This pilot study of combined kidney and hematopoietic stem cell transplantation attempts to
establish a protocol to induce immunological tolerance as a new strategy to prevent renal
graft rejection. If successful, this strategy would restore renal function, while avoiding
the risks associated with long-term standard anti-rejection therapy, and would represent the
first option to cure end-stage renal disease.
Trial design This is an open-label feasibility study of combined Human Leukocyte Antigen
(HLA)-matched sibling hematopoietic stem cell and kidney transplantation. The study will be
performed at the University Hospital of Zurich. The pilot study will include 5 to 8 donors
and 5 to 8 recipients. We expect that 4 out of 5 recipients should be off immunosuppressive
therapy at 6-12 months.
- Non-study-specific interventions before transplantation Donor and recipients will be
screened according to the established internal guidelines for living donor kidney and
hematopoietic stem cell transplantation of the Transplantation Center of the University
- Study-specific interventions before transplantation
- Potential candidates will be informed about this study by the treating physician.
Interested patients will be informed in details about the study protocol, the
potential benefits and risks. The patient will have sufficient time to decide to
participate to this study or to undergo standard transplantation, to read and sing
the informed consent form.
- Total lymphoid irradiation: for the optimal planning of the total lymphoid
irradiation, a mapping CT will be performed 2-4 weeks before therapy and repeated
on day 1 after kidney transplantation.
- Blood draw for establishment of chimerism determination.
- The recipient will undergo one leukapheresis procedure before starting the
conditioning regimen in order to bank cells for future scientific studies.
- Stem cell mobilization and isolation in the donor by leukapheresis will be
performed according to the standard protocols of the Stem cell transplantation
center of the University Hospital Zurich
- Donor-derived hematopoietic progenitor cells will be isolated from peripheral
leukocytes by positive selection (CD34+ cells) using the Magnetic-Activated Cell
Sorting (MACS) technology according to SOPs of the certified hematology laboratory
of the University Children's Hospital Zurich. CD34 negative cells will be analyzed
by Fluorescence-Activated Cell Sorting (FACS) to determine the amount of CD3
positive cells. Stem cells and flow through will be frozen until the transplant
according to standard operating procedure (SOP) at the stem cell transplantation
center at the University Hospital Zurich.
- Since irradiation might reduce fertility the possibility of sperm conservation
before transplantation will be offered to male recipients.
- Induction protocol
- Kidney transplantation (day 0)
- A CT scan will be performed at day 1 after transplantation for a correct definitive
plan of the irradiation protocol.
- Immunosuppression: in the first weeks after kidney transplantation the recipients
will be treated with standard immunosuppression, including methylprednisolone,
prednisone, mycophenolate mofetil and cyclosporine A.
- Additionally the patient will be treated with:
Rabbit anti-thymocyte globulin (ATG): Thymoglobuline® 1.5 mg per kg; 5 daily injections
from day 0 to day 4.
Total lymphoid irradiation: 10 doses of 120 centigray (cGy) (total dose 12 Gy) each to
the supradiaphragmatic lymph nodes, thymus, subdiaphragmatic lymph nodes and spleen; 10
daily doses from day 1 to day 11.
• Hematopoietic stem cell transplantation (day 11 after kidney transplantation):
Infusion of isolated CD34+ hematopoietic progenitor cells (≥10x10^6 cells/kg)
Additionally the patients will receive 1x10^6 CD3+ T cells / kg body weight from the
CD34- fraction to promote the engraftment of hematopoietic progenitor cells (T cell
4. Immunosuppression and anti-microbial prophylaxis
- Methylprednisolone: steroids will be rapidly tapered during the first days after
transplantation. All patients will be off of steroids at day 14.
- Mycophenolate mofetil: 2 g per day, started at day 11 (4 to 6 hours after stem cell
transplantation) and discontinued 1 month after stem cell transplantation.
- Cyclosporine A:
First 3 months: whole blood through level (C0) 250-300 µg/ml
Month 3-6: cyclosporine will be tapered and discontinued at about 6 months if following
criteria will be fulfilled:
- Sustained chimerism for at least 180 days
- No clinical signs of rejection
- Protocol biopsy showing no evidence of acute or chronic rejection
- No clinical signs of graft versus host disease
- Anti-microbial prophylaxis:
Amoxicillin/clavulanic acid 2.2 g preoperatively Sulfamethoxazole/Trimethoprim for 6 months
Valganciclovir: a) low risk (D-R-) - no prophylaxis; b) intermediate risk (R+) - prophylaxis
with valganciclovir 450mg once daily, starting after 1 month post transplant; c) high risk
(D+R-) - prophylaxis with valganciclovir 450mg once daily, starting immediately after
5 Post-operative monitoring
- Donor and recipient will be followed life-long in the outpatient clinic of the
nephrology division according to local practice. During immunosuppression tapering and
in the first months off of immunosuppression renal function will be closely monitored
for an early detection of rejection episodes. Therefore, to participate to the study the
patient has to agree with a weekly creatinine testing, which might also be performed by
the patient's family doctor.
- Graft versus host disease will be monitored clinically at each regular visit as well as
by measurement of liver function tests.
- The donor will be included in the control program of stem cells donors and living kidney
donors as for regular transplant procedures (national registries for living kidney and
stem cell donors)
- Chimerism level in peripheral blood will be regularly assessed
- Kidney allograft biopsies will be performed 6 months (before withdrawing of cyclosporine
- and 1 year after transplantation
- Immune reconstitution will be analyzed by FACS of peripheral blood leukocytes and
additional functional assays in vitro.
- Functional immunological tolerance will be measured in in vitro assays after 1, 2, 6,
12, 18 and 24 months. These additional tests are of scientific interest, but will not
influence clinical patient management.
- Quality of life will be assessed as routinely performed in the context of the Swiss
transplant cohort study (www.stcs.ch)
- Regular monitoring for cancer development as done after conventional transplantation
(skin cancer, breast cancer, prostate cancer).
Duration of subject participation and follow-up The active portion of this trial will begin
approximately 2 months prior to the transplantation and continue until 2 years
post-transplant. Study-related data will be collected for a minimum of 2 years
post-transplant. All subjects will be followed indefinitely for graft and patient survival in
routine clinical follow-ups.