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Journal ArticleDOI

Effect of the immunosuppressive treatment on long-term renal graft survival

01 Jun 2004-Nephrology Dialysis Transplantation (Oxford University Press)-Vol. 19

TL;DR: Triple therapy with Az in 1990 and 1994 and with MMF in 1998 were the most frequently used immunosuppressive regimens in the Spanish kidney transplant population.

AbstractBackground. Although new immunosuppressive agents have improved the results of renal transplants (RTs), long-term graft loss remains high. We evaluated the impact of different immunosuppressive regimens on patient and graft survival. Methods. Data from 3365 patients receiving cadaver RTs in Spain during the years 1990, 1994 and 1998 were retrospectively analysed. All data were entered into a specially designed database. Graft and patient survival rates were estimated by the Cox regression method and results expressed as percentage survival. A maximum-likelihood estimate of the projected graft half-life (median value) was calculated by Weibull regression. Results. In 1990 graft and patient survival differed significantly from the other treatment years (P ¼ 0.0006 and P ¼ 0.0101, respectively). The risk of graft loss was significantly higher for cyclosporine (CsA), prednisone (P) and azathioprine (Az) than for CsA þ P, which in turn was higher than for CsA þ P plus polyclonal antibodies [antilymphocyte globulin (ALG)/antithymocyte globulin (ATG)]. Risk of patient death was also significantly higher for CsA þ P þ Az than for CsA þ P. No significant differences between treatment groups were found in graft and patient survival for 1994 and 1998. The projected median graft life for patients with the most used immunosuppressive regimen for each year was 12.9 years for CsA þ P þ Az and 15.6 years for CsA þ P plus mycophenolate mofetil (MMF). Conclusions. Triple therapy with Az in 1990 and 1994 and with MMF in 1998 were the most frequently used immunosuppressive regimens in the Spanish kidney transplant population. The best results were seen after induction therapy with polyclonal antibodies.

Topics: Population (51%)

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Journal ArticleDOI
TL;DR: Sirolimus may be more cost effective than tacrolimus for the primary prevention of graft rejection in renal transplant recipients in the UK and this finding was robust using statistical economic analysis and univariate sensitivity analysis.
Abstract: Introduction: Immunosuppressive therapy is required to prevent graft rejection. Calcineurin inhibitors such as tacrolimus are paradoxically toxic to the kidney, whereas sirolimus (rapamycin; Rapamune®) is not generally associated with the nephrotoxicity of CNIs. The purpose of this study was to evaluate the relative cost utility of sirolimus versus tacrolimus for the primary prevention of graft rejection in renal transplant recipients in the UK. Methods: A stochastic simulation model was constructed using clinical trial and observational data comparing the two treatments. Time duration was up to 20 years. Costs were from a UK NHS perspective, valued at 2003 prices and discounted at 6%. Benefits were discounted at 1.5%. Simulated events included patient and graft survival, haemodialysis, peritoneal dialysis, re-transplants and acute rejection. Costs were summed for events and various maintenance therapies. Utility was differentially accredited depending upon survival and using the alternative renal replacement therapies. Outcome was predicted using post-transplant creatinine levels up to 3 years. Extensive statistical economic and sensitivity analyses were undertaken. Results: Over the 10-year horizon, sirolimus gained 0.72 years (discounted) of functioning graft over tacrolimus, resulting in an incremental cost per year of functioning graft that was dominant. Over a 20-year time horizon, the cost effectiveness of sirolimus over tacrolimus further improved with an average discounted gain in years of a functioning graft of 1.8 years, resulting in an incremental cost-utility ratio that was also dominant. The number of haemodialysis events was 48 243 for sirolimus recipients versus 127 829 for those receiving tacrolimus and peritoneal dialysis events 40 872 versus 105 249, respectively. Similar values were obtained when real-life observational data on tacrolimus use in Cardiff, Wales were entered into the model. Using data from Cardiff, sirolimus remained dominant over tacrolimus under all scenarios. Conclusion: Our study suggests that sirolimus may be more cost effective than tacrolimus for the primary prevention of graft rejection in renal transplant recipients in the UK. Sirolimus was economically ‘dominant’ under almost all scenarios investigated. This finding was robust using statistical economic analysis and univariate sensitivity analysis.

39 citations


Journal ArticleDOI
TL;DR: In this model analysis, sirolimus was cost-effective compared with cyclosporin for 10 to 20 years after renal transplantation in the United Kingdom, from the perspective of the UK National Health Service and Personal Social Service.
Abstract: Objective: The purpose of this study was to evaluate the cost-effectiveness of sirolimus compared with cyclosporin for the postsurgical management of renal transplant recipients, from the perspective of the UK National Health Service and the Personal Social Service. Methods: A discrete event stochastic simulation model was developed to evaluate both cost-effectiveness and cost utility over 10 and 20 years after transplant using historical data on 937 renal transplant recipients from the University Hospital of Wales in Cardiff, United Kingdom. The simulation was designed to forecast the incidence of acute rejection events, graft failure, retransplant, frequency of hemodialysis (HD) and peritoneal dialysis (PD), and death. Cox proportional hazard models were derived from historical transplant data, in which 1-, 2-, and 3-year post-transplant serum creatinine levels were used as the key drivers for predicting graft success and survival. Costs were reported as year-2003 UK pounds sterling (£1US $1.76). Probabilistic sensitivity analysis was conducted and results reported with particular attention to 2 threshold values, 30,000/QALY and 20,000/QALY Results: Over a 10-year time horizon, treatmentwith sirolimus was projected to produce a gain of 0.60 discounted year of functioning graft with a cost savings of £276 per patient. Over a 20-year time horizon these benefits increased to 1.59 discounted years of functioning graft and a cost savings of 7405 per patient. Using sensitivity analysis of the 10-year model, the only factors found to cause the probability of exceeding a £30,000 ceiling to be >5% were the proportion of subjects maintaining continuous graft function and the use of low-dose cyclosporin. With the 20-year model, sirolimus maintained cost-effectiveness across most scenarios in sensitivity analysis. Conclusions: In this model analysis, sirolimus was cost-effective compared with cyclosporin for 10 to 20 years after renal transplantation in the United Kingdom, from the perspective of the UK National Health Service and Personal Social Service.

30 citations


Journal ArticleDOI
TL;DR: A statistical analogy between the collapse of solids and living organisms is presented and a statistical law governing their probability of death is derived coupling the widely used Weibull Statistics with a general model for ontogenetic growth recently proposed in literature.
Abstract: In this paper we present a statistical analogy between the collapse of solids and living organisms; in particular we deduce a statistical law governing their probability of death. We have derived such a law coupling the widely used Weibull Statistics, developed for describing the distribution of the strength of solids, with a general model for ontogenetic growth recently proposed in literature. The main idea presented in this paper is that cracks can propagate in solids and cause their failure as sick cells in living organisms can cause their death. Making a rough analogy, living organisms are found to behave as "growing" mechanical components under cyclic, i.e., fatigue, loadings and composed by a dynamic evolutionary material that, as an ineluctable fate, deteriorates. The implications on biological scaling laws are discussed. As an example, we apply such a Dynamic Weibull Statistics to large data collections on human deaths due to cancer of various types recorded in Italy: a significant agreement is observed.

7 citations


Posted Content
TL;DR: The main idea presented in this paper is that cracks can propagate in solids and cause their failure as sick cells in living organisms can cause their death.
Abstract: In this paper we derive a statistical law of Life. It governs the probability of death, or complementary of survival, of the living organisms. We have deduced such a law coupling the widely used Weibull statistics, developed for describing the distribution of the strength of solids, with the universal model for ontogenetic growth only recently proposed by West and co-authors. The main idea presented in this paper is that cracks can propagate in solids and cause their failure as sick cells in living organisms can cause their death. Making a rough analogy, living organisms are found to behave as growing mechanical components under cyclic, i.e., fatigue, loadings and composed by a dynamic evolutionary material that, as an ineluctable fate, deteriorates. The implications on biological scaling laws are discussed. As an example of application, we apply such a statistical law to large data collections on human deaths due to cancer of various types recorded in Italy: a relevant agreement is observed.

4 citations


Cites background or methods from "Effect of the immunosuppressive tre..."

  • ...…applied in Biology (Cherkasov et al., 2004; Krishnan et al., 2004; Wu et al., 2004; Ng et al., 2004; Miceli et al., 2004; May et al., 2004; Weston et al., 2004; Molina et al., 2004) we demonstrate in this paper the importance of considering dynamic Weibull parameters, thus a new statistics....

    [...]

  • ...As an example of application, we apply such a statistical law to large data collections on human deaths due to cancer of various types recorded in Italy: a relevant agreement is observed....

    [...]


Journal Article
TL;DR: Providing a non-zero eternal proportion, the modified model would be superior over the unmodified model as a percentage of non-failure cases.
Abstract: Background: We estimated the chronic rejection of kidney transplant using an eternal Weibull regression. Methods: In this historical cohort study, we enrolled all patients with chronic renal failure who were admitted to Shahid Labbafinejad medical center (Tehran, Iran) from 1984 to 2003. Using Matlab 7.0, we considered the eternal proportion θ , as a logistic-type function of the covariates and modified the survival function. We estimated the survival function in unmodified and modified forms using Weibull distribution. Results: The chance of chronic rejection was 1.95 times higher among those who received a kidney transplant before 1996. Considering all cases who received renal transplantation after 1984, males had a chance of rejection 20% less than females. Next to the eternity, Weibull model was fitted to patients who received renal transplantation after 1996. Treatment protocol was changed after 1996 expecting fewer chronic rejections; thereafter, the eternal proportion was estimated to be 0.81. This seems quite considerable as a percentage of non-failure cases. Conclusion: Providing a non-zero eternal proportion, the modified model would be superior over the unmodified model.

2 citations


References
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Journal Article
TL;DR: MMF significantly reduced the rate of biopsy-proven rejection or other treatment failure during the first 6 months after transplantation and was well tolerated, although the 3 g dose was somewhat less well tolerated.
Abstract: Preliminary studies suggested that mycophenolate mofetil (MMF), which inhibits proliferation of T and B cells, may reduce the frequency of acute rejection after renal transplantation. Our randomised, double-blind, multicentre, placebo-controlled study compared the efficacy and safety of MMF with placebo for prevention of acute rejection episodes after first or second cadaveric renal allograft transplantation. 491 patients were enrolled; 166 were assigned placebo, 165 MMF 2 g, and 160 MMF 3 g. Patients also received cyclosporin and corticosteroids. Significantly fewer (p less than or equal to 0.001) patients had biopsy-proven rejection or withdrew early from the trial (for any reason) during the first 6 months after transplantation with MMF 2 g (30.3%) or 3 g (38.8%) than with placebo (56.0%). The corresponding percentages for biopsy-proven rejection were 17.0%, 13.8%, and 46.4%. 28.5% of MMF 2 g and 24.4% of MMF 3 g patients needed full courses of corticosteroids or antilymphocyte agents for treatment of rejection episodes in the first 6 months, compared with 51.8% of placebo recipients. By 6 months, 10.2%, 6.7%, and 8.8% of the patients in the placebo, MMF 2 g, and MMF 3 g groups, respectively, had died or lost the graft. Overall, the frequency of adverse events was similar in all treatment groups, although gastrointestinal problems, leucopenia, and opportunistic infections were more common in the MMF groups and there was a trend for more events in the 3 g than the 2 g group. MMF significantly reduced the rate of biopsy-proven rejection or other treatment failure during the first 6 months after transplantation and was well tolerated, The 3 g dose was somewhat less well tolerated.

1,012 citations


Journal ArticleDOI
TL;DR: Current antirejection therapy, including calcineurin blockers such as cyclosporine and tacrolimus, the interleukin-2 signal-transduction inhibitor sirolimus and the purine-synthesis inhibitor mycophenolate mofetil are discussed, which inhibits the proliferation of T cells and B cells.
Abstract: This article provides a comprehensive, up-to-date review of methods to prevent early and late renal-allograft loss and to improve long-term outcomes in patients. The authors focus particular attention on the problem of late graft loss and discuss current antirejection therapy, including calcineurin blockers such as cyclosporine and tacrolimus, the interleukin-2 signal-transduction inhibitor sirolimus, and the purine-synthesis inhibitor mycophenolate mofetil, which inhibits the proliferation of T cells and B cells.

808 citations


Journal ArticleDOI
TL;DR: Mycophenolate Mofetil therapy decreased the relative risk for development of chronic allograft failure (CAF) by 27% and was independent of its outcome on acute rejection.
Abstract: Background. Mycophenolate Mofetil (MMF) has been shown to significantly decrease the number of acute rejection episodes in renal transplant recipients during the 1st year. A beneficial effect of MMF on long-term graft survival has been more difficult to demonstrate. This beneficial effect has not been detected, despite the impact of acute rejection on the development of chronic allograft nephropathy and experimental evidence that MMF may have a salutary effect on chronic allograft nephropathy independent of that of rejection. Methods. Data on 66,774 renal transplant recipients from the U.S. renal transplant scientific registry were analyzed. Patients who received a solitary renal transplant between October 1, 1988 and June 30, 1997 were studied. The Cox proportional hazard regression was used to estimate relevant risk factors. Kaplan-Meier analysis was performed for censored graft survival. Results. MMF decreased the relative risk for development of chronic allograft failure (CAF) by 27% (risk ratio [RR] 0.73, P<0.001). This effect was independent of its outcome on acute rejection. Censored graft survival using MMF versus azathioprine was significantly improved by Kaplan-Meier analysis at 4 years (85.6% v. 81.9%). The effect of an acute rejection episode on the risk of developing CAF seems to be increasing over time (RR51.9, 1988 ‐91; RR52.9, 1992‐94; RR53.7, 1995‐ 97). Conclusion. MMF therapy decreases the risk of developing CAF. This improvement is only partly caused by the decrease in the incidence of acute rejection observed with MMF; but, is also caused by an effect independent of acute rejection.

394 citations


Journal ArticleDOI
TL;DR: Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.
Abstract: Background Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients. Methods We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL. Results Mean follow-up is 18.1 months (range, 12-26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 and P=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25 T cells compared with cyclosporine. Conclusions Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.

369 citations


Journal ArticleDOI
TL;DR: Short‐term outcomes have improved, based on the observation that rates of rejection within the first year post‐transplant have diminished, and use of antibody treatment for rejection during the first post-transplant year for most organs declined.
Abstract: Over the past decade, immunosuppression therapy has undergone striking changes in the scale and pace by which new immunosuppressive molecules and antibodies have become incorporated into daily transplant medicine. An organ-by-organ review of data reveals several trends. The highest use of induction therapy (over 70% of patients) was reported for simultaneous pancreas kidney (SPK) and pancreas after kidney (PAK) transplants in 2002; use of induction therapy was less common in liver transplants (only 18%). Corticosteroids served as discharge maintenance immunosuppression in over 87% of the recipients of kidney, SPK, PAK and thoracic transplants, and in over 70% of pancreas transplant alone (PTA) recipients. Corticosteroid use in intestine transplants was reported in 64% of recipients in 2002. A shift in the calcineurin inhibitor used for maintenance immunosuppression from cyclosporine to tacrolimus for the majority of patients had occurred for kidney, PAK, SPK, PTA, liver, lung, and heart-lung by 2001. For heart transplants, cyclosporine remained the calcineurin inhibitor of choice; tacrolimus remained the predominant calcineurin inhibitor agent for intestine (since 1994). Use of antibody treatment for rejection during the first post-transplant year for most organs declined. Short-term outcomes have improved, based on the observation that rates of rejection within the first year post-transplant have diminished.

218 citations