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Dirk Kuypers

Publications and source records attributed to Dirk Kuypers.

At least 19 recordsLinked to original sources
PubMed2006

Effects of gastric emptying on oral mycophenolic acid pharmacokinetics in stable renal allograft recipients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Strategies that are more elaborate than measuring predose plasma concentrations are required for the therapeutic monitoring of mycophenolic acid (MPA). * Previous studies in healthy subjects and diabetes patients have suggested that MPA pharmacokinetics are influenced by gastric emptying, but this has not been demonstrated directly. WHAT THIS STUDY ADDS: * This study has investigated the relationship between gastric emptying, measured directly (using the (14)C octanoate and (13)C glycine breath tests) and the steady-state plasma concentration-time profile of MPA. * Delayed gastric emptying was associated with a longer t(max) and lower C(max), but total exposure to MPA was not affected. * The findings suggest that it could be misleading to rely fully on short-term (<2 h) limited sampling strategies for MPA therapeutic monitoring in recipients with gastric emptying disorders, the latter occurring relatively frequently in solid organ transplantation. AIM: To investigate the effect of gastric emptying on the pharmacokinetics of mycophenolic acid (MPA) in renal transplant patients. METHODS: We assessed the effect of gastric emptying on the disposition of MPA in 27 stable renal allograft recipients at 2 years after transplantation. Gastric emptying was measured by the (14)C-octanoate and (13)C-glycine breath test. RESULTS: Delayed gastric emptying was associated with a significantly longer MPA t(max)[1.0 (0.33-2.0) h vs. 0.5 (0.33-1.0) h; mean difference 0.39 h, 95% confidence interval (CI) 0.03, 0.75; P = 0.0289] and with a significant decrease in the maximum MPA concentration after dosing [10.6 (6.5-21.3) mg l(-1)vs. 20.1 (10.7-28.5) mg l(-1); mean difference 6.5 mg l(-1), 95% CI 2.1, 10.9; P = 0.0075]. Despite the substantial effect of delayed gastric emptying rates on MPA C(max) and t(max), total dose-interval exposure, measured by the MPA AUC(0-4), was not affected by the rate of gastric emptying [20.4 (13.9-43.0) mg h(-1) l(-1)vs. 22.4 (13.1-29.8) mg h(-1) l(-1)]. CONCLUSION: Delayed gastric emptying was associated with a slower absorption of MPA, a longer time to reach peak concentrations and lower maximum concentrations. These effects should be taken into account when validating limited (<2 h) sampling strategies to estimate total MPA exposure, which could be unreliable when monitoring patients with gastric emptying disorders.

Adult↗
PubMed2006

Therapeutic drug monitoring of mycophenolate mofetil in transplantation.

A roundtable meeting to discuss the use of therapeutic drug monitoring (TDM) to guide immunosuppression with mycophenolate mofetil was held in New York in December 2004. Existing recommendations for the initial months after transplantation were updated. After ensuring adequate levels of mycophenolic acid (MPA, the active metabolite of mycophenolate mofetil) immediately after transplantation, optimal efficacy may require only a few dose adjustments, because intrapatient variability in exposure seems low. Recommendations based on current knowledge were made for posttransplantation sampling time points and for target MPA concentrations. Algorithms for estimating MPA exposure using limited sampling strategies were presented, and a new assay for MPA discussed. It was agreed that because of interpatient variability and the influence of concomitant immunosuppressants, TDM might help optimize outcomes, especially in patients at higher risk of rejection. The value of TDM in the general transplant population will be assessed from large, ongoing, randomized studies.

Algorithms↗
PubMed2006

Prometheus versus molecular adsorbents recirculating system: comparison of efficiency in two different liver detoxification devices.

Albumin dialysis by the molecular adsorbents recirculating system (MARS) and by fractionated plasma separation, adsorption, and dialysis (Prometheus[PROM]) represent novel nonbiological liver support systems specifically designed to remove albumin-bound substances. Preliminary evidence suggests a favorable impact of MARS on the course and outcome of liver failure. This study aimed at comparing the detoxification capacity of both devices. For this purpose, we performed a retrospective analysis on data prospectively collected in patients with acute-on-chronic liver failure treated with either the MARS (n = 9) or the PROM (n = 9) device on 2-5 consecutive days. Each treatment was performed for at least 5 h at identical blood and dialysate flows. Blood clearances were calculated during the first treatment session for urea nitrogen, creatinine, total bilirubin, and bile acids from paired arterial and venous line samples after 1, 4, and 6 h of treatment. Reduction ratios for all single-treatment sessions, and the overall treatment phase, were calculated from pretreatment and post-treatment values. For all markers but bile acids, the single-treatment as well as the overall treatment phase reduction ratios obtained with PROM were significantly higher compared with those obtained with MARS. PROM led at all time points to higher clearances for all evaluated solutes. Blood clearances of protein-bound substances declined over time with MARS, but not with PROM. In conclusion, a significant decline in the serum level of water-soluble and protein-bound toxins was achieved with both devices. PROM produces higher blood clearances for most toxins, which results in higher delivered treatment doses compared with a matching treatment with MARS.

Adult↗
PubMed2005

Detoxifying capacity and kinetics of prometheus--a new extracorporeal system for the treatment of liver failure.

BACKGROUND/AIMS: Extracorporeal liver support therapies have been used for several decades as a bridging therapy prior to liver transplantation or as an addendum to standard medical therapy. The Prometheus system represents a cell-free, extracorporeal, liver assist method for the removal of both albumin-bound and water-soluble endogenous toxins. The aim of the present study was to evaluate the removal capacity and selectivity of the different inbuilt dialyzers and adsorption columns during a single 6-hour treatment. METHODS: Nine patients with acute on chronic liver failure were included (6 females, age 49+/- 4 years). Levels of endogenous toxins (urea nitrogen [UN, mg/dl], creatinine [Cr, mg/dl], total bilirubin [tB, mg/dl], and bile acids [BA, mumol/l]) and albumin [Alb, g/l] were monitored in blood sampled at different sites (arterial line, venous line and between the absorbers and the high-flux dialyzer) and at various time points (time 0, 30, 60, 120, 240, and 360 min). RESULTS: A significant decrease of the serum level of all toxins was observed (UN 108.7+/- 23.2 vs. 38.1+/- 14.9, Cr 2.4+/- 0.7 vs. 1.2+/- 0.3, tB 31.1+/- 4.1 vs. 17.0+/- 1.6, BA 155.7+/- 32.5 vs. 66.0+/- 15.4; mean+/- SEM, time 0 vs. time 360, signed rank rest, all p< 0.005). The reduction rate of UN, Cr, tB and BA amounted to 68.1+/- 5.1, 45.9+/- 6.2, 41.2+/- 5.1, and 58.2+/- 5.0%, respectively. Blood clearances [Cl, ml/min] of all, but especially of the protein-bound toxins declined over time (Cl UN 171.5+/- 4.3 vs. 142.9+/- 16.8; Cl Cr 135.7+/- 10.0 vs. 111.8+/- 9.1; Cl tB 29.3+/- 5.1 vs. 13.7+/- 3.7; Cl BA 84.9+/- 4.8 vs. 45.1+/- 13.3; time 30 vs. time 360; linear mixed models, all p< 0.005). Serum albumin levels decreased by 2.9+/- 0.9 g/l (signed rank test, p=0.055). Not unexpectedly, tB was almost uniquely cleared by the adsorbers (UN 0.2+/-1.1, Cr 6.9+/- 5.7, tB 92.3+/- 4.2, BA 62.9+/- 3.9% of total Cl). CONCLUSION: Both albumin-bound and water-soluble toxins are adequately removed by the Prometheus system. Our data suggest that the rate and efficacy of removal of albumin-bound toxins is related to both the strength of the albumin binding and the saturation of the adsorption columns. Limited losses of albumin occur during treatment with the Prometheus system.

Bile Acids and Salts↗
PubMed2005

Impact of parathyroidectomy on renal graft function, blood pressure and serum lipids in kidney transplant recipients: a single centre study.

BACKGROUND: Successful kidney transplantation is believed to reverse secondary hyperparathyroidism, but persistent disease has emerged in a significant number of allograft recipients. Parathyroid hormone (PTH) is not only involved in the aetiology of calcium/phosphate abnormalities and osteitis fibrosa, but it is also a permissive factor in the occurrence of hypertension, cardiovascular damage and dyslipidaemia. In experimental renal failure, abrogation of hyperparathyroidism by administration of a calcimimetic or parathyroidectomy (PTX) attenuates progression of renal failure. To evaluate the impact of PTX on blood pressure (BP), renal graft function and serum lipids, we performed a retrospective case-controlled study in renal graft recipients. METHODS: Charts of 1647 kidney allograft recipients, transplanted between 1989 and 2004, were reviewed. Thirty-two patients with a functioning graft and a history of a successful PTX performed at least 9 months after transplantation were identified. Biochemical and clinical data available 6 months pre- and post-PTX were registered. Changes in BP, renal function and serum lipids were assessed. The data were compared with those obtained in a similar time frame in a control group closely matched for date of transplantation. RESULTS: Systolic BP (149.9 vs 141.7 mmHg), diastolic BP (85.6 vs 81.9 mmHg), pulse pressure (64.3 vs 58.8 mmHg), total cholesterol concentration (221.4 vs 211.1 mg/dl) and low-density lipoprotein cholesterol concentration (123.9 vs 106.7 mg/dl) improved significantly after successful PTX. Serum creatinine, conversely, significantly increased after PTX (1.75 vs 2.13 mg/dl, P<0.0001). No significant changes were observed in the control group in the same time period. CONCLUSION: In patients with a functioning renal graft, BP and dyslipidaemia improve, whereas serum creatinine worsens following successful PTX. Our data are in agreement with a stimulatory effect of PTH on plasma renin activity and an inhibitory effect on lipase activity, as previously demonstrated by others. To what extent the increased serum creatinine following PTX reflects a true deterioration of the glomerular filtration rate and/or is the consequence of vitamin D-induced reduction of the renal tubular secretion of creatinine needs to be elucidated by further research.

Blood Pressure↗
PubMed2005

Acute-onset, steroid-sensitive, encapsulating peritoneal sclerosis in a renal transplant recipient.

Encapsulating peritoneal sclerosis is a severe complication of peritoneal dialysis. Immunosuppressive drugs have been claimed to be helpful in the treatment of this disease, although the pathophysiological background is poorly understood. In this report, we present a patient with encapsulating peritoneal sclerosis after successful renal transplantation. Maintenance immunosuppressive therapy consisted of mycophenolate mofetil, tacrolimus, and low-dose corticosteroids. The patient was treated successfully with high doses of corticosteroids. A subsequent relapse of the encapsulating peritoneal sclerosis, probably resulting from fast tapering of the corticosteroid dose, responded well to an increase in corticosteroid dose. Our case strongly supports a therapeutic role for high-dose steroids in the treatment of encapsulating peritoneal sclerosis during its initial inflammatory stage.

Acute Disease↗
PubMed2005

Efficacy and cardiovascular safety of daclizumab, mycophenolate mofetil, tacrolimus, and early steroid withdrawal in renal transplant recipients: a multicenter, prospective, pilot trial.

This single-arm, open-label, pilot study was designed to assess the efficacy and cardiovascular safety profile of daclizumab, a humanized monoclonal interleukin (IL)-2Ralpha antibody, in combination with mycophenolate mofetil (MMF), tacrolimus, and early corticosteroid withdrawal in renal transplant recipients. Seventy-nine renal allograft recipients were treated with daclizumab (1 mg/kg; five doses starting on the day before transplant and then every two weeks), MMF (1 g b.i.d.), tacrolimus (0.2 mg/kg/d), and low-dose prednisolone, which was withdrawn at day 150 after transplant. The rate of acute rejection was determined at 12 months. Lipid profile, oral glucose tolerance, and adverse events were monitored. Of the 76 patients eligible for analysis, eight (10.5%) developed biopsy-proven acute rejection (BPAR). Ten (13.2%) experienced clinical and/or BPAR. Corticosteroids were withdrawn completely in 91% of patients at 12 months. Graft and patient survival were 97.5% and 98.7% respectively. Mean total cholesterol and triglycerides were significantly lower at 12 months post-transplant than at baseline (201 +/- 47.5 vs. 190.8 +/- 43.6 mg/dL, p = 0.005 and 196.2 +/- 133.2 vs. 144.5 +/- 76.8 mg/dL, p < 0.001, respectively). Mean hemoglobin A1c levels did not differ between baseline (5.54%) and 12 months (5.48%). New-onset post-transplant diabetes mellitus occurred in 6.6% of the non-diabetic transplanted patients. The proportion of patients with abnormal oral glucose tolerance test (OGTT) was 47% at 3 months and 39% at 12 months (p = NS). Daclizumab induction in combination with MMF, tacrolimus, and low-dose (followed by withdrawal) prednisolone appears to be effective and safe in patients receiving renal allografts. The regimen appears to be associated with a favorable cardiovascular profile.

Antibodies, Monoclonal↗
PubMed2005

Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients.

Everolimus 1.5 or 3 mg/day was compared with mycophenolate mofetil (MMF) 2 g/day in a randomized, multicenter 36-month trial in de novo renal allograft recipients (n = 588) receiving cyclosporine microemulsion (CsA) and corticosteroids. The study was double-blind until all patients had completed 12 months, then open-label. By 36 months, graft loss occurred in 7.2, 16.7 and 10.7% of patients in the everolimus 1.5, 3 mg/day, and MMF groups, respectively (p = 0.0048 for everolimus 1.5 mg/day vs. 3 mg/day); efficacy failure (biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up) occurred in 33.0, 38.9 and 37.2% of patients (p = 0.455 overall), respectively. Mortality and incidence of BPAR were comparable in all groups. Creatinine values were higher in everolimus groups, requiring a protocol amendment that recommended lower CsA exposure. Diarrhea, lymphocele, peripheral edema and hyperlipidemia were more common among everolimus-treated patients, whereas viral infections, particularly cytomegalovirus infection, increased in the MMF group. Overall safety and tolerability were better with MMF and everolimus 1.5 mg/day than with everolimus 3 mg/day. In conclusion, at 36 months, an immunosuppressive regimen containing everolimus 1.5 mg/day had equivalent patient, and graft survival and rejection rates compared with MMF in de novo renal transplant recipients, whereas everolimus 3 mg/day had inferior graft survival. Renal dysfunction in everolimus cohorts necessitates close monitoring.

Adolescent↗
PubMed2004

Natural history of parathyroid function and calcium metabolism after kidney transplantation: a single-centre study.

BACKGROUND: The natural history of parathyroid function after successful renal transplantation (RT) and the factors predisposing to persistent hyperparathyroidism (HPT) are not well established. A better knowledge of these data may be helpful in the development of algorithms for optimal surveillance and treatment of HPT after successful RT. Our aim was to evaluate the post-transplant natural history of parathyroid function and calcium metabolism in patients with a functional renal graft and to identify risk factors for persistent HPT. METHODS: Charts of 1165 allograft kidney recipients transplanted between 1989 and 2000 were reviewed. Patients with an intact parathyroid hormone (iPTH) level available at the time of transplantation were identified. The charts of the latter patients were checked for a variety of demographic and clinical data, and all determinations of the iPTH concentration available since transplantation were recorded. Serum levels of calcium, phosphorus, alkaline phosphatases and creatinine, concurrently determined, were also registered. RESULTS: After an initial fall, iPTH levels showed a slow but steady decline towards the upper normal limit. The prevalence of persistent HPT, defined as an iPTH level > or =2.5 times the upper normal limit or the need for parathyroidectomy following transplantation, remained stable at approximately 17% up to 4 years after transplantation. Patients with persistent HPT had significantly elevated serum levels of iPTH, calcium and phosphorus at the time of RT, and had spent a longer time on dialysis. Post-transplant iPTH levels correlated significantly with transplant kidney function. CONCLUSION: Kidney transplant recipients with a high iPTH and calcium x phosphate product at the time of transplantation are at risk for persistent HPT especially when renal function is suboptimal. Therapy for persistent HPT, if considered, should be initiated 3 months post-transplantation since further spontaneous improvement of parathyroid function thereafter is limited.

Calcium↗
PubMed2004

Anti-CD20 monoclonal antibody (rituximab) treatment for hepatitis C-negative therapy-resistant essential mixed cryoglobulinemia with renal and cardiac failure.

A case of hepatitis C virus (HCV)-negative essential mixed cryoglobulinemia with initial skin, joint, and liver involvement, complicated by severe renal and cardiac failure and resistant to corticosteroid therapy, plasmapheresis, chlorambucil, and cyclophosphamide is presented. Treatment with an anti-CD20 monoclonal antibody (rituximab) induced a persistent recovery of renal and cardiac function, disappearance of skin and joint lesions, and disappearance of cryoglobulins. In a 24-month follow-up period, our patient remains in remission and free of symptoms.

Adult↗
PubMed2004

The value of tuberculin skin testing in haemodialysis patients.

BACKGROUND: Chronic haemodialysis patients are at increased risk for developing tuberculosis (TB). Appropriate screening methods to detect latent Mycobacterium tuberculosis infection are required. The aim of this prospective multi-centre study was to evaluate the tuberculin skin test (TST) as a screening method for detection of M.tuberculosis infection in haemodialysis patients. METHODS: A total of 224 patients in two haemodialysis centres were prospectively tested, using 2 units of tuberculin PPD RT23. Up to three booster injections were given with a 7 day interval to patients not responding to the previous test. The results were compared with clinical and radiological data. RESULTS: The cumulative prevalence of a positive TST was 14.7% for the first test, 27.8% for the second test and 32.6% for the fourth test. There was no influence of age, gender, haemodialysis centre, dialysis efficiency, nutritional state, levels of zinc, vitamin D therapy, primary renal disease, (previous or active) immunosuppressive therapy or response to hepatitis B vaccination. There was a significant, but weak, correlation between TST positivity and a history of positive TST or TB. Chest radiography and positive TST were not correlated, yet a positive chest X-ray increased the detection of patients with latent M.tuberculosis infection up to 47.8%. CONCLUSIONS: In haemodialysis patients, a positive response of >30% to repeated TST was obtained. Two consecutive TSTs were sufficient to recruit most of the booster reactions. Since only a weak correlation was found with anamnestic data, regular TST evaluation in combination with a chest X-ray, is a useful tool to detect infection with M.tuberculosis in haemodialysis patients.

Adult↗
PubMed2004

Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study.

BACKGROUND: Because humoral immunity is believed to play a pivotal role in the pathogenesis of IgA nephropathy (IgAN), a prospective placebo-controlled randomized study was started in patients with IgAN using mycophenolate mofetil (MMF). METHODS: A total of 34 patients with IgAN were treated with salt intake restriction, angiotensin-converting enzyme (ACE) inhibition and MMF 2 g per day (N= 21) or placebo (N= 13). After 36 months of follow-up clinical, biochemical, and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis. RESULTS: Therapy had to be stopped prematurely in five patients. Two patients (MMF group) evolved to end-stage renal disease (ESRD). There was no difference between groups in the percentage of patients with a decrease of 25% or more in the inulin clearance or with a serum creatinine increase of 50% or more over 3 years. There was also no significant difference between groups in annualized rate of change of serum creatinine, computed by linear regression analysis. No significant difference was noted between groups for inulin clearance, serum creatinine, proteinuria, blood pressure, or other parameters of renal function. Hemoglobin and C-reactive protein were significantly lower in the MMF group compared with the placebo group. As a function of time, a significant decline in both groups was noted of proteinuria, parenchymal thickness of the kidneys and C3d. CONCLUSION: In patients with IgAN at risk for progressive disease, no beneficial effect of 3-year treatment with MMF 2 g per day could be demonstrated on renal function/outcome or proteinuria. However, larger randomized studies are needed to confirm or reject these results.

Adult↗
PubMed2004

Combined 'en bloc' liver and pancreas transplantation in patients with liver disease and type 1 diabetes mellitus.

Liver disease alters the glucose metabolism and may cause diabetes, but this condition is potentially reversible with liver transplantation (LTx). Type 1 diabetes mellitus may be coincidentally present in a LTx candidate and immunosuppressive drugs will aggravate diabetes and make its management more difficult for posttransplant. In addition, diabetes negatively influences outcome after LTx. Therefore, the question arises as to why not transplanting the pancreas in addition to the liver in selected patients suffering from both liver disease and Type 1 diabetes. We report two cases of en bloc combined liver and pancreatic transplantation, a technique originally described a decade ago in the treatment of upper abdominal malignancies but rarely used for the treatment of combined liver disease and Type 1 diabetes. Both recipients are currently liver disease-free and insulin-free more than 2 and 4 years posttransplant, respectively. Surgical, medical and immunological aspects of combined liver-pancreas transplantation are discussed in the light of the existing relevant literature.

Adult↗
PubMed2004

Bartter's and Gitelman's syndromes: from gene to clinic.

Bartter's and Gitelman's syndromes are characterized by hypokalemia, normal to low blood pressure and hypochloremic metabolic alkalosis. Recently, investigators have been able to demonstrate mutations of six genes encoding several renal tubular transporters and ion channels that can be held responsible for Bartter's and Gitelman's syndromes. Neonatal Bartter's syndrome is caused by mutations of NKCC2 or ROMK, classic Bartter's syndrome by mutations of ClC-Kb, Bartter's syndrome associated with sensorineural deafness is due to mutations of BSND, Gitelman's syndrome to mutations of NCCT and Bartter's syndrome associated with autosomal dominant hypocalcemia is linked to mutations of CASR. We review the pathophysiology of these syndromes in relation to their clinical presentation.

Adolescent↗
PubMed2003

Erosive enterocolitis in mycophenolate mofetil-treated renal-transplant recipients with persistent afebrile diarrhea.

BACKGROUND: Diarrhea is the most frequently reported adverse event in mycophenolate mofetil (MMF)-treated transplant patients. The aim of this study was to explore the gastrointestinal tract in MMF-treated renal transplant recipients with persistent afebrile diarrhea to characterize its nature and etiology. METHODS: Renal transplant recipients with persistent afebrile diarrhea (daily fecal output >200 g) were prospectively investigated for infections, morphologic, and functional (gastrointestinal motility and intestinal absorptive capacity) integrity of the gastrointestinal tract; 26 patients met the inclusion criteria. RESULTS: All but one patient had an erosive enterocolitis. Seventy percent of the patients had malabsorption of nutrients, contributing to the diarrhea. In +/-60%, an infectious origin was demonstrated and successfully treated with antimicrobial agents without changes in immunosuppressive regimen. In +/-40%, no infection occurred, but a Crohn's disease-like pattern of inflammation was noted. These patients also had a less pronounced bile-acid malabsorption but a significant faster colonic transit time, correlating with the trough level of mycophenolic acid (MPA). Cessation of MMF, however, was associated with allograft rejection in one third of these patients. CONCLUSIONS: Persistent afebrile diarrhea in renal transplant recipients is characterized by erosive enterocolitis, which is of infectious origin in +/-60%. In +/-40%, a Crohn's disease-like (entero-)colitis was present. Because reduction or cessation of MMF was the only effective therapy, MPA or one of its metabolites may be suggested as a possible cause. However, reduction or cessation of MMF was associated with an increased risk for rejection.

Adult↗