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

Carvalho C, Coentrão L, Bustorff M, Patrício E, Sampaio S, Santos J, Oliveira G, Pestana M. Conversion from sirolimus to everolimus in kidney transplant recipients receiving a calcineurin‐free regimen.
Clin Transplant 2011: 25: E401–E405. © 2011 John Wiley & Sons A/S. Abstract: Background: 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. Methods: 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. Results: 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. Conclusions: 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.     

Tacrolimus with Mycophenolate Mofetil (MMF) or Sirolimus vs. Cyclosporine with MMF in Cardiac Transplant Patients: 1-Year Report

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.     

Experience With the Use of Sirolimus in Liver Transplantation—Use in Patients for Whom Calcineurin Inhibitors Are Contraindicated

Sirolimus (SRL) provides effective immunosuppression for kidney transplantation and may be useful in patients with delayed allograft function after kidney transplantation. We review our experience with SRL in liver transplant recipients for whom calcineurin inhibitors are undesirable. Fourteen patients with renal insufficiency or acute mental status impairment were administered SRL after liver transplantation (5- to 10-mg load, 1 to 4 mg/d). Immunosuppression also consisted of mycophenolate mofetil and corticosteroids. On resolution of neurological or renal dysfunction (return to baseline mental status or serum creatinine level), tacrolimus (TAC) therapy was initiated. Twelve patients received primary transplants, 1 patient received a combined liver-kidney transplant, and 1 patient received a third transplant. Follow-up was 2 to 7 months. Calcineurin inhibitors were initially withheld in 9 patients, and therapy was aborted because of toxicity in the remaining 5 patients. Mean times to the initiation of SRL and TAC therapy were 5.4 ± 4.6 and 26.8 ± 24.4 days, respectively. Serum trough levels of SRL did not correlate with dose or other patient variables. Two patients died after prolonged pretransplantation hospital courses in the intensive care unit. Six patients experienced acute rejection, but only 1 patient required antilymphocyte therapy. Serum creatinine levels at the start of SRL therapy were 2.2 ± 1.1 and 1.2 ± 0.6 mg/dL at 3 months. All 3 patients with neurological indications for SRL had a return to their baseline mental status. All patients had improved liver function chemistry test results and prothrombin times. No patients developed leukopenia or thrombocytopenia. SRL is safe after liver transplantation in patients with acute neurological or renal impairment. SRL is an attractive alternative when calcineurin inhibitors are undesirable, but serum trough levels of SRL should be monitored. A prospective randomized study of an SRL-based calcineurin inhibitor–avoiding regimen compared with standard therapy in patients with renal insufficiency will further evaluate the role for SRL in liver transplantation. (Liver Transpl 2000;6:734-740.)     

Conversion from a calcineurin inhibitor-based immunosuppressive regimen to everolimus in renal transplant recipients: effect on renal function and proteinuria

New immunosuppressive agents are being actively researched to avoid complications of chronic allograft nephropathy (CAN), calcineurin inhibitor (CNI) nephrotoxicity, and posttransplantation cancer. The family of mTOR inhibitors offers a unique immunosuppressive opportunity to avoid CNI toxicity and reduce the incidence of malignancy. Nevertheless, increasing data have demonstrated that sirolimus (SRL), the first mTOR introduced in the treatment of solid organ transplant recipients, induces proteinuria, an adverse event that could produce deterioration of long-term renal function. In this short-term study of patients followed for 1 to 16 months, we examined changes in renal function and proteinuria among renal transplant recipients converted from a CNI-based regimen to an everolimus (EVL)-based one, a recently introduced mTOR inhibitor. Our data showed that renal function can be optimized after conversion to EVL by up to 42% in recipients showing CAN grade 1 or 2, or CNI nephrotoxicity. Importantly, patients who improved their creatinine clearance did not show increased proteinuria measured in a voided specimen as the ratio of urinary protein and creatinine concentration (P/C). These results, if confirmed with long-term follow-up and a larger number of patients, would allow us to consider EVL as a promising agent for maintenance immunosuppressive regimens in kidney transplantation.     

Pharmacokinetics of Sirolimus and Tacrolimus in Pediatric Transplant Patients

To evaluate the pharmacokinetics of Sirolimus (SRL) and Tacrolimus (TAC) in pediatric transplant recipients. Fifty-one SRL and 55 TAC pharmacokinetic profiles were obtained from 20 male and 14 female recipients of liver alone (LTx, n = 23), small bowel alone, and with liver (SBTx, n = 11). The median age was 13.3 years (range 0.9-23.9). Whole blood concentrations of SRL and TAC were determined by liquid chromatography-mass spectrometry (LC-MS) and microparticulate enzyme immunoassay (MEIA-Abbott Laboratories, IL), respectively. Pharmacokinetic (PK) parameters were derived from noncompartmental model analysis. The half-life was estimated using the data points during the terminal disposition phase and area under the concentration (AUC) time curve was calculated within a dosing interval using the trapezoidal method. The dose of SRL or TAC did not correlate with the corresponding AUCs. Trough concentrations of SRL and TAC correlated well with AUC (r = 0.8544 and 0.8603, respectively). Half-life (h) did not differ significantly between different transplant groups for SRL and TAC (SRL: LTx: 21.2 h, SBTx: 19.3 h; TAC: LTx: 14.1 h, SBTx: 12.7 h). Serial PK analysis with the first measurement within 14 days after transplantation revealed no difference in AUC/dose/BSA for SRL, with time. During this period, SRL half-life increased significantly, from 11.2 +/- 1.0-20.1 +/- 3.1 h (n = 4; p = 0.02). After introduction of SRL, TAC half-life did not change (11.6 +/- 3.9-14.0 +/- 10.4, n = 10, P = 0.52) in all the groups analyzed together. TAC AUC/dose/BSA decreased significantly in LTx and SBTx patients (90.9 +/- 55.3 vs. 48.8 +/- 27.3). Trough concentration measurements provide good estimates of SRL and TAC exposure in pediatric transplant recipients. The short half-life of SRL in children may support twice-daily administration early after liver and small intestinal transplantation. During conversion of subjects from TAC to combined TAC and SRL, aggressive therapeutic drug monitoring must be used to individualize therapy and avoid serous adverse events.     

Prospective Clinical Trial Comparing Two Immunosuppressive Regimens, Tacrolimus and Mycophenolate Mofetil Versus Everolimus and Low-Dose Cyclosporine, in De Novo Renal Transplant Recipients: Results at 6 Months Follow-up

Objective

The aim of this study in renal transplant recipients was to compare a tacrolimus plus mycophenolate mofetil (MMF) immunosuppressive regimen with a combination of low dose of cyclosporine and everolimus.

Patients and Methods

Sixty consecutive patients were prospectively assigned to receive tacrolimus and MMF (TAC; n = 30) or everolimus and low-dose cyclosporine (EVL; n = 30). Tacrolimus was dosed seeking a trough blood level of 8 to 10 ng/mL by month 3 and 5 to 8 ng/mL thereafter. Everolimus was dosed seeking a trough blood level of 3 to 8 ng/mL by day 7. Cyclosporine was dosed aiming at a C2 blood level of 350 to 700 ng/mL in the first week and 150 to 400 ng/mL thereafter. All patients received induction with basiliximab and maintenance treatment with corticosteroids.

Results

At 6-months follow-up, patient survival rates (TAC 100% vs EVL 100%) and graft survival rates (TAC 96.7% vs EVL 93.3%) were not significantly different between the groups. Patients in the EVL group showed more acute rejection episodes, but serum creatinine concentrations and creatinine clearances were not significantly different from the TAC group. Among the observed side effects, hypercholesterolemia was significantly higher in the EVL group (total cholesterol: TAC 206 ± 38 vs EVL 250 ± 55 mg/dL; P < .003).

Conclusions

This study showed that the immunosuppressive association of tacrolimus and MMF produced similar acute rejection episodes, graft survivals, and renal function at 6 months after renal transplantation compared with an immunosuppressive combination of everolimus and low-dose cyclosporine. Dyslipidemia was significantly greater among patients who received everolimus.     

Cardiovascular Risk Profile in Kidney Transplant Recipients Treated With Two Immunosuppressive Regimens: Tacrolimus and Mycophenolate Mofetil Versus Everolimus and Low-Dose Cyclosporine

Objective

The aim of this prospective study was to compare the cardiovascular risk (CVR) profile in patients treated with 2 different immunosuppressive regimens: tacrolimus and mycophenolate mofetil (TAC) compared with everolimus and low-dose cyclosporine (EVL).

Patients and Methods

Sixty consecutive renal transplant recipients prospectively assigned to TAC (n = 30) or to EVL (n = 30) were followed for 6 months. TAC group immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil (MMF), and steroid. EVL group immunosuppression consisted of basiliximab, everolimus, and low doses of cyclosporine and steroid. Main CVR factors analyzed were: hypertension, dyslipidemia, posttransplant diabetes mellitus, and weight gain.

Results

Six months posttransplantation, patients in the EVL group showed significantly higher mean serum cholesterol (P < .003) and serum triglyceride levels (P < .027), as well as a greater number of patients were receiving statin treatment (P < .05). Mean systolic blood pressure, mean diastolic blood pressure, number of patients treated for hypertension, number of antihypertensive medications prescribed per patient, posttransplant weight gain, and posttransplant diabetes mellitus were not significantly different among the EVL and TAC groups after 1, 3, and 6 months posttransplantation.

Conclusions

This study showed that at 6 months posttransplantation, patients on EVL displayed significantly greater dyslipidemia with respect to the TAC group. A longer follow-up will be necessary to discover whether the presence of everolimus in the immunosuppressive regimen provides significant benefits for the CVR of renal transplant recipients.     

Common occurrence of everolimus-associated aphthous stomatitis in Japanese heart transplant recipients

Mammalian target of rapamycin (mTOR) inhibitors display antiproliferative effects with less nephrotoxicity than calcineurin inhibitors. However, clinical use of mTOR inhibitors can be associated with a series of adverse events. We experienced cases of aphthous stomatitis associated with everolimus (EVL) in four Japanese heart transplant recipients treated at the target trough EVL blood level after a switch from mycophenolate mofetil between April and December 2007. All four patients developed aphthous stomatitis; three required reduction of the exposure and one, EVL discontinuation due to stomatitis as well as other side effects. All patients recovered from stomatitis after reduction or withdrawal of EVL. Thus, we considered that EVL-related stomatitis might occur commonly among the Japanese population. The proper dosage, effects, and frequency of the side effects of mTOR inhibitors may vary by ethnic population.     

Mycophenolate mofetil vs. sirolimus in kidney transplant recipients receiving tacrolimus-based immunosuppressive regimen

Abstract:  Mycophenolate mofetil (MMF) and sirolimus (SRL) are effective immunosuppressive drugs with distinct safety profile.
Methods:  Kidney transplant recipients receiving tacrolimus (TAC)-based immunosuppressive regimen were randomized to receive fixed daily doses of MMF (2 g/d, n = 50) or SRL (one loading dose of 15 mg, 5 mg/d till day 7 and 2 mg/d thereafter, n = 50) without induction therapy.
Results:  No differences were observed in the incidence of the composite (biopsy-confirmed acute rejection, graft loss or death) end-point (18% vs. 16%, p = 1.000), biopsy confirmed acute rejection (12% vs. 14%, p = 1.000), one-yr patient (94% vs. 98%, p = 0.308), graft (92% vs. 98%, p = 0.168), and death-censored graft survival (98% vs. 100%, p = 0.317) comparing patients receiving MMF or SRL respectively. Patients receiving SRL showed worse safety outcomes, higher mean creatinine (1.6 ± 0.5 mg/dL vs. 1.4 ± 0.3 mg/dL, p = 0.007), higher proportion of patients with proteinuria (52.0% vs. 10.7%, p = 0.041), higher mean urinary protein concentrations (0.3 ± 0.5 g/L vs. 0.1 ± 0.2 g/L, p = 0.012), higher mean cholesterol concentration (217 mg/dL vs. 190 mg/dL, p = 0.030), and higher proportion of patients prematurely discontinued from randomized therapy (26% vs. 8%, p = 0.031).
Conclusion:  In patients receiving TAC, MMF produced similar efficacy but superior safety profile compared with SRL.     

Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes

Induction and maintenance immunosuppression protocols with or without long-term steroid therapy in kidney transplant recipients are variable and are transplant center-specific. The aim of this prospective randomized pilot study was to compare 5-year outcomes in kidney recipients maintained on 4 different calcineurin inhibitor (CNI)-based immunosuppression protocols without long-term steroid therapy. Two hundred consenting patients who received kidney transplants between June 2000 and October 2004 were enrolled in 4 immunosuppression protocol groups, with 50 patients in each group: cyclosporine (CSA)/mycophenolate mofetil (MMF), CSA/sirolimus (SRL), tacrolimus (TAC)/MMF, and TAC/SRL. Induction therapy was done with basiliximab and methylprednisolone. Steroids were withdrawn on post-transplant day 2, and long-term steroid therapy was not used. Demographic characteristics among the four groups were comparable; approximately 50% of the recipients were African American and > or =80% of the kidneys transplanted were from deceased donors. Clinical acute rejection (CAR) was confirmed by biopsy and treated with intravenous pulse steroid therapy. Steroid-unresponsive CAR was treated with Thymoglobulin. Surveillance biopsies were performed at 1, 6, 12, 24, 36, 48, and 60 months to evaluate subclinical acute rejection (SCAR), chronic allograft injury (CAI), and other pathological changes per the Banff 2005 schema. The primary end point was CAR, and secondary end points were 5-year patient and graft survival rates, renal function, SCAR, CAI, and adverse events. In the first year post-transplant, the incidence of CAR was 18% in the CSA/MMF group, 8% in the CSA/SRL group, 14% in the TAC/MMF group, and 4% in the TAC/SRL group (CSA/MMF vs. TAC/SRL; p=0.05). The incidence of SCAR was 22% in the CSA/MMF group, 8% in the CSA/SRL group, 16% in the TAC/MMF group, and 6% in the TAC/SRL group (CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.05). After the first year, the incidences of CAR and SCAR decreased and were comparable in all 4 groups. At 5 years post-transplant, cumulative CAI due to interstitial fibrosis/tubular atrophy (IF/TA), hypertension (HTN), and chronic calcineurin inhibitor (CNI) toxicity was observed in 54%, 48%, and 8% of the CSA/MMF group vs. 16%, 36%, and 12% of the CSA/SRL group vs. 38%, 24% and 6% of the TAC/MMF group vs. 14%, 25% and 12% of the TAC/SLR group (IF/TA: CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.04, HTN: CSA/MMF vs. TAC/MMF and TAC/SRL; p=0.05, CNI toxicity: TAC/SRL and CSA/SRL vs. TAC/MMF; p=0.05). Five-year patient and graft survival rates were 82% and 60% in the CSA/MMF group, 82% and 60% in the CSA/SRL group, 84% and 62% in the TAC/MMF group, and 82% and 64% in the TAC/SRL group (p=0.9). Serum creatinine levels and creatinine clearances at 5 years were comparable among the groups. Our data show that the rates of CAR and SCAR in the first year post-transplant were significantly lower in the CSA/SRL and TAC/SRL groups and that cumulative CAI rates due to IF/TA and HTN at 5 years were significantly lower in the TAC/MMF, TAC/SRL, and CSA/SRL groups than in the CSA/MMF group. Despite significant differences in the incidences of CAR and SCAR and prevalence of different types of CAI at 5 years, renal function and patient and graft survival rates at 5 years were comparable among kidney recipients maintained on 4 different immunosuppression protocols without long-term steroid therapy.     

Risk factors for the development and progression of dyslipidemia after heart transplantation

BACKGROUND: Hyperlipidemia is an important complication after organ transplantation and contributes to the development of posttransplant accelerated coronary artery diseases. METHODS: We have retrospectively evaluated the relative contribution of various risk factors associated with the development and progression of hyperlipidemia in 194 heart transplant recipients by the use of mixed effects multiple linear regression analysis. The demographic characteristics evaluated were primary diagnosis of ischemic heart disease (IHD), gender, and age. Postoperative characteristics included number of treated rejections, dosage of cyclosporine (CYA), tacrolimus (TAC), prednisolone and azathioprine, and concentration of serum creatinine and glucose. The effects of administration of antihypertensive agents, diuretics, and lipid lowering agents were also studied. RESULTS: The total cholesterol concentration increased significantly in the first 3 months posttransplant but gradually decreased thereafter. Total cholesterol and the ratio of low density lipoprotein (LDL) cholesterol to high density lipoprotein (HDL) cholesterol (LDL-C/HDL-C) increased to a greater extent in patients with IHD although female transplant recipients had a greater increase in the total cholesterol concentration. Each episode of rejection increased serum cholesterol by 0.306 mmol/liter (0.258, 0.355) [mean (95% C.I.)] and serum triglyceride by 0.164 mmol/liter (0.12, 0.209) although switching to TAC improved total cholesterol and LDL-C/HDL-C. Administration of frusemide, increased the total cholesterol and LDL-C/HDL-C whereas administration of bumetanide or metolazone increased the concentration of serum triglyceride. Serum glucose was associated with hypertriglyceridemia whereas serum creatinine was associated with increases in the total cholesterol, LDL-C/HDL-C and triglyceride. CONCLUSIONS: We have identified demographic and postoperative covariables that predispose heart transplant recipients to hyperlipidemia. Some of these risk factors, such as the effect of diuretics, have not been identified before in this group of patients and may be amenable to modification or closer control. TAC rather than CYA may be the immunosuppressive of choice for patients who are at greater risk of developing hyperlipidemia.     

Comparative analysis of adverse events requiring suspension of mTOR inhibitors: everolimus versus sirolimus

Background

Inhibitors of mammalian target of rapamycin (mTORi) have been suggested as an alternative to calcineurin inhibitors (CNIs) to treat stable renal transplant recipients. However, their use has been significantly limited owing to a high incidence of side effects.

Objective

To compare the rate of dropout (mTORi elimination and CNI reintroduction) caused by side effects among renal transplant patients converted to everolimus (EVL) or sirolimus (SRL).

Methods

Between October 1999 and February 2010, 409 subjects were converted to an mTORi at least 3 months after transplantation, including 220 (53.8%) to EVL and 189 (46.2%) to SRL. Most patients were under CNI therapy. Patients were followed for a median of 35 months (interquartile range [IQR], 18-50 months).

Results

mTORi treatment was prematurely eliminated due to adverse events in 112 patients. The median time between the initiation of mTORi and discontinuation was 5.7 months (IQR, 1.9-15.7 months; range, 0.2-48 months): 5.5 (IQR, 1.6-16.3) in the EVL group and 7.4 (IQR, 2.6-15.6) in the SRL group. In the EVL group, the drug was stopped in 69 patients (31.4%), and in the SRL group in 43 patients (22.8%; P = .051). The most important causes of discontinuation were severe infections (2.3% in EVL group and 4.8% in SRL group; P = .17), pneumonitis (6.8 % in EVL group and 4.8 in SRL group; P = .38), acute rejection episode (4.1% in EVL group and 1.6% in SRL group; P = .13), proteinuria (4.1% in EVL group and 1.6% in SRL group; P = .13), renal function deterioration (2.3% in EVL group and 2.1% in SRL group; P = .91), and severe dermal eruption (2.3% in EVL group and 0.5% in SRL group; P = .14).

Conclusions

Although the overall incidence discontinuations due to side effects was higher in the EVL group, there was no greater frequency of severe side effects, such as pneumonitis, proteinuria, acute rejection episodes, renal function deterioration, or dermal eruptions.     

Comparison of steroid avoidance in tacrolimus/mycophenolate mofetil and tacrolimus/sirolimus combination in kidney transplantation monitored by surveillance biopsy

BACKGROUND: Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation. METHODS: In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored. RESULTS: Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P = 0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P = 0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy. CONCLUSIONS: Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.     

De Novo Everolimus-Based Therapy in Renal Transplant Recipients: Effect on Proteinuria and Renal Prognosis

Background

In large-scale clinical trials, the proliferation signal inhibitor (PSI) everolimus (EVL) combined with cyclosporine (CsA) and steroids, has been shown to be efficacious among de novo renal transplant recipients. Development of proteinuria has been shown to be an important predictor of renal dysfunction after conversion from CsA to a PSI-based regimen, and a key marker of allograft disease progression. Whether EVL de novo treatment is associated with a similar proteinuric effect is still under investigation.

Methods

We compared the development of proteinuria among a cohort of 24 renal transplant recipients who were prescribed EVL (3 mg/d; n = 12; high-dose group) or 1.5 mg/d (n = 12; standard-dose group), in association with CsA, versus third control cohort of 12 patients who received mycophenolate mofetil (control group). EVL doses were adjusted to achieve trough blood levels of 3-8 ng/mL and 8-12 ng/mL among the standard and high-dose groups, respectively. We assessed renal function and protein excretion over a 2-year observation.

Results

The high-dose group showed a trend toward greater proteinuria than the standard-dose on control groups. They showed significantly greater proteinuria from 9 months until 2 years; 0.86 ± 0.5, 0.5 ± 0.3, 0.47 ± 0.2 g/24 h (P = .03 and P = .02, respectively, at 24 months). Mean proteinuria significantly correlated with mean EVL doses (n = .73; P = .0001). Concomitantly, the estimated glomerular filtration rate (eGFR) was significantly lower among patients treated with EVL 3.0 versus 1.5 mg/d (53.7 ± 24 vs 73.04 ± 17.6 mL/min; P = .037). Among patients in the standard-dose, the eGFR was consistently higher than the control group (62.6 ± 29 mL/min).

Conclusion

EVL/CsA therapy is a safe alternative regimen for de novo renal transplant recipients. Higher EVL doses are correlated with greater increases in proteinuria. The standard EVL dose seems to be useful treatment strategy to prevent acute rejection episodes, with a better renal prognosis in the long term.     

Sirolimus in heart transplantation: a single center initial experience

Sirolimus (SRL) is a potent non-nephrotoxic immunosuppressant. In our unit, SRL was administered to 17 heart transplant (HT) recipients at 1770+/-1234 days' posttransplant surgery, for the following reasons: (1) calcineurin inhibitor (CI) withdrawal due to renal insufficiency (RI; n=6); (2) neurotoxicity (n=1) and pancytopenia (n=1); (3) vascular graft disease (VGD) treatment (n=5); (4) immunosuppression optimization due to lung cancer (n=2); (5) CI use was delayed due to postsurgery RI (n=2). The mean follow-up was 190+/-165 days. Mean SRL doses (mg)/concentrations (ng/mL) at 7 (n=17), 30 (n=14), and 180 (n=8) days were: 1.2+/-0.6/5.9+/-6; 1.6+/-0.8/4.8+/-3.1; and 1.7+/-1.0/5.2+/-3.7. Among group 1, CI patients were discontinued without favorable functional impact. Neurotoxicity and pancytopenia improved, but there were no major clinical events in the VGD group. One "bridge" to CI was successfully performed (postsurgery RI). Total leukocyte count fell while hemoglobin, platelet, and cholesterol profiles were not affected. Ten of 15 patients (67%) were discontinued from CI without rejection and with a dose reduction of mycophenolate mofetil. There were 8 episodes (47%) of SRL-related toxicity, leading to 4 discontinuations (23%); 8 patients (47%) have died during follow-up.This retrospective analysis of outcomes in the context of severe complicated patients suggests that more premature introduction SRL is preferable, particularly in a large patient cohort.     

Sirolimus therapy in liver transplant patients: an initial experience at a single center

Sirolimus (SRL) is an mTOR inhibitor that has been shown, in contrast to calcineurin inhibitors (CNI), to inhibit cancers in experimental models. Since February 2005, we introduced SRL in liver transplant patients in group a, in whom the primary disease was hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic or autoimmune liver cirrhosis, and group b, HCC-negative patients who developed posttransplantation cancers de novo. Of 18 patients in group a, 11 received SRL ab initio (subgroup a1), starting for 10 patients at 66.1+/-29.2 days after surgical healing and after 10 days in 1 case; the remaining 7 patients (subgroup a2) received SRL at 31.2+/-24.2 months. Three patients in group b, included 1 with Kaposi's sarcoma, 1 with bladder cancer, and 1 with thyroid cancer. In this group, SRL was introduced at 80.8+/-40.4 months. In all patients but one, who received a single 5 mg loading dose, SRL was started at 2 mg/d and adjusted to 6 to 8 ng/mL blood levels. CNI drugs, present as primary therapy, were gradually tapered to low levels and eventually stopped. The following observations were drawn from this initial experience: (1) 4/21 (19.0%) patients had to discontinue SRL because of early and late side effects: thrombocytopenia (n=2) and headache with leukopenia and leg edema associated with knee joint arthralgia (n=2); (2) 14 patients (11 in group a and 3 in group b) are still on SRL monotherapy; (3) 1 HCC recurrence and 1 de novo pancreatic adenocarcinoma were observed at 14 and 16 months, respectively (at the time of transplantation, both patients were beyond the MIlan HCC criteria), and (4) 1 patient, from subgroup a1, died after 99 days due to pneumonitis and possible relation to SRL lung toxicity. In conclusion, SRL appeared to be an effective immunosuppressant that could be used as monotherapy in liver transplant patients. Any conclusion on SRL anticancer effects can only come from randomized large studies after long follow-up.     

他克莫司缓释胶囊对肝移植术后稳定期受者安全性和临床疗效评估

目的通过他克莫司缓释胶囊（MR4）的Ⅲ期临床试验（MR4LTxCN02）评价MR4在肝移植术后稳定期受者中的安全性和临床疗效。方法受试者随机分配入MR4或他克莫司（FK506）组,MR4组药物剂量按1：1进行药物转换,每日口服1次;FK506组维持每12h服药1次至试验结束。在为期3个月的临床试验阶段,随访了受试者生命体征、不良事件、血常规、尿常规、肝功能、血糖、血脂及FK506的谷值浓度。随访结果采用SAS8．0统计软件进行了Fisher精确卡方检验及t检验分析。结果MR4组按1：1药物转换后与FK506组具有同等的安全性和临床疗效。与FK506组比较,MR4组具有感冒、上呼吸道感染症状减少倾向,没有增加不良事件或不良反应的发生率。转换药物后的剂量和血药浓度与换药前未发生显著变化;药代动力学检测结果表明,MR4具备缓释剂型的药代动力学特征,并与FK506具有良好的生物等效性。结论MR4与FK506具有同等的安全性和临床疗效,同时简化了服药次数,在提高受者长期依从性以及术后生活质量方面具有较大的优势。     

Severe limb lymphedema in sirolimus-treated patients

We report two kidney transplant recipients who developed severe limb lymphedema under sirolimus (SRL) immunosuppression. The patients received SRL 10 and 2 mg/d to achieve target levels of 10 to 20 ng/mL with tapering doses of prednisone. Renal function and drug levels were monitored monthly. Patient 1 developed lymphedema of the left upper limb 3 years posttransplantation, after having been exposed to high SRL doses in the preceding 2 years (mean SRL dose-9.5 mg/d, mean trough level-26.3 ng/mL, mean serum creatinine-1.63 mg/dL). In patient 2 lymphedema of both upper and lower right limbs occurred 18 months posttransplantation (mean SRL dose-3.2 mg/d, mean trough level-8.8 ng/mL, mean serum creatinine-2.9 mg/dL). Hypercholesterolemia and hypertriglyceridemia were also observed in both patients before SRL reduction/conversion. No signs of hematopoietic toxicity were observed. In both patients magnetic resonance (MR) angiography of the limb was negative for vascular obstruction, and lymphoscintigraphy revealed lymphatic obstruction. In patient 1 lymphedema improved significantly following SRL reduction and lymphatic drainage massage therapy. Patient 2 was converted to cyclosporine (CsA) improving markedly after conversion. Hypercholesterolemia and hypertriglyceridemia also improved significantly in both patients after reduction/conversion. We conclude that SRL may facilitate the occurrence of lymphatic obstruction by mechanisms that are presently unexplained. Lymphedema of the limbs in renal transplant recipients under SRL treatment, especially if on the same side as the hemodialysis access, should warn the transplant physician to rapidly reduce or withdraw SRL before the occurrence of complete obstruction.     

Cardiovascular risk in kidney transplant recipients receiving mammalian target of rapamycin inhibitors

Cardiovascular diseases (CVD) are the leading cause of mortality in renal transplant recipients. Various traditional and unconventional cardiovascular risk factors are potentiated by the adverse effects of immunosuppressive drugs. The mammalian target of rapamycin (mTOR) inhibitors have shown cardioprotective effects in experimental studies, but their influence on CVD in renal transplantation is unclear. The study included 115 kidney transplant recipients treated with mTOR inhibitors with steroids. A group of 38 patients received additionally small doses of calcineurin inhibitor. The control group consisted of 58 kidney transplant recipients randomly chosen among the population of patients transplanted at the same time, who received a calcineurin inhibitor, mycophenolate mofetil or sodium plus steroids. No differences in age, gender, duration of pretransplantat dialysis, time after transplantation, body mass index or glycated hemoglobin existed between the groups. Blood pressure and number of antihypertensive agents, high-density lipoprotein cholesterol, and uric acid levels were similar. The prevalence of diabetic, ischemic, or hypertensive nephropathy as the reason for end-stage renal disease was similar (P = .08). The study group showed higher mean values of total cholesterol (249 vs 204.6 mg/dL; P < .0001) and low-density lipoprotein 136.5 vs 117.7 mg/dL; (P = .015), as well as median values of triglycerides (202 vs 142 mg/dL; P < .0001) and proteinuria (P = .0002). mean estimated glomerular filtration rate was lower in the study group (42.9 vs 51.9 mL/min; P = .0003). Posttransplant diabetes appeared in 38% of the study group compared to 20% of the controls (P = .08). The incidence of coronary artery disease was higher among patients treated with mTOR inhibitors (P = .04). CVD, defined as myocardial infarction, percutaneous coronary intervention, stroke, aortic aneurysm, pulmonary thromboembolism, sudden cardiac death appeared in 26 study group compared with four control patients (P = .24). The risk of any CVD was not significantly higher among patients receiving mTOR inhibitors hazard ratio 1.94; 95% confidence interval 0.83-4.52). In conclusion, no correlation was observed between the duration of mTOR therapy and CVD.