The aim of this project is to enhance transplantation prospects of highly sensitized patients who are waiting for a long time for a suitable kidney graft. Despite their inclusion in the Acceptable Mismatch (AM) program (initiated in The Netherlands…
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Finding new Acceptable HLA mismatches and leading to an increased chance to get
an organ offer.
Secondary outcome
Secondary objectives are patient and graft survival, graft function as assessed
by calculated creatinine clearance, proteinuria, the number and severity of
acute (antibody mediated) rejections, blood pressure (antihypertensive
treatment), monitoring of infections and the occurrence of malignancies.
Background summary
The prospects for highly sensitized patients to receive a donor organ are grim.
This is due to policies that share the assumption that contact with foreign HLA
antigens causes priming of the immune system of the recipient. However, not
every confrontation with foreign HLA antigens will lead to sensitization or to
diminished graft survival. Studies have shown that not all patients
transplanted across a positive historical crossmatch reject their kidney
grafts. Furthermore, transplantation with donor kidneys harbouring HLA
mismatches that are shared by previous blood transfusions, pregnancies and/or
failed transplants is often successful. Today, serological crossmatching is a
routine procedure in clinical organ transplantation. In contrast, T cell
alloreactivity has never been used as parameter for organ allocation. In a
pilot study we have shown that the presence of a naive in vitro T cell
allorepertoire at the day of transplantation in patients with a historical
positive crossmatch is associated with good graft function. For this purpose we
designed a limiting dilution assay that distinguishes naive from primed donor
specific T lymphocytes.
Study objective
The aim of this project is to enhance transplantation prospects of highly
sensitized patients who are waiting for a long time for a suitable kidney
graft. Despite their inclusion in the Acceptable Mismatch (AM) program
(initiated in The Netherlands with support of the Dutch Kidney Foundation), it
is estimated that a mere 60 % of these highly sensitized patients benefit from
this program when studied in a two years period. We hypothesize that there is
room for improvement. We will focus on those patients that are highly
sensitized in historical sera only. In these patients we will analyze the
presence of primed or naïve (or both) CTL against frequently occurring HLA
antigens. HLA antigens for which only naïve CTLs are present will be classified
as AM in the program. This approach will lead to an extension of the potential
donor pool for highly immunized recipients and will enhance transplantation of
this group of difficult patients.
Study design
From the patients blood will be drawn in order to check the presence of
antibodies against the most frequent HLA antigens. Against those antigens
towards no antibodies are present analysis for the presence of primed or naïve
(or both) CTL will be carried out. After consultation with the nephrologist and
transplantation immunologist dealing with specific patient the newly found HLA
antigens will be added to the Acceptable Mismatches of this patient.
In case the patient has not been transplanted within 6 months after the first
blood sample the second blood sample has to be taken and analysed.
Intervention
Mainly the selection of suitable donors will change for a certain patient. The
medical procedure of the transplantation will not differ from that of other
renal transplant recipients besides the fact that the patients will receive a
mild induction therapy with ATG as described in Brennon et al. Treatment with
antithymocyte globulin was initiated intraoperatively, before graft
reperfusion. Subsequent doses were given daily through day 4, for a total dose
of 7.5 mg per kilogram.
Study burden and risks
Burden is minimal: blood will be drawn from a vene in the arm. The risk is to
experience a rejection of the graft which can be treated adequately in most
cases by the current rejection treatment therapies.
Albinusdreef 2
2333 ZA Leiden
Nederland
Albinusdreef 2
2333 ZA Leiden
Nederland
Listed location countries
Age
Inclusion criteria
Older than 18 years.
Patients with renal failure on the Eurotransplant kidney waiting list.
PRA in historical sera higher than 85%.
More than 1 year on the AM list.
A signed "informed consent" form.
Exclusion criteria
1) Patients with severe gastrointestinal disorders, that interfere with their ability to receive or absorb oral medication and patients with severe diarrhea.
2) Patients with active peptic ulcer disease.
3) Patients or their donors with serologic evidence of HIV, HCV or HBsAg in the past.
4) Patients with malignancies (current or history within last 5 years) except non metastatic basal or squamous cell carcinoma of the skin that has been treated successfully.
5) Patients with systemic infection requiring therapy at the time of entry in the study.
6) Patients with any form of substance abuse or psychiatric disorder which in the opinion of the investigator might invalidate patients communication with the clinician.
Design
Recruitment
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| CCMO | NL14100.058.07 |