Cytokines 1: upregulation of cytokine gene expression and cytokine release in postischemic reperfused organs and transplants.
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Biomedical subjects
Publications and source records attributed to W Land.
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The positive influence of simultaneous pancreas and kidney transplantation (PKT) on the development of diabetic microvascular lesions is well established. On the other hand, little is known on its impact on diabetic macrovascular disease, which is still the major cause of death in diabetes, including patients after PKT. In order to evaluate the influence of PKT on the cardiovascular risk profile, we performed a cross-sectional study on 55 patients. Special attention was given to the hemorheological parameters fibrinogen and plasma viscosity, two important cardiovascular risk factors, which so far have found no attention in the field of PKT research. The patients were subdivided into three groups according to their graft function: group 1-26 patients after successful PKT (no insulin dependency, serum creatinine <2 mg%), group 2-23 patients after PKT and rejection of the pancreas graft (insulin dependency, serum creatinine <2 mg%), group 3-6 patients after PKT with pancreas rejection and renal insufficiency (insulin dependency, serum creatinine >2 mg%, no dialysis). There was a high prevalence of arterial hypertension after PKT (group 1: 65%, group 2: 70%, group 3: 100%). Serum lipids were in the normal range as long as renal function was intact. In renal insufficiency, however, LDL-cholesterol and triglycerides were significantly elevated (p < 0.05). Fibrinogen was significantly raised after PKT (p < 0.001), as was plasma viscosity when the pancreas graft was rejected (p < 0.02). There was a tendency towards elevated fibrinogen levels with decreasing graft function. In conclusion, a number of cardiovascular risk factors were identified in patients after PKT, predominantly arterial hypertension and impaired hemorheology, with elevated fibrinogen levels and plasma viscosity. There is a further enhancement with decreasing graft function.
BACKGROUND: To confirm the results of a number of studies conducted in Europe, the United States, and Japan, this multicenter, randomized trial compared the 12-month efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens in the prevention of renal allograft rejection. METHODS: A total of 448 renal transplant recipients were recruited from 15 centers and assigned to receive triple-drug therapy consisting of tacrolimus (n=303) or cyclosporine (n=145) in conjunction with azathioprine and low-dose corticosteroids. RESULTS: At 12 months after transplantation, tacrolimus therapy was associated with a significant reduction in the frequency of both acute (tacrolimus 25.9% vs. cyclosporine 45.7%; P<0.001 [absolute difference: 19.8%, 95% confidence interval: 10.0-29.6%]) and corticosteroid-resistant rejection (11.3% vs. 21.6%; P=0.001 [absolute difference: 10.3%, 95% confidence interval: 2.5-18.2%]). Actuarial 1-year patient (tacrolimus 93.0% vs. cyclosporine 96.5%; P=0.140) and graft survival rates (82.5% vs. 86.2%; P=0.380) did not differ significantly between the two treatment groups. Overall, the safety profiles of the tacrolimus- and cyclosporine-based regimens were quite comparable. Infections, renal impairment, neurological complications, and gastrointestinal complaints were frequently reported but were mostly reversible in both groups. Higher incidences of elevated serum creatinine, tremor, diarrhea, hyperglycemia, diabetes mellitus, and angina pectoris were reported in the tacrolimus treatment group, whereas acne, arrhythmia, gingival hyperplasia, and hirsutism were more frequent with cyclosporine treatment. CONCLUSIONS: The significant reduction in the incidence of episodes of allograft rejection observed with tacrolimus therapy may have important long-term implications given the prognostic influence of rejection on graft survival.
In this paper we report the first successful allogeneic vascularized transplantation of a fresh and perfused human knee joint. A 17-year-old male had lost his knee in a motorvehicle accident. The graft was harvested from a multiorgan donor, perfused with 41 UW solution and transplanted within 21 h. Osteosyntheses were performed employing intramedullary nails. Immunosuppression was based mainly on two drugs: cyclosporin A and azathioprine. Five months after the operation the patient is fully mobilized, and the graft perfusion still intact. Osteotomies of the femur and tibia demonstrate callus formation and osseous consolidation.
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Simultaneous pancreas/kidney transplantation has become a therapeutic approach for patients with renal failure resulting from type-I diabetes mellitus. However, the appropriate route for drainage of the exocrine secretions of the pancreatic gland remains unclear. While bladder drainage is the current state of the art, it is associated with a high frequency of urologic complications like urinary tract infections, hematuria, metabolic acidosis, and reflux pancreatitis.
Prolonged cold ischemia time and the generation of free oxygen radicals during reperfusion are risk factors for allograft arteriosclerosis. Growth factors are the main pro-proliferative mediators of smooth muscle cells in classical and in allograft arteriosclerosis. Superoxide dismutase is an enzyme that catalyzes the dismutation of superoxide anions into hydrogen peroxide. This study was designed to investigate which smooth muscle cell growth factor contribute to the formation of arteriosclerosis in syngenic vascular grafts with prolonged ischemia time, and whether perioperative intravenous administration of recombinant human superoxide dismutase (rh-SOD) prevents arteriosclerosis in these grafts. DA aortas were transplanted into DA recipients. One group of transplants was made with a short ex vivo ischemia time (15 min), while the other group transplant grafts was stored for 24 hr in cold saline. In addition to morphometric quantitation of the histological alterations, RNA isolated from grafts with short cold ischemia time in a semiquantitative polymerase chain reaction specific for various known smooth muscle cell growth factors. Syngeneic grafts with prolonged cold ischemia time showed severe intimal thickening and prominent medical necrosis, which were not seen in control groups. Approximately 3-fold levels of insulin-like growth factor-1 were found in ischemic syngeneic grafts compared with non-ischemic syngenic grafts, whereas epidermal growth factor levels were slightly lower. No changes in other growth factor mRNAs were found. Perioperative treatment with rh-SOD did not have significant effect on the extent of intimal thickening nor on the intensity of medial necrosis in grafts with prolonged ischemia time, and administration of rh-SOD did not change the expression level of insulin-like growth factor-1 in the grafts, either.
Diverse pathogenetic factors may lead to the complex syndrome of early graft dysfunction, an important determinant of later renal graft outcome. That humoral factors could play a prominent role in the development of the syndrome was suggested by the capillary deposition of complement fragment C4d in about 50% of graft biopsies. This study investigates whether the presumed classical activation of complement is derived from preformed antibodies that would possibly react against endothelial HLA-class II molecules. Such antibodies were detectable by flow cytometry using a representative collection of 11 DR-typed lymphoblastoid cell lines (LCL) as targets. Simultaneous discrimination between complement-activating and -nonactivating antibodies was achieved by two-color FACS analysis. Using this method, 44 out of 86 pretransplant serum samples from recipients with early dysfunction showed reactivity against LCL (18 complement-activating, 14 nonactivating, 12 complement-activating non-IgG). Conventional panel-reactivity was observed in 20 sera only (14 also LCL-reactive). Evaluation of corresponding graft biopsies revealed that capillary C4d was associated with LCL (P = 0.018) and panel reactivity (P = 0.015) alone and in combination (P = 0.001; Pearson's chi-square test). Thirteen subsequent graft losses within one year were observed in the LCL-reactive group as compared with seven losses in the nonreactive group (panel-reactive: 7; nonreactive: 13). Thus, measurement of LCL-reactive antibodies in prospective transplant recipients improves the assessment of an individual immunological risk. The results further demonstrate that performed antibodies do not simply reflect the enhanced overall immune reactivity of certain recipients but rather act locally in vivo, thus emphasizing the role of humoral factors in the development of early graft dysfunction.
In order to improve organizational, qualitative, and economic aspects of organ procurement, a model of regionalization was established in the local area of southern Bavaria, as from September 1993, with the following characteristics. A collaborative 24 h-duty schedule with surgeons from all active regional transplant programs. Surgeons are grouped according to their operative qualification level: (1) Group I, capable of retrieving all abdominal organs (liver, pancreas, kidney), (2) Group II, capable of removing kidneys, and (3) Group III, surgical assistance in procurement procedures. All donor organs in the local region are explanted by the local team and foreign recipient centers are supplied with the organs removed by a standardized technique. Only three times during the first, and not once during the second year, did a foreign team insist on traveling to our region to perform a liver retrieval. A survey clearly documented univocal acceptance of this model by donor hospital executives. Simplified organization and less disturbance in operating theaters were among the most frequent arguments in favor, and the familiarity of explant teams in donor hospitals was considered advantageous. Most donor hospitals do not expect to profit in terms of financial savings. When asked for further possible measures to improve organ donation, a clearer legal situation, but also the need for more information and education programs, including better media representation of transplant issues, were cited most frequently. An improvement in financial reimbursements for the donor hospitals as an instrument to enhance willingness for organ donation was not considered essential. In conclusion, our model of regionalization of organ procurement proved to be effective in achieving a high quality of organ retrieval and a reduction in personnel requirements for the transplant centers. In addition, the response from donor hospitals was unequivocally positive and may, thus, positively influence donor activity. Relevant financial savings can result from reduced on-call duties and minimized traveling costs. Further attempts to rationalize organ procurement could possibly include heart(-/lung)surgeons in the regionalized teams.
In the present study, levels of free oxygen radicals, generated in the very early period of reperfusion during human kidney transplantation, were assessed by determination of malondialdehyde (MDA) levels using a high-pressure liquid chromatography (HPLC) method. Renal blood samples were obtained during reperfusion by intraoperative cannulation of the renal vein. Simultaneously, systemic MDA levels were determined. Furthermore, local and systemic levels of interleukin 6 (IL-6), tumor necrosis factor (TNF) receptors, p55 and p75, and vitamin E were measured. In a second group of patients, 500 mg of ascorbic acid were given prior to reperfusion. Renal MDA levels in the control group were always higher compared to systemic levels. IL-6 showed a marked increase shortly after reperfusion in the renal blood. In the scavenger group there was a diminution of these effects. TNF receptor levels and vitamin E remained largely unchanged. The results of this pilot study demonstrated clinically the moderate production of reactive oxygen species and the liberation of IL-6 shortly after reperfusion of human transplanted kidneys. Furthermore, the modulating effect of a radical scavenger on these effects was shown.
Pharmacokinetics of mycophenolic acid (MPA) was analyzed in eight patients with post-transplant acute renal failure. Furthermore, the effect of hemodialysis upon blood levels of MPA and its major metabolite, MPA glucuronide (MPAG), was determined. The mean duration of the posttransplant renal failure was 18 days, but renal function resumed in all patients eventually. The patients were treated with 3 g/day of mycophenolate mofetil for 28 consecutive days combined with cyclosporine A, methylprednisolone, and ATG for induction therapy. In all patients, accumulation of MPAG but not of MPA was observed. MPA trough levels were in the range between 0.5 microgram/ml at day 2 and 2.3 micrograms/ml at the end of the study period. However, this concentration difference did not reach statistical significance. Trough levels of MPAG accumulated, reaching levels as high as 358 micrograms/ml. However, with increasing recovery of renal function, MPAG levels fell to a median trough concentration of 141 micrograms/ml. MPAG, but not MPA, could partially be removed from the circulation by hemodialysis treatment.
Despite encouraging and improving results, organ transplantation is still hampered by a shortage of organs, chronic transplant loss, and a changed patient population. Liberal inclusion criteria for dialysis and/or renal transplantation and the increasing unwillingness to donate organs in some countries had led to a growing imbalance between the numbers of transplantations performed and patients on waiting lists. Until now, poorly understood chronic transplant dysfunction is responsible for a still unchanged graft loss of approximately 5% per year. The patient population has changed to include more multimorbidity and an increasing number of risk factors (age, diabetes mellitus, former [failed] transplantations, or preexisting cardiovascular diseases). The recommendation for a against dialysis or transplantation has become increasingly difficult for the responsible physician. Newly developed immunosuppressant drugs, an increasing consideration regarding living organ donation, or xenotransplantation in the future may solve this dilemma. New reflections and considerations about the ethical background of transplantation medicine are necessary.
Our knowledge of adhesion molecules has exploded over the last 5 years and has swamped most fields of medicine including nephrology. This is not surprising because adhesion molecules play a pivotal role in all aspects of cell to cell contact. Thus, they are involved in important issues, such as fetal development, in any kind of inflammatory or immune response including allograft rejection, as well as thrombus formation, and in tumor growth and metastasis (1-3). This short overview briefly reports some aspects of the biology of relevant adhesion molecules and their significance in inflammatory kidney diseases and in hemodialysis and renal allograft rejection. Finally, new therapeutic opportunities that arise by blocking adhesion molecule function are discussed.
OBJECTIVE: To find out if patients with insulin-dependent diabetes mellitus who had undergone successful pancreas and kidney transplantation thought that their quality of life was better than that of patients before transplantation or patients who had rejected the grafts. DESIGN: Cross-sectional study. SETTING: Teaching hospital, Germany. SUBJECTS: 110 of 143 patients to whom questionnaires had been sent. Patients were divided into those awaiting transplantation who did not require dialysis (n = 9), those awaiting transplantation who were receiving dialysis (n = 27), those with functioning grafts after transplantation (n = 34), those with functioning kidneys taking insulin (n = 34); and those who had rejected both grafts and were being treated with both dialysis and insulin (n = 6). INTERVENTIONS: Short Form (SF) 36 health survey and two visual analogue scales. MAIN OUTCOME MEASURES: Comparison of quality of life scores. RESULTS: The duration of dialysis before transplantation was the only feature that differed significantly between the responders (median 24 (range 0-133) months) compared with the non-responders (16 (0-70) months), p < 0.01. The psychometric quality of the SF 36 yielded good variance and reliability in the subscales, and excellent "scale fit" values (between 90% and 100%). Patients who had undergone successful transplantation scored significantly higher than those who had rejected their pancreatic graft in the subscales "vitality" (mean (SD) transformed score 64.4 (15.2) compared with 55.5 (18.9), p < 0.05), and "general health perception" (60.8(18.2) compared with 50.2 (22.5), p < 0.05). The worst ratings of quality of life were given by patients awaiting transplantation (whether or not they were being dialysed) and those who had rejected both grafts. CONCLUSIONS: The SF 36 health survey is a valid instrument for testing patients' perceptions of outcome after transplantation. Those patients who had undergone successful pancreas and kidney transplantation gave the highest scores.
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