Randomised controlled trialindependent cross-checkabstract checked★ key study I-SRC-102 in-depth review
Stopping tacrolimus after kidney transplant caused rejection
Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients.
Overview
Hricik DE et al.. J Am Soc Nephrol 2015 · PMID 25925687 · DOI 10.1681/ASN.2014121234
In a trial of carefully selected low-risk patients, stopping tacrolimus led to rejection in 4 of 14 and new antibodies in 5 of 14; the trial was stopped.
Does the study support the specific claim? No · Methodological quality: moderate
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Test whether low-risk kidney recipients can stop tacrolimus
- How was the study done?
Randomised trial
- How many people, animals or samples were studied?
Living-donor recipients; 14 in the withdrawal arm
- What was actually found?
High rates of rejection and donor-specific antibodies
- How large was the observed effect?
4/14 rejection; 5/14 new antibodies
- What do the results mean in everyday life?
Even stopping one anti-rejection drug can damage the kidney
- What are the study's limitations?
Small; stopped early
- What does it say about Elawady's specific claim?
Contradicts stopping all immunosuppression
- Do the results apply to Germany and Europe?
High
- What can explicitly not be concluded from this study?
Long-term graft loss rates (trial stopped)
Scientific in-depth review
1. Full reference
- Authors
- Hricik DE et al.
- Journal
- J Am Soc Nephrol
- Year
- 2015
- Identifier
- PMID 25925687 DOI 10.1681/ASN.2014121234
- Verification
- verified – PubMed efetch 2026-10-26; Crossref works record checked
- Retracted
- no
- Corrections
- none
- Extent checked
- abstract only
- Conflicts of interest and funding
Funded by NIAID/NIH (grants listed in PubMed record); no COI statement in record.
2. Research question
Can tacrolimus be withdrawn safely in immunologically quiescent living-donor kidney recipients?
3. Study design and population
- Study design
- Randomised controlled trial – Randomised prospective multicentre trial (CTOT-09), stopped early
- Population
Non-sensitised first living-donor kidney recipients without de novo DSA, rejection or inflammation on 6-month protocol biopsy
- Country
USA
- Period
Published 2015
- Sample size
14 in the tacrolimus-withdrawal arm (randomised subset)
- Inclusion and exclusion criteria
Induction with antithymocyte globulin; tacrolimus, MMF and prednisone; quiescent at 6 months
4. Methods and endpoints
- Exposure / intervention
Weaning off tacrolimus (MMF and prednisone continued)
- Comparator
Remaining on tacrolimus
- Endpoints
Intended: change in fibrosis score at 24 months; observed: acute rejection, de novo DSA
- Statistical methods
Descriptive (trial terminated)
5. Actual results
- Results
Trial terminated prematurely because of unacceptable rates of acute rejection (4 of 14) and/or de novo donor-specific antibodies (5 of 14) in the tacrolimus-withdrawal arm.
- Absolute risks
4/14 (28.6%) acute rejection and 5/14 (35.7%) de novo DSA in the withdrawal arm (recalculated with Wilson CIs in stats/C-SRC-46_transplant.py).
- Authors' conclusion
Complete calcineurin-inhibitor withdrawal must be strongly discouraged in kidney-transplant recipients on standard immunosuppression, even in those judged immunologically quiescent.
6. Strengths
- Randomised design
- Carefully selected lowest-risk patients
- Protocol biopsies and antibody monitoring
7. Weaknesses
- Very small number in withdrawal arm (14)
- Stopped early; primary endpoint not assessed
- Only one drug withdrawn, others continued
8. Risk of bias
- Orienting tool
- RoB 2
- Type of assessment
- simplified assessment (abstract only)
- Full formal assessment
- no
- Overall risk of bias
- some concerns
- Rationale
Open-label, early termination; harm signal is large relative to expectation in a lowest-risk group.
9. Assessment of the statistical interpretation
Wilson 95% CI for rejection 11.7%-54.6%: imprecise, but even the lower bound is a substantial rate for patients selected as lowest risk.
10. Relevance to the specific claim
Directly contradicts the idea that stopping the main anti-rejection drug years after transplant is harmless: even in the safest-looking patients, stopping one drug caused rejection and antibody formation.
11. Independent contrary findings
Rare spontaneously tolerant patients exist (I-SRC-118), but they cannot be identified in advance by routine tests.
12. Transferability to Germany and Europe
Directly applicable.
13. Overall methodological judgement
Small but direct randomised evidence of harm from withdrawing a key immunosuppressant.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | moderate |
| Risk of bias | some concerns |
| Precision of results | low |
| Directness | direct |
| Reproducibility | partly replicated |
| Consistency with the overall evidence | consistent |
| Regional transferability | high |
| Adequacy of the interpretation (by the archive) | not applicable |
14. Open questions
Whether biomarkers (urinary CXCL9, epitope mismatch, ELISPOT) can identify patients who tolerate withdrawal.