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T van Gelder

Publications and source records attributed to T van Gelder.

At least 37 records · Page 2Linked to original sources
PubMed2001

Proteinuria after renal transplantation affects not only graft survival but also patient survival.

BACKGROUND: Proteinuria is associated with an increased risk of renal failure. Moreover, proteinuria is associated with an increased death risk in patients with diabetes mellitus or hypertension and even in the general population. METHODS: One year after renal transplantation, we studied the influence of the presence of proteinuria on the risk of either graft failure or death in all 722 recipients of a kidney graft in our center who survived at least 1 year with a functioning graft. Proteinuria was analyzed both as a categorical variable (presence versus absence) and as a continuous variable (quantification of 24 hr urine). Other variables included in this analysis were: donor/recipient age and gender, original disease, race, number of HLA-A and HLA-B mismatches, previous transplants, postmortal or living related transplantation, and transplantation year. At 1 year after transplantation, we included: proteinuria, serum cholesterol, serum creatinine, blood pressure, and the use of antihypertensive medication. RESULTS: In the Cox proportional hazards analysis, proteinuria at 1 year after transplantation (both as a categorical and continuous variable) was an important and independent variable influencing all endpoints. The influence of proteinuria as a categorical variable on graft failure censored for death showed no interaction with any of the other variables. There was an adverse effect of the presence of proteinuria on the graft failure rate (RR=2.03). The influence of proteinuria as a continuous variable showed interaction with original disease. The presence of glomerulonephritis, hypertension, and systemic diseases as the original disease significantly increased the risk of graft failure with an increasing amount of proteinuria at 1 year. The influence of proteinuria as a categorical variable on the rate ratio for patient failure was significant, and there was no interaction with any of the other significant variables (RR=1.98). The death risk was almost twice as high for patients with proteinuria at 1 year compared with patients without proteinuria. The influence of proteinuria as a continuous variable was also significant and also without interaction with other variables. The death risk increased with increasing amounts of proteinuria at 1 year. Both the risks for cardiovascular and for noncardiovascular death were increased. CONCLUSION: Proteinuria after renal transplantation increases both the risk for graft failure and the risk for death.

Adult↗
PubMed2001

Flow cytometric quantitation of calcium-dependent and -independent mitogen-stimulation of T cell functions in whole blood: inhibition by immunosuppressive drugs in vitro.

We have optimized assays to measure mitogen-stimulated rat lymphocyte activation in whole blood and have used these assays to quantitate the potencies of immunosuppressive drugs with different mechanisms of action. To define the optimal conditions for measuring T cell functions in whole blood, the effects of different concentrations of mitogens that activate T cells through calcium-dependent and -independent pathways were measured over time. Proliferation was measured by tritium-labeled thymidine ([3H]-TdR) incorporation and by flow cytometric analysis of proliferating cell nuclear antigen (PCNA)/DNA content. Furthermore, we detected the increases in percent expression of cell-surface activation antigens (CD25, CD134, CD71, CD11a and CD54). Concanavalin A (Con A) stimulated maximum lymphocyte proliferation and expression of T cell surface activations by 72-96 h, which was 48 h later than stimulation by phorbol 12-myristate 13-acetate (PMA) plus anti-CD28 monoclonal antibody (mAb) or PMA plus ionomycin (IONO). Addition of sirolimus, tacrolimus, cyclosporine or the active metabolite of leflunomide, A77 1726, to mitogen-stimulated whole blood produced drug concentration-dependent inhibitions of lymphocyte proliferation and expression of cell surface activation antigen expression. From these data, we determined drug potencies (inhibitory concentration of 50%, IC(50)) and drug concentrations causing maximum inhibition of T cell functions (I(max)). We developed simple and reproducible assays to measure different lymphocyte functions in whole blood cultures. These assays were used to investigate the mechanisms of different immunosuppressive drugs. These methods can be exploited to measure T cell functions in blood collected from subjects treated with immunosuppressants in vivo.

Aniline Compounds↗
PubMed2001

Reassuring effect of pravastatin on natural killer cell activity in stable renal transplant patients.

BACKGROUND: Administration of pravastatin soon after transplantation successfully lowers cholesterol levels, whereas a reduced number of acute rejection episodes is accompanied by a decrease in natural killer (NK) cell activity. As a consistent low NK cell activity caused by pravastatin might impair tumor surveillance leading to cancer, we studied the effect of pravastatin on NK cell activity in stable renal transplant patients. METHODS: From 14 cyclosporine (CsA)-treated and 11 azathioprine (AZA)-treated patients with hypercholesterolemia, more than 1 year after kidney transplantation, we determined NK cell number and cytotoxic activity before, and at 6 and 12 weeks after, initiating pravastatin treatment. Additionally, cholesterol levels and liver and kidney function parameters were assessed. RESULTS: During pravastatin treatment, total cholesterol and low-density lipoprotein-cholesterol levels decreased significantly in both patient groups. In the CsA group, the number and cytotoxic activity of the NK cells at 12 weeks after institution of pravastatin was in the same range as before pravastatin. Additionally, in the AZA group, pravastatin did not influence the number of NK cells. However, in the AZA group, both the number of NK cells and their cytotoxic activity were significantly (<0.002) lower compared to the values in the CsA group. CONCLUSIONS: In contrast to previous reports on decreased NK cell cytotoxicity caused by pravastatin treatment early after transplantation, we cannot confirm these results in stable kidney recipients. In our hands, NK cell cytotoxicity during pravastatin treatment was within the same range as in the absence of pravastatin. Thus, in view of the potential role of NK cells in tumor surveillance, these data are reassuring.

Anticholesteremic Agents↗
PubMed2001

Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid.

Mycophenolate mofetil (MMF) is almost completely absorbed from the gut and is rapidly de-esterified into its active drug, mycophenolic acid (MPA). The main metabolite is glucuronidated MPA (MPAG), which is excreted into bile and undergoes enterohepatic recirculation. Studies in healthy volunteers treated with cholestyramine show that interruption of the enterohepatic recirculation decreases MPA exposure by approximately 40%. Published data show a difference in mycophenolic acid plasma concentrations between kidney transplant recipients treated with MMF plus cyclosporine (CsA) and those treated with MMF plus tacrolimus (TRL). However, the interpretation of these data is complicated by interpatient differences in variables that may influence MMF pharmacokinetics (e.g., underlying disease, co-medication, and time since transplantation). To understand the influence of TRL and CsA on MMF pharmacokinetics (PK) more completely, the authors eliminated confounding variables in clinical studies by performing drug interaction studies in inbred rats. To achieve a steady state, 3 groups of Lewis rats (n = 8 per group) were treated once daily with oral CsA (8 mg/kg), TRL (4 mg/kg), or placebo on days 0-6 before all rats began once-daily oral treatment with MMF (20 mg/kg) on day 7. Combined treatment with either MMF + CsA, MMF + TRL, or MMF + placebo was continued for 1 week (days 8-14). Thereafter, CsA and TRL treatments were stopped but MMF treatment was continued on days 14-21. Blood was sampled during the 24 hours subsequent to dosing on day 7 (after the first MMF dose), on day 14 (after multiple MMF doses) and on day 21 (after CsA/TRL washout). Rats in the MMF + TRL group and in the MMF + placebo group showed a second peak in the MPA-PK profiles consistent with enterohepatic recirculation of MPA. The MPA-PK profiles for the MMF + CsA-treated animals did not show a second MPA peak. On Day 14, the mean plasma MPA-AUC(0-24 hours) for the CsA-treated animals was significantly less than MPA exposures for rats in the MMF + TRL- and the MMF + placebo-treated groups. Furthermore, in contrast to results from other investigators, co-administration of CsA and MMF significantly increased MPAG-AUC(0-24 hours). Serum creatinines did not differ among rats in the three groups. CsA but not TRL decreased MPA plasma levels and increased MPAG-AUC(0-24 hours). These data suggest that CsA inhibits MPAG excretion into bile and offer an explanation for the well-known increased MPA exposure in organ transplant patients caused by conversion from CsA- to TRL-based immunosuppression.

Animals↗
PubMed2000

Pharmacodynamics of mycophenolic acid in heart allograft recipients: correlation of lymphocyte proliferation and activation with pharmacokinetics and graft histology.

BACKGROUND: Assays of drug blood levels are used for therapeutic immunosuppressive drug monitoring (pharmacokinetics, PK). We monitored lymphocyte functions (pharmacodynamics, PD) in allograft recipients treated with mycophenolic acid (MPA) to determine its mechanisms and the relationships among dose levels, PK, PD, and histological severity of graft rejection. METHODS: Lewis rats transplanted with Brown Norway (BN) rat hearts were treated with different dose levels of MPA for 8, 15, or 29 days at which times grafts were removed and scored for rejection grade. Blood was analyzed (high-performance liquid chromatography) for MPA plasma concentrations (area under the concentration-time curve0-24 hr, C6 hr, trough) and for lymphocyte functions using concanavalin A-stimulated whole blood assays to measure lymphocyte proliferation (tritium labeled thymidine incorporation and flow cytometric bivariate proliferating nuclear cell antigen/DNA analysis) and activation (percent lymphocytes expressing CD25 or CD134). PD values were AUE0-24 hr (area under the PD effect-time curve), maximum inhibition and trough. RESULTS: MPA equipotently suppressed (by flow cytometry) both proliferation and activation and these effects correlated with MPA plasma levels (r2=0.80-0.91). Relationships among MPA dose levels, PK and PD were clear, direct, and reproducible. Correlation coefficients after 8 days of MPA treatment were: 0.90, 0.87, and 0.49 for MPA PK (AUC0-24 hr, C6 hr and trough) versus rejection scores; 0.80-0.89, 0.86-0.92, and 0.25-0.52 for PD flow cytometric assays (AUE0-24 hr, maximum inhibition, and trough) versus rejection scores. CONCLUSIONS: MPA inhibits both lymphocyte proliferation and activation. PD by flow cytometry (FCM) correlates highly with severity of graft rejection, showing that PD of MPA measured in peripheral blood predicts immune cell activity in graft tissue.

Animals↗
PubMed2000

Donor-specific T-cell reactivity identifies kidney transplant patients in whom immunosuppressive therapy can be safely reduced.

BACKGROUND: To reduce the side effects of long-term immunosuppressive therapy, stable renal transplant patients were routinely converted from cyclosporine to either azathioprine or mycophenolate mofetil. Thereafter, the azathioprine and mycophenolate mofetil dose was reduced to 75% at 4 months and to 50% at 8 months after conversion. We questioned whether the T-cell reactivity before conversion was able to predict which patients could be safely converted and tapered in their immunosuppressive load, while remaining free from acute rejection. METHODS: Before conversion, the T-cell reactivity of peripheral blood mononuclear cells against donor and third-party spleen cells were tested in mixed lymphocyte cultures. We measured the frequency of donor and third-party reactive helper T-lymphocyte (HTLpf) and cytotoxic T-lymphocyte (CTLpf) precursors and their avidity for HLA class I antigens using limiting dilution analysis. Peripheral blood mononuclear cells were also stimulated with tetanus toxoid to test the general immune response. RESULTS: The tetanus toxoid response, reactivity to donor and third-party cells as measured in mixed lymphocyte cultures and HTLpf, and the avidity of cytotoxic T-lymphocyte precursors were not predictive for the development of acute rejection. However, significant differences were found in donor-specific CTLpf before conversion, between patients with and without acute rejection after conversion in immunosuppression. The donor-specific CTLpf was significantly lower in patients without compared to those with acute rejection (P=0.01). Additionally, when no CTLpf was detectable before conversion, acute rejection did not occur after conversion. Acute rejection was only diagnosed in patients with detectable CTLpf before conversion. CONCLUSION: The number of donor-specific cytotoxic T-lymphocytes identifies patients in whom the immunosuppressive load can be safely reduced.

Acute Disease↗
PubMed2000

Randomized study on the conversion of treatment with cyclosporine to azathioprine or mycophenolate mofetil followed by dose reduction.

BACKGROUND: The introduction of cyclosporine (CsA) in kidney transplantation has improved early graft survival. However, its long-term use is associated with impairment of renal function and increased cardiovascular risk factors. To avoid CsA-related long-term adverse effects, patients were converted to either azathioprine (AZA) or mycophenolate mofetil (MMF) 1 year after transplantation. METHODS: Between September 1995 and January 1997, 64 stable renal transplant recipients on CsA and prednisone treatment were included in a prospective, randomized study. Patients were randomized for conversion of CsA to 2 mg/kg AZA (n=30) or 1 g of MMF twice daily (n=34). All patients remained on low-dose steroids. To decrease the total immunosuppressive load, a dose reduction in MMF and AZA was performed at 4 and again at 8 months after conversion. Mycophenolic acid trough levels were measured at regular intervals. RESULTS: After conversion, a decrease in serum creatinine was found for both groups: for MMF, 132 to 109 micromol/L (P=0.016); and for AZA, 123 to 112 micromol/L (P<0.0001). After conversion, more acute rejections occurred in the AZA group (11/30) compared to the MMF group (4/34) (P=0.04). Dose reduction of MMF to 500 mg twice daily and of AZA to 1.0 mg/kg elicited three rejections in both groups. The incidence of side effects and infections were similar. CONCLUSION: Discontinuation of CsA spared renal function. In patients converted to MMF significantly less rejections occurred compared to patients converted to AZA. Furthermore, dose reduction of both AZA and MMF is possible in the majority (72%) of the patients.

Adult↗
PubMed2000

Functional responses of T cells blocked by anti-CD25 antibody therapy during cardiac rejection.

BACKGROUND: Despite anti-CD25 (interleukin [IL]-2 receptor alpha chain) monoclonal antibody (mAb) therapy, rejection can still occur. T-cell activation through the IL-2 receptor beta and gamma chains by IL-2 or other growth factors may contribute to this rejection. Recently, we have demonstrated that the T-cell growth factor IL-15 was abundantly present in rejecting cardiac grafts during anti-CD25 mAb treatment. METHODS: To test whether IL-2- and IL-15-responsive T cells play an active role in rejection during anti-CD25 mAb therapy, we measured the frequency of IL-2- and IL-15-proliferative T cells in peripheral blood from treated patients during rejection (n=12). Measurements were made by limiting dilution analysis in the absence and presence of extra in vitro-added mouse anti-human CD25 mAb. RESULTS: In the absence of anti-CD25 mAb, the frequencies of peripheral T cells responding to recombinant human (rh)IL-2 and rhIL-15 from patients were lower than those measured in samples of healthy controls (n=7): median of IL-2-responding T cells 78 per 10(6) (range 31-210 per 10(6)) vs. 154 per 10(6) (122-484 per 10(6), P=0.008) and median of IL-15-responding T cells 62 per 10(6) (range 19-207 per 10(6)) vs. 129 per 10(6) (range 79-192 per 10(6), P=0.02), respectively. In the presence of extra in vitro-added anti-CD25 mAb, frequencies of IL-2-responding T cells from patients significantly decreased, although a considerable number of T cells still proliferated on rhIL-2 (median 85%, range 46-100%). In contrast, the frequencies of IL-15 T cells still responding remained stable (median 2%, range 0-50%, P<0.001). CONCLUSIONS: Treatment with anti-CD25 mAbs cannot provide complete suppression of T-cell function because significant numbers of IL-2- and IL-15-responsive T cells remain present in the peripheral blood of allograft recipients during anti-CD25 mAb treatment.

Animals↗
PubMed2000

Mycophenolic acid trough levels after kidney transplantation in a cyclosporine-free protocol.

Twenty-seven stable kidney transplant recipients treated with cyclosporine and prednisone were converted to mycophenolate mofetil (MMF) and prednisone 1 year after transplantation. After conversion the patients were treated with a standard daily dose of 1 g MMF b.i.d. and 10 mg prednisone for 4 months. Thereafter, two MMF dose reductions were performed with a 4-month interval. Mycophenolic acid (MPA) trough levels were measured at regular intervals. A relation was found between MPA trough levels and MMF dose. The median MPA trough level for patients treated with 1 g MMF b.i.d. was 4.3 microg/ml (0.95-15.5) and 3.0 microg/ml (0.73-7.8) for patients treated with 750 mg b.i.d. (P = 0.0002). The MPA trough levels further decreased from 3.0 to 2.3 microg/ml (0.6-6.63) in patients treated with 500 mg MMF b.i.d. (P = 0.01). Dose reduction of MMF from 1 g to 750 mg b.i.d. could be performed without acute rejections. A further dose reduction to 500 mg b.i.d. elicited 3 rejections. Patients experiencing an acute rejection had a median MPA trough level of 2.3 microg/ml (1.26-3.38) compared to 3.8 microg/ml (1.48-6.52) in patients without an acute rejection (P = 0.25). We conclude that there is a significant relation between MPA trough levels and MMF dose. MPA trough levels were not predictive of rejection in the present study.

Area Under Curve↗