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L B Hilbrands

Publications and source records attributed to L B Hilbrands.

At least 37 records · Page 2Linked to original sources
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↗
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↗
PubMed1998

A randomised, prospective study on the conversion from cyclosporine-prednisone to cyclosporine-azathioprine at 6 months after renal transplantation.

In a randomised prospective trial, we studied the effects of replacement of prednisone (Pred) by azathioprine (Aza), 6 months after transplantation, in stable renal allograft recipients on cyclosporine and prednisone (CsA + Pred). Out of 83 patients, 42 started treatment with CsA + Aza and 41 continued therapy with CsA + Pred. CsA was dosed to achieve a level of 150 ng/ml, the Aza dose was 3 mg/kg per day and the Pred dose was 0.15 mg/kg per day. Eighteen months after randomisation, in the CsA + Aza group 18 of the 42 patients were effectively treated with CsA + Aza. In the main, anaemia, leuco- and thrombocytopenia, and hypocorticism necessitated the reintroduction of Pred in the remaining 24 patients. Compared to the continuation of CsA + Pred, conversion of Pred to Aza resulted in a reduced number of antihypertensive drugs needed, and in lower serum total, LDL and HDL cholesterol levels; the incidence of acute rejections and graft losses was no different. In conclusion, conversion of CsA + Pred to CsA + Aza is a safe option in renal transplant patients with contraindications to long-term corticosteroid treatment.

Adult↗
PubMed1998

Renal and systemic effects of atenolol and tertatolol in renal transplant recipients on cyclosporine A.

BACKGROUND: Hypertension and nephrotoxicity are well-known side-effects of cyclosporine A (CsA). CsA-induced vasoconstriction of the afferent glomerular arteriole probably plays a role in at least the nephrotoxicity. Frequently renal transplant recipients on CsA have to be treated with antihypertensive drugs and for this purpose also beta-blockers are used. Tertatolol is a new beta-blocker with specific vasodilatory properties, and thus might be particularly useful in CsA-treated transplant recipients. METHODS: We studied the systemic and renal haemodynamic effects of atenolol and tertatolol in 12 hypertensive renal transplant recipients on cyclosporine A (CsA). In a cross-over way, all patients were treated with atenolol and tertatolol for 4 weeks each, separated by a wash-out period also of 4 weeks. At the end of each period, the mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured. RESULTS: The mean arterial pressure was lower (P < 0.05) during atenolol (124 +/- 2 mm Hg) and tertatolol (125 +/- 2 mm Hg) treatment compared with washout (132 +/- 4 mm Hg). Also the heart rate was lower (P < 0.01) during atenolol and tertatolol (54 +/- 3 and 55 +/- 2 beats/min respectively) than in the wash-out period (65 +/- 3 beats/min). GFR and RPF were not changed by either beta-blocker. CONCLUSION: In CsA treated renal transplant recipients both atenolol and tertatolol effectively reduced blood pressure. In these patients we found no evidence of a specific vasodilatory effect of tertatolol. Both beta-blockers had no negative influence on renal function. Hence, these cardioprotective agents are an attractive and safe choice for the treatment of hypertension in such patients.

Adrenergic beta-Antagonists↗
PubMed1996

Randomized, prospective trial of cyclosporine monotherapy versus azathioprine-prednisone from three months after renal transplantation.

Cyclosporine (CsA) and prednisone (Pred) are the mostly used drugs for immunosuppression after renal transplantation, but both drugs have marked side effects. Either replacement of CsA by azathioprine (Aza) or withdrawal of prednisone (Pred) resulting in CsA monotherapy can be employed to circumvent the adverse effects in the long run. Both treatment regimens were compared to this prospective randomized trial in patients who were treated with CsA and Pred during the first 3 months after renal transplantation (CsA: n=64, Aza-Pred: n=63, median duration of follow-up: 3.9 years). Estimated graft survival rates at 5 years after transplantation (in patients with a functioning graft at 3 months) were 78% in the CsA group and 87% in the Aza-Pred group. The incidence of a rejection within 3 months after start of steroid withdraw or conversion from CsA to Aza was 30% and 25% respectively (NS). At 2 years after transplantation, serum creatinine levels were lower in the Aza-Pred group (126+/-35 micromol/L) than in the CsA group (180+/-78 micromol/L; P>0.001). There were no differences in blood pressure or incidence of infections between the treatment groups. Treatment-related costs were measured during the first year after transplantation and were lower in the Aza-Pred group (DFL 40,882+/-18,895 vs. DFL 53,484+/-44,828; 1 DFL [Dutch guilder] is about US $0.60; P<0.005). In conclusion, CsA monotherapy and Aza-Pred treatment from 3 months after renal transplantation are comparably effective immunosuppressive treatment regimens, although Aza-Pred therapy results in better graft function. Withdrawal of steroids and replacement of CsA by Aza both carry a substantial risk of rejection. The previously demonstrated cost effectiveness of CsA-containing therapies seems to be limited to the first phase after transplantation. Conversion to Aza-Pred at 3 months after transplantation reduces costs.

Adolescent↗
PubMed1996

Randomized trial of misoprostol in patients with chronic renal transplant rejection.

Chronic vascular rejection is a major cause of long-term graft failure after renal transplantation. We investigated the effect of the addition of misoprostol (200 micrograms four times daily) to standard immunosuppressive therapy on the outcome of chronic rejection in a double-blind, placebo-controlled trial. Patients had to fulfill predefined histological and clinical criteria. After an entry of 40 patients into the study (22 misoprostol, 18 placebo), the inclusion of additional patients was terminated because of a high incidence of withdrawal due to adverse effects. Of the patients who used their study medication for at least 3 months (16 misoprostol, 15 placebo), graft function deteriorated in all but 5 misoprostol-treated and all but 2 placebo-treated patients. There was no difference in dialysis-free survival. Withdrawal because of adverse effects (mainly gastrointestinal complaints) occurred in 3 cases in the placebo group and in 11 cases in the misoprostol group (P < 0.05). In conclusion, we found no evidence for a beneficial effect of misoprostol on the course of chronic renal allograft rejection, while use of the drug was accompanied by a high incidence of side effects.

Adult↗
PubMed1996

Costs of drugs used after renal transplantation.

There are no detailed data on the relative contributions to overall health care costs of the various drugs that are commonly used in renal transplant patients. We performed a cost analysis in 122 patients, using the medical records and our hospital administration service as data sources, for all health care-related costs during the first year after renal transplantation. During the first 3 months all patients were on cyclosporine (CsA) and prednisone. Subsequently, they were randomly allocated to CsA monotherapy or to conversion from CsA to azathioprine. Cost of drugs comprised about 25% of total health care expenses. In CsA-treated patients, the following costs per patient per year were calculated: CsA, DFL 9929 (1 DFL is about US$0.60; 67.5% of total drug costs); antilymphocyte agents, DFL 2613 (17.8%); other immunosuppressive drugs, DFL 455 (3.1%); antimicrobial agents, DFL 687 (4.7%); antihypertensive drugs, DFL 467 (3.2%); remaining drugs, DFL 554 (3.8%). Conversion from CsA to azathioprine resulted in a decrease in mean drug costs for the remainder of the first posttransplant year of DFL 4597 (P < 0.01). Although the incidence of acute rejections tended to be higher after steroid withdrawal than after conversion (39% versus 26%, not significant), the costs of anti-rejection therapy, hospitalization, and laboratory services did not differ. We conclude that CsA is the main determinant of overall drug costs. When compared to CsA monotherapy, conversion from CsA to azathioprine at 3 months after transplantation may result in subsequent cost savings of about DFL 5000 per patient per year without a higher incidence of rejection or graft loss.

Adolescent↗
PubMed1996

Cyclosporin does not inhibit the tubular secretion of creatinine.

BACKGROUND: The immunosuppressive drug cyclosporin is known to impair renal function. The degree of renal dysfunction is usually estimated from the clearance of creatinine (CCr). Theoretically however, a fall in CCr can be caused by a decrease of GFR, an inhibition of the tubular secretion of creatinine, or the combination of both. CsA has convincingly been shown to decrease GFR, but detailed information on the effects of CsA on tubular secretion of creatinine is lacking. METHODS: We performed two studies to investigate the influence of CsA on tubular creatinine secretion. In study A we simultaneously measured CCr and GFR (using inulin) immediately before and 4 weeks after cessation of CsA therapy in 17 renal transplant patients. In study B, the rise in serum creatinine after administration of cimetidine, which blocks the tubular secretion of creatinine, was compared in renal transplant patients treated with either CsA (in whom secretion might already be inhibited) or azathioprine. RESULTS: Study A: After cessation of CsA there was an increase of GFR (54+/-15 vs 63+/-16 ml/min/1.73 m2, PCr (71+/-21 vs 82+/-23 ml/min/1.73 m2; PCr and GFR (a measure of the relative contribution of tubular secretion to the clearance of creatinine) did not change significantly (1.33+/-0.21 vs 1. 32+/-0.30). Study B: In nine couples of patients matched for GFR the relative rises in serum creatinine after administration of cimetidine were 26+/-21% and 22+/-7% for CsA and azathioprine treated patients respectively (NS). CONCLUSION: CsA does not substantially inhibit the tubular secretion of creatinine. A rise in serum creatinine after administration of CsA can thus be attributed completely to a fall in GFR.

Adult↗
PubMed1996

Detailed study of changes in renal function after conversion from cyclosporine to azathioprine.

The renal dysfunction induced by cyclosporine (CsA) has been demonstrated to be at least partially reversible after cessation of CsA therapy. The time course and magnitude of changes in various parameters of renal function after CsA withdrawal have not been studied in detail. We examined 12 renal transplant patients immediately before and 1, 2, and 4 weeks after replacement of CsA by azathioprine at 3 months after transplantation. Nine patients in whom CsA was continued during this period served as a control group. A significant increase in glomerular filtration rate ([GFR] 15 + or - 17%, p <0.01) occurred already in the first week after discontinuation of CsA. From 1 to 4 weeks after conversion, GFR did not significantly increase any further. A fall in serum creatinine (-7 + or - 9%, Ns) paralleled the rise in GFR (r = -0.76, p <0.01), but there was a further decrease of creatinine in the second to fourth week after conversion. Withdrawal of CsA induced a rise in serum magnesium in all patients (0.73 + or - 0.13 vs 0.86 + or - 0.12 mmol/l, p <0.001) as well as a marked decrease in the serum level of urate (0.39 + or - 0.09 vs 0.33 + or - 0.07 mmol/l, p <0.01) within one week. None of the observed changes took place in the control group. In conclusion, a major improvement of GFR occurs within one week after cessation of CsA therapy. Changes in the serum levels of magnesium and urate appear to be the most responsive markers of the renal effects of CsA.

Adult↗
PubMed1995

Medication compliance after renal transplantation.

Noncompliance is known to be an important cause of late graft failure after renal transplantation. We investigated prospectively the degree of compliance with immunosuppressive and antihypertensive drugs during the first year after renal transplantation by monthly pill counts. In addition, we examined whether noncompliance was related to a number of demographic and clinical variables or to the occurrence of rejections. The study population consisted of 127 patients who were involved in a randomized trial comparing cyclosporine monotherapy with azathioprine-prednisone treatment. Average compliance rates approximated 100%, although considerable variability within and between subjects was observed. Using an arbitrary limit to classify patients as compliers or noncompliers, the following frequencies of noncompliance were observed during the study year: cyclosporine, 23%; azathioprine, 13%; prednisone, 23%; atenolol, 36%; and nifedipine, 32%. Average compliance scores for all immunosuppressive drugs were superior to those of antihypertensive medication (P < 0.001). Except for a better compliance for prednisone in men as compared with women, we found no consistent relationship between compliance on the one hand and several demographic variables, graft function, or quality of life on the other hand. Patients who developed one or more acute rejection episodes showed a higher degree of undercompliance, especially for prednisone, than patients without rejections (P < 0.01). Following the occurrence of a rejection episode, compliance scores improved significantly. Keeping in mind the limitations of the pill count method, we conclude that noncompliance with immunosuppressive drugs is not a huge problem during the first year after renal transplantation. However, it is likely that noncompliance contributes to a certain number of acute rejection episodes.

Adult↗
PubMed1995

The effect of immunosuppressive drugs on quality of life after renal transplantation.

This prospective, randomized study investigates the effect of two immunosuppressive treatment regimens on quality of life after renal transplantation. At 3 months after transplantation, patients treated with cyclosporine (CsA) and prednisone (Pred) were allocated to either withdrawal of Pred (n = 60) or to conversion of CsA to azathioprine (Aza) (Aza-Pred, n = 60). Quality of life was evaluated just before randomization, and at 6 and 12 months after transplantation using the Sickness Impact Profile (SIP), the Affect Balance Scale (ABS), the Center for Epidemiological Studies Depression Scale (CES-D), measures of satisfaction with several domains of life experience, and a population-specific physical symptoms questionnaire. In both groups, the overall SIP score as well as the scores on its physical and psychosocial dimensions improved continuously after transplantation, reaching levels that are comparable to those found in the general population. The occurrence of acute or chronic rejection had a significantly negative effect on SIP and CES-D scores. Intention-to-treat analysis showed no differences between groups for scores on SIP, ABS, CES-D, and satisfaction measures. Exclusion of 41 patients who did not strictly adhere to their originally designated therapy showed a tendency for better psychosocial SIP scores in CsA patients (P = 0.05), which mainly resulted from a difference on the category of social interaction (P = 0.01). This difference occurred despite a similar rejection rate and worse renal function in CsA-treated patients. Shortly after steroid withdrawal, a high proportion of CsA patients complained of stiff or painful muscles (CsA: 74%, Aza-Pred: 36%; P = 0.002). Our data indicate that if successfully completed, CsA monotherapy from 3 months after transplantation may lead to a higher degree of psychosocial well-being as compared with conversion from CsA-Pred to Aza-Pred. It seems likely that this advantage is related to the withdrawal of Pred.

Adult↗
PubMed1995

The effects of cyclosporine and prednisone on serum lipid and (apo)lipoprotein levels in renal transplant recipients.

Disturbances of lipid metabolism are frequently encountered after renal transplantation and have been ascribed to the use of cyclosporine (CsA) and corticosteroids, but the individual contribution of each of these drugs remains uncertain. The individual effects of CsA and prednisone (Pred) on serum lipid and (apo)lipoprotein levels were compared in a prospective randomized trial. All patients received CsA and Pred during the first 3 months after transplantation. Subsequently, they were allocated to either withdrawal of Pred or conversion from CsA to azathioprine (Aza). Serum lipids and (apo)lipoproteins, including lipoprotein(a) (Lp(a)), were measured at regular intervals during the first year after renal transplantation. Analysis of variance for repeated measures of the first year results showed higher values for serum triglycerides (P < 0.001) and lower high-density lipoprotein (HDL) cholesterol levels (P < 0.05) in the CsA monotherapy group (N = 59) as compared with the AzaPred group (N = 63). At 1 yr after transplantation, CsA-treated patients had significantly higher Lp(a) levels (CsA: median, 105 (interquartile range 42 to 340) mg/L; Aza-Pred: 46 (25 to 176) mg/L; P < 0.05). The withdrawal of Pred in the CsA group resulted in a large fall in HDL cholesterol (27 +/- 30% at 5 months after transplantation) and an increase in triglycerides (49 +/- 73% at 6 months). A reversion of these changes was observed in patients who were retreated with Pred. Multiple linear regression analysis showed an independent correlation between the use of Pred and HDL cholesterol level, whereas the use of CsA was independently associated with the concentration of Lp(a).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Acute effects of nifedipine in renal transplant recipients treated with cyclosporine or azathioprine.

Cyclosporine (CsA) impairs renal function, probably by preglomerular vasoconstriction. Vasodilating substances may therefore be of benefit to ameliorate CsA-induced renal dysfunction. We studied the acute effects on blood pressure and renal function of the dihydropyridine calcium antagonist nifedipine (10 mg orally) in 20 CsA-treated renal transplant patients. In addition, we compared the effects of nifedipine when given immediately before and 4 weeks after elective conversion from CsA to azathioprine. Compared with placebo (n = 14), administration of nifedipine led to a significant decrease in blood pressure and a strong natriuretic and diuretic response. Despite the reduction in blood pressure, glomerular filtration rate improved from 60 +/- 20 (mean +/- SD) to 69 +/- 24 mL/min/1.73 m2 (P < 0.001) and renal plasma flow (RPF) increased from 260 +/- 87 to 338 +/- 120 mL/min/1.73 m2 (P < 0.001). The combination of a decreased blood pressure with an increased RPF was reflected in a sharp decrease in renal vascular resistance (0.34 +/- 0.18 units v 0.23 +/- 0.10 units; P < 0.001). The conversion from CsA to azathioprine by itself led to significant increases in glomerular filtration rate (62 +/- 15 mL/min/1.73 m2 v 76 +/- 18 mL/min/1.73 m2; P < 0.05) and RPF (280 +/- 86 mL/min/1.73 m2 v 334 +/- 66 mL/min/1.73 m2; P < 0.05). During treatment with azathioprine an effect of nifedipine on glomerular filtration rate and RPF was no longer observed, although the natriuretic effect was similar on both occasions. The decrease in renal vascular resistance was larger during treatment with CsA than during treatment with azathioprine (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Azathioprine↗