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).
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).
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).
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).
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).
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).
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).
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.
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.
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).
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.
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).
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).
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).
1. Knight SR, Morris PJ. Steroid avoidance or withdrawal after renal transplantation increases the risk of acute rejection but decreases cardiovascular risk. A meta-analysis. Transplantation
2010; 89: 1.
2. Luan FL, Steffick DE, Gadegbeku C, et al.. Graft and patient survival in kidney transplant
recipients selected for de novo steroid-free maintenance immunosuppression. Am J Transplant
2009; 9: 160.
3. Vincenti F, Schena FP, Paraskevas S, et al.. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant
recipients. Am J Transplant
2008; 8: 307.
4. Boots JM, Christiaans MH, Van Duijnhoven EM, et al.. Early steroid withdrawal in renal transplantation with tacrolimus dual therapy: a pilot study. Transplantation
2002; 74: 1703.
5. Cole E, Landsberg D, Russell D, et al.. A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients. Transplantation
2001; 72: 845.
6. Matas AJ, Kandaswamy R, Gillingham KJ, et al.. Prednisone-free maintenance immunosuppression—a 5-year experience. Am J Transplant
2005; 5: 2473.
7. Woodle ES, First MR, Pirsch J, et al.. 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: 564.
8. Ahsan N, Hricik D, Matas A, et al.. Prednisone withdrawal in kidney transplant
recipients on cyclosporine and mycophenolate mofetil—a prospective randomized study. Steroid Withdrawal Study Group. Transplantation
1999; 68: 1865.
9. Vanrenterghem Y, van Hooff JP, Squifflet JP, et al.. Minimization of immunosuppressive therapy after renal transplantation: results of a randomized controlled trial. Am J Transplant
2005; 5: 87.
10. Khwaja K, Asolati M, Harmon JV, et al.. Rapid discontinuation of prednisone in higher-risk kidney transplant
2004; 78: 1397.
11. Zeng X, El-Amm JM, Doshi MD, et al.. Intermediate-term outcomes with early steroid withdrawal in African-American renal transplant recipients undergoing surveillance biopsy. Surgery
2007; 142: 538.
12. Pascual J, van Hooff JP, Salmela K, et al.. Three-year observational follow-up of a multicenter, randomized trial on tacrolimus-based therapy with withdrawal of steroids or mycophenolate mofetil after renal transplant. Transplantation
2006; 82: 55.
13. Boardman RE, Alloway RR, Alexander JW, et al.. African American
renal transplant recipients benefit from early corticosteroid withdrawal
under modern immunosuppression. Transplant Proc
2005; 37: 814.
14. Alloway RR, Hanaway MJ, Trofe J, et al.. A prospective, pilot study of early corticosteroid cessation in high–immunologic-risk patients: the Cincinnati experience. Transplant Proc
2005; 37: 802.
15. Kasiske BL, Chakkera HA, Louis TA, et al.. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol
2000; 11: 1910.
16. Pascual J, Quereda C, Zamora J, et al.. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation
2004; 78: 1548.
17. Ioannidis JPA. Some main problems eroding the credibility and relevance of randomized trials. Bull NYU Hosp Jt Dis
2008; 66: 135.
18. Schold JD, Buccini LD, Goldfarb DA, et al.. Patient participation in research among solid organ transplant recipients in the United States. Transplantation
2011; 91: 1424.
19. Hanaway MJ, Woodle ES, Mulgaonkar S, et al.. Alemtuzumab induction in renal transplantation. N Engl J Med
2011; 364: 1909.
20. Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999–2008. Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD.
21. Sureshkumar KK, Thai NL, Hussain SM, et al.. Influence of induction modality on the outcome of deceased donor kidney transplant
recipients discharged on a steroid-free maintenance immunosuppression. Transplantation
2012; 93: 799.
22. Woodle ES, Alloway RR, Buell JF, et al.. Multivariate analysis of risk factors for acute rejection in early corticosteroid cessation regimens under modern immunosuppression. Am J Transplant
2005; 5: 2740.
23. Schold JD, Santos A, Rehman S, et al.. The success of continued steroid avoidance after kidney transplantation in the US. Am J Transplant
2009; 9: 2768.
24. Kumar MS, Heifets M, Moritz MJ, et al.. Safety and efficacy of steroid withdrawal two days after kidney transplantation: analysis of results at three years. Transplantation
2006; 81: 832.
25. Meier-Kriesche HU, Kaza H, Palekar SS, et al.. The effect of daclizumab in a high-risk renal transplant population. Clin Transplant
2000; 14: 509.
26. Press R, Carrasquillo O, Nickolas T, et al.. Race/ethnicity, poverty status, and renal transplant outcomes. Transplantation
2005; 80: 917.
27. Charpentier B, Rostaing L, Berthoux F, et al.. A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients. Transplantation
2003; 75: 844.
28. Mourad G, Garrigue V, Squifflet JP, et al.. Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression. Transplantation
2001; 72: 1050.
29. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care
2010; 33 (suppl 1): S62.
30. Serur D, Saal S, Wang J, et al.. Deceased-donor kidney transplantation: improvement in long-term survival. Nephrol Dial Transplant
2011; 26: 317.
31. Cattaneo D, Perico N, Gaspari F, et al.. Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation. Kidney Int
2002; 62: 1060.
Corticosteroid withdrawal; Kidney transplant; African American; Expanded criteria donor; Delayed graft function
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