Clinical-experimental experience with rapamycin in visceral transplantation
Javier Serradilla1, Rodrigo Papa-Gobbi2, Ane Miren Andrés1, Alba Bueno1, Monserrat Arreola2, Alida Alcolea3, Esther Ramos3, Paloma Talayero4, Mariana Machuca5, Pablo Stringa6, Martin Rumbo6, Francisco Hernández7.
1Pediatric Surgery, Hospital Universitario La Paz, Madrid, Spain; 2Fundación Para La Investigación Biomédica, IdiPAZ - Hospital Universitario La Paz, Madrid, Spain; 3Intestinal Transplantation and Rehabilitation Unit, Hospital Universitario La Paz, Madrid, Spain; 4Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain; 5Laboratorio de Patología Especial, Facultad de Ciencias Veterinarias-UNLP, La Plata, Argentina; 6Instituto de Estudios Inmunológicos y Fisiopatológicos, Facultad de Ciencias Exactas, UNLP-CONICET, La Plata, Argentina; 7EOC of ERN-Transplantchild, IdiPAZ - Hospital Universitario La Paz, Madrid, Spain
Aim: Rapamycin (RAP) has recently demonstrated clear long term benefits in visceral transplantation (VT). However, its use is limited to patients suffering FK side effects and there are no guidelines supporting the timing for a safe and effective switch. Our aim was to review our clinical and experimental experience in the use of RAP after VT.
Materials and Methods: Our series of 107 VT was reviewed. Only patients who survived more than 3 months were included (n=82). They were divided in three groups according to the maintenance immunosuppressive treatment: FK (n=50), switched to RAP (n=24) and combined therapy (RAP+FK; n=8). Patients converted to RAP were divided in two subgroups: early RAP (<6 months after VT, n=12) and late RAP (>6 months after VT, n=20). Causes and timing to introduce RAP, rejection rate and survival were analyzed.
We used an allogeneic VT rat model to analyzed RAP efficacy. Animals received no IS (controls), FK (0,6mg/kg/24hs) or different doses of RAP (1mg and 2mg kg/24h) (n=5 animals/group). Rejection was monitored by clinical scoring and histopathology after 14 days.
Results: RAP was prescribed 10 months (0-99) after VT. Renal failure was the main cause of switching to RAP (28%), followed by hematological syndromes (25%). Rejection rate tended to be lower in patients with RAP, although the differences were not significant (FK 32%, RAP 25%, RAP+FK 37%; p=0.74). Graft survival at 1 and 5 years was significantly higher with RAP [FK 78%/48%, RAP 96%/83%, RAP+FK 86%/63% (p=0.013)]. Patient survival at 1 and 5 years was higher although not significantly in RAP group [FK 82%/64%, RAP 96%/83%, RAP+FK 86%/75% (p=0.27)].
No significant differences were found between early vs late RAP regarding rejection rate (33% vs 25%, p=0.61) graft survival at 1 and 5 years (83%/67% vs 100%/85%, p=0.15) and patient survival at 1 and 5 years (83%/75% vs 100%/85%, p=0.13).
In the experimental model, RAP monotherapy did not show any improvement in survival (control: 9,75 ± 0.25 days; RAP: 11 ± 1 days) or clinical and histological signs of rejection compared to the control group (they both presented moderate-severe histological inflammation at the time of sacrifice). Animals receiving FK treatment did not show clinical signs of rejection and the histological alterations were indeterminate-mild at the time of sacrifice (10-14 days after VT).
Conclusion: Patients switched to RAP had better survival compared to patients with standard immunosuppression. However, the improvement tended to be attenuated in those who were converted early. Experimental results showed that early RAP monotherapy at different doses had poorer results compared to FK groups. Further translational research is warranted to define the optimal timing and schedule for RAP usage.
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