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T van Gelder

Publications and source records attributed to T van Gelder.

At least 55 records · Page 3Linked to original sources
PubMed2000

Mycophenolate mofetil, Cellcept, a new immunosuppressive drug with great potential in internal medicine.

Mycophenolate mofetil is a new immunosuppressive drug, exhibiting its effect through inhibition of proliferation of T- and B-lymphocytes. Superior efficacy of mycophenolate mofetil compared to azathioprine, in combination with cyclosporine and prednisone, in the prevention of acute rejection in organ transplantation has made mycophenolate mofetil one of the standard immunosuppressive drugs after transplantation. Mycophenolate mofetil also is an interesting candidate drug for many other, mainly auto-immune mediated diseases. The use of mycophenolate mofetil in several of these diseases is discussed. The definitive place of mycophenolate mofetil will depend on the results of randomised trials currently under way.

Autoimmune Diseases↗
PubMed2000

The difficult diagnostic approach of the intraperitoneal mesothelioma.

The malignant mesothelioma is a rare tumour with a rising incidence during the past decades [Lancet 1 (1986) 1275; Br J Int Med 28 (1971) 59; Am J Int Med 9 (1986) 397]. The tumour is derived from the mesothelial lining of the pleural cavity, the pericardium or the peritoneum. Mesotheliomas solely involving the peritoneum are particularly rare. Two cases of malignant peritoneal mesotheliomas are described to demonstrate the difficulties in diagnosing this disease. Surgical exploration, either by laparotomy, or preferably by laparoscopy, has been proven valuable as a diagnostic method.

Biopsy, Needle↗
PubMed2000

A longitudinal study of TGF-beta1 protein levels in renal allograft recipients converted from CsA to MMF or AZA.

Cyclosporine (CsA) is thought to enhance transforming growth factor (TGF)-beta1 production in vitro and in vivo and this may have a negative effect on long-term graft survival. Therefore, we studied TGF-beta1, plasma levels in 30 patients before kidney transplantation, after transplantation during CsA treatment and after conversion from CsA to azathioprine (AZA) or mycophenolate mofetil (MMF). We questioned whether TGF-beta1 plasma levels would decrease after the discontinuation of CsA and whether the TGF-beta1 plasma levels did correlate with CsA trough levels and kidney function, measured by serum creatinine levels. TGF-beta1 plasma levels measured 1 yr after transplantation were lower compared to levels measured before transplantation, however not significantly (p = 0.08). After conversion from CsA to MMF or AZA, a slight increase was observed in some patients, but in the total group TGF-beta1 levels remained unaffected. No correlation was found between the TGF-beta1 levels and CsA trough levels nor with creatinine levels. In conclusion, we did not observe higher TGF-beta1 plasma levels in plasma levels of patients receiving CsA treatment compared to blood from the same patients while on AZA or MMF.

Azathioprine↗
PubMed1999

Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients.

BACKGROUND: Triple drug treatment consisting of mycophenolate mofetil (MMF), in a standard dose of 2 g daily, combined with cyclosporine (CsA) and prednisone, has become the standard immunosuppressive regimen after kidney transplantation in many centers. The need for therapeutic drug monitoring of mycophenolic acid (MPA) has not yet been established. Several drug interactions with MMF are known. We investigated the influence of CsA withdrawal on MPA trough levels in renal transplant patients. METHODS: Fifty-two patients were treated with 1 g of MMF twice daily, and prednisone and CsA targeted between 125 and 175 ng/ml for 6 months after transplantation. At 6 months after transplantation, 19 patients were randomized for continuation of triple therapy (group A), 19 patients discontinued CsA (group B), and 14 patients discontinued prednisone (group C). We compared 12-hr fasted MPA trough levels at 6 and 9 months after transplantation within and between these groups. RESULTS: MPA trough levels during treatment with CsA, MMF, and prednisone were significantly lower than those during treatment with MMF and prednisone only (group B); median levels were 1.87 mg/L (range: 0.56-5.27) vs. 3.16 mg/L (range: 0.32-7.78), respectively (P=0.002). MPA trough levels in groups A and C did not change between 6 and 9 months after transplantation; group A median levels were 1.87 (range: 0.31-4.32) vs. 1.53 mg/L (range: 0.36-3.70), and group C median levels were 1.62 (range: 0.69-10.34) vs. 1.79 mg/L (range: 0.54-6.00), respectively. At 9 months after transplantation, patients in whom CsA was discontinued had higher MPA trough levels as compared with patients who continued the use of triple therapy (P=0.001) or patients in whom steroids were withdrawn (P=0.014). CONCLUSION: A significant increase of MPA trough levels was found after discontinuation of CsA (6 months after transplantation), resulting in almost a doubling of MPA trough levels at 9 months after transplantation. This resulted in increased MPA levels in patients without CsA as compared to MPA levels in patients continuing triple therapy or discontinuing prednisone.

Cyclosporine↗
PubMed1999

A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation.

BACKGROUND: Adding a fixed dose of 1 g b.i.d. of mycophenolate mofetil (MMF) to an immunosuppressive regimen consisting of cyclosporine and prednisone results in a 50% reduction in the incidence of acute rejection after kidney transplantation. This study was designed to investigate the relationship between pharmacokinetic data (mycophenolic acid area under the curve; MPA AUC) and the prevention of rejection after kidney transplantation. METHODS: A total of 154 adult recipients of a primary or secondary cadaveric kidney graft were randomly allocated, in this double-blind trial, to receive MMF treatment aimed at three predefined target MPA AUC values (16.1, 32.2, and 60.6 microg x hr/ml). During the first 6 months after transplantation, plasma samples for nine AUCs were collected. After analysis of the samples, a coded dose adjustment advice was generated using a Bayesian algorithm, maintaining the double blinding. Immunosuppressive therapy further consisted of cyclosporine and prednisone. The primary end point of this study was the occurrence of biopsy-proven acute rejection within the 6-month study period. RESULTS: A total of 150 patients were eligible for analysis. Although after day 21, the mean MMF dose was reduced, the mean MPA AUC gradually increased and target MPA AUC values were exceeded in all three groups. The incidences of biopsy-proven acute rejection in the low, intermediate, and high target MPA AUC groups were 14 of 51 (27.5%), 7 of 47 (14.9%), and 6 of 52 (11.5%), respectively. The incidences of premature withdrawal from the study due to adverse events in the three groups were 4 of 51 (7.8%), 11 of 47 (23.4%), and 23 of 52 (44.2%), respectively. Logistic regression analysis showed a highly statistically significant relationship between median ln(MPA AUC) and the occurrence of a biopsy-proven rejection (P<0.001). The logistic regression using median ln(Cpredose) was also statistically significant for this relationship (P=0.01), whereas it was not when using mean MMF dose (P=0.082). In contrast, the logistic regression using mean MMF dose for comparison of patients who successfully completed the study versus patients experiencing premature withdrawal due to adverse events was highly significant (P<0.001), whereas this was not significant when using median ln(Cpredose) (P=0.512) or median ln(MPA AUC) (P=0.434). CONCLUSION: MPA Cpredose and MPA AUC are significantly related to the incidence of biopsy-proven rejection after kidney transplantation, whereas MMF dose is significantly related to the occurrence of adverse events.

Acute Disease↗
PubMed1999

Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation.

BACKGROUND: Despite blockade of the interleukin-2/interleukin 2 receptor (IL-2/IL-2R) pathway by the murine anti-CD25 (i.e., IL-2R alpha chain) monoclonal antibody BT563, cardiac rejection can still occur. In these cases, growth factors other than IL-2 may contribute to allograft rejection. We studied the expression of IL-15, a macrophage-derived cytokine associated with T-cell activation, which interacts with the beta and gamma chains of the IL-2R during rejection episodes under anti-CD25 therapy. METHODS: We measured intragraft IL-15 mRNA expression and the number of IL-15- and CD68-positive cells in posttransplantation endomyocardial biopsies (EMBs; n=45) and in nontransplanted, donor-heart specimens (n=11) by competitive template reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. RESULTS: IL-15 mRNA expression was present in the majority of posttransplantation EMB specimens (91%, 41/45) and in nontransplanted donor-heart specimens (91%, 10/11). Relative IL-15 mRNA levels were neither associated with transplantation nor with rejection status. After transplantation, the number of IL-15- and CD68-positive cells significantly increased (P<0.001), but IL-15-positive cell counts did not reflect the histological rejection grade. Anti-CD25 treatment, in contrast to its effects on the IL-2/IL-2R complex, had no influence on intragraft IL-15 mRNA and protein production. In rejection EMB specimens, during (n=5) and after (n=8) anti-CD25 therapy, no differences in relative IL-15 mRNA levels, or in IL-15- and CD68-positive cell counts, were measured. CONCLUSIONS: After heart transplantation, high numbers of IL-15- and CD68-positive cells infiltrate the graft. This phenomenon is independent of the rejection status. IL-15 remains present during blockade of the IL-2/IL-2R pathway by anti-CD25 monoclonal antibodies, and it may participate in T cell-dependent donor-directed immune responses, thereby explaining the occurrence of rejection in the absence of IL-2.

Antibodies, Monoclonal↗
PubMed1999

The vanishing importance of age in renal transplantation.

BACKGROUND: The growing number of patients awaiting a kidney transplant raises questions about allocation of kidneys to the elderly and about the use of elderly donors. In all reported studies analyzing the influence of age on the outcome after renal transplantation, age is investigated as a categorical variable. METHODS: We studied age both as a categorical (Kaplan-Meier) and as a continuous (Cox) variable in a total of 509 cyclosporine-treated recipients of a primary cadaveric kidney graft who underwent transplantation between July 1983 and July 1997. For the Kaplan-Meier analysis, the population was divided into three comparably sized age groups: 17-43 years (n=171), 44-55 years (n=169), and 56-75 years (n=169). RESULTS: Patient survival was better and graft survival censored for death was worse in the younger patients. Overall graft survival (end point was death or graft failure) was not significantly influenced by age. In the Cox proportional hazards analysis, transplantation year turned out to be an important, independent variable influencing all end points. Because the influence was not linear, three periods were defined in which the relative risk remained stable: 1983-1990, 1991-1993, and 1994-1997. In the second period, the relative risk for transplant failure or death was 49% of that in the first period. In the third period, the relative risk had decreased to 22% of that in the first period. Recipient age and donor age were significant predictors of overall transplant failure. There was no interaction between these variables and transplantation year. Within each transplantation period, an increase in recipient age by 1 year increased the relative risk for overall graft failure by only 1.44%. The influence of donor age followed a J-shaped curve with a minimum at 30 years. The influence of increasing either recipient or donor age was counteracted by the improving results over time. CONCLUSION: Considering the improving results over time, there are, at this moment, no arguments for an age restriction for kidney transplant recipients or donors.

Adolescent↗
PubMed1999

Atypical mycobacterium infection with dermatological manifestation in a renal transplant recipient.

In April 1997, a 58-year-old renal transplant recipient presented with abscess-like nodules in his left calf and on his right foot. Furuncular disease was suspected and the patient was treated with flucloxacillin. However, the lesions increased in size and became ulcerative. In the following 3 months, cultures of punctuated material, blood, and urine remained negative and gram stains did not reveal micro-organisms. In June 1997, acid-fast stains were positive. A diagnosis of a nontuberculous mycobacterium (NTM) infection was made and empirical antimycobacterial therapy was started. The combination of relatively minor symptoms with enlarged purulent lesions, causing severe morbidity, raises the possibility of NTM infection in the immunocompromised patient.

Clarithromycin↗
PubMed1999

Renal graft survival in native and non-native European recipients.

Most studies on the influence of recipient race on kidney transplant survival have been performed in the United States. Generally, they show a lower survival in African-Americans than in Caucasians. Since Rotterdam has gradually become a multi-ethnic society, we were able to study the effect of origin on kidney survival. We restricted our study to recipients of a primary cadaveric kidney graft between July 1983 and July 1997 who received cyclosporin as primary immunosuppression. Patients were divided into two main groups according to origin: European (n = 399) and non-European (n = 110). No statistical differences were found for mean donor age, sex distribution, or the total number of HLA-A and DR mismatches. Non-Europeans had significantly more mismatches on their HLA-B locus (P = 0.01) and recipient age was lower (P = 0.003). The reason non-Europeans had lost their native kidneys was more often hypertension and less often congenital or hereditary diseases compared to Europeans. The causes of death and of transplant failure did not differ. A multivariate Cox proportional hazards analysis did not show European or non-European origin to be an independent predictor of graft survival (two categories, P = 0.25). The variable origin in five categories did show an independent influence on graft survival, with Arab en African recipients running higher risks than European and Asian recipients. We conclude that, in our center, the prognosis after kidney transplantation is comparable for Europeans and non-Europeans; however, in the subcategories, Arab and African recipients have a worse prognosis.

Adult↗
PubMed1999

Effect of mycophenolate mofetil on erythropoiesis in stable renal transplant patients is correlated with mycophenolic acid trough levels.

BACKGROUND: Both mycophenolate mofetil (MMF) and azathioprine (AZA) are immunosuppressive drugs that inhibit purine synthesis. In theory, MMF selectively inhibits lymphocyte proliferation, while AZA has well-known effects on red blood cells and thrombocytes as well. In renal transplant recipients we replaced CsA therapy by MMF in an attempt to reduce the immunosuppressive load 1 year after kidney transplantation. During this study we observed the effect of MMF on haematological parameters such as haemoglobin (Hb), leukocytes, and thrombocytes. METHODS: One year after kidney transplantation 26 stable patients were converted from cyclosporin A (CsA) to MMF (2 g/day). Thereafter, these patients were tapered twice in their MMF dose from 2 g to 1.5 g (4 months after conversion) and from 1.5 to 1 g (8 months after conversion) per day. The Hb levels, leukocyte and thrombocyte counts, and mycophenolic acid (MPA) trough levels were routinely measured. RESULTS: After conversion from CsA to MMF not only creatinine levels and the number of leukocytes, but also the haemoglobin (Hb) level significantly decreased in 21/26 patients (P=0.0004). In eight patients the Hb level dropped more than 1 mmol/l (=1.61 g/dl). Only in two of eight patients was an explanation for blood loss found. The effect on Hb level did not ameliorate after the first MMF dose reduction to 1.5 g/day. After tapering the MMF dose to 1 g/day, the Hb approached the pre-conversion level. Not only the MMF dose but also the mycophenolic acid (MPA) trough level correlated with the Hb level. CONCLUSIONS: After conversion from CsA to MMF 1 year after kidney transplantation, a decrease in Hb level and leukocyte count was observed. The MPA trough level correlated also with the Hb level. The effect on the Hb level was reversible after dose reduction. This finding suggests that MMF exerts a negative effect on erythropoietic cells.

Blood Cell Count↗
PubMed1999

Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a cross-sectional study.

BACKGROUND: Combining cyclosporin (CsA) and prednisone with mycophenolate mofetil (MMF) results in a significant reduction in the rate of biopsy-proven acute rejection after kidney transplantation. This is achieved with a standard daily MMF dosage of 2 or 3 g. Whether monitoring of the pharmacologically active metabolite mycophenolic acid (MPA) will lead to improved safety and efficacy is unclear. METHODS: We monitored MPA trough levels in 18 kidney transplant recipients treated with CsA, prednisone, and MMF (63 samples) and in 11 patients (31 samples) treated with prednisone and MMF only, in a cross-sectional study. All patients were at least 3 months after transplantation with stable graft function. All patients were treated with 2 g MMF for at least 3 months and 10 mg prednisone. RESULTS: The MPA trough levels in the CsA-treated patients were significantly lower (P<0.0001; Mann-Whitney) than those in patients on MMF and prednisone only (mean MPA levels 1.98+/-0.12 vs 4.38+/-0.40 mg/l respectively). CONCLUSIONS: Although all patients were treated with an identical MMF dose, a significant difference was found in the MPA trough levels between CsA- vs non-CsA-treated patients. This suggests that CsA influences the MPA trough level. The level at which CsA affects the MPA trough levels is unclear.

Cross-Sectional Studies↗
PubMed1999

Pharmacodynamics of immunosuppression by mycophenolic acid: inhibition of both lymphocyte proliferation and activation correlates with pharmacokinetics.

Mechanisms of immunosuppressive action of mycophenolic acid (MPA) on rat lymphocytes and correlations among MPA plasma concentrations (pharmacokinetics) and its suppression of immune functions (pharmacodynamics) were studied in vitro and in vivo. In vitro, MPA inhibited concanavalin A-stimulated lymphocyte proliferation in blood [tritium-labeled thymidine ([(3)H]TdR) incorporation, percentage of lymphocytes positive for proliferating cell nuclear antigen, and in S-G(2)M by flow cytometry] and activation (percentage of lymphocytes expressing CD25 or CD134). Maximum percent inhibitions (I(max)) of lymphocyte functions and concentrations of MPA (mg/l in blood) inhibiting 50% of I(max) (IC(50)) were 99%/0.14 mg/l for [(3)H]TdR, 93%/0.28 mg/l for S-G(2)M, 74%/0.29 mg/l for CD25, and 83%/0.24 mg/l for CD134. Blood sampled at different times after single or multiple oral MPA administrations at four dose levels was assayed for lymphocyte functions and MPA plasma concentrations. I(max) (%) and IC(50) (mg/l in plasma by HPLC) were 98 to 99%/0.18 to 0.19 mg/l for [(3)H]TdR, 88 to 98%/0.70 to 0.83 mg/l for S-G(2)M, 60 to 63%/0.65 to 0.81 mg/l for CD25, and 72 to 77%/0.61 to 0.74 mg/l for CD134. IC(50) values for S-G(2)M, CD25, and CD134 were higher after multiple daily treatments than after a single dose. There were clear and direct relationships among MPA dose levels, kinetics of MPA plasma concentrations, and dynamics of lymphocyte functions. MPA treatment in vitro and in vivo inhibits not only mitogen-stimulated lymphocyte proliferation in whole blood but also lymphocyte expression of cell surface cytokine receptors. These two different mechanisms of action may contribute to the therapeutic efficacy of MPA in vivo.

Animals↗
PubMed1998

The effect of tolerance to noninherited maternal HLA antigens on the survival of renal transplants from sibling donors.

BACKGROUND: During pregnancy and nursing, a baby's developing immune system is intimately exposed to the mother's antigens. To determine whether this exposure is of clinical benefit to patients who later receive an allograft as an adult, we analyzed the outcome of primary renal transplantations from sibling donors. METHODS: We retrospectively studied graft survival and rejection episodes in 205 patients who had received renal transplants at nine centers between 1966 and 1996 from sibling donors bearing maternal or paternal HLA antigens not inherited by the recipient. The sibling donors were categorized by analysis of family HLA-typing data. RESULTS: In the multicenter analysis, graft survival was higher at 5 years and at 10 years after transplantation in recipients of kidneys from siblings expressing maternal HLA antigens not inherited by the recipient than in recipients of kidneys from siblings expressing paternal HLA antigens not inherited by the recipient (86 percent vs. 67 percent at 5 years and 77 percent vs. 49 percent at 10 years, P=0.006 for both). Paradoxically, there was a higher incidence of early rejection in the former group, suggesting that fetal and neonatal exposure to maternal antigens results in immunologic priming. Pretransplantation transfusions of donor blood reduced the incidence of acute rejection while preserving the beneficial effect of tolerance to noninherited maternal antigens on graft survival. Since 1986, new immunosuppressive drugs have lessened the short-term, but not the long-term, survival advantage of grafts expressing maternal HLA antigens not inherited by the recipient. CONCLUSIONS: In the transplantation of a kidney from a sibling donor who is mismatched with the recipient for one HLA haplotype, graft survival is higher when the donor has maternal HLA antigens not inherited by the recipient than when the donor has paternal HLA antigens not inherited by the recipient.

Fathers↗
PubMed1998

[Mycophenolic acid: a welcome adjunct immunosuppressant after organ transplants].

Three major double-blind trials in kidney transplantation patients have shown that mycophenolic acid (mycophenolate mofetil), added to an immunosuppressive regimen consisting of cyclosporine and prednisone, reduces the incidence of acute rejection after kidney transplantation by 50%, during the first six months. This statistically significant reduction is achieved equally with daily doses of 2 or of 3 g. In view of the fact that the side effects (diarrhoea, abdominal cramps, leukopenia) are more frequently found in the patients treated with 3 g, it is advised to prescribe 2 g mycophenolic acid. As acute rejection is a risk factor for the development of chronic rejection and because a beneficial effect of mycophenolic acid on chronic rejection in animal models has been observed, there may also be an effect on late graft loss due to chronic rejection after kidney transplantation in man.

Cyclosporine↗