Nephrol Dial Transplant Vol. 19 No. 9 © ERA-EDTA 2004; all rights reserved
Original Article
A strategy to achieve donor-specific hyporesponsiveness in cadaver renal allograft recipients by donor haematopoietic stem cell transplantation into the thymus and periphery
1 Department of Nephrology and Clinical Transplantation, 2 Department of Pathology, Laboratory Medicine, Transfusion Services and Immuno Hematology, 3 Department of Anaesthesiology and Critical Care and 4 Department of Urology and Transplantation Surgery, Institute of Transplantation Sciences (ITS), Institute of Kidney Diseases and Research Centre (IKDRC), Ahmedabad, Gujarat, India
Correspondence and offprint requests to: Dr H. L. Trivedi, FRCP (C), Director, Professor, Institute of Transplantation Sciences (ITS) and Institute of Kidney Diseases and Research Centre (IKDRC), Civil Hospital Campus, Asarwa, Ahmedabad 380 016, Gujarat, India. Email: ikdrcad1{at}sancharnet.in
Introduction. We designed a prospective, randomized clinical trial to evaluate the immune response to thymic and peripheral infusions of donor haematopoietic stem cells (HSCs) to create tolerance in recipients of cadaver renal allografts.
Method. We divided 24 patients into two equal groups. For group A, 350 ml of unfractionated bone marrow (BM) was aspirated from the anterior iliac crests of donor cadavers. A 2 ml aliquot of concentrated marrow was infused into the thymus of the subject and 100 ml into the BM before surgery; the remaining 250 ml was infused peripherally post-transplantation. The mean nucleated cell count inoculated into the thymus was 3.3 x 104 cells/cm3 and into the periphery 8.6 x 107 cells/kg body weight. Group B (controls) underwent renal transplantation directly. Recipients were lymphocytotoxicity cross-match negative in both groups. Group A received low dose prednisolone and cyclosporin; controls also received azathioprine.
Results. Over a mean follow-up of 703 days for both groups, group A had significantly better graft function with minimum acute rejection episodes or cytomegalovirus (CMV) infections, a mean serum creatinine (SCr) of 1.23 mg/dl and no graft or patient loss. Group B, with a mean SCr of 2.19 mg/dl had three patients with single acute rejection episodes, two of whom died following uncontrolled rejection-associated infections. The third patient maintained an SCr of 2.5 mg%. Actuarial graft survival was 87.5% in controls at the end of 2 years compared with group A with 100% graft survival at the end of 2 years.
Conclusion. This novel approach of introducing unfractionated HSCs into the thymus and periphery to create tolerance is safe and efficacious and gives significantly better graft function, minimum acute rejection and no CMV disease with monotherapy.
Keywords: donor-derived haematopoietic stem cells; cadaver renal transplantation; tolerance