Tacrolimus as secondary intervention vs. cyclosporine continuation in patients at risk for chronic renal allograft failure

BACKGROUND: Chronic renal allograft failure (CRAF) is the leading cause of graft loss post-renal transplantation. This study evaluated the efficacy and safety of tacrolimus as secondary intervention in cyclosporine-treated kidney transplantation patients with impaired allograft function as indicated by elevated serum creatinine (SCr) levels. METHODS: Patients receiving cyclosporine-based immunosuppression who had an elevated SCr at least 3 months post-renal transplantation were enrolled. Treatment allocation was 2:1 to switch to tacrolimus or continue cyclosporine. This analysis was performed after 2 yr; patients will be followed for an additional 3 yr. RESULTS: There were 186 enrolled and evaluable patients. On baseline biopsy, 90% of patients had chronic allograft nephropathy. Baseline median SCr was 2.5 mg/dL in both treatment groups. For patients with graft function at month 24, SCr had decreased to 2.3 mg/dL in the tacrolimus-treated patients and increased to 2.6 mg/dL in the cyclosporine-treated patients (p = 0.01). Acute rejection occurred in 4.8% of tacrolimus-treated patients and 5.0% of cyclosporine-treated patients during follow-up. Two-year allograft survival was comparable between groups (tacrolimus 69%, cyclosporine 67%; p = 0.70). Tacrolimus-treated patients had significantly lower cholesterol and low-density lipoprotein levels and also had fewer new-onset infections. Cardiac conditions developed in significantly fewer tacrolimus-treated patients (5.6%) than cyclosporine-treated patients (24.3%; p = 0.004). Glucose levels and the incidences of new-onset diabetes and new-onset hyperglycemia did not differ between treatment groups. CONCLUSIONS: Conversion from cyclosporine to tacrolimus results in improved renal function and lipid profiles, and significantly fewer cardiovascular events with no differences in the incidence of acute rejection or new-onset hyperglycemia.     

Paired kidney analysis of tacrolimus and cyclosporine microemulsion-based therapy in Chinese cadaveric renal transplant recipients

Few studies used paired kidneys for comparison between tacrolimus and cyclosporine in renal transplantation. Most of the published data used whole blood trough levels for drug monitoring. However, the use of limited sampling strategy and abbreviated formula to estimate the 12-h area under concentration-time curve (AUC(0-12)) allowed better prediction of drug exposure. Sixty-six first cadaveric renal transplant recipients receiving paired kidneys were randomized to receive either tacrolimus-based (n = 33) or cyclosporine microemulsion (Neoral)-based therapies (n = 33). Abbreviated AUC(0-12) was used for drug monitoring and dose titration. Mean follow-up duration was 2.8 +/- 2 years. The patient and graft survival were comparable. Fewer incidence of acute rejection was observed in tacrolimus group (15% vs. 27.3%) though the difference was not significant (P = 0.23). The absolute value and the rate of decline of creatinine clearance were both significantly better in tacrolimus-treated patients. Prevalence of hypertension, post-transplant diabetes mellitus, infection, and malignancy were similar in both groups. Prevalence of hypercholesterolemia (11/33 vs. 4/33) and gum hypertrophy (6/33 vs. 1/33) was more common in cyclosporine-treated patients (P = 0.04 in both parameters). This was the first prospective, randomized study with paired kidney analysis showing the renal function was significantly better in tacrolimus-treated patients than in cyclosporine-treated patients.     

Long-term outcomes in liver transplant patients with hepatic C infection receiving tacrolimus or cyclosporine

Choice of calcineurin inhibitor may be a contributing factor to deteriorating patient and graft survival following liver transplantation for hepatitis C virus (HCV). In our multicenter, open-label LIS2T study, de novo liver transplant patients stratified by HCV status were randomized to cyclosporine or tacrolimus. Follow-up data were obtained in an observational study of 95 patients. Mean follow-up was 34 and 37 months, respectively, for cyclosporine-treated (n = 47) and tacrolimus-treated (n = 48) patients. In patients not receiving antiviral therapy, 22 of 31 given cyclosporine (72%) and 24 of 29 given tacrolimus (83%) had biochemical recurrence of HCV. In 68 patients with at least one biopsy, histological evidence of HCV-related hepatitis was present in 27 of 31 (87%) cyclosporine-treated patients and 37 of 37 (100%) tacrolimus-treated patients (P = .02, chi-square test). Three-year actuarial risk of fibrosis stage 2 was 66% with cyclosporine and 90% with tacrolimus; for fibrosis stage 3 or 4 it was 46% and 80%, respectively. Three graft losses were attributed to HCV recurrence in cyclosporine-treated patients and six in tacrolimus-treated patients. Tacrolimus may be associated with increased risk of histological HCV disease recurrence compared to cyclosporine.     

Effect of atorvastatin therapy and conversion to tacrolimus on hypercholesterolemia and endothelial dysfunction after renal transplantation

BACKGROUND: Hypercholesterolemia is a frequent complication in renal transplant patients treated with cyclosporine A (CsA). Whether it is preferable to treat hypercholesterolemia with statins or to switch patients from CsA to tacrolimus (TRL) has not been investigated. METHODS: Twelve CsA-treated kidney transplant recipients with hypercholesterolemia were successively crossed over from CsA alone to: CsA plus atorvastatin; TRL alone; and TRL plus atorvastatin. Total cholesterol (C), Low density lipoprotein (LDL)-C, high density lipoprotein (HDL)-C, LDL and HDL alpha-tocopherol content, lag-time of LDL oxidation, plasma levels of oxidized LDL and the percentage of small dense LDL were assayed at the end of each treatment period. Endothelial function was assessed by high resolution ultrasound measurement of flow-mediated brachial artery vasodilatation (FMD). RESULTS: Atorvastatin therapy was more efficient in reducing total cholesterol and LDL-C levels than conversion from CsA to TRL. Combining TRL with atorvastatin further reduced LDL-C levels as compared to TRL alone, but was no more efficient than the CsA-statin combination. Neither atorvastatin therapy nor conversion to TRL significantly changed the proportion of dense LDL, lipoprotein alpha-tocopherol contents or the lag time of LDL oxidation. Addition of atorvastatin to CsA increased FMD from 4.0+/-1.8% to 6.5+/-4.0% (P<0.05 vs. CsA). Conversion from CsA to TRL caused a slight improvement in FMD (5.1+/-2.1%, P<0.05 vs. CsA). Adding atorvastatin to TRL had no detectable effect on FMD (5.5+/-2.3%, P=NS vs. TRL). CONCLUSIONS: Atorvastatin was more efficient in reducing total and LDL cholesterol levels of CsA-treated renal transplant patients than conversion to TRL and significantly improved endothelial dysfunction.     

Results of a two-center study comparing hepatic fibrosis progression in HCV-positive liver transplant patients receiving cyclosporine or tacrolimus

A 2-center retrospective analysis was performed in 60 patients undergoing liver transplantation for hepatitis C virus (HCV)-related disease (cyclosporine in 20, tacrolimus in 40). Mean (±SEM) follow-up was 23.6 ± 22.5 and 22.3 ± 13.7 months in patients receiving cyclosporine or tacrolimus, respectively. Clinically indicated biopsies were performed in 15/20 cyclosporine patients (75%) and 22/40 tacrolimus patients (55%; P = .17). The Ishak fibrosis score was significantly lower in cyclosporine-treated patients versus tacrolimus-treated patients (mean 1.7 ± 0.4 vs 3.1 ± 0.4; P = .023), as was percentage of fibrosis grade Ishak ≥4 (7% vs 41%; P = .028). The mean time to moderate fibrosis (Ishak score ≥3) was 38.2 ± 15.1 months in cyclosporine patients (4/15) and 23.5 ± 12.6 months in tacrolimus patients (14/22); the difference was not statistically significant (P = .09). This retrospective study suggests that cyclosporine-based immunosuppression is associated with less severe hepatic fibrosis in HCV-positive liver transplant recipients compared with tacrolimus-based regimens, but a larger prospective comparative trial is necessary to confirm these findings.     

Posttransplant diabetes mellitus in kidney allograft recipients: incidence, risk factors, and management

BACKGROUND: Posttransplant diabetes mellitus (PTDM), associated with the use of immunosuppressants, occurs at varying rates in kidney transplant recipients. METHODS: Five transplant centers conducted a retrospective review of 435 kidney recipients completing at least 6 months of follow-up to determine risk factors, incidence, and management strategies for posttransplant glucose intolerance. A distinction was made between hyperglycemia and diabetes. RESULTS: The incidence of PTDM was found to be 4.9%. Among tacrolimus-treated patients it was 5.7%, compared with 3.3% among cyclosporine-treated patients (P=0.453). Mean daily maintenance doses of prednisone and mycophenolate mofetil (MMF) were significantly lower in tacrolimus-treated patients. Significantly more tacrolimus-treated patients were prednisone-free (9.0%/0%; P<0.001). Logistic regression analysis revealed that the absence of an antiproliferative agent correlated with the development of PTDM (odds ratio=3.56; P=0.01). CONCLUSIONS: Based on this study, we propose management guidelines specifically for glucose intolerance developing after renal transplantation. Maintenance of blood glucose levels within strict limits is recommended, and the contribution of immunosuppressive agents to the development of PTDM is accounted for. Gradual tapering of prednisone and tacrolimus is proposed for patients who develop PTDM but also bear minimal risk of rejection. Tapering and eventual withdrawal of insulin should be attempted once blood glucose levels normalize. Switching to the alternative calcineurin inhibitor should only be considered as a late intervention. Tacrolimus therapy should be considered even in patients at high risk for diabetes, because the benefit of reduced acute rejection incidence and severity, as demonstrated in other studies, outweighs the risk of PTDM.     

Lipid abnormalities in stable liver transplant recipients – effects of cyclosporin, tacrolimus, and steroids

Dyslipidemia is common after liver transplantation, but the underlying mechanisms are largely unknown. We studied the lipid profile of 27 liver transplant recipients randomized to receive either cyclosporin (CyA, n = 14) or tacrolimus (n = 13) and compared them with 20 healthy, matched controls. Before transplantation, patients presented low total and low-density lipoprotein (LDL) cholesterol (as compared to controls) that increased shortly, i. e., 3 months, after transplantation. Eighteen months post-transplantation, total and LDL cholesterol levels decreased to pretransplant values but tended to remain higher in CyA-treated patients. However, at that time, prednisone treatment was more prevalent among CyA-treated than tacrolimus-treated patients and fully accounted for the difference in cholesterol levels. Indeed, regardless of therapy, patients not receiving prednisone exhibited lower cholesterol levels than prednisone-treated patients and controls. We conclude that prednisone therapy, rather than CyA or tacrolimus immunosuppression, seems to be the major determinant of increased cholesterol levels. Received: 19 June 1997 Received after revision: 24 October 1997 Accepted: 10 November 1997     

Primary immunosuppression with tacrolimus in kidney transplantation: three-year follow-up in a single center

INTRODUCTION: The 1-year results of the phase III US Multicenter Trial comparing tacrolimus- and cyclosporine (Sandimmun)-based immunosuppressive therapy in kidney transplantation revealed a significant reduction in the incidence and severity of acute rejection episodes among patients maintained on tacrolimus. This retrospective, nonrandomized, single-center study represented 3-year data for patient and graft survival and safety in the tacrolimus-treated patients. METHODS: Among 97 consecutive kidney transplant recipients 41 who received tacrolimus and 56 cyclosporine-based immunosuppression were followed for 3 years for patient and graft survivals and for the incidence of acute rejection episodes as well as serious adverse events. RESULTS: The 3-year patient and graft survival rates for tacrolimus and cyclosporine were similar (91.0% vs 90.2%, 96.5% vs 95.0%). However, the incidence of acute rejection episodes was significantly lower in the tacrolimus (17.1%) compared with the cyclosporine group (35.7%, P = .043). There was a higher incidence of headache, posttransplant diabetes, and alopecia reported in the tacrolimus group, whereas hypertension, hypercholesterolemia, and hirsutism were more frequent in the cyclosporine group. The incidences of hand tremor, hyperkalemia, and viral infections were comparable in both groups. Two patients in the tacrolimus group were converted to cyclosporine due to nephrotoxicity and posttransplant diabetes, respectively, whereas 12 patients in the cyclosporine group were converted to tacrolimus as rescue therapy for acute rejection (41.7%), gingival hyperplasia (33.3%), nephrotoxicity (8.3%), neurotoxicity (8.3%), and hirsutism (8.3%), respectively. CONCLUSION: The 3-year results of tacrolimus treatment show excellent efficacy and safety in kidney transplantation. Due to different side-effect profiles, it is necessary to develop individualized immunosuppressive strategies in kidney transplant recipients.     

Independent effects of cyclosporine and prednisone on posttransplant hypercholesterolemia

To clarify the relative influences of cyclosporine (CsA) therapy, corticosteroid therapy, and other clinical variables on posttransplant hypercholesterolemia, total serum cholesterol levels were measured in 107 renal transplant recipients receiving one of three immunosuppression regimens: CsA and azathioprine (AZA) (group I); CsA, AZA, and prednisone (group II); or AZA and prednisone (group III). Multivariate analysis demonstrated that prednisone therapy, CsA therapy, patient age, and pretransplant cholesterol levels correlated independently with posttransplant cholesterol levels at last follow-up (ranging from 13 to 84 months after transplantation). In 32 patients successfully withdrawn from corticosteroid therapy and maintained on AZA and stable doses of CsA, serum cholesterol decreased from 6.55 +/- 1.1 mmol/L (253.5 +/- 43.1 mg/dL) to 5.27 +/- 1.2 mmol/L (203.9 +/- 45.6 mg/dL). Results of this analysis indicate that prednisone and CsA are independent factors in the pathogenesis of posttransplant hypercholesterolemia. Complete withdrawal of corticosteroids partially corrects hypercholesterolemia in CsA-treated renal transplant recipients.     

Evolution of cardiovascular risk after liver transplantation: A comparison of cyclosporine A and tacrolimus (FK506)

The development of atherosclerotic cardiovascular complications is a common and serious problem for the long-term survivors of organ transplantation. Cyclosporine A plus steroid-based immunosuppression regimens in these patients are associated with the development of hypertension, hyperlipidemia, obesity, and diabetes mellitus. Whether the new immunosuppressive agent tacrolimus (FK506) confers any advantage in terms of these cardiovascular risk factors has been less well studied. We compared serial changes in blood pressure, lipids, body weight, and glucose levels during the first 12 months after liver transplantation in patients using either cyclosporine A (n = 39) or tacrolimus (n = 24)-based immunosuppression. By 12 months, the prevalence of hypertension, hypercholesterolemia, and obesity was increased in the cyclosporine A group compared to tacrolimus: 82% versus 33%, 33% versus 0%, and 46% versus 29%, respectively (all p < .05). Triglyceride and total cholesterol levels were 196 +/- 23 versus 125 +/- 13 mg/dL and 225 +/- 9 versus 159 +/- 7 mg/dL for the cyclosporine A versus tacrolimus groups, respectively (p < .05). Cumulative posttransplant steroid dose was not related to the observed lipid changes in either group, although the increase in triglycerides was positively correlated to weight gain and diuretic use in the cyclosporine A group. The incidence of diabetes mellitus was not increased from baseline in either group. These results indicate that tacrolimus, compared to cyclosporine A, is associated with a less adverse cardiovascular risk profile in the first year after liver transplantation. Whether these differences persist and become clinically relevant to a liver transplant recipient population that is increasingly older and has more preexisting cardiovascular disease remains to be determined. (Liver Transpl Surg 1997 Jan;3(1):1-9)     

A randomized study comparing three cyclosporine-based regimens in cadaveric renal transplantation. Italian Multicentre Study Group for Renal Transplantation (SIMTRe).

Whether it is better to treat renal transplant patients with cyclosporine alone, combined with steroids, or combined with steroids and azathioprine is still unclear. After initial therapy with cyclosporine and steroids, 354 cadaver renal transplant recipients were randomly assigned at the post-transplant day 5 to cyclosporine alone (monotherapy), cyclosporine plus steroids (double therapy), or cyclosporine plus steroids plus azathioprine (triple therapy). Monotherapy patients, after a second acute rejection, were switched to either of the two alternative therapies. According to intention-to-treat (ITT) analysis, the 4-year patient survival was 97% in monotherapy, 91% in double therapy, and 96% in triple therapy; the graft survival including death was 84%, 77%, and 88%, respectively; and the pure graft survival was 87%, 85% and 91%, respectively (P = not significant). Acute rejections were diagnosed in 79 patients in monotherapy, 58 in double therapy, and 59 in triple therapy (P < 0.01). Of the patients on monotherapy, 52% were switched to double or triple therapy. In these patients, the 4-year graft survival including death was 68%, and the pure graft survival was 72%, in comparison with 93% and 94%, respectively, for patients who continued on cyclosporine alone. Patients with renal polycystic disease as a cause of renal failure and with low plasma creatinine at the time of randomization (5 days after transplant) had a higher probability of remaining on monotherapy, wherease those with glomerulonephritis or systemic lupus erythematosus (SLE) and with high plasma creatinine levels at randomization had a higher probability of being switched to double or triple therapy. According to ITT analysis, there were fewer ocular (P < 0.0001), osteomuscular (P < 0.002) and cardiovascular complications (P = 0.05) and fewer patients with hypercholesterolemia (P < 0.0028) in the monotherapy group, with no difference between double and triple therapy. Creatinine clearance at 3 years was lower in monotherapy, but no attrition of renal function was seen over the years in any of the groups. Cyclosporine, however used, provided good results in cadaveric renal transplantation. Triple therapy and monotherapy offered a nonsignificantly better patient and graft survival than double therapy. Patients on monotherapy had a higher risk of acute rejection but had fewer adverse events than those on double or triple therapy. Patients maintained on cyclosporine alone had the best graft survival, whereas those who were assigned to monotherapy and had to add steroids because of multiple rejections had the worst outcome. Therefore, it seems reasonable to limit the choice of monotherapy to patients without immune-mediated renal diseases and with good graft function in the early post-transplant period.     

Tacrolimus-based triple-drug immunosuppression minimizes serum lipid elevations in pediatric cardiac transplant recipients.

BACKGROUND: Immunosuppression with corticosteroids and cyclosporine has been associated with hyperlipidemia, a risk factor for post-transplant coronary artery disease. The recent development of tacrolimus has created an alternative to cyclosporine-based triple drug immunotherapy. One potential benefit that has been reported in patients receiving tacrolimus is a minimization of elevation of both total and LDL cholesterol, compared to those increases observed in patients receiving cyclosporine-based immunosuppression. It is unclear in previous studies whether this beneficial effect is related to tacrolimus directly or to its corticosteroid sparing potential. To study this relationship, we compared lipid profiles from pediatric cardiac transplant recipients treated with corticosteroids, and either cyclosporine or tacrolimus. METHODS: The study group consisted of 23 patients (mean age = 12.3 years) with pre-transplant and serial post-transplant determinations of total cholesterol, LDL, HDL, and triglycerides. Patients were separated into 4 study groups, defined by immunosuppressive regimen (cyclosporine vs. tacrolimus) and prednisone dose (>0.10 mg/kg/day vs. < or =0.10 mg/kg/day). RESULTS: Patients who received cyclosporine and higher doses of prednisone experienced a mean 74 mg/dl increase from baseline in total cholesterol (p = .0001). None of the other 3 treatment groups demonstrated a statistically significant elevation. Similar trends were observed in LDL and triglyceride alterations between the 4 study groups. Interestingly, patients treated with tacrolimus and higher doses of prednisone demonstrated a significant rise in HDL from baseline (p = .0001), although those who received cyclosporine and higher dose prednisone failed to exhibit this rise. CONCLUSION: The minimal degree of lipid alteration seen in patients receiving tacrolimus and higher doses of prednisone indicates that this effect was not solely based upon the steroid-sparing properties of tacrolimus therapy. The data also suggests a possible synergistic effect between cyclosporine and higher doses of prednisone on hyperlipidemia. Therefore, in pediatric patients requiring higher corticosteroid doses late after transplantation, use of tacrolimus rather than cyclosporine may lead to more favorable lipid profiles and help minimize the risk of post-transplant coronary arteriopathy.     

Treatment of hypercholesterolemia with ezetimibe in the kidney transplant population

BACKGROUND: Given the high incidence of lipid abnormalities, high burden of cardiovascular disease, and high proportion who do not achieve target levels despite therapy in the kidney transplant population, additional lipid lowering strategies are needed. METHODS: This was a nonrandomized, open-label, single-cohort evaluation of ezetimibe, a novel cholesterol absorption inhibitor, in 40 stable kidney transplant recipients with hypercholesterolemia. RESULTS: After 4 weeks of therapy total and LDL cholesterol were reduced by 23 +/- 13% (P < .0001) and 33 +/- 15% (P < .0001), respectively. The drug was equally effective in patients on cyclosporine (19), tacrolimus (13), or sirolimus (8), but more effective (P = .0006) when used in combination with a statin (41 +/- 13% reduction in LDL, n = 22) compared with monotherapy (24% +/- 13%, n = 18). There were no significant effects on serum creatinine, drug levels, body weight, or liver function tests. CONCLUSIONS: Ezetimibe is an effective LDL cholesterol-lowering agent in the kidney transplant population. Further studies are warranted in a larger population not only to examine the extent of cardiovascular risk reduction but also to detect unwarranted toxicity.     

Relative risk of new-onset diabetes during the first year after renal transplantation in patients receiving tacrolimus or cyclosporine immunosuppression

Clinical trials have consistently shown a higher incidence of new-onset diabetes mellitus with tacrolimus than cyclosporine. However, in protocol-driven studies steroid doses are comparable in both treatment arms, while in clinical practice steroid dose used in conjunction with tacrolimus or cyclosporine may differ. This retrospective study analysed renal transplant recipients without pre-existing diabetes receiving tacrolimus (n = 100) or cyclosporine (n = 100) for whom one-year follow-up data were available. Diabetes was defined as use of insulin or oral hypoglycemic agents; fasting glucose >6.9 mmol/L; or non-fasting glucose >11 mmol/L on three consecutive occasions. Tacrolimus-treated patients were significantly older than cyclosporine-treated patients (49 +/- 14 vs. 44 +/- 13 yr, p < 0.05) and received a significantly lower cumulative dose of corticosteroids over the first three months post-transplant (1284 +/- 379 vs. 1714 +/- 486 mg, p < 0.0001). At 3, 6, 9 and 12 months significantly more tacrolimus-treated patients had new-onset diabetes than cyclosporine- treated patients. At 12 months, 18 patients receiving tacrolimus and two receiving cyclosporine had diabetes (p < 0.0001). There was a clear relationship between age and incidence of new-onset diabetes at three months in the tacrolimus cohort. After stratifying patients by age group, the frequency of diabetes was significantly higher with tacrolimus than with cyclosporine in patients aged 40-60 yr [8/46 (17.4%) vs. 2/48 (4.2%), p < 0.05] and >60 yr [9/28 (32.1%) vs. 0/14 (0%), p < 0.05]. The mean tacrolimus trough level during the first three months was similar in patients with diabetes (13.1 +/- 2.3 ng/mL) or without diabetes (13.0 +/- 2.8 ng/mL, n.s.). These results indicate that new-onset diabetes is strongly and significantly associated with tacrolimus vs. cyclosporine in renal transplant recipients, even when steroid dosing is lower with tacrolimus.     

Conversion from cyclosporine to tacrolimus in patients at risk for chronic renal allograft failure: 60-month results of the CRAF Study

BACKGROUND: This study compared the long-term effects of switching from cyclosporine to tacrolimus on the incidence, progression, and severity of chronic renal allograft failure in patients with elevated serum creatinine levels. METHODS: Patients were assigned randomly (2:1) to switch to tacrolimus or remain on cyclosporine. Tacrolimus was initiated at 1/50th of the cyclosporine dose or 0.15 mg/kg/day, whichever dose was lower, to maintain trough concentrations between 5 and 15 ng/mL. Cyclosporine doses were adjusted to achieve trough concentrations between 100 and 300 ng/mL. RESULTS: At 60 months, the median change from baseline in serum creatinine was -0.2 mg/dL in the tacrolimus group and 0.3 mg/dL in the cyclosporine group (P=0.003). Median change in estimated creatinine clearance was 1.2 mL/min in the tacrolimus group and -4.1 mL/min in the cyclosporine group (P=0.019). The incidence of new-onset diabetes, hyperglycemia, hypertension, lymphoma, and malignancies was generally low and comparable between groups. Fewer patients in the tacrolimus group than in the cyclosporine group developed new cardiac conditions (11% vs. 28%, P=0.004), had low-density lipoprotein (LDL) cholesterol values more than 130 mg/dL (29% vs. 57%, P=0.002), or developed hyperlipidemia (24% vs. 67%, P=0.046) during the 60-month follow-up period. Despite these changes, patient and graft survival were similar for both groups. CONCLUSION: Switching from cyclosporine to tacrolimus resulted in improved renal function and a reduction in the occurrence of new-onset cardiac conditions and hyperlipidemia, with no increase in the incidence of new-onset diabetes or new-onset hyperglycemia. However, after 5 years there was no impact on patient or graft survival.     

Assessment of the frequency and costs of posttransplantation hospitalizations in patients receiving tacrolimus versus cyclosporine

We assessed the frequency and costs of hospitalizations in patients receiving tacrolimus (FK506) compared with patients receiving cyclosporine A for immunosuppression during 1 year after kidney transplantation. Four hundred twelve cadaveric kidney transplant recipients were randomized onto a phase III, prospective, multicenter, clinical trial. Hospital billing data were collected for 1 year posttransplantation. Total inpatient costs were calculated from billed charges and standardized to 1995 US dollars. Medical resource utilization rates and inpatient costs were compared between treatment groups using unpaired Student's t-tests. Complete billing data (transplantation and all posttransplantation hospitalizations) were available for 65% (268 of 412) of the study patients. Among tacrolimus and cyclosporine patients with complete billing data, the rates of allograft rejection were 32% and 47%, respectively (P=0.009), and the rates of rehospitalization during the year after transplantation were 53% and 63%, respectively (P=0.080). The mean per-episode rehospitalization costs were significantly lower among tacrolimus-treated patients compared with cyclosporine-treated patients ($7,495 v $11,497; P=0.031), and the mean total rehospitalization costs were significantly lower in the tacrolimus group compared with the cyclosporine group ($8,550 v $14,869; P=0.029). In addition, the total 1-year hospitalization costs (including transplantation and posttransplantation hospitalizations) were significantly lower in the tacrolimus group compared with the cyclosporine group ($53,435 v $61,191; P=0.046). Compared with cyclosporine-based immunosuppression, tacrolimus-based immunosuppression for kidney transplant recipients was associated with a significantly lower rate of rejection, which was associated with significantly lower per-episode rehospitalization costs, lower total 1-year rehospitalization costs, and lower total 1-year hospitalization costs.     

Serum lipid abnormalities in pediatric liver transplant patients.

Little is known about serum lipid abnormalities in pediatric liver transplant recipients. We performed a longitudinal cohort review of 102 outpatient pediatric liver recipients surviving greater than 6 months and immunosuppressed with cyclosporine and prednisone (+/- azathioprine). The median age was 6 years, median months posttransplant 25, and male-to-female ratio 1:1.5. The average cholesterol (mean of individual means) was 177 +/- 45 mg/dl and average triglyceride level 158 +/- 71 mg/dl. The mean percent of cholesterol levels greater than 170 mg/dl and triglyceride levels greater than 140 mg/dl was 47% and 50%, respectively. Age, obesity, sex, and family history of risk factors had no significant effect on cholesterol or triglyceride levels. Bivariate regression analysis showed no meaningful association between cholesterol or triglyceride levels and cyclosporine levels, cyclosporine dose, prednisone dose, or diastolic blood pressure. Triglyceride and cholesterol neither increased nor decreased with time posttransplant. The rate of change of triglyceride or cholesterol could not be predicted by the rate of change of cyclosporine levels (or dose), or prednisone dose. We found no evidence that rises or falls in cholesterol or triglyceride levels coincided with rises or falls in either cyclosporine level or prednisone dose. Cholestasis was significantly associated with increased cholesterol and triglyceride levels (P = 0.05). A multivariate analysis was unable to predict cholesterol or triglyceride levels from three predictors: cyclosporine level, prednisone dose, and liver function. The mean dietary intake of fat and cholesterol was above RDA and exercise patterns were suboptimal in school-aged children. Conclusions: 50% of children had a mean cholesterol greater than 75th percentile (170 mg/dl); 20% were above the 95th percentile; 56% had a mean triglyceride level greater than 140 mg/dl. By these criteria the majority of pediatric liver transplant patients have lipid abnormalities that may predispose them to atherosclerosis in later life.     

A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years

BACKGROUND: The 1-year results of the Phase III U.S. Multicenter Trial comparing tacrolimus (FK506)- and cyclosporine (CsA)-based immunosuppressive therapy in kidney transplantation revealed a significant reduction in the incidence and severity of acute rejection episodes among patients maintained on tacrolimus. The present report at 5 years of follow-up focuses on the long-term impact of tacrolimus treatment on kidney allograft outcome. METHODS: The study protocol permitted crossover of patients to the alternate treatment arm under stringent conditions. The effect of crossover on graft survival was analyzed. Cardiovascular risk factors and serious adverse events were also monitored over 5 years. RESULTS: Intent-to-treat analysis revealed equivalent patient and graft survival between treatment arms at 5 years of follow-up (79.1% vs. 81.4%; P=0.472 and 64.3% vs. 61.6%; P=0.558 among tacrolimus and CsA-treated patients, respectively). However, the rate of crossover was significantly higher among patients randomized to receive CsA-based therapy (27.5% vs. 9.3%; P<0.001). The incidence of treatment failure (43.8% vs. 56.3%; P=0.008) was significantly lower among tacrolimus-treated patients. Graft survival was significantly improved in the tacrolimus treatment arm when crossover due to rejection was counted as graft failure (63.8% vs. 53.8%; P=0.014). Tacrolimus therapy was also associated with a significantly reduced requirement for medications to control hypertension and hyperlipidemia. There was a substantial rate of reversal of tacrolimus-associated insulin dependence. CONCLUSION: Tacrolimus-based therapy resulted in significantly reduced risk of graft failure, without an increase in the incidence of adverse events associated with long-term immunosuppression.     

Hyponatraemia and hyperkalaemia are more frequent in renal transplant recipients treated with tacrolimus than with cyclosporin. Further evidence for differences between cyclosporin and tacrolimus nephrotoxicities.

BACKGROUND: This study was designed to examine the hypothesis that the nephrotoxicities caused by cyclosporin and tacrolimus might differ in respect of sodium and potassium handling. METHODS: 125 patients were studied retrospectively for the first 90 days after renal transplantation. Eighty were treated initially with cyclosporin and 45 with tacrolimus. RESULTS: A serum sodium level of <135 mmol/l was present for 542/5171 (10.5%) days under tacrolimus treatment compared with 377/5486 (6.9%) days under cyclosporin treatment (P < 0.0001). Severe hyponatraemia, below 120 mmol/l, was also more prevalent under tacrolimus than cyclosporin treatment, P < 0.025. Nine patients, all receiving tacrolimus, were treated with fludrocortisone for fluid depletion and/or hyponatraemia. Serum potassium levels were higher in tacrolimus-treated patients (P < 0.0001), and subjects with hyponatraemia were more likely to experience hyperkalaemia (P < 0.0001). CONCLUSIONS: Hyponatraemia and hyperkalaemia were more frequent in tacrolimus-treated subjects. Taken together with previous work showing that hyperuricaemia is more frequent with cyclosporin treatment, and hypomagnesaemia with tacrolimus treatment, these findings are consistent with qualitative differences between the nephrotoxicities of cyclosporin and tacrolimus.     

Cardiovascular risk factors in 116 patients 5 years or more after liver transplantation

We assessed the cardiovascular risk factors (CVRFs) in 116 stable liver transplant patients surviving for 5 years or more (median: 102 months). The prevalence of smokers was 29.3%, hypertension 49.1%, obesity 22.4%, hypercholesterolemia 34.5%, hypertriglyceridemia 11.2%, and hyperhomocysteinemia 57.8%. Diabetes was found in 21.5% of the patients, being more frequent in patients with hepatitis-C-virus infection (31.8% vs 15.3%; P=0.03). Patients on cyclosporine therapy had a higher prevalence of hypertension, hypercholesterolemia and hyperhomocysteinemia than those treated with tacrolimus. Multivariate analysis showed only an association between cyclosporine therapy and cholesterol concentrations (odds ratio:1.02; 95% confidence interval (CI): 1.00-1.03; P=0.01). The prevalence of hypertension, diabetes, hypercholesterolemia and hypertriglyceridemia was lower at the time of the study than at 1 and 3 years after transplantation ( P<0.05), probably related to steroid withdrawal. Comparing 87 patients' CVRFs with the general Spanish population, we found that the age-gender standardized prevalence ratio was not different: smoking 1.46 (95% CI: 0.88-1.76), obesity 1.16 (95% CI: 0.60-1.44), hypertension 1.55 (95% CI: 0.98-1.81), and hypercholesterolemia 0.64 (95%CI: 0.35-1.90). We conclude that the prevalence of CVRFs in liver transplant patients after 5 years or more is lower that found in the first years after the transplantation, and no different from that found within the Spanish population.