Biomedical subjects

Y Vanrenterghem

Publications and source records attributed to Y Vanrenterghem.

At least 19 recordsLinked to original sources

PubMed2007

Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study.

Although the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus are highly effective immunosuppressants, they are associated with serious side effects. There is great interest in immunosuppressive regimens that permit reduction or elimination of CNIs, while maintaining adequate immunosuppression and acceptable acute rejection rates. Patients (n = 536) receiving their first renal allograft were randomized to one of three immunosuppressant regimens: daclizumab, mycophenolate mofetil (MMF), corticosteroids (CS) and low-dose CsA (target trough levels of 50-100 ng/mL), weaned from month 4 and withdrawn by month 6; daclizumab, MMF, CS and low-dose CsA; or MMF, CS and standard-dose CsA. Mean GFR 12 months after transplantation (primary end point) was not statistically different in the CsA withdrawal and low-dose CsA groups (both 50.9 mL/min/1.73 m(2)) vs. the standard-dose CsA group (48.6 mL/min/1.73 m(2)). At 12 months, the incidence of biopsy-proven acute rejection was significantly higher in the CsA withdrawal group (38%) vs. the low- or standard-dose CsA groups (25.4% and 27.5%, respectively; p < 0.05). In summary, a regimen of continuous low-dose CsA with MMF, CS and daclizumab induction is a clinically safe and effective immunosuppressive regimen in renal transplant recipients.

Adrenal Cortex Hormones↗

PubMed2006

Superior dialytic clearance of beta(2)-microglobulin and p-cresol by high-flux hemodialysis as compared to peritoneal dialysis.

Both residual renal and dialytic clearance confer to the total solute clearance in dialysis patients. Dialytic clearances of the middle molecule beta-microglobulin (beta(2)M) and the protein-bound solute p-cresol (pcr) are generally believed to be higher with peritoneal dialysis (PD) as compared to hemodialysis (HD). Supportive data, however, are lacking. We performed a single-center cross-sectional observational study including 70 unselected patients treated with either high-flux HD (n=20) or PD (n=50). Mid-day serum levels (PD) and time-averaged concentrations (HD) of the water-soluble solutes urea nitrogen, creatinine and phosphate, the middle molecule beta(2)M, and the protein-bound solute pcr were determined. Dialytic solute clearances (l/week/1.73 m(2)) were calculated from total dialysate collection during the mid-week session in HD and 24 h dialysate collection in PD. Renal clearances were calculated for each of the respective solutes from a timed urine collection. Total clearances were obtained by summation. HD delivered significantly higher clearances of all retention solutes studied. This superiority was especially pronounced for pcr (30.9+/-62.7 vs 4.4+/-2.3, HD vs PD, P<0.0001) and beta(2)M (28.6+/-6.6 vs 5.8+/-3.1, HD vs PD, P<0.0001). Renal clearances, conversely, were significantly higher in patients on PD. Serum levels of all solutes but pcr were significantly lower in HD than in PD. Both a higher residual renal function and a lower generation rate contribute to the lower pcr levels in PD. In conclusion, superior dialytic clearance of both water-soluble solutes, beta(2)M, and pcr is achieved by high-flux HD as compared to PD.

Adult↗

PubMed2006

Acarbose treatment lowers generation and serum concentrations of the protein-bound solute p-cresol: a pilot study.

Several protein-bound uremic retention solutes (including p-cresol) originate from colonic bacterial fermentation of protein. Higher colonic availability of carbohydrates drives this process towards lower production of toxic metabolites. Small intestinal alpha-glucosidase inhibitors like Acarbose (Glucobay) enhance the amount of undigested carbohydrates reaching the colon. We studied the effect of Acarbose on generation and serum concentrations of p-cresol. Nine healthy volunteers (age 25 (22-36) years) with a creatinine clearance of 89.6 ml/min/1.73 m(2) (85.5-116.4) were treated with Acarbose for 3 weeks. Dose was gradually increased to reach 300 mg/day after 1 week. Blood sampling, 24-h urine and stool collections on 3 consecutive days were performed before and during the last days of the treatment period. p-Cresol generation was estimated from mean 24-h urinary elimination. Gastrointestinal side effects, if present, were mild to moderate. Serum concentrations of p-cresol declined significantly after Acarbose treatment (before: 1.14 mg/l (0.93-3.03); after: 1.11 mg/l (0.31-1.82); P=0.047). Urinary excretion of p-cresol, reflecting its colonic generation rate, was significantly lower after treatment (before: 29.93 mg/day (6.79-75.19); after: 10.54 mg/day (1.08-30.85); P=0.031). The fecal excretion of nitrogen increased after treatment (before: 1.04 g/day (0.47-2.29); after: 1.99 g/day (0.76-3.08); P=0.047). This pilot study suggests that Acarbose treatment lowers generation and serum concentrations of the protein-bound uremic solute p-cresol. Although further confirmation is warranted, the data may point to a novel treatment option for chronic kidney disease patients in view of the potential toxic effects of p-cresol and related substances.

Acarbose↗

PubMed2006

Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients.

Based on in vitro data, protein-bound uremic retention solutes have increasingly been recognized to play a pathophysiological role in the uremic syndrome. p-Cresol, a representative of this group of molecules, has been shown to be implicated in uremic immunodeficiency and endothelial dysfunction, potentially linking its serum levels to mortality. Thus far, however, no clinical information on this issue is available. To determine the relationship between p-cresol and all-cause mortality, 175 prevalent hemodialysis (HD) patients were enrolled in a prospective study. At baseline, serum levels of the water-soluble solutes urea, creatinine, and phosphate, the middle molecule beta2-microglobulin, total and free concentrations of the protein-bound solute p-cresol, and several risk factors for mortality were evaluated. During a median follow-up of 34 months, 60 patients died. Baseline comorbidity (Davies score) (hazard ratio (HR), 1.49; 95% confidence interval (95% CI), 1.19-1.86), impaired nutritional status (HR, 4.22; 95% CI, 2.15-8.29), time since initiation of dialysis (HR, 0.98; 95% CI, 0.97-1.00), and higher free concentrations of the protein-bound solute p-cresol (HR, 2.28; 95% CI, 1.12-4.64) were independently associated with mortality (multivariate Cox proportional hazards analysis). Our data suggest that free serum levels of p-cresol, a representative of the protein-bound uremic retention solutes, are associated with mortality in HD patients. These findings may encourage nephrologists to widen their field of interest beyond the scope of small water-soluble uremic solutes and middle molecules.

Adult↗

PubMed2006

Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study.

Tacrolimus combined with mycophenolate mofetil (MMF) is an effective regimen in kidney transplantation. This study compared the efficacy of combining tacrolimus and two different dosages of sirolimus with an established tacrolimus-MMF regimen. Each day in addition to tacrolimus, 325 patients received 2 mg sirolimus (TAC-SRL2 mg), 325 patients received 0.5 mg sirolimus (TAC-SRL0.5 mg) and 327 patients 1 g MMF (TAC-MMF). The initial tacrolimus dose was 0.2 mg/kg/day. Sirolimus patients received loading doses of 6 or 1.5 mg, and daily doses of 2 or 0.5 mg thereafter. Steroid administration was identical for all groups. The incidence of biopsy-proven acute rejection was lower in the TAC-SRL2 mg group (15.7%) compared with the TAC-SRL0.5 mg (25.2%, p = 0.003) and the TAC-MMF groups (22.3%, p = 0.036). Six-month graft survival was 91.0% (TAC-SRL2 mg), 92.6% (TAC-SRL0.5 mg) and 92.4% (TAC-MMF); the respective values for patient survival were 98.1%, 97.8% and 97.9%. Thirty-four patients (10.5%), 19 patients (5.8%) and 16 patients (4.9%) in the TAC-SRL2 mg, TAC-SRL0.5 mg and TAC-MMF groups, respectively, discontinued the study because of adverse events. Hyperlipemia was reported more often in the TAC-SRL2 mg group (24.0%) compared with 19.4% (TAC-SRL0.5 mg) and 11.0% (TAC-MMF; p < 0.05). Combining 2 mg sirolimus/day with tacrolimus results in lower rates of acute rejection, but a higher incidence of adverse events.

Adult↗

PubMed2006

Hypertensive brain stem encephalopathy in a patient with chronic renal failure.

Hypertensive brain stem encephalopathy is a rare disorder that can be seen in severe hypertensive encephalopathy. Patients with chronic renal failure are more prone to develop this disorder because a mild elevation of the blood pressure can already induce brain changes. It is important to diagnose this entity as soon as possible because the symptoms and brain stem lesions are reversible following treatment and because it is important to exclude brain stem ischemia in the diagnostic work-up. Brain MRI and particularly diffusion weighted images are crucial for this purpose.

Aged↗

PubMed2005

Different evolution of trough and dose levels during the first year after transplantation for tacrolimus versus cyclosporine.

At present, the two calcineurin inhibitors-cyclosporine (CsA) and tacrolimus (FK506)-are among the most frequently used immunosuppressants in clinical transplantation. Both drugs share variable oral bioavailability, which necessitates intense drug monitoring. This variability is attributed to large interindividual differences in drug catabolism by cytochrome P450 3A4/5 (CYP3A4/5) and drug efflux by P-glycoprotein (PGP). In addition, the activity of both CYP3A4 and PGP can vary substantially within the same individual due to environmental factors such as concomitant intake of inducing/inhibiting medications (eg, rifampicin/sporanox) or food substances (eg, grapefruit juice). More recently, an inducing effect of methylprednisolone on intestinal and hepatic CYP3A4 has been shown. Also, an influence of gender on CYP3A4 activity (being higher in women) has been reported. Once CsA and FK506 are absorbed and reach the bloodstream, both drugs are avidly bound to erythrocytes (up to 95% for FK506 and 50% for CsA) and plasma proteins, leaving only a small fraction of circulating active drug. This phenomenon also limits further hepatic catabolism and hence clearance of drug, which is influenced by hematocrit and levels of plasma proteins such as albumin. The aim of the present study was to compare the influence of changing steroid doses, hematocrit, and albumin on trough and dose levels of FK506 versus CsA during the first year after transplantation. In addition, the evolution of trough and dose levels of FK506 versus CsA was stratified according to gender.

Adrenal Cortex Hormones↗

PubMed2005

Combined therapy with atorvastatin and calcineurin inhibitors: no interactions with tacrolimus.

Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback. Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4+PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Calcium channel blockade and preservation of renal graft function in cyclosporine-treated recipients: a prospective randomized placebo-controlled 2-year study.

BACKGROUND: Studies have provided conflicting results as to the protective role of calcium channel blockers (CCB) in cyclosporine-treated patients with regard to blood pressure control and preservation of renal graft function. Lacidipine is a dihydropyridine CCB that possesses antioxidative, anti-atherosclerotic, and anti-adhesion properties and was shown to prevent cyclosporine-induced nephrotoxicity in a rat model. METHODS: We conducted a multicenter prospective, randomized, placebo-controlled study in 131 de novo recipients of a cadaveric renal allograft on cyclosporine therapy. The aim of this 2-year study was to assess the effects of lacidipine on graft function (plasma iohexol clearance), renal plasma flow, anastomotic arterial blood flow, deterioration of renal function, blood pressure, acute rejection, and hospitalization rate. RESULTS: A total of 118 recipients were available for intention-to-treat analysis on efficacy (lacidipine: n=59; placebo: n=59). Graft function assessed by serum creatinine concentration and glomerular filtration rate measured as plasma iohexol clearance, was persistently better in lacidipine-treated patients from 1 year onwards (respectively, P<0.01 and P<0.05). Renal plasma flow and anastomotic blood flow were not significantly higher in lacidipine-treated patients. Three patients on lacidipine therapy and four on placebo experienced treatment failure defined as an increase in serum creatinine from baseline of more than 60% (log-rank test: P=0.57). Study groups did not differ in acute rejection rate, trough blood cyclosporine concentrations, blood pressure, number of antihypertensive drugs, hospitalization rate, and adverse event rate. CONCLUSIONS: The use of calcium channel blockers in cyclosporine-treated renal recipients results in a significantly better allograft function at 2 years and this effect is independent of blood pressure lowering.

Acute Disease↗

PubMed2004

CYP3A4 and P-glycoprotein activity in healthy controls and transplant patients on cyclosporin vs. tacrolimus vs. sirolimus.

This study aimed to determine the impact of maintenance immunosuppressive therapy with cyclosporin A (CsA), tacrolimus (FK506) and sirolimus (Rapa) on the in vivo activity of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (PGP) in renal transplant patients. The activity of these four elimination pathways was measured by the recently validated intravenous (iv) and per oral (po)14C erythromycin breath and urine test. In addition, overall hepatic P450 activity was measured by the (13)C aminopyrin breath test. Three groups of stable renal transplant patients on maintenance therapy with corticosteroids (CS) and mycophenolate mofetil (MMF) plus either CsA or FK506 or Rapa were examined. A significant increase in intestinal CYP3A4 activity and a significant decrease in hepatic and intestinal PGP activity was seen in patients on CsA in comparison with those on FK506 or Rapa (p < 0.01). A similar analysis in six healthy volunteers at baseline and after intake of CsA, FK506 and Rapa confirmed the results seen in the patients. There was no difference in CYP3A4 and PGP activity in the patients taking either FK506 or Rapa and healthy controls. These data suggest that a different pattern of drug interactions might be expected in patients treated with CsA vs. FK506/Rapa.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Clinical use of rapamycin in renal allograft recipients identifies its relevant toxicity profile and raises unsolved questions: a single-center experience.

Rapamycin is an immunosuppressive drug with a distinct and unique mode of action and a specific side effect profile. We report here briefly on our personal clinical experience using this immunosuppressive drug in different combinations and settings. Rapamycin is without any doubt an efficient drug capable of preventing acute allograft rejection in a variety of immunosuppressive combinations. It is also a very potent drug that is not devoid of serious side effects. Infectious complications as a result of strong inhibition of the immune system are a frequent cause of hospitalization with severe morbidity and even mortality. Fungal infections and pneumonia are among the most devastating complications. As clinical experience with rapamycin grows and the therapeutic window of the drug can be further narrowed, these infectious complications will improve. Wound healing problems and lymphocoeles form another frequent surgical dilemma and are related to the antiproliferative properties of rapamycin. Last, hyperlipidemia warrants the use of statins in the majority of rapamycin-treated patients and whether this unfavorable side effect will offset the theoretically beneficial cardiovascular effects of the drug remains to be determined in controlled trials with long-term follow-up. Finally, the specific antiproliferative properties of rapamycin and the fact that it exerts no nephrotoxicity make this drug an alternative for calcineurin inhibitors and could make it an ideal candidate for treating chronic allograft dysfunction.

Female↗

PubMed2003

The use of an anti-CD25 monoclonal antibody and mycophenolate mofetil enables the use of a low-dose tacrolimus and early withdrawal of steroids in renal transplant recipients.

BACKGROUND: Reducing calcineurin-inhibitor-induced nephrotoxicity and simultaneously avoiding long-term steroid related side-effects is a desirable goal in renal transplantation. We examined the hypothesis that using anti-CD25 monoclonal antibody induction and mycophenolate mofetil (MMF) would allow the lowering of target pre-dose blood concentrations of tacrolimus immediately after transplantation and subsequently stopping steroids at 5 months. METHODS: Eighty-two kidney recipients were enrolled in a single-center study comparing two tacrolimus-based protocols. Group I (n = 41) patients received a standard-dose tacrolimus (blood concentration 10-15 ng/mL) with MMF and a standard dose corticosteroid. Group II (n = 41) patients were treated with a low-dose tacrolimus (blood concentration 5-10 ng/mL) and MMF, a low-dose corticosteroid (stopped after 5 months) and induction with daclizumab. RESULTS: Patient (95.1 versus 100%) and graft survival (92.6 versus 97.5%) at 1 yr were not different between groups. Patients of group II experienced significantly less acute rejections than group I (17.1 versus 41.4% p = 0.03). Delayed graft function occurred less often in group II (5 versus 12% p = 0.43). Graft function at 1 yr was significantly better in group II (serum creatinine 1.49 versus 1.69 mg/dL and creatinine clearance 59.6 versus 49 mL/min; p < 0.05). Corticosteroids could be stopped after 5 months in 82.9% of group II patients. CONCLUSION: A regimen consisting of anti-CD25 monoclonal antibody induction and MMF allows the safe and efficient use of low-target pre-dose trough concentrations of tacrolimus and enables the early discontinuation of steroids. Preliminary results indicate a better 1-yr graft function compared to a normal-dose tacrolimus regimen.

Antibodies, Monoclonal↗

PubMed2003

Mycobacterial infection after renal transplantation in a Western population.

Mycobacterial infection is a serious opportunistic infection in renal transplant recipients. The incidence is higher in developing than in developed Western countries. This study is a single-centre retrospective review of the records of 2502 renal transplant recipients in Belgium. Fourteen cases of mycobacterial infection (9 Mycobacterium tuberculosis and 5 atypical mycobacterial infection) were diagnosed. The time interval between transplantation and diagnosis was 64 +/- 80 months (mean +/- SD, range 5-188) for M. tuberculosis and 92 +/- 75 months (range 14-209) for atypical mycobacterial infection. The localisation of M. tuberculosis was pulmonary/pleural in 67% and extrapulmonary in 33%. The atypical mycobacterial infections were located in skin, tendons, and joints. Eight patients received IV prednisolone pulse therapy for acute rejection long before the time of mycobacterial infection. The initial antimycobacterial therapy consisted of a combination of isoniazid, rifampicin, and ethambutol in all patients. In patients with M. tuberculosis infection, a good response to antimycobacterial therapy was obtained. In patients with atypical mycobacterial infection, initial treatment was successful in 3 out of 5 patients, in 1 patient recurrence was diagnosed and in another patient, who is still under treatment at present, the initial treatment was adjusted after identification of the atypical mycobacterium and its antibiogram. The incidence of mycobacterial infection after renal transplantation did not increase with newer immunosuppressive therapy. The major risk factor is the total dose of corticosteroids. All patients responded well without major reductions in immunosuppressive therapy. Chemoprophylaxis for high-risk patients still is recommended.

Adult↗

PubMed2003

Long-term pharmacokinetic study of the novel combination of tacrolimus and sirolimus in de novo renal allograft recipients.

It was recently shown in two randomized studies that combining sirolimus (rapamycin) and tacrolimus is very efficient in renal transplantation. However, little is known about the long-term pharmacokinetics of this combination. We performed simultaneous AUC measurements (area under the concentration curves) of sirolimus and tacrolimus at 1, 3, and 12 months posttransplantation in nine de novo recipients treated with this drug combination to characterize the evolution of the pharmacokinetics of both drugs and to investigate possible interactions between the two compounds. Patients were treated with a standard-dose tacrolimus or with a reduced-dose tacrolimus in combination with sirolimus and corticosteroids. This long-term pharmacokinetic study has shown that when sirolimus is combined with tacrolimus, dose changes of sirolimus are reflected by pharmacokinetic exposure parameters. Patients taking a low dose of sirolimus in combination with a standard dose tacrolimus might require sirolimus dose increments over time to maintain constant exposure to sirolimus. Further prospective dose-controlled studies are necessary to investigate a possible effect of a standard-dose tacrolimus on long-term sirolimus bioavailability and/or metabolism. Dose reductions of tacrolimus in both study groups were reflected by concordant decreasing pharmacokinetic exposure parameters, which illustrates the common clinical practice of reducing the dose of calcineurin inhibitor as time elapses after transplantation.

Dose-Response Relationship, Drug↗

PubMed2003

Twelve-month evaluation of the clinical pharmacokinetics of total and free mycophenolic acid and its glucuronide metabolites in renal allograft recipients on low dose tacrolimus in combination with mycophenolate mofetil.

BACKGROUND: The establishment of a rationale for therapeutic drug monitoring for mycophenolic acid (MPA) and outlining a therapeutic window remains a challenging task in renal transplantation. Furthermore, the pharmacokinetic characteristics of free and total MPA and its glucuronides depend directly or indirectly on graft function and the type of co-administered calcineurin-inhibitor. METHODS: The authors conducted a prospective 12-month multicenter pharmacokinetic study on MPA (MPA, free MPA, free fraction MPA) and its metabolites (MPAG, Acyl-MPAG). The aim of this study was to examine the long-term pharmacokinetic characteristics of MMF when combined with tacrolimus in renal allograft recipients and to identify a possible relationship between these pharmacokinetic parameters and clinical outcome parameters. RESULTS: They have demonstrated that in renal transplant recipients MPA, free MPA, Acyl-MPAG and MPAG have a particular pharmacokinetic profile when combined with tacrolimus which differs from the combination with CsA. They could not establish a relationship between pre-dose trough concentration of MPA and its metabolites and clinical efficacy endpoints and drug-related adverse events, except for anemia. CONCLUSIONS: These findings suggest that trough plasma concentration monitoring of MPA and its metabolites might not provide a useful clinical tool for guiding MMF dose adjustments to avoid drug-related toxicity. More extensive pharmacokinetic measurements like area under the concentration curves might be necessary for routine therapeutic drug monitoring of MMF.

Adult↗

PubMed2003

Measurement of hepatic and intestinal CYP3A4 and PGP activity by combined po + iv [14C]erythromycin breath and urine test.

The aim of the present study was to develop a test for measuring hepatic and intestinal removal of cytochrome p-450 3A4 (CYP3A4)- and P-glycoprotein (PGP)-dependent xenobiotics that would be applicable for clinical use in humans. Orally and intravenously administered [N-methyl-14C]erythromycin was used for evaluation of 14C-labeled excretion dynamics in breath and urine. Simultaneous breath and urine test measurements were performed in 32 healthy volunteers and in 23 renal transplant recipients. Mathematical analysis of the excretion rate of labeled CO2 in breath and labeled carbon in urine resulted in 1). separation of both CYP3A4 and PGP activity in the liver and the intestinal mucosa and 2). numerical calculation of the dynamics of the different processes. The test was sufficiently sensitive to detect theoretically predicted process-specific pharmacological modulations by different drugs in healthy volunteers and after recent renal transplantation. It is concluded that the combined oral and intravenous erythromycin breath and urine test is a reliable and noninvasive test to measure phenotypic intestinal and hepatic CYP3A4 and PGP activity and may be a promising tool for prediction of drug interactions and dose adjustment of many pharmacotherapeutics in clinical practice, e.g., immunosuppressive agents after renal transplantation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Long-term changes in mycophenolic acid exposure in combination with tacrolimus and corticosteroids are dose dependent and not reflected by trough plasma concentration: a prospective study in 100 de novo renal allograft recipients.

Tacrolimus and cyclosporine A have different effects on exposure to concomitantly administered mycophenolate mofetil (MMF), measured as the mycophenolic acid (MPA) dose interval area under the plasma concentration versus time curve (AUC0-12 h) or the plasma MPA predose concentration (C0). This has led to recommendations in using a 50% lower dose of MMF in combination with tacrolimus compared to cyclosporin A. At present, no long-term data are available regarding the pharmacokinetics (PK) of different dosages of MMF in combination with tacrolimus and the clinical variables that influence the dose-exposure relationship of MPA. A prospective 12-month pharmacokinetic study was performed in 100 de novo renal transplant recipients treated with two different MMF dosages (1 g/day vs. 2 g/day) in combination with tacrolimus and corticosteroids. MPA AUC data were collected 7 days, 6 weeks, and 3 and 12 months posttransplantation, and model-independent PK parameters were calculated. Clinical variables that could possibly influence MPA PK were evaluated. The MPA AUC0-12 h significantly increased toward 6 weeks (p < 0.05) but only in the 2-g MMF dosing group. The MPA AUC0-12 h in the 1-g MMF group reached its nadir at 3 months, while in the 2-g MMF group, it remained elevated until 3 months, returning to baseline values by 12 months. This differential evolution in exposure was not only inadequately reflected by the corresponding MPA C0 concentrations, but the MPA C0 concentrations also were not significantly different between the two dosing groups at early postgrafting (day 7) and at 12 months. Using multiple stepwise regression analysis, C0 (r = 0.51, p < 0.0001) and end-of-dose interval MPA plasma concentration (C12: r2 = 0.61, p < 0.0001) were found to poorly predict MPA AUC0-12 h, while MPA plasma concentrations at 4 hours (C4: r2 = 0.85, p < 0.0001) and 6 hours postdosing (C6: r2 = 0.83, p < 0.0001) were superior but hampered by a large prediction bias and imprecision. An abbreviated 2-hour AUC measurement (r2 = 0.78), using three sampling points (C0, C40 [MPA plasma concentration 40 min postdosing], C2), provided the best compromise between a monitoring tool that is theoretically ideal and practically feasible. MPA pharmacokinetics were not influenced by recipient age, gender, and body weight or by serum albumin concentrations, allograft function, or corticosteroid or tacrolimus dose. Mild hepatic dysfunction early after grafting did result in significantly reduced MPA exposure (MPA AUC0-12 h, p = 0.01 and C0, p = 0.03). In this study, it was demonstrated for the first time that the dynamics of long-term MPA pharmacokinetics in combination with tacrolimus differ according to the daily MMF dose and that this effect is not adequately reflected by MPA trough concentrations. Using the latter as a routine measure for therapeutic drug monitoring might mislead clinicians into drawing wrong conclusions in terms of relating questions of efficacy or toxicity to MPA exposure.

Analysis of Variance↗

PubMed2003

Transcatheter embolization of biopsy-related vascular injuries in renal allografts. Long-term technical, clinical and biochemical results.

PURPOSE: Biopsy-related vascular injuries in renal transplants are rare, but they can lead to dramatic clinical symptoms prompting immediate treatment. Transcatheter embolization is a known minimally invasive technique to treat some form of arterial bleeding. This study evaluated the efficacy of this technique in iatrogenic biopsy-related vascular lesions in renal allografts. MATERIAL AND METHODS: Between 1993 and 2001, 13 patients were treated by percutaneous transcatheter intervention. Indications for embolization were hypovolemic shock due to perinephric hematoma (n = 5), persistent macroscopic hematuria (n = 7) and an asymptomatic large intrarenal pseudoaneurysm in 1 patient. Selective angiography revealed an arteriovenous fistula (n = 7), a pseudoaneurysm (n = 6), and perinephric contrast extravasation (n = 4). RESULTS: In all patients, successful embolization of the feeding artery could be performed; in 11 patients it was performed in one session, in 2 patients an additional session was needed. In 1 patient thrombosis of a segmental artery occurred immediately after embolization, but was successfully treated by short-term in situ thrombolysis. Clinical symptoms disappeared in all patients. Serum creatinine levels (determined 30 and 60 days after embolization, compared to the level before embolization) decreased significantly in 10 patients; a progressive deterioration of the renal function was observed in 3 patients. CONCLUSIONS: Transcatheter embolization is a safe and effective endovascular technique to treat biopsy-related vascular injuries in renal transplants. In the vast majority of cases an immediate clinical success and significant benefit in renal function can be obtained and the longevity of the allograft after successful embolization mainly depends on the natural (medical) outcome.

Adult↗