First human double hand transplantation: efficacy of a conventional immunosuppressive protocol

Based on the results achieved in single human hand transplantations, we decided to perform the first double hand transplantation with a conventional immunosuppressive protocol in a patient with a high potential for functional recovery. Two years after transplantation the efficacy and the safety of this immunosuppressive protocol are evaluated. The recipient was a 33-yr-old man suffering from a traumatic amputation of both hands in 1996. Five HLA-A, -B, and -DR mismatches were present with the donor; T and B cell cross-match was negative. Immunosuppressive protocol included tacrolimus, prednisone, mycophenolate mofetil and, for induction, antithymocyte globulins and then anti CD25 monoclonal antibody. Reconstitution of lymphocyte populations proceeded normally. Neither anti-HLA antibodies nor chimerism in peripheral blood were detected. Two episodes of acute rejection characterized by maculopapular lesions occurred on days 53 and 82 after transplantation. Skin biopsies revealed a dermal lymphocytic infiltrate. Both episodes were completely and rapidly reversed by topical clobetasol and increased systemic corticosteroid therapy. The only side-effects related to treatment were reversible serum sickness and hyperglycemia. No infectious complications and malignancies occurred. No signs of graft-versus-host disease have been detected. This case of double hand transplantation shows that conventional immunosuppression is effective and safe to ensure survival and functional recovery of the grafted limb.     

Analysis of a single-center experience with mycophenolate mofetil based immunosuppression in renal transplantation

Purpose. Acute rejection continues to be a major clinical issue in renal transplantation. Three large multicenter trials have demonstrated a 50% decline in biopsy‐proven rejection when mycophenolate mofetil (MMF) was given to renal transplant recipients with corticosteroids and cyclosporine. The purpose of this study was to compare the 6‐month outcome of renal transplant recipients using MMF and non‐MMF based immunosuppression protocols over a 4‐year period at a single center.
Methods. This retrospective study analyzed three patient groups defined by their immunosuppression protocol. The first group included patients who received a quadruple immunosuppression regimen of antilymphocyte induction (ATG), cyclosporine (CYA), azathioprine (AZA), and corticosteroids (CCS), and were transplanted between October 1993 and May 1995 (AZA group). The second group included patients who received a triple immunosuppression regimen of CYA, MMF, and CCS, and were transplanted between June 1995 and May 1996 (MMF group). The third group included patients who were transplanted between January 1997 and December 1997, and received an immunosuppression regimen of CYA and MMF with a reduced CCS dosing schema (reduced steroid group (RST)). Data were collected from a retrospective review of inpatient and outpatient clinical records.
Results. A total of 325 patients were included in the study (106 AZA, 106 MMF, 113 RST). The demographic characteristics of the three groups were similar; however, the mean donor age for the AZA group was 40±15.1 years versus 33±14.1 years and 34±13.1 years for the MMF and RST groups, respectively (p<0.043). The incidence of acute, biopsy‐proven rejection at 6 months was significantly less in the MMF group when compared with the AZA group [16 (15.1%) versus 35 (33%) patients, p=0.002]. However, the incidence of acute, biopsy‐proven rejection in the RST group (35 patients, 31%) was similar to that of the AZA group. Kaplan–Meier estimates for the cumulative incidence of acute rejection demonstrated a significant difference between the MMF group and the other two groups (p=0.0059). The AZA group had more severe rejection as demonstrated by the more frequent use of antilymphocyte therapy for rejection treatment (68.4% episodes) compared with the MMF (38.9%) and RST (47.6%) groups. After 6 months of follow‐up, 11 patients had lost their grafts (8, AZA; 1, MMF; 2, RST). One patient died in each of the AZA and RST groups due to hemorrhage and a pulmonary embolus, respectively. Four AZA patients were diagnosed with a malignancy (three post‐transplant lymphoproliferative disorder, one squamous skin cell carcinoma) compared with 2 MMF patients (prostate cancer, basal skin cell carcinoma) and no RST patients. Herpes zoster was the only infection that occurred more frequently in the MMF group (p=0.03). No other differences in infection rates were noted among the three groups. The initial length of hospital stay declined significantly over the 4‐year study period [11±4.3 d (AZA), 7.0±4.0 d (MMF), 6.2±3.3 d (RST), p<0.001]. Total number of hospital days for the first 6 months also followed a similar declining pattern. Despite using intravenous cyclosporine immediately post‐transplant in the MMF and RST groups, the incidence of delayed graft function was similar among the three groups. Average serum creatinine at 1 month was significantly lower in the MMF group (p=0.008), but no difference was noted at 3 and 6 months when compared with the AZA and RST groups.
Conclusion. This retrospective analysis indicates that MMF is an effective immunosuppressant. Decreased length of stay and less steroid resistant rejections with MMF is favorable for decreased hospital costs. However, the rebound in rejection rate with the RST group suggests that further study is needed to define the optimal use of this agent in combination with others to maximize effectiveness and minimize negative side effects.     

Combination therapy with tacrolimus and mycophenolate mofetil: effects of early and late minimization of mycophenolate mofetil after renal transplant

The objectives of the study were: (i) to compare the efficacy and safety of minimizing mycophenolate mofetil (MMF) early (30 d) or late (90 d) after renal transplantation, when used in combination with tacrolimus; (ii) to retrospectively investigate factors associated with early, acute rejections and (iii) to investigate the pharmacokinetic interaction between tacrolimus and diltiazem. A prospective, randomized, multicenter, open-label study was conducted in 124 de novo kidney transplant recipients. Efficacy and safety outcomes were assessed for 180 d after transplantation and subjects were followed-up for a mean duration of 5.1 yr. The efficacy and safety outcomes were comparable whether the dose of MMF was minimized early or late. The incidence of early, acute rejection episodes was higher for recipients who were younger, received a graft from an unrelated donor or failed to achieve adequate tacrolimus concentrations (trough > 10 ng/mL) in the first seven d after transplant. Concomitant use of diltiazem had a tacrolimus-sparing effect in some subjects. Based on these results, we support the achievement of a high target tacrolimus concentration within the first week after renal transplant and suggest that early minimization of MMF can be achieved when used in combination with tacrolimus.     

Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation

BACKGROUND: Corticosteroid-free maintenance immunosuppression after organ transplantation eliminates the well-known corticosteroid-related side effects and may help to improve long-term outcome. We investigated whether a corticosteroid-free tacrolimus (Tac)/mycophenolate mofetil (MMF) regimen, in combination with daclizumab (Dac) induction therapy, provides adequate immunosuppression after renal transplantation. METHODS: This 6-month, open-label, multicenter, parallel-group study involved 538 renal patients randomized (1:1) to a Dac/Tac/MMF regimen (n = 260) or a Tac/MMF/corticosteroids regimen (n = 278) as a control group. RESULTS: Of the patients who completed the study, 88.8% in the Dac/Tac/MMF group were free from corticosteroid therapy at month 6. The incidence of biopsy-proven acute rejection was 16.5% in both treatment groups; the incidence of biopsy-proven corticosteroid-resistant acute rejection was 4.3% and 5.0% with Tac/MMF/corticosteroids and Dac/Tac/MMF, respectively (P = NS for both comparisons). Renal function was also similar in both groups: median serum creatinine at month 6 was 125.0 micromol/L (Tac/MMF/corticosteroids) and 131.0 microml/L (Dac/Tac/MMF), P = 0.277. The overall safety profile was similar with both regimens. However, compared with the Tac/MMF/steroid regimen, a significantly reduced incidence of new-onset insulin-dependent diabetes mellitus (5.4% vs. 0.4%, P = 0.003) was found with steroid-free immunosuppression. Moreover, mean total cholesterol concentrations increased from baseline in the Tac/MMF/corticosteroids group by 0.19 mmol/L, whereas in the Dac/Tac/MMF group, levels decreased by 0.19 mmol/L, P = 0.005. CONCLUSIONS: Corticosteroid-free immunosuppression with a Dac/Tac/MMF regimen is as effective at preventing acute rejection after renal transplantation as a standard triple regimen of Tac/MMF/corticosteroids. Furthermore, the safety benefits reported with Dac/Tac/MMF treatment may help improve the long-term outcome for renal-transplant patients.     

Allogenic grafting of vascularized bone segments under immunosuppression. Clinical results in the transplantation of femoral diaphyses

Trauma surgery lack, substitute, for the reconstruction of large defects of the long bones. Encouraged by the promising results of bone allotransplantation in animal models, we successfully performed vascularized bone transplantation in humans. Vascularized femoral diaphyses were allogenically transplanted into three patients suffering from chondrosarcoma or post-traumatic osteomyelitis with postoperative immunosuppression. The bone segments were harvested from multi-organ donors and perfused with UW solution. After back-table preparation, the grafts were transplanted into the defect zone. Interlocking devices were used in these operations. Vascular anastomoses were performed in end-to-side technique. The early clinical course of the patients was not free of anatomical, technical, or immunological complications. However, all patients are currently free of malignancy and infection. They are also free of pain and full weight bearing. We conclude that allogenic grafting of vascularized bone segments has the potential to become an alternative for the replacement of large bone defects. Received: 21 July 1997 Received after revision: 17 December 1997 Accepted: 9 January 1998     

The psychological assessment of candidates for reconstructive hand transplantation

Standardized psychological assessment of candidates for reconstructive hand transplantation (RHT) is a new approach in transplantation medicine. Currently, international guidelines and standardized criteria for the evaluation are not established. Patients suffering from the loss of a hand or an upper extremity have to cope with multiple challenges. For a selected group of patients, RHT represents an option for restoring natural function and for regaining daily living independence. The identification of at-risk patients and those requiring ongoing counseling due to poor coping or limited psychological resources are the primary focus of the psychological assessment. We have developed the 'Innsbruck Psychological Screening Program for Reconstructive Transplantation (iRT-PSP)' which utilizes a semi-structured interview and standardized psychological screening procedures and continuous follow-up ratings. Between January 2011 and October 2011, four candidates were evaluated using the iRT-PSP. Psychological impairments including social withdrawal, embarrassment, reduced self-esteem, and a depressive coping style were identified and poor quality of life was reported. The motivation for transplantation was diverse, depending on many factors such as bi- or unilateral impairment, native or accidental loss of hand, and social integration.     

Excellent outcome of ABO-incompatible living kidney transplantation under pretransplantation immunosuppression with tacrolimus, mycophenolate mofetil, and steroid

INTRODUCTION: ABO-incompatible living kidney transplantation (LKT) has been performed to widen the indications for kidney transplantation. Since 2001, using a 7-day period of pretransplantation immunosuppression with tacrolimus (FK) plus mycophenolate mofetil (MMF) plus methylprednisolone (MP), we have observed a marked reduction in acute humoral/vascular rejection without any serious complications. PATIENTS AND METHODS: Forty-five adult patients underwent ABO-incompatible LKT at our institute between January 2000 and September 2002. There were 20 men and 25 women of mean age 33 years. Plasmapheresis was performed to remove anti-AB antibodies prior to kidney transplantation. In 2000, 13 patients were treated with FK plus MMF plus MP without 7-day pretransplantation immunosuppression (group 1). Since January 2001, we have administered FK (0.1 mg/kg/d) plus MMF (1-2 g/d) plus MP (125 mg/d) concomitantly with plasmapheresis starting from 7 days before transplantation in 32 patients (group 2). Splenectomy was performed at the time of kidney transplantation in all patients. RESULTS: Patient survival rate was 100% in both treatment groups. Graft survival rate was 92% and 97% in groups 1 and 2, respectively. One patient in group 1 lost the graft due to severe pancreatitis and 1 patient in group 2, due to severe humoral rejection. The incidence of acute rejection was 56% and 19% in group 1 and group 2, respectively. No patient experienced any lethal infectious complication. CONCLUSION: Pretransplantation immunosuppression for 7 days using FK, MMF, and MP in ABO-incompatible LKT provides an excellent outcome without severe infectious complications.     

Kidney transplantation during the first trimester of pregnancy: immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone

We present a case of living, related-donor kidney transplantation during the first trimester of pregnancy. The patient received mycophenolate mofetil (MMF), tacrolimus, and prednisone throughout the entire pregnancy. This is the first reported case of use of MMF during pregnancy. The mother did well, except for mild preeclampsia and mild renal insufficiency at term. The baby girl was born prematurely at week 353/7. The only possible teratogenic effects detected included hypoplastic nails and short fifth fingers. No chromosomal abnormalities were found. The child is growing and developing normally. Although we do not recommend the use of mycophenolate mofetil during pregnancy based on this experience, it is reassuring to know that a successful outcome can be expected in mothers treated with MMF during pregnancy.     

Five-year results of renal transplantation on immunosuppressive triple therapy with mycophenolate mofetil

Mycophenolate mofetil (MMF) combined with cyclosporine and prednisolone significantly lowers acute rejection frequency in the early post-renal transplantation phase. To date only registry data with very high transplant numbers have shown that MMF significantly influences long-term outcome. A comparative retrospective analysis of the 5-yr results with MMF in a single transplant center was thus undertaken vs. other standard immunosuppressive regimens. The results of 1579 renal transplantations were grouped by treatment modality, subjected to Kaplan-Meier analysis, and compared using the log rank test. Both the total population and subgroups showed a non-significant trend towards better graft survival with MMF, evident at 2 yr and persisting for 5 yr. Extrapolation indicates that on combination therapy with MMF vs. azathioprine, approximately 10% more patients will be alive at 10 yr with a functional graft.     

Tacrolimus and mycophenolate mofetil as first line immunosuppression after lung transplantation

The optimal maintenance therapy after lung transplantation remains to be established. The aim of this study was to analyse the impact of tacrolimus and mycophenolate mofetil (MMF) as first line immunosuppression on long-term survival and Bronchiolitis Obliterans Syndrome (BOS). From January 1996 through December 2006, all 155 recipients receiving tacrolimus and MMF as maintenance immunosuppression were included in this study. Tacrolimus and MMF was discontinued in 36 patients (23.2%). The overall survival rates were 91.6% at 6 months, 86.4% at 1 year, 74.9% at 3 years, 60.3% at 5 years and 32.4% at 10 years. The overall freedom from acute rejection was 74.6%, 63.2% and 59.4% at 1, 3, and 5 years respectively. The overall BOS-free survival was 95.6% at 1 year, 88.4% at 3 years, 69.5% at 5 years and 30.5% at 10 years. The development of BOS ≥ 1 was associated with a significantly increased risk of death and reduced long-term survival. The combination of tacrolimus and MMF offers safe and reliable maintenance immunosuppression after lung transplantation. However, substantial improvements of long-term survival and freedom from BOS might only be achieved by a change in organ allocation policies and patient management beyond differential immunosuppressive protocols.     

The renal benefit of mycophenolate mofetil after liver transplantation

Haywood S, Abecassis M, Levitsky J. The renal benefit of mycophenolate mofetil after liver transplantation.
Clin Transplant 2011: 25: E88–E95. © 2010 John Wiley & Sons A/S. Abstract: Background: The risk and benefit of adding mycophenolate mofetil (MMF) to a standard immunosuppressive regimen at the time of liver transplantation (LT) is not well described. Methods: We performed a retrospective case–control analysis comparing one‐yr outcomes of all LT recipients at our institution treated with post‐operative tacrolimus (TAC), MMF, and steroids vs. TAC and steroids. Results: A total of 101 LT recipients (50:51 case:control) were analyzed. Despite more renal dysfunction at LT, the MMF + TAC group had similar serum creatinine (Cr) and glomerular filtration rate (GFR) as the TAC group one‐yr post‐LT. In this time period, Cr decreased (1.57–1.22 mg/dL, p = 0.04) and GFR increased (57.5–65.1 mL/min per 1.73 m², p = 0.05) in the MMF + TAC group, while Cr increased (1.11–1.35, p < 0.01) and GFR declined (73.5–60.1, p < 0.001) in the TAC group. These findings occurred without a difference in absolute rejection episodes, hospitalizations, infections, deaths, or time to above events (p > 0.05). Subgroup analysis of patients stratified by pre‐transplant renal dysfunction (Cr ≥ 1.2 mg/dL) supported the previous. MMF was reasonably well tolerated with a low rate of discontinuation. Conclusions: The use of adjunctive MMF immediately after LT may protect against calcineurin inhibitor nephrotoxicity, potentially without the need for dose reduction or increased risk of adverse events.     

Heart transplantation under cyclosporine or tacrolimus combined with mycophenolate mofetil or everolimus

Objective

In this study, we examined whether cyclosporine was effective when combined with everolimus in clinical heart transplantation (HT).

Patients and Methods

From August 2004 to July 2007, 108 adult patients underwent primary HT. The main exclusion criteria were: donors >60 years; cold ischemia times >6 hours; recipients of multiorgan transplantation or a previous transplantation; and panel-reactive antibodies ≥25%. The cyclosporine plus everolimus regimen (group CE, n = 32) was suggested first; upon refusal or if the recipient or donor was positive for hepatitis B surface antigen or PCR + hepatitis C infection, then patient was randomly assigned to success cyclosporine plus mycophenolate mofetil (MMF; group CM, n = 24) or tacrolimus plus MMF (group TM, n = 25). All patients underwent similar operative procedures and postoperative care with protocol endomyocardial biopsies.

Results

No 30-day mortality was noted in any group. The efficacy failure rates were 3%, 25%, and 16% in groups CE, CM, and TM, respectively (P = .04 between groups CE and CM). The 1-year survivals were 96.7% ± 18.1%, 89.7% ± 29.8%, and 81.0% ± 35.5% for groups CE, CM, and TM, respectively (P = .04 between groups CE and TM). The 3-year survival rates were 91.9% ± 28.3%, 79.8% ± 46.0%, and 81.0% ± 35.5% in groups CE, CM, and TM, respectively.

Conclusions

The 3 immunosuppressive regimens offered good efficacy after HT. The cyclosporine plus everolimus regimen showed a significantly better result with less efficacy failure (compared with cyclosporine plus MMF: 3% vs 25%) and better 1-year survival compared with tacrolimus plus MMF: 96.7% vs 81.0%.     

Use of low dose tacrolimus, mycophenolate mofetil and maintenance IL-2 receptor blockade in an islet transplant recipient

Abstract:  The utilization of dual maintenance therapy with tacrolimus and sirolimus (the Edmonton protocol) has been widely adopted as standard immunosuppression for islet cell transplantation. This immunosuppression regimen has numerous toxicities including renal dysfunction, anemia, and recurrent aphthous ulcers. We present a case of a 63-yr-old Caucasian female who received an isolated islet transplant. Over the first six months post-transplant, the patient developed severe anemia, intractable aphthous ulcers, and renal dysfunction. Islet transplant function was excellent and the patient is insulin-independent since the end of the second month post-transplant. However, because of the above toxicities, a decision was made to change her immunosuppression regimen eight months post-transplant to low dose tacrolimus, mycophenolate mofetil, and a monthly maintenance infusion of daclizumab. Since then, her aphthous ulcers have disappeared, renal function has improved, and islet cell function remains stable.     

Long-term viability of articular cartilage after microsurgical whole-joint transplantation and immunosuppression with rapamycin, mycophenolate mofetil, and tacrolimus

The survival or rejection of articular cartilage in heterotopic vascularized joint transplants in rats immunosuppressed with rapamycin (SDZ RAD), mycophenolate mofetil (MMF), and tacrolimus was evaluated histologically up to 1 year after surgery. The vascularized knee joint of an ACI donor rat was transplanted to the groin of a Lewis recipient rat. Nonimmunosuppressed allografts were evaluated after 6 weeks and 3 months, and immunosuppressed allografts and control isografts were evaluated after 6 weeks, 3 months, 6 months, and 1 year. No rejection was seen in the control isografts. All allografts without immunosuppression were rejected at 6 weeks and 3 months. Eighteen of 21 knee joint transplants immunosuppressed with SDZ RAD and 17 of 22 knee joint transplants immunosuppressed with MMF were rejected between 6 weeks and 1 year. SDZ RAD and MMF caused significant side effects including compromised wound healing and bone marrow suppression culminating in weight loss and death. Eighteen of 19 knee joints immunosuppressed with tacrolimus showed no signs of rejection up to 1 year after surgery. Long-term intermittent immunosuppression with tacrolimus was significantly superior to SDZ RAD and MMF in preventing rejection of the transplanted articular cartilage of a vascularized knee joint allograft up to 1 year after surgery.     

Daclizumab induction and maintenance steroid-free immunosuppression with mycophenolate mofetil and tacrolimus to prevent acute rejection of hepatic allografts

Steroid-free immunosuppressive regimens reduce corticosteroid-related side effects in liver transplant recipients although their efficacy is very variable. We evaluated the efficacy and safety of a steroid-free regimen in a 6-month, open-label, multicenter, pilot study, which involved 102 liver transplant patients treated with daclizumab (2 mg/kg within 6 h following transplant and 1 mg/kg on day 7), mycophenolate mofetil (MMF, 1 g b.i.d) and tacrolimus (trough levels of 5-15 ng/ml in the first month and 5-10 ng/ml thereafter). One intra-operative dose of methylprednisolone was administered. At 6 months, the acute rejection rate was 9.8%, and patient and graft survival rates were 96% and 95%, respectively. Acute rejection rates were similar for hepatitis C-positive patients (8.6%) and hepatitis C-negative patients (10.4%). Infections occurred in 22% of patients; most cases were considered mild or moderate. Post-transplantation hypertension and diabetes mellitus developed in 37% and 14% of patients, respectively, during the study period, but were markedly less frequent (8% and 6%, respectively) at 6 months. Hypercholesterolemia was observed in only 2% of patients. In conclusion, the steroid-free immunosuppressive regimen of daclizumab, MMF, and tacrolimus effectively prevents acute rejection after liver transplantation without decreasing safety.