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W Weimar

Publications and source records attributed to W Weimar.

At least 127 records · Page 7Linked to original sources
PubMed1998

Immunogenic human leukocyte antigen class II antigens on human cardiac valves induce specific alloantibodies.

BACKGROUND: The kinetics of panel reactive antibodies (PRA) and incidence of antibodies directed against human leukocyte antigen (HLA) class II were studied in patients who received a cryopreserved cardiac valve allograft. METHODS: A complement-dependent microlymphocytotoxicity test was used to determine the percentage of panel reactive antibodies. Anti-HLA class II antibodies were measured by two-color fluorescence assays. RESULTS: The panel reactive antibodies became positive in 25 (78%) of 32 recipients between 1 and 16 months after implantation. Antibodies against HLA class II antigens were detected in 11 (37%) of 30 patients. In 9 (82%) of 11 cases these antibodies were donor specific. The induction of antibodies against donor HLA class II antigens suggests that intact HLA class II antigens are expressed by viable cells within the graft. Dithiothreitol analysis showed that the antibodies were of the immunoglobulin G type. Apparently, the HLA class II antigens are expressed in an immunogenic way, as activation of specific T-helper cells is essential for the switch from immunoglobulin M to immunoglobulin G antibodies. CONCLUSIONS: Allogeneic valve transplantation is associated with the production of donor-specific anti-HLA class I and II antibodies that could contribute to graft failure. This possibly detrimental effect might be prevented by cross matching in sensitized patients.

Adult↗
PubMed1998

The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation.

BACKGROUND: Mycophenolate mofetil, a pro-drug for mycophenolic acid, reduces the likelihood of allograft rejection after renal transplantation. We studied the relationship between mycophenolic acid pharmacokinetics and the likelihood of rejection in a randomized concentration-controlled trial. METHODS: Under double-blind conditions, recipients of kidney transplants were followed for evidence of allograft rejection for 6 months. In addition to mycophenolate mofetil, patients received usual doses of cyclosporine (INN, ciclosporin) and corticosteroids. The dose of mycophenolate mofetil (given twice daily) was controlled by feedback, with mycophenolic acid area under the concentration-time curve (AUC) as the controlled variable. Patients were randomly assigned to 1 of 3 target AUC groups. RESULTS: Logistic regression analysis showed a significant (P < .0001) relationship between mycophenolic acid AUC and the likelihood of rejection. High mycophenolic acid values were associated with a very low probability of rejection. An AUC of 15 micrograms.h/mL yielded 50% of maximal achievable efficacy with a 4% change of efficacy for a 1 microgram.h/mL change in AUC at the midpoint of the logistic curve. Exploratory analyses showed other variables (e.g., the maximum observed plasma concentration, predose plasma concentration, and drug dose) had poorer predictive power for the rejection outcome. Bivariate regression confirmed the importance of AUC as a highly predictive variable and showed low predictive value of other variables, once the contribution of AUC had been considered. The characteristic side effects of mycophenolate mofetil therapy appeared related to drug dose but not to mycophenolic acid concentration. CONCLUSIONS: The AUC of mycophenolic acid is predictive of the likelihood of allograft rejection after renal transplantation in patients receiving mycophenolate mofetil.

Area Under Curve↗
PubMed1998

The application of human monoclonal antibodies for monitoring donor derived soluble HLA class I molecules in the serum of heart transplant recipients.

Increased levels of both donor and recipient derived HLA molecules can be found in serum and plasma of transplanted patients during rejection. Recent data suggest that levels of donor specific soluble HLA Class I (sHLA-1) correlate better with graft rejection than total sHLA Class I [1, 2]. Therefore, quantification of donor specific soluble counterparts of HLA Class I in the serum of the recipient may be a new way for non-invasive monitoring of rejection after organ transplantation. Up to now, only a limited number of mouse monoclonal antibodies (alpha HLA-A2, and alpha HLA-B7) has been used in enzyme linked immunosorbent assays (ELISAs) to detect donor specific HLA molecules in the plasma of transplant recipients. To monitor other donor-recipient combinations, we tested some of our HLA Class I specific human monoclonal antibodies, routinely used in complement dependent cytotoxicity, for their suitability in ELISA based assays. In the present model system, we used alpha HLA-A9 (BvK5C4) or alpha HLA-A3 (OK2F3) hybridoma-supernatant to set up a sHLA-A9 and sHLA-A3 specific ELISA. In a pilot study we show that these assays were sensitive enough to detect an increase of donor specific sHLA-I during rejection in the plasma of two heart transplant recipients. Use of a large set of human hybridoma's will enable monitoring most recipient/donor combinations in the near future.

Animals↗
PubMed1998

Mutual tolerance after liver and not after heart transplantation? Evaluation of patient-anti-donor and donor-anti-patient responses by mixed lymphocyte culture.

The ultimate goal in organ transplantation is the induction of donor-specific transplantation tolerance. The fact that in some patients it is possible to withdraw immunosuppressive therapy completely, suggests that immunological adaptation or donor-specific nonresponsiveness can occur following transplantation. In earlier studies we have shown that after blood transfusion, the mixed lymphocyte reactivity of the donor against patient peripheral blood mononuclear lymphocytes taken after blood transfusion gradually decreased with time. This may reflect the induction of an immunoregulatory mechanism, which protects the recipient against an immune reaction of the donor, enhancing a state of mixed chimerism. A similar phenomenon might also play a role in the immunological mechanism leading to transplantation tolerance. Therefore, we studied responses in patients with a well-functioning liver and heart transplant using a primed lymphocyte test (PLT) and a mixed lymphocyte culture (MLC). Two years after liver transplantation the PLT and MLC responses of patient against donor were decreased significantly compared to the situation before transplantation. The response of donor against patient was also lower two years after transplantation. The decreased responses were donor-specific since responses to third-party cells generally remained unchanged. In heart transplant recipients we could not detect a donor-specific downregulation. The reversed response, of donor against patient, was not different from responses of third-party against patient cells. Therefore, we conclude that donor-specific nonresponsiveness is not induced in patients with well-functioning heart transplants. In contrast, after a successful liver transplantation the response of patient against donor is decreased, as is the reversed response. It may be valuable to test whether in liver transplant patients withdrawing or reducing of maintenance immunosuppression is permitted for patients who appear to have developed two-way donor-specific hyporeactivity.

Cells, Cultured↗
PubMed1998

Kinetics of circulating cytotoxic T lymphocyte precursors that have a high avidity for donor antigens: correlation with the rejection status of the human cardiac allograft.

Studies on graft infiltrating cells demonstrated that accumulation of cytotoxic T lymphocytes (CTL) with high avidity for donor antigens (Ag) coincided with acute cardiac rejection. In the present study, we analyse whether such high-avidity CTL are present within the peripheral blood of cardiac transplant recipients and whether their kinetics correspond with the rejection status of the allograft. Using limiting dilution analysis (LDA), donor-specific CTL were enumerated in serial blood samples of seven patients. From each patient, 7-11 samples were obtained during the first year after transplantation and up to three samples were obtained at a later date. Enumerated donor-specific CTL were divided into CTL with high or low avidity for donor Ag, depending on their sensitivity to CD8-blocking. In contrast to the situation in the graft, the donor-specific CTL present within the peripheral blood were CTL precursors (pCTL) and not fully mature CTL (cCTL). The number of donor-specific pCTL among peripheral blood cells fluctuated irrespective of the rejection grade of the allograft, indicating that the frequency of circulating donor-specific CTL does not reflect the immunological status of the allograft. During acute cardiac rejection, 66% (median) of the circulating donor-specific pCTL had a high avidity for donor Ag. This percentage significantly exceeded pre- and postrejection values obtained during the first year post-transplantation (median, 39% and 37%, respectively). The disparity in avidity increased even further more than 1 year after transplantation, when stable engraftment was achieved. Among donor-specific pCTL in peripheral blood, those with a high avidity were absent (median, 0%). Hence the avidity of circulating donor-specific CTL might inform us about the immune status of the cardiac allograft.

Antigens↗
PubMed1998

Angiotensin-converting enzyme inhibition does not correct early defects in renal and vascular permeability in diabetes mellitus.

1. In diabetes mellitus a selective increase in the excretion of albumin generally precedes the occurrence of demonstrable loss of glomerular size-selectivity. However, even in this (microalbuminuric) phase of diabetic nephropathy a defect in glomerular barrier function can be demonstrated during infusion of atrial natriuretic peptide. 2. The aim of this study was to investigate whether angiotensin-converting enzyme inhibition could prevent the proteinuric response to atrial natriuretic peptide in these patients. We performed infusions of atrial natriuretic peptide (0.01 microgram min-1 kg-1) in 10 patients with insulin-dependent diabetes mellitus and microalbuminuria (urinary albumin excretion 90 +/- 44 mg/day), both before and after 1 month of treatment with enalapril (20 mg once daily). 3. Despite a 40% reduction in proteinuria, angiotensin-converting enzyme inhibition did not prevent the atrial natriuretic peptide-induced increase in protein excretion. Both before and during angiotensin-converting enzyme inhibition, atrial natriuretic peptide infusion resulted in a significant increase in the fractional excretion of large dextran molecules, which is compatible with an increase in flow through large unrestrictive 'shunt' pores. Atrial natriuretic peptide infusion also induced an increase in the transcapillary escape rate of albumin and angiotensin-converting enzyme inhibition also failed to prevent this effect of atrial natriuretic peptide on peripheral capillary permeability. 4. We conclude that angiotensin-converting enzyme inhibition during 1 month does not correct the capillary barrier function defect in patients with diabetes mellitus and microalbuminuria that is unmasked by atrial natriuretic peptide infusion.

Albuminuria↗
PubMed1998

The frequency and avidity of committed cytotoxic T lymphocytes (cCTL) for donor HLA class I and class II antigens and their relation with graft vascular disease.

Cellular immune processes may trigger the development of graft vascular disease (GVD). CD4 and CD8 cytotoxic T lymphocytes that infiltrate the allograft could play a role in the development of GVD. We studied the presence of in vivo primed or committed CTL (cCTL) and their avidity for donor HLA class I and class II antigens in graft-infiltrating lymphocyte cultures propagated from endomyocardial biopsies derived from patients with and without signs of GVD. The fraction of cCTL with high avidity for HLA class I or class II antigens was estimated by the addition of anti-CD8 or anti-CD4 MoAbs to the cytotoxic phase of the limiting dilution analysis. In the first year after transplantation no difference in the frequency of donor-specific class I cCTL between patients with and without GVD was found. Addition of anti-CD8 MoAb revealed that most cultures predominantly consisted of cCTL with low avidity for donor HLA class I antigens, irrespective of the development of GVD at 1 year after transplantation. However, in patients who did not develop GVD, the frequency of cCTL with donor HLA class II specificity was significantly higher than in patients who did develop GVD. The avidity for donor HLA class II antigens was comparable in both groups. A high frequency of donor-specific cCTL for HLA class II antigens seems to be a protective factor against the development of GVD. These cCTL might be cytotoxic for cells involved in GVD development, e.g. activated endothelium and smooth muscle cells of donor origin.

Antibodies, Monoclonal↗
PubMed1998

Hepatitis B and hemodialysis: the impact of universal precautions in preventing the transmission of bloodborne viruses.

A detailed description is presented of the hemodialysis treatment for 6 weeks of a patient strongly positive for hepatitis B virus ([HBV], hepatitis B surface antigen, hepatitis B e antigen, HBV DNA), which was performed without any special precautions. All 59 patients potentially exposed to the HBV-positive patient, of whom 29 appeared fully unprotected by antibody, were followed for at least 9 months but remained negative. This illustrates the feasibility of following Universal Precautions instead of using exceptional procedures for one single agent.

Adult↗
PubMed1998

Renal insufficiency after heart transplantation: a case-control study.

BACKGROUND: In Rotterdam 304 heart transplants have been performed since 1984. End-stage renal failure, necessitating renal replacement therapy, has developed in 24 patients (8%) after an interval of 25-121 months (median 79 months). After starting renal replacement therapy one-year survival was only 60%. Overall survival after heart transplantation, however, was favourable: 5 and 10 year survival rates of 79% and 50% respectively. METHODS: A case-control study was performed to identify possible risk factors in cases who went on to develop end-stage renal failure compared to controls. RESULTS: We found that renal failure was not limited to elderly patients with ischaemic heart disease, but also occurred in young patients having dilated cardiomyopathy. A significant rise in the serum creatinine was found in cases compared to controls as early as 3 months after transplantation. Cyclosporin dose and trough levels were not different between cases and controls. Neither were there differences in the use of calcium-antagonists or other antihypertensive drugs, allopurinol or diuretics. Rejection incidence was also similar between the two groups. CONCLUSIONS: Renal failure after heart transplantation is a long term complication of cyclosporin use that is not limited to elderly patients with ischaemic heart disease. Cyclosporin dose and trough levels in the cases were not different from patients maintaining stable good renal function, indicating that cyclosporin nephrotoxicity is the result of an individually determined susceptibility to cyclosporin. Suggestions for future strategies to prevent renal failure are given.

Adolescent↗
PubMed1998

Forearm vasorelaxation in hypertensive renal transplant patients: the impact of withdrawal of cyclosporine.

OBJECTIVE: To determine whether cyclosporine A-induced hypertension in renal transplant recipients is accompanied by impairment of endothelium-dependent vasodilatation, which has been suggested by in-vitro and in-vivo animal experiments. DESIGN AND METHODS: In-vivo endothelium-dependent and endothelium-independent vasodilatation, and plasma concentrations of vasoactive hormones in 16 renal transplant patients were determined while they were being treated with cyclosporine A, and 16 weeks later, after their treatment had been changed to azathioprine therapy. The vasodilator response of the forearm vascular bed was measured by strain gauge venous occlusion plethysmography during intra-arterial infusion of acetylcholine (endothelium-dependent vasodilatation) and nitroprusside (endothelium-independent vasodilatation). Postischemic reactive flow was measured after 10 min of arterial occlusion. In addition, plasma concentrations of norepinephrine, and the prostanoids prostaglandin E2 and thromboxane B2, and also concentration of cyclosporine A in blood, were measured. Glomerular filtration rate and renal blood flow were estimated 1 day before the plethysmography study during each treatment period. RESULTS: Upon changing from cyclosporine A to azathioprine treatment, mean arterial pressure fell significantly by 12+/-3% (P< 0.05). Glomerular filtration rate and renal blood flow increased by 13+/-5 and 19+/-8%, respectively (both P< 0.05), while renal vascular resistance fell by 48+/-11% (P< 0.01). Both baseline forearm blood flow and baseline forearm resistance did not change after conversion (5.7+/-0.7 versus 4.9+/-0.6 ml/100 ml/min, and 27.3+/-4.2 versus 26.2+/-3.2 arbitrary units). The absolute and relative forearm blood flow responses, and forearm vascular resistance responses to infusions of acetylcholine and nitroprusside were similar during treatments with cyclosporine A and azathioprine. Peak postischaemic forearm blood flow was 42+/-12% higher during cyclosporine A treatment than it was during azathioprine treatment (P< 0.05), but the minimal postischaemic forearm vascular resistance did not differ for these treatments. Plasma prostaglandin E2 and thromboxane B2 levels decreased by 34+/-7 and 45+/-8%, respectively, after changing treatment, but norepinephrine levels did not change. CONCLUSIONS: Our data indicate that cyclosporine A-induced hypertension in renal transplant recipients is not accompanied by an increase in forearm vascular resistance. In addition, changing from cyclosporine A to azathioprine treatment did not cause changes in endothelial vasodilator functioning, although mean arterial pressure decreased significantly. Our results do not support the hypothesis that attenuation of endothelial vasodilator functioning contributes to the development of cyclosporine A-induced hypertension.

Adult↗
PubMed1998

The nature of acute rejection is associated with development of graft vascular disease after clinical heart transplantation.

BACKGROUND: To determine mechanisms that trigger graft vascular disease (GVD) after heart transplantation, we studied parameters that reflect both early and late intragraft allogeneic reactions. METHOD: With reverse transcriptase-polymerase chain reaction analysis, mRNA expression of interleukin-2 (IL-2), interleukin-4, interleukin-6, interleukin-10, interferon-gamma, platelet-derived growth factor-alpha, and transforming growth factor-beta was measured in endomyocardial biopsy (EMB) specimens obtained from 34 recipients during the first acute rejection episode (n = 29) or at a comparable time after transplantation for patients without rejection (n = 5) and at time of assessment of GVD by coronary angiography at 1 year (n = 34). RESULTS: At the time of assessment of GVD, mRNA expression of IL-2, interleukin-4, and interleukin-6 were barely detectable, whereas messenger coding for interferon-gamma, interleukin-10, transforming growth factor-beta, and platelet-derived growth factor-alpha genes were constitutively expressed. Moreover, intragraft mRNA patterns of cytokines and growth factors between patients with GVD (n = 17) or without GVD (n = 17) were comparable. In contrast, during the first acute rejection episode a completely different pattern was found. Development of GVD was associated with IL-2 mRNA expression and not with the other cytokines analyzed. IL-2 mRNA was present in 77% of rejection EMB specimens obtained from patients with GVD versus 33% of the EMB specimens obtained from patients without GVD (p = 0.03) and not detectable in EMB specimens obtained from patients with no rejection. Also nonimmunologic risk factors such as longer ischemia time (median 193 vs 141 minutes; p = 0.002) and higher donor age (median 32 vs 23 years; p = 0.02) were associated with GVD. But no relation was found between these nonimmunologic risk factors and IL-2-positive acute rejections. CONCLUSIONS: Nonspecific risk factors and IL-2-positive rejections may independently trigger GVD after clinical heart transplantation.

Acute Disease↗
PubMed1998

Increased intragraft IL-15 mRNA expression after liver transplantation.

To study T-cell/macrophage interactions at the molecular level in clinical allograft rejection, we measured intragraft mRNA expression of the T-cell derived cytokine IL-2 and the macrophage derived chemokine IL-15, a novel cytokine associated with T-cell activation, in post-transplant liver biopsies (n = 33) and in non-transplanted control liver tissue by reverse transcriptase-polymerase chain reaction (RT-PCR). We analyzed biopsies without evidence of rejection (n = 12), with spontaneously resolving histological rejection (n = 10), or with histological rejection accompanied with clinical rejection (n = 11) defined by rising serum bilirubin and aspartate amino transaminase levels. IL-15 mRNA expression was present in the majority of post-transplant liver biopsies (91%, 30/33) and was significantly upregulated as compared with non-transplanted liver tissue (p = 0.005). However, the increased intragraft IL-15 mRNA level was not indicative for rejection. In contrast to intragraft IL-15 mRNA expression, IL-2 mRNA transcription was measured in the minority of the post-transplant liver biopsies (15%, 5/33) and not detectable in control specimens. In addition, IL-2 mRNA was almost specifically measured in rejection biopsies concurrent with graft dysfunction (36%, 4/11 versus 1/22 without clinical rejection; p = 0.03). No relation between intragraft IL-2 and IL-15 mRNA expression was found. The IL-15 mRNA expression levels were not higher in the IL-2 negative rejections compared with those in IL-2 positive rejections. To conclude, in contrast to IL-2, the function of IL-15 in T-cell mediated rejection remains unclear. The overall high IL-15 mRNA levels in sites of immune responses suggests that the macrophage-derived mediator IL-15 is involved in a constant flow of T-cells from the circulation into the graft.

Biopsy↗
PubMed1997

Losartan, an angiotensin-II receptor antagonist, reduces hematocrits in kidney transplant recipients with posttransplant erythrocytosis.

BACKGROUND: Posttransplant erythrocytosis (PTE) occurs in 10-15% of patients with a well-functioning kidney transplant and is associated with increased morbidity. Although the mechanism of PTE is unknown, PTE responds to inhibitors of ACE (ACE-i) in most cases. ACE converts angiotensin I to angiotensin II and is a metabolizer of a number of other peptides. METHODS: Because ACE-i frequently show side effects we wanted to elucidate the pathway by which ACE-i mediate their effect in PTE. Therefore, we treated eight patients (five with newly diagnosed PTE, two with PTE unresponsive to ACE-i, and one with PTE responsive to ACE-i, which had to be withdrawn due to side effects) with 50 mg of the type 1 angiotensin II receptor antagonist losartan for at least 14 weeks. RESULTS: Hematocrit values in the two patients who were unresponsive to ACE-i did not change significantly. In contrast, hematocrits decreased in all the other six patients from 0.53+/-0.02 to 0.44+/-0.02 after 14 weeks of treatment with losartan (mean +/- SE; P<0.005, paired t test). Graft function, cyclosporine concentration, and leukocyte and platelet count remained stable. The serum potassium level rose in one patient from 6.0 to 6.8 mmol/L but remained stable in all other patients. CONCLUSIONS: We conclude that blockade of the type 1 angiotensin II receptor is safe and effective in treating PTE.

Angiotensin Receptor Antagonists↗
PubMed1997

Infections after renal allograft failure in patients with or without low-dose maintenance immunosuppression.

BACKGROUND: Failed renal allografts are sometimes left in situ for additional clearance and urine production during hemodialysis or peritoneal dialysis, and low-dose immunosuppressive medication is often continued in such patients. We compared the morbidity and mortality due to infections between patients with (group A) or without (group B) low-dose immunosuppression (i.e., transplantectomy). METHODS: In a hospital-based cohort study, we analyzed data from patient files. We evaluated 37 patients who received 42 kidney transplantations between May 1975 and November 1995. RESULTS: A total of 2.28 vs. 0.68 infections/patient-year were found in groups A and B, respectively. The odds ratio of one or two infections developing for patients in group A compared with group B was 14.2 (95% confidence interval, 1.4-143.4; P<0.025) and 4.3 (95% confidence interval, 1.1-17.3; P<0.04). A total of five lethal infections were found in group A; no lethal infections were found in group B. CONCLUSIONS: The increase in serious and life-threatening infections associated with even low-dose immunosuppression argues in favor of discontinuation of these drugs. The removal of failed renal allografts should be considered.

Adult↗