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Purpose: Induction immunosuppression therapy is used to support optimal outcomes in kidney transplantation. This study was to assess the cost-effectiveness of rabbit antithymocyte globulin (r-ATG) versus ATG-Fresenius (ATG-F) in kidney transplantation in the Chinese setting from the perspective of the health care payer., Methods: A 2-part survival model was developed, consisting of a short-term part and a long-term part. The short-term part analyzed the first year, using the decision tree, and consisted of the functioning transplant, acute rejection (AR), delayed graft function (DGF), dialysis, and death health states. The long-term part analyzed 2 to 5 years, using Markov model, and consisted of the functioning transplant, chronic dysfunction, recurring primary disease, dialysis, and death health states, with capture of the association between DGF and graft loss. Costs, including drug acquisition and other direct medical costs, were derived from China IQVIA database (formerly known as IMS) hospitaldatabase, chart review, and physician interviews. Clinical outcomes and utility were retrieved from published literature. The model calculated quality-adjusted life-years (QALYs) and total costs per patient. Costs and QALYs were discounted at an annual rate of 3.5%. Univariate sensitivity analysis and probability sensitivity analysis (PSA) were conducted to assess the impact of uncertainty of the variables on the results., Findings: Patients who received r-ATG had more clinical effectiveness than patients who received ATG-F mainly because of less AR, DGF, and dialysis. The incremental QALY was 0.01 over a 1-year time horizon and 0.0496 over a 5-year time horizon. R-ATG and ATG-F drug costs were ¥10,783 and ¥8409, respectively. However, the total treatment costs of the r-ATG arm were lower than the ATG-F arm because of lower costs related to DGF, AR, dialysis, and adverse events. In total, r-ATG saved ¥5423 over the 1-year and ¥7042 over the 5-year time horizon. R-ATG was dominant with lower total direct medical costs and higher QALYs compared with ATG-F. Both univariate sensitivity analysis and PSA found the robustness of the model results. PSA results indicated that r-ATG was cost-effective compared with ATG-F in 86.81% of the simulations, considering <3 times the gross domestic product per capita as the threshold., Implications: From the perspective of the health care payer, r-ATG should be considered as the preferred treatment agent for induction therapy for Chinese patients undergoing kidney transplantation because of its lower overall medical costs and greater QALYs gained compared with ATG-F. The study was limited by lack of long-term efficacy data among the Chinese population and lack of comprehensive real-world higher quality costs data., (Copyright © 2018. Published by Elsevier Inc.)

Background: Immunosuppression is required in kidney transplantation to prevent rejection and prolong graft survival. We conducted an economic evaluation to support England's National Institute for Health and Care Excellence in developing updated guidance on the use of immunosuppression, incorporating new immunosuppressive agents, and addressing changes in pricing and the evidence base., Methods: A discrete-time state transition model was developed to simulate adult kidney transplant patients over their lifetime. A total of 16 different regimens were modelled to assess the cost-effectiveness of basiliximab and rabbit anti-thymocyte globulin (rabbit ATG) as induction agents (with no antibody induction as a comparator) and immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept as maintenance agents (with ciclosporin and azathioprine as comparators). Graft survival was extrapolated from acute rejection rates, graft function and post-transplant diabetes rates, all estimated at 12 months post-transplantation. National Health Service (NHS) and personal social services costs were included. Cost-effectiveness thresholds of £20 000 and £30 000 per quality-adjusted life year were used., Results: Basiliximab was predicted to be more effective and less costly than rabbit ATG and induction without antibodies. Immediate-release tacrolimus and mycophenolate mofetil were cost-effective as maintenance therapies. Other therapies were either more expensive and less effective or would only be cost-effective if a threshold in excess of £100 000 per quality-adjusted life year were used., Conclusions: A regimen comprising induction with basiliximab, followed by maintenance therapy with immediate-release tacrolimus and mycophenolate mofetil, is likely to be effective for uncomplicated adult kidney transplant patients and a cost-effective use of NHS resources., (© Crown copyright 2017.)

Renal transplantation is the best therapeutic option for end-stage chronic renal disease. Assuming that it is more advisable if performed early, we aimed to show the clinical, social, and economic advantages in 70% of our patients who were dialyzed only for a short period. For this purpose, we retrospectively collected data over 28 years in 142 kidney transplants performed in patients with <6 weeks on dialysis. 66% of our patients were 30-60 years old; 98% of the patients had living donors. At transplantation, 64% of our patients had no public support; however, 64% of them returned to work and got health insurance 2 months later. Full rehabilitation was achieved in all cases, including integration to the family, return to full-time work, school and university, sports, and reproduction. Immunosuppression consisted of 3 drugs, including steroids, cyclosporine, and azathioprine or mycophenolate. The cost in the 1st year, including patient and donor evaluation, surgery, immunosuppression, and follow-up, was $13,300 USD versus $22,320 for hemodialysis. We conclude that preemptive renal transplantation with <6 weeks on dialysis is the best therapeutic option for end-stage renal failure, especially in developing countries such as Bolivia, where until last year, full public support for renal replacement therapy was unavailable., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The hypothesis tested in this experiment was that Trichostrongylus colubriformis infection would reduce growth rates of grazing meat-breed lambs; however production loss would be reduced by suppression of the host immune response. The experiment had a 3×2 factorial design using 6-7 month old meat-breed lambs which remained uninfected or infected (IFY) with 2000 or 4000 T. colubriformis L3/week for 12 weeks and were immunosuppressed (SUPY) using methylprednisolone acetate once weekly or remained non-immunosuppressed (SUPN). Immunosuppression increased worm egg counts (WEC) of infected lambs (SUPY 2421 eggs per gram (epg), SUPN 1154 epg on day 84, p<0.05) and T. colubriformis burdens (p<0.05-0.10) and reduced circulating eosinophils (p<0.05 on days 11, 42, 56 and 84) and intestinal total antibody titres (p<0.02). There was a significant (p<0.05) interaction between the main effects of infection and immunosuppression with infection having a larger negative effect on the liveweight of non-immunosuppressed lambs. The immunological response of the host to T. colubriformis infection accounted for 75% of the overall cost of infection (3.1kg) with the majority of this cost occurring during the first 35 days of infection. In contrast, most of the cost associated with the direct effect of infection occurred after day 35. These results confirm in grazing meat-breed lambs that the host's immunological response to T. colubriformis infection is the major component of production loss., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Generic immunosuppressive drugs are available in Europe, Canada, and the United States. Between countries, there are large differences in the market penetration of generic drugs in general, and for immunosuppressive drugs in particular. The registration criteria for generic immunosuppressive drugs are often criticized. However, it is unlikely that the criteria for registration of narrow therapeutic index drugs are going to change, and bioequivalence studies, performed in healthy volunteers, will remain the backbone of the registration process. It would be good if the registration authorities would demand that all generic variants of an innovator drug have the same pill appearance to reduce errors and promote drug adherence.To allow for safe substitution, a number of criteria need to be fulfilled. Generic substitution should not be taken out of the hands of the treating physicians. Generic substitution can only be done safely if initiated by the prescriber, and in well-informed and prepared patients. Payers should refrain from forcing pharmacists to dispense generic drugs in patients on maintenance treatment with innovator drug. Instead, together with transplant societies, they should design guidelines on how to implement generic immunosuppressive drugs into clinical practice. Substitutions must be followed by control visits to check if the patient is taking the medication correctly and if drug exposure remains stable. Inadvertent, uncontrolled substitutions from 1 generic to another, initiated outside the scope of the prescriber, must be avoided as they are unsafe. Repetitive subsequent generic substitutions result in minimal additional cost savings and have an inherent risk of medication errors.

Beta-cell replacement is the only physiologically relevant alternative to insulin injections in patients with type 1 diabetes (T1D). Pancreas and islet transplantation from deceased organ donors can provide a new beta-cell pool to produce insulin, help blood glucose management, and delay secondary diabetes complications. For children and adolescents with T1D, whole pancreas transplantation is not a viable option because of surgical complications, whereas islet transplantation, even if it is procedurally simpler, must still overcome the burden of immunosuppression to become a routine therapy for children in the future., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Induction therapy in renal transplantation reduces the incidence of acute rejection (AR) in expanded criteria donation (ECD) and donation after cardiac death (DCD). We compared the efficacy of Thymoglobulin (Sanofi-Aventis, Spain), ATG Fresenius (ATG-Fresenius, Spain), and Simulect (Novartis Farm, Spain) in a calcineurin-free protocol in ECD and DCD renal transplantation by evaluating patient survival, graft survival, and AR at 1 year and overall costs., Methods: An observational retrospective study was performed using our database of 289 consecutive cadaveric ECD renal transplant recipients (n = 178) and DCD recipients (n = 111) from April 1999 to December 2011. Induction therapy consisted of Simulect, Thymoglobulin, and ATG Fresenius. Calcineurin-inhibitor (CNI)-free maintenance therapy consisted of mycophenolate mofetil or sodium and steroids., Results: There were no differences in the patients' demographic characteristics or patient and graft survival. One-year AR rates were equivalent (ECD: 10%, 19.1%, 17.7% versus DCD: 14.3%, 7.1%, 16.7%). Leukopenia and thrombopenia were significantly more frequent in the ECD group treated with polyclonal induction. The average total cost of transplantation was higher in the ECD group but there were no significant differences in the average total cost between ECD and DCD: 39,970.31 ± 7,732€ versus 35,058.34 ± 6,801€ (P = NS)., Conclusion: Our study shows the same efficacy with polyclonal and monoclonal antibody induction and a CNI-free treatment regimen in ECD and DCD renal transplantation with no differences in overall costs at 1 year after transplantation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Immunosuppression (IS) in islet transplantation (Tx) is a double-edged sword: it prevents immunoreaction but has the potential to impair islet engraftment. The aim of this study was to identify in murine animal models the IS platform with the best balance between these two opposite effects., Methods: To study the impact of IS on islet engraftment diabetic C57BL/6 mice were transplanted with 350 syngeneic islets through the portal vein and treated once-daily with either rapamycin (RAPA; 0.1-0.5-1 mg/kg ip), tacrolimus (FK506; 0.1-0.5-1 mg/kg ip), mycophenolate mofetil (MMF; 60-120-300 mg/kg oral) or vehicle for 14 days. Islet function was evaluated by measuring not-fasting glycemia and by performing an IVGTT on days 15 and 30 post-Tx., Results: RAPA ≥0.5 mg/Kg, FK506 ≥0.5 mg/Kg, and MMF ≥120 mg/kg had detrimental effects on islet engraftment but not on the function of islets already engrafted in the liver. The effect on engraftment was irreversible and persisted even after IS withdrawal. The lower dose of IS that did not affect engraftment was tested for preventing rejection in the full mismatch allogeneic Tx BALB/c to C57BL/6 model. RAPA and/or FK506 were inefficient in preventing rejection, even when anti-IL2R mAb was added to the IS regimen. On the other hand, MMF alone or in association with FK506 significantly prolonged the time to islet rejection., Conclusion: IS showed profound dose-dependent deleterious effects on islet cell engraftment. The MMF/FK506 combination proved the best balance with less toxicity at the time of engraftment and more efficacy in controlling graft rejection.

Acquired severe aplastic anaemia (AA) is a serious condition caused by immune-triggered bone marrow failure. For patients not eligible for bone marrow transplantation, treatment of choice is immunosuppression by a combined treatment with antithymocyte globulin (ATG) and cyclosporine. The debate on treatment optimization in AA is focused on conflicting data regarding ATG preparations from horse (h-ATG) versus rabbit (r-ATG), recently favouring h-ATG. H-ATG has been withdrawn from the European market in 2007. Reimbursement for imported preparations from outside Europe is frequently denied in negotiations with statutory health insurance companies. This raises the question of whether h-ATG is cost effective and a sensible investment with regard to healthcare budgets as well as patient health. We modelled the cost effectiveness of r-ATG versus h-ATG based on a recent randomized trial and cost data provided by the hospital pharmacy of Jena University Hospital. We calculated the amount of life years gained and the average incremental costs per life year gained when comparing h-ATG and r-ATG. Our calculations revealed average incremental costs per life year gained of 11,033.80 for the examined patient population treated with h-ATG when compared to r-ATG. Assuming a cost effectiveness threshold of 25,000-35,000 per life year gained, our calculations demonstrate cost effectiveness of h-ATG as compared to r-ATG.

Kidney transplantation has become an effective treatment for end-stage renal failure. This study analyzed trends in immunosuppressive agent use after renal transplantation at a medical center in southern Taiwan over a 9-year period (2000-2008) seeking to determine whether the trends were consistent with clinical trial outcomes and published guidelines. We identified adult outpatients who had diagnoses of renal transplantation and who had concurrent immunosuppressive drug claims. From 2000-2008, we discovered 39,189 prescriptions related to kidney transplantation. The overall medication consumption showed an increase from 4.9% to 31.9%. Cyclosporine was the main determinant of overall drug costs during these 9 years. The long-term prescribing trend for immunosuppressive use among renal transplantation outpatients showed a clear change during the course of the study. Tacrolimus and sodium mycophenolate/mycophenolate mofetil were used increasingly as combination therapy. However, our survey revealed that management of this transplantation population, especially regarding the use of either calcineurin inhibitor or corticosteroids, was based on potential long-term side effects., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Between August 2006 and August 2009, 34 ethnic Mongolians were the recipients of a kidney transplant at the Central Clinical Hospital in Ulaanbaatar, Mongolia. In 31 of the operations the donor was either a sibling or parent. In 4 recipients the donors were 2 recently deceased accident victims following controlled cardiac arrest and after next of kin permission. All 4 recipients are alive with life-supporting function. Appropriate legislation was passed in 2008. Thirty-one of the 34 recipients (91%) are alive. The 1-year patient and graft survival is 91% and 82%, respectively. In all cases, recipients received 1 dose of Campath 1 preoperatively followed by monotherapy with either Cyclosporin or Tacrolimus. Due to the remote geographical location of some of the recipients, appropriate serum drug levels were difficult to monitor. Azathioprine was therefore added in the last 13 recipients. Except for acute rejection episodes, no patients received steroid therapy. There were 7 diagnosed and treated acute rejections in the 34 recipients (21%). The mean annual cost of the immunosuppressive therapy period compared favorably with neighboring China and with costs in Spain. We conclude that the use of Campath 1 together with a non-steroid maintenance immunosuppressive regimen provides both economical and acceptable graft and patient survival in a developing country.,

Background: Cost of post liver transplant immunosuppression is a major financial burden to patients in developing countries. In India, generic varieties of various immunosuppressants are often used without any definite evidence to their efficacy. This study was aimed at studying the dosage, side effect profile and cost of post-liver transplant immunosuppression using generic products in Indian population following living donor liver transplantation (LDLT)., Methods: Data on dose, cost, and toxicity of immunosuppression were retrieved retrospectively from case records of 59 patients who had undergone LDLT at our center., Results: Adequate immunosuppression was obtained by tacrolimus (Pangraf(®)-Panacea) of 0.04 to 0.05 mg/Kg, and mycophenolate (Mycept(®)-Panacea) of 500 to 1,000 mg; the acute rejection rate was 15% during the first month. Serum tacrolimus levels were 5.4 to 7.3 ng/mL. The cost of immunosuppression varied from Rs. 28,705 in the first month to Rs. 8,820 per month at the end of first year, amounting to an average monthly cost of Rs. 17,250. Approximately 23% and 51% of cost was for mycophenolate and for drug level measurement of tacrolimus, respectively., Conclusion: Average cost of immunosuppression after LDLT in India is much lower than that reported elsewhere in the world, since lower drug doses are needed and cheaper generic drugs are available. This can be reduced further by decreasing the frequency of tacrolimus drug level measurement.

Background: The first generic tacrolimus product gained Food and Drug Administration approval in August 2009. This prospective, observational trial sought to determine the need for dose titrations and measure drug cost savings on conversion to generic tacrolimus., Methods: Transplant recipients on stable tacrolimus doses were converted from brand to generic tacrolimus on a mg:mg basis. Data were collected at the time of generic conversion (study arm) and at a time point exactly 6 months before conversion (control arm) for all subjects., Results: Seventy conversions from four centers are reported. Subjects were a mean of 70 months after kidney (n=37), liver (n=28), or multiorgan (n=5) transplant. In the study arm, mean tacrolimus doses were 4.4 and 4.5 mg/d and mean tacrolimus trough concentrations were 5.8 and 5.9 ng/mL before and after conversion, respectively. In the control arm, mean tacrolimus doses were 4.6 and 4.6 mg/d and mean tacrolimus trough concentrations were 6.1 and 5.9 ng/mL before and after the control time point, respectively. Dose titrations occurred in five patients (7%) in the control arm and 15 patients (21%) in the study arm (P=0.028). Mean monthly drug costs were $645 for brand, $593 for generic, and $595 for generic after dose titrations. Mean monthly patient copays were $38 for brand and $15 for generic., Conclusions: These cumulative data show that dose requirements and trough levels are similar between brand and generic tacrolimus and that generic substitution allows for savings. However, postconversion monitoring is prudent as patients may require dose titration.

Objectives: Steroids have had the main role in renal transplant for more than 4 decades. However, chronic use of steroids is associated with many comorbidities, owing to a lack of assessing cost-benefit of steroid avoidance in live-donor renal allotransplants. In this prospective, randomized, controlled study, we aimed to assess the cost-benefit of a steroid-free immunosuppression regimen among Egyptian live-donor renal transplants., Materials and Methods: One hundred patients were randomly allocated to receive tacrolimus, mycophenolate mofetil, and steroids for only 3 days (n=50 patients; study group) or tacrolimus, mycophenolate mofetil, and steroids on a maintenance basis (n=50 patients; control group). All patients received basiliximab (Simulect) induction, with median follow-up of 12 months., Results: Both groups showed comparable graft and patient survivals, rejection episodes, and graft functioning. Posttransplant comorbidities were significantly more prevalent in the steroid-maintenance group. Hypertension was detected in 4% of steroid-free group versus 24% in the steroid-maintenance group (P = .0009). Posttransplant diabetes mellitus, serious infections, and hyperlipidemia were significantly more prevalent in the steroid-maintenance group (P < .05). Associated hospitalization costs were 2.2-fold higher in the steroid-maintenance group than they were in the steroid-free group. One year after transplant, the cost of managing posttransplant comorbidities was significantly higher in steroid-maintenance group, despite comparable costs of immunosuppression., Conclusions: In low, immunologic risk recipients of live-donor renal transplants, using basiliximab induction and maintenance with tacrolimus, mycophenolate mofetil, steroid avoidance was associated with lower first annual total costs despite comparable immunosuppression costs, which was attributed to lower costs of associated morbidities.

Aims: To describe the dynamic of a model of public government partnership for dialysis and transplantation in developing countries., Materials: A model was established on the philosophy of public-government partnership to provide an integrated dialysis and transplant service "Free with dignity" with lifelong follow-up care and medications. The government provided 50% of funds and the public was motivated to donate the rest. This included affluent individuals, corporations, business houses and the general public., Results: This model has been sustained for the last two decades. In 2008, 655,000 patients were treated at SIUT. Over 600 patients are dialyzed each day with a total of 165,411 dialysis sessions/year. Thus far 2,249 transplants have been performed, 431 in 2008. One- and 5-year graft survival rates were 92% and 85%, respectively. The laboratory performed 4.1 million tests and radiological investigations numbered 164,217. Over $ 6 million were spent on medications. Free services offered by the model have motivated the government to increase its funding from $ 2.1 million in 1998 to $ 10 million in 2008 and the public has matched these figures with total donations exceeding $ 20 million., Conclusions: For transplantation to be successful in developing countries, it has to be made available to the common people who constitute 90% of the population. Our model of public-government partnership has made dialysis and transplantation available to the disenfranchised with lifelong follow-up and medications. Transplantation has become relevant to them, resulting in societal acceptance of transplantation as a preferred mode of therapy. This has motivated society to support both living related and deceased donor programs.

Of the numerous risks associated with immunotherapy for the prevention of rejection, cost is perhaps the most universal. In the USA and some other countries, the costs of immunosuppression make transplantation unavailable for some medically viable transplant candidates, and for others who receive a transplant, the long-term costs are economically crippling. Minimization and tapering of immunosuppression, use of generics, manipulation of metabolism, infection surveillance instead of prophylaxis, and advantageous routes of administration are some strategies that can be employed to reduce immunotherapy expense. Using these strategies, we describe an immunosuppression regimen for kidney transplantation that might be only a third of the cost of current 'standard' regimens in the USA. Such a regimen might allow some patients who might not otherwise qualify economically to safely receive a kidney transplant. The purpose of creating an alternative, lower-cost immunotherapy regimen is to give patients a choice. Responsible stewardship of scarce donor organs is the primary, and clearly appropriate, limiting factor.

Background: In the prospective, randomized, multicenter APOMYGRE trial conducted in France, concentration-controlled mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) exposure significantly reduced the treatment failure and acute rejection during the first posttransplantation year compared with fixed-dose MMF. This analysis investigated the cost effectiveness of dose individualization., Method: The study included 65 patients per group (intent-to-treat population). Treatment failure (primary efficacy endpoint) was defined as death, graft loss, acute rejection, or MMF discontinuation because of adverse effects. Data on hospitalizations, drugs prescribed, physicians' fees, laboratory expenses, ambulatory visits, and transportation were retrieved. Costs were calculated from the French National Health System perspective., Results: The mean (95% confidence interval) total yearly cost per patient was Euro 47,477 (Euro 43,933; Euro 51,020) in the concentration-controlled group and Euro 46,783 ( Euro 44,152; Euro 49,414) in the fixed-dose group (P=0.7). The observed incremental cost-effectiveness ratio was Euro 3757 per treatment failure (Purchasing Power Parities United States/France: $4129). Hospitalization and drug costs accounted for approximately 50% and 25% of total costs, respectively. The cost for MPA area under the concentration-time curve and dose calculation was Euro 452 per patient, less than 1% of the total cost., Conclusion: In the APOMYGRE trial, therapeutic MPA monitoring using a limited sampling strategy reduced the risk of treatment failure and acute rejection in renal allograft recipients during the first 12 months posttransplantation, at neutral cost.

Gender issues in clinical transplantation affect outcomes at many levels beyond immunologic concerns; for example, immunosuppressive drugs may influence hormone levels. Most immunosuppressive agents are categorized as "C" by the U.S. Food and Drug Administration, meaning that risks can not be excluded. To optimize renal allograft survival is crucially important in Taiwan because of the limited resources to treat irreversible renal failure. This survey sought to investigate which gender undergoing renal transplantation required greater health care expenditures, using the records of a medical center in Southern Taiwan. We analyzed not only the number of female and male recipients, but also the health care costs. All of the recipients were categorized into 4 groups based on gender and age (40 years). The prescribing patterns in this study were separated into 2 groups by gender to examine differences. From 2000 to 2008, a total of 145 outpatient visits and 8,446 prescriptions met the criteria of renal transplant cases. We also computed the gender proportion of our patients. In conclusion, gender did not influence graft recipient expenditures in our hospital., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objective: Steroids have played a major role in renal transplantation for more than four decades. However, chronic use of steroids is associated with a lot of comorbidities. This study aimed to assess the cost-benefit of steroid-free immunosuppression regimen in a prospective randomized controlled study of live donor renal transplantation, which was lacking in the literature., Material and Methods: One-hundred patients were randomized to receive tacrolimus (Tac), mycophenolate mofetil (MMF), basiliximab (Simulect) induction and steroids only for 3 days (50 patients, study group) or Tac, MMF, Simulect induction and steroid maintenance (50 patients, control group). Median follow-up was 12 months., Results: Both groups showed comparable graft and patient survival, rejection episodes and graft function. Post-transplant hypertension was detected in 4% of the steroid-free group and 24% of the steroid maintenance group (p = 0.0009), while post-transplant diabetes mellitus was detected in 4% and 16% of these two groups, respectively (p = 0.037). By the end of the first year, the cost of managing post-transplant morbidities was significantly higher in the steroid maintenance group, despite the comparable cost of immunosuppression., Conclusions: Among low immunological risk recipients of live donor renal transplants, steroid avoidance was feasible, safe and with less morbidity, using Simulect induction, and tacrolimus and MMF as maintenance immunosuppression. Steroid avoidance was associated with a lower total cost despite comparable immunosuppression cost, which was attributed to the lower cost of associated morbidities.

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression, graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially on the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research.

Background: Induction immunosuppression is perceived as an expensive therapy, so is often given only to select patients. This study evaluated the cost-effectiveness of antibody induction comparing interleukin-2 receptor antagonists (IL2Ra) to standard therapy with no induction or induction with polyclonal antibodies., Methods: A Markov model was developed to estimate costs and health outcomes [survival (life years saved, LYS) and quality-adjusted survival (QALYs)] for the alternative strategies. Outcome data were obtained from a meta-analysis of randomized trials and large-scale renal registries., Results: IL2Ra offers improved survival of 0.21 LYS (2.5 months) and 1.42 QALYs compared with no induction, with a cost saving over 20 years of $79,302 per patient treated regardless of risk profile. The incremental benefits of IL2Ra compared with polyclonal antibody induction therapy were 0.35 LYS (4.3 months) and 0.20 QALYs, with an incremental cost of $5144 per patient. The incremental cost-effectiveness ratio (ICER) of IL2Ra compared to polyclonal induction was $14,803 per LYS and $25,928 per QALY. Sensitivity analyses showed that IL2Ra remained more effective and less expensive than no induction. When IL2Ra was compared to polyclonal induction, the model was sensitive to changes in the cost of induction and the probability of malignancy. Over the range of all other variables tested, IL2Ra was cost-effective compared to polyclonal induction., Conclusions: Adopting IL2Ra as induction immunosuppression for kidney transplant recipients improves survival and QALYs and is less costly than no induction. It also represents good value for money compared to polyclonal induction.

On January 1, 2000, Medicare extended the coverage of immunosuppression medications from 3 years to life for elderly and disabled kidney transplant recipients. This research estimates the impact of extending this lifetime coverage to all kidney transplant recipients on Medicare's cash flows. The study finds that extending coverage to all kidney transplant recipients would have increased Medicare's net cash outflows if the coverage were extended for patients of all income levels. There is evidence that extending coverage to only patients in the lowest income quartile could have resulted in a net cost savings to Medicare.

After renal transplantation, immunosuppressive regimens associated with high short-term survival rates are not necessarily associated with high long-term survival rates, suggesting that regimens may need to be optimized over time. Calcineurin inhibitor (CNI) withdrawal from a sirolimus-based immunosuppressive regimen may maximize the likelihood of long-term graft and patient survival by minimizing CNI-associated nephrotoxicity. In this study, a lifetime Markov model was created to compare the cost-effectiveness of a sirolimus-based CNI withdrawal regimen (sirolimus plus steroids) with other common CNI-containing regimens in adult de novo renal transplantation patients. Long-term graft survival was estimated by renal function and data from published studies and the US transplant registry, including short- and long-term outcomes, utility weights, and health-state costs were incorporated. Drug costs were based on average daily consumption and wholesale acquisition costs. The model suggests that treatment with sirolimus plus steroids is more efficacious and less costly than regimens consisting of a CNI, mycophenolate mofetil, and steroids; therefore, CNI withdrawal not only shows potential for long-term clinical benefits but also is expected to be cost-saving over a patient's life compared with the most commonly prescribed CNI-containing regimens.

In a 20-year period in a single institution, 34 patients with chronic, refractory autoimmune thrombocytopenic purpura were prospectively treated with ex vivo anti-D opsonized autologous red blood cells. All patients had received previous treatment with steroids and/or immunosuppressive agents, and 11 had been splenectomized. Twenty one patients had an increase in the platelet count; in five cases, the increase was more than 50 x 10(9)/L platelets and in 16 the increase was more than 100 x 10(9)/L platelets. Early responses were observed in 20 patients and late responses in seven, whereas seven patients (20%) did not respond at all. Nine of the 20 individuals who achieved an ER had a subsequent drop in the platelet count; however, only three had a drop below 50 x 10(9)/L. When last censored, of the 34 patients, 24 (70%) had a platelet count above 50 x 10(9)/L. The 84-month thrombocytopenia-free (over 50 x 10(9)/L platelets) status of the whole group is 70%, whereas the 84-month complete remission (over 100 x 10(9)/L platelets) status of the whole group is 50%. It is concluded that the use of ex vivo anti-D opsonized red blood cells may represent another, substantially cheaper treatment of patients with chronic, refractory, autoimmune thrombocytopenic purpura.

Objectives: To review the clinical and cost-effectiveness of basiliximab, daclizumab, tacrolimus, mycophenolate mofetil (MMF), mycophenolate sodium (MPS) and sirolimus as possible immunosuppressive therapies for renal transplantation in children., Data Sources: Electronic databases were searched up to November 2004., Review Methods: Data from selected studies were extracted and quality assessed. An economic model [Birmingham Sensitivity Analysis paediatrics (BSAp)] was produced based on an adaptation of a model previously developed for the assessment of the cost-effectiveness of immunosuppressants in adults following renal transplant., Results: For the addition of basiliximab, one unpublished paediatric randomised control trial (RCT), reported that the addition of basiliximab to tacrolimus-based triple therapy (BTAS) failed to significantly improve 6-month biopsy-proven acute rejection (BPAR), graft function, graft loss and all-cause mortality. No significant difference between groups was seen in 6-month or 1-year or longer graft loss, all-cause mortality and side-effects. In a meta-analysis of adult RCTs, the addition of basiliximab to a ciclosporin, azathioprine and steroid regimen (CAS) significantly reduced short-term BPAR. There was no significant difference in short- or long-term graft loss, all-cause mortality or side-effects. One adult RCT was included for the addition of daclizumab to CAS, which reported reduced 1-year BPAR, although no difference between groups was seen in either 1- or 3-year graft loss, all-cause mortality and side-effects. For tacrolimus versus ciclosporin, one unpublished paediatric RCT found that a regimen of tacrolimus, azathioprine and a steroid (TAS) reduced 6-month BPAR and improved graft function [glomerular filtration rate (GFR)] compared with CAS. This improvement in BPAR with tacrolimus was as shown in the meta-analysis of adult RCTs. There was evidence, particularly in children, that in comparison with ciclosporin, tacrolimus may reduce long-term graft loss, although there is no benefit on total mortality. The total level of withdrawal in children was reduced in children receiving tacrolimus. Adult RCTs showed an increase in post-transplant diabetes mellitus with tacrolimus. For MMF versus azathioprine, a meta-analysis of adult RCTs showed MMF [regimen of ciclosporin, MMF and a steroid (CMS)] to reduce 1-year BPAR compared with azathioprine (CAS). There was evidence, particularly in children, that in comparison with azathioprine, tacrolimus may reduce long-term graft loss, although there is no benefit on total mortality. There was an increase in the level of cytomegalovirus infection with MMF, although the overall level of withdrawal due to adverse events was not different to that of azathioprine-treated adults. No study comparing MPS with azathioprine (CAS) was identified. In an adult RCT comparing MMF with MPS, there was no significant difference between groups in 1-year efficacy or side-effects. One unpublished paediatric RCT assessed the addition of sirolimus to CAS. BPAR, graft loss and all-cause mortality were not reported. In two adult RCTs, compared with azathioprine, sirolimus reduced 1-year BPAR, reduced graft function (as assessed by an increased serum creatinine) and increased the level of hyperlipidaemia. No significant differences were seen in other efficacy and side-effect outcomes. On an adult RCT comparing sirolimus with ciclosporin, there were no significant differences between groups in 1-year efficacy or side-effects with the exception of an increased level of hyperlipidaemia with sirolimus substitution. Both the assessment group and drug companies assessed the cost-effectiveness of the newer renal immunosuppressants currently licensed in children using an adaptation (BSAp) of the Birmingham Sensitivity Analysis (BSA) model. This model is based on a 10-year extrapolation of 1-year BPAR results sourced from paediatric RCTs or adult RCTs (where paediatric RCTs were not available). The addition of basiliximab and that of daclizumab to CAS was found to increase quality-adjusted life-years (QALYs) and decreased overall costs, a finding that was robust to sensitivity analyses. The incremental cost-effectiveness ratio (ICER) of replacing ciclosporin with tacrolimus was highly sensitive to the selection of the hazard ratio for graft loss from acute rejection, dialysis costs and the incorporation (or not) of side-effects. The ICERs for tacrolimus versus ciclosporin ranged from about 46,000 pounds/QALY to about 146,000 pounds/QALY. Although sensitive to varying the hazard ratio for graft loss with acute rejection, the ICER for replacing azathioprine with MMF remained in excess of 55,000 pounds/QALY., Conclusions: In general, compared with a regimen of ciclosporin, azathioprine and steroid, the newer immunosuppressive agents consistently reduced the incidence of short-term biopsy-proven acute rejection. However, evidence of the impact on side-effects, long-term graft loss, compliance and overall health-related quality of life is limited. Cost-effectiveness was estimated based on the relationship between short-term acute rejection levels from RCTs and long-term graft loss. Both the addition of daclizumab and that of basiliximab were found to be dominant strategies, that is, regarding cost savings and increased QALYs. The incremental cost-effectiveness of tacrolimus relative to ciclosporin was highly sensitive to key model parameter values and therefore may well be a cost-effective strategy. The incremental cost-effectiveness of MMF compared with azathioprine, although also sensitive to model parameter, was unattractive. There is a particular need for RCTs to assess the use of MMF, MPS and daclizumab for renal transplantation in children where no such evidence currently exists. Future comparative studies need to report not only on the impact of the newer immunosuppressants on short- and long-term clinical outcomes but also on side-effects, compliance, healthcare resource, costs and health-related quality of life.

Highly sensitized patients (anti-HLA) on the kidney waiting list wait longer for a suitable crossmatch negative organ. At the moment there are two strategies to enhance transplantation of these patients. One approach is the determination of acceptable HLA mismatches and application of this knowledge for the selection of crossmatch negative donors, and the second is the desensitization of patients with intravenous immunoglobulin-based protocols to enable transplantation of an organ from a donor towards which antibodies were originally present. Both approaches have advantages and disadvantages and are only successful in a proportion of the patients. The optimal solution is an integrated strategy whereby desensitization is used for those patients for whom the acceptable mismatch approach is not successful.

In 3 renal transplant cohorts treated in Spain in 1990, 1994, and 1998 (total number, 3279), we studied the frequency of certain cardiovascular risk factors. Their effect on the cost of drugs was assessed from the data from 1 center; the mean cost of antihypertensive agents per patient-year was 349 euros, and of lipid-lowering drugs was 294 euros. Between 1990 and 1998 the frequency of use of antihypertensive agents at 2 years increased from 70% to 80%, and that of lipid-lowering agents from 12% to 46% (P < .001). Patients received various regimens of immunosuppression at the second year, as follows: (1) steroid-free: cyclosporine, 2.3%; tacrolimus, 9.9%; cyclosporine plus mycophenolate, 16.2%; and tacrolimus plus mycophenolate, 11.8% (P < .001); (2) antihypertensive agents: 74.9% of patients receiving tacrolimus, with or without mycophenolate, versus 80.7% of those receiving cyclosporine (P = .022); (3) lipid-lowering drugs: 28.4% of patients receiving tacrolimus, with or without mycophenolate, versus 51.1% of those receiving cyclosporine (P < .001). The increase in associated drug costs must be added to the recent large increase in the cost for immunosuppressive agents, which rose from 3854 euros per year, in 1990 to 5374 euros per year in 1998. A lower cost of associated drugs tends to lessen the overall cost of therapies with tacrolimus. Because cardiovascular disease is the main cause of death, these findings should be taken into account in the assessment of the long-term cost-benefit ratio.

Background: The new immunosuppressive drugs control acute rejection better, and have potentially short-term economic advantages. However, their long-term cost-effectiveness must still be determined. The Spanish study of chronic transplant nephropathy provides data that facilitates the assessment of the economic importance of maintenance immunosuppression (MI)., Methods: We determined the frequency of use of the different MI drugs and their combinations in three renal transplantation cohorts performed in 1990, 1994 and 1998 (total: 3279), and their evolution over time. Based on the real costs found in a medium-sized service in our country at the end of 2000, the mean annual costs of MI drugs were calculated. We performed a multivariate analysis of graft survival in the 1998 cohort., Results: In 1990 and 1994, cyclosporine (CsA) with or without azathioprine (AZA) was used almost exclusively as the initial MI drug. In 1998, 76% received mycophenolate mofetil (MMF) and 20% tacrolimus (TAC). During their follow-up, a growing number of patients from the 1990 and 1994 groups were converted to MMF (12 and 17%) and TAC (4 and 8%), while the treatment of those from 1998 remained stable. Using prices from the year 2000, the mean cost of the MI at the end of the first year in 1998 (5380) was almost double that of 1994 (2902) and 1990 (2855). In these two groups, the mean cost remained stable until 1996; afterwards, it increased in both, more rapidly in the 1994 (24.8%) than in the 1990 (17.3%) group, although it remained significantly inferior to that of 1998. Correction for the evolution of the drug prices and the peseta purchasing value lessened these changes in an important way. The new regimens allowed for the withdrawal of steroids in a greater proportion of cases; TAC was associated with a less frequent use of lipid-lowering drugs and antihypertensive drugs. In the whole patient group, the regimens with MMF and/or TAC showed a tendency to greater mean life of the organs, but without reaching statistical significance in the multivariate analysis of patients in 1998., Conclusions: The introduction of new drugs in the MI applied in Spain has had an important economic impact since 1996. Their cost-effectiveness is still pending confirmation in our country.

Objective: To evaluate the cost of islet transplantation in type 1 diabetic patients with a functional renal graft in a multicenter network., Research Design and Methods: The study involved nine diabetic patients transplanted in the Swiss-French Groupe Rhône-Alpes, Rhin et Geneve pour la transplantation d'Ilots Langerhans (GRAGIL) consortium between March 1999 and June 2000. The direct medical costs were estimated from Social Security's perspective from the inclusion of the patient to 1 year after transplantation. All cost components were computed separately and included evaluation, screening and candidacy, organ retrieval, islet processing, pancreas and islet transportation, hospitalization for transplantation, follow-up, medications (immunosuppressive, antidiabetic, and adjuvant drugs), and adverse events requiring hospitalization., Results: During the study period, 56 pancreata were processed and 14 islet preparations were transplanted. The average cost of an islet transplantation (procedure and 1-year follow-up) was 77,745 euro (French rate, year 2000). The four main cost components were islet preparation (30% of the total cost), adverse events (24%), drugs (14%), and hospitalization (13%)., Conclusions: Overall costs of islet transplantation are slightly higher than those of pancreas transplantation. The cell isolation process is a critical point; a reduction in overall cost will require more efficient ways of isolating high yields of viable islets. Costs generated by shipments within the GRAGIL network did not represent an economic burden. It can be expected that the costs will decrease with growing experience and improving technology.

Background: The choice of induction immunosuppression for kidney transplantation in elderly recipients is dictated by the consideration of the risk of infection as well as efficacy in the prevention of acute rejection, thus allowing a reduction in subsequent maintenance immunosuppression and its attendant long-term adverse effects., Objective: To compare the efficacy and safety of the antibody induction immunosuppression strategies in elderly recipients of kidney transplants., Patients and Methods: We present retrospective data analysis on 183 kidney transplant recipients > or = 60 years of age at Hahnemann University Hospital (Philadelphia, PA, USA) over a 12-year period. We compared four consecutive cohorts of kidney transplant recipients receiving lymphocyte immune globulin, equine antithymocyte globulin (ATGAM) [n = 29]; muromonab CD3 (OKT3) [n = 45]; basiliximab (Simulect) with corticosteroid maintenance [n = 40]; and Simulect without corticosteroid maintenance (n = 69)., Results: Delayed graft function (DGF) was observed in 48% of patients receiving ATGAM, 35.6% in the OKT3 group and 35% in the Simulect group with corticosteroid maintenance and 36.2% in the Simulect group without corticosteroid maintenance. The rejection rate within the first 3 months was 31% in the ATGAM and OKT3 groups, 17.5% in the Simulect group with corticosteroid maintenance and 14.5% in the Simulect group without corticosteroid maintenance. These differences for DGF and acute rejection were statistically significant between patients receiving ATGAM and OKT3, ATGAM or OKT3 and both groups of Simulect (all p < 0.05). Patients receiving Simulect were free of adverse effects typically encountered by patients receiving polyclonal and monoclonal antibodies for induction. Patients receiving Simulect had much shorter hospital stays and benefited from significant reduction of costs compared with other groups., Conclusion: Our data indicate that kidney transplant recipients > or = 60 years of age benefit from induction therapy with Simulect followed by corticosteroid-free maintenance immunosuppression.

Reduced-intensity conditioning that harnesses the potential of a graft-versus-tumor (GVT) effect has been proposed as an alternative to conventional myeloablative allogeneic stem cell transplantation. The primary aim is engraftment and this can be achieved with minimal immunosuppression. In this report, we describe the use of such regimens for CML in 17 patients who received human leukocyte antigen (HLA)-matched sibling allografts. Conditioning was with fludarabine, antithymocyte globulin (ATG) and busulfan for the first 11 patients, whereas fludarabine, busulfan and TBI were used for the remaining six patients. Engraftment was prompt in most of the cases. Complications and need for supportive therapy in the immediate post-transplant period were reduced drastically. Only two patients (both in the TBI group) died within the first 100 days. Acute graft-versus-host disease (GVHD) grade II-IV was seen in seven patients. Complications occurred later on. Chronic GVHD was observed in 11/17 patients. Lung infection and GVHD were the major killers. In surviving patients, after a median follow-up of 30 months (range 37-21 months), 6/17 (35.3%) are alive. Five are disease free and one patient is still in relapse even after a second donor lymphocyte infusion. Total treatment time and cost were more than with conventional transplants. We conclude that reduced-intensity transplantation still requires further refinement.

We have used a novel method to conduct non-myeloablative stem cell transplantation (NST), making the following changes in previous methods: Use of the cheapest conditioning drugs, tailored number of apheresis sessions in the donors, elimination of ganciclovir and IgG, outpatient conduction when possible, diminished number of transfusions of blood products and diminished number of donor lymphocyte infusions. With this method, we have prospectively conducted 70 allografts in patients with different diseases: Chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplasia, thalassemia major, relapsed Hodgkins disease, Blackfan-Diamond syndrome and aplastic anemia. In them, the median granulocyte recovery time to 0.5 x 10(9)/L was 11 d, whereas the median platelet recovery time to 20 x 10(9)/L was 12 d. Twenty patients did not need red blood cell transfusions and 17 did not need platelet transfusions. In 55 individuals (78%), the procedure could be completed fully on an outpatient basis. Follow-up times range between 30 and 800 d.: Four patients failed to engraft and recovered endogenous hemopoiesis; 16 patients (23%) developed acute graft versus-host disease (GVHD) whereas 28 (49%) developed chronic GVHD. Thirty two patients (47%) have died: 21 with a relapsing disease and seven as a result of GVHD; the median post-trasplant survival (SV) was 420 d., whereas the 12-mo. SV was 42%. The 100-day mortality was 3.8% and the transplant-related mortality was 14.2%. The median cost of the allografts was 18,000.00 US dollars. This method could be particularly adequate in developing countries, where very few individuals can afford the cost of a conventional bone marrow transplantation procedure.

Unlabelled: Most pharmacoeconomic studies of mycophenolate mofetil have focused on its use as part of maintenance immunosuppression for renal transplantation, involving short-term (3 to 12 months) time frames. In general, mycophenolate mofetil reduced the treatment costs for rejection episodes and graft failure which offset its higher drug acquisition cost compared with azathioprine. Several cost analyses have been modelled on the large multicentre trials of adult renal transplant recipients. The use of mycophenolate mofetil was associated with either cost savings or no additional costs after 6 or 12 months in French, US and Canadian analyses of triple or quadruple immunosuppressant therapy. A further cost analysis utilising a registry database of renal transplant recipients in the US found mycophenolate mofetil to be cost saving compared with azathioprine after 6.4 years when evaluating costs due to graft loss only. Of the limited cost-effectiveness analyses with the drug, one US study modelled the 1- and 10-year cost effectiveness of mycophenolate mofetil and various other immunosuppressants used in combined regimens. Long-term use of mycophenolate mofetil was less cost effective than other regimens, but the use of long-term mycophenolate mofetil in high-risk patients was shown to be a relatively cost-effective strategy. In another US analysis comparing mycophenolate mofetil with azathioprine as part of quadruple therapy, mycophenolate mofetil was associated with slightly lower costs during the first year after renal transplantation as well as improved clinical outcomes., Conclusion: Pharmacoeconomic studies support the use of mycophenolate mofetil as part of immunosuppressant therapy in renal transplantation, at least in the short term. Although the cost effectiveness of mycophenolate mofetil in the long term is less clear, limited pharmacoeconomic data available appear promising. Among issues to be examined in future economic analyses in renal transplantation are the calcineurin-sparing potential of mycophenolate mofetil and the feasibility of using more efficient mycophenolate mofetil dosage regimens when using the drug on a long-term basis. Additional pharmacoeconomic analyses of mycophenolate mofetil are also needed in other types of solid organ transplantation.