Nateglinide improves postprandial hyperglycemia and insulin secretion in renal transplant recipients

BACKGROUND: Postprandial hyperglycemia (PPHG) frequently occurs among renal transplant recipients (RTR). Reduced early insulin response (EIR) after a meal leads to impaired suppression of endogenous glucose production and subsequently PPHG, which is a risk factor for cardiovascular disease. Nateglinide is a rapid acting insulin secretagogue inducing an EIR after a meal. Our main objective was to investigate the safety and effect of nateglinide treatment on postprandial plasma glucose excursions and insulin secretion in RTR with PPHG. PATIENTS AND METHODS: A total of 14 Caucasian RTR with new-onset diabetes mellitus (NODM; n = 6) or impaired glucose tolerance (IGT; n = 8) were included. The insulin response and glucose excursions were measured for 240 min after a standardized liquid meal at baseline and after two-wk treatment with nateglinide. RESULTS: Treatment with nateglinide was followed by a significant decrease in mean two-h plasma glucose from 10.5 mmol/L (3.1) to 7.6 mmol/L (2.1; p < 0.001) and a decline in total postprandial area under the curve (AUC) of glucose concentration (p < 0.001). Both estimated EIR and the late insulin response increased significantly (p = 0.008 and p = 0.003, respectively). No serious adverse event was observed during the study period. CONCLUSIONS: Treating RTR with nateglinide for two-wk significantly improved PPHG, increased the insulin response following a standardized meal and was well tolerated.     

Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients.

BACKGROUND: Hypertension and hyperuricaemia are common side-effects of cyclosporin A (CsA) treatment in renal transplant recipients. While it is well established that the calcium channel blocker amlodipine can control CsA-induced hypertension effectively in this patient population, recent evidence suggests amlodipine might also reduce hyperuricaemia. The present study was designed to compare the effects of the calcium channel blocker amlodipine (5-10 mg/day) and the beta-adrenoceptor antagonist tertatolol (5-10 mg/day) on CsA-induced hyperuricaemia in post-renal transplant recipients with hypertension. METHODS: Forty-eight hypertensive renal transplant recipients on a stable dose of CsA were randomized in a double-blind, parallel-group manner to receive either amlodipine (n = 24) or tertatolol (n = 24) for 60 days. The primary outcome measure was the change from baseline in serum uric acid concentration. Secondary analyses of efficacy were based on changes in renal function and blood pressure. RESULTS: Amlodipine significantly decreased serum uric acid levels from 483 +/- 99 to 431 +/- 110 microM/l (P < 0.001), while tertatolol significantly increased uric acid from 450 +/- 98 to 476 +/-84 microM/l (P = 0.006). Amlodipine also significantly increased glomerular filtration rate (P = 0.0048) and the clearance rate of uric acid (P = 0.023) and it reduced the fractional proximal tubular reabsorption of sodium (P < 0.001), compared with tertatolol. Renal plasma flow and filtered fraction were unaffected by both treatments, as was trough CsA blood concentration. Amlodipine lowered systolic blood pressure to a significantly greater extent than did tertatolol (P = 0.007). The time-dependent profile of diastolic blood pressure did not differ significantly between treatment groups. Both drugs were well tolerated. CONCLUSIONS: Amlodipine could be more appropriate than tertatolol for CsA-induced hypertension and hyperuricaemia in renal transplant recipients.     

Everolimus with early withdrawal or reduced‐dose calcineurin inhibitors improves renal function in liver transplant recipients: A systematic review and meta‐analysis

Calcineurin inhibitors (CNI) are the mainstay of immunosuppression after liver transplantation (LT), but CNIs are associated with significant nephrotoxicity. Recently, mTOR inhibitors such as sirolimus and everolimus (EVR) have been used with or without CNIs in LT recipients for their renal‐sparing effect. We conducted a systematic review and meta‐analysis of randomized controlled trials (RCT) that examined the effect of EVR with CNI minimization or withdrawal on renal function in LT recipients. RCT of primary adult LT recipients with baseline GFR >30 mL/min who received EVR with CNI minimization or withdrawal were included. Four RCTs (EVR n=465, control n=428) were included. In three RCTs, EVR was initiated 4 weeks following LT; these studies were used to assess the primary outcome. All four studies were used to assess the secondary outcomes. Based on this study, EVR use with CNI minimization in LT recipients is associated with improved renal function at 12 months by GFR of 10.2 mL/min (95% CI: 2.75‐17.8). EVR use was not associated with an increased risk of biopsy‐proven acute rejection (RR 0.68, 95% CI: 0.31‐1.46), graft loss (RR 1.60, 95% CI: 0.51‐5.00), or mortality (RR 1.34, 95% CI 0.62‐2.90). However, it was associated with an increased risk of overall infections (RR 1.45, 95% CI: 1.10‐1.91).     

Short-term treatment with rosiglitazone improves glucose tolerance, insulin sensitivity and endothelial function in renal transplant recipients.

BACKGROUND: Insulin resistance (IR) contributes to the development of glucose intolerance (post-transplant diabetes mellitus or impaired glucose tolerance) following renal transplantation. Furthermore, endothelial dysfunction (ED) is associated with IR. Glucose intolerance, IR and ED are all independent risk factors for cardiovascular disease. Therefore, treatment with insulin sensitizers may benefit glucose-intolerant renal transplant recipients. The main objectives of the present study were to investigate the effect of 4 weeks' treatment with the PPAR-gamma agonist rosiglitazone on insulin sensitivity, plasma glucose and endothelial function in renal transplant recipients with glucose intolerance. Safety parameters were also addressed. METHODS: A total of 10 glucose-intolerant renal transplant recipients were treated with rosiglitazone (initially 4 mg/day increasing to 8 mg/day after 1 week). A hyperinsulinaemic euglycaemic glucose clamp, an oral glucose tolerance test and endothelial function assessment with laser Doppler flowmetry were performed both at baseline and at follow-up. RESULTS: Treatment with rosiglitazone was followed by a significantly improved mean glucose disposal rate (from 6.5 to 9.1 g/kg/min; P = 0.02) and a significant decline in fasting and 2 h plasma glucose (from 6.4 to 5.8 mmol/l, P = 0.01 and from 14.2 to 10.6 mmol/l, P = 0.03, respectively). Furthermore, a significant improvement in endothelial function was demonstrated (AUC(ACh); from 389 to 832 AU x min, P = 0.04). No serious adverse events or hypoglycaemic episodes were observed. CONCLUSIONS: Four weeks' treatment with rosiglitazone was associated with increased insulin sensitivity, lowered fasting and 2 h plasma glucose and improved endothelial function in renal transplant recipients with glucose intolerance. The drug was well tolerated and may be a good alternative for treating these patients.     

Association between insulin resistance and endothelial dysfunction in renal transplant recipients

BACKGROUND: Endothelial dysfunction is a common finding in renal transplant recipients (RTR) and is related to impaired local regulation of vasodilative and vasoconstrictive substances, such as nitric monoxide (NO) and endothelin-1 (ET-1). In non-transplanted patients, an association between impaired endothelial function and insulin resistance has been shown. Whether such an association also exists in RTR is unknown. OBJECTIVE: The aim of the present study was to examine whether insulin resistance is associated with endothelial dysfunction in RTR. MATERIAL AND METHODS: A total of 47 RTR in a stable phase six yr post-transplant were included in the statistical analysis. The immunosuppressive therapy was based on cyclosporine and prednisolone. Non-invasive assessment of endothelial function was performed with laser Doppler flowmetry of the forearm skin vasculature after local acetylcholine stimulation. Oral glucose tolerance tests comprising both glucose and insulin measurements were used to calculate insulin sensitivity (IS) indices. NO, ET-1 and von Willebrand factor were measured in fasting plasma samples. RESULTS: Normal glucose tolerance was found in 31 RTR. In these subjects, both IS (r(2) = 0.164, p = 0.044) and plasma NO (r(2) = 0.326, p = 0.002) were significantly correlated with endothelial function. Patients with glucose intolerance (n = 16) had higher plasma ET-1 and lower NO levels, but the association between IS and endothelial function was not significant in these subjects. In the total patient cohort, IS and endothelial function tended to be correlated (p = 0.127). CONCLUSIONS: Endothelial dysfunction is significantly associated with insulin resistance in normoglycemic RTR but explains a rather small part of the variation. In glucose-intolerant recipients, IS appears to be more critically dependent on other factors not revealed in the present study.     

Stable graft function after reduction of calcineurin inhibitor dosage in paediatric kidney transplant patients.

BACKGROUND: Chronic calcineurin inhibitor (CNI) toxicity contributes to the development and progression of chronic allograft nephropathy (CAN), which is still the major cause of transplant dysfunction and graft loss. Reduction in dosage of CNI may delay the development of CAN, leading to longer graft survival. METHODS: Therefore, 19 paediatric kidney transplant patients under immunosuppressive therapy with CNI (12/19 ciclosporin A, CSA, 7/19 tacrolimus, Tac), mycophenolat mofetil and some patients on steroids were included in a prospective study. Over a period of 9 months CNI dosage was stepwise reduced from CSA trough levels of 100-150 ng/ml to 50-70 ng/ml and Tac trough levels of 5-8 ng/ml to 2-3 ng/ml, respectively. RESULTS: Glomerular filtration rate was stabilized in patients after CSA and Tac reduction. One borderline rejection occurred in a patient prior to reduction of Tac. In patients on CSA, one interstitial cellular rejection (BANFF IA) was noted. Reduction of CNI had no significant effects on blood pressure, lipid status and the infection frequency. CONCLUSIONS: In paediatric kidney transplant patients, reduction of CNI down to low trough levels stabilizes renal function. However, the risk of acute rejection episodes may be increased. Therefore, further studies based on protocol biopsies within a randomized trial are warranted.     

Relationship between pharmacokinetics and pharmacodynamics of calcineurin inhibitors in renal transplant patients

The calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs, which are typically employed in the field of organ transplantation. Both drugs have narrow therapeutic indices, highly variable pharmacokinetics, and are associated with severe adverse effects. In current clinical routine, the dose finding of CNIs is based on the measurement of their blood concentrations. However, this method is limited in its ability to determine the biological impact of the drug. Alternative monitoring strategies, focusing on the pharmacodynamics of CNIs, could help to personalize drug dosing and optimize the treatment with CNIs. Therefore, we analyzed the relationship between pharmacokinetic and pharmacodynamic of the CNIs CsA (n = 9) and Tac (n = 8) in stable renal transplant patients during a 12‐h dosing period. We observed a significant decrease in the drug–blood concentration during the course of the day and in parallel a significant recovery of T cell function. In addition, our data document that analysis of intracellular interleukin (IL)‐2 production and determination of the IL‐2 release are accurate parameters for monitoring the pharmacodynamics of CNIs.     

Tuberculosis in renal transplant recipients on various immunosuppressive regimens.

BACKGROUND: Mycophenolate mofetil (MMF) and tacrolimus (TAC) are more potent than conventional immunosuppressive drugs, i.e. azathioprine, cyclosporin and prednisolone, and may be associated with an increase in the incidence of infections in the post-transplantation (post-tx) period. The aim of this study was to determine if the use of either or both of MMF and TAC for immunosuppression in renal transplant recipients increases the prevalence or modifies the clinical presentation of tuberculosis (TB), when compared with conventional therapy. METHODS: The medical records of 443 adult patients who received a kidney transplant between 1994 and 2002 were reviewed retrospectively. Comparisons were made between patients who had conventional immunosuppressive treatments (cyclosporin, azathioprine and prednisolone) or an alternative regimen (including MMF, TAC or both). RESULTS: We found 20 patients (4.5%) to have post-tx TB. There were 13 cases of TB (age 38.9+/-10.6 years) among 328 patients who received conventional immunosuppressants (group I) (4.0%) and seven cases (age 24.2+/-7.4 years) among 115 (6.1%) who received an alternative immunosuppressive regimen (group II) (P>0.05). The patients in group II were younger than the patients in group I (P = 0.002). A significantly higher number of patients in group II developed TB within the first 6 months post-tx (P = 0.042). However, there was no significant difference between the two groups regarding clinical and radiographic presentations or outcomes. CONCLUSIONS: Immunosuppression with TAC or MMF is associated with the development of TB earlier in the post-tx period and in younger patients.     

Acute effect of cyclosporin on renal function following the initial changeover to a microemulsion formulation in stable kidney transplant patients

Potential differences in the acute effect of cyclosporin on renal function when dosed orally as the current market formulation or following a milligram-to-milligram conversion to a new microemulsion formulation were investigated in 14 stable kidney transplant patients. The study consisted of three sequential periods of 2 weeks duration each. Patients entered (period I) and completed (period III) the investigation with the market formulation and received the microemulsion formulation in period II; individualized cyclosporin doses remained unchanged throughout the study. Over one steady-state dosing interval at the end of each study period, whole blood cyclosprin pharmacokinetic profiles were assessed in parallel with endogenous creatinine clearances over sequential 1-to 2-h intervals. The rate and extent of cyclosporin absorption were significantly greater (P<0.01) from the microemulsion formulation with average increases of 73% in peak concentration and 44% in area under the curve compared to the market formulation. Sequential creatinine clearances exhibited a transient decrease with the nadir occurring on average between 4 and 6h post dose followed by a rapid return to baseline. Specifically in period I on the market formulation, clearances decreased from a baseline of 71.7±20.6 to a minimum of 51.1±17.9 ml/min per 1.73 m² (similar values in period III) and from 76.8±24.8 to 53.5±17.5 ml/min per 1.73 m² in period II on the microemulsion. Neither the baseline nor minimum clearances were significantly different among the study periods. Hence, the pharmacokinetic differences between the formulations did not acutely influence the pattern of glomerular filtration rate following the initial milligramto-milligram changeover in stable renal transplant patients.     

A 6-year prospective study on new onset diabetes mellitus, insulin release and insulin sensitivity in renal transplant recipients.

BACKGROUND: It is well known that both insulin resistance and insulin deficiency are involved in the pathogenesis of post-transplant diabetes mellitus (PTDM), but the relative importance of the two different mechanisms is still under debate. The present prospective longitudinal study was performed over 6 years to investigate the impact of impaired insulin secretion (ISec) and insulin sensitivity (IS) in the development of PTDM in renal transplant recipients. METHODS: A total of 95 non-diabetic patients underwent a 75 g oral glucose tolerance test (OGTT) 10 weeks post-transplant. Six years later, 63 of these recipients were re-examined, the majority (n = 58) with an OGTT. Fasting, 1- and 2-h insulin and glucose levels were measured and used to estimate the insulin secretory response and IS both at baseline and at follow-up. RESULTS: The proportion of recipients with normal glucose tolerance (NGT) rose from 46% (baseline) to 65% (follow-up) (P = 0.008), and median fasting and 2-h serum glucose were reduced by 0.7 mmol/l (P < 0.001) and 1.3 mmol/l (P = 0.039), respectively. The recipients with PTDM at follow-up had a significant decline in the estimated median first and second phase ISec (-58 and -47%, respectively, P = 0.005 for both). The patients who normalized their glucose tolerance from PTDM or IGT at baseline to NGT at follow-up increased their IS significantly (68%, P = 0.002) without significant alterations in ISec. CONCLUSIONS: Impaired ISec seems to be the dominant mechanism in the development of PTDM after renal transplantation. In contrast, normalization of glucose intolerance is associated with improved IS.     

Magnesium excretion and hypomagnesemia in pediatric renal transplant recipients

Background: We investigated magnesium excretion and rate of hypomagnesemia in pediatric renal transplant recipients. Method: The medical records of 114 pediatric renal transplant recipients were retrospectively evaluated. After exclusion of 23 patients, 91 patients were included in the study. We recorded serum magnesium levels at the time of measurement of urine magnesium wasting. Results: Mean serum magnesium levels were 1.73?±?0.22?mg/dL and 38 of the patients (41%) had hypomagnesemia. There was a negative correlation between serum magnesium levels and estimated glomerular filtration rate and serum tacrolimus trough level (r?=??0.215, p?=?0.040 and r?=??0.409, p?=?0.000, respectively). Also, there was a statistically significant positive correlation between serum magnesium levels and transplantation duration (r?=?0.249, p?=?0.017). Mean fractional magnesium excretion was 5.9?±?3.7% and 59 patients (65%) had high magnesium excretion. There was a significant negative correlation between fractional magnesium excretion and estimated glomerular filtration rate (r?=??0.432, p?=?0.001). There was a significant positive correlation between fractional magnesium excretion and serum creatinine (r?=?0.379 p?=?0.003). Conclusion: Patients with higher tacrolimus trough blood levels, lower glomerular filtration rate and at early posttransplant period had risk of hypomagnesemia.     

Potential cardiovascular risk factors in paediatric renal transplant recipients

Cyclosporin (CsA) therapy is associated with side effects such as hypertension, hyperlipidemia and nephrotoxicity. Tacrolimus (Tac) has been shown to be more favourable in this respect. We retrospectively analysed office blood pressure (BP), serum total cholesterol (TC) and fasting glucose levels, and estimated graft function profiles in paediatric (n =56) and young adult (n =14) renal transplant recipients whose maintenance immunosuppressive regimen was based upon CsA (n =38) or Tac (n =32) given with mycophenolate mofetil and corticosteroids. The analysis was performed at four different time-points: at 1, 6, 12, and 24 months post-transplant, respectively. Baseline characteristics were comparable between treatment groups. Differences for both systolic and diastolic BP, and graft function between treatment groups became significant from month 1 and throughout the 2-year period. Values (mean ± SD) for CsA-treated and Tac-treated recipients at 2 years were 118.8±11.1 / 74.6±7.4 mmHg vs 109.3±11.2 / 67.2±7.8 mmHg for systolic and diastolic BP, respectively, p <0.005/0.005; and 72.0±18.5 ml/min vs 84.0±22.4 ml/min per 1.73 m² for graft function, respectively, p <0.01. Office hypertension, defined as the use of antihypertensive medication at month 24, was significantly associated with CsA-therapy (², p <0.01). TC levels became significantly lower at months 6, 12, and 24 in the Tac group compared with the CsA group. Hypercholesterolemia, defined as TC200 mg/dl, was significantly associated with CsA-based immunosuppressive regimen at months 6, 12, and 24 post-transplant (², p <0.05, p <0.001, and p <0.01, respectively). Although Tac therapy was associated with higher glucose levels, no recipient developed post-transplant diabetes mellitus. The number of recipients who experienced acute rejections was comparable in both groups. In conclusion, Tac-based immunosuppressive therapy was found to be associated with more favourable potential risk-factor profiles for cardiovascular disease and better graft function at 2 years post-transplant compared with CsA-therapy.     

The effect of calcineurin inhibitors on endothelial function in renal transplant recipients

Endothelial dysfunction is of vital importance, as it may cause ischemia and dysfunction in various organs. Despite, this problem has been well documented in patients with end-stage renal disease (ESRD), there is not enough data considering this issue following renal transplantation. One of the potential causes of endothelial dysfunction in renal transplant recipients may be administration of calcineurin inhibitors. The aim of this study is to evaluate the effects of two different calcineurin inhibitors [cyclosporin A (CsA) and tacrolimus (FK506)] on endothelial function in renal transplant patients. Forty-four renal transplant recipients [22 on FK506 (group I) and 22 on CsA (group II)] were studied. Endothelial functions of the brachial artery were evaluated by using high resolution vascular ultrasound. Endothelium-dependent and -independent vasodilations were assessed by establishing reactive hyperemia and using sublingual nitroglycerine (NTG), respectively. Results are presented as percentage change from baseline values. Significant endothelial dysfunction was noted in renal transplant patients treated with CsA. While endothelium-dependent vasodilation was 12.1 +/- 5.1% in group I and it was 6.5 +/- 3.7% in group II (p < 0.001). The increase in brachial artery diameter after sublingual NTG was 20.1 +/- 6.3 and 12.7 +/- 5.6% in groups I and II, respectively. This indicates that the endothelium-dependent and -independent vasodilation of the patients on FK506 is better preserved than the patients on CsA therapy. Besides, blood flow volume (BFV) increase was 51.2 +/- 39.4 and 43.9 +/- 24.3%, in groups I and II, respectively, in reactive hyperemia period (p > 0.05). Post-transplant course of renal transplant recipients is complicated by endothelial dysfunction. This problem is more prominent in patients on CsA therapy, which can predispose these patients to more frequent cardiac complications.     

The calcineurin activity profiles of cyclosporin and tacrolimus are different in stable renal transplant patients

Cyclosporin and tacrolimus remain the cornerstone immunosuppressive drugs in organ transplantation. Dosing and monitoring these drugs is based on pharmacokinetic protocols, but measuring a pharmacodynamic parameter, calcineurin phosphatase (CaN) activity, could be a valuable supplement in determining optimal doses. Forty stable renal transplant patients were investigated three times in a 6-month period. Blood samples were drawn at 0, 1, 2, 3 and 4 h after oral intake of tacrolimus (FK) or cyclosporin at days 1 and 180. At day 90, one blood sample at trough level (FK) or C2 level (cyclosporin A, CsA) was drawn. CaN activity was determined in whole blood as the release of 32P from a phosphorylated peptide. Activity of the 32P was quantitated by liquid scintillation and results converted to Units CaN, utilizing a calibration curve with CaN. We demonstrated that calcineurin activity profiles at days 1 and 180 were the same for both drugs. Furthermore, we found that patients treated with tacrolimus or cyclosporin displayed different calcineurin activity profiles. We found that cyclosporin displayed greater calcineurin inhibition than tacrolimus. We have demonstrated that the two drugs exert significantly different effects on calcineurin activity in renal transplant patients with stable, well-functioning grafts and that tacrolimus-treated patients can maintain good, stable graft function with minimal CaN inhibition.     

Cinacalcet's effect on the pharmacokinetics of tacrolimus, cyclosporine and mycophenolate in renal transplant recipients.

BACKGROUND: The calcimimetic drug cinacalcet offers a novel therapeutic option to treat post-transplant hypercalcemia and hyperparathyroidism; however, the interaction with calcineurin inhibitors and mycophenolate has not been evaluated. METHODS: In the present study the effects of cinacalcet on the pharmacokinetics of cyclosporine A (CsA), tacrolimus (Tac) and mycophenolate were investigated in 14 renal transplant recipients with stable renal function (mean creatinine 126.4 +/- 45.3 micromol/L). The patients were treated with either CsA (n = 8) or Tac (n = 6) in combination with mycophenolate/azathioprine and steroids. Twelve-hour pharmacokinetic investigations to measure CsA and its six main metabolites, Tac and mycophenolate concentrations were performed before and after 1-week treatment with 30 mg cinacalcet once daily. RESULTS: Cinacalcet treatment induced a significant 14.3 +/- 12.1% decrease in Tac AUC(0-12) (P = 0.039). Tac C(max), T(max) and T(1/2) also tended to decrease. The pharmacokinetics of CsA and mycophenolate were not significantly affected by concomitant treatment with cinacalcet. However, the secondary CsA metabolite, AM19, showed a significant increase of 9.0 +/- 9.5% during cinacalcet treatment (P = 0.040). Renal function decreased significantly from 78 +/- 11 to 72 +/- 12 mL/min (P = 0.019) and correlated with the increased levels of metabolite AM19 in the CsA group. Renal function was unchanged in the Tac group. CONCLUSION: Cinacalcet treatment showed a moderate effect on the Tac, but not CsA or mycophenolate, pharmacokinetics after 1-week concomitant treatment. This interaction appears to have minor clinical relevance. However, it is advisable to monitor renal function in CsA-treated patients due to the observed decrease in renal function.     

Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results.

BACKGROUND: Comparison studies of calcineurin inhibitors as cornerstone immunosuppressants in renal transplantation have demonstrated that tacrolimus consistently reduces acute rejection rates and, in some studies, also improves long-term renal outcome in comparison to cyclosporin A (CsA). The aim of the present 2 year follow-up of the European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was to investigate long-term clinical outcome in terms of rate of acute rejection, graft and patient survival and graft function. METHODS: The European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was a randomized, comparative 6 month trial of the calcineurin inhibitors tacrolimus and CsA in combination with both azathioprine and steroids. The intent-to-treat population (ITT) consisted of 286 patients in the tacrolimus arm and 271 in the CsA microemulsion (CsA-ME) arm. Whereas whole blood level targets were 10-20 and 5-15 ng/ml for tacrolimus and 100-400 and 100-200 ng/ml for CsA during months 0-3 and 4-6, respectively, during the investigator-driven follow-up after termination of the main study (months 7-24) no specific calcineurin inhibitor target levels were required. Follow-up data were collected at 2 years post-transplantation from 237 (82.9% of the ITT population) patients who received tacrolimus and 222 (81.9% of the ITT population) patients who received CsA-ME. RESULTS: Calculated on ITT populations, mortality (2.0% vs 3.3%; P<0.05 in Kaplan-Meier analysis) was lower, but rate of graft loss (9.3% vs 11.2%; P = 0.12 in Kaplan-Meier analysis) was not significantly different after 2 years with tacrolimus- vs CsA-ME-based immunosuppression. Biopsy-proven acute rejection was significantly lower (19.6%) with tacrolimus than with CsA-ME (37.3%) during months 0-6 (P<0.0001), but was not significantly different during months 7-12 and 13-24 of follow-up (1.7% and 0.8% with tacrolimus and 4.7% and 0.9% with CsA-ME, respectively). A composite endpoint consisting of graft loss, patient death and biopsy-proven acute rejection occurred significantly more frequently in CsA-ME patients than in tacrolimus patients (42.8% vs 25.9%; P<0.001) during 24 months follow-up. Renal function 2 years post-transplant, measured by serum creatinine concentrations, was significantly better in tacrolimus-based compared with CsA-ME-based immunosuppression (136.9 vs 161.6 micromol/l; P<0.01). Cornerstone immunosuppression remained unchanged in 82.5% and 66.2% of patients treated with tacrolimus and CsA-ME, respectively. At 2 years, more patients in the tacrolimus arm were off steroids and received calcineurin inhibitor monotherapy, and fewer tacrolimus patients remained on a triple immunosuppressive regimen. The cardiovascular risk profile was affected favourably in the tacrolimus arm, with lower cholesterol and triglyceride concentrations (despite less use of cholesterol-lowering drugs); no significant difference in requirement for antidiabetic medication was noted. CONCLUSIONS: The 2 year study results confirm that tacrolimus is a highly efficacious cornerstone immunosuppressant in kidney transplantation. Tacrolimus-based immunosuppression may induce long-term benefits with regard to graft function and graft survival. The overall side-effect profile is considered to be favourable.     

Calcineurin inhibitor withdrawal and conversion to mycophenolate mofetil and steroids in cardiac transplant recipients with chronic renal failure: a word of caution

Abstract: Background: Chronic renal failure (CRF) is a common complication of calcineurin inhibitor (CNI)‐based immunosuppression following cardiac transplantation (HTx). The aim of this prospective study was to evaluate the impact of an immunosuppressive conversion from CNIs to mycophenolate mofetil (MMF) and steroids in cardiac transplant recipients with CRF on renal and cardiac graft function. Methods: Since 1999, 12 HTx recipients (10 men; 58 ± 3.6 yr of age; 8.7 ± 4.2 yr after HTx) with CNI‐based immunosuppression and a calculated creatinine clearance (CreaCl) <50 mL/min were included. Most patients (10/12) were on cyclosporine and two patients were on tacrolimus prior inclusion. MMF was started with 0.5 g/d and adjusted according to the target trough levels (2–4 ng/mL). Prednisone dosage was 0.4 mg/kg. Subsequently, CNIs were completely withdrawn. Acute rejection episodes were excluded one and three months after conversion by endomyocardial biopsy and by echocardiography every three months thereafter. Results: After a mean follow‐up of 20 ± 16 months, CreaCl improved significantly: pre‐conversion vs. post‐conversion: 32.8 ± 12.2 mg/dL vs. 42.8 ± 21.14 mg/dL, p = 0.03. However, four acute rejection episodes occurred and patients were reconverted to CNIs. Additionally, six patients had a new onset of graft vessel disease (GVD) one yr after conversion. As a result of these adverse events, the study was stopped after inclusion of only 12 of the scheduled 30 patients. Conclusions: Conversion to MMF and steroids after HTx improves renal function, but increases the risk for recurrent rejection and GVD. Therefore, MMF and steroids should only be considered in patients with a markedly low risk for rejection.