Intra‐patient variability (IPV) of tacrolimus trough level has been associated with poor outcome after kidney transplantation. These findings were derived from single‐center analyses and restricted ...mainly to measurements early after transplantation. We analyzed in a multicenter effort whether high IPV of tacrolimus levels at posttransplant years 1, 2, and 3 was associated with impaired clinical outcome. More than 6600 patients who received a deceased donor kidney transplant during 2000‐2014 and had a functioning graft for >3 years were studied. Graft survival was significantly impaired with increasing IPV (P < 0.001). As compared to patients with a low IPV of <30%, the risk of graft loss during years 4‐6 increased 32% in patients with an IPV of 30% to 44% and 66% in patients with an IPV of ≥45% (P = 0.002 and P < 0.001). About one‐third of patients showed an IPV of ≥30% with substantially impaired outcome. Even in patients with good outcome during the first 3 posttransplant years, a high IPV was associated with inferior graft survival. Our data indicate that a fluctuating tacrolimus trough level at years 1, 2, and 3 posttransplant is a major problem in kidney transplantation.
A multicenter analysis of more than 6,600 deceased donor kidney transplants indicates that high intra‐patient variability of tacrolimus trough levels late after transplantation occurs in as many as 32% of patients and is associated with substantially impaired outcomes.
Split‐liver transplantation offers a solution to the organ shortage problem. However, the outcomes of extended right lobe liver transplantation (ERLT) and whether it is a suitable alternative to ...full‐size liver transplantation (FSLT) remain controversial. We compared the outcomes of ERLT and FSLT in adult recipients of 43,409 first deceased donor liver transplantations using Cox regression. We also analyzed 612 ERLT and 1224 FSLT 1:2 matched cases to identify factors that affect ERLT outcome. The risk of graft loss was significantly higher following ERLT than following FSLT during the first posttransplantation year in the matched and unmatched collective (hazard ratio HR, 1.39 and 1.27 and P = 0.01 and 0.006, respectively). Every additional hour of cold ischemia time (CIT) increased the risk of 1‐year graft loss by 10% in the ERLT group compared with only 3% in the FSLT group (P = 0.003 and <0.001, respectively). Importantly, the outcome of ERLT and FSLT did not differ significantly if the CIT was below 10 hours (HR, 0.71; P = 0.22). One‐year graft and patient survival were lower in high‐risk ERLT recipients with a Model for End‐Stage Liver Disease (MELD) score of ≥20 (HR, 1.88; P = 0.03 and HR, 2.03; P = 0.02). In the male recipient–male donor combination, ERLT recipients had a higher risk of 1‐year graft loss than FSLT recipients (HR, 2.44; P = 0.006). This was probably because of the significantly higher MELD score in ERLT recipients (P = 0.004). ERLT in adults is an adequate alternative to FSLT and offers an elegant solution to the problem of organ shortage as long as the cold storage is less than 10 hours and the recipient’s MELD score is <20.
With graft survival rates steadily improving during the recent years, there is debate whether donor kidneys should still be allocated according to compatibility for human leukocyte antigens (HLA).
...Recent studies argue for continued kidney exchange efforts for achieving better HLA compatibility. In this modern era of immunosuppression, better HLA matching is associated not only with better graft survival, but also with the administration of lower dosages of immunosuppressive agents, a lower incidence of side-effects of immunosuppression such as non-Hodgkin lymphoma, hip fractures, and death from infection, and a lower grade of sensitization if a patient has lost a kidney graft and is relisted for a retransplant.
Despite the overall improved graft survival rates in the recent years, the data continue to support organ sharing based on HLA matching in kidney transplantation.
Summary
Adolescent and young adult age is a high‐risk window with an alarmingly increased likelihood of premature kidney graft loss due to immunological rejection. Using the large database of the ...Collaborative Transplant Study, we analyzed whether a more intense and less variable exposure to tacrolimus could counteract this young age‐related enhanced immunoreactivity. Kidney graft recipients aged 12–23 years (n = 964) with a 1‐year tacrolimus trough level between 4.0 and 10.9 ng/ml had a 5‐year graft survival rate of 85.1%, significantly better than the poor 66.1% rate in patients with a trough level below 4.0 ng/ml who showed a 2.38‐fold increased risk of graft loss in the multivariable analysis (P < 0.001). This association was not apparent in young children aged 0–11 years (n = 455) and less pronounced in adults aged 24–34 years (n = 1466). However, an intra‐patient variability of tacrolimus (IPV) trough level ≥1.5 at post‐transplant years 1 and 2 was associated with an increased graft loss risk in both 12‐ to 23‐year‐old and 0‐ to 11‐year‐old recipients (P < 0.001 and P = 0.045). Patients with high IPV made up as many as 30% of kidney graft recipients, indicating that a more intense and less variable exposure to tacrolimus could improve graft survival strongly in this high‐risk group.
Seroconversion after COVID‐19 vaccination is impaired in kidney transplant recipients. Emerging variants of concern such as the B.1.617.2 (delta) and the B.1.1.529 (omicron) variants pose an ...increasing threat to these patients. In this observational cohort study, we measured anti‐S1 IgG, surrogate neutralizing, and anti‐receptor‐binding domain antibodies three weeks after a third mRNA vaccine dose in 49 kidney transplant recipients and compared results to 25 age‐matched healthy controls. In addition, vaccine‐induced neutralization of SARS‐CoV‐2 wild‐type, the B.1.617.2 (delta), and the B.1.1.529 (omicron) variants was assessed using a live‐virus assay. After a third vaccine dose, anti‐S1 IgG, surrogate neutralizing, and anti‐receptor‐binding domain antibodies were significantly lower in kidney transplant recipients compared to healthy controls. Only 29/49 (59%) sera of kidney transplant recipients contained neutralizing antibodies against the SARS‐CoV‐2 wild‐type or the B.1.617.2 (delta) variant and neutralization titers were significantly reduced compared to healthy controls (p < 0.001). Vaccine‐induced cross‐neutralization of the B.1.1.529 (omicron) variants was detectable in 15/35 (43%) kidney transplant recipients with seropositivity for anti‐S1 IgG, surrogate neutralizing, and/or anti‐RBD antibodies. Neutralization of the B.1.1.529 (omicron) variants was significantly reduced compared to neutralization of SARS‐CoV‐2 wild‐type or the B.1.617.2 (delta) variant for both, kidney transplant recipients and healthy controls (p < .001 for all).
A third mRNA vaccine dose increases immunogenicity in most kidney transplant recipients but, in comparison to healthy controls, kidney recipients have significantly reduced cross‐neutralizing antibody activity against the immune‐escaping B.1.1.529 (omicron) variant.
We analyzed in a cohort of 68,606 first deceased donor kidney transplantations reported to the Collaborative Transplant Study whether an epitope-based matching of donor-recipient pairs using the ...Predicted Indirectly ReCognizable HLA Epitopes algorithm (PIRCHE-II) is superior to currently applied HLA antigen matching. PIRCHE-II scores were calculated based on split antigen HLA-A, -B, -DRB1 typing and adjusted to the 0-6 range of HLA mismatches. PIRCHE-II scores correlated strongly with the number of HLA mismatches (Spearman ρ = 0.65,
< 0.001). In multivariable analyses both parameters were found to be significant predictors of 5-year death-censored graft loss with high prognostic power hazard ratio (HR) per adjusted PIRCHE-II score = 1.102, per HLA mismatch = 1.095;
-value PIRCHE-II: 9.8, HLA: 11.2;
< 0.001 for both. When PIRCHE-II scores and HLA mismatches were analyzed simultaneously, their predictive power decreased but remained significant (PIRCHE-II:
= 0.002; HLA:
< 0.001). Influence of PIRCHE-II was especially strong in presensitized and influence of HLA mismatches in non-sensitized recipients. If the level of HLA-incompatibility was low (0-3 mismatches), PIRCHE-II scores showed a low impact on graft survival (HR = 1.031) and PIRCHE-II matching did not have additional significant benefit (
= 0.10). However, if the level of HLA-incompatibility was high (4-6 mismatches), PIRCHE-II improved the positive impact of matching compared to applying the traditional HLA matching alone (HR = 1.097,
= 0.005). Our results suggest that the PIRCHE-II score is useful and can be included into kidney allocation algorithms in addition to HLA matching; however, at the resolution level of HLA typing that is currently used for allocation it cannot fully replace traditional HLA matching.
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