Improvement in Renal Function After Late Conversion to Sirolimus-Based Immunosuppression in Composite Tissue Allotransplantation

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Renal dysfunction after composite tissue allograft transplantation is not common (1); however, it is identifiable in 36.6% of cardiac allograft recipients under calcineurin inhibitor (CNI) therapy (2). Sirolimus has been used as a substitute for CNI when CNI toxicity has occurred in recipients of kidney allografts during the maintenance phase of treatment. A randomized controlled trial demonstrated a statistically significant improvement in glomerular filtration rate (GFR) of 12.9 mL/min after conversion to sirolimus, in comparison with the deterioration in GFR in the kidney grafts of patients given regimens based on CNI (3). We carried out a retrospective analysis to evaluate the renal function of the recipients of bilateral hand allografts who were initially given immunosuppression treatment based on tacrolimus but were switched subsequently to sirolimus.Three patients received hand allografts that had been recovered from heart-beating brain-dead multiorgan donors who were matched on the basis of sex and blood group (4–7). The induction protocol consisted of alemtuzumab (30 mg administered before revascularization; Mabcampath; Bayer Schering Pharma, Berlin, Germany) and methylprednisolone (500 and 250 mg on the first and second postoperative days, respectively). Afterward, patients were given tacrolimus (initial trough level 15 ng/mL, tapered to 12 ng/mL after 3 months; Prograf; AstellasPharma, Berlin, Germany) and mycophenolate mofetil (2 g/day; CellCept; Roche, Basel, Switzerland). Tapering doses of prednisone were given in two cases, whereas an early steroid withdrawal protocol was followed in one case. All the patients required conversion to sirolimus (Rapamune; Wyeth, Madison, NJ), with the aim of maintaining trough levels at 15 ng/mL.The primary outcome measure was the change in serum creatinine (SCr) level and the GFR at 6 months after conversion, compared with those at the time of conversion. Because GFRs based on 24-hour urine sampling were not always available, it was estimated using the formula developed by the Chronic Kidney Disease Epidemiology Collaboration research group (8). Markov chain Monte Carlo sampling was used to obtain the highest posterior density 95% confidence intervals (CIs) of the fixed effect parameters and the associated P values (9).The first recipient was converted to sirolimus directly because of a suspected loss of visual acuity on postoperative day 190 (7). The two other patients presented with increased SCr level. After the switch, two recipients developed mouth ulcers, which resolved using nistatin wipes. The first patient developed a grade II acute rejection of the Banff classification (10) 25 days after conversion but responded promptly to methylprednisolone boluses (500 mg on 3 consecutive days). After 260 days, they developed a dermatitis-like lesion that was ascribed to sirolimus (11) and mimicked an episode of rejection, but it was resolved a few weeks after reduction of the sirolimus level to 9 ng/mL. The second patient developed, after conversion on postoperative day 668, a cutaneous erosion on the dorsum of the left forearm that showed a marked histologic parakeratosis compatible with a mixed fungal–bacterial infection. Cultures yielded no results, but the lesion responded to topical ketoconazole. The third patient presented with increased SCr level, severe anemia without other cytopenias, several hypertensive episodes that were resistant to two antihypertensive drugs, and headache. The regimen was changed over to sirolimus on postoperative day 336. Eight days after conversion, a grade I episode of rejection occurred. The blood pressure and SCr level decreased after conversion. At 68 days after conversion, given that the skin lesions did not respond to steroid boluses and therapy adjustment, a rescue treatment for rejection was prescribed.

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