Background: Rapid steroid withdrawal (RSW) is used increasingly in kidney transplantation but long-term outcomes in African-American (AA) recipients are not well known. We compared 1 and 5 year transplant outcomes in a large cohort of AA patients who were maintained on continued steroid therapy (CST) to those who underwent RSW. Methods: Post-transplant courses of A as receiving kidney allografts from 2003-2011 at two urban transplant centers in Chicago were followed. Prior to outcome analysis, we used Inverse Probability of Treatment Weights (IPTW) to match the two groups on a set of baseline risk factors. Graft and patient survival, GFR at 1 and 5 years, incidence and type of rejection, incidence of post-transplant diabetes mellitus (PTDM), delayed graft function, CMV and BK viremia were compared. Results: There were 150 AA recipients in the CST analytic group and 157 in the RSW analytic group. Graft and patient survival was similar between the two groups. Rates of CMV viremia were higher in the RSW compared to the CST analytic group at 1 year. Biopsy-proven acute rejection and PTDM were similar between the RSW and CST groups. Conclusions: In AA recipients, RSW has similar long-term outcomes to CST.
With the availability of more potent immunosuppressive medications, a number of studies have been published over the last two decades evaluating the role of steroid withdrawal in kidney transplantation. The general consensus is that rapid steroid withdrawal (RSW) when compared to continued steroid therapy (CST) is safe and effective and many centers are moving toward a RSW protocol [
We present data comparing RSW AA recipients to CST AA recipients from two urban centers in Chicago. In the CST group, corticosteroids were tapered to maintenance 5 mg daily dosing by 30 days post-transplantation. In the RSW group, steroids were withdrawn within 5 days post-transplantation. To our knowledge this is the only comparison study between RSW and CST in AA recipients. Further, it represents the largest cohort of AAs and the longest outcome data to date in this population.
We retrospectively reviewed data from AA transplant recipients at two Chicago-area academic medical centers from 2003 to 2011. During this period, The University of Chicago followed a continued steroid therapy (CST) protocol, and the University of Illinois employed a rapid steroid withdrawal protocol (RSW). Practice patterns at each center post-transplant are summarized in
Primary end-points included patient, graft, and death-censored graft survival. Secondary end-points included the estimated glomerular filtration rate (eGFR) at 1 and 5 years as determined by the Modification of Diet in Renal Diseases (MDRD) equation, the 1 and 5 year incidence of acute cellular and humoral rejection, and cumulative incidence of post-transplant diabetes mellitus (PTDM) defined as the a fasting glucose >126 mg/dL or random glucose >200 mg/dL requiring the initiation of oral anti-hyperglycemic or insulin based agents after transplant.
Patients in the CST group were induced with 4 doses of anti-thymocyte globulin (maximum dose 100 mg/day). Either mycophenolate mofetil 1000 mg twice a day or mycophenolate sodium 720 mg twice was used as an anti-proliferative agent. Corticosteroid treatment included intravenous methylprednisolone followed by a taper to maintenance steroid dosing of 5 mg per day at 1 month post-transplant. Patients were maintained on tacrolimus with target 12-hr trough level ranging 6 - 9 ng/ml for the first six months and then 4 - 7 ng/ml thereafter (
In the RSW group, patients were induced with 5 doses of 1.5 mg/kg/day anti-thymocyte globulin based on ideal body weight. Mycophenolate mofetil 1000 mg twice a day or mycophenolate sodium 720 mg twice a day
CST | RSW | |
---|---|---|
Induction Therapy | Anti-thymocyte globulin 1.5 mg/kg × 4 doses (maximum 100 mg/ day) Methylprednisolone | Anti-thymocyte globulin 1.5 mg/kg (ideal body weight) × 5 doses (no maximum dose) Methylprednisolone |
Maintenance immunosuppression | Tacrolimus (trough level) ・ 0 - 6 months - 6 - 9 ng/mL ・ >6 months - 4 - 7 ng/mL Mycophenolate mofetil 1000 mg bid or mycophenolate sodium 720 mg bid Prednisone taper to 5 mg daily by 1 month | Tacrolimus (trough level) ・ 0 - 2 months - 8 - 12 ng/mL ・ >2 months - 5 - 10 ng/mL Mycophenolate mofetil 1000 mg bid or mycophenolate sodium 720 mg bid Prednisone tapered off by day 6 |
Infection Prophylaxis | CMV ・ Valganciclovir for 3 months ・ Acyclovir × 1 month for low-risk Pneumocystis ・ TMP/SMX single strength daily x 6 months ・ TMP/SMX single strength three times weekly indefinitely Fungal ・ Oral Fluconazole × 1 month | CMV ・ Valganciclovir for 6 months ・ Acyclovir × 1 month for low-risk Pneumocystis ・ TMP/SMX single strength daily × 12 months Fungal ・ Oral nystatin × 5 days |
Diagnosis and Management of Rejection | Biopsy-proven only Banff 1A/1B ・ Methylprednisolone 500 mg daily × 3 days ・ Oral taper afterwards Banff 2A/2B/3 ・ Anti-thymocyte globulin | Empiric or biopsy-proven Banff 1A/1B/Empiric ・ Methylprednisolone 500 mg daily × 3 days Banff 2A/2B/3 ・ Anti-thymocyte globulin |
was also used as an anti-proliferative agent, and prednisone was tapered quickly from 1 mg/kg/day to 0.25 mg/ kg/day and off by post-operative day 6. Patients were maintained on tacrolimus with target trough of 8 - 12 ng/mL in the first 2 months, followed 5 - 10 ng/mL thereafter.
The CST group received valganciclovir cytomegalovirus (CMV) prophylaxis for 3 months in the intermediate risk (donor CMV positive/negative and recipient CMV positive) and high risk group (donor CMV positive and recipient CMV negative). All recipients also received trimethoprim/sulfamethoxazole single-strength daily for Pneumocystis prophylaxis in the first 6 months and then three times weekly indefinitely post-transplantation. Fluconazole fungal prophylaxis was provided for 1 month immediately post-transplantation.
The recipients in the RSW group that were at intermediate or high risk for CMV infection received valganciclovir for 6 months and all recipients received trimethoprim/sulfamethoxazole single-strength daily for the first 12 months post-transplant. No fungal prophylaxis is provided after discontinuation of steroids. For both the CST and RSW groups, acyclovir HSV prophylaxis was used for 1 month if recipients were low risk for CMV (donor and recipient CMV negative).
The incidence of rejection was determined by either biopsy-proven rejection or empiric treatment for rejection as described below. The types of rejection were determined using the Banff ’05 criteria when possible. In cases where C4d staining was not done, the Banff ’97 criteria were used. Cases that had both an acute cellular component and antibody-mediated component were categorized as antibody-mediated rejection.
The diagnosis and management of rejection varied slightly between the two groups. In the CST group, all clinically suspected rejections had an ultrasound-guided renal allograft biopsy performed. For Banff 1A or 1B acute cellular rejection (ACR), patients were treated with methylprednisolone 500 mg daily for 3 days followed by a quick taper. Banff 2A or greater ACR were treated with anti-thymocyte globulin. For the RSW group, treatment for clinically suspected rejection without biopsy or a borderline/Banff 1A or 1B ACR included methylprednisolone 500 mg daily for 3 days without an oral taper. Patients with Banff 2A or greater ACR were treated with anti-thymocyte globulin, dosed according to ideal body weight. As per protocol, subjects with first time rejections in the RSW group were not started on oral steroid therapy.
To assess the baseline differences in patients from the two centers, we examined the difference in means and standardized difference in means (Cohen’s D statistic) for a set of demographic and clinical characteristics determined prior to the transplant. The two samples were out of balance with respect several important risk factors. To reduce bias from these baseline differences, we estimated propensity scores using a logistic regression of treatment group membership (RSW/CST) on a list of donor, recipient, and transplant factors including recipient age, gender, body mass index, history of diabetes, pre-transplant dialysis, time on dialysis, primary renal disease, PRA ≥ 30%, Hepatitis C; donor age, gender, race, body mass index (BMI), type; HLA matches, CMV risk, and transplant era. Next, we used inverse probability of treatment weights (IPTW) to assign a weight to each member of the CST group (control). To avoid instability from very large weights, the weights in the CST group were normalized and individuals were trimmed from the sample if their weight represented more than 5% of the sum of the weights. To maintain symmetry, we also excluded individuals in the RSW group (treatment) if they had propensity scores greater than the minimum propensity score among the individuals who were trimmed from the control group. We examined several candidate specifications for the propensity score model and selected the specification that achieved the most balanced sample. Categorical and continuous outcomes were estimated using IPTW for proportions and means, respectively, and with 95% confidence intervals.
We used Kaplan-Meier analysis with IPTW to compare graft and patient survival between the two groups. A Cox proportional hazards model using IPTW (unadjusted model) was used to estimate the effect of the maintenance regimen on survival with adjustments for recipient (model 1), donor, and transplant covariates (model 2). The addition of covariates into the Cox proportional model with IPTW provides a doubly robust estimation that increases the chances of an accurate estimation of the outcome [
From 2003 to 2011, 194 patients from the CST group and 212 from the RSW group were initially included in the study.
Prior to outcome analysis, a basic question is whether the analytic sample is sufficiently balanced for sound causal inference. There is no universal standard to apply, of course. However, from a clinical perspective, the analytic sample appears well balanced with respect to key risk factors. In addition, the standardized mean difference in covariates (Cohen’s D) is well below 0.25 standard deviations for each of the baseline covariates so that the remaining imbalances is not “too large” from the perspective of one common rule of thumb in the statistical matching literature [
Graft, death-censored graft, and patient survival were assessed at 1, 3, and 5 years after transplant. In the CST analytic group, there were 25 graft failures and 24 deaths during the follow up period while the RSW analytic group had 24 graft failures and 18 deaths (
The causes of graft failure and patient death with a functioning graft are shown in
Unmatched Cohort | Matched Cohort | |||||
---|---|---|---|---|---|---|
CST (n = 194) | RSW (n = 212) | Cohen’s D | CST (n = 150a) | RSW (n = 157) | Cohen’s D | |
Age at Transplant (Years) | 49.5 (13.4) | 51.0 (12.6) | 0.12 | 51.7 (15.2) | 51.4 (13.1) | −0.02 |
Male Recipient | 58% | 65% | 0.14 | 60% | 62% | 0.04 |
Body Mass Index (kg/m2) | 29.4 (6.3) | 30.5 (7.1) | 0.16 | 29.7 (7.1) | 30.2 (7.1) | 0.07 |
Deceased Donor | 89% | 49% | −0.81 | 69% | 62% | −0.14 |
Extended Criteria Donor | 15% | 15% | −0.01 | 18% | 17% | −0.03 |
Donation after Cardiac Death | 25% | 5% | −0.90 | 7% | 7% | 0.00 |
Diabetes | 31% | 41% | 0.20 | 32% | 39% | 0.13 |
Cause of ESRD | ||||||
Diabetes | 25% | 31% | 0.13 | 26% | 30% | 0.09 |
Hypertension | 51% | 50% | −0.02 | 50% | 50% | 0.01 |
FSGS | 9% | 6% | −0.13 | 5% | 6% | 0.05 |
Other | 15% | 14% | −0.05 | 19% | 13% | −0.16 |
Hepatitis C | 4% | 12% | 0.26 | 8% | 8% | 0.02 |
Dialysis Pre-Transplant | 96% | 85% | −0.32 | 93% | 94% | 0.04 |
Time on Dialysis (Years) | 4.7 (3.2) | 3.4 (3.4) | −0.38 | 4.2 (3.2) | 3.9 (3.3) | −0.08 |
Donor Age (Years) | 41.2 (15.4) | 38.3 (14.9) | −0.19 | 39.5 (15.8) | 39.6 (15.6) | 0.01 |
Black Donor | 26% | 60% | 0.70 | 47% | 54% | 0.14 |
Male Donor | 62% | 53% | −0.18 | 55% | 59% | 0.07 |
Donor BMI | 28.3 (7.1) | 28.9 (6.5) | 0.09 | 28.0 (7.2) | 28.1 (6.4) | 0.02 |
HLA Matches | ||||||
0 - 2 | 64% | 53% | −0.21 | 56% | 56% | 0.00 |
3 - 4 | 28% | 37% | 0.17 | 35% | 36% | 0.02 |
5 - 6 | 8% | 10% | 0.07 | 9% | 8% | −0.03 |
PRA > 30% | 22% | 8% | −0.55 | 11% | 10% | −0.06 |
CMV Risk | ||||||
Low | 11% | 6% | −0.22 | 9% | 8% | −0.04 |
Intermediate | 79% | 84% | 0.14 | 83% | 84% | 0.03 |
High | 10% | 10% | 0.00 | 8% | 8% | −0.01 |
Transplant Era | ||||||
2003-2005 | 26% | 25% | −0.04 | 27% | 25% | −0.05 |
2006-2008 | 37% | 30% | −0.16 | 27% | 32% | 0.11 |
2009-2012 | 37% | 46% | 0.18 | 46% | 43% | −0.06 |
Reported as either mean (standard deviation) or proportions. aWeighted total, rounded to the nearest whole number.
of graft failure were similar between the two groups with interstitial fibrosis/tubular atrophy being the most common followed by acute rejection. The causes of death were difficult to determine for a number of cases, particularly in the RSW group. However, it appeared that the most common causes were either cardiovascular, infectious, or due to malignancy.
CST (n = 150a) | RSW (n = 157) | ||||
---|---|---|---|---|---|
na | Incidence (95% CI) | n | Incidence (95% CI) | p-Value | |
Graft Failure | 25 | 17% (9% - 28%) | 24 | 15% (10% - 22%) | 0.82 |
Cause of Graft Failure | 0.64 | ||||
Acute Rejection | 3 | 14% (3% - 42%) | 7 | 29% (14% - 51%) | |
Primary | 3 | 14% (3% - 42%) | 1 | 4% (0% - 26%) | |
Infectious | 0 | 0% | 1 | 4% (0% - 26%) | |
Recurrence | 5 | 21% (4% - 60%) | 2 | 8% (2% - 29%) | |
Interstitial Fibrosis/Tubular Atrophy | 9 | 37% (14% - 68%) | 8 | 33% (17% - 55%) | |
BK Nephropathy | 3 | 13% (2% - 51%) | 4 | 17% (6% - 38%) | |
Other | 0 | 1% (0% - 11%) | 1 | 4% (0% - 26%) | |
Deaths with a Functioning Graft | 24 | 16% (8% - 27%) | 18 | 11% (7% - 18%) | 0.40 |
Cause of Death | 0.51 | ||||
Cardiovascular | 8 | 34% (10% - 70%) | 3 | 17% (5% - 42%) | |
Infectious | 4 | 18% (5% - 50%) | 2 | 11% (3% - 37%) | |
Malignancy | 5 | 22% (4% - 66%) | 2 | 11% (3% - 37%) | |
Cerebrovascular | 0 | 3% (0% - 19%) | 1 | 6% (0% - 33%) | |
Unknown | 5 | 20% (5% - 53%) | 9 | 50% (28% - 72%) | |
Other | 1 | 3% (0% - 21%) | 1 | 6% (0% - 33%) |
aweighted total, rounded to the nearest whole number.
Unadjusteda | Model 1b | Model 2c | |
---|---|---|---|
Graft Survival | 0.79 (0.48 - 1.31) | 0.81 (0.47 - 1.38) | 0.71 (0.38 - 1.34) |
Death-Censored Graft Survival | 0.88 (0.44 - 1.77) | 0.95 (0.49 - 1.85) | 0.91 (0.43 - 1.91) |
Patient Survival | 0.69 (0.32 - 1.51) | 0.62 (0.24 - 1.65) | 0.57 (0.20 - 1.67) |
aUnadjusted model with Inverse Probability Treatment Weight (IPTW) adjustment only; bmodel 1 includes IPTW plus recipient age, gender, BMI, diabetes, pre-transplant dialysis, dialysis time, cause of ESRD (hypertension, lupus, or other vs diabetes), PRA > 30%, and Hepatitis C status; cmodel 2 includes model 1 plus donor type (cadaver vs living), expanded criteria donor, donation after circulatory death, HLA matches, donor age, donor gender, donor race (black vs other), donor BMI, CMV risk (intermediate, high vs low), and transplant era (2006-2008, 2009-2012 vs 2003-2005).
The eGFR at 1 and 5 years after transplant are shown in
The incidence of rejection and types of rejection are shown in
CST (n = 150a) | RSW (n = 157) | ||||||
---|---|---|---|---|---|---|---|
na | Weighted Mean (95% CI) | n | Weighted Mean (95% CI) | p-Value | OR (95% CI) | p-Value | |
GFR at 1 Year (mL/min/1.73 m2) | 140 | 60.0 (51.7 - 68.3) | 132 | 52.9 (50.1 - 55.8) | 0.11 | ||
Living Donor | 47 | 51.9 (41.1 - 62.7) | 52 | 53.4 (49.4 - 57.3) | 0.80 | ||
Deceased Donor | 93 | 64.1 (53.5 - 74.7) | 80 | 52.7 (48.7 - 56.6) | 0.047 | ||
GFR at 5 Years (mL/min/1.73 m2) | 49 | 50.7 (40.9 - 60.6) | 46 | 52.2 (45.6 - 58.8) | 0.80 | ||
Living Donor | 18 | 42.9 (27.7 - 58.2) | 21 | 53.4 (45.4 - 61.3) | 0.23 | ||
Deceased Donor | 31 | 55.3 (44.1 - 66.5) | 25 | 51.3 (41.1 - 61.4) | 0.59 | ||
na | Weighted% (95% CI) | n | Weighted% (95% CI) | p-Value | |||
Delayed Graft Function | 48 | 32% (23% - 43%) | 16 | 10% (6% - 16%) | <0.001 | 0.15 (0.06 - 0.35) | <0.001 |
Post-Transplant Diabetes Mellitus | 28 | 25% (14% - 41%) | 22 | 22% (15% - 31%) | 0.66 | 0.85 (0.32 - 2.24) | 0.74 |
BK Viremia | 16 | 10% (5% - 20%) | 28 | 18% (13% - 25%) | 0.15 | 2.72 (1.22 - 6.04) | 0.014 |
CMV Viremia | 17 | 11% (5% - 21%) | 37 | 24% (18% - 31%) | 0.04 | 4.14 (1.81 - 9.44) | 0.001 |
Rejection at 1 Year | 15 | 10% (5% - 18%) | 51 | 32% (26% - 40%) | <0.001 | 4.26 (1.99 - 9.13) | <0.001 |
Rejection at 5 Year | 23 | 15% (9% - 25%) | 69 | 44% (36% - 52%) | <0.001 | 4.71 (2.40 - 9.23) | <0.001 |
Biopsy Proven Rejection at 1 Year | 15 | 10% (5% - 18%) | 28 | 18% (13% - 25%) | 0.10 | 2.04 (0.92 - 4.55) | 0.08 |
Biopsy Proven Rejection at 5 Year | 23 | 15% (9% - 25%) | 37 | 24% (18% - 31%) | 0.13 | 1.95 (0.98 - 3.88) | 0.06 |
Types of Rejection (Biopsy-Proven) | <0.001 | ||||||
Grade 1 | 5 | 22% (7% - 50%) | 28 | 70% (54% - 82%) | |||
Grade 2 | 15 | 68% (42% - 87%) | 2 | 5% (1% - 18%) | |||
Grade 3 | 0 | 0% (0% - 3%) | 0 | 0% | |||
Antibody-Mediated Rejection | 2 | 9% (3% - 24%) | 5 | 12% (5% - 27%) | |||
Borderline Rejection | 0 | 0% (0% - 2%) | 5 | 12% (5% - 27%) |
aweighted total, rounded to the nearest whole number.
were similar (18% vs 10%, p = 0.10). The types of biopsy-proven rejection varied by group with more grade 1 and borderline rejections in the RSW analytic group while grade 2 rejections were more common in the CST analytic group.
The incidence of delayed graft function was much higher among the CST analytic group compared to the RSW analytic group (32% vs 10%, p < 0.001) (
Among the RSW group, 20 of the 157 individuals were started on prednisone after their transplant (
n | Percentage of RSW (n = 157) | |
---|---|---|
Started on Prednisone | 20 | 6.5% |
Reasons for Starting Prednisone | ||
Rejection | 7 | 35% |
Leukopenia | 5 | 25% |
BK Nephropathy | 2 | 10% |
GI Intolerance | 2 | 10% |
Malignancy | 1 | 5% |
FSGS | 1 | 5% |
Pregnancy | 1 | 5% |
FK Toxicity | 1 | 5% |
The most common cause of starting prednisone was rejection (35%). The next most common cause was leukopenia at 25% while BK nephropathy and GI intolerance to mycophenolate mofetil or mycophenolate sodium were each 10%. Of the 20 individuals, 13 (65%) were started in the first year of transplant.
The use of RSW has become more common practice in the management of renal allografts to prevent the side effects of prolonged corticosteroid use. Of patients transplanted in 2011, nearly 40% of recipients were discharged off steroid maintenance with nearly 30% remaining steroid-free at 1 year post-discharge [
There were few statistically significant differences in allograft function or rejection outcomes within the first year of transplantation (
The practice of using an RSW protocol has improved corticosteroid related complications in renal transplant recipients [
Few studies have specifically addressed the clinical outcomes in AA kidney transplant recipients with regards to RSW [
While this study includes one of the largest cohorts of African-Americans, the study does have some limitations. First, the study was conducted as a retrospective chart review at two centers where differences in practice may have affected the results. The major difference is type of kidney donors used between the groups, specifically the higher percentage of deceased donors in the CST group compared to the percentage of living donors within the RSW group. To minimize these differences, we used propensity score weighting to match individuals between the two groups and removed matched samples where a few individuals in the control group represent a disproportionately high number in the treatment group. We then adjusted for the covariates along with propensity score weighting to give a doubly robust estimation to further minimize the biases. Other variations include CMV management post-transplant and goal trough levels of tacrolimus being different between groups. Interestingly, CMV viremia was seen more in the RSW with the longer valganciclovir prophylaxis. And while we were unable to gather the data on trough levels in either group, the lower target levels of tacrolimus in the CST group may explain why eGFR was higher then in this group. Finally, the high number of empirically treated rejections in the RSW group likely underestimates the biopsy-proven rejection rate since other studies of steroid withdrawal have shown higher rejection rates. Despite these significant differences in practice between these two centers where these differences could bias the outcomes in favor of the CST protocol, we still found no difference in graft and patient survival. However, more prospective, long-term, controlled studies are needed to confirm these findings before recommending the routine use of RSW protocols in African-American kidney transplant recipients.
We conclude that a RSW regimen is comparable in graft and patient survival to a CST regimen in AA recipients.
The authors declare no conflicts of interest. Sanjeev Akkina’s effort was supported by the National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases grant DK084121. The results presented in this paper have not been published previously in whole or part, except in abstract form.
W. JamesChon,AmishiDesai,CoadyWing,DivyaArwindekar,IgnatiusY. S. Tang,Michelle A.Josephson,SanjeevAkkina, (2016) Impact of Maintenance Steroids versus Rapid Steroid Withdrawal in African-American Kidney Transplant Recipients: Comparison of Two Urban Centers. International Journal of Clinical Medicine,07,204-216. doi: 10.4236/ijcm.2016.73021
AA: African-American
ACR: Acute cellular rejection
BMI: Body mass index
CMV: Cytomegalovirus
CST: Continued steroid therapy
DCD: Donation after circulatory death
ECD: Expanded criteria donors
IPTW: Inverse probability of treatment weights
PRA: panel reactive antibodies
PTDM: Post-transplant diabetes mellitus
RSW: Rapid steroid withdrawal