Yves Vanrenterghem

Publications (134)644.84 Total impact

• Article: Post-transplant lymphoma of the pancreatic allograft in a kidney-pancreas transplant recipient: a misleading presentation.

  Kristine Dyckmans, Evelyne Lerut, Pieter Gillard, Matthias Lannoo, Nadine Ectors, Anne Hoorens, Chantal Mathieu, Willy Coosemans, Yves Vanrenterghem, Dirk Kuypers
  Nephrology Dialysis Transplantation 12/2006; 21(11):3306-10. · 3.40 Impact Factor
• Article: Late referral of patients with chronic kidney disease: no time to waste.

  Ben Sprangers, Pieter Evenepoel, Yves Vanrenterghem
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  ABSTRACT: The prevalence of patients with chronic kidney disease (CKD) in the US population is approximately 11%, and because of the increase in life expectancy and in diabetic nephropathy incidence, an exponential increase is predicted for the next decades. During the past decade, evidence that the progression of CKD can be attenuated by a multifactorial therapeutic approach has been increasing. However, a substantial percentage of patients with CKD will have progression to CKD stage V (ie, need for renal replacement therapy). Late referral of these patients (ie, <1 to 6 months before the start of renal replacement therapy) has been shown to be associated with higher mortality, morbidity, and costs. However, up to 64% of patients with CKD are still referred late. This review presents the available data on the epidemiology, causes, and consequences of late patient referral. Furthermore, it offers information to prevent late referral, improve CKD patient care, and change clinical practice.
  Mayo Clinic Proceedings 11/2006; 81(11):1487-94. · 5.70 Impact Factor
• Article: Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients.

  Maarten Naesens, Dirk R J Kuypers, Kristin Verbeke, Yves Vanrenterghem
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  ABSTRACT: Mycophenolic acid (MPA) is glucuronidated by uridine diphosphate-glucuronosyltransferases (UGTs) to its pharmacologically inactive 7-O-glucuronide metabolite (MPAG). MPAG is excreted into the bile via the multidrug resistance-associated protein 2 (MRP2/ABCC2), which is essential for enterohepatic (re)circulation (EHC) of MPA(G). The objective of this study was to determine the relationship between single nucleotide polymorphisms (SNPs) in the MRP2 (G-1549A, G-1023A, A-1019G, C-24, G1249A, C3972T and G4544A) and UGT1A9 (C-2152T, T-275AandT98C) genes and MPA pharmacokinetics in 95 renal allograft recipients at days 7, 42, 90, and 360 after transplantation. In addition to mycophenolate mofetil, all patients received tacrolimus and corticosteroids as immunosuppression. At day seven after transplantation, in the absence of the MRP2 C-24T SNP, mild liver dysfunction was associated with significantly lower MPA dose-interval exposure and higher MPA oral clearance, while liver dysfunction did not affect MPA pharmacokinetics in patients with the MRP2 C-24T variant. A similar effect is noted for the C-3972T variant, which is in linkage disequilibrium with C-24T. At later time points after transplantation the MRP2 C-24T SNP was associated with significantly higher dose-corrected MPA trough levels. Patients with the MRP2 C-24T variant had significantly more diarrhea in the first year after transplantation. The MRP2 C-24T and C-3972T polymorphisms protect renal transplant recipients from a decrease in MPA exposure associated with mild liver dysfunction. Furthermore, this study suggests that the C-24T SNP is associated with a lower oral clearance of MPA in steady-state conditions.
  Transplantation 11/2006; 82(8):1074-84. · 4.00 Impact Factor
• Article: Nonadherence with immunosuppressive drugs: U.S. compared with European kidney transplant recipients.

  Kris Denhaerynck, Ariane Desmyttere, Fabienne Dobbels, Philip Moons, Jim Young, Bonita Siegal, Stuart Greenstein, Jürg Steiger, Yves Vanrenterghem, Jean-Paul Squifflet, Johannes P van Hooff, Sabina De Geest
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  ABSTRACT: System factors increasingly are suggested as important yet understudied correlates of nonadherence. To explore the relationship between healthcare system and prevalence of nonadherence with immunosuppressive regimen by studying variation in nonadherence between European and US kidney transplant recipients and as well as nonadherence in European countries. We performed a secondary data analysis on data collected in 3 independent cross-sectional studies using comparable methodology including patients from the United States, the Netherlands, Belgium, and Switzerland. Nonadherence was measured using 1 item of the Siegal questionnaire. Patients were categorized as nonadherent if they reported missing a dose of immunosuppression in the last 4 weeks. Analyses were performed by multiple mixed logistic regression, with center as a random effect and clinical and demographical differences between groups as fixed effects. 1563 U.S. and 614 European patients from 3 different countries (Belgium [n=187], the Netherlands [n=85], and Switzerland [n=342]) were included. Prevalence of nonadherence in the United States and Europe was 19.3% and 13.2.%, respectively. This higher nonadherence in US patients was confirmed in a multiple logistic regression analysis (OR = 1.78; 95% CI, 1.10-2.89). Nonadherence differed between Belgium (16%) and the Netherlands (14.1%) (OR = 0.27; 95% CI, 0.09-0.80) and between Belgium and Switzerland (11.4%; OR = 0.17; 95% CI, 0.0-0.42). This is the first study showing differences in prevalence of nonadherence between European and US patients and among European patients. Further research should aim at unraveling the dynamics explaining these differences.
  Progress in transplantation (Aliso Viejo, Calif.) 10/2006; 16(3):206-14. · 1.03 Impact Factor
• Article: Prospective Study of Bkv Viral Load, Subclinical Histology and Exposure to Tacrolimus and Mycophenolic Acid in Renal Allograft Recipients

  Maarten Naesens, Evelyne Lerut, Boudewijn Van Damme, Robert Snoeck, Yves Vanrenterghem, Dirk RJ Kuypers
  Transplantation 07/2006; 82(1):682-683. · 4.00 Impact Factor
• Article: Association of Three Polymorphisms With Acute Rejection After Kidney Transplantation: An Exploratory Pharmacogenetic Analysis of A Randomized Multicenter Clinical Trial (the Caesar Study)

  Josep Grinyo, Yves Vanrenterghem, Bjorn Nashan, Flavio Vincenti, Henrik Ekberg, Olivia Spleiss, Michelle Rashford, Clare Nasmyth-Miller, Laurent Essioux
  Transplantation 07/2006; 82(1):410-411. · 4.00 Impact Factor
• Article: Clinically relevant drug interaction between voriconazole and tacrolimus in a primary renal allograft recipient.

  Dirk R Kuypers, Kathleen Claes, Pieter Evenepoel, Yves Vanrenterghem
  Transplantation 07/2006; 81(12):1750-2. · 4.00 Impact Factor
• Article: Comparison of peritoneal dialysis and haemodialysis after renal transplant failure.

  Hylke de Jonge, Bert Bammens, Wim Lemahieu, Bart D Maes, Yves Vanrenterghem
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  ABSTRACT: A growing number of patients are returning to dialysis after renal transplant failure. The aim of this study is to determine whether peritoneal dialysis (PD) is a safe and good treatment option for these patients. All patients returning to PD or haemodialysis (HD) after renal transplant failure before 1 October 2002 at the University Hospital Gasthuisberg, Leuven, Belgium, were evaluated. Data were collected until death, retransplantation (reTx), transfer to HD or PD or until 1 January 2003. Twenty-one patients starting PD (PDpostTx-group) and 39 patients starting HD (HDpostTx-group) after renal transplant failure were included in the study. There were no significant differences in age, sex, serum albumin- and CRP-levels at baseline. The total time on renal replacement therapy at transplant failure and time to transplant failure did not differ between the two groups either. Furthermore, the baseline comorbidity was similar in both groups. During follow-up, the outcome did not differ significantly between the two groups. However, there was a tendency towards higher patient survival and reTx tended to be more frequent in the PDpostTx-group. Moreover, patients in the HDpostTx-group tended to accrue more new comorbidity. The incidence of peritonitis and the evolution of dialysis adequacy (renal and peritoneal Kt/V and creatinine clearances) with time in the PDpostTx-group was similar to that seen in our centre's PD patients who had never undergone transplantation before. This study suggests that the outcome in patients starting PD after renal transplant failure is at least as good as the outcome in those starting HD. Although these observational findings warrant further confirmation, PD therefore can be regarded as a safe and good treatment option for patients returning to dialysis after renal transplant failure.
  Nephrology Dialysis Transplantation 06/2006; 21(6):1669-74. · 3.40 Impact Factor
• Article: Prometheus versus molecular adsorbents recirculating system: comparison of efficiency in two different liver detoxification devices.

  Pieter Evenepoel, Wim Laleman, Alexander Wilmer, Kathleen Claes, Dirk Kuypers, Bert Bammens, Frederik Nevens, Yves Vanrenterghem
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  ABSTRACT: 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.
  Artificial Organs 05/2006; 30(4):276-84. · 2.00 Impact Factor
• Article: Secondary renal amyloidosis due to long-standing tubulointerstitial nephritis in a patient with Sjögren syndrome.

  Vanessa Ooms, Marc Decupere, Evelyne Lerut, Yves Vanrenterghem, Dirk R J Kuypers
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  ABSTRACT: A 53-year-old patient with long-standing primary Sjögren syndrome presented with acute renal failure and nephrotic syndrome caused by secondary (AA) renal amyloidosis. Ten years before, he had been admitted because of exacerbation of the systemic disease. At that time, a pseudolymphoma of the kidney was diagnosed. To our knowledge, this is the first report of a patient with primary Sjögren syndrome and secondary (AA) amyloidosis with amyloid deposition in the kidneys causing nephrotic syndrome.
  American Journal of Kidney Diseases 12/2005; 46(5):e75-80. · 5.43 Impact Factor
• Article: The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients.

  Dirk R J Kuypers, Maarten Naesens, Severine Vermeire, Yves Vanrenterghem
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  ABSTRACT: Mycophenolic acid (MPA), an effective immunosuppressive drug used in renal transplantation, is extensively glucuronidated by several uridine diphosphate-glucuronosyltransferases (UGTs) into an inactive 7-O-glucuronide and, to a lesser extent, into a pharmacologically active acyl-glucuronide. Experiments using human liver microsomes have shown that T--275A and C--2152T single-nucleotide polymorphisms (SNPs) of the UGT1A9 promoter region are associated with higher hepatic expression of UGT1A9 and increased in vitro glucuronidation activity for MPA. The distribution of UGT1A9 promoter region T-275A and C-2152T SNPs and the less frequent UGT1A9*3 coding region mutation, which results in decreased in vitro activity, was determined in 95 de novo renal recipients. The impact of these UGT1A9 SNPs on early clinical MPA pharmacokinetics was evaluated. Only in patients taking 2 g mycophenolate mofetil daily was a decreased MPA exposure observed in those who carried either the T-275 A or the C-2152 T polymorphism (or both) compared with those who did not (area under concentration-time curve [AUC] from 0 to 12 hours, 31.7+/--17.6 mg.h/L versus 63.6+/--30.9 mg.h/L [P=.009]; predose trough plasma concentration, 1.23 +/--.25 mg/L versus 2.84+/--1.64 mg/L [P=.04]). The partial MPA AUC from 6 to 12 hours (AUC6--12)-an estimate of MPA enterohepatic recirculation-and the ratio between partial MPA AUC6--12 and dose-interval AUC from 0 to 12 hours decreased when either or both UGT1A9 promoter region SNPs were present (AUC6--12, 6.2+/-5.4 mg.h/L versus 21.5+/-14.9 mg.h/L [P=.002]; ratio, 18.4%+/- 7.8% versus 31.7%+/- 8.8% [P=.002]). The T-275A and C-2152T SNPs of the UGT1A9 gene promoter are associated with significantly lower MPA exposure in renal recipients treated with 2 g mycophenolate mofetil daily, and part of this effect is caused by interruption of enterohepatic recirculation of MPA.
  Clinical Pharmacology &#38 Therapeutics 11/2005; 78(4):351-61. · 6.04 Impact Factor
• Article: Efficacy and cardiovascular safety of daclizumab, mycophenolate mofetil, tacrolimus, and early steroid withdrawal in renal transplant recipients: a multicenter, prospective, pilot trial.

  Daniel Abramowicz, Yves Vanrenterghem, Jean-Paul Squifflet, Dirk Kuypers, Michel Mourad, Michel Meurisse, Martin Wissing
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  ABSTRACT: 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.
  Clinical Transplantation 09/2005; 19(4):475-82. · 1.67 Impact Factor
• Article: Adjuvant low-dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients.

  Dirk R J Kuypers, Ann-Karolien Vandooren, Evelyne Lerut, Pieter Evenepoel, Kathleen Claes, Robert Snoeck, Lieve Naesens, Yves Vanrenterghem
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  ABSTRACT: BK virus interstitial nephritis (BKVIN) is a serious complication after kidney grafting, necessitating drastic reduction of immunosuppressive therapy in order to enable viral clearance. Despite these measures, progressive graft dysfunction and graft loss occur in the majority of recipients. We diagnosed BKVIN in 21 recipients grafted between 1998 and 2004. Eight of 21 patients were treated with weekly, adjuvant low-dose cidofovir in addition to reduction of immunosuppressive therapy. BKVIN caused irreversible deterioration of graft function in all patients but renal function stabilized after antiviral treatment (creatinine clearance: 51.8-32 mL/min; p=0.001) and no graft loss occurred in cidofovir-treated recipients during 24.8 (8-41) months follow-up. Peak serum cidofovir concentrations were dose-dependent and attained approximately one-tenth of thein vitroEC50 for cidofovir against BK-virus, while pre-treatment with probenecid did not alter peak serum concentrations nor affected the incidence of nephrotoxicity. In fact, no cidofovir-related renal toxicity occurred; few patients had minor transient side effects (nausea, skin rash). In contrast, 9 of 13 patient who received no adjuvant cidofovir therapy lost their graft after median 8 (4-40) months. In this selected group of recipients with BKVIN, the use of adjuvant low-dose cidofovir therapy resulted in prolonged graft survival and stabilized graft function.
  American Journal of Transplantation 09/2005; 5(8):1997-2004. · 6.39 Impact Factor
• Article: Impact of parathyroidectomy on renal graft function, blood pressure and serum lipids in kidney transplant recipients: a single centre study.

  Pieter Evenepoel, Kathleen Claes, Dirk Kuypers, Bart Maes, Yves Vanrenterghem
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  ABSTRACT: 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. 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. 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. 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.
  Nephrology Dialysis Transplantation 09/2005; 20(8):1714-20. · 3.40 Impact Factor
• Article: Time profiles of peritoneal and renal clearances of different uremic solutes in incident peritoneal dialysis patients.

  Bert Bammens, Pieter Evenepoel, Kristin Verbeke, Yves Vanrenterghem
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  ABSTRACT: Residual renal function (RRF) contributes substantially to the adequacy of peritoneal dialysis (PD). In the presence of RRF, maintenance of an adequate fluid balance is facilitated, level of systemic inflammation is lower, and renal endocrine functions are preserved. The beneficial impact of RRF also may be related to the preservation of specific renal elimination mechanisms, such as tubular metabolism or secretion, which are crucial for the removal of some uremic retention solutes. Time profiles of peritoneal and renal clearances of urea nitrogen (60 d), creatinine (113 d), phosphate (96 d), the middle molecule beta2-microglobulin (beta2M; 11.8 kd), and the protein-bound solute p-cresol (108 d) were investigated prospectively in 24 incident PD patients. Data were analyzed by using the linear mixed models procedure. During a median follow-up of 7.2 months (range, 5.6 to 8.6 months), RRF (P = 0.001) and 24-hour urine volume (P = 0.004) declined significantly. Twenty-four-hour peritoneal drainage volume increased (P < 0.0001). Renal clearances of urea nitrogen (P = 0.0002), creatinine (P = 0.001), and phosphate (P = 0.001) decreased. Peritoneal clearances of these solutes increased (P = 0.002, P < 0.0001, and P < 0.0001, respectively). There was a decline in renal clearances of beta2M (P = 0.0004) and p-cresol (P < 0.0001). No change in peritoneal clearances of these solutes was noted (P = 0.188 and P = 0.559, respectively). Increasing PD dose may compensate for deteriorating RRF with respect to the elimination of water-soluble solutes. This is not the case for the middle molecule beta2M and the protein-bound solute p-cresol.
  American Journal of Kidney Diseases 09/2005; 46(3):512-9. · 5.43 Impact Factor
• Article: Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase.

  Dirk R J Kuypers, Geert Verleden, Maarten Naesens, Yves Vanrenterghem
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  ABSTRACT: The tuberculostatic compound rifampin (INN, rifampicin) induces the expression of a number of drug metabolism-related genes involved in multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), cytochromes (cytochrome P450 [CYP] 3A4), uridine diphosphate-glucuronosyltransferases, monoamine oxidases, and glutathione S -transferases. Drugs that depend on these enzymes for their metabolism are prone to drug interactions when coadministered with rifampin. A novel, clinically relevant drug interaction is described between rifampin and mycophenolate mofetil (MMF), a cornerstone immunosuppressive molecule used in solid organ transplantation. Long-term rifampin therapy caused a more than twofold reduction in dose-corrected mycophenolic acid (MPA) exposure (dose-interval area under the concentration curve from 0 to 12 hours [AUC 0-12]) when administered simultaneously in a heart-lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout (dose-corrected AUC 0-12 after rifampin withdrawal, 19.7 mg.h.L-1.g -1 versus 6.13 mg.h.L-1.g-1 before rifampin withdrawal [221% change]; dose-uncorrected AUC 0-12 after rifampin withdrawal, 29.6 mg.h/L [daily MMF dose, 3 g] versus 18.4 mg.h/L [daily MMF dose, 6 g] during rifampin administration [60.8% change]). Failure to recognize this drug interaction could potentially lead to MPA underexposure and loss of clinical efficacy. The effect of rifampin on MPA metabolism can, at least in part, be explained by simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA.
  Clinical Pharmacology &#38 Therapeutics 08/2005; 78(1):81-8. · 6.04 Impact Factor
• Article: The molecular adsorbent recycling system (MARS) and transmembrane transport of albumin-bound toxins.

  Pieter Evenepoel, Bert Bammens, Frederik Nevens, Alexander Wilmer, Yves Vanrenterghem
  Liver Transplantation 08/2005; 11(7):853-4; author reply 855. · 3.39 Impact Factor
• Article: High anti-double-stranded DNA antibodies and progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus.

  Stefaan J Vandecasteele, Bart Maes, Kathleen Claes, Raf Sciot, Yves Vanrenterghem
  Nephrology Dialysis Transplantation 07/2005; 20(6):1246-7. · 3.40 Impact Factor
• Article: Cytochrome P450 3A4 and P-glycoprotein activity and assimilation of tacrolimus in transplant patients with persistent diarrhea.

  Wim Lemahieu, Bart Maes, Kristin Verbeke, Paul Rutgeerts, Karel Geboes, Yves Vanrenterghem
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  ABSTRACT: Renal transplant recipients suffering from persistent diarrhea have been repeatedly reported to have increased tacrolimus (Tac) trough levels. This study aimed to explore this phenomenon in detail in 15 renal transplant recipients with diarrhea, whose immunosuppression consisted of corticosteroids, mofetil mycophenolate and Tac. Both hepatic and intestinal CYP3A4 and PGP activity, important determinants of Tac bioavailability, were assessed, together with global CYP activity and investigations for gastrointestinal infection, function and morphology. Global CYP, CYP3A4, PGP and trough/dose levels of Tac were compared with diarrhea-free controls. In addition, a pharmacokinetic study of Tac was performed in 11 patients affected by diarrhea versus 9 controls. As expected, diarrhea was associated with increased Tac trough levels. An even stronger, significant increase of dose-normalized Tac levels was observed between 90 and 360 min after Tac intake. Time to peak concentration and drug half-life, however, were not altered. In addition, a concomitant decrease (+/-50%) of intestinal PGP activity was noticed in patients with diarrhea. For global CYP, CYP3A4 and hepatic PGP activity no such differences were noted. This pattern was not influenced by the specific cause of diarrhea. These data strongly suggest that persistent diarrhea is associated with an increased oral bioavailability of Tac.
  American Journal of Transplantation 07/2005; 5(6):1383-91. · 6.39 Impact Factor
• Article: FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation.

  Helio Tedesco-Silva, Georges Mourad, Barry D Kahan, Josep Grinyo Boira, Willem Weimar, Shamkant Mulgaonkar, Björn Nashan, Soren Madsen, Bernard Charpentier, Pascale Pellet, Yves Vanrenterghem
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  ABSTRACT: FTY720 is the first of a new drug class: sphingosine-1-phosphate receptor agonist. Its effect relates to the modulation of lymphocytes trafficking from blood and peripheral tissues to lymph nodes. This is the first study to evaluate the efficacy and safety of FTY720 in de novo renal transplantation. This phase 2a, multicenter, open-label, dose-finding study compared FTY720 (0.25, 0.5, 1.0, or 2.5 mg) with mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids. Patients (n=208) received FTY720 (n=167) or MMF (n=41) for 3 months followed by a 3-month follow-up. The incidence of biopsy-confirmed acute rejection at month 3 was 23.3%, 34.9%, 17.5%, and 9.8%, respectively, with FTY720 at doses of 0.25, 0.5, 1.0, and 2.5 mg, versus 17.1% with MMF. The incidence for the composite endpoint (biopsy-confirmed acute rejection, graft loss, or death) was lowest with FTY720 at a dose of 2.5 mg at month 3 (14.6%) compared with FTY720 at doses of 0.25 mg (25.6%), 0.5 mg (34.9%), and 1.0 mg (17.5%), and MMF (19.5%). Safety was comparable between FTY720 and MMF group. The main difference in tolerability was a mild and transient reduction in heart rate. A decrease in peripheral lymphocytes occurred in patients receiving FTY720, as expected from the mode of action, and this was reversible after treatment cessation. FTY720 at 2.5 mg was found to be as effective as MMF in combination with cyclosporine for the prevention of acute rejection after renal transplantation. FTY720 was well tolerated and not associated with the side effects commonly observed with immunosuppressant therapies.
  Transplantation 07/2005; 79(11):1553-60. · 4.00 Impact Factor