Maintenance Kidney Transplant Recipients Research Articles

Immunosuppressive regimens following kidney transplantation in five European countries: The observational RECORD study

Abstracts Objective: To examine current immunosuppressive regimens administered to kidney transplant recipients (KTRs) in South-eastern Europe. Methods: This was a 12-month, multicenter, non-interventional, prospective, observational study of immunosuppressive regimens in adult de novo and maintenance KTRs. The primary endpoint was to identify the number, type, dosage and trough concentrations (C0) of immunosuppressive medications. Results: Data were available for 1774 KTRs from five countries (Bulgaria [n = 109], Croatia [n = 339], Romania [n = 647], Serbia [n = 434] and Slovenia [n = 245]). The most common immunosuppressive regimen in all countries was a triple therapy regimen (de novo KTRs, 67.9 – 100% at baseline and 67.3 – 100% at end of study; maintenance KTRs, 48.8 – 90.7% and 43.2 – 90.1%, respectively). The most frequent regimen in de novo KTRs comprised tacrolimus, mycophenolate mofetil (MMF) or mycophenolate sodium (MPS), and corticosteroids. In maintenance KTRs, the most frequent regimen was tacrolimus or cyclosporine, and MMF or MPS, with or without corticosteroids. A C0 of Conclusions: Triple therapy—comprising a calcineurin inhibitor (CNI; tacrolimus or cyclosporine), antiproliferative drugs (MMF or MPS) and corticosteroids—was the most common immunosuppressive regimen used in KTRs in South-eastern Europe. Individual CNI C0 were below the target range in a substantial proportion of KTRs, highlighting the need to maintain therapeutic drug monitoring of immunosuppressive therapy in this patient population.

Effective and Safe Reduction of Conventional Immunosuppressants Using Everolimus in Maintenance Kidney Transplant Recipients

BackgroundAdverse events due to conventional immunosuppressive therapy decrease both graft and patient survival. We aimed to establish a new protocol using everolimus (EVR) to safely minimize conventional immunosuppressants in maintenance kidney transplant recipients. MethodsA total of 86 consecutive kidney transplant recipients with no complications were maintained with triple-drug combination therapy (conventional group). In case of complications, the administration of very low-dose tacrolimus (C0: 5.0 to <3.0 ng/mL), reduced mycophenolate mofetil (1000–1500 to 500–1000 mg), and EVR (C0: 3.0–5.0 ng/mL) and methylprednisolone withdrawal (2–4 to 0 mg) were simultaneously conducted (EVR group). Graft survival and acute rejection rate were compared between groups. Within the EVR group, the dose of conventional immunosuppressants was compared between pre- and post-EVR administration. Renal function was evaluated 1 year post-EVR administration. ResultsAll grafts survived in the conventional (n = 50) and EVR (n = 36) groups, and biopsy-proven acute rejection rate exhibited no significant difference between these groups (12% vs 17%; P = .55). Furthermore, no acute rejection occurred post-EVR administration. In the EVR group, all immunosuppressants significantly decreased post-EVR administration compared with those pre-EVR administration (P < .01), and serum creatinine significantly improved at postoperative year 1 (P = .031). ConclusionsEVR administration enables very low-dose tacrolimus administration, helps reduce mycophenolate mofetil and steroid withdrawal, and ameliorates renal function in maintenance kidney transplant recipients experiencing complications associated with conventional immunosuppressive therapy.

A multicenter, randomized trial of increased mycophenolic acid dose using enteric-coated mycophenolate sodium with reduced tacrolimus exposure in maintenance kidney transplant recipients

Mycophenolic acid (MPA) dose is frequently reduced in tacrolimus-treated kidney transplant patients, but alternatively the recommended MPA dose can be maintained with reduced tacrolimus exposure. In a 6-month, multicenter, randomized, openlabel study, maintenance kidney transplant patients receiving MPA (mycophenolate mofetil 1g/d or enteric-coated mycophenolate sodium (EC-MPS) 720 mg/d) and tacrolimus were randomized to convert to EC-MPS 1,440 mg/d with reduced tacrolimus (n = 46), or receive EC-MPS 720 mg/d with unchanged tacrolimus (n = 48). Mean estimated GFR (eGFR, aMDRD) at Month 6 was 49.1 ± 11.1 and 44.7 ± 11.5 ml/min/1.73 m2 in the EC-MPS 1,440 mg and 720 mg groups, respectively (p = 0.07). The primary endpoint, change in eGFR from Day 0 to Month 6, was 2.48 ± 0.95 ml/min/1.73 m2 with EC-MPS 1,440 mg and -0.48 ± 0.93 ml/min/1.73 m2 with EC-MPS 720 mg (difference 2.96 ml/min/1.73 m2; 95% CI 0.32 - 5.60; p = 0.028). There were no deaths, graft losses or acute rejections. Adverse events were more frequent with EC-MPS 1,440 mg than 720 mg (66.7% vs. 44.7%, p = 0.034). Adverse events with suspected relation to EC-MPS occurred in 26.7% and 21.3% of patients, respectively (p = 0.59). Conversion of kidney transplant patients to increased MPA dosing using EC-MPS 1,440 mg/d, with reduced tacrolimus exposure, appears an effective immunosuppression strategy and may improve renal function. Adverse events overall, but not those with a suspected relation to EC-MPS, were higher with ECMPS 1,440 mg/d.

Treatment of Anemia With Epoetin in Kidney Transplant Recipients

The aim of this study was to analyze the prevalence and efficacy of renal anemia treated with epoetin in maintenance kidney transplant recipients in Slovenia. By the end of 2009, 107 out of 537 patients (19.9%) had been treated with epoetin. A cohort of 49 patients (45.8%) were analyzed in detail: 11 patients received epoetin alpha, 18 epoetin beta, 10 darbepoetin alpha, and 10 patients received methoxy polyethylene glycol-epoetin beta. The median epoetin dose was 0.36 µg/kg body weight per week. The median serum laboratory parameters were as follows: hemoglobin 120 g/L, hematocrit 0.36, ferritin 332 ng/mL, transferrin saturation 34%, serum creatinine 145 µmol/L, serum albumin 41 g/L, intact parathyroid hormone 79 ng/L, and C-reactive protein 3 mg/L. We concluded that the prevalence of renal anemia in kidney transplant recipients treated with epoetin was approximately 20%, and laboratory parameters suggested that the treatment of renal anemia in this study cohort was optimal.

Conversion from sirolimus to everolimus in kidney transplant recipients receiving a calcineurin‐free regimen

Everolimus (EVL) and sirolimus (SRL) were introduced into immunosuppressive regimens, in an attempt to replace or reduce the dose of the nephrotoxic calcineurin inhibitors (CNI). In our institution, due to an administrative decision, conversion from SRL to EVL, was carried out, providing us the opportunity to investigate the effectiveness and safety profile of both drugs and to review the practical conversion dose between them. We retrospectively analyzed the medical records of 51 maintenance kidney transplant recipients receiving an SRL-based CNI-free regimen, who were switched to EVL. SRL dose was concentration controlled to a through level of 4-8 ng/mL. Patients were converted to a variable dose of EVL that was adjusted to achieve a trough concentration of 3-8 ng/mL. SRL mean dose at time of conversion was 2.0 ± 0.9 mg/d. Initial EVL mean dose was 1.3 ± 0.5 mg/d. Six months after conversion, mean EVL trough level was 6.2 ± 2.8 ng/mL. EVL dose at this point was 2.0 ± 0.9 mg/d, which was not statistically different from SRL dose at the time of conversion (p = 0.575), suggesting a conversion factor of 1:1. During this six month period post conversion, no significant changes were observed in serum creatinine, hematocrit level, platelet count, proteinuria or lipid levels. No patient experienced an acute rejection episode. Conversion from SRL to EVL in renal transplant recipients receiving a CNI-free immunosuppressive regimen can be performed safely with a low trough level range of EVL. We report for the first time a conversion factor between SRL and EVL.

Effect of Diabetes Mellitus on Mycophenolate Sodium Pharmacokinetics and Inosine Monophosphate Dehydrogenase Activity in Stable Kidney Transplant Recipients

Effect of diabetes mellitus on mycophenolic acid (MPA) pharmacokinetics and catalytic activity of inosine monophosphate dehydrogenase (IMPDH) was investigated in maintenance kidney transplant recipients. Demographically matched diabetic (n=9) and nondiabetic (n=9) patients were included in a 12-hour open-label, steady-state study after oral administration of enteric-coated mycophenolate sodium. Concentrations of total MPA and free MPA, MPA-glucuronide, and acyl-MPA-glucuronide were measured and oral acetaminophen absorption was used as a marker for gastric-emptying rate. Median (range) of MPA area under the curve(0-12) was 36.7 (range, 16.4-116.4) mg*h/L in diabetic and 48.2 (range, 34.9-80.1) mg*h/L in nondiabetic patients (P=0.49). All other primary pharmacokinetic parameters, including time to maximum concentration, for total or unbound MPA as well as MPA metabolites were comparable. In contrast, IMPDH activity was 17.5+/-2.8 versus 46.6+/-2.5 nmol XMP/h/microg protein in diabetics and nondiabetics, respectively (P<0.0001) and was significantly lower in the diabetics irrespective of concomitant therapy with cyclosporine or tacrolimus. This study demonstrated that diabetes does not alter MPA pharmacokinetics when administered as enteric-coated mycophenolate sodium; however, IMPDH activity appeared to be significantly lower in patients with diabetes independent of the unbound or total concentrations of MPA. Further investigations are warranted to investigate the regulation of IMPDH enzyme in patients with diabetes.

Conversion to C2 monitoring of cyclosporine A exposure in maintenance kidney transplant recipients: Results at 3 years

Conversion to C2 monitoring of cyclosporine A exposure in maintenance kidney transplant recipients: Results at 3 years

Conversion to C2 monitoring of cyclosporine A exposure in maintenance kidney transplant recipients: Results at 3 years

It has been suggested that conversion from monitoring cyclosporine A (CsA) trough level to the level 2 hours after the morning dose (C2 ) may have clinical benefits in maintenance adult renal transplant recipients, but evidence supporting such a suggestion presently is very limited. We enrolled 188 maintenance patients to investigate the clinical impact of the adjustment of CsA dose according to C2 levels over 3 years (target, 800 ng/mL). Patient and graft survival rates were 100% and 98.4%, respectively. C2 monitoring led to a reduction in CsA dose in 49.4% of patients and an increase in more than 20% of patients without an increase in acute rejection risk and clinically overt nephrotoxicity. Patients in the greatest quartile of C2 levels showed the lowest serum creatinine levels (P = 0.009), the greatest creatinine clearance values (P = 0.0006), and the lowest prevalence of chronic allograft nephropathy (P = 0.01). By means of multivariate analysis, C2 levels were the most relevant independent predictors of graft deterioration (change in serum creatinine level from baseline to end of study > or =0.5 mg/dL [> or =44 micromol/L]). Receiver operating characteristic analysis showed an inflection point of mean C2 level versus risk for graft deterioration at less than 661 ng/mL. In maintenance renal transplant recipients, conversion to C2 monitoring is a seemingly safe option with good graft performance after 3 years. Mean C2 levels greater than 661 ng/mL seem to be associated with better long-term graft function and a lower prevalence of biopsy-proven chronic allograft nephropathy, at least during a 3-year follow-up.

Experience with cyclosporine: approaching the therapeutic window for C2 levels in maintenance kidney transplant recipients

This study was aimed to evaluate the clinical benefit of C 2 monitoring in 191 stable renal transplant patients previously monitored by C 0. All patients had been transplanted for at least 1 year and received cyclosporine (CsA)-based immunosuppression since the start. At the inceptions C 0 levels were significantly correlated with C 2 values ( P < .0001). Patients with starting C 2 levels >1000 ng/mL showed significantly higher levels of serum creatinine (sCr) both at inception (1.66 ± 0.50 vs 1.44 ± 0.41 mg/dL; P = .0021) and at the end of a 2-year follow-up (1.84 ± 0.80 vs 1.46 ± 0.51 mg/dL; P = .005). C 2 monitoring revealed that a high percentage of patients were overexposed to CsA, mainly in the subgroup with most recent renal engraftments (12 to 24 months). The switch to C 2 monitoring was associated with a slower deterioration of graft function ( P = .02). Further, the mean values of C 2 over a 2-year follow-up were inversely correlated with sCr at the end of follow-up ( P = .0005). Finally, patients with mean threshold C 2 levels above 720 ng/mL, roughly corresponding to the median value of C 2, showed significantly lower levels of sCr at the end of follow-up ( P = .0004). In conclusion, C 2 monitoring of maintenance renal transplant patients allows one to identify a significant percentage of overexposed subjects, possibly limiting the rate of progression of chronic graft dysfunction. Target range values between 700 and 900 ng/mL appear to be associated with better long-term kidney graft function.