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Reducing steroids following solid organ transplantation

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A Basu
MD FRCS (Edin)
Assistant Professor of Surgery

R Shapiro
MD
Professor of Surgery
Director
Kidney, Pancreas and Islet Cell Transplantation
Thomas E Starzl Transplantation Institute
University of Pittsburgh
Pittsburgh
USA
E:shapiror@msx.upmc.edu

Long-term steroid administration after solid organ transplantation is associated with a number of well known side-effects. Methods of withdrawing or avoiding steroids following renal transplantation were discussed in the last issue. Here we look at some of the strategies used to reduce steroids following other types of solid organ transplantation.

Pancreas transplantation
Reduction of steroid use is extremely desirable in pancreas transplantation, given the association between chronic steroid therapy and hypertension, hyperlipidaemia and glucose intolerance.(1)

Retrospective studies
In a report from Pittsburgh, 147 pancreas transplants were performed in 141 patients.(2) After excluding 23 patients (early graft loss in 17 patients, retransplantation in five patients, and prior heart transplant in one patient) from analysis, complete steroid withdrawal was achieved in 58 (47%) patients, with a mean time to steroid withdrawal of 15.2±8 months. Patient, pancreas and kidney survival rates at 1 year were 100%, 100%, and 98% (off steroids), versus 97%, 91% and 96% (on steroids, all nonsignificant). The cumulative risk of rejection was 74% for patients off steroids versus 76% for patients on steroids. Mean fasting blood glucose levels were 98±34mg/dl (off steroids) and 110±41mg/dl (on steroids, nonsignificant). Mean glycosylated haemoglobin levels were 5.2±0.9% (off steroids) and 6.2±2.1% (on steroids, p=0.02). These data demonstrated that steroid withdrawal can be achieved in pancreas transplant patients under tacrolimus-based immunosuppression. Steroid withdrawal is associated with excellent patient and graft survival.

Of the 360 recipients who underwent a pancreas transplant between 1 January 1994 and 30 June 1998 at University of Minnesota,(1) 12 simultaneous pancreas– kidney (SPK) and 12 pancreas after kidney (PAK) had attempted steroid withdrawal. All 14 patients were on tacrolimus and mycophenolate mofetil. Of the 14 recipients, 10 (71%) remained off steroids at a mean follow-up of 18 months (range 5–51 months). Two patients remained on steroids because of acute rejection and two patients because of leucopenia and the inability to tolerate a full dose of mycophenolate mofetil. Steroid withdrawal was unsuccessful in both pancreas transplant alone recipients and in two of the 12 simultaneous pancreas–kidney transplant recipients. With a mean follow-up of 18 months, 71% of the patients remain off steroids. Following steroid withdrawal, there was a mean decrease in serum cholesterol of 20mg/dl, two patients had a significant decrease in systolic blood pressure, and four had noted weight loss.

Prospective trials
Based on their retrospective study, the Minnesota group started a prospective trial of steroid withdrawal in pancreas transplantation.(3) Only recipients with functioning grafts >-6 and <-36 months after SPK or PAK transplants were enrolled. All patients received triple therapy for maintenance immunosuppression using tacrolimus and mycophenolate mofetil, with the following inclusion criteria:

  • Low maintenance steroid dose 0.075mg/kg.
  • Mycophenolate mofetil >-0.75g orally twice a day.
  • Tacrolimus levels >-8mg/ml.

A total of 55 patients (29 SPK, 26 PAK) were randomised to standard immunosuppression or steroid withdrawal over 4–8 weeks. Six recipients dropped out of the study group and two dropped out of the control group. Median follow-up after transplantation was 27 months in the SPK category and 26 months in the PAK category, and from randomisation, 10 months in both categories. Steroid withdrawal at least 6 months after a successful pancreas transplant did not decrease patient or graft survival, nor did it increase the rate of graft loss from rejection or the incidence of rejection. There was a better quality of life and reduction in cholesterol levels with 6 months’ follow-up in the steroid withdrawal group.

A trial of rapid corticosteroid elimination (RCE) (6 days) has been reported in 40 SPK transplant patients.(4) Induction was done with antithymocyte globulin. Maintenance immunosuppression was with tacrolimus plus mycophenolate mofetil in 20 patients and tacrolimus plus sirolimus in 20 patients. Patient and graft survival and rejection rates were compared with historical controls (n=86). One-year patient, kidney, and pancreas survival rates in the RCE group were all 100%, and in the historical control group they were 96.5%, 93% and 91.9% respectively.(4) The 1-year rejection-free survival rate in the RCE recipients was 97%, versus 80.2% in the historical control group. At 6 and 12 months’ post-transplant, serum creatinine values remained stable in all the groups.

Islet cell transplantation
Seven consecutive patients with type 1 diabetes underwent islet transplantation with a glucocorticoid-free immunosuppressive regimen consisting of sirolimus, tacrolimus and daclizumab.(5) All seven patients quickly attained sustained insulin independence after transplantation of 11,547±1,604 islet equivalents/kg body weight (median follow up 11.9 months). Mean glycosylated haemoglobin levels were normal after transplantation in all recipients, and the mean amplitude of glycaemic excursions were significantly reduced after attainment of insulin independence. Islet transplantation can result in insulin independence with excellent metabolic control when glucocorticoid-free immunosuppression is combined with an infusion of an adequate islet mass.

T-lymphocyte depletion strategies
By using the same therapeutic principles as used in kidney transplantation alluded to earlier, Corry et al reported their experience in ten cadaveric kidney-pancreas and four pancreas-only transplant recipients.(6) Pretransplant host preconditioning was done with an infusion of thymoglobulin 3–5mg/kg. Monotherapy with tacrolimus (trough target 10ng/ml) was begun 18–24 hours after organ revascularisation. Thirteen of the 14 pancreas and all ten cotransplanted kidneys functioned well, with a follow-up of 2.5 months to >6 months. Eleven of the 14 patients were on tacrolimus monotherapy. A single pancreas loss occurred at five months secondary to arterial thrombosis.

Liver transplantation
Graft loss to acute or chronic rejection is rare after liver transplantation. Acute rejection does not have a negative impact on long-term graft survival. Hence, steroid withdrawal has been studied in retrospective studies and in clinical trials; steroid avoidance protocols have also been undertaken.

Belli et al did a randomised study in which patients were tapered from 200mg of IV methylprednisolone on day 1 to 20mg of prednisolone between days 6 and 90.(7) Steroids were then progressively withdrawn over 4–6 weeks under ciclosporin or tacrolimus monotherapy. This “Milan Protocol” allowed successful steroid withdrawal in 80–90% of patients.

A three-step reduction in steroid dosage has been used in paediatric liver transplantation.(8) These steps include:

  • Reduction to baseline, physiological prednisolone doses (0.25mg/kg/day) administered daily, by 2–3 months after orthotopic liver transplant.
  • A progressive switch to alternate-day steroid therapy (0.5mg/kg four times daily) at 4–6 months.
  • Slow reduction of the alternate-day steroid dosage, with decreases every 2–4 weeks to achieve steroid withdrawal

Pretransplant or de novo post-transplant autoimmune hepatitis constitute the main contraindications for steroid withdrawal. Available data regarding steroid withdrawal in paediatric liver transplantation suggest that the earlier the steroid withdrawal, the greater the benefits to be expected for children, particularly growth, and the greater the risks to the graft, particularly acute and chronic rejection.

Ringe et al used a single intraoperative dose of prednisolone, followed by maintenance immunosuppression with tacrolimus and mycophenolate mofetil.(9) One-year and two-year graft survival rates were 86.7% and 83.9%, respectively, with an acute rejection rate of 26.2%. A total of 73% of patients remain off steroids.

In a retrospective analysis of 834 adult primary liver transplant recipients at Pittsburgh,(10) 97% of patients receiving tacrolimus were weaned off steroids but 24% required reinstitution. Reasons for reinstitution included late rejection, recurrent disease, renal impairment and/or the need for kidney transplantation, and other concomitant medical conditions.

Heart transplantation
In addition to avoiding steroid-related side-effects, in heart transplantation the hope is that steroid-withdrawal will control post-transplant arteriosclerosis. In a study from North Carolina,(11) 63 heart transplants were performed on triple-drug immunosuppression. By 24 months’ post- transplant, 70% of patients were withdrawn from steroids. Survival at 1, 3, and 5 years was 98±2%, 93.2±3.8% and 88.3±6%. Freedom from rejection at 6 months was 60.7±6.5%, at 1 year 60.7±6.5%, and at 2 years 58.5±6.7%. Freedom from infection was 78.5±5.5% at 6 months, 76.5±5.7% at 1 year and 72±6.2% at 2 years.

In another study, 72 patients(52.5%) underwent successful prednisolone withdrawal at an average of 13 months after heart transplantation while 65 patients (47.5%) did not achieve steroid-free immunosuppression.The estimated risk of acute rejection after achieving steroid-free immunosuppression was 50% at 21 months. Survival at 5 years after heart transplantation was 92.9% in the steroid withdrawal group and 72.3% in those still taking steroids (p<0.01). Black recipient race was associated with reduced survival time in both groups.(12)

The Toronto group reported their experience with mycophenolate mofetil in 21 paediatric heart transplant patients.(13) Twenty-eight per cent of the patients were successfully weaned off steroid therapy, and 20% had reduction of their steroid doses; 14% returned to steroids because of significant rejection.

Conclusion
There are a number of successful strategies for reducing steroid usage in solid organ transplant recipients. While steroid withdrawal has been achieved successfully, steroid avoidance is the goal of more recent studies. With the successful introduction of several new immunosuppressive agents in the last decade, steroid avoidance may well be routinely achievable in the majority of patients. T-cell depletion strategies followed by monotherapy may be particularly attractive. This approach has the added advantage of near-tolerance induction, although clinical experiences are still being evaluated, and the results may vary depending on the organ involved.

References

  1. Humar A, Parr E, Drangstveit MB, et al. Steroid withdrawal in pancreas transplant recipients. Clin Transplant 2000;14:75-8.
  2. Jordan ML, Chakrabarti P, Luke P, et al. Results of pancreas transplantation after steroid withdrawal under tacrolimus immunosuppression. Transplantation 2000;69:265.
  3. Gruessner RWG, Sutherland DER, Parr E, et al. A prospective, randomised, open-label study of steroid withdrawal in pancreas transplantation – a preliminary report with 6-month follow up. Transplant Proc 2001;33:1663-4.
  4. Kaufman DB, Leventhal JR, Koffron AJ, et al. A prospective study of rapid corticosteroid elimination in simultaneous pancreas-kidney transplantation. Transplantation 2002;73:169-77.
  5. Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet transplantations in seven patients with Type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Eng J Med 2000;343:230-8.
  6. Corry RJ, Potdar S, Shapiro R, et al. Pancreas and kidney-pancreas transplantation under a tolerogenic regimen of preconditioning with thymoglobulin and post-transplant tacrolimus. Transplantation 2002;74S:46.
  7. Belli LS, DeCarlis L, Rondinara G, et al. Early cyclosporine monotherapy in liver transplantation: a 5-year follow up of a prospective, randomised trial. Hepatology 1998;27:1524-9.
  8. Reding R. Steroid withdrawal in liver transplantation: benefits, risks and unanswered questions. Transplantation 2000;70:405-10.
  9. Ringe B, Braun F, Schütz E, et al. A novel management strategy of steroid-free immunosuppression after liver transplantation: efficacy and safety of tacrolimus and mycophenolate mofetil. Transplantation 2001;71:508-15.
  10. Jain AB, Kashyap R, Marsh W, et al. Reasons for long-term use of steroids in primary adult liver transplantation under tacrolimus. Transplantation 2001;71:1102-6.
  11. Oaks TE, Wannenberg T, Close SA, et al. Steroid-free maintenance immunosuppression after heart transplantation. Ann Thor Surg 2001;72:102-6.
  12. Felkel TO, Smith AL, Reichenspurner HC, et al. Survival and incidence of acute rejection in heart transplant recipients undergoing successful withdrawal from steroid therapy. J Heart Lung Transplant 2002;21:532-9.
  13. Dipchand AI, Benson L, McCrindle BW, et al. Mycophenolate mofetil in pediatric heart transplant recipients: a single center experience. Pediatr Transplant 2001;5:112-8.

Resources
American Society of Transplant Surgeons
W:www.asts.org
The Transplantation Society
W:www.transplantation-soc.org



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