Peter J. H. Smak Gregoor

Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR‐1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus

The calcineurin inhibitors cyclosporine (INN, ciclosporin) and tacrolimus have a narrow therapeutic index and show considerable interindividual variability in their pharmacokinetics. The low oral bioavailability of calcineurin inhibitors is thought to result from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and CYP3A5 and the multidrug efflux pump P‐glycoprotein, encoded by MDR‐1.

Withdrawal of Cyclosporine or Prednisone Six Months after Kidney Transplantation in Patients on Triple Drug Therapy: A Randomized, Prospective, Multicenter Study

Uncertainty exists regarding the necessity of continuing triple therapy consisting of mycophenolate mofetil (MMF), cyclosporine (CsA), and prednisone (Pred) after kidney transplantation (RTx). At 6 mo after RTx, 212 patients were randomized to stop CsA (n = 63), stop Pred (n = 76), or continue triple drug therapy (n = 73). The MMF dose was 1000 mg twice daily, target CsA trough levels were 150 ng/ml, and Pred dose was 0.10 mg/kg per d. Follow-up was until 24 mo after RTx. Biopsy-proven acute rejection occurred in 14 (22%) of 63 patients after CsA withdrawal compared with 3 (4%) of 76 in the Pred withdrawal group (P = 0.001) and 1 (1.4%) of 73 in the control group (P = 0.0001). Biopsy-proven chronic rejection was present in one patient in the control group, in nine patients after CsA withdrawal (P = 0.006 versus control group); and in four patients after discontinuation of Pred (NS). Graft loss occurred in two versus one patient after CsA or Pred withdrawal, respectively, and in two patients in the control group (NS). Patients who successfully withdrew CsA had a significantly lower serum creatinine during follow-up. Pred withdrawal resulted in a reduction in mean arterial pressure, and the total cholesterol/HDL ratio increased. In conclusion, rapid CsA withdrawal at 6 mo after RTx results in a significantly increased incidence of biopsy-proven acute and chronic rejection. Pred withdrawal was safe and resulted in a reduction in mean arterial pressure. However, patient and graft survival and renal function 2 yr after RTx were not different among groups.

Infections after renal allograft failure in patients with or without low-dose maintenance immunosuppression.

BACKGROUND Failed renal allografts are sometimes left in situ for additional clearance and urine production during hemodialysis or peritoneal dialysis, and low-dose immunosuppressive medication is often continued in such patients. We compared the morbidity and mortality due to infections between patients with (group A) or without (group B) low-dose immunosuppression (i.e., transplantectomy). METHODS In a hospital-based cohort study, we analyzed data from patient files. We evaluated 37 patients who received 42 kidney transplantations between May 1975 and November 1995. RESULTS A total of 2.28 vs. 0.68 infections/patient-year were found in groups A and B, respectively. The odds ratio of one or two infections developing for patients in group A compared with group B was 14.2 (95% confidence interval, 1.4-143.4; P<0.025) and 4.3 (95% confidence interval, 1.1-17.3; P<0.04). A total of five lethal infections were found in group A; no lethal infections were found in group B. CONCLUSIONS The increase in serious and life-threatening infections associated with even low-dose immunosuppression argues in favor of discontinuation of these drugs. The removal of failed renal allografts should be considered.

15-year follow-up of a multicenter, randomized, calcineurin inhibitor withdrawal study in kidney transplantation

Background Calcineurin inhibitors (CNIs) are essential immunosuppressive drugs after renal transplantation. Because of nephrotoxicity, withdrawal has been a challenge since their introduction. Methods A randomized multicenter trial included 212 kidney patients transplanted between 1997 and 1999. All patients were initially treated with mycophenolate mofetil (MMF), cyclosporine A (CsA), and prednisone (pred). At 6 months after transplantation, 63 patients were randomized for MMF/pred, 76 for MMF/CsA, and 73 for MMF/CsA/pred. Within 18 months after randomization 23 patients experienced a rejection episode: MMF/pred (27.0%), MMF/CsA (6.8%) and MMF/CsA/pred (1.4%) (P<0.001). Results During 15 years of follow-up, 73 patients died with a functioning graft, and 43 patients lost their graft. Ninety-six were alive with a functioning graft. Intention-to-treat analysis did not show a significant difference in patient and graft survival. In multivariate analysis, death-censored graft survival was significantly associated with serum creatinine at 6 months after transplantation and maximum PRA but not with the randomization group. CNI withdrawal did not result in a reduced incidence of or death by malignancy or cardiovascular disease. Death-censored graft survival was significantly worse in those patients randomized for CNI withdrawal that had to be reverted to CNI. Independent of randomization group, compared with no rejection, death-censored graft survival was significantly worse in 23 patients with acute rejection after randomization. Conclusion Fifteen years after conversion to a CNI free regimen, there was no benefit regarding graft and patient survival or regarding prevalence of or death by comorbidities. However, rejection shortly after CNI withdrawal was associated with decreased graft survival.

Formation of donor-specific human leukocyte antigen antibodies after kidney transplantation: Correlation with acute rejection and tapering of immunosuppression

Background. Before kidney transplantation, a serological crossmatch is routinely performed between donor and recipient to prevent hyperacute rejection by donor-specific anti-human leukocyte antigen (HLA) antibodies. After transplantation, the presence of these antibodies is not routinely monitored. We wanted to know whether donor-specific anti-HLA antibodies are detectable during acute rejection (AR), before or after reduction of immunosuppression in kidney transplant recipients who were converted from cyclosporine A (CsA) to the less nephrotoxic azathioprine (AZA) or mycophenolate mofetil (MMF) at 1 year after transplantation. Methods. Plasma samples were collected before transplantation, at several time points after transplantation, and during AR. Antibodies were measured in 29 patients: 5 patients with AR during the first year after transplantation (before conversion), 14 patients with AR after conversion or dose-reduction of AZA or MMF, and a control group of 10 patients without AR during a follow-up of 2 years (1 year before and 1 year after conversion of immunosuppression). Antibodies were measured by complement-dependent cytotoxicity assay, enzyme-linked immunosorbent assay (ELISA), and flow-cytometry in a crossmatch with donor spleen cells. Results. Donor-specific antibodies were not detectable after transplantation in the control group without AR, nor in patients with AR shortly after transplantation during CsA therapy. After conversion from CsA to AZA or MMF, antibodies appeared only in one patient after graft failure followed by transplantectomy and in patients during AR on AZA but not on MMF therapy. Conclusion. In this patient group, we could not detect donor-specific antibodies during CsA treatment, not even at the time of AR using three different techniques. Donor-specific antibodies were primarily present during AR in patients converted from CsA to AZA and were not found in the sera from patients converted to MMF.

Mycophenolate mofetil, Cellcept®, a new immunosuppressive drug with great potential in internal medicine

Mycophenolate mofetil is a new immunosuppressive drug, exhibiting its effect through inhibition of proliferation of T- and B-lymphocytes. Superior efficacy of mycophenolate mofetil compared to azathioprine, in combination with cyclosporine and prednisone, in the prevention of acute rejection in organ transplantation has made mycophenolate mofetil one of the standard immunosuppressive drugs after transplantation. Mycophenolate mofetil also is an interesting candidate drug for many other, mainly auto-immune mediated diseases. The use of mycophenolate mofetil in several of these diseases is discussed. The definitive place of mycophenolate mofetil will depend on the results of randomised trials currently under way.

A psychometric analysis of the Rotterdam Renal Replacement Knowledge-Test (R3K-T) using item response theory

Knowledge is a prerequisite for promoting well‐informed decision‐making. Nevertheless, there is no validated and standardized test to assess the level of knowledge among renal patients regarding kidney disease and all treatment options. Therefore, the objective of this study was to investigate the psychometric properties of such a questionnaire for use in research and practice. A 30‐item list was validated in four groups: (1) 187 patients on dialysis, (2) 82 patients who were undergoing living donor kidney transplantation the following day, (3) the general population of Dutch residents (n = 515) and (4) North American residents (n = 550). The psychometric properties of the questionnaire were examined using multidimensional item response theory (MIRT). Norm references were also calculated. Five items were found to distort ability estimates (Differential item functioning; DIF). MIRT analyses were subsequently carried out for the remaining 25 items. Almost all items showed good discrimination and difficulty parameters based on the fitted model. Two stable dimensions with 21 items were retrieved for which norm references for the Dutch and North American, dialysis and transplantation groups were calculated. This study resulted in a thorough questionnaire, the Rotterdam renal replacement knowledge‐test, which enables reliable testing of patients knowledge on kidney disease and treatment options in clinic and research.

Tacrolimus and Pure Red-Cell Aplasia

In August 2002, a 20-year-old female, with end-stage renal disease due to SLE, received a 1-1-1 HLA A,B,Dr mismatched kidney from her 20-year-old brother. The transplantation was uneventful. At the time of transplantation there was no active SLE and the patient had been on hemodialysis for 2 months. Before transplantation an adequate hemoglobin level was achieved using b-erythropoeitin subcutaneously. Post-transplantation immunosuppressive drugs consisted of tacrolimus, mycophenolate mofetil and prednisone, other medicaments used were omeprazole 40 mg and co-trimoxazole 480 mg. From day 30 after transplantation a slow decrease in hemoglobin to 3.8 mmol/L (6.12 g/dL) at day 60 was observed, despite tapering and eventually discontinuing MMF. Blood transfusion was necessary. All other medicaments except for prednisone and tacrolimus were stopped. Hereafter the hemoglobin again dropped to 3.8 mmol/L in 2 months, with an absent reticulocyte response with adequate folate and ferritine levels. A bone marrow biopsy revealed pure red-cell aplasia. No giant pronormoblasts with prominent cytoplasmic inclusions were present. Additional laboratory results showed no activity of SLE, repeated negative erythropoeitin-antibody tests, no signs of a thymoma on CT-scan and repeated negative serology and PCR for B-19 virus (5). This PCR used for the quantitative detection of B19 DNA is based on real-time PCR using ABI Prism SDS7700 (TaqMan), which allows precise quantitation of viral loads over seven orders of magnitude. Each individual sample includes an exogenous internal control (internal quality marker) to prevent false negative results. This marker is a linearized plasmid containing the identical sequence of the B19 target sequence but with an altered probe hybridization site. Both B19 and the internal quality marker will be amplified and co-detected because of different labeled probes.

Justification for a home-based education programme for kidney patients and their social network prior to initiation of renal replacement therapy

In this article, an ethical analysis of an educational programme on renal replacement therapy options for patients and their social network is presented. The two main spearheads of this approach are: (1) offering an educational programme on all renal replacement therapy options ahead of treatment requirement and (2) a home-based approach involving the family and friends of the patient. Arguments are offered for the ethical justification of this approach by considering the viewpoint of the various stakeholders involved. Finally, reflecting on these ethical considerations, essential conditions for carrying out such a programme are outlined. The goal is to develop an ethically justified and responsible educational programme.

Therapeutic drug monitoring in solid-organ transplant recipients

With the recent introduction of a number of new immunosuppressive drugs there is an unprecedented interest in therapeutic drug monitoring of immunosuppressive drugs. Most published data on therapeutic drug monitoring in transplantation come from retrospective studies and show a correlation between drug concentrations and toxicity or between concentrations and efficacy. No randomized studies have compared traditional dosing (dose reduction if side effects occur, dose increase if insufficient efficacy is shown) with concentration-controlled dosing. Nevertheless, for a number of immunosuppressive drugs pharmacokinetic monitoring, based on trough levels, is routine practice. Pharmacodynamic monitoring of immunosuppressive drugs has not reached the stage of widespread clinical application. Prospective investigations on the contribution of therapeutic drug monitoring may result in further improvement in the safety and efficacy of our immunosuppressive regimens and more refined methods for therapeutic drug monitoring.