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Autologous CD34+ Cell Transplantation: A Safe and Feasible Treatment for Critical Limb Ischemia in Hemodialysis Patients

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Review of “Autologous Granulocyte Colony-Stimulating Factor-Mobilized Peripheral Blood CD34 Positive Cell Transplantation for Hemodialysis Patients with Critical Limb Ischemia: A Prospective Phase II Clinical Trial” from STEM CELLS Translational Medicine by Stuart P. Atkinson 

Patients suffering from advanced stage of peripheral artery disease can progress to critical limb ischemia (CLI), where the severe obstruction of the arteries reduces blood flow to the extremities, leading to pain and tissue/limb loss. The combination of CLI with the additional need for hemodialysis (HD) in a subset of patients leads to an overall poor prognosis [1]. Can stem cell therapy aid these patients?

The transplantation of unselected peripheral blood mononuclear cells (PB-MNCs) provided favorable outcomes in non‐HD CLI; however, the same study reported disappointing outcomes in CLI patients undergoing HD [2]. Some studies have reported the transplantation of PB purified CD34+ stem/progenitor cells, although the efficacy of treatment has yet to be confirmed under adequate trial conditions [3, 4]. Furthermore, CLI patients undergoing HD exhibit severely decreased numbers of PB CD34+ cells due to uremic condition and inflammation, thereby representing a further problem to this approach [5, 6].

Now, the laboratory of Takayasu Ohtake (Shonan Kamakura General Hospital, Kamakura, Japan) has conducted a prospective interventional phase II clinical trial of autologous granulocyte colony‐stimulating factor (G‐CSF)‐mobilized PB‐derived CD34+ cell transplantation focusing on CLI patients undergoing HD. Their new STEM CELLS Translational Medicine report suggests this strategy to be a safe, feasible, and effective approach for patients normally suffering from poor prognosis [7].

 Here are all the details on this promising new trial:

  • Mobilization by G‐CSF treatment significantly increased the number of CD34+ cells collected from PB
  • CD34+ cell transplantation caused no major therapy-related adverse events in the six male CLI patients enrolled (with seven legs affected by CLI in total and five cases of diabetes)
    • All patients survived for 12 months without amputations, thereby suggesting efficacy
  • CD34+ cell transplantation significantly improved rest pain scale and ulcer size compared with baseline
    • Three of the five ulcers completely healed within 12 weeks
  • Clinical severity significantly improved at 24 weeks and again at 52 weeks post CD34+ cell transplantation and displayed 
    • The trial discovered an improvement rate from CLI stage to non‐CLI stage of 83.3% at 52 weeks and significant advances in total walking distance and microcirculation of ischemic limbs 

Overall, this small study establishes autologous CD34+ cell transplantation as a safe and feasible treatment for critical limb ischemia in hemodialysis patients. The authors now hope to continue with long‐term observation and larger‐scale clinical studies to confirm the potential benefits in the hope of treating patients with life‐threatening CLI who require HD.

For more on CD34+ cell therapy and all the new approaches for CLI treatment, stay tuned to the Stem Cells Portal.

References

  1. Liu T, Liang KV, Rosenbaum A, et al., Peripheral vascular disease severity impacts health outcomes and health-related quality of life in maintenance hemodialysis patients in the HEMO Study. Nephrol Dial Transplant 2012;27:2929-36.
  2. Horie T, Onodera R, Akamastu M, et al., Long-term clinical outcomes for patients with lower limb ischemia implanted with G-CSF-mobilized autologous peripheral blood mononuclear cells. Atherosclerosis 2010;208:461-6.
  3. Kawamoto A, Katayama M, Handa N, et al., Intramuscular transplantation of G-CSF-mobilized CD34(+) cells in patients with critical limb ischemia: a phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial. Stem Cells 2009;27:2857-64.
  4. Tanaka R, Masuda H, Kato S, et al., Autologous G-CSF-mobilized peripheral blood CD34+ cell therapy for diabetic patients with chronic nonhealing ulcer. Cell Transplant 2014;23:167-79.
  5. Pala C, Altun I, Koker Y, et al., The effect of diabetes mellitus and end-stage renal disease on the number of CD34+ cells in the blood. Ann Hematol 2013;92:1189-94.
  6. Jourde-Chiche N, Dou L, Sabatier F, et al., Levels of circulating endothelial progenitor cells are related to uremic toxins and vascular injury in hemodialysis patients. J Thromb Haemost 2009;7:1576-84.
  7. Ohtake T, Mochida Y, Ishioka K, et al., Autologous Granulocyte Colony-Stimulating Factor-Mobilized Peripheral Blood CD34 Positive Cell Transplantation for Hemodialysis Patients with Critical Limb Ischemia: A Prospective Phase II Clinical Trial. Stem Cells Translational Medicine 2018;7:774-782.