantation. Wiley-Blackwell: Oxford, UK, 2009; pp 1367–1381.

    Chapter  Google Scholar 

  12. Brown JMY . Fungal infections after hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, Blume KG (eds). Thomas' Hematopoietic Cell Transplantation. Wiley-Blackwell: Oxford, UK, 2009; pp 1346–1366.

    Chapter  Google Scholar 

  13. Ito JI . Herpes simplex virus infections. In: Appelbaum FR, Blume KG, Forman SJ (eds). Thomas' Hematopoietic Cell Transplantation. Wiley-Blackwell: Oxford, UK, 2009; pp 1382–1387.

    Chapter  Google Scholar 

  14. Ho DY, Arvin AM . Varicella-zoster virus infections. In: Appelbaum FR, Forman SJ, Negrin RS, Blume KG (eds). Thomas' Hematopoietic Cell Transplantation. Wiley-Blackwell: Oxford, UK, 2009; pp 1388–1409.

    Chapter  Google Scholar 

  15. Ruutu T, Eriksson B, Remes K, Juvonen E, Volin L, Remberger M et al. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood 2002; 100: 1977–1983.

    Article  CAS  Google Scholar 

  16. Chandler WL, Jelacic S, Boster DR, Ciol MA, Williams GD, Watkins SL et al. Prothrombotic coagulation abnormalities preceding the hemolytic-uremic syndrome. N Engl J Med 2002; 346: 23–32.

    Article  CAS  Google Scholar 

  17. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118: 255–267.

    Article  CAS  Google Scholar 

  18. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  Google Scholar 

  19. Hingorani SR, Guthrie K, Batchelder A, Schoch G, Aboulhosn N, Manchion J et al. Acute renal failure after myeloablative hematopoietic cell transplant: incidence and risk factors. Kidney Int 2005; 67: 272–277.

    Article  Google Scholar 

  20. Pettitt AR, Clark RE . Thrombotic microangiopathy following bone marrow transplantation. Bone Marrow Transplant 1994; 14: 495–504.

    CAS  PubMed  Google Scholar 

  21. Brandao LR, Kletzel M, Boulad F, Kurtzberg J, Maloney K, Fligman I et al. A prospective longitudinal multicenter study of coagulation in pediatric patients undergoing allogeneic stem cell transplantation. Pediatr Blood Cancer 2008; 50: 1240–1246.

    Article  Google Scholar 

  22. Heissig B, Lund LR, Akiyama H, Ohki M, Morita Y, Romer J et al. The plasminogen fibrinolytic pathway is required for hematopoietic regeneration. Cell Stem Cell 2007; 1: 658–670.

    Article  CAS  Google Scholar 

  23. Hingorani SR, Seidel K, Lindner A, Aneja T, Schoch G, McDonald G . Albuminuria in hematopoietic cell transplantation patients: prevalence, clinical associations, and impact on survival. Biol Blood Marrow Transplant 2008; 14: 1365–1372.

    Article  Google Scholar 

  24. Toto RD . Microalbuminuria: definition, detection, and clinical significance. J Clin Hypertens (Greenwich) 2004; 6: 2–7.

    Article  CAS  Google Scholar 

  25. Couriel D, Caldera H, Champlin R, Komanduri K . Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Cancer 2004; 101: 1936–1946.

    Article  Google Scholar 

  26. Krenger W, Hill GR, Ferrara JL . Cytokine cascades in acute graft-versus-host disease. Transplantation 1997; 64: 553–558.

    Article  CAS  Google Scholar 

  27. Takatsuka H, Wakae T, Mori A, Okada M, Suehiro A, Okamoto T et al. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome following allogeneic bone marrow transplantation. Bone Marrow Transplant 2002; 29: 907–911.

    Article  CAS  Google Scholar 

  28. Seconi J, Watt V, Ritchie DS . Nephrotic syndrome following allogeneic stem cell transplantation associated with increased production of TNF-alpha and interferon-gamma by donor T cells. Bone Marrow Transplant 2003; 32: 447–450.

    Article  CAS  Google Scholar 

  29. Teshima T, Ordemann R, Reddy P, Gagin S, Liu C, Cooke KR et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med 2002; 8: 575–581.

    Article  CAS  Google Scholar 

  30. Xu Y, Hagege J, Mougenot B, Sraer JD, Ronne E, Rondeau E . Different expression of the plasminogen activation system in renal thrombotic microangiopathy and the normal human kidney. Kidney Int 1996; 50: 2011–2019.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Institutes of Health (NIDDK) K23 DK63038, American Society of Nephrology/Renal Physicians Association Health Scholars Grant and the National Kidney Foundation Young Investigators Grant received by Dr Hingorani. The authors would like to thank Gary Schoch for creating the analysis data set.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S R Hingorani.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hingorani, S., Seidel, K., Pao, E. et al. Markers of coagulation activation and acute kidney injury in patients after hematopoietic cell transplantation. Bone Marrow Transplant 50, 715–720 (2015). https://doi.org/10.1038/bmt.2015.2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2015.2

This article is cited by

Search

Quick links