Author Information1
Paul, Krittika2; Sankara, Veda3; Yu, Claire4
(Editor: Li, Meng-Hao)
1 All authors are listed in alphabetical order
2 Monta Vista High School, CA, 3Independence High School, VA, 4Marriotts Ridge High School, MD, 5George Mason University, VA
Background
Intestinal transplants were originally offered to patients with intestinal failure (IF) who could not continue with parenteral nutrition (PN), which is intravenous feeding. The most common cause of IF is short bowel syndrome, in which the absence or removal of the small intestine causes the body’s inability to absorb enough nutrients. In the past, a small number of patients receiving an intestinal transplant made it difficult to determine the best time to administer a transplant, and many patients, as a result, were referred to a transplant too late. Now, intestinal transplants are offered as an alternative to PN. It is especially important to care for highly immunosuppressed patients after the transplant, since they are more susceptible to bacterial colonization and infection, leading to sepsis [5]. Liver transplants and intestinal transplants are known to be some of the most complex transplants. Patients who required liver transplants specifically have dealt with the scarcity of donors in the past ten years, such that “the waiting list increased more than sixfold from 2,902 patients in 1993 to 18,047 patients in 2001” (Brown, 2004). Intestinal transplant patients suffer from acute rejection leading to them requiring intense immunosuppressants, which leads to a weaker immune system and susceptibility to infections [1,2,7]. Intestinal re-transplantation is generally challenging to succeed due to the immunological complexities. In a study conducted by Kubal et al. (2018), 15 out of 23 intestine re-transplant patients died, “nine (60%) resulted from complications associated with a compromised host immune status: graft versus host disease (GVHD) affecting bone marrow (three cases), persistent viral infection (three cases), post-transplant lymphoproliferative disorder (PTLD (one case), metastatic cancer (one case), multi-drug resistant polymicrobial sepsis (one case),…and four deaths (27%) resulted from severe rejection”. Re-transplantation often requires additional immunosuppressive drugs, weakening patients’ immune systems to dangerous levels that lead to worse outcomes and higher mortality rates from infections and malignancies [4]. Yet, in selected recipients, re-transplantation seems beneficial. Often, when patients experience immune rejection to their primary transplant causing graft loss, re-transplantation allows for a therapeutic option. Since patients’ condition after re-transplantation is generally very similar to that of primary transplantation, doctors can usually predict more accurate dosages of immunosuppressants and better methods that allow for a higher success rate [8]. In fact, taking “timing of re-transplantation, graftrectomy prior to re-transplant allowing an immunosuppression free state, inclusion of the liver, and preserved renal function” all play a part in beneficial re-transplantation procedures [3].
Objective
The study investigated how transplant outcomes (graft failure and patient mortality) vary by re-transplantation among intestine-alone and liver-intestinal transplant patients.
Methods
A retrospective analysis was performed using the UNOS database between January 1, 1990 and July 30, 2022. The basic patient, donor, and transplant characteristics were compared by basic demographics (age, sex, and ethnicity) as well as re-transplantation between intestine-alone transplants and liver-intestine transplants using t and chi-sq. tests. Survival curves and both transplantation and re-transplantation outcome estimates were obtained using KM models and with an understanding of patient mortality and graft failure as the end-points. Cox regression analysis models further analyzed variables (recipient age, brain dead or DCD-affected donors, and re-transplantation) that affected graft failure percentages. All analyses were done with R and the statistical significance was defined by p<0.50.
Results
Table 1: Cox Regression Model for Intestine-only Transplantation
In intestine-only transplants, older patients had a higher graft failure rate of 1.2% (HR=1.012, p=0.015). Expanded donors and DCD increased graft failure rate by 1020% (HR=11.20, p<0.001). Re-transplant increased graft failure rate by 106.2% in intestine-only patients (HR=2.062, p<0.001).
Table 2: Cox Regression Model for Liver-Intestinal Transplantation
In liver-intestine transplants, older patients had a 4.2% higher rate of graft failure (HR=1.042, p=0.038). Expanded donors, including the brain dead and those with DCD, had a 218.1% increased rate of graft failure (HR=3.181, p=0.278). Patients who underwent a re-transplant had a 218.9% greater graft failure rate (HR=3.189, p=0.062).
Table 3: Descriptive Analysis for Patient Characteristics
| Patient Characteristics | First-time transplant(N = 43) | Re-transplant(N = 40) | P-value |
| Male n (%) | 207.00(47.81%) | 23.00(57.50%) | 0.241 |
| Age, mean (sd) | 41.86 (12.66%) | 35.83(13.05%) | 0.004 |
| Black, n (%) | 49.00(11.32%) | 2.00(5.00%) | 0.292 |
| Asian, n (%) | 7.00(1.62%) | 4.00(10.00%) | 0.009 |
| Wait time(days), median (sd) | 46.00(144.79) | 152.50(294.49) | <0.001 |
| BMI at removal, n (%) | 23.31(4.42%) | 22.41(3.66%) | 0.173 |
The re-transplant recipients are more likely to be male than female compared to the first-time transplant recipients. The recipients of the re-transplant are older than the first-time transplant recipients. Black recipients are less likely to do first-time transplantation or re-transplantation compared to other races. Asian recipients generally require re-transplantation more compared to other races: possibly due to lower success rates. First-time recipients generally have shorter wait times than re-transplantation recipients. First-time recipients generally have greater body mass indexes compared to the re-transplant recipients; however, the difference is not in the extremes (Table 3).
Table 4: Descriptive Analysis for Donor Characteristics
| Donor Characteristics | First-time transplant(N = 43) | Re-transplant(N = 40) | P-value |
| Male, n (%) | 266.00(61.43%) | 21.00(52.50%) | 0.269 |
| Age, mean(sd) | 28.52(10.21%) | 29.25(9.77%) | 0.381 |
| White, n (%) | 286.00(66.05%) | 29.00(72.50%) | 0.408 |
| Black, n (%) | 78.00(18.01%) | 3.00(7.50%) | 0.091 |
| Asian, n (%) | 10.00(2.31%) | 0.00(0.00%) | >0.999 |
| Diabetes, n (%) | 44.00(10.16%) | 7.00(17.50%) | 0.178 |
| Donor BMI | 22.93(3.62%) | 23.90(4.04%) | 0.403 |
| Expanded donor including DCD | 2.00(0.51%) | 1.00(2.86%) | 0.225 |
Male donors seem to be more common compared to females for providing organs. The age of donors for re-transplantation is older than first-time transplantation. Organ donations from white donors are generally used for re-transplantation compared to first-time transplantation; the most common race for donations. Donations from black donors are more common for first-time transplantation compared to re-transplantation. Donations from Asian donors are likely used for first-time transplantation; they are generally never used for re-transplantation. Organs from diabetic donors are generally used for re-transplantation rather than first-time transplantation. Organs from donors with a higher BMI are used more commonly for re-transplantation than first-time transplantation (Table 4).
Table 5: Descriptive Analysis for Transplant Characteristics
| Transplant Characteristics | First-time transplant(N = 43) | Re-transplant(N = 40) | P-value |
| HLA mismatch Level, mean (sd) | 4.38(1.24%) | 4.76(0.96%) | 0.113 |
| Locally shared, n (%) | 112.00(25.87%) | 21.00(52.50%) | <0.001 |
| Regionally shared, n (%) | 58.00(13.39%) | 10.00(25.00%) | 0.045 |
| Nationally shared n, (%) | 263(60.74%) | 9.00(22.50%) | <0.001 |
The donors and recipients have a higher rate of HLA mismatch during re-transplantation compared to first-time transplantation. Organ donations for re-transplantation are generally locally shared compared to first-time transplantation. Similar to the locally-shared results, organ donations for re-transplantation are normally regionally shared compared to first-time transplantation. Organ donations that are nationally shared are used more commonly for first-time transplantation compared to re-transplantation (Table 5).
Statistically, for transplantation, there are more elderly recipients and donors compared to younger recipients and donors. This is proven by data that states that the mean of ages (sd) for first-time TX (n=433) is 41.86(12.66%). Despite such data, according to Cox regression models, it is shown that older people experience graft failure more often by 1.2% (HR=1.012, p=0.015). An expanded criteria for donors and donors with circulatory death (DCD) increased the risk of graft failure by 10.2 times (HR=11.2, p<0.001). For intestine-alone re-transplant patients, the chance of graft failure was 1.62 times higher than first-time transplant recipients. (HR=2.062, p<0.001).
For liver-intestinal transplantation, older people experience an increased rate of graft failure by 4.2% (HR=1.042 and p=0.038). Being an expanded donor increased the risk of graft failure rate by 218.1% in liver-intestinal transplantation (HR=0.278 and p=0.278). Patients undergoing a re-transplant for a liver-intestinal transplant experience higher rates of graft failure rate by 218.9%. Transplantation using organs from DCD or brain dead has extremely high percentages of graft failure for liver-intestinal transplantation compared to intestine-alone transplantation. In contrast, the graft failure percentage increases for patients with old age in liver-intestinal transplants compared to intestine-only transplantation (HR=1.012, p<0.001).
Figure 1: Kaplan Meier Survival Curves by Re-transplantation Status for Intestine-alone Transplants
Re-transplant patients for intestine-only generally experience lower graft survival and patient mortality rates compared to first-time transplant patients (Figure 1, p<0.001).
Figure 2: Kaplan Meier Survival Curves by Re-transplantation Status for Liver-Intestinal Transplants
Similar to intestine-alone transplants, re-transplant patients for liver-intestinal transplants face lower graft survival estimates (Figure 2, Left Panel, p<0.001). Between 750 days and 1750 days, re-transplant patients experience higher patient mortality rates compared to first-time transplant patients (Figure 2, Right Panel, p<0.001).
Conclusions
Intestine-only and liver-intestinal transplant patients. who underwent re-transplantation suffered from higher rates of graft failure and patient mortality over time. Generally, patients needing liver-intestinal transplantation suffered greater patient mortality rates compared to intestine-alone transplant patients over time. In terms of graft survival estimates, both intestine-alone and liver-intestinal transplant patients suffered similar rates of graft failure. All data mentioned in this study is statistically significant (p<0.05).
References
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4. Kubal, Chandrashekhar A et al. “Challenges with Intestine and Multivisceral Re-Transplantation: Importance of Timing of Re-Transplantation and Optimal Immunosuppression.” Annals of transplantation vol. 23 98-104. 6 Feb. 2018, doi:10.12659/aot.908052
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