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The function of the efflux pump P-glycoprotein (Pgp) and ABCB1 single nucleotide polymorphisms (SNPs) should be considered as important tools to deepen knowledge of drug nephrotoxicity and disposition mechanisms. The aim of this study is to investigate the association of C3435T, G2677T, C1236T, and T129C ABCB1 SNPs with Pgp activity and exposure to different immunosuppressive drugs in renal transplant patients. Patients included in the Symphony Pharmacogenomic substudy were genotyped for ABCB1 SNPs. According to the design, patients were randomized into four immunosuppressive regimens: low and standard dose of cyclosporine (n = 30), tacrolimus (n = 13), and sirolimus (n = 23) concomitantly with mycophenolate and steroids. Pgp activity was evaluated in PBMC using the Rhodamine 123 efflux assay. TT carrier patients on C3435T, G2677T, and C1236T SNPs (Pgp-low pumpers) showed lower Pgp activity than noncarriers. Pgp-high pumpers treated with cyclosporine showed lower values of Pgp function than macrolides. There was a negative correlation between cyclosporine AUC and Pgp activity at 3 months. Results did not show any correlation between tacrolimus and sirolimus AUC and Pgp activity at 3 months. We found an important role of the ABCB1 SNPs Pgp function in CD3(+) peripheral blood lymphocytes from renal transplant recipients. Pgp activity was influenced by cyclosporine but not macrolides exposure., (© 2012 The Authors Transplant International © 2012 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd.)

Introduction: The relationship between anticalcineurin (CNI) drugs and the development new-onset diabetes mellitus after kidney transplantation (NODAT) is well established. Among these agents cyclosporine shows lesser diabetogenicity than tacrolimus. It has been described that conversion from tacrolimus to cyclosporine improves glycemic control; however, there are no studies showing whether this reduced risk is maintained upon long-term follow-up., Objective: To evaluate whether CNI drugs conversion from tacrolimus to cyclosporine helps to maintain better glycemic control., Materials and Methods: We retrospectively evaluated the evolution of glucose metabolism at 5 years after conversion from tacrolimus to cyclosporine in eight patients (six men) with NODAT. Mean age was 42.8 ± 15 years, and time after transplantation to conversion 128 ± 40 months. We analyzed fasting serum glucose, lipid metabolism, renal function, and cyclosporine levels at 0, 6, 12, 24, 36, 48, and 60 months after conversion., Results: At 6 months after conversion, improved glucose metabolism was observed (268 ± 161 versus 121 ± 31 mg/dL; P < .01) although it was minimal in one case with persistent high blood glycemic levels. Only two patients maintained a normal glucose at the end of follow-up. Five subjects showed increased glycemia at 12 to 24 months after conversion requiring antidiabetic therapy: three patients, insulin and two oral antidiabetic agents. Two patients lost their allografts due to chronic rejection at 32 and 50 months respectively. Among the other six patients, renal function remained stable (1.9 ± 0.6 versus 2.11 ± 0.97 mg/dL; P = NS). There was no significant differences among the other variables. Cyclosporine levels remained stable during the follow-up., Conclusion: Conversion of renal transplant patients with NODAT from tacrolimus to cyclosporine improves glucose metabolism in the short term but glycemia increases thereafter., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The purpose of two similarly designed multicenter, prospective, parallel-group, open-label studies was to evaluate early cyclosporine (CsA) elimination versus minimization from an everolimus-CsA-steroid regimen in de novo renal transplant patients., Methods: Within 24 hours after transplantation, 170 renal transplant patients received everolimus (trough levels 3-8 ng/mL), CsA, and steroids. Those eligible (n = 114) were randomized (1:1) at 3 months to have CsA elimination by month 4 to 6 (±1 week) with everolimus trough levels maintained at 6 to 12 ng/mL or CsA minimization, until 12 months. The randomized population excluded those who discontinued the study prior to randomization due to adverse events, acute rejection episodes of Banff grade IIb/III, or worsening renal function during the month prior to randomization., Results: At 12 months, the estimated glomerular filtration rate (Nankivell) with CsA elimination was noninferior versus CsA minimization (P < .0001, α-level 0.05; 90% confidence interval 0.6-8.5) by 7 mL/min/1.73 m(2) (noninferiority margin). Composite efficacy failure was comparable with CsA elimination and CsA minimization (18.9% and 17.5%, respectively, P = 1.000) and no graft loss or death was reported after randomization. Cytomegalovirus infections were rare under everolimus treatment, and no pneumonitis episode was reported., Conclusion: In our selected randomized study population, immediate initiation of everolimus allowed CsA elimination. Renal function was stable on everolimus-based, CsA-free maintenance regimen without compromising efficacy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Due to its low level of nephrotoxicity and capacity to harness tolerogenic pathways, sirolimus (SRL) has been proposed as an alternative to calcineurin inhibitors in transplantation. The exact mechanisms underlying its unique immunosuppressive profile in humans, however, are still not well understood. In the current study, we aimed to depict the in vivo effects of SRL in comparison with cyclosporin A (CSA) by employing gene expression profiling and multiparameter flow cytometry on blood cells collected from stable kidney recipients under immunosuppressant monotherapy. SRL recipients displayed an increased frequency of CD4 + CD25highFoxp3 + T cells. However, this was accompanied by an increased number of effector memory T cells and by enrichment in NFkB-related pro-inflammatory expression pathways and monocyte and NK cell lineage-specific transcripts. Furthermore, measurement of a transcriptional signature characteristic of operationally tolerant kidney recipients failed to detect differences between SRL and CSA-treated recipients. In conclusion, we show here that the blood transcriptional profile induced by SRL monotherapy in vivo does not resemble that of operationally tolerant recipients and is dominated by innate immune cells and NFkB-related pro-inflammatory events. These data provide novel insights on the complex effects of SLR on the immune system in clinical transplantation., (©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Exposure to mycophenolic acid (MPA), the primary active metabolite of mycophenolate mofetil (MMF), is correlated with therapeutic efficacy of MMF but varies depending on the concomitantly administered immunosuppressive drugs., Methods: A 3-month pharmacokinetic substudy of the prospective, randomized, multicentre, open-label Symphony study was performed. Eighty-three adult renal transplant patients received standard-dose cyclosporine, MMF 2 g/day and corticosteroids, or daclizumab induction, MMF 2 g/day and corticosteroids plus low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus. The area under the concentration-time curve (AUC(0-12)) of MPA and its metabolites between treatment groups was compared. Pharmacokinetic sampling was performed before MMF administration and at 20, 40, 75 min; 2, 3, 6, 8, 10 and 12 h post-dose on Day 7 and Months 1 and 3., Results: Compared with standard-dose cyclosporine, patients receiving low-dose tacrolimus or low-dose sirolimus had significantly higher AUC(0-12) values for MPA at Day 7 and Month 1 and for free MPA at Day 7, and significantly lower AUC(0-12) values for 7-O-MPA-glucuronide (MPAG) at Month 1 and for acyl-glucuronide at Months 1 and 3 (P < 0.05). AUC(0-12) of MPA and free MPA was significantly greater with low-dose tacrolimus and low-dose sirolimus than with low-dose cyclosporine in the first month (P < 0.05). The ratio of MPA to MPAG exposure was significantly higher in the three low-dose groups than in the standard-dose cyclosporine group (P < 0.05)., Conclusions: Standard- and low-dose cyclosporine reduces the exposure of MPA and free MPA compared to low-dose tacrolimus or low-dose sirolimus in patients given the same dose of MMF.

Introduction: Renal function predicts graft survival in kidney transplant patients. This study compared the 2-year evolution of renal function in patients treated with cyclosporine or tacrolimus in combination with mycophenolate mofetil (MMF) and prednisone., Methods: We studied 1558 cadaveric renal transplant recipients from 14 Spanish hospitals between January 2000 and December 2002. Of these, 1168 were treated with tacrolimus and 390 with cyclosporine. The primary efficacy endpoint was long-term renal function. Renal function was measured by serum creatinine and glomerular filtration rate (GFR) by creatinine clearance calculated from the Cockcroft-Gault formula. This report summarizes the 2-year results., Results: At 24 months the tacrolimus group showed significantly better serum creatinine (1.5 +/- 0.7 vs 1.8 +/- 0.8 mg/dL, P < .001) and GFR (60.5 +/- 20.9 mL/min vs 47.9 +/- 10.0, P < .001) than the cyclosporine group. Additionally, recipients with ideal graft donors (23.5 +/- 2.8 vs 24.0 +/- 2.9 years) had a better serum creatinine at 2 years (1.23 +/- 0.2 vs 1.5 +/- 0.4 mg/dL, P < .05). Multivariate analysis showed that tacrolimus was an independent factor associated with better renal function: odds ratio 1.6, 95% confidence interval (1.2 to 2.2), P < .001., Conclusions: Patients with a renal transplant treated with tacrolimus in combination with MMF and prednisone displayed better renal function at 2 years than those who received cyclosporine.

Introduction: Efficacious prophylaxis of acute rejection episodes (ARE) requires adequate exposure to each component of the immunosuppressive treatment from the first days after renal transplantation. The aim of the present study was to evaluate the correlation between cyclosporine (CsA) and mycophenolic acid (MPA) exposure based upon pharmacokinetics (PK) and pharmacodynamics (PD) and 6-month biopsy-proven acute rejection (BPAR) episodes and chronic allograft nephropathy on 6 month protocol biopsies., Patients and Methods: We examined twenty-two first or second de novo renal transplant recipients treated with steroids, Sandimmune Neoral (CsA) and Myfortic (720 mg twice a day). PK (C0, C2, and AUC(0-12h)) for both drugs were determined on days 7, 90, and 180. Calcineurin activity, interleukin-2 and interferon-gamma synthesis as well as %CEM were tested at days 7 and 180. CsA dosages were adjusted by C2 monitoring. Collected data included: BPAR during the first 6 months and Banff histological parameters on the 6-month protocol biopsies., Results: Eighteen of 22 patients completed 1 year follow-up under treatment. The 6-month BPAR was 18% (4/22). Six-month protocol biopsies in 50% of 14 recipients showed chronic allograft nephropathy 1. At day 7, CsA C2 and AUC median values were 138 ng/mL and 6377 ng x h/mL, while C0 MPA was 1.0 microg/mL and AUC = 23.9 microg x h/mL. CsA C2 medians at 3 and 6 months were 1468 and 1720 ng/mL. MPA-AUC reached therapeutic targets at 3 months (32.3 microg x h/mL) and was 48.3 microg x h/mL at 6 months. Patients with BPAR showed lower CsA AUC (P = .06) and a significantly lower baseline inhibition of calcineurin activity (P < .005) than patients with no BPAR. An increase in mesangial matrix in 6-month protocol biopsies correlated with higher CsA C2 (P = .01). All biomarkers evaluated were significantly inhibited compared with the standard population., Conclusions: When Myfortic is administered together with CsA, it is advisable to begin with higher doses (720 mg x 3 days) to reach adequate PK targets and improve BPAR rates. To prevent chronic allograft nephropathy, lower CsA C2 should be targeted from 3 months.

Posttransplant diabetes mellitus (PTDM) occurs in approximately 15% to 20% of renal transplant patients. It has important clinical implications for graft function and survival. Anticalcineurin drugs are associated with an increased risk of developing PTDM. There is a little evidence that conversion from tacrolimus to cyclosporine (CsA)-based immunosuppression improves glucose metabolism and reverses diabetes. This prospective study included nine renal transplant patients (mean age of 34 +/- 20) with PTDM under immunosuppression with tacrolimus. Five were switched directly to CsA and the other four (glycemia > 250 mg/dL) required insulin and were simultaneously switched to CsA. Basal blood levels of tacrolimus were 7.9 +/- 1.9 ng/dL. Conversion was associated with an early, significant improvement of glycemia and HbA1c blood levels (P < .01). At the end of the follow-up, the glycemia (105 +/- 20 mg/dL) and Hb1Ac (5.1 +/- 0.4 mg/dL) were normal. Insulin was discontinued between 3 and 6 months in all patients who required it at the beginning. Cholesterol did not change significantly and triglycerides decreased significantly (basal 210 +/- 85 mg/dL, at 12 months 125 +/- 29, P < .01). Graft function was stable with a mean serum creatinine of 1.7 +/- 0.2 mg/dL. CsA blood levels remained stable during all follow-up periods (P = NS). There were neither episodes of acute rejection nor secondary effects related to the medication. In summary, renal transplant patients receiving tacrolimus who develop PTDM may display better control of hyperglycemia by a switch to CsA.

FTY720 is a novel immunomodulator being investigated for rejection prophylaxis in renal transplantation when combined with full-dose cyclosporine (CsA; FDC). This 1-year phase II study compared FTY720 plus FDC (Neoral) with FTY720 plus reduced-dose CsA (RDC) and mycophenolate mofetil (MMF) plus FDC in de novo renal transplant patients. Patients were randomized 2:2:2:1 to FTY720 5 mg plus RDC (n = 72); FTY720 2.5 mg plus RDC (n = 74); FTY720 2.5 mg plus FDC (n = 76); or MMF plus FDC (n = 39) for 12 months. CsA exposure in the RDC group was reduced on average by 50% as assessed by C(2) monitoring. The primary efficacy endpoint was the composite incidence of biopsy-proven acute rejection (BPAR), graft loss, death or premature study discontinuation. The incidences for this composite endpoint were 24% and 22%, respectively, for FTY720 5 mg plus RDC and FTY720 2.5 mg plus FDC versus 39% for MMF plus FDC. Patients receiving FTY720 2.5 mg plus RDC were discontinued from treatment due to risk of under-immunosuppression. FTY720 2.5 mg plus FDC and FTY720 5 mg plus RDC were safe and effective in de novo renal transplant patients over 12 months.

Background: In earlier registry analyses, cyclosporine at doses of < 3 mg/kg/d at 1 year post-renal transplantation has been associated with significant graft loss or reduction in renal function. Improvements in cyclosporine formulation with increased bioavailability, plus the use of more efficient comedications, may now confer better outcomes. To determine the effect of the 1-year cyclosporine microemulsion (CsA-ME) dose on renal allograft function at 5 years, we analyzed data collected from 2889 patients with documented graft survival to year 5 in a prospective, multinational, observational study-Neoral MOST., Results: Glomerular filtration rate (GFR) at year 1 was 63 +/- 20 mL/min and 59 +/- 22 mL/min at year 5. The multivariate analysis including year 1 CsA-ME dose as factor and GFR at 1 year as covariate revealed the most significant factors affecting GFR at year 5 were 1-year GFR, donor age > 60 years, and CsA-ME dose at 1 year. Risk factors associated with reduction in 5-year GFR (<65 mL/min) included donor or recipient age >60 years, delayed graft function, cadaveric donor, previous graft, and acute rejection. CsA-ME dose <3 mg/kg/d was found to protect GFR. Analysis of GFR at each year posttransplantation (Wilcoxon model) found 1-year CsA-ME (cutoff 3 mg/kg/d) had a significant effect at each time point., Conclusions: Compared to higher doses, CsA-ME <3 mg/kg/d at year 1 posttransplantation is associated with increased preservation of renal allograft function at year 5.

Introduction: Low-density lipoprotein (LDL) oxidation is considered a key factor in the biological processes that trigger and accelerate atherosclerosis. Reported data suggest that tacrolimus improves the lipid profile in renal transplant recipients., Objective: The objective of this study was to analyze the effect of converting from cyclosporine to tacrolimus on lipoprotein oxidation in renal transplant recipients., Methods: We studied a group of 12 recipients (6 men and 6 women of mean age 55 +/- 11 years) treated with a cyclosporine-mycophenolate mofetil (MMF)-prednisone combination that was converted to tacrolimus-MMF-prednisone because of gingival hyperplasia. The LDL fraction was isolated by density-gradient ultracentrifugation. Oxidative stress was studied before converting (baseline) and at 6 and 12 weeks, thereafter by in vivo oxidation analysis of LDL, a direct assay of oxidized LDL (oxLDL) and oxLDL autoantibodies (Ab-oxLDL) using enzyme-immunoassay techniques. We measured total cholesterol (TC), triglyceride, LDL-cholesterol, high-density lipoprotein (HDL)-cholesterol, ApoA1, ApoB, and Lp(a) levels., Results: The change to tacrolimus resulted in significant decreases in TC levels, 213 +/- 30 (B) versus 185 +/- 27 (12s) (P < .01); LDL, 129 +/- 24 (B) versus 104 +/- 14 (12s) (P = .002); and ApoB 98 +/- 15 (B) versus 85 +/- 10 (12s) (P < .01). HDL levels significantly increased (45 +/- 10 vs 48 +/- 10 [12s]; P = .018), whereas oxLDL concentrations decreased significantly after conversion (B) (55.42 +/- 10.61 vs 12s 45.76 +/- 10.21; P < .01). Converting to tacrolimus produced a nonsignificant decrease in Ab-oxLDL (baseline 204.88 +/- 134.49 vs 12s 179.51 +/- 143.54). A correlation was observed between LDL and oxLDL (r = 65, P = .02 [B] and r = 0.7, P = .01 [12s]) but not between oxLDL levels and Ab-oxLDL concentration (r = -0.05, P = .87 [3] and r = -0.1, P = .77 [12s])., Conclusions: In renal transplantation, tacrolimus therapy was associated with a better lipid profile and lower in vivo LDL oxidation when compared with cyclosporine treatment.

Unlabelled: The introduction of cyclosporine in kidney transplantation rapidly improved short and medium term graft and patient survival rates. Initially many trials used cyclosporine monotherapy to avoid steroid toxicity, but high acute rejection rates lead to a change in the immunosuppressant scheme. The use of prophylactic steroids significantly decreased acute rejection rates, but the long-term benefit of such a reduction has not been assessed., Methods: Retrospective analysis of the impact of early acute rejection on long-term outcome (10 years) in 264 consecutive renal transplants performed in a single institution between 1986 and 1993 using cyclosporine monotherapy (CM) (n=139) versus cyclosporine and prednisone (CS) (n=125). Different protocols were used for elderly or immunological high-risk patients and for transplants with delayed graft function and therefore these patients are not included. The incidence and severity of acute rejection episodes and long-term patient and graft survivals were analyzed., Results: At 1 year, acute rejection episodes showed significantly higher frequency in the CM group than in the CS group (72.66% vs 46.40%). Nevertheless, graft and patient survival rates were similar at 1, 5, and 10 years (Graft: 96.38%, 78.77%, and 59.84% vs 92.59%, 75.62%, and 53.44%;, Patient: 99.27%, 95.06%, and 84.76% and 95.9%, 93.09%, and 88.28%)., Conclusion: The addition of prophylactic steroids decreases the incidence of acute rejection but does not improve the long-term graft survival. These findings suggest that in an era of new immunosuppressants, fewer acute rejection episodes will be evident requiring more effort to detect and treat subclinical rejections.

Background: There is a correlation between cyclosporine (CsA) pharmacokinetics (PK) and pharmacodynamics (PD), especially 2 hours after drug administration., Aim: To evaluate the relationship between CsA PK and PD profiles in two groups of stable renal transplant patients treated with CsA alone or CsA plus mycophenolate mofetil (CsA+MMF), so as to define the best target for C2 and clarify the impact of concomitant immunosuppression., Methods: Thirty-eight stable renal transplant recipients were treated with CsA (n=20) or CsA+MMF (n=18). Twelve nontreated normal healthy controls (NHC) were also included. Calcineurin activity (CNa), IL-2 production, and CsA levels were measured at 0 and 2 hours postdose., Results: There were no significant differences in median CsA C2 values and CNa between the CsA alone and the CsA+MMF groups (388 microg/L and 497.5 microg/L and CNa 2h; 3.92% alkaline phosphatase [AP]; 3.94% AP, respectively). In vitro production of IL-2 was significantly lower in the CsA+MMF group than in the CsA group (median IL-2 2h: 280.52 ng/L, 169.48 ng/L, P<.001). The correlations (r) between C2 and CNa 2h were: CsA r=0.74; CsA+MMF r=0.84 (P<.001 in both cases)., Conclusions: In stable renal transplant patients, median CsA C2 values below 500 microg/L were associated with inhibition of CNa and IL-2 synthesis. CNa and IL-2 production may be good biological markers of CsA immunosuppression. The measurement of CNa depends mainly on CsA concentration, whereas in vitro IL-2 production reflects the effect of both CsA and MMF. Further studies are necessary to define the optimal C2 target concentration and the possible impact of concomitant immunosuppression.

Background: Peritransplant risk factors influence short-term and long-term graft survival, and 1-year serum creatinine is known to predict long-term graft survival. To examine interrelationships between risk factors, renal function at 1 year, and long-term graft function in patients maintained on cyclosporine, we analyzed data collected from 10,692 de novo or maintenance renal transplant recipients in an ongoing international, prospective, observational study--Neoral-MOST (Multinational Observational Study in renal Transplantation). The effect of donor age, delayed graft function, acute rejection, donor type, panel-reactive antibodies, and previous graft on 1- and 5-year renal function and their relationship to 1-year serum creatinine was assessed., Results: Donor age, delayed graft function, acute rejection, and donor type significantly increased the risk for serum creatinine > 130 micromol/L at 1 year posttransplant, and 1-year serum creatinine was the strongest predictor of 5-year renal function. After adjustment for 1-year serum creatinine, an ongoing influence was observed for donor age, donor type, and previous graft. Delayed graft function and acute rejection had a significant effect on serum creatinine at year 1 but no additional impact on long-term graft function., Conclusions: Serum creatinine at 1 year is influenced by risk factors known to affect overall graft survival and is predictive of 5-year renal graft function. The effects of delayed graft function and acute rejection appear to be limited to their influence on serum creatinine at 1 year, whereas donor type and previous graft predominantly affect later stages of graft life.

Calcineurin inhibitors (CIs) contribute to cardiovascular risk (CR) in renal transplant (RT) patients. However, the CR profile in RT patients without preexistent diabetes is not well known. We compared CR factors in 191 nondiabetic RT recipients with functioning grafts beyond 1 year, receivingly either CsA (Neoral; n=100) or tacrolimus (Tac; n= 91). Clinical data and pretransplant CR profiles were similar in both groups. There were no differences in acute rejection episodes and graft survival rates during follow-up. The overall proportions of posttransplant diabetes (9% versus 6%), and of hypertension (73% vs 63%) were similar in both groups. Hyperlipidemia was more frequent in the CsA group (58% vs 31%; P=.0001). The cholesterol levels in the CsA group showed at 3 months (232+/-47 vs 202+/-42 m/dL; P=.0001), 6 months (232+/-49 vs 205+/-41 mg/dL; P=.0001), and 12 months (217+/-50 vs 202+/-40 mg/dL; P=.028), despite receiving a greater proportion of lipid-lowering drugs (49% vs 15%; P=.0001). Logistic regression analysis showed that CsA was an independent predictor of posttransplant hyperlipidemia (OR: 5.8, CI 95%; 3.3-10.7; P=.0001) as were age, female gender, pretransplant dyslipidemia, and body mass index (BMI). Interestingly, an interaction was observed between pretransplant BMI and CIs: Among pretransplant normal weight patients (BMI <25 kg/m2), CsA produced a greater incidence of hyperlipidemia than tacrolimus (58% vs 23%; P=.0001) while not among patients who were overweight (BMI >25 kg/m2: pretransplant 58% vs 42%; P=.341). In conclusion, CsA confers a higher risk of hyperlipidemia after RT in nondiabetic patients, particularly those with normal pretransplant weight.

We investigated the relationship between the pharmacokinetics and pharmacodynamics of cyclosporine in 15 stable renal transplant patients in order to define an effective and safe therapeutic range. The area under the curve of the first 4 h (AUC(0-4)), trough (C(0)) and 2 h (C(2)) levels showed median values of 1655 ng x h/ml, 114 ng/ml and 384 ng/ml, respectively. C(2) showed a strong correlation with AUC(0-4) (r=0.942, p=0.0005). C(0) correlated poorly with C(2) and AUC(0-4) (r=0.596, p=0.019 and r=0.538, p=0.031, respectively). Calcineurine activity (CNa) was 6.74% at 0 h and 3.90% at 2 h, representing significant reductions (82% and 89.6%, respectively; p<0.0005) compared with normal healthy controls (median basal value 37.4%). IL-2 production was 349 pg/ml at 0 h and 276.35 pg/ml at 2 h; both results were significantly lower (reductions of 44.5% and 56.1%, respectively; p=0.04 and 0.005) than the controls of 629.1 pg/ml. IFN-gamma at 2 h post-dose (8.16 UI/ml) was significantly lower (72.1% reduction, p=0.005) than in controls (29.2 UI/ml). There was a good correlation between CNa and IFN-gamma production, particularly at 2 h post-dose (r=0.537, p=0.007), and a fair correlation between CNa and IL-2 concentration (p=0.030, r=0.426). C(2) showed an inverse significant correlation with CNa (Spearman's p=0.000, r=-0.753), IL-2 (p=0.000, r=-0.725) and IFN-gamma (p=0.000, r=-0.701) production. In treated patients, the Emax inhibitory sigmoidal model showed that a C(2) of 279 ng/ml was needed to achieve a 50% inhibition (EC50) of IL-2 and INF-gamma production. The results demonstrated a significant inhibition of calcineurin activity and IL-2 and IFN-gamma production in patients receiving cyclosporine monotherapy compared to healthy controls. A median C(2) value of 384 ng/ml was associated with a good degree of inhibition of CNa and IL-2 and IFN-gamma synthesis, and the lack of rejection episodes and relevant toxicity.

Aim: Hepatic metabolism of sildenafil uses the same metabolic pathway as the calcineurin inhibitors (cyclosporine/tacrolimus), through the CYP3A4 isoenzyme. The aim of this pilot study was to evaluate the potential interaction between sildenafil therapy and circulating levels of cyclosporine and tacrolimus in a group of steady-state renal transplant recipients with erectile dysfunction., Material and Methods: A prospective pilot study of sildenafil interactions was carried out in 9 stable male renal transplant recipients with severe erectile dysfunction (mean age 50 +/- 8 years, range 38-64). All patients were receiving therapy with calcineurin inhibitors (5 with cyclosporine and 4 with tacrolimus). Erectile dysfunction was evaluated by clinical history, physical examination, International Index of Erectile Function (IIEF) questionnaire and the nocturnal penile tumescence test (RigiScan). Each patient received a first dose of 50 mg of sildenafil, one hour before sexual activity and a second dose at 72 hours of 50 or 100 mg according to the clinical response to the first dose. We evaluated the efficacy and safety of sildenafil and the evolution of cyclosporine-tacrolimus levels. Cyclosporine and tacrolimus trough whole blood concentrations were determined in basal conditions (before starting sildenafil) and on days 1, 4 and 7 after sildenafil therapy., Results: Eighty-nine percent of patients (n = 8) required a complete 100 mg dose of sildenafil. There was a positive clinical response in two-thirds of cases (6 patients). In 5 patients (55%) sildenafil administration produced a complete response, in one patient the response was incomplete, and in the remaining 3 cases (33%) no clinical response was observed. Associated side effects included self-limited tachycardia in one patient and mild visual disturbances in another. Cyclosporine and tacrolimus levels remained stable in all patients. There were no significant differences in circulating levels of cyclosporine (basal 120 +/- 47; day 1: 116 +/- 55; day 4: 123 +/- 56 and day 7: 121 +/- 56 ng/ml p = NS) or tacrolimus (basal 11.6 +/- 1.3; day 1: 11.9 +/- 1.3; day 4: 11.1 +/- 1.0 and day 7: 11.8 +/- 0.9 ng/ml p = NS) over the study period., Conclusions: Sildenafil therapy is safe and effective for the treatment of erectile dysfunction in renal transplant recipients. Recommended therapeutic doses of sildenafil did not modify cyclosporine and tacrolimus trough blood levels.

Background: Renal transplant recipients experience adverse events attributed to corticosteroid therapy., Methods: This was a multicenter, randomized, double-blind, 6-month, controlled steroid dose-reduction study in renal transplant recipients with an unblinded 6-month follow-up. In the low/stop arm, corticoste. roids were given at half the dosage of control for 3 months from the date of transplantation, and then withdrawn. Both arms received mycophenolate mofetil and cyclosporine. The primary endpoint was the incidence of biopsy-proven acute rejection at 6 months posttransplantation., Results: There were 248 patients in the control group and 252 in the low/stop group. At 6 months the low/stop group had more biopsy-proven acute rejection episodes than the control (23% vs. 14%; P=0.008). At 12 months this increased to 25% vs. 15%. Most rejections were Banff grade I. Twelve-month graft loss was 5% in the low/stop group vs. 4% in the control. At 6 and 12 months serum cholesterol (P<0.01, P<0.01), triglycer. ides (P<0.01, P<0.01), and systolic blood pressure (P<0.001, P<0.001) were lower in the low/stop group. Diastolic pressure was lower (P<0.01) and lumbar spine bone density was greater (P<0.01) in the low/ stop group at 12 months., Conclusions: In renal transplant recipients treated with mycophenolate mofetil and cyclosporine, reduction and early withdrawal of the prophylactic corticosteroid dose is feasible without an unacceptable increase in serious rejection episodes. This is accompanied by a significant reduction of steroid-related adverse events.

: BackgroundThere is a correlation between cyclosporine (CsA) pharmacokinetics (PK) and pharmacodynamics (PD), especially 2 hours after drug administration.: AimTo evaluate the relationship between CsA PK and PD profiles in two groups of stable renal transplant patients treated with CsA alone or CsA plus mycophenolate mofetil (CsA+MMF), so as to define the best target for C2 and clarify the impact of concomitant immunosuppression.: MethodsThirty-eight stable renal transplant recipients were treated with CsA (n = 20) or CsA+MMF (n = 18). Twelve nontreated normal healthy controls (NHC) were also included. Calcineurin activity (CNa), IL-2 production, and CsA levels were measured at 0 and 2 hours postdose.: ResultsThere were no significant differences in median CsA C2 values and CNa between the CsA alone and the CsA+MMF groups (388 μg/L and 497.5 μg/L and CNa 2h; 3.92% alkaline phosphatase [AP]; 3.94% AP, respectively). In vitro production of IL-2 was significantly lower in the CsA+MMF group than in the CsA group (median IL-2 2h: 280.52 ng/L, 169.48 ng/L, P < .001). The correlations (r) between C2 and CNa 2h were: CsA r = 0.74; CsA+MMF r = 0.84 (P < .001 in both cases).: ConclusionsIn stable renal transplant patients, median CsA C2 values below 500 μg/L were associated with inhibition of CNa and IL-2 synthesis. CNa and IL-2 production may be good biological markers of CsA immunosuppression. The measurement of CNa depends mainly on CsA concentration, whereas in vitro IL-2 production reflects the effect of both CsA and MMF. Further studies are necessary to define the optimal C2 target concentration and the possible impact of concomitant immunosuppression. [Copyright &y& Elsevier]