Matthias Behrend

Adverse gastrointestinal effects of mycophenolate mofetil: Aetiology, incidence and management

Mycophenolate mofetil (MMF) is a relatively new immunosuppressive drug. It inhibits inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine synthesis, and thus causes lymphocyte-selective immunosuppression. Large clinical trials have revealed the efficacy of MMF in the prevention of allograft rejection when administered together with cyclosporin or tacrolimus and corticosteroids.Although the adverse effect profile of MMF is comparatively benign, gastrointestinal adverse effects are a major concern. These effects are partially explained by the increased immune suppression, by the mode of action and by interactions, particularly with other immunosuppressants. The aetiology of the rarest gastrointestinal adverse effects is still not completely clear. Therapy depends upon the clinical gravity of the adverse effects and is therefore a case of waiting and observing. An adjustment of dosage of immunosuppressants according to the clinical situation and, particularly in the case of MMF, spreading the total dosage over more than 2 daily doses are often sufficient. Should adverse effects persist for a longer period of time and be of a more serious nature, a comprehensive invasive diagnostic process is necessary, including endoscopy and biopsy and the search for opportunistic infections. In this case, dosage reduction or the complete withdrawal of MMF seems to be unavoidable.Severe gastrointestinal complications with MMF are rare, but when they do occur they may require extensive diagnosis and treatment. In the future, therapeutic drug monitoring and, where necessary, pharmacological modifications of MMF could lead to a further reduction of adverse effects with an equal or even increased efficacy.

Long-term Follow-up after Adrenalectomy for Primary Aldosteronism

The objective of this study was to assess the long-term effects of adrenalectomy on the blood pressure and antihypertensive medication in patients with primary aldosteronism (PA). Twenty-four patients (15 female and 9 male) with a mean age of 48.3 ± 10.8 years underwent surgery for PA in our institution between 1988 and 2001. All subjects were re-examined with a complete clinical work-up after a mean follow-up period of 86 ± 48 months, including blood pressure readings (<140/90 mmHg defined as normal), endocrine adrenal function, and specific medication. All patients suffered from hypertension (onset 8.5 ± 5.5 years prior to surgery). In 92% of the patients, hypokalemia was present (onset 2.0 ± 2.6 years prior to surgery). The histopathologic examinations revealed unilateral adenomas in 23 patients and a bilateral hyperplasia in one patient. At follow-up, 33% (8) of the patients were completely cured (normal blood pressure and no antihypertensive treatment), with seven of these eight patients being under 50 years of age at the time of surgery. One patient revealed a contralateral aldosterone-secreting adrenal adenoma during the subsequent endocrine and imaging examination 44 months after the first operation. Despite normalized plasma-aldosterone concentration (PAC), plasma-renin-activity (PRA) and serum potassium levels, a long-lasting insufficiently treated hypertension due to the delayed diagnosis in patients with PA may explain the persistent blood pressure elevation, indicating the necessity of a life-long, regular control of the blood pressure and antihypertensive medication.

Incidence of Pneumocystis carinii pneumonia after renal transplantation : Impact of immunosuppression

The incidence and potential risk factors of Pneumocystis carinii pneumonia (PCP) in our population of renal transplant recipients were analyzed retrospectively. Of 1427 patients who received transplants between January 1986 and June 1994, 1192 were evaluated. Four different immunosuppressive regimens were applied: (1) cyclosporine (CsA) + prednisolone (Pred), (2) CsA + azathioprine (Aza, 2 mg/kg/day) + Pred, (3) CsA + Aza + antithymocyte globulin, and (4) (after December 1, 1993, European multicenter trial) FK506 + Aza (1 mg/kg/day) + Pred. No prophylaxis against PCP was performed. Before December 1, 1993, three PCPs in 494 patients on protocol 2 or 3 occurred (0.6%). Afterward, seven PCPs in 77 patients occurred (9%): three in 38 patients on protocol 2 (7.8%) and four in 28 patients on protocol 4 (14.3%). Comparing patients with PCP on CsA and FK506, the mean Aza dose was 2.40 and 1.32 mg/kg/day, five and two patients received additional steroids, antibody treatment was used in three and no patients, and CMV infections occurred in five and two patients, respectively. The incidence of PCP with a moderate CsA-based immunosuppressive regimen is low and seems to occur only in cases of additional immunosuppressive cofactors. Despite a general increase of PCP, its incidence was highest in patients on FK506 with fewer immunosuppressive cofactors. Thus, prophylaxis against PCP after renal transplantation should be performed, if not in every renal transplant recipient, at least in case of treatment with additional steroids, antibodies, or FK506.

Lipoprotein patterns in renal transplant patients: a comparison between FK 506 and cyclosporine A patients.

Lipoprotein patterns in renal transplant patients: a comparison between FK 506 and cyclosporine A patients.

Presentation and therapy of myelolipoma

Abstract  Background:  Adrenal myelolipoma is a rare and benign, hormonally inactive tumor frequently discovered incidentally. Because of the increasing rate of detection of adrenal myelolipoma, use of the correct diagnostic examination and treatment, with respect to surgical excision or regular controls, is continually gaining importance. We report herein on the largest series of surgically treated patients with adrenal myelolipoma from a single institute.

High mortality from urothelial carcinoma despite regular tumor screening in patients with analgesic nephropathy after renal transplantation

Patients with end-stage renal failure due to analgesic nephropathy have an increased risk of developing a urothelial carcinoma. To determine the impact of renal transplantation on the frequency of urothelial carcinomas, we analyzed 2072 patients who underwent 2371 renal transplantations between 1968 and 1993, including 78 (3.8%) with clinically proven analgesic nephropathy. Before and after transplantation a regular tumor screening was performed in patients with analgesic nephropathy by urine cytology and abdominal sonography. In 11 of the 78 patients with analgesic nephropathy (14.1%; age 51–66 years, 40–108 months after initiation of dialysis treatment, 5–77 months after transplantation), a urothelial carcinoma of the native urinary tract, especially the kidneys, was diagnosed. Therapy comprised nephroureterectomy (n=6), transurethral resection (n=6) and/or cystectomy (n=2). Seven patients died due to tumor progression 16.3 (4–33) months postoperatively and one patient died due to a perioperative complication. Despite regular tumor screening after transplantation, the diagnosis of a urothelial carcinoma was made very late, leading to a high tumor-related mortality. As a consequence, we suggest that a bilateral nephroureterectomy should be performed prophylactically in patients with proven analgesic nephropathy. In addition, a cystoscopy with lavage cytology testing of the bladder should be performed twice a year.

Influence of Suture Material and Technique on End-to-End Reconstruction in Tracheal Surgery: An Experimental Study in Sheep

Resection and end-to-end anastomosis of the trachea represent the preferred treatment for various benign and malignant diseases involving the trachea. Various studies have reported conflicting results with alternative techniques and suture materials for tracheal anastomosis. Our objective was to evaluate three frequently used techniques concerning stenosis rate and histological reaction in a large-animal species. Tracheal resection of 3 cm and end-to-end anastomosis were performed in 15 sheep with the use of three different techniques. In the first group, an interrupted suture with polyglactin, in the second group an interrupted suture with polydioxanone, and in the last group a continuous suture with polypropylene were used. The animals were killed 1, 2, 4, 8, and 24 weeks postoperatively. The luminal stenosis was determined by means of computerized planimetry. All three techniques appeared to be appropriate for tracheal anastomosis. The luminal stenosis developed within the first 8 weeks after surgery. A cross-sectional area of approximately 40–70% was finally achieved. Differences dependent on the suture material are less important than the technical details of the operation.

Immune-adhesion molecules in the prevention of allograft rejection and reperfusion injury

Control of the immune system is of indispensable importance for graft acceptance and function. Immunological changes in the graft before and after organ harvesting, the transplantation procedure itself and the organ recipients clinical state contribute to the immune response. Leukocyte trafficking [1] into a graft is regulated by various signal transducing molecules, which have been characterised during the past years. Ligand molecules on endothelial cells and in the organ parenchyma are the counterparts for leukocyte adhesion and tissue infiltration. The expression of these ligand molecules is regulated by soluble factors and cell-cell interactions [2]. The regulation of tissue inflammation and repair mechanisms involving components of the immune system therefore depends on a number of cell-surface interactions. The processes of intravascular adhesion, transmigration and infiltration by leukocytes and platelets are mainly mediated by receptor ligand interactions with target cells (cell-cell) and extracellular matrix proteins (cell-matrix). The main molecular families of adhesion receptor/ligand molecules have been identified. Today, we are still far from understanding this network of interactions. The numbers of molecules and factors involved are still increasing. This review summarises the currently available knowledge on the intervention in this system by monoclonal antibodies (mAbs), peptides and blocking agents. From this review, it is evident that further investigations are justified.

Mycophenolate mofetil (Cellcept)

Mycophenolate mofetil (MMF) is a new immunosuppressive drug designed to inhibit inosine monophosphate dehydrogenase (IMPDH). IMPDH is a key enzyme in the purine synthesis pathway of lymphocytes. IMPDH is crucially important for the proliferative responses of human T- and B-lymphocytes. Therefore, inhibition of IMPDH leads to selective lymphocyte suppression. Following successful testing in different in vitro and animal models, MMF entered clinical trials, where it has been used in combination with cyclosporin and steroids. MMF has rapid and complete absorption following oral administration. Pilot studies suggested a significant reduction in the incidence of rejection at doses of 1-3 g/day. These data led to the initiation of 3 pivotal trials, in which MMF was compared against different standard immunosuppressive protocols. Nearly 1500 patients were enrolled in these 3 randomised, double-blind, multicentre studies of the addition of MMF to standard immunosuppressive protocols for the prevention of acute renal allograft rejection. After six months, the rate of biopsy-proven rejection was significantly reduced. The adverse event profile resembles that of triple therapy with azathioprine: primarily involving the gastrointestinal (GI) tract, the haematopoietic system and the occurrence of opportunistic infections. MMF affords improved immunosuppressive therapy following renal, and probably other solid organ, transplantation. It is licensed for the prevention of acute renal allograft rejection in most countries around the world.

The Mechanical Influence of Tissue Engineering Techniques on Tracheal Strength: An Experimental Study on Sheep Trachea

Tissue engineering is an attractive concept for facilitating the transplantation of different tissue types with a low immunogeneity and a well-preserved tissue structure. We examined the influence of treatment with trypsin/ethylenediamine tetraacetic acid (EDTA) on the mechanical properties of tracheae. Fresh sheep tracheae were stored in a trypsin/EDTA solution for various periods of time (24, 46, and 72 h) and their breaking strength was subsequently examined. The results were compared with native trachea. The treatment with trypsin/EDTA results in a considerable reduction of the mechanical stability under load, in this case compared with the tensile strength, that does not correlate with the results obtained from light-optical microscopy. The results from this study reveal that tissue preparation with trypsin/EDTA does not seem to be a suitable method of preparatory treatment of tracheae intended for transplantation.