Immunosuppression Regimen Use and Outcomes in Older and Younger Adult Kidney Transplant Recipients: A National Registry Analysis : Transplantation

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Original Clinical Science—General

Immunosuppression Regimen Use and Outcomes in Older and Younger Adult Kidney Transplant Recipients: A National Registry Analysis

Lentine, Krista L. PhD1; Cheungpasitporn, Wisit MD2; Xiao, Huiling MS1; McAdams-DeMarco, Mara PhD3; Lam, Ngan N. MD4; Segev, Dorry L. PhD3; Bae, Sunjae PhD3; Ahn, JiYoon B. PhD3; Hess, Gregory P. MD5; Caliskan, Yasar MD1; Randall, Henry B. MD1; Kasiske, Bertram L. MD6; Schnitzler, Mark A. PhD1; Axelrod, David A. MD7

Author Information

1 Saint Louis University, Saint Louis, MO.

2 University of Mississippi Medical Center, Jackson, MS.

3 Johns Hopkins School of Medicine, Baltimore, MD.

4 University of Calgary, Calgary, AB, Canada.

5 Drexel University, Philadelphia, PA.

6 Hennepin County Med Center, Minneapolis, MN.

7 University of Iowa, Iowa City, IA.

Received 23 July 2020. Revision received 26 September 2020.

Accepted 22 October 2020.

This work was funded by a grant from National Institute of Diabetes and Digestive and Kidney Disease R01DK120518. K.L.L. is supported by the Mid-America Transplant/Jane A. Beckman Endowed Chair in Transplantation.

The authors declare no conflicts of interest.

K.L.L. and W.C. are cofirst authors.

M.A.S. and D.A.A. are cosenior authors.

K.L.L. and M.A.S. participated in study design, acquisition of data and regulatory approvals, interpretation, and writing of the article. W.C., N.N.L., and D.A.A. participated in study design, interpretation, and writing of the article. H.X. participated in data analysis and article preparation. M.M-.D., D.L.S., S.B., J.B.A., G.P.H., Y.C., H.B.R. and B.L.K. participated in study design, interpretation, and article review/critical editing.

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).

Correspondence: Krista L. Lentine, PhD, St Louis University Transplant Center, 1402 S. Grand Blvd, St. Louis, MO 63104. ([email protected]).

Transplantation 105(8):p 1840-1849, August 2021. | DOI: 10.1097/TP.0000000000003547

Abstract

INTRODUCTION

Kidney transplantation is the preferred treatment option for patients with kidney failure, providing superior clinical outcomes at lower healthcare costs than chronic dialysis.1 In recent years, the number of elderly patients with kidney failure has risen substantially worldwide, due to a global increase in the aging population, improved survival on dialysis,2-5 and increased referral of older patients for transplantation.6-8 The growing number of elderly kidney transplant candidates is correlated with a rise in the number and proportional representation of elderly kidney transplant recipients.9,10 In the United States (US), the percentage of kidney transplant recipients aged >65 years increased from 14% in 1999 to 24% in 2018.2,9,11 Similar trends have been observed in other countries.12,13

Older recipients appear to have improved short-term death-censored graft survival as compared to younger patients, perhaps due to immunosenescence and decreased acute rejection risk.14,15 While the incidence of acute rejection tends to fall with age, the risk of allograft loss following a rejection event is significantly increased in elderly recipients.5,16 Older recipients also carry a higher risk of chronic allograft loss resulting from a variety of age-related immune and nonimmune factors.17,18 Age-related immunologic and nonimmunologic changes increase the susceptibility of elderly recipients to posttransplant cardiovascular disease, infection, and malignancy, contributing to significant morbidity and mortality.17 In aggregate, the increased risk of death among older recipients results in lower 5-year kidney allograft survival rates compared with younger recipients.9,14,15

Immunosuppressive (ISx) management in older kidney transplant recipients is complex, given increased risk of infection and malignancy after transplant in this population,16,19-23 reduced immunogenicity,24,25 and greater likelihood of receiving a higher-risk donor organ.11 General guidelines suggest that tacrolimus (Tac), mycophenolate mofetil (MMF), and corticosteroids be used as first-line maintenance ISx agents following kidney transplantation, which remains the most commonly prescribed ISx protocol across all age groups.2,24,26 However, age-related immune dysfunction and associated comorbidities make older recipients more susceptible to complications associated with ISx agents.17,27 Thus, practitioners have considered tailoring ISx protocols for older kidney transplant recipients, such as favoring steroid avoidance/withdrawal, antimetabolite avoidance, and mammalian target of rapamycin inhibitor (mTORi)-based regimens (with calcineurin inhibitor [CNI] avoidance or minimization protocols).2,5,17,28-31 Robust data to guide these decisions are lacking as most reports are the result of small, single-center observational studies with limited follow-up.2,5 These trials lack sufficient sample size to adjust for pertinent donor and recipient characteristics beyond recipient age.

Given the paucity of trial data on preferred ISx regimen in the older kidney transplant recipients, we examined the impact of early ISx regimen selection (induction and maintenance over the first 6 mo) on outcomes in a national cohort of US transplant recipients with sufficient sample size to adjust for potential confounding effects including donor characteristics. Our goal was to examine associations of ISx regimen selection with graft and patient survival among older (age ≥65 y) and younger (age 18–64 y) recipients. By providing data from a large, robust national cohort, we hope to inform ISx regimen selection for at-risk older adults and plan future study to better tailor management of older kidney transplant recipients.

MATERIALS AND METHODS

Data Source and Sampling

Study data were drawn from US Renal Data System (USRDS) records, which integrate Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) records with Medicare billing claims. The primary study sample comprised adult (age ≥18 y) recipients of kidney-only transplants in the United States from 2005 to 2016 with Medicare as the primary payer for the first 6 months posttransplant and ISx data available during this period. Because our primary exposure was based on pharmacy claims for ISx, we also required Medicare-reimbursed fills for ISx in the first 6 months after transplantation. Younger and older adults were defined by age 18–64 versus ≥65 years, respectively, consistent with Medicare payments guidelines that provide coverage based on age 65 and geriatrics/gerontology standards.32 This study was deemed to be Human Subjects Exempt by the Institutional Review Board of Saint Louis University.

Definition of Immunosuppression Regimens

The use of induction agents was defined by OPTN reporting. Early maintenance ISx regimen was defined using Medicare pharmacy claims for ISx agents submitted within the first 6 months after transplant, reimbursed through part B or part D benefits. Patients were classified based on induction and maintenance ISx regimens into 7 study regimens, similar to previous methods33:

  1. Triple maintenance, after T cell–depleting induction: antithymocyte globulin (TMG)/alemtuzumab (ALEM) + Tac + MPA (mycophenolic acid: MMF or mycophenolate sodium)/azathioprine (AZA) + prednisone (Pred).
  2. Triple maintenance, after IL2rAb induction: IL2rAb + Tac + MPA/AZA + Pred.
  3. Steroid avoidance/withdrawal, after T cell–depleting induction: TMG/ALEM + Tac + MPA/AZA, without Pred
  4. Steroid avoidance/withdrawal, after IL2rAb induction: IL2rAb + Tac + MPA/AZA, without Pred.
  5. Antimetabolite avoidance: Tac alone or Tac + Pred.
  6. mTORi-based regimens.
  7. Cyclosporine (CsA)-based regimens.

Triple maintenance therapy with T cell–depleting induction was considered the reference regimen as it was the most frequently used regimen during the study period. MPA included mycophenolate mofetil and mycophenolate sodium. IL2rAb included the 2 agents available in the United States in the study period, basiliximab and daclizumab. Groups 5–7 were defined to be independent of induction. Patients in groups 1–5 did not receive mTORi or CsA. mTORi-based ISx was classified before CsA-based ISx to enable assignment of mutually exclusive regimens, as per previous methods.34 mTORi- and CsA-based regimens were not further subclassified due to low frequencies of patients treated with these regimens. Specific data on fill patterns, regimen weaning, compliance, and drug levels are not provided in this database.

Covariate and Outcome Measures

Transplant recipient clinical and demographic characteristics, as well as characteristics of the donated organ and other transplant factors, were defined by the OPTN Transplant Candidate Registration and Transplant Recipient Registration forms (Table 1).

TABLE 1. - Distributions of early immunosuppression regimen use among kidney transplant recipients according to baseline clinical traits (N = 67 362)
TMG/ALEM + triple therapy (reference) (N = 30 134) (%) IL2rAb + triple therapy (N = 10 836) (%) TMG/ALEM + Tac + MPA/AZA, no Pred (N =13 055) (%) IL2rAb + Tac + MPA/AZA, no Pred (N = 1553) (%) Tac, Tac + Pred (N = 2034) (%) mTORi-based (N = 5043) (%) CsA-based (N = 4707) (%)
Age (y)
 18–64 47.0 14.7 19.2 1.8 3.1 7.7 6.6
 ≥65 36.9 21.1 20.1 4.1 2.8 6.7 8.3
Sex
 Male 42.3 17.2 20.1 2.4 3.1 7.9 7.0
 Female 48.4 14.5 18.2 2.1 3.0 6.9 6.9
Race
 White 39.5 17.9 20.1 3.0 3.4 8.2 7.9
 African American 53.4 12.5 17.8 1.3 2.7 7.3 5.1
 Hispanic 45.2 16.2 20.8 2.2 2.4 6.4 6.8
 Other 40.3 19.8 17.5 2.7 3.2 6.3 10.3
Employment status
 Working 43.4 15.9 21.5 2.4 3.7 7.2 5.9
 Not working 45.1 16.4 18.8 2.4 2.8 7.7 6.9
Body mass index (kg/m2)
 <18.5 47.5 17.4 13.7 2.8 3.8 7.8 7.1
 18.5–24.9 45.3 16.9 17.8 2.4 3.1 7.5 7.0
 25.0–29.9 43.9 16.9 19.0 2.6 3.0 7.9 6.8
 ≥30.0 45.6 14.9 20.7 2.0 2.8 7.0 7.0
Comorbid conditions
 Hypertension 43.5 16.0 19.5 2.4 3.0 8.4 7.3
 Diabetes mellitus 41.6 16.7 20.9 2.7 3.1 7.3 7.7
 Coronary artery disease 36.2 16.7 19.6 3.7 3.4 10.6 9.8
 Cerebral vascular disease 34.1 16.1 24.2 2.6 1.5 10.9 10.7
 Peripheral vascular disease 42.0 17.7 20.2 3.0 2.3 7.0 7.8
 COPD 33.6 14.0 21.4 4.8 3.3 11.3 11.6
 Hepatitis C positive 43.9 18.2 14.7 2.9 3.2 6.7 10.4
Cause of ESKD
 Hypertension 46.6 15.2 19.3 2.0 2.7 8.0 6.3
 Diabetes mellitus 41.2 16.8 21.6 2.8 3.0 7.1 7.6
 Glomerulonephritis 48.0 15.3 17.6 2.0 3.0 7.3 6.7
 Polycystic kidney disease 41.9 16.0 21.5 2.1 3.4 8.3 6.7
 Other 43.5 18.4 16.5 2.7 3.8 7.4 7.8
Duration of dialysis (mo)
 None (preemptive) 28.9 22.7 22.4 4.5 4.3 7.7 9.4
 >0–24 35.1 20.8 20.6 3.7 3.6 8.3 7.9
 25–60 42.9 16.0 21.3 2.2 3.1 7.9 6.7
 >60 53.1 13.1 16.7 1.5 2.5 6.7 6.5
Most current PRA level (%)
 <10 39.0 18.6 21.6 2.7 3.2 7.6 7.4
 10–79 55.2 11.9 15.7 1.4 2.8 6.9 6.1
 ≥80 70.2 6.0 11.0 0.5 2.2 5.2 4.9
HLA mismatches
 Zero A, B, DR 39.9 17.8 17.2 5.2 3.3 7.6 8.9
 Zero DR 45.1 15.0 20.5 2.2 3.1 7.0 7.0
 Other 45.1 16.1 19.4 2.1 3.0 7.5 6.8
Cold ischemia time (h)
 ≤12 42.1 19.0 18.5 2.7 3.0 7.9 6.9
 13–24 48.4 14.9 18.1 1.8 2.9 7.2 6.7
 25–36 48.3 13.0 20.6 1.5 2.9 7.0 6.7
 >37 43.3 7.9 32.7 1.2 2.9 7.1 4.9
Previous organ transplant
 Yes 59.2 10.0 11.5 1.3 3.3 7.8 7.1
 No 42.2 17.2 20.8 2.5 3.0 7.4 7.0
Donor type
 Living donor 34.6 20.5 22.3 3.9 3.2 7.7 7.8
 Deceased, KPDI <20 45.7 16.8 17.7 2.1 3.9 6.7 7.1
 Deceased, KDPI 20–85 49.0 14.2 18.5 1.7 2.7 7.3 6.7
 Deceased, KDPI >85 44.0 14.5 20.4 2.3 2.9 9.7 6.4
Transplant era
 2005–2008 33.8 15.5 19.7 3.1 4.6 11.7 11.7
 2009–2012 45.2 16.3 20.4 2.5 2.8 6.5 6.3
 2013–2016 53.4 16.4 18.0 1.4 1.9 5.1 3.9
Percentages are row percentages. P < 0.05 for comparison of distributions of ISx regimen across all traits, due to large sample size.
“Other race” includes Asian, Native American, Pacific Islander, and multiracial.
ALEM, alemtuzumab; AZA, azathioprine; COPD, chronic obstructive pulmonary disease; CsA, cyclosporine A; ESKD, end-stage kidney disease; IL2, interleukin-2; ISx, immunosuppressive; IL2rAb, interleukin-2–receptor antibody; KDPI, Kidney Donor Profile Index; MPA, mycophenolic acid; mTORi, mammalian target of rapamycin inhibitor; no Pred, no prednisone use posttransplant; PRA, panel reactive antibody; Pred, prednisone use documented posttransplant; Tac, tacrolimus; TMG, antithymocyte globulin; triple therapy, Tac + MPA/AZA + Pred.

Graft failure was defined as return to maintenance dialysis or retransplant. Patient death was defined by transplant center reports to OPTN and supplemented with the Social Security Death Master File. All-cause graft failure included graft loss due to death. The OPTN queries centers for information on acute rejection according to periods covered by specific reporting forms (0–6 mo, 7–12 mo, then annually), but dates of acute rejection within reporting periods are not collected. We defined acute rejection from OPTN records according to center reports occurring in a reporting period, as per prior methods.33,35,36 Rejection was analyzed through 3 years, given declining incidence and completion of rejection reporting beyond 3 years.

Statistical Analyses

Clinical characteristics of the study sample were described as proportions. Continuous variables were categorized into clinically relevant strata. Missing categorical covariate data were grouped with the absence of a characteristic when such categories were relevant or into a category distinct from the reference group. Distributions of the ISx regimen use according to baseline characteristics were compared by the chi-square test.

The analysis was stratified based on age group (18–64 versus ≥65 y). Given ISx ascertainment during the first 6 months after transplant, origin time for outcomes analyses began at 6 months posttransplant. Death-censored graft survival, patient survival, and all-cause graft survival over time after 6 months posttransplant were estimated using the Kaplan-Meier method. The adjusted association of ISx regimen with graft failure and mortality (adjusted hazard ratio [aHR], 95%LCLaHR95%UCL) >6 months-to-5 years after transplant was assessed using multivariable Cox proportional hazards analysis, adjusted for recipient, donor, and transplant factors (Table 1). At-risk time was censored at 5 years posttransplant or the end of the study (December 31, 2016). Logistic regression was used to assess the adjusted odds ratio (aOR) of any acute rejection event >6 months-to-3 years after transplant. Outcome models were also stratified by quintile of the propensity for assignment to each ISx regimen compared with the reference regimen in binomial logistic regression, as per previous methods.33

The primary comparisons examined outcomes associated with each regimen compared with the reference regimen within older and younger adults. We also assessed for interactions between ISx regimens and age groups by testing interaction terms in the model. A P value <0.05 was considered statistically significant. Data management and analysis were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).

RESULTS

Clinical Characteristics

Of 193 984 kidney transplant recipients in the study period, 67 362 had Medicare claims data for study ISx regimens within the first 6 months after transplant. Compared with recipients without available data for inclusion, the study sample of Medicare beneficences included a higher representation of older (22.7% versus 14.9%) and patients who were non-White (54.2% versus 45.6%) and unemployed (73.8% versus 53.4%) (Table S1, SDC, https://links.lww.com/TP/C61). Medicare beneficiaries also had longer periods of pretransplant dialysis (>60 mo: 39.9% versus 24.4%) with correspondingly fewer living donor transplants (22.8% versus 41.4%).

Recipient characteristics were associated with the ISx regimen selection (Table 1). Use of some regimens was less common in older compared with younger recipients, including TMG/ALEM + triple maintenance (36.9% versus 47.0%), TMG/ALEM + steroid avoidance (19.2% versus 20.1%), antimetabolite avoidance (2.8% versus 3.1%), and mTORi-based (6.7% versus 7.7%). Conversely, IL2rAb + triple maintenance (21.1% versus 14.7%), IL2rAb + steroid avoidance (4.1% versus 1.8%), and CSA-based (8.3% versus 6.6%) were more common in older compared with younger recipients. Compared with White patients, African American patients more commonly received TMG/ALEM + triple maintenance (53.4% versus 39.5%) and less commonly received IL2rAb + triple maintenance (12.5% versus 17.9%) or steroid-free regimens (17.8% versus 20.1%). Use of TMG/ALEM + triple maintenance was substantially more common among highly sensitized patients with panel reactive antibody ≥80% compared with those with panel reactive antibody <10% (70.2% versus 39.0%), while use of IL2rAb + triple maintenance was less common (6.0% versus 18.6%). Use of TMG/ALEM + triple maintenance was also more common among retransplant recipients, while the use of CsA and mTORi-based regimens decreased in more recent years of study. Similar patterns were seen in the distribution of ISx regimen use by baseline traits among both younger and older patients (Table S2A and S2B, SDC, https://links.lww.com/TP/C61).

Acute Rejection

Compared with younger patients, older recipients experienced a lower risk of acute rejection >6 months-to-3 years for all regimens except IL2rAb + triple therapy (Figure 1). Among older recipients, the unadjusted incidence of acute rejection was significantly higher in those who received mTORi-based (11.0%) and CsA-based (10.8%) regimens, and significantly lower in those who received TMG/ALEM + Tac + MPA/AZA (5.3%) than those on the maintenance regimen (7.4%). Similar patterns were noted among younger adults, when comparing the unadjusted incidence of acute rejection patients who received TMG/ALEM + triple maintenance (11.7%) to those who received TMG/ALEM + Tac + MPA/AZA (7.5%), IL2rAb + Tac + MPA/AZA (8.6%), Tac, Tac + Pred (9.9%), mTORi-based (15.6%), and CsA-based (15.3%) ISx regimens (Figure 1).

F1
FIGURE 1.:
Acute rejection incidence >6 mo-to-3 y after kidney transplant, by early ISx regimen and recipient age. *P < 0.05 for comparison to reference regimen, within each age group. ALEM, alemtuzumab; AZA, azathioprine; CsA, cyclosporine; ISx, immunosuppressive; MPA, mycophenolic acid; mTORi, mammalian target of rapamycin inhibitor; Pred, prednisone; Tac, tacrolimus; TMG, antithymocyte globulin.

Compared with the reference regimen, the incidence of acute rejection varied significantly by ISx after multivariate adjustment (Figure 2A). Patients aged ≥65 years receiving TMG/ALEM + steroid avoidance (aOR, 0.440.520.61) and IL2rAb + steroid avoidance (aOR 0.390.550.79) experienced lower adjusted risk of acute rejection, while CsA-based ISx was associated with increased risk (aOR, 0.981.191.43). Similarly, among recipients aged 18–64 years, TMG/ALEM + steroid avoidance (aOR, 0.640.700.76) was associated with a lower risk of acute rejection, while IL2rAb + triple ISx (aOR, 1.051.141.23), mTORi-based (aOR, 1.371.501.65), and CsA-based (aOR, 1.431.591.77) regimens were also associated with increased risk of acute rejection.

F2
FIGURE 2.:
Relative risks of acute rejection (A), death-censored graft failure (B), death (C), and all-cause graft failure (2D) according to early ISx regimen and recipient age. Confidence intervals designate comparison of each regimen to the reference regimen within age groups. *P < 0.05 for the test of the interaction of age group and regimen effects. ALEM, alemtuzumab; AZA, azathioprine; CsA, cyclosporine; ISx, immunosuppression; KTx, kidney transplant; MPA, mycophenolic acid; mTORi, mammalian target of rapamycin inhibitor; Pred, prednisone; Tac, tacrolimus; TMG, antithymocyte globulin.

Death-censored Graft Failure

Unadjusted death-censored graft failure >6 months-to -5 years after kidney transplant among patients aged ≥65 years who received TMG/ALEM + triple ISx (8.2%) was similar to patients treated with IL2r + triple ISx (7.4%) and TMG/ALEM + Tac/MMF (8.3%), but lower than those treated with Tac + antimetabolite avoidance (11.7%), mTORi-based (16.3%), or CsA-based (12.4%) regimens (Figure 3A). Conversely, recipients aged 18–64 years who received the reference regimen had higher death-censored graft failure (13.9%) rates than patients who received IL2rAb + triple ISx (12.5%), TMG/ALEM + steroid avoidance (10.6%), or IL2rAb + steroid avoidance (10.8%), but lower than in those who received mTORi-based (19.3%) or CsA-based (16.3%) regimens.

F3
FIGURE 3.:
Death-censored draft failure (A) and death (B) incidence >6 mo-to-5 y after transplant, according to early ISx regimen and recipient age. ALEM, alemtuzumab; AZA, azathioprine; CsA, cyclosporine; ISx, immunosuppression; KTx, kidney transplant; MPA, mycophenolic acid; mTORi, mammalian target of rapamycin inhibitor; Pred, prednisone; Tac, tacrolimus; TMG, antithymocyte globulin.

After covariate and propensity adjustment, compared with older recipients on the reference regimen, Tac + antimetabolite avoidance (aHR, 1.091.592.31), mTORi-based (aHR, 1.702.142.71), and CsA-based (aHR, 1.411.782.25) regimens were significantly associated with higher adjusted death-censored graft failure risk (Figure 2B). Among recipients aged 18–64 years, TMG/ALEM + steroid avoidance (aHR, 0.710.790.86) was associated with significantly lower risk of death-censored graft failure compared with the reference regimen, whereas mTORi-based (aHR, 1.291.431.59) and CsA-based regimens (aHR, 1.161.311.47) were associated with significantly increased death-censored graft failure risk. Interaction testing demonstrated that these risks varied significantly by age for TMG/ALEM + steroid avoidance, Tac + antimetabolite avoidance, mTORi-based, and CsA-based regimens.

Patient Mortality

Among adults age 18–64 years, compared with patient mortality >6 months-to-5 years among those who received the reference regimen of TMG/ALEM + triple ISx (11.2%), unadjusted mortality was significantly higher in those who received Tac + antimetabolite avoidance (14.0%), mTORi-based (14.2%), or CsA-based (13.9%) regimens (Figure 3B). Among patients aged ≥65 years, compared with mortality in those who received the reference regimen (24.0%), unadjusted mortality was significantly higher in patients who received mTORi-based (29.3%) and CsA-based (31.6%) regimens and lower in those who received IL2rAb + triple maintenance (21.9%) and TMG/ALEM + steroid avoidance (21.0%). Distribution of causes of death varied by ISx regimen, but patterns were generally similar across age groups excepted as shown (Figure S1A, SDC, https://links.lww.com/TP/C61).

After covariate and propensity adjustment, in older recipients, Tac + antimetabolite avoidance (aHR, 1.001.241.55), mTORi-based (aHR, 1.061.241.44), and CsA-based (aHR,1.201.371.57) regimens were associated with significantly higher mortality than the reference regimen (Figure 2C). Similarly, in recipients aged 18–64 years, TMG/ALEM + steroid avoidance (aHR, 0.780.860.95) was associated with significantly lower mortality compared with the reference regimen, whereas Tac + antimetabolite avoidance (aHR, 1.131.351.61), mTORi-based (aHR, 1.151.291.45), and CsA-based regimens (aHR,1.101.241.40) were associated with significantly higher mortality (Figure 3). There were no significant interactions of age and regimen for patient mortality.

Graft Failure

Among older adults, compared with the reference regimen, Tac + antimetabolite avoidance (aHR, 1.141.401.73), mTORi-based (aHR, 1.281.481.71), and CsA-based (aHR, 1.351.531.75) regimens were significantly associated with all-cause graft failure >6 months-to-5 years posttransplant (Figure 2D). In younger patients, compared with the reference regimen of TMG/ALEM + triple maintenance, adjusted all-cause graft failure risk was significantly lower in those who received TMG/ALEM + steroid avoidance (aHR, 0.750.810.87), but significantly higher in those who received mTORi-based (aHR, 1.271.381.51) and CsA-based (aHR, 1.141.251.38) regimens. These effects differed significantly by age for TMG/ALEM + steroid avoidance, IL2rAb + steroid avoidance, Tac + antimetabolite avoidance, and CsA-based regimens. The cause of graft failure differed by regimen and recipient age. Graft loss due to rejection was a more common cause of graft loss in older patients, while recurrent disease occurred more frequently in younger patients (Figure S1B, SDC, https://links.lww.com/TP/C61).

DISCUSSION

We examined associations of early posttransplant kidney transplant ISx regimen with graft and patient survival in a large national cohort of older and younger adults and observed several key findings. First, there has been a significant shift in ISx regimen away from CsA- and mTORi-based regimens to Tac-based regimens accompanied by greater use of T cell–depleting antibodies. This shift occurred across age groups. Second, while older adults are less likely than younger patients to be maintained on triple therapy with T cell–depleting induction, many older patients are still exposed to potent ISx regimens despite growing evidence of immunosenescence and higher risks of infection and malignancy in older transplant patients. Finally, lower-intensity ISx regimens (steroid-sparing or IL2rAb induction with triple therapy) have statistically equivalent graft outcomes to T cell–depleting antibodies with triple ISx in older patients and in the case of steroid-sparing regimens, lower risks of acute rejection and death.

In the older transplant recipient population, immunosenescence is considered a shift from naive T cells toward relatively more memory T cells, leading to reduced immune reactivity.18,37-39 While older recipient age appears protective against acute rejection,5,16 age-related immune dysfunction and associated comorbidities make the older recipients more susceptible to complications from ISx agents such as infections and cancer.5,17,20,22,27,40,41 These complications can result in death, and lower-intensity ISx may be protective, as observed in this study. Among older kidney transplant recipients, the dominant cause of allograft loss is death with functioning graft.40,42 Compared with kidney transplant recipients aged 18–29 years, previous studies have shown that those aged >65 years had a 7-fold risk of death with function due to greater burdens of cardiovascular mortality.13,43 Therefore, tailoring of early ISx regimens to minimize the risks of accelerated cardiovascular disease should be considered, particularly those that eliminate corticosteroids.2,44

Although corticosteroids have traditionally been a mainstay of maintenance ISx in kidney transplant recipients, the elderly are more susceptible than younger patients to corticosteroid-related side effects, including infections, posttransplant diabetes, fractures, and myopathy.44,45 Previous systematic reviews have demonstrated that early steroid withdrawal/avoidance is well tolerated in low-risk kidney allograft recipients treated with modern potent ISx; however, data evaluating this strategy in older recipients were lacking due to lack of data sets with sufficient sample sizes.46-49 Recently, using the OPTN/UNOS database, Harris et al50 evaluated the outcomes of kidney transplant recipients aged >65 years with steroid avoidance/early withdrawal (based on steroid use at discharge), and found comparable patient survival and death-censored graft survival at 3 years. This study of Medicare-insured US kidney transplant recipients has the benefit of observing actual medication fill patterns. We report significantly reduced mortality among recipients (both older and younger groups) managed with steroid avoidance/withdrawal after T cell–depleting induction. These data support the move to further personalize the ISx regimen according to recipient and donor characteristics and limit exposure to more intense ISx regimens.

Although supporting evidence is limited, mTORi-based regimens (either de novo or conversion) have been suggested as an option to reduce CNI exposure, preserve renal function, and improve survival.51 The use of mTORi has also been associated with a lower incidence of posttransplant malignancy in the clinical trials52-54 and further supported by an analysis of UNOS database (with a 60% reduction in the risk of any posttransplant malignancy and a 55% reduction in the risk of solid malignancy).55 The TRANSFORM study was conducted to compare the outcomes of 2037 kidney transplant recipients randomized to standard dose CNI + MMF versus reduced CNI + mTORi (everolimus).56 Compared with standard dose CNI + MMF, the reduced CNI + mTORi group had comparable allograft function with a significantly lower incidence of viral infections at 1-year posttransplant. The mean age of patients was 49.3 years, and follow-up time was only at 1 year posttransplant.56 Notably, the use of mTORi was associated with an increased risk of impaired wound healing, interstitial lung disease, and lipid abnormalities.51

However, it is not clear whether mTORi trial data generalize to the older adult population who may be more at risk of complications from antimetabolites and mTORis. The SENATOR trial, conducted by 2 German centers in the European Senior Program, reported increased adverse events in older patients transitioned from CNIs to everolimus.57 In this trial, kidney transplant recipients aged >65 years receiving their first kidney from an older deceased donor aged (>65 y) were randomized to standard therapy with CNI and MMF or conversion from standard therapy to MMF + everolimus with basiliximab at week 7. Only 77 (37.2%) of 207 enrolled patients were randomized, with the majority of patients excluded due to abnormal laboratory values or acute rejection (17% of trial participants) before randomization. Among the patients who were converted, those who remained on everolimus had comparable kidney function at 6 months posttransplant. However, there was a higher rate of discontinuation of trial assigned regimen (27.8% versus 0%) and acute rejection (21.9% versus 10%) among patients randomized to everolimus.57 In this study, older patients treated initially with mTORi-based regimens experienced a 2-fold greater odds of death-censored graft failure and higher risk-adjusted mortality. These data suggest that mTORi treatment should be undertaken cautiously in older patients.

The addition of MMF allows CNI and steroid doses to be decreased or withdrawn, with a positive impact on long-term allograft outcome. Earlier studies showed concern regarding increased adverse events with MMF among older transplant recipients, especially opportunistic infection, graft loss, and mortality,58,59 and thus, antimetabolite avoidance regimen has been proposed as a potential regimen for older recipients.5,11,17,27,31,59 However, there are conflicting data on the effect of MMF on infectious complications in older kidney transplant recipients,58-60 and a subsequent study demonstrated the benefits and safety of MMF in older recipients aged ≥55 years.60 Nevertheless, limitations of this study included small sample size and differences in length of follow-up evaluation between each study group.60 In our study, we demonstrated that antimetabolite avoidance was associated with higher risks of graft failure and mortality among older recipients in comparison with steroid avoidance and triple therapy regimens, suggesting that the benefit of elimination are offset by complications.

The field has also moved away from CsA-based ISx. CsA-based regimens decreased from 11.7% of patients to 3.9% between 2005 and 2016. CsA is generally believed to be less potent than Tac resulting in inferior outcomes after transplant.61 In this analysis, CsA-based regimens were associated with higher rates of death-censored graft failure and mortality for younger and older patients. These findings may reflect altered CNI pharmacokinetics in older patients. In a prospective study of nearly 2500 patients, CNI levels were 50% higher in patients aged ≥65 years, potentially due to changes in CYP3A4 with aging.62 This enhanced CNI level is compounded by greater variation in CsA levels in older adults, particularly with generic formulations, which may contribute to the observed adverse outcomes. Consequently, older patients without conditions that preclude the use of Tac (eg, severe neurologic side effects) appear to benefit from early Tac-based therapy.

While a national linkage of transplant registry and pharmacy claims offers the opportunity to study the impact of early ISx regimen on outcomes with sufficient sample size, diversity of management approaches, and follow-up to generate meaningful conclusions, there are inherent limitations in this type of analysis. First, this is a retrospective analysis of Medicare beneficiaries, and results may not generalize to kidney transplant recipients with private insurance.63 Given the focus on elderly patients, these Medicare data are likely an accurate reflection of outcome in this age group as the proportion of older adults was enriched in this sample. Second, exact ISx exposure, weaning plans, drug levels, and side effects are not available using these data. However, the assignment to the ISx regimen is likely to be accurate because, unlike center reported data in UNOS, these data represent paid claims in the Medicare system. A pharmacy data confirms that prescriptions were filled, medication adherence may vary across different regimens, and therapeutic drug level monitoring was not available. As the pharmacokinetics of CNIs change with older age and maintenance therapy with CNIs among older transplant recipients potentially needs more frequent monitoring and adjustments, it is possible that observed outcome differences were due to medication management as well as selection.64 While we assume lower exposure in patients on only 2 maintenance medications, this is not validated with objective measures. Third, it is possible that the choice of ISx regimen might have been affected by uncaptured risk factors in the database such as prior history of malignancy, biopsy data, other donor characteristics, intolerance of standard medications, or inability to afford these medications. For example, mTORi-based regimens may have been selected for recipients who received allografts with higher chronic Banff scores and higher vascular intimal thickening on biopsy data to avoid CNI toxicity. Conversely, patients with new-onset diabetes mellitus after transplant may have been switched to CSA to avoid this use. Fourth, early ISx choice is highly influenced by center practices.34 Consequently, center practice associated with higher graft failure may be associated with the use of nonstandard ISx. The USRDS database does not provide center identifiers and, therefore, we could not independently assess the impact of center performance patterns on patient outcomes with different ISx regimens.

In summary, ISx selection after kidney transplant should be personalized based on donor and recipient risk factors. Older patients represent a growing but high-risk population of kidney transplant recipients. Our results suggest that reduced exposure to ISx may be beneficial. Alternative regimens, including CsA- and mTORi-based maintenance therapy, were associated with higher-risk rates of adverse outcomes. Further study is needed to characterize the impact of alternations of pharmacokinetics associated with aging on transplant outcomes.

ACKNOWLEDGMENTS

The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US government.

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