Early Steroid Withdrawal in Black Transplant Patients: A Selective Process

Blacks have historically shown inferior outcomes after kidney transplantation, with more acute rejection (AR) and shorter allograft survival compared with nonblacks (1,2). Reasons for inferior survival have been well delineated and include socioeconomic factors (3), delays in transplantation (4), a greater percentage of deceased and marginal donor kidneys (5,6), worse HLA matching (7), and differences in pharmacogenetics. Black patients have greater variability in CYP3A5 alleles, leading to variable metabolism of calcineurin inhibitor (CNI) therapy (8), and studies have shown lower initial levels of tacrolimus (TAC) and the need for higher dosages, on average, to achieve comparable levels versus nonblacks (9). In addition, the ABCB1 gene that encodes for the p-glycoprotein efflux membrane transporter responsible for cellular excretion of CNIs may have differences in expression between groups. One preliminary study showed an augmentation of ABCB1 gene expression in peripheral mononuclear cells in black men relative to nonblacks at 4 hours after cyclosporin A (CsA) dosing, and ABCB1 expression correlated highly with CsA clearance (10). Regardless of the mechanism, black kidney recipients have been shown to have more AR and lower rates of infectious death after kidney transplantation, suggesting a relative resistance to typical immunosuppression (11).

Given such risks, it may seem foolish to entertain the idea of corticosteroid withdrawal in black kidney recipients. Randomized trials have brought the safety of such a practice into question. In the 1990s, the Steroid Withdrawal Study Group analyzed 166 primary kidney transplant recipients treated with CsA and mycophenolate mofetil (MMF). Those with no early rejection were randomized at 3 months post-transplantation to undergo a blinded prednisone taper over 8 weeks versus maintenance at 10 mg/d (12). The study was terminated early due to a greater rate of rejection in patients on steroid withdrawal, approaching 30% at 1 year. The 26 black recipients withdrawn from steroids had a disproportionately high rate of rejection, approaching 40% at 1 year versus 16% for nonblacks.

More recently, the Astellas Corticosteroid Withdrawal Study Group randomized 397 kidney recipients with no early rejection and no delayed graft function (DGF) to early steroid withdrawal (ESW) versus chronic corticosteroid therapy (CCS) (13). All patients received induction therapy with antithymocyte globulin (ATG) or IL-2 receptor Abs, and all were maintained on TAC and MMF. Patients were randomized by donor source and black race, with 76 black recipients studied overall. Biopsy-proven AR rates overall were 17.8% in patients on steroid withdrawal versus 10.8% in patients on steroid maintenance (P=0.06 and significant by Kaplan–Meier analysis [P=0.04], respectively). Surprisingly, rejection rates were similar in blacks with ESW and CCS (17.6% versus 16.7%, respectively). In a post hoc analysis, there was a more than doubling in the rate of chronic allograft nephropathy (CAN) in patients on ESW overall (9.9% versus 4.1% in CCS; P=0.03), and 37% of patients with CAN lost their grafts during the study. In 3-year preliminary data, black patients on ESW had a higher rate of CAN at 14.7% versus 4.8% in black patients on CCS (P=0.20; World Transplant Congress, 2006).

Black patients have additionally shown less success in maintaining steroid-free therapy after ESW. A recent multicenter observational study found that 35.7% of black recipients were steroid free at 1 month post-transplantation compared with 41.0% of nonblacks (P=0.03) (14). At 1 year, the rate of steroid-free therapy dropped to 27.3% in the black cohort and increased slightly to 42.8% in the nonblack cohort (P<0.001). From registry data, black race was shown to be an independent risk factor for steroid resumption at 6 months after ESW in deceased donor recipients (15).

In this issue of the Clinical Journal of the American Society of Nephrology, Taber et al. (16) retrospectively analyzed registry data on adult black kidney recipients transplanted from January of 2000 to December of 2009 and stratified patients by ESW versus CCS at the time of initial discharge after transplantation. Patients with early death or graft loss within a month were excluded from analysis. Approximately 22% of black recipients (n=5825) underwent ESW during this period. Not surprisingly, there were many measureable differences between the ESW group and the larger CCS cohort, including more recent year of transplantation, greater use of cytolytic induction therapy, older recipient age, more living donor transplants, and less Ab sensitization in patients on ESW. In an attempt to overcome these differences, the investigators used propensity score matching to identify a subgroup of 5565 patients on CCS who matched well with the ESW group.

The authors found that, compared with the CCS group, the ESW group had a lower rate of rejection overall (11.3% versus 13.0%; P=0.001). Overall graft loss (including death) was similar between groups, but the ESW group had a patient survival benefit for the duration of the study (hazard ratio, 0.91; P=0.02). Data on death-censored allograft survival were not analyzed and would likely have required a competing risks model to control for patient mortality. Overall graft and patient survival rates were superior in the ESW cohort specifically in patients who received cytolytic induction therapy, TAC, and MMF/mycophenolic acid (MPA) and did not have DGF. Alternatively, in cohorts lacking those variables, there was an increase in overall graft loss and mortality relative to patients on CCS. In terms of induction therapy, the outcomes corroborated findings from a recent registry analysis that showed superior overall transplant survival in patients on ESW who received ATG compared with no induction or IL-2 receptor Ab therapy (17).

Although cause of death was not available in the study by Taber et al. (16), one may infer that a survival benefit with ESW was related to a lower rate of death related to infection and sepsis. However, the finding that a survival benefit was gained specifically in patients on ESW receiving cytolytic induction therapy and more potent maintenance therapy with TAC and MMF/MPA suggests that mortality may rather be related to allograft survival. Data on death were captured using the Social Security Death Index and included death after allograft failure, when mortality rates are known to spike in transplant recipients (18).

What do we make of the findings of this study? Is ESW protective against AR in blacks? This is unlikely on the basis of outcomes from randomized trials. Will ESW improve long-term patient and allograft survival in blacks? More likely, the ESW cohort reflects a particularly low-risk group identified early post-transplantation. The 1-year and overall AR rates were just 9.3% and 11.3%, respectively, in ESW recipients compared with a 1-year AR rate of 14.5% in all black recipients from 2000 to 2008 (1) and a 12.9% overall rate in 567 black recipients treated with ATG, TAC, MMF, and CCS from the authors’ own center (9). Additionally, the 5-year overall graft survival of 80.2% in patients on ESW was impressive and compares with a rate well below 80% in blacks from recent Scientific Registry of Transplant Recipients data (19).

Clearly, the ESW cohort studied in this article was a carefully selected group. To state that black recipients with ESW have less rejection and better graft survival is analogous to the observation that living kidney donors live longer than the general population or matched controls (20,21). Donating a kidney does not make one live longer, but being approved as a kidney donor is associated with a favorable prognosis. Similarly, being one of the roughly 20% of black recipients chosen to undergo ESW in recent years was predictive of superior outcomes and suggests that transplant practitioners are cautious and skilled in their selection process. Although center-level effect was not available in this analysis, a previous registry study showed a survival advantage with ESW but only among centers that were selective in choosing patients for withdrawal (22).

For those on the front lines of kidney transplant care, there are multiple factors that may influence the decision to maintain or eliminate steroid therapy. The occurrence of early AR during the hospital stay would push most providers toward CCS. In addition, sluggish initial kidney function (even in the absence of DGF) may make providers reluctant to eliminate steroids. Other factors that could influence this decision are difficult to capture in registry data and include patient education, affordability of immunosuppression, ability to achieve therapeutic levels of CNI therapy, and tolerability of MMF/MPA agents.

On the basis of the outcomes observed in this analysis, transplant practitioners have identified a subset of black patients who have succeeded with ESW. We should continue to be careful and selective, and Taber et al. (16) have provided additional guidance on adjunct therapy and clinical data associated with improved outcomes in these patients. Whether black patients on ESW would have done better or worse with CCS therapy remains unclear on the basis of this analysis. It may be that ESW is safe and even beneficial in a select group of black patients, and risk is clearly variable within the black community. For optimal patient selection, we need to continue to rely on data from randomized trials as a guide. There were just 76 black recipients in the Astellas Trial overall, but most were enrolled into the study over 15 years ago (13). Follow-up data on patient and allograft survival from that well designed randomized study are lacking and could add valuable insight into the long-term risks and benefits of ESW in blacks.

Disclosures

None.