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Jean Colaneri, ACNP, CNN, is Clinical Nurse Specialist/Acute Care Nurse Practitioner, Renal/Pancreas Transplant Unit, Albany Medical Center Hospital, Albany, NY. She is a member of the Northeast Tri-State Chapter of ANNA.

Acknowledgments: The author would like to acknowledge the following students at the Albany Medical College for data collection and analysis for the early steroid-withdrawal protocol: James Jaber, PhD, Salah Baydoun, and Paul Feustel, PhD.

Since the first renal transplant was performed over 50 years ago, steroids have been of great short-term benefit in preventing acute transplant rejection, but a source of multiple long-term difficulties for recipients of organ transplants. Long-term steroid use is responsible for many adverse effects that have an impact on the quality of life of people who have been transplanted. These adverse effects include bone and muscle wasting, especially avascular necrosis of the hip joint, eventually requiring hip replacement surgery for one or both hip joints. Steroids increase the appetite, which may cause significant weight gain. Weight gain frequently results in higher blood pressures, worsening glycemia, and increased pressure on hips, knees, and ankles as well as misalignment of the spine, leading to back pain. Steroids commonly cause cosmetic concerns such as Cushingoid facial appearance, abdominal striae, and increased abdominal fat deposition, leading to concerns with body image for all recipients of transplants.

Early Steroid Withdrawal Protocol

In February 2003, our renal transplant program began to withdraw steroids early in the post-transplant phase. Since then, we have gained experience with this regimen in over 150 recipients of renal transplants and have compiled data on 84 of those with a mean follow-up interval of 15.5 months. These recipients have been compared to 50 historical recipients who were prescribed continued steroids (methylprednisolone) for long- term maintenance. Demographic data, patient and graft survival, acute rejection rate, mean serum creatinine and complications associated with immunotherapy were compared between the two groups. Limitations to this study were acknowledged to be the small number of patients studied, limited long-term follow-up (1.3 years), and the fact that this is a single center study.
Our early steroid withdrawal protocol includes the use of anti-thymocyte globulin (Thymoglobulin®) and high dose steroids rapidly tapered and then discontinued on the seventh postoperative day. On the last day that steroids are given, sirolimus (Rapamune®) is begun and titrated to a therapeutic trough level of 8 ng/ml in the initial post-transplant period. If toxicity is observed, such as neutropenia or thrombocytopenia, the target trough level is lowered. In addition, intravenous mycophenolate mofetil (Cellcept®) is begun on postoperative day 0 at 2 grams daily in divided doses. Tacrolimus (Prograf®) is generally not begun until the creatinine level is less than 4.0 or is showing signs of rapid improvement. It is titrated to a trough level of 8 ng/ml in the initial post-transplant period.

Results
Out of 84 recipients of renal transplants, three individuals have lost the graft within 1 year, translating into a 95% one-year graft survival (identical to that of the historical control of 50 patients who remained on steroids). The rate of acute rejection is 11% (compared to 10% acute rejection rate of those remaining on steroids, which was not significant (p=0.93), and all acute rejections have responded to short-term, high dose steroid boluses. Five patients have had to return to steroids due to either a rejection episode or recurrence of disease in the allograft. There have been no patient deaths. No patients on the steroid-free regimen have required joint replacements and the mean weight gain for a 12-month period was 4 pounds. Historical data on 50 recipients who were on steroids showed a mean weight gain of 11.3 pounds. Differences in weight gain were not significant at a p level of 0.034.

No immunosuppressive regime is without adverse effects and our center’s immune suppressant protocol has spawned several issues which have required medical and nursing interventions. Forty-two percent of the patients were unable to maintain goal hemoglobins of 11-12 mg/dl and 62% required epoetin alpha (Procrit®) or darbepoetin (Aranesp®) injections and supplemental oral iron for several months post-transplant. This is likely due to suppression of the bone marrow by the strong combination of anti-proliferative immunosuppressives that are used for induction therapy, especially anti-thymocyte globulin (Thymoglobulin®) in combination with mycophenolate mofetil (Cellcept®) and sirolimus (Rapamune®). It is not unusual to have patients with neutropenia and thrombocytopenia which is also due to the marrow suppressive effects of the combination of immunosuppressives. Dose reduction or temporary cessation of Rapamune® or Cellcept® is instituted in these cases.

On initial institution of our early steroid withdrawal protocol, three patients experienced recurrence of autoimmune renal disease, requiring the reinstitution of steroids. Through this experience, we found that steroids should not be withdrawn in those patients with a risk of recurrent renal disease in the transplant, such as those with focal segmental glomerulosclerosis (FSGS) or IgA or IgM nephropathy. For decades, steroids have been a mainstay of therapy for exacerbations of autoimmune renal disorders and may assist in prevention of recurrent disease in the allograft.

Finally, several recipients have developed painful mouth sores, delayed wound healing, lymphoceles (which can surround and compress the allograft, leading to mechanical dysfunction), or severe hyperlipidemia, attributable to the use of Rapamune®. Although steroids also contribute to increased serum lipids, Rapamune® can profoundly increase LDL and triglycerides in some patients. In fact, one young Caucasian male had a fasting cholesterol of over 700, requiring discontinuation of Rapamune® and reinstitution of steroid therapy. (He eventually lost his graft in less than 3 years due to chronic allograft nephropathy (CAN). One factor associated with CAN is hyperlipidemia.) Since we no longer administer large loading doses of Rapamune® to attain therapeutic levels quickly, the incidence of lymphoceles has decreased substantially.

Conclusion
In summary, it is only recently, since the advent of more potent immunosuppressive medications, that steroid withdrawal has become possible with excellent 1-year graft and patient survival results. In 2003, the most recent data available, 15% of patients with renal transplants in the U.S. were discharged on a steroid-free regimen and 9% of these were able to remain steroid-free in the post-discharge period. (Shapiro et al., 2005). Our hope for the future of recipients of transplants is for improved long-term graft survival combined with fewer disabling side effects from the immunosuppressive regimen. Long term, multi-center studies of adequate numbers of recipients of renal transplants will determine the efficacy and impact on quality of life of new immunosuppressive strategies.

References
Shapiro, R., Young, J.B., Milford, E.L., Trotter, J.F., Bustami, R.T., & Leichtman, A.B. (2005). Immunosuppression: Evolution in practice and trends, 1993-2003. American Journal of Transplantation, 5(4.2), 874-886.

Additional Reading
Woodle, E.S., Vincenti, F., Lorber, M., Gritsch, H.A., Hricik, D., & Washburn, K., et al. (2005). A multicenter pilot study of early (4-day) steroid cessation in renal transplant recipients under simulect, tacrolimus and sirolimus. American Journal of Transplantation, 5, 157-166.