Pharmacogenetics in immunosuppressive therapy: the best thing since TDM?
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Clinical Trials as Topic↗
Biomedical subjects
Teun van Gelder
Publications and source records attributed to Teun van Gelder.
Mycophenolic acid in diabetic renal transplant recipients: pharmacokinetics and application of a limited sampling strategy.
Limited sampling strategies may be useful in optimizing therapeutic drug monitoring of mycophenolic acid (MPA). Their use, however, may be limited by several patient factors, including comorbidity. In this study the pharmacokinetics of MPA in diabetic and nondiabetic renal transplant recipients were compared, and it was evaluated whether a limited sampling strategy developed and validated for nondiabetic patients can also be used in diabetic patients. The pharmacokinetics of MPA were analyzed on days 7 and 11 after transplantation in 136 renal transplant patients, among whom 7 patients had diabetes. All patients received cyclosporine and corticosteroids as maintenance immunosuppressive therapy. A limited sampling strategy [AUC (mg x h/L) = 7.182 + 4.607 C0 + 0.998 C0.67 + 2.149 C2] was developed and validated for nondiabetic patients and was subsequently tested for its usefulness in diabetic patients. Diabetic renal transplant patients did not have significantly different dose-normalized MPA area under concentration-time curve (AUC), MPA clearance, or MPA maximum concentration (Cmax). However, in diabetic patients Tmax (time of Cmax, 1.59 hours) was higher than for nondiabetic patients (0.67 hours) on day 11 (P = 0.04). The developed and validated limited sampling strategy performed acceptably, estimating MPA AUC in nondiabetic patients with a mean bias of 0.2 mg x h/L (95% confidence interval from -1.3 to 1.6 mg x h/L). Applying the limited sampling strategy in diabetic patients revealed a mean bias of -1.5 (-5.7, 2.7 mg x h/L). In conclusion, although diabetic renal transplant patients exhibit increased Tmax, this does not affect the accuracy of the limited sampling strategy.
Adult↗
Steroid-withdrawal at 3 days after renal transplantation with anti-IL-2 receptor alpha therapy: a prospective, randomized, multicenter study.
Steroids have been included in most immunosuppressive regimens after renal transplantation, but are feared for their side-effects. We conducted a prospective multicenter study to investigate whether it is feasible to withdraw steroids early after transplantation with the use of anti-IL-2Ralpha induction, tacrolimus and mycophenolate mofetil (MMF). A total of 364 patients were randomized to receive either two doses of daclizumab (1 mg/kg) and, for the first 3 days, 100 mg of prednisolone (daclizumab group n = 186), or steroids (tapered to 0 mg at week 16; controls n = 178). All patients received tacrolimus and MMF. The incidence of biopsy-confirmed acute rejection at 12 months was not different between the daclizumab group (15%) and the controls (14%) (95% confidence interval of difference: -6 to + 8%, NS). Graft survival at 12 months was comparable in the two groups (daclizumab group: 91%; controls: 90%). Mean arterial blood pressure, serum lipids, and incidence of patients with hyperglycemia were temporary lower in the daclizumab group compared with controls. The immunosuppressive regimen of the daclizumab group was associated with increased costs. In conclusion, with the use of anti-IL-2Ra induction and daily therapy with tacrolimus and MMF it is feasible to withdraw steroids at 3 days after renal transplantation.
Adolescent↗
Ten-year follow-up of recipients of a kidney or heart transplant who received induction therapy with a monoclonal antibody against the interleukin-2 receptor.
OBJECTIVES: Twelve years ago, we performed two randomized clinical trials to investigate safety and efficacy of induction therapy with BT563, a highly potent murine monoclonal antibody against the interleukin-2 receptor after kidney and heart transplantation. We analyzed the long-term safety and efficacy data from all 120 patients who participated in the two randomized trials after kidney and heart transplantation 10 years ago. MATERIALS AND METHODS: One of these two trials was a randomized, double-blind, placebo-controlled trial, with 60 primary and secondary kidney allograft recipients (cadaveric and living-related donors). The control group was treated with the standard regimen at that time, consisting of cyclosporin and prednisone. In the study group, BT563 was added for 10 days. The second trial was a randomized, double-blind trial, with 60 recipients of a primary heart transplant. In that study, we compared induction therapy with BT563 with the standard regimen at that time, consisting of cyclosporin, prednisone, and OKT3 (both induction agents were given for 7 days). RESULTS: Patient survival in the kidney trial was excellent: in the BT563 group, 24 patients were alive (80%), and in the placebo, group 21 (70%) 10 years after transplantation. Also, graft survival was good: in the BT563 group, 63.3% of the kidneys (19/30) were functioning, in the placebo group, 72.4% (21/29) were functioning (P = 0.455). Also, in the heart study, patient (and graft) survival was excellent: 18 patients were alive in the BT563 group (58%), and in the OKT3 group, 21 (72%) patients were alive (P = ns). No increase in the incidence of malignancies was observed between patients treated with BT563 compared with the control groups. Patients following heart transplantation more often suffered from a malignancy than did patients after kidney transplantation (20/60 vs 10/59). CONCLUSIONS: We report follow-up data on all patients participating in the two randomized trials, and our data reflect a total of 932 years of patient follow-up. Patient and graft survival appear to be excellent in both the BT563-treated patients and the control groups. BT563 treatment was not associated with an increased likelihood of developing infections or malignancies.
Antibodies, Monoclonal↗
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.
Acute Disease↗
Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil.
BACKGROUND: In an attempt to reduce calcineurin inhibitor toxicity, transplant patients treated with tacrolimus can be switched to maintenance treatment with sirolimus. METHODS: In a prospective, randomized, multicenter trial, 33 kidney transplant recipients on steroid-free maintenance treatment with tacrolimus and mycophenolate mofetil continued tacrolimus and mycophenolate mofetil (control group, n=18) or were converted from tacrolimus to sirolimus (study group, n=15) at 1 year after transplantation. RESULTS: The study was prematurely stopped as a result of a cluster of nine patients suffering from painful oral ulcerations in the study group. Oral ulcerations did not occur in the control group. The authors here report on the individual cases suffering from this side effect of the instituted immunosuppressive regimen. CONCLUSIONS: The authors review the literature with respect to the occurrence of oral ulcers associated with the use of sirolimus or mycophenolate mofetil and speculate on the causes of the high incidence of oral ulcers in their study group. Possible explanations are overimmunosuppression during the period of the conversion from tacrolimus to sirolimus without antiviral prophylaxis, the use of the oral emulsion instead of tablets, or the lack of corticosteroid co-administration.
Adult↗
Living kidney donors and hypoxia-inducible factor-1alpha.
BACKGROUND: Hypoxia inducible factor (HIF)-1, a heterodimeric transcription factor composed of alpha and beta subunits, is induced in the adaptive response to hypoxia and is critical for initiating the transcriptional activation of growth factors. We speculate that prolonged ischemia and hypoxia time leads to the production of HIF-1alpha, which in turn induces the production of fibrogenic cytokines in the graft. METHODS: To investigate our hypothesis, we measured the expression of HIF-1alpha in time-zero biopsy specimens from living-donor kidneys (< or =2.5 hr of ischemia) and cadaveric donor kidneys (12-32 hr of ischemia). RESULTS: By real time reverse-transcriptase polymerase chain reaction analysis, the mRNA expression level of HIF-1alpha was fivefold lower in time-zero biopsy specimens from living-donor kidneys than in specimens from cadaveric donor kidneys. In these time-zero biopsy specimens, the mRNA expression level of the fibrogenic cytokine transforming growth factor-beta was also significantly lower (twofold). CONCLUSIONS: Low HIF-1alpha mRNA expression levels correlate with short ischemia times and prevent the transcription of fibrogenic cytokines that initiate the irreversible process of graft fibrosis.
Biopsy↗
Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus.
BACKGROUND: The calcineurin inhibitors cyclosporine (INN, cyclosporin) 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. OBJECTIVE: Our objective was to determine the role of genetic polymorphisms in CYP3A4, CYP3A5, and MDR-1 with respect to interindividual variability in cyclosporine and tacrolimus pharmacokinetics. METHODS: Kidney transplant recipients receiving cyclosporine (n = 110) or tacrolimus (n = 64) were genotyped for CYP3A4*1B and *3, CYP3A5*3 and *6, and MDR-1 C3435T. Dose-adjusted trough levels were determined and correlated with the corresponding genotype. RESULTS: Tacrolimus dose-adjusted trough levels were higher in CYP3A5*3/*3 patients (n = 45) than in *1/*3 plus *1/*1 patients (n = 17), as follows: median and range, 94 (34-398) ng/mL per mg/kg versus 61 (37-163) ng/mL per mg/kg (P <.0001, Mann-Whitney test). CYP3A4*1B allele carriers (n = 10) had lower tacrolimus dose-adjusted trough levels compared with those in patients with the wild-type (*1/*1) genotype (n = 54): median and range, 57 (40-163) ng/mL per mg/kg versus 89 (34-398) ng/mL per mg/kg) (P =.003, Mann-Whitney test). No evidence was found supporting a role for the MDR-1 C3435T polymorphism in tacrolimus dose requirement. None of the polymorphisms studied correlated with cyclosporine dose-adjusted predose concentrations. CONCLUSION: As a group, patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target predose concentrations compared with CYP3A5*1 allele carriers, whereas CYP3A4*1B carriers require more tacrolimus to reach target trough concentrations compared with CYP3A4*1 homozygotes.
Calcineurin Inhibitors↗
Amiodarone therapy before heart transplantation as a predictor of thyroid dysfunction after transplantation.
BACKGROUND: In recent years we have observed new cases of thyroid disease occurring after heart transplantation (HTx). In these patients, the presence of this disease complicates their post-transplant course and occasionally results in life-threatening thyrotoxicosis. The present study examines the incidence and risk factors of thyroid disease in these patients with special emphasis on the use of amiodarone before HTx. Recommendations for follow-up of thyroid disease in HTx patients are discussed. METHODS: A study was performed on a cohort of 380 patients who received HTx in Rotterdam between January 1, 1985 and April 1, 2001. Twenty patients (5%) developed thyroid dysfunction after HTx, 10 of whom had been treated with amiodarone before HTx. RESULTS: Cumulative survival curves showed that most patients (60%) developed thyroid dysfunction within the first year after HTx (median interval between HTx and diagnosis was 9 months). Using univariate Cox regression analysis, amiodarone was a significant predictor for the development of thyroid dysfunction (hazards ratio 5.2, 95% confidence interval 2.5 to 10.8). After adjustment for age, gender, heart disease and Quetelet index, amiodarone remained a significant predictor. CONCLUSIONS: Our study clearly shows that, despite discontinuation of amiodarone treatment at the time of the HTx procedure, patients remain at risk for developing thyroid disease. HTx recipients treated with amiodarone before HTx should therefore be monitored carefully for development of thyroid dysfunction, especially within the first post-transplant year.
Adolescent↗
Tacrolimus dose requirement in renal transplant recipients is significantly higher when used in combination with corticosteroids.
AIMS: To evaluate the effect of corticosteroids on tacrolimus pharmacokinetics. METHODS: In a randomized trial, kidney transplant recipients were treated with tacrolimus and mycophenolate mofetil with either daclizumab (n = 31) or 3 months of prednisone (n = 34). Tacrolimus dose-adjusted predose concentrations (C0) at month 1-6 were compared between both groups and within the corticosteroid group before and after prednisone withdrawal. RESULTS: At month 1 the tacrolimus dose-adjusted C0 in the corticosteroid group was 83 +/- 8 vs 119 +/- 17 ng ml-1 mg-1 kg-1 in the daclizumab group. The tacrolimus dose-adjusted C0 within the corticosteroid group at month 1 and 2 was 42% and 29% lower compared with month 4 (P < 0.001). CONCLUSIONS: A higher tacrolimus dose is required to reach target concentrations when used in combination with corticosteroids.
Adrenal Cortex Hormones↗
Differential intragraft cytokine messenger RNA profiles during rejection and repair of clinical heart transplants. A longitudinal study.
After clinical heart transplantation, ischemia, acute rejection, and repair mechanisms can trigger the up-regulation of cytokines. To investigate the cytokine profile early after transplantation, we monitored messenger RNA (mRNA) expression levels of tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-beta (TGF-beta), platelet-derived growth factor-A (PDGF-A), and basic fibroblast growth factor (bFGF) by reverse transcriptase-polymerase chain reaction (RT-PCR) in serial endomyocardial biopsies ( n=123) from 16 cardiac allograft recipients during the first 3 post-operative months. In the first month, mRNA expression levels of MCP-1, TNF-alpha, TGF-beta, and bFGF were significantly higher than in the period thereafter (acute rejection episodes excluded). Acute rejection (International Society for Heart and Lung Transplantation (ISHLT) rejection grade >2) was strongly associated with the level of TNF-alpha mRNA. After acute rejection episodes, rising mRNA expression levels of PDGF-A and bFGF were found. The association between TNF-alpha mRNA and acute rejection reflects the importance of this cytokine in allogeneic responses. Elevated growth factor expression levels indicate repair responses after tissue damage due to either the transplantation procedure (surgery, ischemia, reperfusion) or acute allograft rejection.
Acute Disease↗
Prediction of mortality in heart transplant recipients by stress technetium-99m tetrofosmin myocardial perfusion imaging.
Cardiac allograft vasculopathy is a major cause of mortality in heart transplant recipients. The aim of this study was to assess the prognostic value of stress myocardial perfusion imaging in heart transplant recipients. We studied 166 patients (age 54 +/- 10 years, 140 men) by symptom-limited bicycle exercise or dobutamine (up to 40 microg/kg/min) stress myocardial perfusion imaging 7.4 +/- 2.5 years after heart transplantation. An intravenous dose of 370 MBq of technetium-99m tetrofosmin was injected at peak stress and 24 hours after the stress test. An abnormal test was defined as reversible or fixed perfusion defects. Perfusion abnormalities were detected in 55 patients (33%). During a median follow-up of 2.5 years, 54 deaths (33%) occurred, 16 of which were due to cardiac causes. The incidence of perfusion abnormalities was higher in patients with subsequent cardiac death than in patients without subsequent cardiac death (69% vs 29%, p = 0.01). In an incremental multivariate Cox analysis, cardiac death was not predicted by age, gender, duration of transplantation, number of rejection episodes, or cytomegalovirus infection. In the next step, stress test parameters were added. The peak rate-pressure product was the only significant predictor at this step (risk ratio 0.84, 95% confidence interval 0.73 to 0.97, chi-square 7.7, p = 0.006). In the final step, the presence of abnormal myocardial perfusion was an independent predictor of cardiac death (risk ratio 3.5, 95% confidence interval 1.6 to 11.7, chi-square 4.7, incremental to clinical and stress test variables, p = 0.01). It is concluded that stress myocardial perfusion imaging with technetium-99m tetrofosmin single-photon emission computed tomography provides incremental data for the prediction of cardiac death in heart transplant recipients.
Echocardiography, Stress↗
Antidiuretic hormone release during laparoscopic donor nephrectomy.
BACKGROUND: During laparoscopic procedures, increased intra-abdominal pressure may cause transient renal dysfunction due to impaired renal blood flow and induction of neurohormones. However, the relationship between antidiuretic hormone (ADH) secretion and increased intra-abdominal pressure is poorly understood. HYPOTHESIS: Laparoscopic donor nephrectomy (LDN) is associated with an increase in plasma ADH concentration, which influences renal function in both the donor and transplanted graft. OBJECTIVES: To evaluate plasma ADH levels during LDN and to correlate ADH levels with graft function. DESIGN AND INTERVENTIONS: In 30 patients who underwent LDN, plasma ADH levels were collected before insufflation, during surgery, after desufflation, and 24 hours after the procedure. In 6 patients who had open donor nephrectomy, blood samples were obtained as controls. Furthermore, graft function, operative characteristics, and clinical outcome were compared. SETTING: University hospital. RESULTS: In the LDN group, mean ADH levels during pneumoperitoneum and 30 minutes postinsufflation were significantly higher compared with preinsufflation values (P<.001). Twenty-four hours after LDN, mean ADH levels had returned to normal values. There were no significant differences in ADH levels in the open donor nephrectomy group. No significant differences in either intraoperative diuresis, blood pressure readings, or postoperative graft function were documented among the 2 groups. CONCLUSIONS: In this study, LDN was associated with an increase in plasma ADH that appeared to be related to increased intra-abdominal pressure. We conclude that the increased ADH concentrations during LDN are not associated with clinically significant changes in either the kidney donor or the transplanted graft.
Adult↗
Novel assays of multiple lymphocyte functions in whole blood measure: new mechanisms of action of mycophenolate mofetil in vivo.
The antiproliferative effects of MMF are believed to be the mechanism of its immunosuppressive action. We further investigated the mechanisms of action by assessing the pharmacodynamics (PD) of MMF in treated animals using whole blood assays not only of lymphocyte proliferation but also of activation. In vitro, different MPA concentrations were added to rat whole blood. In vivo, Lewis rats were treated with single doses of 5, 10 or 20 mg/kg MMF (n = 6 rats/dose group). Blood was obtained before and at different times after drug administration. For both in vitro and in vivo studies, different mitogens with calcium-dependent (TCR) or -independent (co-stimulatory) pathways of lymphocyte activation were added to the blood for stimulation. Proliferation was measured by [3H]TdR incorporation and by flow cytometric detection of DNA content. Activation was measured by changes in T cell surface expression of CD25, CD134, CD71, CD11a and CD54. In vitro and in vivo studies showed a dose-dependent inhibition by MPA and MMF, respectively, of lymphocyte proliferation and surface antigen expression. We observed high correlations between MMF PD effects over time with both MMF dose and MPA plasma concentrations in vivo. We show that MMF, apart from its antiproliferative effect, induced a dose-dependent suppression of calcium-dependent and -independent stimulated expression of important lymphocyte cell surface antigens. These data suggest that the ex vivo assessment of immune function in whole blood can uncover new mechanisms of MMF action. Our results demonstrated that the measurement of the PD is a means to assess the functional effects of MMF after its administration in vivo.
Animals↗
How pharmacokinetic and pharmacodynamic drug monitoring can improve outcome in solid organ transplant recipients.
Within the field of solid organ transplantation there is an unprecedented interest in therapeutic drug monitoring of immunosuppressive drugs. Ideally therapeutic drug monitoring should cost-effectively lead to improved efficacy of the drug and to a reduction in side effects. Therapeutic drug monitoring will be most effective if there is a large interpatient variability and a small intrapatient variability. Therapeutic drug monitoring in transplantation is largely based on correlations between drug concentrations and toxicity or between drug concentrations and efficacy. Pharmacodynamic monitoring of immunosuppressive drugs has not reached the stage of widespread clinical application. In part this is caused by the fact that most of the pharmacodynamic assays are time-consuming, costly and in some cases only give a result after several days of incubation. Another reason for the limited interest in pharmacodynamic monitoring is the lack of data showing improved outcome if dose adjustment is based on pharmacodynamics rather than pharmacokinetics. On the other hand, such data are also lacking for pharmacokinetic monitoring. Prospective investigations on the contribution of therapeutic drug monitoring may result in further improvement of the safety and efficacy of our immunosuppressive regimens and more refined methods for therapeutic drug monitoring. There is no contest between pharmacokinetic and pharmacodynamic monitoring. Most likely the results of both ways of monitoring will be complementary.
Animals↗
Pharmacodynamics of mycophenolate mofetil after heart transplantation: new mechanisms of action and correlations with histologic severity of graft rejection.
The primary mechanism of action in vivo of mycophenolate mofetil (MMF) is believed to be inhibition of lymphocyte proliferation. We used novel assays of lymphocyte functions (pharmacodynamics, PD) in whole blood collected from rat heart allograft recipients treated with MMF to investigate the mechanisms of action of the active metabolite of MMF, mycophenolate acid (MPA) in vivo. Allograft recipients were treated orally once daily with 3 different doses of MMF. Seven days after transplantation, blood was collected 24h after the penultimate dose and several timepoints after the last dose, after which grafts were removed for microscopic grading of rejection. Lymphocytes in whole blood samples were mitogen stimulated through calcium-dependent and -independent signaling pathways. Inhibition of PD was measured by lymphocyte proliferation and expression of several surface antigens on T cells, and was calculated as area under the time-inhibition of immune function effect curve (AUE0-24h). We found that inhibition of lymphocyte proliferation and antigen expression by MPA correlated highly with MMF-dose, MPA level and with the histologic severities of graft rejection (p <0.05). In summary, MPA suppressed lymphocyte proliferation and expression of T-cell surface antigens in whole blood collected from MMF-treated allograft recipients, thus demonstrating the multiple mechanisms of suppression of rejection on peripheral blood T cells after MMF treatment.
Animals↗
Impact of intraoperative donor management on short-term renal function after laparoscopic donor nephrectomy.
OBJECTIVE: To determine whether intraoperative diuresis, postoperative recovery, and early graft function differ between laparoscopic open nephrectomy (LDN) and open donor nephrectomy (ODN). SUMMARY BACKGROUND DATA: Laparoscopic donor nephrectomy can reduce donor complications in terms of decreased pain and shorter convalescence. Although its technical feasibility has been established, concerns have been raised about the impaired renal function resulting from pneumoperitoneum and short- and long-term function of kidneys removed by LDN. METHODS: Between December 1997 and December 2000, 89 LDNs were performed at the authors' institution. These were compared with 83 conventional ODNs performed between January 1994 and December 1997. Graft function, intraoperative variables, and clinical outcome were compared. RESULTS: Laparoscopic donor nephrectomy was attempted in 89 patients and completed in 91% (81/89). Length of hospital stay was significantly shorter in the laparoscopic group. During kidney dissection, the amount of fluids administered and intraoperative diuresis were significantly lower for LDN. In recipients, mean serum creatinine was higher after LDN compared with ODN 1 day after surgery. From postoperative days 2 until 28, there were no differences in serum creatinine. Graft survival rates were similar for LDN and ODN. CONCLUSIONS: Donors can benefit from an improvement in postoperative recovery after LDN. Assessment of an adequate perioperative hydration protocol is mandatory to ensure optimal kidney quality during laparoscopic procurement. The initial graft survival and function rates justify continued development and adoption of LDN.
Adult↗
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.
Adult↗