Induction Therapy With Antithymocyte Globulin and Delayed Calcineurin Inhibitor Initiation for Renal Protection in Liver Transplantation: A Multicenter Randomized Controlled Phase II-B Trial
Calcineurin inhibitor (CNI)-based immunosuppression in liver transplantation (LTx) is associated with acute and chronic deterioration of kidney function. Delaying CNI initiation by using induction rabbit antithymocyte globulin (rATG) may provide kidneys with adequate time to recover from a perioperative insult reducing the risk of early post-LTx renal deterioration.
METHODS:This was an open-label, multicenter, randomized controlled clinical trial comparing use of induction rATG with delayed CNI initiation (d 10) against upfront CNI commencement (standard of care [SOC]) in those patients deemed at standard risk of postoperative renal dysfunction following LTx. The primary endpoint was change in (delta) creatinine from baseline to month 12.
RESULTS:Fifty-five patients were enrolled in each study arm. Mean tacrolimus levels remained comparable in both groups from day 10 throughout the study period. A significant difference in delta creatinine was observed between rATG and SOC groups at 9 mo (P = 0.03) but not at month 12 (P = 0.05). Estimated glomerular filtration rate levels remained comparable between cohorts at all time points. Rates of biopsy-proven acute rejection at 1 y were similar between groups (16.3 versus 12.7%, P = 0.58). rATG showed no significant adverse effects. Survival at 12 mo was comparable between groups (P = 0.48).
CONCLUSIONS:Although the use of induction rATG and concurrent CNI deferral in this study did not demonstrate a significant difference in delta creatinine at 1 y, these results indicate a potential role for rATG in preserving early kidney function, especially when considered with CNI deferral beyond 10 d or lower target tacrolimus levels, with acceptable safety and treatment efficacy.
CET Conclusion
| Reviewer: | Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford |
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| Conclusion: | This well-designed multicentre study investigated the use of ATG as a CNI-sparing agent immediately post liver transplant. Recipients were randomised to ATG induction with delayed tacrolimus initiation (to day 10) versus standard of care. The authors report that whilst there was a significantly lower rise in serum creatinine levels to month 9 post-op, this benefit was lost by month 12, and no significant difference in eGFR was seen at any timepoint. Despite a significant clinical benefit, use of ATG appeared safe, and rejection rates were similar between arms. In terms of study design, blinding would clearly have been desirable although not essential given the objective nature of the primary endpoint. Choice of serum creatinine as a primary endpoint, rather than eGFR, is suboptimal and the authors recognize this in their discussion. If you look closely at the figures, GFR loss over 12 months was 14 ml/min in the ATG group, and 20ml/min in the standard of care group. If replicated in a larger sample, and particularly if maintained over longer follow-up, this could be of clinical significance. |
Methodological quality
| Jadad score | 3 |
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| Allocation concealment | YES |
| Data analysis | PER PROTOCOL |
Metadata
| Funding: | Industry funding |
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| Publication type: | Multicenter Study, Randomized Controlled Trial, Randomised Controlled Trial |
| Trial registration: | ClinicalTrials.gov - NCT02544113 |
| Organ: | Liver |
| Language: | English |
| Author email: | eghtesb@ccf.org |
| MeSH terms: | Antilymphocyte Serum; Calcineurin Inhibitors; Creatinine; Graft Rejection; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney; Kidney Transplantation; Liver Transplantation; Tacrolimus; 0 (Antilymphocyte Serum); 0 (Calcineurin Inhibitors); 0 (Immunosuppressive Agents); AYI8EX34EU (Creatinine); WM0HAQ4WNM (Tacrolimus) |