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Keywords:

  • Kidney transplantation;
  • prednisone-free maintenance immunosuppression

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Concern persists that prednisone-free maintenance immunosuppression in kidney transplant recipients will be associated with an increase in late allograft dysfunction and graft loss. We herein report 5-year follow-up of a trial of prednisone-free maintenance immunosuppression. From October 1, 1999, through January 31, 2005, at our center, 589 kidney transplant recipients were treated with a protocol incorporating discontinuation of their prednisone on postoperative day 6. At 5 years, actuarial patient survival was 91%; graft survival, 84%; death-censored graft survival, 92%; acute rejection-free graft survival, 84% and chronic rejection-free graft survival, 87%. The mean serum creatinine level (±SD) at 1 year was 1.6 ± 0.6; at 5 years, 1.7 ± 0.8. In all, 86% of kidney recipients with functioning grafts remain prednisone-free as of April 30, 2005.

As compared with historical controls, recipients on prednisone-free maintenance immunosuppression had a significantly lower rate of a number of complications, including cataracts (p < 0.001), posttransplant diabetes mellitus (p < 0.001), avascular necrosis (p = 0.001), and fractures (p = 0.004). We conclude that prednisone-related side effects can be minimized in a protocol incorporating prednisone-free maintenance immunosuppression. Five-year graft outcome remains good.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Prednisone is associated with numerous side effects, including hypertension, osteoporosis (and fractures), avascular necrosis, cataracts, mood alterations, posttransplant diabetes, easy bruisability and skin changes. Most kidney transplant recipients, when asked which immunosuppressive agent they would most like to discontinue, name prednisone (1). Nonetheless, withdrawal of prednisone late posttransplant, even in carefully selected recipients, has resulted in an increased risk of acute rejection and of graft loss (2,3).

Recently, we and others have shown that discontinuation of prednisone in the first week posttransplant (or transplantation without any use of prednisone at all) is associated with a low subsequent rate of acute rejection (4–14). However, concern persists that such protocols will be associated with an increased risk of late allograft dysfunction and graft loss. In reality, the literature does not substantiate this concern—only one study has reported good early outcome but worse late outcome after prednisone withdrawal (15). However, to address the ongoing worry, we herein present our 5-year outcome after rapid discontinuation of prednisone in a cohort of kidney transplant recipients.

Material and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

From October 1, 1999, through January 31, 2005, at our center (minimum follow-up: 3 months), 589 kidney transplant recipients started on a protocol incorporating discontinuation of their prednisone on postoperative day (POD) 6. Initially, this protocol (approved by the Human Subjects Committee) applied only to recipients of first living donor (LD) transplants; in October 2000, we expanded it to apply to all recipients of first and second LD and first and second deceased donor (DD) transplants. Currently, we only exclude from this protocol recipients taking prednisone at the time of their transplant, recipients requiring prednisone for an underlying disease and recipients who have undergone three or more transplants. Excluded recipients are maintained on 5 mg of prednisone per day beginning on POD 6. Other than these limitations, all recipients (low and high immunologic risk) are treated with prednisone-free maintenance immunosuppression.

Our immunosuppressive protocol has been described in detail (11). Briefly, recipients are treated with Thymoglobulin (Genzyme Corp., Cambridge, MA) (1.25–1.5 mg/kg/day) for 5 days, with the first dose given in the operating room, and prednisone for 6 days (methylprednisolone 500 mg, given in the operating room, followed by prednisone, 1 mg/kg on POD 1; 0.5 mg/kg on POD 2 and 3; and 0.25 mg/kg on POD 4 and 5). Initially, recipients also received cyclosporine (CSA) (adjusted to achieve blood levels of 150–200 ng/ml by high-performance liquid chromatography (HPLC) for the first 3 months) and mycophenolate mofetil (MMF) (1 g twice daily). Since March 1, 2000, we have been conducting a randomized study (also approved by the Human Subjects Committee) of CSA-MMF versus tacrolimus (TAC)-sirolimus (SRL) as part of our prednisone discontinuation protocol. To date, we have found no difference between the CSA-MMF and TAC-SRL groups in acute rejection or graft survival rates (12), so for the purposes of this report, we have analyzed all of our prednisone-free maintenance immunosuppression data in the aggregate. Some recipients on our prednisone discontinuation protocol chose not to participate in our randomized study of CSA-MMF versus TAC-SRL, and so were treated with CSA-MMF; thus, the total number of recipients in our current report is 589.

For recipients with delayed graft function (DGF), we extended the course of Thymoglobulin (to a maximum 10 doses) and delayed introduction of the calcineurin inhibitor. Recipients with >25% increase in serum creatinine level from baseline underwent percutaneous allograft biopsy. Rejection episodes were treated with a rapid steroid taper; steroid-resistant rejection episodes and histologically severe rejection episodes were treated with antibody (OKT3 or Thymoglobulin) therapy. After antirejection therapy, most recipients had 5 mg of prednisone daily added to their maintenance immunosuppression; some insisted on returning to prednisone-free immunosuppression.

All recipients were treated with prophylactic ganciclovir or valganciclovir for 3 months posttransplant. Pneumocystis prophylaxis was with trimethoprim-sulfamethoxazole; in patients with sulfa allergies, dapsone or aerosolized pentamidine was used. Fungal prophylaxis was with oral clotrimazole or nystatin for 3 months posttransplant.

For recipients on our prednisone-free maintenance protocol, we studied actuarial patient and graft survival rates, death-censored graft survival rates and biopsy-proven acute rejection-free and chronic rejection (chronic allograft nephropathy)-free graft survival rates; renal function (mean serum creatinine levels) at each year posttransplant; and the incidence and number of steroid- and immunosuppression-related side effects, including cataracts, fractures, avascular necrosis, skin cancer, posttransplant lymphoproliferative disease (PTLD), posttransplant diabetes mellitus (PTDM) (defined as post-discharge new need for insulin or oral hypoglycemic agents) and cytomegalovirus (CMV) disease (defined as treatment with valganciclovir or ganciclovir).

We also compared the incidence of side effects in recipients on our prednisone-free maintenance protocol versus those in a historical cohort (n = 465) (from January 1, 1996, through December 31, 2000). The historical cohort consisted of first and second LD and DD transplant recipients treated with polyclonal antibody, a calcineurin inhibitor, either MMF or azathioprine and a prednisone taper (1 mg/kg/day tapered to 0.4 mg/kg/day by 1 month and to 0.15 mg/kg/day by 1 year).

We estimated actuarial patient, graft and rejection-free graft survival rates (intention-to-treat analysis) by using Kaplan-Meier life table analyses. To compare differences between groups, we used log-rank and Wilcoxon tests. Similarly, we used log-rank tests to compare the rates of development of side effects in our prednisone-free maintenance group versus historical controls.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Of the 589 kidney transplant recipients on our prednisone-free maintenance protocol, 423 were LD recipients and 166 were DD recipients; 534 (91%) were first transplant recipients and 55 (9%) were retransplant recipients. Mean recipient age (±SD) was 47 ± 14 years. Most (89%) of the recipients were white; 61% were male. The most common primary renal disease was diabetes (33%). Of DD recipients, 20% had DGF; 31% had peak panel-reactive antibody (PRA) levels >10%. Of LD recipients, 160 (38%) had an unrelated donor transplant; 9% had peak PRA levels >10%.

Patient and graft survival

Actuarial survival for LD and DD transplant recipients on prednisone-free maintenance immunosuppression is shown in Figure 1.

imageimageimage

Figure 1. (A) Actuarial patient survival, (B) graft survival and (C) death-censored graft survival for 589 kidney transplant recipients on prednisone-free immunosuppression (intention-to-treat analysis). Number of patients reaching each year shown in 1A.

For the entire group of 589 recipients on prednisone-free maintenance immunosuppression, the actuarial patient survival rate at 1 year was 97%; at 5 years, 91%. The actuarial graft survival at 1 year was 95%; at 5 years, 84%. The death-censored graft survival at 1 year was 98%; at 5 years, 92% (Table 1).

Table 1.  Actuarial acute and chronic rejection-free survival: prednisone-free maintenance protocol
 LD recipientsDD recipients
Acute rejection-free survival
 3 months93%98%
 6 months91%88%
 12 months89%84%
 24 months88%81%
 36 months88%80%
 48 months86%80%
 60 months85% 
Chronic rejection-free survival
 12 months98%94%
 24 months95%93%
 36 months94%92%
 48 months91%90%
 60 months87% 

We found no significant difference in patient, graft or death-censored graft survival rates between LD and DD recipients (Figure 2). Of note, we found no marked worsening of late graft outcome.

imageimageimage

Figure 2. (A) Actuarial patient survival, (B) graft survival, and (C) death-censored graft survival for 423 living donor and 166 deceased donor kidney transplant recipients on prednisone-free maintenance immunosuppression. No significant differences found.

Rejection

Actuarial biopsy-proven acute rejection-free and chronic rejection (chronic allograft nephropathy)-free graft survival rates for LD and DD transplant recipients on prednisone-free maintenance immunosuppression are shown in Table 1. For LD recipients, we noted a trend toward lower acute rejection rates than DD recipients (p = 0.07); we found no difference in chronic rejection rates.

Side effects

The incidence of specific side effects for recipients on prednisone-free maintenance immunosuppression is shown in Table 2. As compared with historical controls (data not shown), prednisone-free recipients had a significantly lower rate of CMV infection (p < 0.001), PTDM (p < 0.001), cataracts (p < 0.001), avascular necrosis (p < 0.001), non-PTLD malignancy (p = 0.02) and fractures (p = 0.04).

Table 2.  Adverse events in recipients on prednisone-free maintenance protocol
 12 months60 months
  1. *24 skin, 6 other

Cytomegalovirus (CMV)8%12%
Fractures2%6%
Osteonecrosis0%0.1%
Cataracts
 Nondiabetics1%3%
 Diabetics2%9%
PTDM1%1%
PTLD0.01%1%
Non-PTLD malignancy*3%12%

Other outcome measures

For recipients on prednisone-free immunosuppression, 60 grafts have failed (44 LD, 16 DD). Causes of graft failure included death with function (n = 29), chronic rejection (n = 13), technical loss (n = 6), primary nonfunction (n = 3) and 1 each of calcineurin toxicity, malignancy, noncompliance, recurrent disease, acute rejection with simultaneous infection and hyperacute rejection. Mean serum creatinine level (±SD) at 1 year posttransplant was 1.6 mg/dL (± 0.6); at 5 years, 1.7 (± 0.8) mg/dL.

Of the 589 recipients, 62 underwent a pancreas transplant after their kidney transplant and started prednisone as part of their immunosuppression for the pancreas transplant. Thus, they were dropped from our analysis at the time of the pancreas transplant. Of the remaining recipients with functioning grafts, 86% were still prednisone-free as of April 30, 2005. Of the kidney transplant alone recipients, the most common reason for resuming prednisone was an acute rejection episode.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The most important observation based on our current data is that we found no late deterioration in graft function or in graft survival for recipients on prednisone-free maintenance immunosuppression. In 1992, Sinclair (15) reported the results of a multicenter trial (patient enrollment from 1982 to 1985) in which kidney transplant recipients, who were on CSA and prednisone (without active evidence of rejection), were randomized at 90 days posttransplant to continue on CSA and either low-dose prednisone or placebo. Of note, the two groups had similar outcome for the subsequent year. However, thereafter, graft loss increased in the placebo group (Figure 3); in an analysis after 5-year follow-up, the placebo group had significantly worse graft survival (p = 0.03).

image

Figure 3. Actuarial patient and graft survival curves for kidney transplant recipients randomly assigned 90 days post-transplant to receive either placebo (- - -) or low-dose prednisone (—), then followed for at least 5 years. (Reproduced from ‘Low-dose steroid therapy in cyclosporine-treated renal transplant recipients with well-functioning grafts,’ CMAF, September 1992; 147(5), pages 645–657, by permission of the publisher—© 1992 Canadian Medical Association.)

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Five-year outcome for recipients in our series differed from the results of the multicenter study reported by Sinclair (15). At least six explanations are possible.

First, we are reporting actuarial 5-year survival rates of an observational study. At the time of our analysis, only 27 patients had reached 5 years. Sinclair's was a prospective randomized study, and all recipients had been followed at least 5 years at the time of the report.

Second, our maintenance immunosuppression included two drugs, whereas in Sinclair's multicenter study, maintenance immunosuppression was cyclosporine monotherapy.

Third, we stopped prednisone on POD 6, whereas in Sinclair's multicenter study, it was stopped at 3 months. Outcomes appear to differ between studies reporting rapid prednisone discontinuation and those reporting prednisone withdrawal at 3 months or later (2,3). It is not clear why rapid prednisone discontinuation has succeeded, yet late prednisone withdrawal has failed. Our maintenance immunosuppressive drugs for many of the recipients on our prednisone-free maintenance protocol—that is, CSA and MMF—were identical to those used in two trials of late prednisone withdrawal, both of which showed increased acute rejection rates in the withdrawal groups (16,17). One major difference between our study and these two recent trials is our routine use of polyclonal antibody for induction therapy. Also important, perhaps, is that we gave the first antibody dose pre-vascularization. In fact, the European late prednisone withdrawal trial did not show an increased rejection rate in the subgroup receiving antibody induction therapy (16). An alternative explanation is that prednisone results in increased cytokine receptor expression on T cells, but simultaneously causes decreased cytokine release (18). Late prednisone withdrawal may result in cytokine release into an environment of upregulated receptors.

Fourth, we routinely used induction therapy, whereas in the multicenter study, the use of induction therapy was not required and was not reported.

Fifth, our study was done in a completely different era (1999–2004) than the multicenter study (1982–1985).

Sixth, the multicenter study was done at a time when the association between acute rejection episodes and late graft outcome was not recognized (19,20). Thus, in that study, patients were eligible for enrollment if they had not had an acute rejection episode in the previous 2 weeks, with no stratification into groups based on prior history of acute rejection. In addition, the multicenter study did not report the rate of acute rejection after randomization. Therefore, it is unknown whether the worse late graft survival rate in its prednisone withdrawal group could be explained by an increased incidence of acute rejection episodes after prednisone withdrawal.

Another important observation based on our current data is that, as compared with historical controls (a relatively recent cohort, from 1996 to 2000), our recipients on prednisone-free maintenance immunosuppression had a significantly lower rate of CMV disease (p < 0.001), PTDM (p < 0.001), cataracts (p < 0.001), avascular necrosis (p < 0.001), non-PTLD malignancy (p = 0.02) and fractures (p = 0.004). At the same time, acute rejection and 5-year graft loss rates were reasonably low. The lower incidence of CMV and non-PTLD malignancies in our current series may be, in part, due to era effects or a different patient population. But the significant diminution of other side effects, in combination with the acceptable graft survival, suggest that it is time for transplant programs to consider eliminating prednisone—at least from immunosuppressive protocols for low-risk recipients. We and others have also reported successful prednisone-free maintenance immunosuppression in higher-risk groups—for example, children, blacks, those with high PRA levels and those with DGF (9,21).

One limitation of our study is that it is a single-center analysis. The pros and cons of single-center versus multicenter reports have been described (22). Our study has the advantage of being coordinated by a small group of people with a well-defined decision-making and patient care algorithm. Because of the very few limitations to enrollment, the data may apply to large numbers of recipients. However, most recipients in our study were white, and 72% of the transplants used LDs. Although we have used our protocol for 166 DD transplant recipients, additional studies with larger numbers of minority recipients and DD recipients are necessary.

A second limitation is that we are reporting actuarial, and not actual, 5-year results. Only 27 recipients had reached 5 years at the time of the data analysis. One advantage of actuarial analyses is that they permit calculation and presentation of the data before all the recipients reach a defined endpoint. But the limitations of this type of analysis need to be recognized—for both our survival and side effect outcomes.

A third limitation is that we have not done protocol biopsies. Although mean creatinine levels remain stable in our patient population, it may be that we are missing some progressive fibrosis due to the absence of prednisone maintenance therapy.

A fourth limitation is that our study is not randomized. We began with a pilot study; the rate of acute rejection was so low that we immediately incorporated the protocol into routine use. Recently, ter Meulen et al. reported the 12-month results of a prospective randomized study in which 364 kidney transplant recipients (on TAC and MMF) received either two doses of anti-IL-2 receptor antibody (daclizumab) and 3 days of prednisone versus steroids for 16 weeks (13). At 12 months, they found no difference between the two groups' biopsy-proven acute rejection or graft survival rates. Of interest, the cardiovascular risk effect profile was temporarily better in the daclizumab group, but at 1 year, there was no difference.

The study by ter Meulen is the only published prospective randomized study of early (<1 week) steroid withdrawal. Their study and numerous other single-center reports have noted a low rate of acute rejection episodes with early steroid withdrawal protocols. But, for most such studies, average follow-up has been ≤12 months. An ongoing concern is what constitutes acceptable ‘long-term’ follow-up for steroid-free maintenance immunosuppression protocols. Prednisone is an anti-inflammatory drug. Therefore, it can always be argued that in the absence of prednisone, more long-term scarring of the kidney (chronic allograft nephropathy) is likely. Our study suggests that 5-year outcome is acceptable, but it does not answer the question of whether or not function will markedly deteriorate at 7, 10, 15 or 20 years posttransplant. Ideally, a prospective randomized trial, with adequate enrollment and long-term follow-up, should be done. However, given our current experience and, in particular, the improved side effect profile we have noted in recipients on steroid-free maintenance immunosuppression, we would find it difficult to randomize a large cohort of our patients to a prednisone-containing study arm.

All recipients on our prednisone withdrawal protocol received a calcineurin inhibitor (either CSA or TAC) as part of their immunosuppressive therapy. Long-term calcineurin inhibitor use has been associated with hypertension and nephrotoxicity (22). In addition, both CSA and TAC have drug-specific side effects. Thus, another immunosuppressive strategy might be to minimize or eliminate calcineurin inhibitors. Recently, some authors reported low acute rejection rates and excellent short-term graft survival using protocols that either avoided or discontinued calcineurin inhibitors (23–28). However, all of those protocols incorporated long-term maintenance prednisone. If both calcineurin-sparing and prednisone-sparing protocols are found to improve long-term outcome (e.g. better patient and graft survival, minimization of side effects), future trials will be needed to define a reasonable balance. Or, perhaps development of new immunosuppressive agents will permit protocols that are free of both prednisone and calcineurin inhibitors (29).

In conclusion, in spite of excellent short-term outcome, concern persists that immunosuppressive protocols incorporating prednisone avoidance or rapid discontinuation will lead to late graft dysfunction and increased graft loss. We now report an 84% 5-year graft survival rate (92% death-censored graft survival) and stable serum creatinine levels for recipients on our prednisone-free maintenance protocol.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We thank Mary Knatterud for editorial assistance and Stephanie Daily for preparation of the manuscript. We also thank the transplant fellows and coordinators as well as all of the other physicians, nurses and administrative staff who helped care for the patients and made this large-scale study possible.

This study was supported by Fujisawa Healthcare, Genzyme, NIH DK13083.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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