Evaluation of Antithymocyte Globulin and Basiliximab as Induction Therapy in Kidney Transplant Recipients
Author Information1
Arnav Bhalla2, Hamsini Katasani3, Kyle Herdrich4
1All authors are listed in alphabetical order
2 Thomas Jefferson High School for Science and Technology, VA, 3Chantilly High school, VA, 4Troy High School, CA
Background
The roles of induction and maintenance therapies are becoming increasingly critical in promoting the long-term success of renal transplants and the reduction of post-surgery acute rejection. From 1998 to 2007, 78% of kidney transplant recipients (KTR) in the U.S. received immunosuppressive induction therapy [1]; fast forward to 2014, that percentage increased to 90%. [2] The three most popular antibodies used in induction therapy for KTRs in the U.S. are Antithymocyte Globulin (“Thymo”), Basiliximab (“Simulect”), and Alemtuzumab (“Campath”). According to Koyawala, et al., rabbit Thymo is used in approx. 50% of indication therapies for KTRs, Basiliximab 20%, and Campath 15%. [2] Thymo is a polyclonal antibody and lymphocyte-depleting agent sourced from rabbits or horses that were immunized with human thymocytes. [3] By reducing the count of T cells, Thymo prevents KTRs’ white blood cells from rejecting the transplanted organs. Rabbit Thymo was approved in 2017 for KTRs’ induction therapy. Before then, Basiliximab was the only FDA approved induction agent for KTRs in the U.S. Basiliximab is a chimeric mouse-human antibody and an interleukin-2 receptor antagonist (IL2RA) agent that decreases patients’ T cell production by blocking certain receptors on T cells. On the other hand, Campath is a lab-produced humanized rat monoclonal antibody that works to deplete capable immune cells, T and B cells. [4]
In terms of efficacy, outcomes, and side effects after renal transplantation, Thymo and Campath are found to be most effective at preventing rejection among high-risk kidney recipients; however, Thymo is also correlated with higher rate of infections, cancer, and lymphoproliferative disease incidents. [3, 5, 6] In contrast, Basiliximab recipients showed the lowest rate of infections and side effects. Cost-wise, Basiliximab is a more cost-effective alternative to Thymo for standard- and low-risk KTRs. [3, 5] An analysis of ten randomized controlled trials (over 1200 patients included) compared the efficacy of Campath relative to IL2RAs (Basiliximab and Daclizumab) and Thymo. [4] The 2012 study found that Campath resulted in a lower rate of biopsy-proven acute rejection than the induction using IL2Ras, but there was no significant difference when compared to rabbit Thymo. The study also found no apparent difference in terms of graft loss, patient death, and new-onset diabetes mellitus among the induction agents.
On the other hand, a 2019 study by Alloway et.al. examined the results of two international randomized trials (508 KTRs included) to compare the efficacy of rabbit Thymo vs. Basiliximab. [7] The study found that 1 year and 5 years after transplantation, the rate of reported treatment failures was nearly 11% lower in rabbit Thymo recipients compared to the Basiliximab recipients. Furthermore, the 10-year data of the rabbit Thymo recipients showed a 10% lower acute rejection rate than the Basiliximab recipients.
One new development in renal induction therapy is the combined use of Thymo and Basiliximab. The combined therapy has been used as a feasible alternative for patients who could not take full dosage of Thymo due to various health reasons such as thrombocytopenia, leukopenia, or cytokine release syndrome. Since Basiliximab on its own was sometimes considered too weak to prevent graft failure, an induction therapy consisting of both Thymo and Basiliximab became a plausible option. A 2023 retrospective study of 80 KTRs showed that one-year graft survival rate was not significantly different between the Basiliximab recipients and the Thymo-Basiliximab-combined recipients, suggesting a positive support for the dual induction therapy consisted of low-dosage Thymo and Basiliximab. [8] On the other hand, a national study published in 2021 by Lam et. al [9] concluded that patients who received the Thymo-Basiliximab combined induction therapy have an increased risk of graft loss and mortality five years after transplantation when compared to those who received Thymo-only induction therapy. This study analyzed data of over 150,000 KTRs from a national registry between 2005 and 2018. The other new trend worth noting is the exclusion of steroids from maintenance therapy. Due to their anti-inflammatory and immunosuppressive properties, steroids have historically been used to prevent acute rejection after renal surgeries. However, long-term steroid use could cause adverse side effects such as osteoporosis, cataract, and higher cardiovascular and infection risks. A 2016 study by Haller et al. found that the acute rejection risk was noticeably higher for patients who were subjected to steroid reduction or withdrawal. [10] However, a couple other studies found steroid reduction techniques to be safe and effective as steroid-based maintenance therapy, and that steroid withdrawal are especially beneficial to certain patient groups, including African American recipients, sensitized patients, and pediatric patients. [11, 12]
The purpose of this study is two-fold: One is to evaluate whether the combined Thymo-Basiliximab induction therapy is as effective as other regimens (Thymo, Simulect, Campath) in preventing graft failures and patient death. The other is to examine whether the steroid-free maintenance therapy is as effective as the steroid-included maintenance therapy in graft failures and patient mortality.
Materials and Methods
Data and Data Sources
A retrospective analysis was performed using the United Network of Organ Sharing (UNOS) database between January 1, 2010 and June 30, 2022. Established by the U.S. Congress in 1984, UNOS is a non-profit organization that administers the Organ Procurement and Transplantation Network in the United States; it also manages the national transplant waiting list. The data we sourced from the UNOS transplant database exclude pediatric patients, recipients of pediatric donors, and multiple-organ transplants. Separate UNOS data files that record the follow-up information and immunosuppressive induction and maintenance therapies at the time of discharge were merged to the main data that record the information at the time of transplant and conventional transplant outcome data (e.g., graft failure and patient mortality). For immunosuppressive regimens, our analysis included the kidney transplant recipients who received either Antithymocyte Globulin (ThymoGlobulin®), Alemtuzumab (Campath®), Basiliximab (Basiliximab®) or Daclizumab (Zenapax) for induction, and Calcineurin inhibitors (CI, Cyclosporine or Tacrolimus), MMF (Mycophenolic acid), and Prednisone for the maintenance at the time of discharge. In addition, Basiliximab and Daclizumab were merged into one group in our study. Our final dataset contained the data of 165,060 kidney transplant recipients, 98,457 (60%) of those received Antithymocyte Globulin, 28,199 (17%) received Alemtuzumab, 32,550 (20%) received either Basiliximab or Daclizumab, and 5,854 (3%) received the Thymo-Basiliximab combination for induction therapy. For the maintenance regimen, 112,420 (68%) KTRs received the combination of CI and MMF with Prednisone while the remaining 52,640 (32%) received CI and MMF without Prednisone.
Outcome and Explanatory Variables
Two transplant outcomes, graft failure and patient mortality, were compared by six immunosuppressant therapies – four induction therapies (Thymo, Campath, Basiliximab, Thymo-Basiliximab combined) and two maintenance therapies (Prednisone-free or Prednisone-included). Kidney transplant recipient characteristics examined include age, sex, ethnicity (White, African American, Hispanic, Asian, Other), days on organ waitlist, whether a retransplant recipient, and diabetes status, BMI, dialysis status, glomerular filtration rate (GFR), and calculated panel reactive antibody (cPRA) at the time of transplant. For donor characteristics, we queried age, sex, ethnicity, BMI, creatinine level, diabetes status, history of hypertension, and measures for organ quality including Kidney Donor Profile Index (KDPI), kidneys from the donors with cardiac death (DCD) and expanded criteria donors (ECD). Additional transplant-related variables, such as HLA mismatch level as well as cold ischemic time (CIT) and organ sharing status (local, regional and national), were also studied.
Statistical Analysis
The basic patient, donor, and transplant characteristics were compared to using t-test or ANOVA for continuous, and Chi-sq. tests for categorical variables, depending on the sample size and the distribution of the variables included. Survival curves and the estimates for the outcomes were obtained using the Kaplan-Meier (KM) Product Limit method. In the survival analyses of transplant outcomes, graft failure (for graft survival) or patient mortality (for patient survival) were the endpoints. The recipients who did not experience any of these endpoints or whose health or graft/patient status was unknown were censored on the last follow-up or the last day of the study. For those outcome variables used in the KM survival analyses, corresponding multivariable Cox regression analyses were also performed to investigate the risk factors for respective outcomes after controlling for covariates. As in other regressions, the induction and maintenance immunosuppressive regimens, as well as aforementioned recipient, donor, and transplant characteristics were investigated as potential risk factors. Statistical significance was set at 95% confidence level and defined by p<0.05 in the analysis.
Results
Table 1 demonstrates significant variations in patient, donor, and transplant characteristics across four induction therapy regimens: Thymo, Campath, Basiliximab, and Thymo-Basiliximab combined. Most notably, patients who received the Thymo-Basiliximab combined induction were more likely to be male (64.26%, p<0.001), African American (34.95%, p<0.001) or Hispanic (25.78%), have longer wait time (537 days, p<0.001), diabetes at the time of transplant (36.65%, p<0.001), on dialysis (77.81%, p<0.001) and have lower GFR (12.62, p<0.001) at the time of transplant. Meanwhile, donors of patients who received Thymo-Basiliximab combined induction therapy were more likely to be male (56.71%, p<0.001), African American (15.63%, p<0.001), Hispanic (22.84%, p<0.001), have a higher level of creatinine (1.49, p<0.001), hypertensive (26.47%, p<0.001), higher BMI (28.49, p<0.001), higher KDPI (0.48, p<0.001), and Expanded Criteria Donor (14.67%, p<0.001). In terms of transplant characteristics, recipients of combined Thymo-Basiliximab induction were more likely to receive kidneys that had a higher level of HLA mismatch (4.16, p<0.001), longer Cold Ischemic hours (19.92, p<0.001), and were either regionally (13.38%, p<0.001) or nationally (15.49%, p<0.001) shared.
Table 2 exhibits variations in patient, donor, and transplant characteristics across two maintenance therapy regimens: the Prednisone-free therapy and the Prednisone-included therapy. Most notably, patients who received the Prednisone-free maintenance therapy were more likely to be male (63.85%, p<0.001), older in age (52.42, p<0.001), White (50.60%, p<0.001), have shorter wait time (427 days, p<0.001), diabetes at the time of transplant (36.23%, p<0.001), higher BMI (28.78, p<0.001), have lower cPRA (14.37, p<0.001), and higher GFR (13.40, p<0.001) at the time of transplant. On the other hand, donors of patients who received Prednisone-free maintenance therapy were more likely to be older in age (42.31%, p<0.001), White (69.86%, p<0.001), diabetes at the time of transplant (44.87%, p<0.001), and have higher KDPI (0.44, p<0.001). Regarding transplant characteristics, recipients of Prednisone-free maintenance therapy were more likely to receive kidneys that had a shorter Cold Ischemic time (12.45 hours, p<0.001) and were locally (82.07%, p<0.001) shared.
Table 1: Descriptive Analysis by Induction Therapy
| Thymo (n = 98,457) | Campath (n = 28,199) | Basiliximab (n = 32,550) | Thymo+ Basiliximab (n = 5,854) | p-value | |
| Patient Characteristics | |||||
| Male, n (%) | 58,291 (59.20%) | 17,190 (60.96%) | 21,816 (67.02%) | 3,762 (64.26%) | <0.001 |
| Age, mean (sd) | 51.70 (13.42) | 50.36 (12.90) | 55.06 (14.49) | 53.36 (13.88) | <0.001 |
| Race, n (%) | |||||
| White | 44,017 (44.71%) | 13,263 (47.03%) | 18,067 (55.51%) | 1,942 (33.17%) | <0.001 |
| African American | 29,145 (29.60%) | 7,709 (27.34%) | 5,389 (16.56%) | 2,046 (34.95%) | <0.001 |
| Hispanic | 16,625 (16.89%) | 5,383 (19.09%) | 5,759 (17.69%) | 1,509 (25.78%) | <0.001 |
| Asian | 7,006 (7.12%) | 1,224 (4.34%) | 2,648 (8.14%) | 299 (5.11%) | <0.001 |
| Other | 1,664 (1.69%) | 620 (2.20%) | 687 (2.11%) | 58 (0.99%) | <0.001 |
| Wait time (in days), median (IQR) | 523.00 (829.30) | 408.00 (756.32) | 394.00 (752.59) | 537.00 (775.30) | <0.001 |
| Retransplant, n (%) | 13,880 (14.10%) | 3,4 (10.65%) | 1,732 (5.32%) | 502 (8.58%) | <0.001 |
| Diabetes at the time of TX, n (%) | 33,631 (34.19%) | 9,555 (34.04%) | 11,781 (36.24%) | 2,145 (36.65%) | <0.001 |
| BMI at the time of TX, mean (sd) | 28.55 (5.49) | 28.90 (5.53) | 28.13 (5.23) | 28.10 (5.33) | <0.001 |
| Dialysis at the time of TX, n (%) | 74,168 (75.88%) | 20,191 (72.30%) | 21,691 (67.61%) | 4,439 (77.81%) | <0.001 |
| cPRA at the time of TX, mean (sd) | 25.59 (36.98) | 18.98 (32.85) | 7.93 (20.61) | 14.42 (29.48) | <0.001 |
| GFR at the time of TX, mean (sd) | 13.19 (4.75) | 13.10 (4.65) | 13.90 (4.42) | 12.62 (4.71) | <0.001 |
| Donor Characteristics | Thymo (n = 98,457) | Campath (n = 28,199) | Basiliximab (n = 32,550) | Thymo+ Basiliximab (n = 5,854) | p-value |
| Male, n (%) | 53,998 (54.84%) | 14,519 (51.49%) | 16,066 (49.36%) | 3,320 (56.71%) | <0.001 |
| Age, mean (sd) | 41.57 (12.92) | 41.64 (12.97) | 43.50 (13.18) | 42.86 (13.10) | <0.001 |
| Race, n (%) | |||||
| White | 68,369 (69.44%) | 19,270 (68.34%) | 22,619 (69.49%) | 3,410 (58.25%) | <0.001 |
| African American | 12,281 (12.47%) | 3,549 (12.59%) | 2,986 (9.17%) | 915 (15.63%) | <0.001 |
| Hispanic | 13,585 (13.80%) | 4,465 (15.83%) | 5,012 (15.40%) | 1,337 (22.84%) | <0.001 |
| Asian | 2,980 (3.03%) | 617 (2.19%) | 1,352 (4.15%) | 150 (2.56%) | <0.001 |
| Other | 2,794 (2.84%) | 863 (3.06%) | 1,152 (3.54%) | 98 (1.67%) | <0.001 |
| Creatinine at the time of TX, mean (sd) | 1.30 (1.16) | 1.30 (1.24) | 1.25 (1.14) | 1.49 (1.36) | <0.001 |
| Diabetes at the time of TX, n (%) | 32,971.00 (33.71%) | 12,468.00 (44.44%) | 16,296.00 (50.33%) | 1,962.00 (33.64%) | <0.001 |
| Hypertensive at the time of TX, n (%) | 22,573.00 (23.12%) | 5,914.00 (21.10%) | 6,370.00 (19.70%) | 1,541.00 (26.47%) | <0.001 |
| BMI at the time of TX, mean (sd) | 28.22 (6.29) | 28.23 (6.11) | 27.82 (5.90) | 28.49 (6.21) | <0.001 |
| KDPI, mean (sd) | 0.43 (0.26) | 0.43 (0.26) | 0.45 (0.26) | 0.48 (0.26) | <0.001 |
| Donor after Cardiac Death, n (%) | 17,178.00 (17.45%) | 3,851.00 (13.66%) | 3,426.00 (10.53%) | 919.00 (15.70%) | <0.001 |
| Expanded Criteria Donor, n (%) | 10,471.00 (10.64%) | 2,715.00 (9.63%) | 3,494.00 (10.73%) | 859.00 (14.67%) | <0.001 |
| Transplant Characteristics | Thymo (n = 98,457) | Campath (n = 28,199) | Basiliximab (n = 32,550) | Thymo+ Basiliximab (n = 5,854) | p-value |
| HLA mismatch level, mean (sd) | 3.98 (1.54) | 3.95 (1.53) | 3.78 (1.68) | 4.16 (1.43) | <0.001 |
| Cold Ischemic time (hrs), mean (sd) | 13.96 (10.23) | 11.75 (9.97) | 10.47 (9.90) | 19.92 (15.80) | <0.001 |
| Locally shared, n (%) | 75,977.00 (77.17%) | 23,459.00 (83.19%) | 27,894.00 (85.70%) | 4,164.00 (71.13%) | <0.001 |
| Regionally shared, n (%) | 9,931.00 (10.09%) | 2,285.00 (8.10%) | 2,310.00 (7.10%) | 783.00 (13.38%) | <0.001 |
| Nationally shared, n (%) | 12,547.00 (12.74%) | 2,455.00 (8.71%) | 2,346.00 (7.21%) | 907.00 (15.49%) | <0.001 |
Table 2: Descriptive Analysis by Maintenance Therapy
| CI, MMF w/o Prednisone (n = 52,640) | CI, MMF + Prednisone (n = 112,420) | p-value | |
| Patient Characteristics | |||
| Male, n (%) | 33,610 (63.85%) | 67,449 (60.00%) | <0.001 |
| Age, mean (sd) | 52.42 (13.60) | 52.09 (13.68) | <0.001 |
| Race, n (%) | |||
| White | 26,634 (50.60%) | 50,655 (45.06%) | <0.001 |
| African American | 12,416 (23.59%) | 31,873 (28.35%) | <0.001 |
| Hispanic | 9,393 (17.84%) | 19,883 (17.69%) | 0.435 |
| Asian | 3,319 (6.31%) | 7,858 (6.99%) | <0.001 |
| Other | 878 (1.67%) | 2,151 (1.91%) | <0.001 |
| Wait time (in days), median (IQR) | 427.00 (744.97) | 498.00 (826.51) | <0.001 |
| Retransplant, n (%) | 3,841.00 (7.30%) | 15,277.00 (13.59%) | <0.001 |
| Diabetes at the time of TX, n (%) | 19,020.00 (36.23%) | 38,092.00 (33.92%) | <0.001 |
| BMI at the time of TX, mean (sd) | 28.78 (5.50) | 28.38 (5.41) | <0.001 |
| Dialysis at the time of TX, n (%) | 36,618.00 (70.58%) | 83,871.00 (75.17%) | <0.001 |
| cPRA at the time of TX, mean (sd) | 14.37 (28.87) | 23.50 (35.93) | <0.001 |
| GFR at the time of TX, mean (sd) | 13.40 (4.54) | 13.27 (4.74) | 0.016 |
| Donor Characteristics | |||
| Male, n (%) | 27,261.00 (51.79%) | 60,642.00 (53.94%) | <0.001 |
| Age, mean (sd) | 42.31 (12.96) | 41.87 (13.03) | <0.001 |
| Race, n (%) | |||
| White | 36,775.00 (69.86%) | 76,893.00 (68.40%) | <0.001 |
| African American | 6,125.00 (11.64%) | 13,606.00 (12.10%) | 0.006 |
| Hispanic | 7,719.00 (14.66%) | 16,680.00 (14.84%) | 0.355 |
| Asian | 1,471.00 (2.79%) | 3,628.00 (3.23%) | <0.001 |
| Other | 1,332.00 (2.53%) | 3,575.00 (3.18%) | <0.001 |
| Creatinine at the time of TX, mean (sd) | 1.31 (1.20) | 1.30 (1.17) | 0.868 |
| Diabetes at the time of TX, n (%) | 23,502.00 (44.87%) | 40,195.00 (35.98%) | <0.001 |
| Hypertensive at the time of TX, n (%) | 11,183.00 (21.38%) | 25,215.00 (22.61%) | <0.001 |
| BMI at the time of TX, mean (sd) | 28.16 (6.10) | 28.15 (6.22) | 0.07 |
| KDPI, mean (sd) | 0.44 (0.26) | 0.43 (0.26) | <0.001 |
| Donor after Cardiac Death, n (%) | 7,231.00 (13.74%) | 18,143.00 (16.14%) | <0.001 |
| Expanded Criteria Donor, n (%) | 5,388.00 (10.24%) | 12,151.00 (10.81%) | <0.001 |
| Transplant Characteristics | |||
| HLA mismatch level, mean (sd) | 3.94 (1.56) | 3.94 (1.57) | 0.797 |
| Cold Ischemic time (hrs), mean (sd) | 12.45 (11.34) | 13.42 (10.16) | <0.001 |
| Locally shared, n (%) | 43,200.00 (82.07%) | 88,294.00 (78.54%) | <0.001 |
| Regionally shared, n (%) | 4,008.00 (7.61%) | 11,301.00 (10.05%) | <0.001 |
| Nationally shared, n (%) | 5,432.00 (10.32%) | 12,823.00 (11.41%) | <0.001 |
Graft Failure
Figure 1 compares the graft failure rates by induction therapy for an observation period of five years (1,825 days). According to the KM Survival curves, patients who received the Thymo-Simulect combined induction therapy had a significantly shorter graft survival time (or higher graft failure probabilities) compared to patients who received other types of induction therapy. Meanwhile, Figure 2 compares the graft failure rates by maintenance therapy for an observation period of five years. According to the KM Survival curves, patients who received the Prednisone-free maintenance therapy had a significantly longer graft survival time (or lower graft failure probabilities) compared to patients who received the Prednisone-included therapy. Once the bivariate relationships between the graft failure rates and the Thymo-Simulect combined induction therapy, and between the graft failure rates and the Prednisone-free maintenance have been confirmed to be statistically significant, we proceeded to perform Cox regression analyses to consider other variables that may also be impacting graft failure.
Table 3 summarizes the results of Cox Regressions for patient and transplant characteristics, showing risk factors correlated with graft failure adjusted for covariates. For kidney transplant recipients, having a higher KDPI (HR=2.626, p<0.001), being diabetes (HR=1.446, p<0.001), being on dialysis (HR=1.312, p<0.001), being male (HR=1.248, p<0.001), being retransplant patient (HR=1.157, p<0.001) increased the risk of graft failure by 163%, 45%, 31%, 25%, and 16% respectively. Having a higher HLA mismatch level (HR=1.042, p<0.001), being older (HR=1.019, p<0.001), and having a higher BMI at the time of transplant (HR=1.014, p<0.001) also increased the risk of graft failure by 4%, 2% and 1% respectively. On the other hand, receiving a locally shared kidney (HR=0.942, p=0.030) and having a higher GFR (HR=0.985, p<0.001) decreased the risk of graft failure by 6% and 4% respectively. Having considered the impact of patient and transplant characteristics on the graft failure rates, we also performed Cox regressions to compare the impact of induction and maintenance therapies on graft failure rates. Our study found that recipients of Thymo, Simulect, and Thymo-Simulect inductions experienced similar graft failure rates during a five-year observation period; however, recipients of Campath induction had 9% higher graft failure rates compared to recipients of Thymo-only induction. We also found that the Prednisone-included maintenance therapy increases the graft failure rate by 7% compared to the Prednisone-free maintenance therapy.
Figure 1: Graft Failure KM Survival Rates by Induction Therapy
Figure 2: Graft Failure KM Survival Rates by Maintenance Therapy
Table 3: Graft Failure Cox Regression Results
| Patient Characteristics | HR | p-value | [95% | C.l.] |
| Male patient | 1.248 | <0.001 | 1.192 | 1.307 |
| Recipient age | 1.019 | <0.001 | 1.017 | 1.021 |
| Total days on waiting list (including inactive time) | 1.000 | 0.013 | 1.000 | 1.000 |
| Retransplant recipient | 1.157 | <0.001 | 1.077 | 1.243 |
| BMI at the time of transplant | 1.014 | <0.001 | 1.010 | 1.019 |
| Diabetic patient | 1.446 | <0.001 | 1.383 | 1.512 |
| Dialysis status | 1.312 | <0.001 | 1.250 | 1.377 |
| cPRA at the time of transplant | 1.002 | <0.001 | 1.001 | 1.003 |
| Glomerular filtration rate (GFR) at the time of transplant | 0.985 | <0.001 | 0.981 | 0.990 |
| Kidney Donor Profile Index (KDPI) | 2.626 | <0.001 | 2.410 | 2.861 |
| HLA mismatch level | 1.042 | <0.001 | 1.027 | 1.057 |
| Kidney’s cold ischemic time (hours) | 1.004 | 0.002 | 1.002 | 1.007 |
| Locally shared organ | 0.942 | 0.030 | 0.893 | 0.994 |
| Induction/Maintenance Therapy Administered: | HR | p-value | [95% | C.l.] |
| Alemtuzumab induction1 | 1.092 | 0.004 | 1.028 | 1.159 |
| Basiliximab induction1 | 1.058 | 0.055 | 0.999 | 1.120 |
| Antithymocyte Globulin + Basiliximab induction1 | 1.094 | 0.114 | 0.979 | 1.222 |
| CI + MMF + Prednisone maintenance2 | 1.073 | 0.005 | 1.021 | 1.128 |
| HR = Hazard Ratio, C.I. = Confidence Interval | ||||
| Notes: | ||||
| 1 The reference group is the patients who received only Antithymocyte globulin (Thymo) for induction. | ||||
| 2 The reference group is the recipients who received CI and MMF without prednisone for maintenance therapy. | ||||
Patient Mortality
Figure 3 compares the patient mortality rates by induction therapy for an observation period of five years. According to the KM Survival curves presented, patients who received the Thymo-Simulect combined induction therapy had a significantly shorter patient survival time (or higher patient mortality probabilities) compared to patients who received other types of induction therapy. Figure 4 compares the patient mortality rates by maintenance therapy for an observation period of five years. The KM Survival curves show that patients who received the Prednisone-free maintenance therapy had a significantly longer patient survival time (or lower patient mortality probabilities) compared to patients who received the Prednisone-included maintenance therapy. Now that the relationships between the patient mortality rates and the Thymo-Simulect combined induction therapy, and between the patient mortality rates and the Prednisone-free maintenance therapy have been confirmed to be statistically significant, we proceeded to perform Cox regression analyses to consider other variables that may also be impacting patient mortality.
Table 4 summarizes the results of Cox Regressions for patient and transplant characteristics, showing risk factors correlated with patient mortality adjusted for covariates. For kidney transplant recipients, having a higher KDPI (HR=2.035, p<0.001), being diabetes (HR=1.696, p<0.001), being on dialysis (HR=1.412, p<0.001), being male (HR=1.254, p<0.001), being retransplant patient (HR=1.163, p<0.001) increased the risk of patient mortality by 104%, 70%, 41%, 25%, and 16% respectively. Being older (HR=1.050, p<0.001), higher HLA mismatch level (HR=1.020, p<0.001), and higher BMI at the time of transplant (HR=1.015, p<0.001) also increased the risk of patient mortality by 5%, 2% and 2% respectively. On the other hand, higher GFR (HR=0.987, p<0.001) decreased the risk of patient mortality by 1%. Meanwhile, we also compared the impact of induction and maintenance therapies on patient mortality rates. Our review found that recipients of Thymo and Thymo-Simulect inductions had similar patient mortality rates; however, recipients of Campath and Simulect inductions had 8% higher patient mortality rates compared to recipients of Thymo induction. We also observed that the Prednisone-included maintenance therapy increases the graft failure rate by 11% compared to the Prednisone-free maintenance therapy.
Figure 3: Patient Mortality KM Survival Rates by Induction Therapy
Figure 4: Patient Mortality KM Survival Rates by Maintenance Therapy
Table 4: Patient Mortality Cox Regression Results
| Patient Characteristics | HR | p-value | [95% | C.l.] |
| Male patient | 1.254 | <0.001 | 1.192 | 1.32 |
| Recipient age | 1.05 | <0.001 | 1.048 | 1.053 |
| Total days on waiting list (including inactive time) | 1.000 | <0.001 | 1.000 | 1.000 |
| Retransplant recipient | 1.163 | <0.001 | 1.073 | 1.261 |
| BMI at the time of transplant | 1.015 | <0.001 | 1.010 | 1.019 |
| Diabetic patient | 1.696 | <0.001 | 1.617 | 1.779 |
| Dialysis status | 1.412 | <0.001 | 1.340 | 1.489 |
| cPRA at the time of transplant | 1.003 | <0.001 | 1.002 | 1.004 |
| Glomerular filtration rate (GFR) at the time of transplant | 0.987 | <0.001 | 0.982 | 0.993 |
| Kidney Donor Profile Index (KDPI) | 2.035 | <0.001 | 1.856 | 2.231 |
| HLA mismatch level | 1.02 | 0.012 | 1.004 | 1.037 |
| Kidney’s cold ischemic time (hours) | 1.004 | 0.003 | 1.001 | 1.006 |
| Induction/Maintenance Therapy Administered: | ||||
| Alemtuzumab induction1 | 1.076 | 0.032 | 1.006 | 1.151 |
| Basiliximab induction1 | 1.077 | 0.016 | 1.014 | 1.145 |
| Antithymocyte Globulin + Basiliximab induction1 | 1.109 | 0.088 | 0.985 | 1.25 |
| CI + MMF + Prednisone maintenance2 | 1.114 | <0.001 | 1.055 | 1.176 |
| HR = Hazard Ratio, C.I. = Confidence Interval | ||||
| Notes: | ||||
| 1 The reference group is the patients who received only Antithymocyte globulin (Thymo) for induction. | ||||
| 2 The reference group is the recipients who received CI and MMF without prednisone for maintenance therapy. | ||||
Conclusion
Our first objective was to determine whether the Thymo-Simulect combination would be as effective as the most popular induction therapies. Based on our analysis, we determined that in terms of preventing graft failure, the combined Thymo-Simulect induction therapy is as effective as Thymo-only and Simulect-only inductions; in addition, it is more effective than the Campath induction. In terms of preventing patient mortality, the combined Thymo-Simulect induction therapy is as effective as the Thymo-only induction, and more effective than the Simulect and the Campath inductions. We noted that the Campath induction increased the graft failure rate by 9.2% and increased the patient mortality rate by 7.6% compared to the Thymo-only induction. Recipients of the Simulect induction had similar graft failure rate as those of Thymo induction; however, the Simulect induction increases the patient mortality rate by 7.7% compared to Thymo induction. Regarding our other objective, we concluded that the Prednisone-free maintenance therapy is more effective in preventing graft failure and patient mortality than the Prednisone-included maintenance therapy.
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