Biomedical subjects

W Weimar

Publications and source records attributed to W Weimar.

At least 37 records · Page 2Linked to original sources

PubMed2004

The use of cyclosporine in renal transplantation.

The introduction of cyclosporine (CsA) into clinical practice resulted in a dramatic reduction in the incidence and severity of acute rejection. As a result, short-term and medium-term kidney allograft survival increased greatly. However, the long-term patient and graft survival have not improved to a similar degree. This can partly be attributed to the side effects of CsA and partly to the fact that the use of CsA has not led to a reduced incidence of chronic allograft nephropathy. Thus, there has been a continuing search for strategies that minimize CsA toxicity but maintain adequate immunosuppression. This has resulted in the development of the CsA microemulsion formulation and improved methods for therapeutic drug monitoring. With the introduction of newer immunosuppressive drugs, early CsA withdrawal and CsA-free immunosuppressive therapy have become feasible. However, CsA weaning or complete avoidance is associated with a slightly higher risk of acute rejection, and the long-term efficacy and safety of such strategies remain to be established. Therefore, it is to be expected that in the near future CsA will remain part of the standard immunosuppressive regimen in many transplant centers.

Clinical Trials as Topic↗

PubMed2004

Apoptotic death of infiltrating cells in human cardiac allografts is regulated by IL-2, FASL, and FLIP.

INTRODUCTION: In vitro studies have shown that apoptotic cell death is triggered by a IL-2-dependent activation of the Fas-FasL pathway and that this pathway can be inhibited by FLIP. METHODS: To define whether FLIP regulates apoptotic death of graft infiltrating T-cells during IL-2-mediated rejection, we analyzed endomyocardial biopsies (EMB) from cardiac allograft recipients for CD3, DNA strand breaks (TUNEL assay), FLIP (mRNA and protein), and FasL mRNA expression. RESULTS: Apoptosis was present in CD3+ T-cell infiltrates. The number of TUNEL-stained mononuclear cells was inversely correlated with FLIP mRNA expression levels (P=.09). FLIP protein was present in 5% to 10% of the infiltrating cells and was constitutively produced by cardiomyocytes irrespective of the rejection grade. Rejection biopsies had elevated IL-2 and FasL mRNA expression levels compared to the expression levels before and after acute rejection (P=.03 and P=.11), while FLIP mRNA expression levels were significantly decreased during rejection (P=.05). CONCLUSION: Our results indicate that during the IL-2-induced rejection process, infiltrated T cells become more sensitive to apoptosis.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Laparoscopic versus open donor nephrectomy: ureteral complications in recipients.

OBJECTIVES: To describe our experience with laparoscopic donor nephrectomy (LDN) and open donor nephrectomy (ODN) regarding ureteral complications. LDN has proved to be safe and to offer significant benefits to the donor compared with ODN. Of major importance is the effect of the surgical technique on the graft. Studies have shown an increased incidence of ureteral complications in recipients of laparoscopically procured kidneys. Operative reconstruction results in additional morbidity for the recipient. METHODS: Living donors and their recipients, who underwent surgery from January 1994 to April 2002, were included in this retrospective study. A total of 122 LDN and 77 ODN recipients were included. RESULTS: Of the 122 LDN and 77 ODN recipients, 15 (12%) and 10 (13%), respectively, required percutaneous nephrostomy drainage. In total, 5 LDN (4.1%) and 5 ODN (6.5%) recipients required reconstruction of the ureter because of obstruction of the ureter or urine leakage (P value not statistically significant, excluding reconstruction required for technical errors). The operating time, warm ischemia time, and serum creatinine were comparable between recipients with or without ureter complications requiring reconstruction. CONCLUSIONS: In our experience, LDN was not associated with an increased incidence of ureteral complications in the recipient compared with ODN.

Adult↗

PubMed2003

The superior results of living-donor renal transplantation are not completely caused by selection or short cold ischemia time: a single-center, multivariate analysis.

BACKGROUND: The results of living-donor (LD) renal transplantations are better than those of postmortem-donor (PMD) transplantations. To investigate whether this can be explained by a more favorable patient selection procedure in the LD population, we performed a Cox proportional hazards analysis including variables with a known influence on graft survival. METHODS: All patients who underwent transplantations between January 1981 and July 2000 were included in the analysis (n=1,124, 2.6% missing values). There were 243 LD transplantations (including 30 unrelated) and 881 PMD transplantations. The other variables included were the following: donor and recipient age and gender, recipient original disease, race, current smoking habit, cardiovascular disease, body weight, peak and current panel reactive antibody, number of preceding transplants and type and duration of renal replacement therapy, and time since failure of native kidneys. In addition, the number of human leukocyte antigen identical combinations, first and second warm and cold ischemia periods, left or right kidney and fossa, donor kidney anatomy, donor serum creatinine and proteinuria, and transplantation year were included. RESULTS: In a multivariate model, donor origin (PMD vs. LD) significantly influenced the graft failure risk censored for death independently of any of the other risk factors (P=0.0303, relative risk=1.75). There was no time interaction. When the variable cold ischemia time was excluded in the same model, the significance of the influence of donor origin on the graft failure risk increased considerably, whereas the magnitude of the influence was comparable (P=0.0004, relative risk=1.92). The influence of all other variables on the graft failure risk was unaffected when the cold ischemia period was excluded. The exclusion of none of the other variables resulted in a comparable effect. Donor origin did not influence the death risk. CONCLUSION: The superior results of LD versus PMD transplantations can be partly explained by the dichotomy in the cold ischemia period in these populations (selection). However, after adjustment for cold ischemia periods, the influence of donor origin still remained significant, independent of any of the variables introduced. This superiority is possibly caused by factors inherent to the transplanted organ itself, for example, the absence of brain death and cardiovascular instability of the donor before nephrectomy.

Adult↗

PubMed2003

Anti-CD25 monoclonal antibody therapy affects the death signals of graft-infiltrating cells after clinical heart transplantation.

BACKGROUND: To define whether immunosuppressive agents that block the interleukin (IL)-2 pathway could prevent activation-induced cell death of activated T cells in the graft, we measured expression of IL-2, IL-2 receptor alpha chain (CD25), IL-15, Fas, and Fas ligand by real time reverse transcription-polymerase chain reaction in cardiac allografts. METHODS: We characterized the phenotype of the infiltrating cells (CD3, CD68, CD25) by immunohistochemistry. The proportion of apoptotic graft-infiltrating cells was determined by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining. We analyzed endomyocardial biopsy specimens from cardiac allograft recipients who were treated with anti-CD25 monoclonal antibody (mAb) induction therapy (daclizumab) or with matching placebo in combination with cyclosporine, steroids, and mycophenolate mofetil. RESULTS: Treatment with anti-CD25 mAb affected the number of infiltrating CD3 and CD68 cells and the IL-2-regulated apoptotic pathway. During anti-CD25 mAb treatment, significantly lower intragraft IL-2 and CD25 mRNA transcription levels and decreased numbers of CD25+ T cells were found compared with the levels measured in endomyocardial biopsy specimens from placebo-treated patients (5- to 10-fold, P=0.002 and P<0.0001, respectively). In these samples the intragraft mRNA expression levels of IL-15 were also lower (P=0.02). Inhibition of the IL-2 pathway by anti-CD25 mAb therapy was accompanied by reduced mRNA and protein of Fas ligand and not by reduced Fas expression (P=0.001 and P=0.03). TUNEL staining revealed that the proportion of graft-infiltrating cells was lower in the anti-CD25 mAb patient group than the proportion of apoptotic cells in patients receiving placebo (P=0.06). CONCLUSION: Our data suggest that immunosuppressive agents that affect the IL-2 pathway hinder the mechanism of activation-induced cell death by which the immune system eliminates alloreactive cells.

Antibodies, Monoclonal↗

PubMed2003

[Kidney transplantation: more kidneys from living donors, individualised immunosuppression and better results].

In the period 1996-2001, the number of transplanted postmortal kidneys decreased from 425 to 380, while at the same time the number of kidneys transplanted from living donors increased from 81 in 1996 to 155 per year in 2001. There was a striking increase in the proportion of living non-related donors (59/155). Although the short-term results of kidney transplantation have improved, and kidneys are very rarely lost as a consequence of acute rejection, the average life of a transplanted kidney has scarcely improved. Chronic allograft dysfunction is now the major cause of transplant loss. This process is hardly influenced by the immunosuppressive drugs currently used. To improve the cardiovascular risk profile, several centres discontinue the use of cyclosporin, tacrolimus or prednisone at 6 or 12 months after transplantation or substitute these with other drugs. This is complicated by acute rejection episodes in 10-20% of patients. With the arrival of a number of new immunosuppressive drugs the risk of rejection might be reduced.

Graft Rejection↗

PubMed2003

[Twenty-five years of cyclosporin use in transplantation medicine].

Cyclosporin has greatly improved the short and medium-term outcomes for solid organ transplantation. However, the effect on the long-term outcome has been less impressive. This can partly be attributed to the side effects of cyclosporin, and partly to the fact that the use of cyclosporin has not led to a reduced incidence of chronic allograft nephropathy. Efforts to minimise these side effects have led to the development of the microemulsion form of cyclosporin and improved methods for therapeutic drug monitoring (dosage based on blood levels instead of body weight). Finally, the introduction of new immunosuppressive drugs has made it possible to further reduce the dose of cyclosporin; this might eventually lead to cyclosporin-free immunosuppressive regimens.

Cyclosporine↗

PubMed2003

Ischemia times and donor serum creatinine in relation to renal graft failure.

BACKGROUND: The results of renal transplantation are dependent on many variables. To simplify the decision process related to a kidney offer, the authors wondered which variables had the most important influence on the graft failure risk. METHODS: All transplant patients (n=1,124) between January 1981 and July 2000 were included in the analysis (2.6% had missing values). The variables included were donor and recipient age and gender, recipient original disease, race, donor origin, current smoking, cardiovascular disease, body weight, peak and current panel reactive antibody (PRA), number of preceding transplants, type and duration of renal replacement therapy, and time since failure of native kidneys. Also, human leukocyte antigen (HLA) identity or not, first and second warm and cold ischemia times, left or right kidney and fossa, donor kidney anatomy, donor serum creatinine and proteinuria, and transplantation year were included. RESULTS: In a multivariate model, cold ischemia time and its time-dependent variable significantly influenced the graft failure risk censored for death (P<0.0001) independent of any of the other risk factors. The influence primarily affected the risk in the first week after transplantation; thereafter, it gradually disappeared during the first year after transplantation. Donor serum creatinine also significantly influenced the graft failure risk in a time-dependent manner (P<0.0001). The risk of a high donor serum creatinine is already enlarged in the immediate postoperative phase and increases thereafter; the curve is closely related to the degree of the elevation. The other variables with a significant influence on the graft failure rate were, in order of decreasing significance, recipient age, donor gender, donor age, HLA identity, transplantation year, preceding transplantations, donor origin, and peak PRA. CONCLUSIONS: Donor serum creatinine and cold ischemia time are important time-dependent variables independently influencing the risk of graft failure censored for death. The best strategy for improving the results of cadaveric transplantations is to decrease the cold ischemia time and to allocate kidneys from donors with an elevated serum creatinine to low-risk recipients.

Adult↗

PubMed2003

Live donor nephrectomy and return to work: does the operative technique matter?

BACKGROUND: Several studies report an earlier return to work after minimal invasive kidney donation compared to open donor nephrectomy. However, this variation in outcome might be influenced by other factors than the surgical technique used, such as the advice given by the physician regarding return to work. In this study, we compare the absence from work after open (ODN), laparoscopic (LDN), and hand-assisted donor nephrectomy (HA) performed in the Netherlands, in relation to the advice given. METHODS: Questionnaires containing questions about return to work or return to daily activities were sent to 78 donors from three hospitals. In the HA and ODN hospitals, advice on full return to work was 3 months. In contrast, advice given in the LDN hospital was 6 weeks. RESULTS: After LDN, donors resumed their work after 6 weeks, 5 weeks faster compared to ODN (p = 0.002) and HA (p <0.001). Complete return to work occurred 9 weeks sooner in the LDN group compared to the ODN and HA groups (both p <0.001). In the unemployed group, there was no significant difference in length until full return to daily activities. CONCLUSION: Return to work is influenced by the advice on return to work given by the physician as well as the morbidity associated with the surgical approach.

Absenteeism↗

PubMed2003

Unusual presentation of herpes virus infections in renal transplant recipients exposed to high mycophenolic acid plasma concentrations.

Viral infections constitute an important problem for transplant recipients and their physicians. Often the balance between adequate and over-immunosuppression is hard to find and therapeutic drug monitoring might be a welcome adjunct in the management of transplant patients. We report four renal transplant recipients with extra-ordinary presentations of viral disease who were all treated with mycophenolate mofetil and in whom high mycophenolic acid (MPA) trough levels were found. High MPA levels may reflect over-immunosuppression resulting in infectious complications.

Adult↗

PubMed2003

Patients on chronic hemodialysis have no intrinsic lymphocyte defect upon stimulation with interleukin-2, interleukin-15 or tumor necrosis factor-alpha.

BACKGROUND: Patients on chronic hemodialysis (HD) suffer from general immune incompetence, resulting in a high incidence of infectious complications, impaired response to vaccinations and a high incidence of malignancy. Although various abnormalities in T cell function of HD patients have been described, it remains unclear whether this is due to an intrinsic T cell defect. AIM: In the present study we tested the capacity of T cells to proliferate upon stimulation with antigen-presenting cell and T-cell-derived cytokines. METHODS: The proliferation capacity of lymphocytes obtained from patients on HD and healthy controls was determined by measuring the proliferation of peripheral blood mononuclear cells (PBMC) after stimulation with rhIL-2, rhIL-15, rhTNF-alpha, or combination of those cytokines. In all samples the percentage of alpha/beta TCR-positive T cells was measured. RESULTS: After isolation of PBMC the percentage of T cells varied from 70% (before stimulation) to 80% (after stimulation). IL-2, IL-15 and TNF-alpha all induced PBMC proliferation, while the combination TNF-alpha plus IL-2 or TNF-alpha plus IL-15 appeared to be additive. No difference between PBMC from HD patients and controls was found. CONCLUSION: We conclude that lymphocytes from HD patients have no intrinsic defects in their proliferation capacity after stimulation with IL-2, IL-15 or TNF-alpha, in vitro, as the increase in counts per minute is predominant.

Cell Division↗

PubMed2002

Technical considerations and pitfalls in laparoscopic live donornephrectomy.

BACKGROUND: Recent developments in laparoscopic solid organ surgery suggest a possible reduction in postoperative discomfort and disability for kidney donors. Technical aspects and the influence of surgical experience in laparoscopic donor nephrectomy were evaluated. METHODS: The clinical outcome of 57 laparoscopic donor nephrectomies (LapNx) was compared with that for a historic control group of 27 open donor nephrectomies (OpenNx). RESULTS: Three conversions to open nephrectomy (5.2%) were necessary. Postoperative complications were minor and comparable in both groups. Patients who underwent laparoscopic surgery demonstrated significantly less postoperative pain and a shorter hospital stay, but operative time and warm ischemia time were significantly longer. Graft survival after LapNx was 100% during a median follow-up period of 13 months. Operative time for LapNx decreased considerably with experience gained and seemed to be less for right nephrectomy. Stenotic ureter-bladder anastomoses occurred after LapNx in four patients during the first half year (7.0%), but this problem seemed to be resolved after modification of the technique. CONCLUSION: LapNx is associated with less postoperative discomfort and improved convalescence.

Case-Control Studies↗

PubMed2002