Advertisement

MSCs for Renal Repair

  • Anna M. Gooch
  • Christof Westenfelder
Chapter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Acute kidney injury (AKI), the abrupt loss of renal function that results from ischemia, sepsis, or nephrotoxin-induced damage to vascular and tubular structures, is characterized by inflammatory processes, cellular apoptosis, and necrosis. Patient mortality remains high and treatment is largely supportive. Even mild AKI can lead to chronic kidney disease (CKD), further underscoring the urgent need for therapeutic innovations. Mesenchymal stromal cells’ (MSCs) potent anti-inflammatory, immunomodulatory, organ protective, and reparative properties make them excellent potential candidates for prevention and treatment of AKI. Multiple preclinical studies using various AKI models have confirmed that, via paracrine mechanisms, MSC treatment improves survival, ameliorates and reverses injury, and prevents progression to CKD. Preliminary results from the first Phase I clinical trial (safety, preliminary efficacy), in which we infused allogeneic MSCs into subjects at high risk for AKI following on-pump cardiac surgery, paralleled preclinical observations, suggesting that MSC therapy is safe and effective in preventing both postoperative AKI and progression to CKD.

Keywords

Chronic Kidney Disease Coronary Artery Bypass Grafting Acute Kidney Injury Mesenchymal Stromal Cell Acute Kidney Injury Network 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

At the time of the Phase I clinical trial, both Christof Westenfelder and Anna Gooch were either consultants to or recipients of research support from AlloCure, Inc., the trial’s sponsor. Currently, both authors declare they have no competing interests. The authors’ research was also in part supported by funds from the Merit Review program of the Veterans Administration, Washington, DC, the National Institutes of Health, the American Heart Association, the National Kidney Foundation, the Western Institute for Biomedical Research, and AlloCure, Inc. The human MSCs that were administered to study subjects in the Phase I clinical trial were prepared in the cGMP Cell Therapy Facility of the University of Utah. The outstanding skills of the PIs (Dr. John Doty, Intermountain Medical Center, Murray, Utah; Dr. David Affleck, St. Mark’s Hospital, Salt Lake City, Utah), Co-PIs (Drs. Benjamin Horne and Brent Muhlestein, Intermountain Medical Center; Drs. Shreekanth Karwande and Gilbert Schorlemmer, St. Mark’s Hospital), and study nurses (Jean Flores, Intermountain Medical Center; Analee Creer, St. Mark’s Hospital) are gratefully acknowledged. The contributions of the members of the Data and Safety Monitoring Board for this trial, Drs. C. Kablitz, George R. Reiss, and Srinivasan Beddhu, are also greatly appreciated. Finally, the excellent bench and regulatory work of Zhuma Hu and Drs. Ping Zhang and Florian Tögel was invaluable for the successful conduct of the preclinical studies and the clinical trial.

References

  1. 1.
    Uchino S (2006) The epidemiology of acute renal failure in the world. Curr Opin Crit Care 12(6):538–543PubMedCrossRefGoogle Scholar
  2. 2.
    Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P (2004) Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8(4):R204–R212PubMedCrossRefGoogle Scholar
  3. 3.
    Nickolas TL, O’Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N et al (2008) Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med 148(11):810–819PubMedGoogle Scholar
  4. 4.
    Rosner MH, Okusa MD (2006) Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 1(1):19–32PubMedCrossRefGoogle Scholar
  5. 5.
    Rosner MH, Portilla D, Okusa MD (2008) Cardiac surgery as a cause of acute kidney injury: pathogenesis and potential therapies. J Intensive Care Med 23(1):3–18PubMedCrossRefGoogle Scholar
  6. 6.
    Hsu CY, Ordonez JD, Chertow GM, Fan D, McCulloch CE, Go AS (2008) The risk of acute renal failure in patients with chronic kidney disease. Kidney Int 74(1):101–107PubMedCrossRefGoogle Scholar
  7. 7.
    Palomba H, de Castro I, Neto AL, Lage S, Yu L (2007) Acute kidney injury prediction following elective cardiac surgery: AKICS score. Kidney Int 72(5):624–631PubMedCrossRefGoogle Scholar
  8. 8.
    Goldberg R, Dennen P (2008) Long-term outcomes of acute kidney injury. Adv Chronic Kidney Dis 15(3):297–307PubMedCrossRefGoogle Scholar
  9. 9.
    Hobson CE, Yavas S, Segal MS, Schold JD, Tribble CG, Layon AJ et al (2009) Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery. Circulation 119(18):2444–2453PubMedCrossRefGoogle Scholar
  10. 10.
    Ishani A, Xue JL, Himmelfarb J, Eggers PW, Kimmel PL, Molitoris BA et al (2009) Acute kidney injury increases risk of ESRD among elderly. J Am Soc Nephrol 20(1):223–228PubMedCrossRefGoogle Scholar
  11. 11.
    Basile DP, Donohoe D, Roethe K, Osborn JL (2001) Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol 281(5):F887–F899PubMedGoogle Scholar
  12. 12.
    Togel F, Westenfelder C (2009) Stem cells in acute kidney injury repair. Minerva Urol Nefrol 61(3):205–213PubMedGoogle Scholar
  13. 13.
    Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW (2005) Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 16(11):3365–3370PubMedCrossRefGoogle Scholar
  14. 14.
    Ishani A, Nelson D, Clothier B, Schult T, Nugent S, Greer N et al (2011) The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death. Arch Intern Med 171(3):226–233PubMedCrossRefGoogle Scholar
  15. 15.
    Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P et al (2004) Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 15(6):1597–1605PubMedCrossRefGoogle Scholar
  16. 16.
    Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG et al (2007) Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11(2):R31PubMedCrossRefGoogle Scholar
  17. 17.
    Chronopoulos A, Cruz DN, Ronco C (2010) Hospital-acquired acute kidney injury in the elderly. Nat Rev Nephrol 6(3):141–149PubMedCrossRefGoogle Scholar
  18. 18.
    Waikar SS, Liu KD, Chertow GM (2008) Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol 3(3):844–861PubMedCrossRefGoogle Scholar
  19. 19.
    Goligorsky MS (2008) Immune system in renal injury and repair: burning the candle from both ends? Pharmacol Res 58(2):122–128PubMedCrossRefGoogle Scholar
  20. 20.
    Togel FE, Westenfelder C (2010) Treatment of acute kidney injury with allogeneic mesenchymal stem cells: Preclinical and initial clinical data. In: Goligorski MS (ed) Regenerative nephrology. Elsevier Inc., Oxford, pp 313–37. London, UK; Burlington, Mass, and San Diego, CA.Google Scholar
  21. 21.
    Kinsey GR, Li L, Okusa MD (2008) Inflammation in acute kidney injury. Nephron Exp Nephrol 109(4):e102–e107PubMedCrossRefGoogle Scholar
  22. 22.
    Molitoris BA, Sutton TA (2004) Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int 66(2):496–499PubMedCrossRefGoogle Scholar
  23. 23.
    Simmons EM, Himmelfarb J, Sezer MT, Chertow GM, Mehta RL, Paganini EP et al (2004) Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int 65(4):1357–1365PubMedCrossRefGoogle Scholar
  24. 24.
    Togel FE, Westenfelder C (2010) Mesenchymal stem cells: a new therapeutic tool for AKI. Nat Rev Nephrol 6(3):179–183PubMedCrossRefGoogle Scholar
  25. 25.
    Sutton TA, Molitoris BA (1998) Mechanisms of cellular injury in ischemic acute renal failure. Semin Nephrol 18(5):490–497PubMedGoogle Scholar
  26. 26.
    Okusa MD (2002) The inflammatory cascade in acute ischemic renal failure. Nephron 90(2): 133–138PubMedCrossRefGoogle Scholar
  27. 27.
    Sutton TA, Fisher CJ, Molitoris BA (2002) Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int 62(5):1539–1549PubMedCrossRefGoogle Scholar
  28. 28.
    Sutton TA, Mang HE, Campos SB, Sandoval RM, Yoder MC, Molitoris BA (2003) Injury of the renal microvascular endothelium alters barrier function after ischemia. Am J Physiol Renal Physiol 285(2):F191–F198PubMedGoogle Scholar
  29. 29.
    Allgren RL, Marbury TC, Rahman SN, Weisberg LS, Fenves AZ, Lafayette RA et al (1997) Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med 336(12):828–834 [Clinical Trial Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov’t]PubMedCrossRefGoogle Scholar
  30. 30.
    Endre ZH, Walker RJ, Pickering JW, Shaw GM, Frampton CM, Henderson SJ et al (2010) Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial). Kidney Int 77(11):1020–1030PubMedCrossRefGoogle Scholar
  31. 31.
    Hirschberg R, Kopple J, Lipsett P, Benjamin E, Minei J, Albertson T et al (1999) Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure. Kidney Int 55(6):2423–2432PubMedCrossRefGoogle Scholar
  32. 32.
    Jo SK, Rosner MH, Okusa MD (2007) Pharmacologic treatment of acute kidney injury: why drugs haven’t worked and what is on the horizon. Clin J Am Soc Nephrol 2(2):356–365PubMedCrossRefGoogle Scholar
  33. 33.
    Deans RJ, Moseley AB (2000) Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28(8):875–884PubMedCrossRefGoogle Scholar
  34. 34.
    Frank MH, Sayegh MH (2004) Immunomodulatory functions of mesenchymal stem cells. Lancet 363(9419):1411–1412PubMedCrossRefGoogle Scholar
  35. 35.
    Bi B, Schmitt R, Israilova M, Nishio H, Cantley LG (2007) Stromal cells protect against acute tubular injury via an endocrine effect. J Am Soc Nephrol 18(9):2486–2496PubMedCrossRefGoogle Scholar
  36. 36.
    Herrera MB, Bussolati B, Bruno S, Fonsato V, Romanazzi GM, Camussi G (2004) Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury. Int J Mol Med 14(6):1035–1041PubMedGoogle Scholar
  37. 37.
    Morigi M, Imberti B, Zoja C, Corna D, Tomasoni S, Abbate M et al (2004) Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J Am Soc Nephrol 15(7):1794–1804PubMedCrossRefGoogle Scholar
  38. 38.
    Lange C, Togel F, Ittrich H, Clayton F, Nolte-Ernsting C, Zander AR et al (2005) Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int 68(4):1613–1617PubMedCrossRefGoogle Scholar
  39. 39.
    Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C (2005) Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 289(1):F31–F42PubMedCrossRefGoogle Scholar
  40. 40.
    Togel F, Cohen A, Zhang P, Yang Y, Hu Z, Westenfelder C (2009) Autologous and allogeneic marrow stromal cells are safe and effective for the treatment of acute kidney injury. Stem Cells Dev 18(3):475–485PubMedCrossRefGoogle Scholar
  41. 41.
    Togel F, Weiss K, Yang Y, Hu Z, Zhang P, Westenfelder C (2007) Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol 292(5):F1626–F1635PubMedCrossRefGoogle Scholar
  42. 42.
    Togel F, Westenfelder C (2007) Adult bone marrow-derived stem cells for organ regeneration and repair. Dev Dyn 236(12):3321–3331PubMedCrossRefGoogle Scholar
  43. 43.
    Imberti B, Morigi M, Tomasoni S, Rota C, Corna D, Longaretti L et al (2007) Insulin-like growth factor-1 sustains stem cell mediated renal repair. J Am Soc Nephrol 18(11): 2921–2928PubMedCrossRefGoogle Scholar
  44. 44.
    Togel F, Zhang P, Hu Z, Westenfelder C (2009) VEGF is a mediator of the renoprotective effects of multipotent marrow stromal cells in acute kidney injury. J Cell Mol Med 13(8B): 2109–2114PubMedCrossRefGoogle Scholar
  45. 45.
    Duffield JS, Park KM, Hsiao LL, Kelley VR, Scadden DT, Ichimura T et al (2005) Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J Clin Invest 115(7):1743–1755PubMedCrossRefGoogle Scholar
  46. 46.
    Li L, Huang L, Sung SS, Lobo PI, Brown MG, Gregg RK et al (2007) NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J Immunol 178(9):5899–5911PubMedGoogle Scholar
  47. 47.
    Lin F, Moran A, Igarashi P (2005) Intrarenal cells, not bone marrow-derived cells, are the major source for regeneration in postischemic kidney. J Clin Invest 115(7):1756–1764PubMedCrossRefGoogle Scholar
  48. 48.
    Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F et al (2009) Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 20(5):1053–1067PubMedCrossRefGoogle Scholar
  49. 49.
    Gatti S, Bruno S, Deregibus MC, Sordi A, Cantaluppi V, Tetta C et al (2011) Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol Dial Transplant 26(5):1474–1483PubMedCrossRefGoogle Scholar
  50. 50.
    Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY et al (2002) Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci USA 99(13):8932–8937PubMedCrossRefGoogle Scholar
  51. 51.
    Horwitz EM, Prather WR (2009) Cytokines as the major mechanism of mesenchymal stem cell clinical activity: expanding the spectrum of cell therapy. Isr Med Assoc J 11(4):209–211PubMedGoogle Scholar
  52. 52.
    Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I et al (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371(9624):1579–1586PubMedCrossRefGoogle Scholar
  53. 53.
    Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M et al (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363(9419):1439–1441PubMedCrossRefGoogle Scholar
  54. 54.
    Gooch A, Doty J, Flores J, Swenson L, Toegel FE, Reiss GR et al (2008) Initial report on a phase I clinical trial: prevention and treatment of post-operative acute kidney injury with allogeneic mesenchymal stem cells in patients who require on-pump cardiac surgery. Cell Ther Transplant 1(2):31–35Google Scholar
  55. 55.
    Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75(3):389–397PubMedCrossRefGoogle Scholar
  56. 56.
    Sundin M, Ringden O, Sundberg B, Nava S, Gotherstrom C, Le Blanc K (2007) No alloantibodies against mesenchymal stromal cells, but presence of anti-fetal calf serum antibodies, after transplantation in allogeneic hematopoietic stem cell recipients. Haematologica 92(9):1208–1215PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department is NephrologyUniversity of Utah and VA Medical CentersSalt Lake CityUSA
  2. 2.Section of NephrologyUniversity of Utah and VA Medical CentersSalt Lake CityUSA

Personalised recommendations