Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine

BACKGROUND: Historically, the acute rejection rates in simultaneous pancreas-kidney (SPK) recipients have been extremely high (50-80%), with many second and third rejection episodes despite the use of quadruple immunosuppression (antibody induction and cyclosporine [CsA]-azathioprine [AZA]-based maintenance immunosuppression). Although this acute rejection has rarely led to graft loss, it has been a great cause of morbidity and of significantly increased cost. In an attempt to decrease the acute rejection rate and related morbidity in SPK transplant recipients, we compared two "state-of-the-art" immunosuppression regimens in a prospective, randomized, single-center study. METHODS: Patients who received SPK transplants were randomized to receive either tacrolimus (TAC) and mycophenolate mofetil (MMF, n=18) or CsA (Neoral formulation) and MMF (n=18). All patients received OKT3 induction and prednisone, which was tapered to 5 mg/day by 6 months after transplantation. All rejection episodes were biopsy proven. In addition, metabolic control (HgbA1C, hypertension, serum cholesterol), drug toxicity, and infection also were measured. Data were compared with that of a historical group (n=18) who received conventional CsA (Sandimmune formulation) and AZA-based immunosuppression. RESULTS: The incidence of biopsy-proven acute rejection was 11% in both the TAC-MMF and CsA-MMF groups with only two patients in each group experiencing a rejection episode. This rejection rate was significantly decreased from that of the CsA-AZA historical group (77%, P<0.01). There were no significant differences in infection rates, including cytomegalovirus, or in metabolic control (HgbA1C, hypertension, and cholesterol levels). All patients remained on their initial immunosuppression regimen for the first 3 months after transplantation. Between 3 and 6 months after transplantation, three patients were switched from TAC to CsA for recurrent migraine headaches, posttransplant diabetes, and chronic cytomegalovirus infection. Two patients in the CsA-MMF group died of nonimmunologic causes (aspiration pneumonia and arrhythmia) between 3 and 6 months after transplantation. CONCLUSIONS: The data from this study show that MMF treatment significantly decreases the incidence of biopsy-proven acute rejection in SPK transplant recipients compared with AZA-treated historical controls. In addition, we conclude that TAC and CsA (Neoral), when combined with MMF, yield similar, low acute rejection rates with similar graft function and metabolic control.     

Follicular fluid immunoreactive-inhibin concentrations in relation to follicular diameter and estradiol-17 beta, progesterone and testosterone concentrations in individual ovarian follicles in buffalo, Bubalus bubalis

BACKGROUND: Mycophenolate mofetil reduces episodes of biopsy-proven acute cellular rejection or treatment failure in the first year after kidney transplantation; however, limited data exist regarding the efficacy after lung transplantation. METHODS: In a 2-center, nonrandomized concurrent cohort study (level III evidence), we analyzed the incidence of biopsy-proven acute cellular rejection (International Society for Heart and Lung Transplantation grade > or=A2) and decrement in pulmonary function during the first 12 months after successful lung transplantation. All patients received induction immunosuppression with antithymocyte globulin (< or=5 days' duration), cyclosporine and prednisone, in addition to either mycophenolate mofetil (2.0 g/d) [n=11] or azathioprine (1 to 2 mg/kg per day) [n=11]. RESULTS: During the first 12 months after lung transplantation, the mycophenolate mofetil group experienced significantly fewer episodes of acute cellular rejection than the azathioprine group (0.26+/-0.34 vs 0.72+/-0.43 episodes/100 patient-days [mean+/-SD], p < 0.01; 95% CI for the difference=0.126 to 0.813). The change in forced expiratory volume -1 second [deltaFEV1] (liters) between the 3rd and 12th months after lung transplantation was analyzed for the two treatment groups. For this interval, deltaFEV1 for the mycophenolate mofetil group was +0.158+/-0.497 L vs -0.281+/-0.406 L for the azathioprine group (p < 0.05; 95% CI for difference=+0.0356 to 0.843). During the first year, there was 1 death in each group attributed to bronchiolitis obliterans syndrome with concurrent pneumonia. There were no differences in incidence of cytomegalovirus or bacterial infections between the treatment groups; however, a higher prevalence of aspergillus sp airway colonization in bronchoalveolar lavage fluid was observed for the mycophenolate mofetil group (p < .05). The prevalence of bronchiolitis obliterans syndrome at 12 months was 36% for the azathioprine group vs 18% for the mycophenolate mofetil group (p=NS). CONCLUSIONS: Our preliminary experience with mycophenolate mofetil after lung transplantation suggests a decreased incidence of biopsy-proven acute cellular rejection. Furthermore, less decline in FEV1 after 12 months may suggest a reduced incidence or delayed onset for development of bronchiolitis obliterans syndrome. Prospective randomized trials with low beta error (level I evidence) should be performed to assess the efficacy of mycophenolate mofetil vis-à-vis acute allograft rejection and bronchiolitis obliterans syndrome.     

A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group

BACKGROUND: Tacrolimus (FK506), a macrolide molecule that potently inhibits the expression of interleukin 2 by T lymphocytes, represents a potential major advance in the management of rejection following solid-organ transplantation. This randomized, open-label study compared the efficacy and safety of tacrolimus-based versus cyclosporine-based immunosuppression in patients receiving cadaveric kidney transplants. METHODS: A total of 412 patients were randomized to tacrolimus (n=205) or cyclosporine (n=207) after cadaveric renal transplantation and were followed for 1 year for patient and graft survival and the incidence of acute rejection. RESULTS: One-year patient survival rates were 95.6% for tacrolimus and 96.6% for cyclosporine (P=0.576). Corresponding 1-year graft survival rates were 91.2% and 87.9% (P=0.289). There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the tacrolimus group (30.7%) compared with the cyclosporine group (46.4%, P=0.001), which was confirmed by blinded review, and in the use of antilymphocyte therapy for rejection (10.7% and 25.1%, respectively; P<0.001). Impaired renal function, gastrointestinal disorders, and neurological complications were commonly reported in both treatment groups, but tremor and paresthesia were more frequent in the tacrolimus group. The incidence of posttransplant diabetes mellitus was 19.9% in the tacrolimus group and 4.0% in the cyclosporine group (P<0.001), and was reversible in some patients. CONCLUSIONS: Tacrolimus is more effective than cyclosporine in preventing acute rejection in cadaveric renal allograft recipients, and significantly reduces the use of antilymphocyte antibody preparations. Tacrolimus was associated with a higher incidence of neurologic events, which were rarely treatment limiting, and with posttransplant diabetes mellitus, which was reversible in some patients.     

Withdrawal of immunosuppression: implications for composite tissue allograft transplantation

Complete or partial withdrawal of immunosuppression is a desirable goal for physicians managing solid organ transplant recipients and has particular appeal for the management of composite tissue allograft recipients. Experience to date with steroid withdrawal or cyclosporine withdrawal in organ transplant recipients suggests that the risks of acute rejection are minimized with slow tapering of the drugs and when drug withdrawal is attempted many months or years after transplantation. Unfortunately, the full benefits of withdrawing any component of a multidrug immunosuppression regimen can probably be achieved only when the drug is withdrawn relatively early after transplantation. Thus, there is a need for improved immunologic monitoring to facilitate withdrawal of immunosuppression in any setting. Because steroid withdrawal might be particularly advantageous to the recipient of a composite tissue allograft, further experience is needed to determine the safety of steroid withdrawal with newer immunosuppressants such as tacrolimus, mycophenolate mofetil, and sirolimus.     

Management of posttransplant lymphoproliferative disease in pediatric liver transplant recipients receiving primary tacrolimus (FK506) therapy

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) after pediatric liver transplantation has been associated with high mortality rates. METHODS: The present study examined 282 consecutive pediatric liver transplant recipients from October 1989 to June 1996 who received primary tacrolimus immunosuppression. The aim was to determine the incidence of PTLD, management strategies, and patient outcome. RESULTS: The incidence of PTLD was 13% (361282) with a mean age of 5.5+/-0.7 years (range 0.6 to 15) at diagnosis. The average time from transplantation to PTLD was 10.1+/-2.1 months. Initial treatment of PTLD consisted of reduction (3 patients) or discontinuation (33 patients) of tacrolimus and initiation of antiviral therapy (intravenous ganciclovir, 14 patients; intravenous acyclovir, 22 patients; or both, 5 patients). Alpha-interferon was used in four patients (two successfully). One patient also received gamma-interferon, chemotherapy, and radiation for a central nervous system lesion. Chemotherapy was also used in one patient with Burkitt's, whereas one patient with a pulmonary lesion received additional radiation therapy. Three patients received supportive surgery for gastrointestinal involvement, and one patient had a splenectomy for hemolysis. Overall mortality was 22% (8/36) with 5 (14%) PTLD-related deaths (disseminated disease, 4 patients; bowel perforation, 1 patient). Of 31 survivors, 23 had acute rejection at a median time of 24 days after PTLD, with 2 patients developing chronic rejection. One patient required retransplantation. Present immunosuppression consists of tacrolimus monotherapy in 14 patients, tacrolimus/prednisone in 8 patients, and none in 6 patients. CONCLUSION: In summary, PTLD can be successfully treated with reduction of immunosuppression and administration of antiviral agents in most patients. The management of rejection after PTLD requires reassessment of disease status and judicious reintroduction of immunosuppression therapy.     

Prevention of transplant rejection: current treatment guidelines and future developments

In the past 2 decades, progressive improvements in the results of organ transplantation as a therapeutic strategy for patients with end-stage organ disease have been achieved due to greater insight into the immunobiology of graft rejection and better measures for surgical and medical management. It is now known that T cells play a central role in the specific immune response of acute allograft rejection. Strategies to prevent T cell activation or effector function are thus all potentially useful for immunosuppression. Standard immunosuppressive therapy in renal transplantation consists of baseline therapy to prevent rejection and short courses of high-dose corticosteroids or monoclonal or polyclonal antibodies as treatment of ongoing rejection episodes. Triple-drug therapy with the combination of cyclosporin, corticosteroids and azathioprine is now the most frequently used immunosuppressive drug regimen in cadaveric kidney recipients. The continuing search for more selective and specific agents has become, in the past decade, one of the priorities for transplant medicine. Some of these compounds are now entering routine clinical practice: among them are tacrolimus (which has a mechanism of action similar to that of cyclosporin), mycophenolate mofetil and mizoribine (which selectively inhibit the enzyme inosine monophosphate dehydrogenase, the rate-limiting enzyme for de novo purine synthesis during cell division), and sirolimus (rapamycin) [which acts on and inhibits kinase homologues required for cell-cycle progression in response to growth factors, like interleukin-2 (IL-2)]. Other new pharmacological strategies and innovative approaches to organ transplantation are also under development. Application of this technology will offer enormous potential not only for the investigation of mechanisms and mediators of graft rejection but also for therapeutic intervention.     

Preliminary risk-benefit assessment of mycophenolate mofetil in transplant rejection

Mycophenolate mofetil (the morpholinoethyl ester of mycophenolic acid) inhibits de novo purine synthesis via the inhibition of inosine monophosphate dehydrogenase. Its selective lymphocyte antiproliferative effects involve both T and B cells, preventing antibody formation. Mycophenolate mofetil has immuno-suppressive effects alone, but is used most commonly in combination with other immunosuppressants. Mycophenolate mofetil, in combination with cyclosporin and corticosteroids, has been studied in large, randomised clinical trials involving nearly 1500 renal allograft transplant recipients. These trials demonstrated that mycophenolate mofetil is significantly more effective in reducing treatment failure and acute rejection episodes than placebo or azathioprine. Additionally, mycophenolate mofetil may be able to reduce the occurrence of chronic rejection. Mycophenolate mofetil is relatively well tolerated. The most common adverse effect reported is gastrointestinal intolerance; haematological aberrations have also been noted. The reversible cytostatic action of mycophenolate mofetil allows for dose adjustment or discontinuation, preventing serious toxicity or an overly suppressed immune system. Cytomegalovirus tissue invasive disease and the development of malignancies are concerns that merit evaluation in long term follow-up studies. Mycophenolate mofetil does not cause the adverse effects typically associated with other commercially available immunosuppressant medications such as nephrotoxicity, hepatotoxicity, hypertension, nervous system disturbances, electrolyte abnormalities, skin disorders, hyperglycaemia, hyperuricaemia, hypercholesterolaemia, lipid disorders and structural bone loss. Based on preliminary information, a positive benefit-risk ratio has been demonstrated with the use of mycophenolate mofetil in the prophylaxis of rejection in cadaveric renal allograft transplantation. Data from studies in other types of organ transplants are promising, but are too limited to draw clear conclusions. Long term follow-up studies are required to confirm these observations. Although mycophenolate mofetil is expensive, the beneficial effects on the reduction of rejection, treatment failure and related expenses suggest that it is most likely to be cost effective.     

Immunology in clinical practice. VI. Current immunosuppressive drugs

Immunosuppressive drugs are agents capable of modulating at least one type of immune response in vivo at doses with tolerable side-effects. Classical immunosuppressive drugs include corticosteroids, azathioprine, cyclophosphamide, methotrexate and cyclosporine. In the past two years tacrolimus and mycophenolate mofetil were registered as immunosuppressive drugs. Tacrolimus interferes with the calcium-dependent signal transduction of T-lymphocytes. Mycophenolate mofetil is an inhibitor of purine synthesis by inhibition of the enzyme inosine monophosphate dehydrogenase. Both tacrolimus and mycophenolate mofetil have proven efficacy in both prevention and treatment of acute allograft rejection. The new drugs are stronger than the classical ones but do not cause more adverse reactions. The value in clinical medicine of some new, promising immunosuppressive drugs, i.e. sirolimus (rapamycin), mizoribine, brequinar and leflunomide remains to be proven.     

A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone, and mycophenolate mofetil in primary adult liver transplant recipients: an interim report

BACKGROUND: Tacrolimus (Tac) and mycophenolate mofetil (MMF) are newly approved immunosuppressive agents. However, the safety and efficacy of the combination of MMF and Tac in primary liver transplantation has not been determined. METHODS: An Institutional Review Board-approved, open-label prospective randomized protocol was initiated to study the efficacy and toxicity of Tac and steroids (double-drug therapy) versus Tac, steroids, and MMF (triple-drug therapy) in primary adult liver transplant recipients. Both groups of patients began on the same doses of Tac and steroids. Patients randomized to triple-drug therapy also received 1 g of MMF twice a day. RESULTS: Between August 1995 and January 1997, 200 patients were enrolled, 99 in double-drug therapy and 101 in triple-drug therapy. All patients were followed until May 1997, with a mean follow-up of 12.7 months. During the study period, 28 of 99 patients in double-drug therapy received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 61 patients in triple-drug therapy discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. By an "intention-to-treat analysis," the actuarial 1-year patient survival rate was 85.1% in double-drug therapy and 83.1% in triple-drug therapy (P=0.77). The actuarial 1-year graft survival rate was 80.2% for double-drug therapy and 79.2% for triple-drug therapy (P=0.77). Forty-one patients (41.4%) in double-drug therapy and 32 (31.7%) in triple-drug therapy had at least one episode of rejection, but this was not statistically significant (P=0.15). The mean maintenance dose of corticosteroids was slightly lower in triple-drug compared with double-drug therapy. CONCLUSION: Patient and graft survival rates were similar in both groups. There was a trend to a lower incidence of rejection, reduced nephrotoxicity, and a lesser amount of maintenance corticosteroids in triple-drug therapy compared with double-drug therapy.     

Renal function improves in liver transplant recipients when switched from a calcineurin inhibitor to sirolimus

Sirolimus (Rapamune; Wyeth-Ayerst, Philadelphia, PA) is a newer immunosuppressive drug with no known acute or chronic nephrotoxic effects; however, limited data are available in liver transplant recipients. We prospectively evaluated changes in renal function in liver transplant recipients after conversion from a calcineurin inhibitor to sirolimus monotherapy. We measured serial serum creatinine levels in liver transplant recipients with chronic nephrotoxicity caused by calcineurin inhibitors before and after conversion to sirolimus therapy. Estimated glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease formula. Change in eGFR over time, incidence of acute hepatocellular rejection, and adverse events while being administered sirolimus monotherapy were recorded. Mean interval between liver transplantation and initiation of sirolimus therapy was 310 weeks (range, 9 to 780 weeks). Of 21 patients included in our study, 18 patients were converted to sirolimus monotherapy and 3 patients were switched to sirolimus and low-dose steroid therapy. Patients were followed up for a mean of 66.8 +/- 38.9 (SD) weeks after conversion. Renal function improved in 71% of patients (15 of 21 patients). Median eGFR improved significantly from 34 mL/min/1.73 m2 at the time of conversion to 43 mL/min/1.73 m2 at the last follow-up (27% increase in eGFR; P = 001). Median monthly change in eGFR was from -0.25 mL/min/1.73 m2 pre-sirolimus therapy to +1.28 mL/min/1.73 m2 post-sirolimus therapy (P =.09). Adverse events were mostly mild and self-limited. Only 1 patient developed biopsy-proven acute cellular rejection, which was treated with sirolimus and mycophenolate mofetil. Two patients discontinued sirolimus therapy because of toxicity (oral ulceration, 1 patient; interstitial pneumonitis, 1 patient). Renal function improved significantly in the majority of liver transplant recipients with renal insufficiency caused by calcineurin inhibitors when converted to sirolimus therapy. Sirolimus monotherapy provided adequate immunosuppression with a low incidence of acute cellular rejection and minimal adverse events.     

Prednisone withdrawal 14 days after liver transplantation with mycophenolate: a prospective trial of cyclosporine and tacrolimus

BACKGROUND: The long-term complications of immunosuppressive therapy such as diabetes, hypercholesterolemia, and hypertension are a major source of morbidity in liver transplant recipients. In this prospective, randomized, open-label study we completely withdrew prednisone (PRED) 14 days after liver transplantation in an effort to decrease these metabolic complications. Patients were maintained on mycophenolate mofetil (MMF) in combination with either cyclosporine (CsA; Neoral formulation) or tacrolimus (TAC). Thus, we also were able to compare CsA to TAC in patients not receiving PRED with respect to efficacy, toxicity, and effect on posttransplant metabolic complications. METHODS: A total of 71 patients were randomized to receive either TAC-MMF (n=35) or CsA-MMF (n=36) after liver transplantation and were analyzed for patient and graft survival. Fifty-eight patients continued the immunosuppressive protocol for at least 6 months after transplantation and were analyzed for the incidence of acute rejection and the prevalence of diabetes, hypertension, and hypercholesterolemia. RESULTS: The 6-month patient survival rates were 94.4% for CsA-MMF and 88.6% for TAC-MMF. Corresponding 6-month graft survival rates were 88.7% and 85.71% with no immunologic graft losses in either group. The incidence of biopsy-proven acute rejection was 46% for CsA-MMF and 42.3% for TAC-MMF. Six patients were converted from CsA to TAC (four for recurrent rejection) and seven patients were converted from TAC to CsA (four for neurotoxicity). Only one patient (in the TAC-MMF group) developed new-onset posttransplant diabetes. In contrast, four of eight patients in the CsA-MMF group who were diabetic before transplant became nondiabetic in the first 3 months after transplant. The mean serum cholesterol level was significantly lower in the TAC-MMF group than in the CsA-MMF group (145.2+/-41.8 mg/dl and 190.3+/-62.2, respectively; P<0.001) and the incidence of hypertension was lower in the TAC-MMF group (12% vs. 30.3% in the CsA-MMF group, P<0.01). Both groups had a lower incidence of metabolic complications compared with a historical group (n=100) maintained on CsA and PRED (10 mg/day at 6 months). CONCLUSIONS: MMF in combination with either TAC or CsA allows withdrawal of PRED 14 days after liver transplantation with a moderate rejection rate and no immunologic graft losses. Early PRED withdrawal decreases posttransplant diabetes, hypercholesterolemia, and hypertension, but patients maintained on TAC have lower serum cholesterol levels and a lower incidence of hypertension than CsA-treated patients.     

Review of immunosuppression for lung transplantation. Novel drugs, new uses for conventional immunosuppressants, and alternative strategies

The history, pharmacokinetics, mechanisms of action, and experimental as well as clinical data on the immunosuppressive potential of the novel drugs tacrolimus (FK506), sirolimus (rapamycin), mycophenolic acid (mycophenolate mofetil), and leflunomide (and its malononitriloamide analogues) are provided. Novel approaches with the following conventional immunosuppressants are outlined: methotrexate, aerosolized immunosuppression and the implementation of steroid taper. Total lymphoid irradiation and photopheresis for treatment of recurrent rejection are also discussed.     

Adult heart transplantation under tacrolimus (FK506) immunosuppression: histopathologic observations and comparison to a cyclosporine-based regimen with lympholytic (ATG) induction

BACKGROUND: Tacrolimus (FK506) is an effective immunosuppressant for human heart transplantation, but information about its effects on cardiac allograft and nonallograft kidney and liver histopathologic study is limited. METHODS: We therefore reviewed 1145 endomyocardial biopsy specimens and eight autopsy results from 80 heart transplant recipients who received tacrolimus as baseline immunosuppression. These were compared with 619 endomyocardial biopsy specimens and four autopsy results from 51 patients treated with cyclosporine-based immunosuppression with lympholytic induction (CLI) by use of rabbit anti-thymocyte globulin. Twenty-one histologic features including the International Society for Heart and Lung Transplantation histopathologic grade were retrospectively assessed without knowledge of the treatment regimen. The lymphocyte growth index on biopsy specimens obtained from these patients was also compared. RESULTS: In general, there were no qualitative differences in the histopathologic appearance of various allograft syndromes between tacrolimus- and CLI-treated patients. Thus histopathologic criteria used to diagnose various graft syndromes are applicable under tacrolimus immunosuppression. However, early (between 10 and 30 days) after transplantation, biopsy specimens from patients treated with tacrolimus showed a significantly higher percentage of inflamed fragments (p = 0.02), the inflammation tended to be more severe (p = 0.09), and the rejection grade tended to be slightly higher (p = 0.08). In contrast, during the late transplantation period (275 to 548 days), biopsy specimens from patients treated with CLI showed a significantly higher percentage of inflamed fragments (p = 0.03), more severe inflammation (p = 0.03), higher rejection grades (p = 0.01), and a higher frequency of Quilty lesions (p = 0.05). Although overall freedom from any grade 3A or higher rejection was greater in the CLI-treated arm, tacrolimus was successfully used to treat refractory rejection in three patients from the CLI-treated arm. Concern has been raised in the literature about the possibility of tacrolimus being a direct hepatotoxin and an accelerant of allograft obliterative arteriopathy. However, no evidence to support either of these contentions was detected in this patient population. In contrast, tacrolimus is clearly nephrotoxic, although similar to cyclosporine in this regard. CONCLUSIONS: Tacrolimus is an effective immunosuppressive drug for heart transplantation. The cardiac allograft histopathologic study of patients treated with tacrolimus immunosuppression does not significantly differ from those given conventional, cyclosporine-based triple therapy with lympholytic induction.     

A study comparing mycophenolate mofetil to azathioprine in simultaneous pancreas-kidney transplantation

BACKGROUND: Mycophenolate mofetil (MMF; Cell-Cept) is a potent and selective inhibitor of B and T lymphocyte proliferation that has proven effective in reducing the incidence of acute rejection in cadaveric kidney transplant recipients in several randomized, blinded clinical studies. Because the frequency and characteristics of rejection episodes may be different and more severe after combined pancreas-kidney transplantation, we hypothesized that MMF would have a significant impact on pancreas-kidney rejection and graft outcome. Therefore, we compared the efficacy of MMF versus azathioprine (AZA) in cyclosporine-treated simultaneous pancreas-kidney transplantations. METHODS: A retrospective comparison of 358 consecutive primary SPK transplantations performed from 1990 to 1997 was conducted. Patients received either MMF (n=109, 3 g/day) or AZA (n=249, 2 mg/kg q.d.) in combination with cyclosporine-based immunosuppression. All patients received a quadruple-drug sequential induction protocol with either OKT3 or Atgam. Several outcome parameters, including patient and graft survival rates and frequency of rejection, were analyzed. RESULTS: MMF-treated patients demonstrated a markedly reduced rate of biopsy-proven kidney rejection (31 vs. 75% AZA, P=0.0001), clinically significant pancreas rejection (7 vs. 24% AZA; P=0.003), and steroid-refractory rejection (15 vs. 52% AZA; P=0.01). As a result, kidney and pancreas allograft survival was significantly better in MMF patients compared with AZA patients (2-year survival rates: kidney, 95 vs. 86%; and pancreas, 95 vs. 83%). Although surgical infections after transplantation were more frequent in MMF patients, MMF patients were more likely to have undergone enteric drainage. Importantly, we did not observe an increased incidence of any of the bacterial, fungal, or viral infections that typically plague immunosuppressed transplant recipients. CONCLUSIONS: This retrospective study demonstrates that MMF is a highly effective immunosuppressant in SPK transplantation. It is not associated with an increased risk of opportunistic infections when a balanced immunosuppressive management approach is used. MMF strikingly reduces the frequency of acute cellular and steroid-resistant rejection. As a result of this combined experience, it is not unexpected then that we observe significantly improved graft survival rates in MMF-treated SPK patients compared with patients receiving a more traditional immunosuppressive regimen.     

Mycophenolic acid: a welcome adjunct immunosuppressant after organ transplants

Three major double-blind trials in kidney transplantation patients have shown that mycophenolic acid (mycophenolate mofetil), added to an immunosuppressive regimen consisting of cyclosporine and prednisone, reduces the incidence of acute rejection after kidney transplantation by 50%, during the first six months. This statistically significant reduction is achieved equally with daily doses of 2 or of 3 g. In view of the fact that the side effects (diarrhoea, abdominal cramps, leukopenia) are more frequently found in the patients treated with 3 g, it is advised to prescribe 2 g mycophenolic acid. As acute rejection is a risk factor for the development of chronic rejection and because a beneficial effect of mycophenolic acid on chronic rejection in animal models has been observed, there may also be an effect on late graft loss due to chronic rejection after kidney transplantation in man.     

Fluoroquinolones as treatment for patients with lower respiratory tract infections caused by Streptococcus pneumoniae

BACKGROUND: Mycophenolate mofetil (MMF) has been previously shown to prevent functional deterioration in an experimental model of chronic renal allograft rejection. METHODS: In this retrospective case-control study, patients with chronic rejection who were receiving cyclosporine or tacrolimus and who had MMF added to their immunosuppressive regimen were compared with patients with chronic rejection who were not receiving MMF. Patients were matched for serum creatinine levels and transplant duration at the time MMF was begun. RESULTS: In the MMF group, the average dose of MMF was 1482 mg/day with an average duration of 19.3 months. Over 36 months, including 12 months before MMF and up to 24 months on MMF, there was no difference in serum creatinine levels between the two groups. Cyclosporine levels and dose were no different. CONCLUSIONS: In this small, retrospective, preliminary study, adding MMF to maintenance immunosuppression provided no clear benefit to renal allograft recipients with established chronic rejection. Larger prospective randomized studies are needed.     

Higher cholesterol in human LDL is associated with the increase of oxidation susceptibility and the decrease of antioxidant defence: experimental and simulation data

BACKGROUND: Kaposi's sarcoma (KS) is an human herpesvirus 8-associated tumor, occurring in immunocompromised patients. We report here an increased incidence of KS among kidney graft recipients (KGRs) during the last 2 years, concomitant to the introduction of the immunosuppressant mycophenolate mofetil (MMF). METHODS: A total of 1835 KGRs, receiving organs between 1987 and 1997, were surveyed for the development of KS. A total of 371 patients received therapy including MMF (group A), whereas 1464 patients were treated with an MMF-free protocol (group B). RESULTS: 3/371 patients (0.8%) of group A versus 2/1464 patients (0.1%) of group B developed KS. In group A, KS became evident 7+/-2 months after initiation of MMF therapy. CONCLUSIONS: At our center, during the last 2 years, the incidence of KS has increased in KGRs, and it is not clear whether the introduction of MMF contributes to the phenomenon.     

Does wearing a necktie influence patient perceptions of emergency department care?

This study compared the early clinical course of 9 pediatric heart transplantation recipients treated with cyclosporine A-based immunosuppression with 10 similarly aged recipients treated with tacrolimus-based therapy. One-year follow-up after transplantation revealed that tacrolimus-treated children had similar left ventricular function, experienced fewer episodes of severe rejection, were more rapidly weaned from corticosteroids, and had relatively few side effects from immunosuppression compared with cyclosporine A-treated children.     

Unraveling the mysteries of environmental medicine

BACKGROUND: In an outbred pig model of total bowel transplantation, we previously showed that simultaneous donor-specific bone marrow infusion (DSBMI), rather than promoting engraftment, sensitizes recipients and causes rejection; it also aggravates the risk of generalized graft-versus-host disease (GVHD) and infection, and tends to reduce recipient and graft survival. Small and large animal models of bone marrow-induced transplant tolerance suggest that some form of recipient preconditioning (RPC) may facilitate engraftment of co-transplanted bone marrow cells and fully expose their tolerogenic potential. METHODS: In a preclinical model, we prospectively studied the effect of RPC on simultaneous DSBMI and total (i.e., small and large) bowel transplantation. RPC consisted of whole body irradiation with 400 R (day 0); some recipients additionally received horse anti-pig antithymocyte globulin (days -2, -1, and 0). We studied six groups of outbred pigs, all of which underwent at least a total bowel transplant: group 1, nonimmunosuppressed control pigs (n=5); group 2, nonimmunosuppressed DSBMI pigs (n=13); group 3, tacrolimus pigs (n=7); group 4, DSBMI+tacrolimus pigs (n=15); group 5, RPC+nonimmunosuppressed DSBMI pigs (n=11); and group 6, RPC+DSBMI+tacrolimus pigs (n=14). RESULTS: RPC did not prolong overall survival at 7, 14, 21, and 28 days after transplant. Survival rates were 100%, 100%, 86%, and 71% in group 3; 71%, 43%, 29%, and 29% in group 6; 55%, 9%, 0%, and 0% in group 5; and 60%, 0%, 0%, and 0% in Group 1. Moreover, RPC (groups 5 and 6) increased the incidence of death from rejection, GVHD, and infection when compared with group 3. Survival was significantly higher for RPC+DSBMI+tacrolimus pigs (group 6), compared with RPC+nonimmunosuppressed DSBMI pigs (group 5). Survival greater than 28 days was noted only in pigs that received tacrolimus after transplant: 71% in group 3 versus 29% in group 6. With both RPC and DSBMI (groups 5 and 6), rejection, GVHD, and infection were not mutually exclusive events. In groups 5 and 6, at autopsy, the incidence of rejection and GVHD was 17%; rejection and infection, 17%; and GVHD and infection, 45%. A combination of all three immunologic events was noted in 14%. CONCLUSIONS: RPC, combined with DSBMI, and with or without posttransplant immunosuppression, does not prolong survival after total bowel transplantation. Rather, it increases the incidence of death from rejection, GVHD, infection, or a combination of these three immunologic events. According to this preclinical study, RPC and unmodified DSBMI do not improve patient and graft outcome after total bowel transplantation and need to be refined before being applied clinically.