…But Not All Patients Should be Steroid-Free Posttransplant

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Glucocorticoids (more commonly referred to as steroids) have been a key component of posttransplant immunosuppression and rejection treatment since the 1960s, the very early days of solid organ transplantation. At the time, steroids, in combination with azathioprine (Aza) or other mercaptopurine analogs, were the most common oral maintenance immunosuppressive agents used. Graft survival was not great, but in the absence of steroids, graft rejection and loss were almost assured.

Over the next few decades, many newer and more potent immunosuppressive agents were developed, leading to remarkable declines in early acute rejection (AR) rates and some improvements, to a lesser degree, in graft survival. With these results, many investigators justifiably questioned the time-honored belief that steroids were still needed. Initial studies focused on steroid “withdrawal,” i.e., the phased removal of steroids at some point after transplant, in a select group of patients who were considered “low-risk” (usually those without prior AR episodes). Many of these studies showed an unacceptably high rate of AR postwithdrawal (1, 2), leading to the belief that patients developed an immunological dependency on steroids once they began receiving this class of drugs.

Are steroids necessary with modern immunosuppressants?

Because these studies occurred in the cyclosporine (CsA)-Aza era, prior to introduction of tacrolimus and mycophenolate, the question remained as to whether steroids were needed with modern immunosuppression drugs. Steroid withdrawal at time points at or beyond three months posttransplant in a CsA-mycophenolate–based regimen was associated with more AR episodes (3, 4). But the metabolic benefits included less hypertension and less hyperlipidemia, two major cardiovascular risk factors.

In order to get around the “dependency” phenomenon, regimens were devised that eliminated steroids completely (avoidance) or exposed patients to steroids only for a brief period posttransplant, in most cases less than a week (minimization). Prospective limited center studies with historical controls suggested no detriment in terms of AR increase or worse graft survival (59). In fact, many perceived benefits were noted, such as reduced incidence of hypertension, better linear growth in children, better cosmetic appearance, and better compliance with medications.

Yet the gold standard for evidence-based medicine remains the randomized controlled trial. Initial results were promising in terms of steroid withdrawal with modern immunosuppression. Vincenti et al. found that addition of the induction antibody basiliximab and a change from Aza to mycophenolate allowed for safe early steroid withdrawal or minimization (10). The incidence of biopsy-proven AR at 12 months was not significantly different between the steroid withdrawal group (20 percent) and the standard treatment group (16 percent). Allograft function and incidence of adverse events and infections were similar between the two groups. Now the question was whether steroid avoidance was better than minimization.

Avoidance versus minimization

The FREEDOM study was a large prospective randomized controlled trial that compared three groups head to head: steroid maintenance, early steroid withdrawal by day seven, and steroid avoidance (11). The results of the study were very clear: a graded increase in one-year AR incidence going from 19 percent in the maintenance group to 29 percent in the withdrawal group to 36 percent in the avoidance group. Mean glomerular filtration rate (GFR) at one year was identical in all three groups, as was short-term graft survival. Hypertension incidence was slightly lower in the avoidance group. In short, from the authors’ perspective, the randomized prospective trial showed some detriment and some benefit to avoiding steroids, in contrast to prior historically controlled studies, which showed only benefits.

In an editorial accompanying the FREEDOM study, Meier-Kriesche et al. pointed out that the steroid avoidance group had a greater percentage of living donors, generally associated with better outcomes (12). The study was open-label. In the intent-to-treat analysis, the incidence of biopsy-proven acute rejection was statistically higher in both the steroid avoidance (31.5 percent) and the steroid withdrawal (26.1 percent) arms compared with the steroid maintenance group (14.7 percent).

Hricik has provided further insight into this study’s results (13). The graft survival rates were similar among the three groups, but the study was not powered to detect differences in graft survival. The metabolic benefits observed were modest (fewer antihyperglycemic medications in the steroid-free group and less frequent lipid-lowering agents in the steroid withdrawal group), but actual incidences of diabetes mellitus were the same in all groups. Lipid levels were not measured. Less weight gain was seen only in the steroid withdrawal group, not in the avoidance group.

The groups did not remain as they were initially assigned: 12 percent of steroid maintenance subjects were not on steroids at 12 months, and a substantial minority of steroid-sparing subjects started steroids through the course of the study. The patient population was set up to be standard immune risk, but only 1.2 percent of participants were African Americans, a traditionally high-risk group. To these comments, I would add that the study was designed with basiliximab, CsA, and enteric-coated mycophenolate as concomitant medications, a combination of drugs all manufactured by one company but not commonly used clinically in the United States.

Another recently published trial by Woodle et al. looked at early (within seven days) withdrawal (minimization) versus long-term steroid maintenance in prospective randomized cohorts receiving tacrolimus and mycophenolate mofetil (14). Complete steroid avoidance was not tested in this trial, but blinding was maintained for five years.

In the Woodle study, 386 subjects were divided into two groups. The early withdrawal group had a significantly higher biopsy-proven AR rate of 17.8 percent versus 10.8 percent (P = 0.04) for the long-term steroid maintenance group. Graft survival and kidney allograft function at five years posttransplant were similar. Five-year death-censored graft loss was 5.8 percent with early withdrawal and 3.6 percent with maintenance. Cockroft-Gault GFR was 58.6 mL/min in the early withdrawal group and 59.8 mL/min in the maintenance group. Once again, metabolic benefits were modest. Serum triglycerides were better with steroid early withdrawal at earlier time points, but no different between groups at the study end point of five years. Newly onset diabetes requiring treatment was also no different (early withdrawal, 20.5 percent; long-term steroid maintenance, 20.9 percent), although the percentage of patients who needed insulin was less in the early steroid withdrawal group.

Steroids in children

The NIH-funded SNS01 prospective randomized controlled trial of steroid avoidance versus maintained steroids in children is nearing completion. Analysis of 12-month clinical end points was presented by Minnie Sarwal, MD, PhD, at the American Transplant Congress in 2008. The incidence of AR and graft loss were identical in both groups, as were the improvements in linear height and incidence of hypertension. Thus, the primary end point, a significant difference in delta height Z-score, was not met. Among the exclusion criteria for steroid avoidance were subjects with percent reactive antibody (PRA) > 20 percent, repeat transplants, those needing steroids for primary disease, and presence of delayed graft function.

The only steroid late withdrawal trial conducted in children was the NIH-funded SW01 trial conducted between 1999 and 2004, before the SNS01 trial. These children all received basiliximab, tacrolimus, sirolimus, and prednisone until month six. If no ARs had occurred and the six-month protocol biopsy was free of subclinical rejection, then those children were randomized to wean off steroids or stay on. The trial enrolled 276 children but was stopped six months prior to expected completion due to a high incidence of posttransplant lymphoproliferative disorder in both study arms (15). What is notable is that the steroid withdrawal group was doing better in terms of graft survival and graft function than the maintained group. The difference did not quite reach statistical significance, but the likelihood that the steroid withdrawal group was worse is extremely remote.

Another highly rated form of evidence-based medicine is the Cochrane review system. Pascual et al. recently published a systematic review of steroid avoidance or withdrawal, evaluating 30 studies containing 5949 patients (16). Patients on any steroid-sparing strategy showed a higher risk of graft loss (excluding death) than those with conventional steroid use [relative risk (RR), 1.23; 95 percent confidence interval (CI), 1.00 to 1.52]. Acute rejection was also more frequent (RR, 1.27; 95 percent CI, 1.14 to 1.40).

Sarwal will argue that steroid avoidance is not inferior and may remove one drug from a long list of medications that transplant patients need to take daily. Although steroid avoidance certainly may be feasible for some recipients, the following groups may not be candidates for steroid avoidance: patients with high PRA levels or the need for steroids for primary renal disease (such as lupus nephritis) and those with delayed graft function (DGF). DGF, as defined by need for dialysis in the first week posttransplant, currently occurs in 24 percent of all deceased donor kidney transplants in the United States. Milder degrees of kidney injury, called slow graft function by some, are much more frequent.

Steroid avoidance and acute rejection

What about those patients on steroid avoidance in whom an AR occurs? Are these patients at risk for worse outcomes if they stay steroid-free? There are no rigorous data at present. However, Humar et al. provided some indication of possible outcomes in a retrospective uncontrolled analysis (17). They looked at 842 adult kidney transplant recipients on a steroid minimization protocol. Of these, 17.7 percent, or 149, had at least one AR episode. Thirty-four percent of these patients restarted maintenance steroids; the other 66 percent remained steroid-free. The choice was not randomized; physician preference and concomitant diabetes played a significant role. Not restarting steroids after the first AR resulted in a borderline increase in risk for a second AR episode (RR = 2.1; P = 0.07). The study suggested that some patients might be worse off if steroids were not restarted, although graft survival was not different between the two retrospective groups.

An analysis of the Scientific Registry of Transplant Recipients (SRTR), to be presented by Santos et al. at the American Transplant Congress this month, supports this view. This study looked at all solitary kidney transplants performed between 2002 and 2006. By 12 months posttransplant, 34 percent of recipients who were reported as steroid-free at initial discharge were now on steroids. The patients who restarted were predictable: African Americans, retransplants, those with high PRAs, and those who received expanded criteria kidneys. Patients newly started on steroids had a 20 percent increased risk of graft loss compared to those maintained on steroids from the start.

In summary, while steroid avoidance might be a suitable strategy for a select group of patients, a significant number will not qualify. Patients with high PRAs or a prior transplant comprise an ever-increasing proportion of the transplant population. Furthermore, published studies did not enroll African Americans to a significant extent, yet this group is known to be at higher immunologic risk. DGF occurs in a quarter of all deceased donor kidney transplant recipients. A significant minority of such recipients will have a greater propensity to immunologic events requiring steroid use pretransplant.

Potential side benefits of steroid avoidance or minimization have been much more modest in the recently reported randomized controlled trials than in prior series. Whether steroid minimization is better than avoidance when DGF is present is unknown. Furthermore, late steroid withdrawal may not be as bad as previously thought, with the switch from CsA-Aza to tacrolimus-mycophenolate mofetil–based maintenance immunosuppression.

References

1. 

Kasiske BL, Chakkera HA, Louis TA, Ma JZ: A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000; 11(10):1910–7.

2. 

Pascual J, Quereda C, Zamora J, Hernandez D: Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transpl 2004; 78(10):1548–56.

3. 

Ahsan N, Hricik D, Matas A, Rose S, Tomlanovich S, Wilkinson A, et al.: Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil—a prospective randomized study. Steroid Withdrawal Study Group. Transpl 1999; 68(12):1865–74.

4. 

Vanrenterghem Y, Lebranchu Y, Hene R, Oppenheimer F, Ekberg H: Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transpl 2000; 70(9):1352–9.

5. 

Cole E, Landsberg D, Russell D, Zaltzman J, Kiberd B, Caravaggio C, et al.: A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients. Transpl 2001; 72(5):845–50.

6. 

Elias TJ, Bannister KM, Clarkson AR, Russ GR, Mathew TH, Barratt LJ, et al.: Excellent long-term graft survival in low risk, primary renal allografts treated with prednisolone-avoidance immunosuppression. Clin Transpl 2000; 14(2):157–61.

7. 

Sarwal MM, Vidhun JR, Alexander SR, Satterwhite T, Millan M, Salvatierra O, Jr.: Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab induction in pediatric renal transplantation. Transpl 2003; 76(9):1331–9.

8. 

Shapiro R, Ellis D, Tan HP, Moritz ML, Basu A, Vats AN, et al.: Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation. J Pediatr 2006; 148(6):813–8.

9. 

Matas AJ, Kandaswamy R, Gillingham KJ, McHugh L, Ibrahim H, Kasiske B, et al.: Prednisone-free maintenance immunosuppression—a 5-year experience. Am J Transpl 2005; 5(10):2473–8.

10. 

Vincenti F, Monaco A, Grinyo J, Kinkhabwala M, Roza A: Multicenter randomized prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, cyclosporine microemulsion and mycophenolate mofetil. Am J Transpl 2003; 3(3):306–11.

11. 

Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J: A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transpl 2008; 8(2):307–16.

12. 

Meier-Kriesche HU, Magee JC, Kaplan B. Trials and tribulations of steroid withdrawal after kidney transplantation. Am J Transpl 2008; 8(2):265–6.

13. 

Hricik DE. Comparing early withdrawal or avoidance of steroids with standard steroid therapy in kidney transplant recipients. Nat Clin Pract Nephrol 2008; 4(7):360–1.

14. 

Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P: A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248(4):564–77.

15. 

McDonald RA, Smith JM, Ho M, Lindblad R, Ikle D, Grimm P, et al.: Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids. Am J Transpl 2008; 8(5):984–9.

16. 

Pascual J, Zamora J, Galeano C, Royuela A, Quereda C: Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev 2009; (1):CD005632.

17. 

Humar A, Gillingham K, Kandaswamy R, Payne W, Matas A: Steroid avoidance regimens: a comparison of outcomes with maintenance steroids versus continued steroid avoidance in recipients having an acute rejection episode. Am J Transpl 2007; 7(8):1948–53.