Kerstin Claesson

Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine.

BACKGROUND Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus. METHODS In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n=42) or sirolimus (n=41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. RESULTS At 12 months, graft survival (98% sirolimus vs. 90% CsA), patient survival (100% vs. 98%), and incidence of biopsy-confirmed acute rejection (41% vs. 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P< or =0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with sirolimus. CONCLUSIONS Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.

Sirolimus Allows Early Cyclosporine Withdrawal in Renal Transplantation Resulting in Improved Renal Function and Lower Blood Pressure.

Introduction. This study evaluated whether cyclosporine (CsA) could be eliminated from a sirolimus (Rapamune, rapamycin, SRL)-CsA-steroid (ST) regimen at 3 months. Methods. This was an open-label study conducted in Europe, Australia, and Canada. Upon enrollment, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of sirolimus (troughs>5 ng/ml), CsA, and steroids. At 3 months±2 weeks, eligible patients were randomized (1:1) to remain on SRL-CsA-ST or to have CsA withdrawn and therapy continued with SRL (troughs 20–30 ng/ml)-ST. Results. At 12 months, overall graft and patient survival were 89.1% and 94.9%, respectively. In the 430 (82%) randomized patients, there was no difference in graft survival (95.8% vs. 97.2%, SRL-CsA-ST vs. SRL-ST) or patient survival (97.2% vs. 98.1%, respectively). The incidence of biopsy-confirmed primary acute rejection was 13.1% during the prerandomization period. After randomization, the acute rejection rates were 4.2% and 9.8% for SRL-CsA-ST and SRL-ST, respectively (P =0.035). Renal function (calculated glomerular filtration rate, 57 vs. 63 ml/min, P <0.001) and blood pressure significantly improved when CsA was withdrawn. Hypertension, CsA nephrotoxicity, hyperuricemia, and Herpes zoster occurred statistically more frequently in patients remaining on CsA, whereas thrombocytopenia, abnormal liver function tests, and hypokalemia were reported more often for SRL-ST therapy. Conclusion. Sirolimus, CsA, and steroids for 3 months posttransplant, followed by elimination of CsA, is a safe and effective alternative to continuous therapy with sirolimus, CsA, and steroids that can result in better renal function and lower blood pressure.

Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposis sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.

Sirolimus‐Based Therapy Following Early Cyclosporine Withdrawal Provides Significantly Improved Renal Histology and Function at 3 Years

Graft function and histology are predictive of renal transplant survival. The Rapamune Maintenance Regimen study demonstrated that early cyclosporine (CsA) withdrawal from a sirolimus (SRL)‐CsA‐steroid (ST) regimen improved renal function and blood pressure. We report the protocol‐mandated biopsy findings from that study. Renal transplant patients (n = 430) receiving SRL‐CsA‐ST were randomized at 3 months after transplantation to remain on SRL‐CsA‐ST, or to have CsA withdrawn (SRL‐ST group). Protocol‐mandated biopsies were performed at engraftment and at 12 and 36 months. Two pathologists blindly evaluated 484 biopsies to obtain the Chronic Allograft Damage Index (CADI) scores. At 36 months among patients with serial biopsies (n = 63), the mean CADI score was significantly lower with SRL‐ST(4.70 vs. 3.20, p = 0.003), as was the mean tubular atrophy score (0.77 vs. 0.32, p < 0.001). All six components of the CADI score were numerically lower in SRL‐ST group; moreover, inflammation and the tubular atrophy scores decreased significantly in the SRL‐ST group between 12 and 36 months. The calculated glomerular filtration rate at 36 months was significantly better in the CsA‐withdrawal group (54.8 vs. 68.2 mL/min, p = 0.009). In conclusion, withdrawing CsA from the SRL‐CsA‐ST regimen resulted in improved renal histology and function.

Preservation of the canine liver for 24-48 hours using simple cold storage with UW solution.

The results of a series of 29 orthotopic liver transplants in the dog are described. The livers were preserved in a new cold storage fluid, UW solution, and were successfully transplanted after periods of storage of 24, 30, 36, and 48 hr. All six animals transplanted after 24 hr survived beyond 5 days after transplantation and had excellent graft function. Four of six survived for at least 5 days after 30 hr of cold storage, and five of five after 36 hr. Five of six consecutive dogs that received transplants that had been cold-stored for 48 hr survived for 5 or more days. This solution represents a substantial advance over all existing cold storage solutions for liver preservation.

Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study.

Introduction. The purpose of this study was to evaluate early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen. Methods. Within 48 hr after transplantation, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of SRL (troughs >5 ng/mL; immunoassay), CsA, and ST. Those eligible (430) were randomly assigned (1:1) at 3 months ± 2 weeks to remain on triple-drug therapy (SRL-CsA-ST group) or to have CsA withdrawn and SRL trough concentrations targeted to 20 to 30 ng/mL (SRL-ST group) until month 12, and 15 to 25 ng/mL thereafter. Results. At 24 months, there were no statistically significant differences in patient survival (94.0% vs. 95.3%), graft survival (91.2% vs. 93.5%), acute rejection after randomization (5.1% vs. 9.8%) or discontinuations (34% vs. 33%) for SRL-CsA-ST versus SRL-ST, respectively. Serum creatinine level was significantly better in patients who had CsA withdrawn (167 vs. 128 &mgr;mol/L, P <0.001), as was the slope of 1/creatinine. Similarly, systolic blood pressure was lower in patients who had CsA withdrawn (141 vs. 134 mm Hg, P <0.001). High-density lipoprotein cholesterol was significantly higher in the SRL-ST group, whereas total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were not significantly different. Hypertension, creatinine increase, abnormal kidney function, toxic nephropathy, edema, hyperuricemia, cataracts, Herpes zoster, and malignancy were reported significantly more often in patients continuing CsA. Thrombocytopenia, hypokalemia, abnormal liver function tests, abnormal wound healing, ileus, and pneumonia were reported significantly more frequently with SRL-ST. Conclusion. Data at 2 years confirm that early CsA withdrawal followed by an SRL-ST maintenance regimen results in long-term improvement in both renal function and blood pressure, without increased risk of graft loss or late acute rejection.

Dose Optimization Of Mycophenolate Mofetil When Administered With A Low Dose Of Tacrolimus In Cadaveric Renal Transplant Recipients

Background. Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. Methods. Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. Results. At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P =0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P <0.05). Conclusions. Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

Preservation of dog liver, kidney, and pancreas using the Belzer-UW solution with a high-sodium and low-potassium content

The UW solution developed for cold storage of the liver, pancreas, and kidney was used in a modified form in this study and tested in the orthotopic transplantation of dog livers, kidneys, and pancreases preserved for 48 hr. The modification was the alteration of the concentrations of potassium and sodium. The original UW solution contained 120 mM K+ and 30 mM Na+. In this study the Na+ was 140 mM and the K+ only 9 mM, all other agents were identical to the original UW solution. Six of 11 dogs survived with livers preserved for 48 hr. The five deaths were due to technical complications and unrelated to preservation failure. Postoperative AST and partial thromboplastin time (PTT) values were lower (statistically significant on days 1, 3, and 4) in livers preserved in the high Na+ UW solution than as previously shown in the high-k+ UW solution. Other measures of liver function (bilirubin and fibrinogen) were similar between the high-Na+ and high-K+ groups. Six dogs survived with kidneys preserved for 48 hr in the high-Na+ UW solution. The results were comparable to those obtained with the high K+ solution. Four of six dogs survived for up to 28 days with pancreases preserved for 48 hr. The two deaths were due to technical complications unrelated to preservation failure. Three of the four dogs had normal blood glucose values for one month, and intravenous glucose tolerances test on day 7 and 28 were identical to those obtained in pancreases preserved with the high-K+ UW solution. The high-Na+ version of the UW solution appears equally or slightly more effective for 48-hr organ preservation than the original high-K+ UW solution. The use of a high-Na+ UW solution reduces the problems of hyperkalemic cardiac arrest in in situ flushing of the donor for multiple organ harvesting and in transplantation of the liver. Thus, with this solution livers do not need to be flushed with a low K+-containing solution prior to transplantation.

Kinetics and dynamics of single oral doses of sirolimus in sixteen renal transplant recipients

Sirolimus is a new immunosuppressive drug that has been evaluated in animal experiments. The current study was conducted on humans with reformulated sirolimus in doses from 3 mg/m2 to 15 mg/m2. Sixteen renal transplant recipients were included in this phase I study to determine the safety, tolerance, and preliminary pharmacokinetics of increasing single doses of orally administered sirolimus. All 16 patients had stable renal graft function after a renal transplant at least 6 months before the study. Basal immunosuppression consisted of cyclosporine and prednisolone (n = 10) or cyclosporine, azathioprine, and prednisolone (n = 6). Four groups (I, 3 mg/m2; II, 5 mg/m2; III, 10 mg/m2; IV, 15 mg/m2) of four patients were assigned randomly to receive sirolimus (n = 3) or placebo (n = 1). Among the 12 patients who received sirolimus, five had mild transient study events such as headache, nausea, mild dizziness, hypoglycemia, epistaxis, and decrease in platelets. No serious adverse events occurred and no nephrotoxic effects could be related to the single dose administration of sirolimus. The only study event that was judged as probably related to sirolimus was the single case of thrombocytopenia. The other events were evaluated as possibly related. Thrombocytopenia occurred at the highest dose level (15 mg/m2 sirolimus). In two of the patients in the placebo group, slight elevations of liver enzymes and serum amylase were seen. Blood and plasma sirolimus concentrations were analyzed by an electrospray-high performance liquid/mass spectrophotometric (ESP-HPLC/MS) method Sirolimus showed an extensive red blood cell distribution with a mean blood/ plasma ratio of 49.1. The elimination half-life ranged from 43.8 to 86.5 hours (mean 56.9 hours). The Cmax and the area under the concentration versus time curves (AUC) correlated reasonably with doses from 3 to 15 mg/m2. The oral dose clearance ranged from 42 to 339 ml/h.kg. No clinically significant differences were seen in the trough concentrations of cyclosporine or the AUCs before and after the administration of sirolimus. Administration of single oral doses of sirolimus from 3 to 15 mg/m2 was safe and well tolerated in stable renal transplant recipients. Thrombocytopenia may be the dose-limiting toxicity. Additional phase II and phase III clinical trials will define the immunosuppressive efficacy of sirolimus.

Health-related quality-of-life outcomes of sirolimus-treated kidney transplant patients after elimination of cyclosporine A: results of a 2-year randomized clinical trial.

Background. This study compared 2-year health-related quality-of-life (HRQL) outcomes of sirolimus (SRL)-treated kidney transplant patients after elimination of cyclosporine A (CsA) to patients continuing on a combined CsA and SRL regimen. Methods. A randomized, open-label, clinical trial was performed in Europe, Australia, and Canada. Four hundred thirty kidney transplant patients were randomly assigned to sirolimus plus steroids (ST) (n=215) or SRL and CsA+ST (n=215) therapy after 3 months of combined SRL+CsA+ST treatment. HRQL was measured using the Kidney Transplant Questionnaire (KTQ) and the SF-36 Health Survey at month 3 (time of randomization) and months 12 and 24 after transplantation. Repeated-measures analysis of covariance was used to evaluate treatment differences in HRQL scores over the 2-year period. Results. HRQL scores were available for 361 (86%) eligible study patients. Statistically significant treatment-by-assessment time interactions, favoring SRL+ST, were found on KTQ Fatigue (P =0.0158) and Appearance scores (P =0.0007). No treatment differences were observed in KTQ Physical Symptom, Uncertainty-Fear, and Emotion scores. Statistically significant treatment-by-assessment time interactions were observed for SF-36 Vitality scores (P =0.0203) but not other SF-36 scores (P >0.05). For Vitality scores, the SRL+ST group remained stable (mean, 0.4-point change) from month 3 to month 24 compared with decreases in the SRL+CsA+ST group (mean, −6.5-point change). Conclusions. SRL-based therapy with early elimination of CsA results in fewer appearance-related problems, less fatigue, and better vitality compared with continuous treatment with SRL, CsA, and ST.