Calvin R. Stiller

A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation

Mycopehenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multi-center trial to compare the efficacy and safety of MMF and azathioprine within standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3g group (P=0.0045) and 38.2 % in the MMF 2g group (P=0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1 %, 10.4% and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were tested for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.

Successful small-bowel/liver transplantation

A patient with the short-gut syndrome and antithrombin III deficiency underwent small bowel and liver grafting a year ago. Transient, mild graft-versus-host disease and intestinal rejection occurred within 2 months of grafting and were easily managed. Parenteral nutrition was discontinued 8 weeks after surgery. The patient has maintained normal nutritional indices while on an unrestricted oral diet. Small-bowel/liver grafting is feasible for patients with the short-gut syndrome and associated liver disorders. Further experience is needed to determine the specific risks, benefits, and general applicability of this procedure.

Fibrous hyperplasia of the gingiva: A side effect of cyclosporin A therapy

Abstract The clinical and histopathologic findings in six patients with gingival fibrous hyperplasia associated with cyclosporin A (CyA) therapy are described. The clinical and histopathologic findings are considered to be indistinguishable from the gingival hyperplasias induced by the anticonvulsant drug, phenytoin (diphenylhydantoin).

Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients

Reported side-effects of tacrolimus, a potent immunosuppressive agent, have not included cardiotoxicity. We describe 5 consecutive paediatric transplant recipients (3 small bowel with or without liver and 2 liver) who received tacrolimus. 2 developed congestive heart failure and hypertrophic obstructive cardiomyopathy which resolved after changing to cyclosporin. In the other 3 patients the cardiomyopathy regressed or improved with a lower dose of tacrolimus or after stopping the drug.

CYCLOSPORIN PREVENTS DIABETES IN BB WISTAR RATS

Cyclosporin (U.S.A.N. cyclosporine) was used prophylactically to suppress the development of insulin-dependent diabetes mellitus in BB Wistar rats. In this rat strain diabetes spontaneously develops between 60 and 120 days of age and this condition resembles human type 1 diabetes. In 30 (75%) out of 40 control rats glycosuria and hyperglycaemia developed and these rats became insulin-dependent. Their pancreases showed partial to complete destruction of the islets of Langerhans by lymphocytic infiltration. None of the 40 cyclosporin-treated rats became diabetic and their pancreases were histologically normal. Serum cyclosporin was monitored in a subgroup and the dosage was adjusted accordingly; neither hepatotoxicity nor nephrotoxicity was seen in the treated animals.

IMMUNOLOGICAL AND PHARMACOLOGICAL MONITORING IN THE CLINICAL USE OF CYCLOSPORIN A

Immunological reactivity to donor antigens and serum concentrations of cyclosporin A were monitored in six patients after renal transplantation. At concentrations of 0.1--1.0 microgram/ml cyclosporin A prevented both donor-specific immune reactivity and clinical rejection during the early post-transplant course. Measurement of cyclosporin A levels and immunological indices allowed individual adjustment of the dosage so as to give excellent early graft function with few adverse effects.

The Effects of Erythromycin in Patients Treated with Cyclosporine

Excerpt The clinical introduction of cyclosporine heralded a new class of immunoregulatory drugs with specific inhibitory effects on T-cell functions and elaborated products (1, 2). Cyclosporines ...

The effects of intravenous anaesthetic agents on human neutrophil chemiluminescence

Intact neutrophil function is essential for the defence against infection. Any alteration in neutrophil function, which decreases their ability tu phagocytose and kill bacteria, might contribute to mortality and morbidity. We investigated the effects of clinical concentrations of thiopentone, Alfathesin, methohexitone, morphine, lidocaine and diazepam on the microbicidal oxidative function of human neutrophils. The. oxidative activity was assessed utilizing the technique of chemiluminescence, which is a measure office radical generation. Thiopentone and Alfathesin produced a significant dose dependent depression in chemiluminescence. There was a 21 per cent reduction in activity with thiopentone 5 μg.ml-1, a concentration equivalent to the free plasma concentration achieved following an anaesthetizing dose of thiopentone. There was a 55 per cent reduction in chemiluminescence at an alphaxolone concentration of 1.25 μg.ml-1, a concentration equivalent to the free plasma level obtained after induction of Alfathesin anaesthesia. The effect of thiopenione and Alfathesin was reversed by cell washing. Methohexitone, morphine, diazepam, and lidocaine caused no significant reduction in chemiluminescence over the dose ranges studied.These observations indicate that thiopentone and Alfathesin con adversely affect leucocyte functionin vitro and, therefore, may contribute to impaired host resist ance in the perioperative period and in the intensive care unit.RésuméIl est essentiel dans la défense contre l’infection de maintenir intacte la fonction des leucocytes neutrophiles. Toute altérationde cette fonction, en diminuant la capacité de phagocytes et de tuer les bactéries, peut contribuer à la mortalité et à la morbidité. Nous avons étudié les effets de concentrations cliniques de thiopental, alphatélin, méthohexital, morphine, xylocaïne et de diazépam sur In fonction oxydative bactéricide des neutrophiles humains. L’activité bactéricide fut évaluée en utilisant la chemoluminescence qui est une mesure de la génération de radicaux libres. Le thiopental et l’alphathésin produisent une diminution significative et proportionnelle à la dose de la chemoluminescence. Il y a eu une réduction de 27 pour cent avec le thiopental 5 μg.ml-1, (concentration équivalente à la concentration libre plasmatique obtenue à la suite d’une dose anesthésique de thiopental). Il y a eu une réduction de 55 pour cent de la chemoluminescence avec une concentration d’alphaxolone de 1.25 μg.ml-1, (concentration équivalente à la concentration plasmatique libre obtenue après induction à l’alphathésin). Les effets du thiopental et de l’alphathésin ont été annulés après lavage des cellules. Le méthohexital, la morphine, le diazépam et la xylocaïne n’ont pas provoqué de réduction significative de chemoluminescence dans l’échelle des doses étudiées.Ces observations indiquent que le thiopental et l’alphathésin peuvent atteindre la fonction leucocytaire in-vitro et de ce fait, peuvent contribuer à une résistance amoindrie de l’hôte durant la période péri-opératoire et le séjour aux soins intensifs.

BENEFICIAL EFFECT OF OPERATION-DAY BLOOD-TRANSFUSIONS ON HUMAN RENAL-ALLOGRAFT SURVIVAL

In 56 patients 1-year renal-graft survival was significantly better (71% vs 40%) in those who had received blood before operation, confirming previous observations. In addition, transfusion on the day of operation proved to have been beneficial, both in those previously transfused (82% vs 64%) and in those never previously transfused (71% vs 28%). Irrespective of pretransplant transfusion, 1-year graft survival was significantly better (79% vs 44%) in those transfused on the day of operation.

Anti-Donor Immune Responses in Prediction of Transplant Rejection

We assessed various immune responses against donor tissue to determine their value in the diagnosis and prediction of clinical rejection episodes. Twenty-six consecutive clinical renal-transplant recipients were examined. Cell-mediated lymphocytotoxicity preceded and accompanied 41 of 45 rejection episodes (P less than 0.001). Complement-dependent antibody was present in 12 of 15 rejections (P less than 0.002)--four not accompanied by, and eight in association with, cell-mediated lymphocytotoxicity. Mixed lymphocyte reactivity or nonreactivity and inhibition by autologous serum occurred equally often in rejection and quiescence. Lymphocyte-dependent antibody occurred during both rejection episodes and quiescent phases, with a greater frequency during quiescence (P = 0.05). Cell-mediated lymphocytotoxicity was the best predictor of rejection (P less than 0.05). Cell-mediated lymphocytotoxicity was the best predictor of rejection (P less than 0.001), and was more easily suppressed by standard immunosuppressive therapy, than complement-dependent antibody. If specific cell-mediated lymphocytotoxicity, with or without antibody, recurred after rejection therapy, the graft underwent further rejection.