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Early Corticosteroid Withdrawal in Recipients of Renal Allografts

A Single-Center Report of Ethnically Diverse Recipients and Recipients of Marginal Deceased-Donor Kidneys

Aull, Meredith J.1; Dadhania, Darshana2,3; Afaneh, Cheguevara1; Leeser, David B.1,3; Hartono, Choli2,3; Lee, Jun B.2,3; Serur, David2,3; Del Pizzo, Joseph J.1,5; Suthanthiran, Manikkam3,4; Kapur, Sandip1,3,6

doi: 10.1097/TP.0b013e318265c461
Clinical and Translational Research
Free
SDC

Background Candidacy for kidney transplantation is being progressively liberalized, and the safety and efficacy of early withdrawal of corticosteroids in high-risk patients have not been fully characterized.

Methods We analyzed the safety and efficacy of an early corticosteroid withdrawal regimen of rabbit antithymocyte globulin induction, tacrolimus, mycophenolate mofetil, and steroid withdrawal by day 5 after transplantation in our study cohort of 634 kidney transplant recipients that included 27% African American and 18% Hispanic recipients. Fifty-five percent of the recipients were recipients of deceased-donor kidneys, and 46% of deceased-donor kidneys were kidneys from expanded criteria donors.

Results Kaplan-Meier patient survival at 1, 3, and 5 years after transplantation was 98.6%, 94.6%, and 90.2%, and death-censored graft survival was 96.2%, 91.9%, and 87.6%, respectively. During a mean follow-up of 57 months, 89.3% of patients remained off of corticosteroids, and the incidence of acute rejection including subclinical rejection identified by protocol biopsy was 12.0%. Multivariable analysis identified age older than 60 years as protective against (P=0.01) and the African American ethnicity as a risk factor for (P=0.03) rejection. Delayed graft function (P<0.0001), rejection (P<0.0001), and transplant panel reactive antibody 20% or more (P=0.03) were risk factors for graft loss. Opportunistic infections included viral in 15.3%, fungal in 1.6%, and parasitic in 0.6% of the patients. Posttransplantation malignancy occurred in 9.1% of patients.

Conclusions An early corticosteroid withdrawal regimen of rabbit antithymocyte globulin induction, tacrolimus, and mycophenolate mofetil is associated with excellent patient and kidney graft survival in an ethnically diverse population with risk factors for poor outcomes.

1 Division of Transplantation Surgery, Department of Surgery, NewYork-Presbyterian/Weill Cornell Medical Center, New York, NY.

2 The Rogosin Institute, New York, NY.

3 Department of Transplantation Medicine, NewYork-Presbyterian/Weill Cornell Medical Center, New York, NY.

4 Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian/Weill Cornell Medical Center, New York, NY.

5 Department of Urology, NewYork-Presbyterian/Weill Cornell Medical Center, New York, NY.

6 Address correspondence to: Sandip Kapur, M.D., 525 E. 68th St. Baker Bldg., 19th Floor, Room 1919/Box 98 New York, NY 10065.

This research was partially funded by an unrestricted educational grant from Genzyme Corporation (formerly Sangstat Medical Corporation).

The authors declare no conflicts of interest.

E-mail: sak2009@med.cornell.edu

M.J.A., D.D., and S.K. participated in performing the research, analyzing data, and writing the article. C.A. participated in analyzing data and writing the article. D.B.L., C.H., J.B.L., D.S., and J.D.P. participated in performing the research. M.S. participated in performing the research and writing the article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Received 30 April 2012.

Accepted 20 June 2012.

Long-term use of corticosteroids (CSs) after transplantation increases morbidity and health-related costs (1). The percentage of kidney transplant recipients discharged without CSs has increased from 3.7% in 2000 to 32.6% by 2006 in the United States (2). CS withdrawal (CSWD) is not new, but only recently successful outcomes have been obtained (3–7) because of the availability of potent immunosuppressive medications and improved success seen with early versus late CSWD (8). Analysis of the Scientific Registry of Transplant Recipients (SRTR) comparing 16,491 kidney transplant recipients discharged on a CS-free regimen to 79,264 patients on CS maintenance found better patient and graft survival at 4 years after transplantation in the CS-free group. Because of potential bias in recipient selection, superiority of the regimen cannot be established, but there seems to be no detrimental effect from CS-free regimens in select patients (2).

Successful outcomes have been reported with early CSWD in large studies of low–immunologic-risk patients (3–7, 9–12) and smaller studies of high-risk patients (10, 11, 13, 14). Meta-analysis of early CSWD trials demonstrated significant increase in acute rejection (AR) and graft loss (15). A meta-analysis that included cyclosporine or tacrolimus plus mycophenolate mofetil (MMF)–containing regimens found increased risk of AR (risk ratio=2.28) but not graft loss (risk ratio=0.73) (16). The results of a randomized, multicenter, double-blind, placebo-controlled trial of early CSWD using induction therapy, tacrolimus, and MMF found that despite higher AR in the CSWD group (17.8% vs. 10.8% in steroid group; P=0.058), death-censored graft loss was similar (5.8% vs. 3.6%, respectively; P=not significant), and CSWD-related metabolic benefits were observed (7).

Although these important trials began to set the stage for widespread application of CSWD, patients included in these trials may not reflect the “real world” population; therefore, generalizability of the results to the broader kidney transplant population remains a challenge (17, 18). Importantly, the major randomized controlled trials excluded patients receiving expanded criteria donor (ECD) kidneys (19) and kidneys from donors older than 65 years (16) and patients developing delayed graft function (DGF) (16).

Herein, we report outcomes with an early CSWD regimen in 634 ethnically diverse renal allograft recipients, many of whom received an ECD kidney and experienced DGF. The primary finding from our single-center study is that early CSWD is safe and efficacious in a renal transplant cohort that is representative of emerging U. S. transplant recipients, and the patient and graft outcomes in this high-risk population compare favorably with the data from the SRTR of patients managed with CSs and data from relatively low-risk patients receiving CSWD regimens.

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RESULTS

Kidney Transplant Recipient Characteristics

Between November 2001 and April 2008, 634 kidney transplant recipients at our center received an early CSWD regimen (rabbit antithymocyte globulin [rATG]+CS×5 days, tacrolimus, and MMF) (Table 1). Mean (SD) posttransplantation follow-up is 56.5 (24.6) months at the time of report preparation (11/2011). Recipients were 51 (15) years of age; 63.9 % of whom were male; 27% were African American; 18%, Hispanic; and more than 50% received a deceased-donor (DD) transplant, 46% of whom received an ECD kidney. DGF occurred in 38% (133/350) of DD recipients and 2.5% (7/284) of living-donor (LD) recipients. Diabetes mellitus (DM; 25.9%), glomerular disease (23.5%), and hypertension (15%) were leading causes of chronic kidney disease.

TABLE 1

TABLE 1

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Patient Survival

Kaplan-Meier (KM) actuarial patient survival of kidney transplant recipients receiving early CSWD was 98.6% at 1 year, 94.6% at 3 years, and 90.2% at 5 years. Figure 1(A–C) shows patient survival, stratified by kidney donor type, in patients receiving early CSWD. Patient survival data from the SRTR are also shown to illustrate the safety of CSWD in our high-risk recipients (20).

During the mean follow-up of 57 months, 62 (9.8%) patients died because of cardiovascular disease (n=12), infection (n=11), malignancy (n=10), stroke (n=3), gastrointestinal bleed (n=2), perioperative complications (n=2), liver failure (n=2), and other/unknown causes (n=20). Most patients (47 [76%] of 62) died with a functioning graft.

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Graft Survival and Graft Function

KM death-censored graft survival was 96.2% at 1 year, 91.9% at 3 years, and 87.6% at 5 years. Figure 1(D–F) shows graft survival, stratified by kidney donor type, in patients receiving early CSWD. Graft survival data from the SRTR are also shown to illustrate the efficacy of the regimen (20).

Seventy-two grafts (11.4%) were lost from reasons other than death: chronic allograft nephropathy/transplant glomerulopathy (n=14), primary nonfunction (n=8), AR (n=8), nonadherence (n=7), donor-derived disease (n=6), thrombosis (n=5), polyomavirus-associated nephropathy (PVAN) (n=5), acute kidney injury (n=5), infection (n=4), recurrent disease (n=3), and other/unknown causes (n=7).

Mean (SD) serum creatinine level at 1 year was 1.6 (0.6) mg/dL, 1.5 (0.6) mg/dL at 3 years, and 1.5 (0.7) mg/dL at 5 years after transplantation, whereas tacrolimus troughs were 6.9 (4.3), 6.2 (2.4), and 5.8 (1.9) ng/mL, respectively. Figure S1(A and B) (see SDC, http://links.lww.com/TP/A702) illustrates longitudinal creatinine and tacrolimus values in patients with a functioning allograft.

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Acute Rejection

As a safety measure and to evaluate subclinical rejection with the early CSWD regimen, willing patients were enrolled in a protocol biopsy study. A total of 164 patients underwent 237 protocol biopsies at 1 (n=84), 3 (n=54), 6 (n=59), and 12 months (n=40) after transplantation (Tables 1 and 2), with a subclinical AR rate of 1.3% (3/237) (Table 2).

TABLE 2

TABLE 2

The incidence of biopsy-confirmed AR, including the subclinical rejection, was 12.0% (76/634) during follow-up (Fig. 2 and Table 2). KM analysis showed AR rates of 6.6% at 1 year, 11.0% at 3 years, and 12.8% at 5 years (Fig. 2A). Median time to AR was 9.8 months (range, 0.3–64.1 months). Among the 76 AR biopsies, 48 (63.2%) were acute T-cell–mediated rejection, 16 (21.0%) were antibody-mediated rejection, and 12 (15.8%) had features of both (Fig. 2B).

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

Reversibility of AR, defined as functioning graft 6 months after treatment, is presented in Figure 2C. Twenty-two (28.9%) patients lost their graft a median of 129 days after AR (range, 0–1799 days). AR was a significant risk factor for graft loss (P<0.0001) (Fig. 2D).

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Univariate Analysis of AR and Graft Loss

We investigated risk factors for AR and graft loss in patients treated with CSWD. Patients were less likely to experience AR if they were 60 years or older (5.9% vs. 14.8% if <60; P=0.002) or if they had type 2 DM (6.6% vs. 13.9% without type 2 DM; P=0.02) (see Table S1, SDC, http://links.lww.com/TP/A702). Rejection was higher in patients with a peak panel reactive antibody (PRA) of 20% or greater (18.4% vs. 10.4% if <20%; P=0.02) and in African American recipients (18.1% vs. 9.7% in non–African Americans; P=0.006)

Graft loss was higher in African American recipients (19.3% vs. 8.6% in non-African Americans; P=0.0003), in those who received a DD transplant (14.9% vs. 7.4% in LD recipients; P=0.005), in those with peak PRA of 20% or greater (19.2% vs. 9.6% if <20%; P=0.004), and in those with a transplant PRA of 20% or greater (29.4% vs. 11.0% if <20%; P=0.05) (see Table S2, SDC, http://links.lww.com/TP/A702). Risk was also higher in patients with DGF (25.5% vs. 7.5% without DGF; P<0.0001) or AR (35.5% vs. 8.2% without AR; P<0.0001). Additional factors included in the univariate analyses for AR and graft loss are listed in Tables S1 and S2 (see SDC, http://links.lww.com/TP/A702).

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Multivariable Analysis of AR and Graft Loss

We examined for independent risk factors for AR and graft loss using multivariable analysis. Variables significantly associated with AR or graft loss by univariate analyses were included in the multivariable analysis (Table 3). Risk of AR remained lower in patients 60 years or older (hazard ratio [HR]=0.45; P=0.01), whereas African American recipients remained at a higher risk (HR=1.70; P=0.03).

TABLE 3

TABLE 3

Pretransplantation PRA of 20% or more (HR=3.32; P=0.03), DGF (HR=4.05; P<0.0001), and AR (HR=4.57; P<0.0001) were independent risk factors for graft loss. The African American race was marginally associated with graft failure (HR=1.61; P=0.06).

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Requirement for Corticosteroids

Sixty-eight patients (10.7%) required introduction of maintenance CSs. Reasons included rejection (n=40), pancreas transplant (n=10), kidney biopsy findings (not rejection) (n=7), recurrent disease (n=4), suspected rejection (no biopsy) (n=2), MMF intolerance (n=2), tacrolimus toxicity (n=1), malignancy (n=1), and pregnancy (n=1). Overall KM estimates of those remaining off of maintenance CS at posttransplantation years 1 through 5 were 93.2%, 91.0%, 90.1%, 89.7%, and 89.4%, respectively, and is shown, stratified by donor type, in Figure 1G.

Temporary reintroduction of CS occurred in 54 patients (8.5%), who received a short course and were then rapidly tapered off. Reasons included rejection (n=13), serum sickness (n=12), gout (n=9), neutropenia (n=3), tacrolimus toxicity (n=3), and miscellaneous (n=14).

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Cardiovascular Risk

A subanalysis of the first 258 patients to receive the CSWD regimen was performed to assess new-onset DM (NODM), hypertension, dyslipidemia, and weight gain (see Methods and Table S3, SDC, http://links.lww.com/TP/A702). NODM occurred in 7.1%. Blood pressure improved at all time points, in conjunction with significant reduction in antihypertensive medications needed during the first posttransplantation year. Lipids remained stable; the use of lipid-lowering agents did increase over time. Weight gain occurred through 3 years after transplantation (mean, 5.5 kg).

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Posttransplantation Complications: Infection

One-hundred thirteen viral illnesses were observed in 97 patients (15.3%): tissue-invasive cytomegalovirus (CMV) (n=20; 3.2%), CMV viremia (n=18; 2.8%), PVAN (n=12; 1.9%), polyomavirus viremia (n=13; 2.1%), herpes zoster (n=31; 4.9%), herpes simplex (n=8; 1.3%), adenovirus (n=4; 0.6%), varicella zoster (n=3; 0.5%), West Nile (n=1), parvovirus (n=1), HHV-6 viremia (n=1), and Epstein-Barr virus viremia (n=1) (0.2% each). Ten patients (1.6%) developed invasive fungal infection, including esophageal candidiasis (n=4), pneumocystis jiroveci (n=2), aspergillus brain abscess (n=1), cryptococcal meningitis (n=1), pulmonary cryptococcus (n=1), and fungal peritonitis (n=1). Four patients (0.6%) developed parasitic infection, including cryptosporidium (n=2) and strongyloides (n=2).

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Posttransplantation Complications: Malignancy

Fifty-eight recipients (9.1%) were diagnosed with 73 malignancies during follow-up, including squamous cell carcinoma (n=21), basal cell carcinoma (n=13), posttransplantation lymphoproliferative disease (n=5), renal cell carcinoma (native) (n=6), prostate (n=4), lung (n=3), melanoma (n=3), unspecified skin (n=2), bladder (n=2), and colon (n=2). There was one case each of squamous cell carcinoma of the vocal cords, lung, and anus; cholangiocarcinoma, maltoma, and leiomyosarcoma; and oropharyngeal, pancreatic, thyroid, cervical, breast, and uterine cancers.

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DISCUSSION

In a patient population at risk for poor outcomes caused by recipient or donor risk factors (27% are African Americans, 18.5% are Hispanics, 55% received a DD kidney with 38% DGF, and 46% received DD kidneys from ECD), our early CSWD regimen was associated with excellent outcomes; KM patient survival was 90.2% at 5 years, whereas death-censored graft survival was 87.6%. Rejection rates were 6.6% at 1 year, 11.0% at 3 years, and 12.8% at 5 years, despite inclusion of both borderline and subclinical rejections. It is noteworthy that a relatively short course of rATG (no prolongation in patients with DGF) and low-dose MMF was used. Our results in ethnically diverse recipients and recipients of marginal DD kidneys are comparable with those observed by Matas et al. (6), with a recipient cohort comprised primarily of whites and recipients of LD grafts (89% white and 72% received a LD kidney), and also with the outcomes reported in DD transplant recipients by Sureshkumar et al. (21). Our results compare favorably with outcomes reported by the SRTR; (20) 5-year actuarial ECD graft survival was 73.4% in our cohort, compared with 56.9% nationally.

In the multivariable analysis of risk for rejection with CSWD regimens by Woodle and colleagues (22), risk was higher in repeat transplant recipients, transplant PRA greater than 25%, DGF, human leukocyte antigen DR mismatch greater than 0, the African American race, type 1 DM, and the female gender. Our univariate analysis showed some similarities, although only the African American race was statistically significant in the multivariable model, whereas older age was a protective factor.

To our knowledge, our report is the largest series to date of early CSWD in African American recipients, whose outcomes (actuarial graft survival at 1 and 5 years of 92.9% and 78.5% and AR rates of 9.0% and 19.1%, respectively) occurred in the setting of more than 70% of these patients receiving a DD kidney. African Americans were at a higher risk for rejection (P=0.03) and graft loss (P=0.06) in our analysis and have been reported to be at a higher risk for return to CS therapy after initial early steroid withdrawal (23). Zeng et al. (11) used a similar induction regimen and found an 18% AR rate and 89% graft survival at 23 months after transplantation in 57 African American recipients, 81% of whom received a DD transplant. Using basiliximab induction, Kumar et al. (24) observed 1-year biopsy-proven AR of 16% in 103 African American patients receiving early CSWD. It seems that utilization of rATG induction is necessary for optimum outcomes after early CSWD in African American recipients, although this population seems to be at a high risk for rejection regardless of induction agent used.

Our series also represents the largest report of CSWD in the Hispanic population, whose immunologic risk has been debated. In our 117 Hispanic patients, actuarial AR rate at 5 years is 15.2%, whereas graft survival is 88.7%. Other centers report high rates of AR in Hispanic patients, and consider this population to be high risk, similar to African Americans (25, 26). In our analysis, despite a similar rejection rate (15.2% vs. 19.1% in African Americans; P=0.4), graft survival at 5 years was better in Hispanic recipients (88.7% vs. 78.5% in African Americans; P=0.05).

The utilization of our CSWD regimen in 107 patients older than 60 years is another unique aspect of our study. These patients were protected from AR (HR=0.45). Further analysis is necessary to establish that the risks of infection and malignancy are acceptable with this type of immunosuppression regimen in the older kidney transplant population.

Our low AR rates were observed without clinical evidence of excessive immunosuppression. Viral infection was the most common infection; however, the combined incidence of CMV was 6%, whereas PVAN was seen in 1.9% of patients. This is comparable to others showing a 7% to 8% incidence of CMV in patients receiving CSWD under rATG induction (6, 11) and much lower than early experiences using rATG with steroid maintenance (27, 28). Incidence of fungal and parasitic opportunistic infections was also low. Malignancy occurred in 9.1% of patients during the follow-up period, comparable to other CSWD experiences (10% to 12% at 5 years) (6, 7).

Similar to controlled trials of CSWD regimens after kidney transplantation, our patients experienced excellent blood pressure control, stable lipids, and low rates of NODM (7, 19). Weight gain occurred, similar to other reports (7, 19, 23). We recognize that our incidence of NODM may be underestimated because of the inability to distinguish whether fasting blood glucose tests were performed, thus preventing us from using established diagnostic criteria for type 2 DM in all patients (29). Because cardiovascular disease is the leading cause of mortality in kidney recipients beyond the first posttransplantation year, improvement or stabilization of these risk factors may ultimately lead to lower morbidity and mortality. Although difficult to directly attribute to CSWD because of the variety of factors impacting cardiovascular health, the apparent patient survival benefit in our ECD recipients is of great interest.

There are several limitations to our study, primarily, lacking a control group and being a single-center experience. Because of a short period between the initiation of a tacrolimus-based maintenance regimen in all of our patients and the introduction of the CSWD regimen, we did not have a meaningful number of historical controls. However, our well-defined protocol-driven regimen does add strength to the analysis because all patients received the same regimen regardless of risk factors and is thus one of the largest series using a consistent induction and maintenance regimen. The results in our diverse population may also be more generalizable to the broader population of kidney transplant recipients as compared with the controlled trials performed to date.

Our single-center experience demonstrates that a standardized early CSWD regimen enables excellent outcomes in a racially diverse population with traditional risk factors for graft loss. To our knowledge, this is the largest series of early CSWD in African American, Hispanic, and ECD kidney transplant recipients, as well as in recipients 60 years or older. Multivariable analysis did not reveal unexpected risk factors but are rather consistent with established risk factors for AR and graft loss in the general population of kidney transplant recipients treated with a steroid replete regimen. Early and 5-year results are very encouraging; however, longer-term follow-up is essential to determine the impact of early CSWD on longer-term patient and graft survival.

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MATERIALS AND METHODS

Evolution of Early CSWD Regimen at Our Center

In November 2001, we initiated an early CSWD regimen as the standard for low-risk, nonhaploidentical recipients. Based on our positive clinical experience, the regimen was extended to DD kidney recipients by January 2003. Exclusions to the protocol can be found in the SDC Methods (see SDC, http://links.lww.com/TP/A702). Two hundred twenty-eight of the DD transplant recipients in this report were previously described in another publication from our center (30).

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Protocol Biopsy Group

As a safety measure and to evaluate rates of subclinical rejection (AR found incidentally on biopsy without rise in serum creatinine), willing patients receiving the early CSWD regimen were enrolled in the protocol biopsy study.

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Ethics Review

The institutional review board of Weill Cornell Medical College approved the review of the early CSWD regimen (protocol # 0407007315) and protocol biopsy study (protocol # 0111005226).

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Early CSWD Regimen

Induction consisted of rATG 1.5 mg/kg per day (postoperative days 0–4). Maintenance immunosuppression included tacrolimus (initiated postoperative day 2; target trough, 10–12 ng/mL by IMX [Abbott Diagnostics, Abbott Park, IL] ×3 months) and MMF (2 g/day). In late 2002, MMF was reduced to 1 g/day (non–African Americans) because of neutropenia and published data showing CSWD increases mycophenolic acid exposure (31). Steroids were administered within 60 min before each rATG dose (cumulative dose, 995-mg methylprednisolone). Information regarding opportunistic infection prophylaxis and treatment of rejection are provided in the SDC Methods section (see SDC, http://links.lww.com/TP/A702).

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Statistical Analysis

The intention-to-treat population was used to calculate patient and graft survival and incidence of AR. Descriptive statistics were used to summarize demographics and transplant characteristics. All data elements were treated as binary or categorical. Initial bivariate analyses were performed using Fisher exact test to examine the associations between potential predictors and the outcomes of interest. Cox proportional hazards methodology was used for both univariate and multivariable modeling of the outcome variables. Variables included in the analysis are listed in Tables S1 and S2 (see SDC, http://links.lww.com/TP/A702). Variables significantly associated with AR and graft loss in the univariate analyses were included in multivariable analyses. KM methodology was used to calculate actuarial patient and graft survival and rejection rates, using MedCalc for Windows, version 11.6.0 (MedCalc Software, Mariakerke, Belgium). Cox proportional hazards modeling was performed using SAS 9.1 (SAS Institute, Cary, NC).

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Keywords:

Corticosteroid withdrawal; Kidney transplant; African American; Expanded criteria donor; Delayed graft function

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