Transplant Candidates of 70+ Years Have Superior Survival If Receiving Pre-Emptively a Living Donor Kidney.

Background: The number of kidney transplant recipients over 70 years of age is increasing but detailed data on patient and graft survival in the modern era of immune suppression are few. Methods: A single-center cohort of patients of 70 years and older (n = 349) at time of kidney transplantation from 2010-2020 were followed until January 2023. Results: The median age was 73 years with a median follow-up of 4.3 years. Fifty percent of recipients of a living donor kidney (LDK, n = 143) received their graft pre-emptively. Cumulative death-censored graft survival was excellent in the LDK group and reached 98% at 5 years vs. 85% in the deceased donor kidney (DDK) group. Primary non-function (38%) and rejection (43%) were the major causes of graft loss in the first year after DDK transplantation. Rejection-related graft loss was 4.6% during follow-up. Median recipient survival was superior in the subgroup of pre-emptively transplanted LDK patients compared to non-pre-emptively LDK transplanted patients (11.1 versus 6.2 years). Non-pre-emptively transplanted patients had a significantly increased incidence of infection (HR 3.81, 1.46-9.96) and cardiovascular-related causes of death (HR 3.35, 1.16-9.71). Pre-emptive transplantation was also associated with a significantly improved graft survival in the DDK recipients but this result was confounded by significantly better HLA matching and younger donor age in this group. Conclusions: Pre-emptive LDK transplantation in patients of 70 years or older confers superior graft and recipient survival.

Ellipro scores of donor epitope specific HLA antibodies are not associated with kidney graft survival.

In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants.

Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation.

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level.

Imlifidase Desensitization in HLA-incompatible Kidney Transplantation: Finding the Sweet Spot.

Imlifidase, derived from a Streptococcus pyogenes enzyme, cleaves the entire immunoglobulin G pool within hours after administration in fully cleaved antigen-binding and crystallizable fragments. These cleaved fragments can no longer exert their antibody-dependent cytotoxic functions, thereby creating a window to permit HLA-incompatible kidney transplantation. Imlifidase is labeled, in Europe only, for deceased donor kidney transplantation in highly sensitized patients, whose chances for an HLA-compatible transplant are negligible. This review discusses outcomes of preclinical and clinical studies on imlifidase and describes the phase III desensitization trials that are currently enrolling patients. A comparison is made with other desensitization methods. The review discusses the immunological work-up of imlifidase candidates and especially the "delisting strategy" of antigens that shift from unacceptable to acceptable with imlifidase desensitization. Other considerations for clinical implementation, such as adaptation of induction protocols, are also discussed. Imlifidase cleaves most of the currently used induction agents except for horse antithymocyte globulin, and rebound of donor-specific antibodies should be managed. Another consideration is the timing and interpretation of (virtual) crossmatches when bringing this novel desensitization agent into the clinic.

Single-Cell RNA Sequencing of Donor-Reactive T Cells Reveals Role of Apoptosis in Donor-Specific Hyporesponsiveness of Kidney Transplant Recipients.

After kidney transplantation (KT), donor-specific hyporesponsiveness (DSH) of recipient T cells develops over time. Recently, apoptosis was identified as a possible underlying mechanism. In this study, both transcriptomic profiles and complete V(D)J variable regions of TR transcripts from individual alloreactive T cells of kidney transplant recipients were determined with single-cell RNA sequencing. Alloreactive T cells were identified by CD137 expression after stimulation of peripheral blood mononuclear cells obtained from KT recipients (N = 7) prior to and 3-5 years after transplantation with cells of their donor or a third party control. The alloreactive T cells were sorted, sequenced and the transcriptome and T cell receptor profiles were analyzed using unsupervised clustering. Alloreactive T cells retain a highly polyclonal T Cell Receptor Alpha/Beta repertoire over time. Post transplantation, donor-reactive CD4+ T cells had a specific downregulation of genes involved in T cell cytokine-mediated pathways and apoptosis. The CD8+ donor-reactive T cell profile did not change significantly over time. Single-cell expression profiling shows that activated and pro-apoptotic donor-reactive CD4+ T cell clones are preferentially lost after transplantation in stable kidney transplant recipients.

Lowering maintenance immune suppression in elderly kidney transplant recipients; connecting the immunological and clinical dots.

The management of long-term immune suppressive medication in kidney transplant recipients is a poorly explored field in the area of transplant medicine. In particular, older recipients are at an increased risk for side effects and have an exponentially increased risk of infection-related death. In contrast, an aged immune system decreases the risk of acute T-cell-mediated rejection in older recipients. Recent advances in alloimmunity research have shown a rapid and substantial decline in polyfunctional, high-risk CD4+ T cells post-transplantation. This lowers the direct alloreactivity responsible for T-cell-mediated rejection, also known as donor-specific hyporesponsiveness. Chronic antibody-mediated rejection (c-aABMR) is the most frequent cause of kidney graft loss in the long term. However, in older adults, c-aABMR as a cause of graft loss is outnumbered by death with a functioning graft. In addition, DSA development and a diagnosis of c-aABMR plateau ~10 years after transplantation, resulting in a very low risk for rejection thereafter. The intensity of immune suppression regimes could likely be reduced accordingly, but trials in this area are scarce. Tacrolimus monotherapy for 1 year after transplantation seems feasible in older kidney transplant recipients with standard immunological risk, showing the expected benefits of fewer infections and better vaccination responses.

Increasing Kidney-Exchange Options Within the Existing Living Donor Pool With CIAT: A Pilot Implementation Study.

Computerized integration of alternative transplantation programs (CIAT) is a kidney-exchange program that allows AB0- and/or HLA-incompatible allocation to difficult-to-match patients, thereby increasing their chances. Altruistic donors make this available for waiting list patients as well. Strict criteria were defined for selected highly-immunized (sHI) and long waiting (LW) candidates. For LW patients AB0i allocation was allowed. sHI patients were given priority and AB0i and/or CDC cross-match negative HLAi allocations were allowed. A local pilot was established between 2017 and 2022. CIAT results were assessed against all other transplant programs available. In the period studied there were 131 incompatible couples; CIAT transplanted the highest number of couples (35%), compared to the other programs. There were 55 sHI patients; CIAT transplanted as many sHI patients as the Acceptable Mismatch program (18%); Other programs contributed less. There were 69 LW patients; 53% received deceased donor transplantations, 20% were transplanted via CIAT. In total, 72 CIAT transplants were performed: 66 compatible, 5 AB0i and 1 both AB0i and HLAi. CIAT increased opportunities for difficult-to-match patients, not by increasing pool size, but through prioritization and allowing AB0i and "low risk" HLAi allocation. CIAT is a powerful addition to the limited number of programs available for difficult-to-match patients.

Polyfunctional donor-reactive T cells are associated with acute T-cell-mediated rejection of the kidney transplant.

Acute T-cell-mediated rejection (aTCMR) still remains a clinical problem after kidney transplantation despite significant improvements in immunosuppressive regimens. Polyfunctional T cells, i.e. T cells producing multiple pro-inflammatory cytokines, are believed to be the most relevant T cells in an immune response. The aim of this study was to determine whether polyfunctional donor-reactive T cells are associated with aTCMR. In a case-control study, 49 kidney transplant recipients with a biopsy-proven aTCMR in the first year after transplantation were included, as well as 51 controls without aTCMR. Circulating donor-reactive T cells were identified by the expression of CD137 after short-term co-culture with donor antigen-presenting cells. Polyfunctional donor-reactive T cells were further characterized by dissection into different T-cell subsets encompassing the spectrum of naïve to terminally differentiated effector T cells. Prior to kidney transplantation, proportions of donor-reactive CD4+ (0.03% versus 0.02%; P < 0.01) and CD8+ (0.18% versus 0.10%; P < 0.01) CD137++ T cells were significantly higher in recipients with a biopsy-proven aTCMR versus non-rejectors. Polyfunctionality was higher (P = 0.03) in this subset of CD137-expressing T cells. These cells were predominantly of the EM/EMRA-phenotype, with polyfunctional donor-reactive CD137++CD4+ T cells predominantly co-expressing CD28 whereas approximately half of the polyfunctional CD137++CD8+ T cells co-expressed CD28. In addition, at the time of aTCMR, polyfunctional donor-reactive CD137++ CD4+, but not CD8+, T cells, were specifically decreased by 75% compared to before transplantation in recipients with as well as those without an aTCMR. Prior to transplantation, the proportion of polyfunctional donor-reactive CD137++ T cells is associated with the occurrence of a biopsy-proven aTCMR within the first year after transplantation.

Unilateral renal atrophy 4 years after renal sympathetic denervation: a case report.

Renal sympathetic denervation (RDN) carries a low risk of renal artery stenosis, and most cases occur within the first year. However, limited data are available on long-term incidence. Here, we present a case of a 68-year-old woman who underwent radiofrequency RDN for resistant hypertension. Ambulatory blood pressure improved following RDN and uptitration of antihypertensive drugs. Between year 3 and 4 after RDN, eGFR reduced from 87 to 50 ml/min per 1.73 m 2 . Ultrasound imaging revealed left renal atrophy, while subsequent magnetic resonance angiography showed a haemodynamically significant stenosis of the left renal artery. The patient remained in good clinical condition with stable blood pressure, while eGFR mildly deteriorated during a 6-year follow-up period. This case of renal artery stenosis occurred in a patient with multiple risk factors. A causal relationship to the RDN procedure cannot be confirmed nor ruled out. Long-term surveillance for adverse events should be considered in all RDN patients.

The Incidence of Antibody-Mediated Rejection Is Age-Related, Plateaus Late After Kidney Transplantation, and Contributes Little to Graft Loss in the Older Recipients.

It is not known whether antibody-mediated rejection (ABMR) is age-related, whether it plateaus late after transplantation, and to what extent it contributes to graft loss in older recipients. Patients transplanted between 2010 and 2015 (n = 1,054) in a single center had regular follow-up until January 2023. Recipients were divided into age groups at transplantation: 18-39 years ("young"), 40-55 years ("middle age"), and >55 years ("elderly"). Ten years after transplantation the cumulative % of recipients with ABMR was 17% in young, 15% in middle age, and 12% in elderly recipients (p < 0.001). The cumulative incidence of ABMR increased over time and plateaued 8-10 years after transplantation. In the elderly, with a median follow-up of 7.5 years, on average 30% of the recipients with ABMR died with a functional graft and ABMR contributed only 4% to overall graft loss in this group. These results were cross-validated in a cohort of recipients with >15 years follow-up. Multivariate cox-regression analysis showed that increasing recipient age was independently associated with decreasing risk for ABMR. In conclusion, the cumulative risk for ABMR is age-dependent, plateaus late after transplantation, and contributes little to overall graft loss in older recipients.

Tacrolimus Monotherapy is Safe in Immunologically Low-Risk Kidney Transplant Recipients: A Randomized-Controlled Pilot Study.

In this randomized-controlled pilot study, the feasibility and safety of tacrolimus monotherapy in immunologically low-risk kidney transplant recipients was evaluated [NTR4824, www.trialregister.nl]. Low immunological risk was defined as maximal 3 HLA mismatches and the absence of panel reactive antibodies. Six months after transplantation, recipients were randomized if eGFR >30 ml/min, proteinuria <50 mg protein/mmol creatinine, no biopsy-proven rejection after 3 months, and no lymphocyte depleting therapy given. Recipients were randomized to tacrolimus/mycophenolate mofetil (TAC/MMF) or to taper and discontinue MMF at month 9 (TACmono). 79 of the 121 recipients were randomized to either TACmono (n = 38) or TAC/MMF (n = 41). Mean recipient age was 59 years and 59% received a living donor transplant. The median follow-up was 62 months. After randomization, 3 TACmono and 4 TAC/MMF recipients experienced a biopsy-proven rejection. At 5 years follow-up, patient survival was 84% in TACmono versus 76% in TAC/MMF with death-censored graft survival of 97% for both groups and no differences in eGFR and proteinuria. Eleven TACmono recipients had an infectious episode versus 22 TAC/MMF recipients (p < 0.03). Donor-specific anti-HLA antibodies were not detected during follow-up in both groups. Tacrolimus monotherapy in selected immunologically low-risk kidney transplant recipients appears safe and reduces the number of infections.

The number of donor HLA-derived T cell epitopes available for indirect antigen presentation determines the risk for vascular rejection after kidney transplantation.

The role of the indirect T-cell recognition pathway of allorecognition in acute T cell-mediated rejection (aTCMR) is not well defined. The amount of theoretical T-cell epitopes available for indirect allorecognition can be quantified for donor-recipient combinations by the Predicted Indirectly ReCognizable HLA Epitopes algorithm (PIRCHE-II). The PIRCHE-II score was calculated for 688 donor kidney-recipient combinations and associated with the incidence of first-time diagnosed cases of TCMR. A diagnosis of TCMR was made in 182 cases; 121 cases of tubulo-interstitial rejection cases (79 cases of borderline TCMR, 42 cases of TCMR IA-B) and 61 cases of vascular TCMR (TCMR II-III). The PIRCHE-II score for donor HLA-DR/DQ (PIRCHE-II DR/DQ) was highly associated with vascular rejection. At one year after transplantation, the cumulative percentage of recipients with a vascular rejection was 12.7%, 8.6% and 2.1% within respectively the high, medium and low tertile of the PIRCHE-II DR/DQ score (p<0.001). In a multivariate regression analysis this association remained significant (p<0.001 for PIRCHE-II DR/DQ tertiles). The impact of a high PIRCHE-II DR/DQ score was mitigated by older recipient age and a living donor kidney. In conclusion, indirect antigen presentation of donor HLA-peptides may significantly contribute to the risk for acute vascular rejection.

Minimal Development of Liver Fibrosis in Adult Tolerant Liver Transplant Recipients Late After Immunosuppressive Drug Weaning and Transplantation.

BACKGROUND: Operationally tolerant liver transplant (LTx)-recipients can be weaned off immunosuppressive (IS) drugs without development of graft rejection. However, it is feared that liver fibrosis might develop after complete IS weaning. The purpose of this small single-center study was to assess liver fibrosis in adult tolerant LTx recipients long after LTx and IS weaning. METHODS: Liver fibrosis was assessed in adult tolerant LTx-recipients (n = 9) using noninvasive transient elastography and measurements of multiple pro- and antifibrotic serum markers associated with liver fibrosis. The data was collected for 2 subsequent years; 8 and 9 years after IS weaning and 19 and 20 years after transplantation. Healthy individuals (n = 9) matched for age and sex were included as a reference for fibrosis-related serum markers. This study was conducted in accordance with the Declaration of Helsinki and approved by the medical ethics committee of our institution. RESULTS: Transient elastography indicated that 7 of 9 tolerant LTx recipients had no or minimal liver fibrosis (F0-F1), whereas 2 recipients had moderate or severe liver fibrosis (F2-F3). Most fibrosis-related serum markers in tolerant LTx recipients were within or close to the range obtained for healthy individuals. CONCLUSIONS: The results from this small, single-center study indicated that most adult tolerant LTx recipients have no or minimal liver graft fibrosis long after transplantation and IS weaning, and their fibrosis-related serum marker profile indicates an absence of a profibrotic status.

Progressive Loss of Donor-Reactive CD4+ Effector Memory T Cells due to Apoptosis Underlies Donor-Specific Hyporesponsiveness in Stable Renal Transplant Recipients.

Following kidney transplantation, donor-specific hyporesponsiveness (DSH) may develop, defined as a lowered response of alloreactive T cells, specifically directed to donor Ag. This study aimed to characterize the nature of DSH through multiparameter flow cytometric assays measuring changes in phenotype and function of donor-reactive T cells after transplantation. This study characterized donor-reactive T cells, identified by CD137 expression, from the peripheral blood of stable human kidney transplant recipients (n = 47) before, at 3-5 y after, and >5 y after transplantation. The phenotype (T cell subset, differentiation status, and transcription factor expression) and function (proinflammatory cytokine production) of CD4+ and CD8+ donor-reactive CD137+ T cells was evaluated by both supervised and unsupervised analyses. Results demonstrated a decline in CD4+ donor-reactive T cells within the first 3-5 y after transplantation. Predominantly, the population of effector memory T cells capable of producing two or more proinflammatory cytokines was affected. This decline was strongly correlated with reduced proliferation of CD4+ T cells to donor Ag. The donor-reactive CD8+ T cells declined substantially only after >10 y. The frequency of T cells reactive to unrelated alloantigens did not alter significantly after transplantation, excluding an aspecific effect of immunosuppressive medication. After transplantation, an increase in donor Ag-induced apoptosis was found, specifically within the donor-reactive CD4+ memory T cell subsets. In conclusion, a significant decrease in donor-reactive polyfunctional effector memory CD4+ T cells underlies the development of DSH in kidney transplant recipients, which is likely mediated by specific activation-induced cell death.

A Novel Technique for the Generation of Substantial Numbers of Functional Resident T Cells from Kidney Tissue.

Studying functionality and antigen-specificity of resident kidney T cells derived from a kidney biopsy is hampered by the lack of sufficient numbers of T cells obtained by the standard method of enzymatic tissue dissociation. Enzymatic dissociation of kidney tissue was compared to a novel method of whole kidney tissue culture allowing T cells to migrate into the medium in the presence of exogenous IL-2 and IL-15. T cell numbers were quantified and phenotype of resident T cells (CD69+CD103+/−), TCR Vß repertoire and functional characteristics were analyzed with multi-parameter flow cytometry. Renal tissue culture for four weeks in the presence of exogenous IL-2 and IL-15 yielded significantly higher numbers of T cells (1.3 × 104/mm3) when compared to cultures without exogenous cytokines (71/mm3) or direct isolation by enzymatic dissociation (662/mm3 T cells, p < 0.05). The proportion of T cells with a resident phenotype did not change in the tissue culture; percentages amounted to 87.2% and 85.1%, respectively. In addition, frequencies of CD4+, CD8+, CD4−CD8−, T cells and MAIT T cells remained similar. For both CD4+ and CD8+, T cells had a more differentiated memory phenotype after tissue culture, but the distribution of TCR Vß families did not change. In addition, the predominant Th1 cytokine secretion profile and poly-functionality of resident kidney T cell remained intact. T cell proliferation potential was not affected, excluding exhaustion and enrichment of BKV- and CMV-reactive resident T cells was observed. In conclusion, the kidney tissue culture method yields significantly increased numbers of resident T cells without major effects on composition and functionality.

Causes of Kidney Graft Failure in a Cohort of Recipients With a Very Long-Time Follow-Up After Transplantation.

Background: Biopsy-proven causes of graft loss many years after kidney transplantation are scarcely documented. Methods: Patients transplanted between 1995 and 2005 (n = 737) in a single center were followed on a regular basis until 2021. The recipients were divided according to age at transplantation into 3 groups; 18-39 years (young), 40-55 years (middle age), and older than 55 years (elderly). For cause biopsies of renal transplants were clustered into the categories, rejection, IFTA, return original disease, and diagnosis of de novo kidney disease. Results: Rejection was the main cause of graft failure censored for death at every time period after transplantation. The incidence of T cell-mediated rejection (TCMR) became rare 6 years after transplantation while the cumulative incidence of antibody-mediated rejection (ABMR) increased over time (1.1% per year). ABMR was not diagnosed anymore beyond 15 years of follow-up in recipients without pre-transplant donor-specific antibodies (DSA). An episode of TCMR was associated with an increased incidence of ABMR diagnosis in the short-term but did not increase the overall incidence of AMBR not in the long-term. Death as a cause of graft failure was an important competitive risk factor long after transplantation and resulted in a significantly lower frequency of rejection-related graft loss in the elderly group (11 vs. 23% in the young group at 15 year follow-up). Conclusion: Rejection is a major cause of graft loss but recipient's age, time after transplantation, and the presence of DSA before transplantation determine the relative contribution to overall graft loss and the type of rejection involved.

Combined Analysis of Transcriptome and T-Cell Receptor Alpha and Beta (TRA /TRB ) Repertoire in Paucicellular Samples at the Single-Cell Level.

With the advent of next-generation sequencing (NGS) methodologies, the total repertoires of B and T cells can be disclosed in much more detail than ever before. Even though many of these strategies do provide in-depth and high-resolution information of the immunoglobulin (IG) and/or T-cell receptor (TR) repertoire, one clear disadvantage is that the IG/TR profiles cannot be connected to individual cells. Single-cell technologies do allow to study the IG/TR repertoire at the individual cell level. This is especially relevant in cell samples in which much heterogeneity of the cell population is expected. By combining the IG/TR repertoire with transcriptome data, the reactivity of the B or T cell can be associated with activation or maturation stages. An additional advantage of such single-cell technologies is that the combination of both IG and both TR chains can be studied on a per cell basis, which better reflects the antigen receptor reactivity of cells. Here we present the ICELL8 single-cell method for the parallel analysis of the TR repertoire and transcriptome, which is especially useful in samples that contain relatively few cells.

Activated CD4+ T Cells and Highly Differentiated Alloreactive CD4+ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients.

Spontaneous operational tolerance to the allograft develops in a proportion of liver transplantation (LT) recipients weaned off immunosuppressive (IS) drugs. Several studies have investigated whether peripheral blood circulating T cells could play a role in the development or identify operational tolerance, but never characterized alloreactive T cells in detail due to the lack of a marker for these T cells. In this study, we comprehensively investigated phenotypic and functional characteristics of alloreactive circulating T cell subsets in tolerant LT recipients (n = 15) using multiparameter flow cytometry and compared these with LT recipients on IS drugs (n = 23) and healthy individuals (n = 16). Activation-induced CD137 was used as a marker for alloreactive T cells upon allogenic stimulation. We found that central and effector memory CD4+ T cells were hyporesponsive against donor and third-party splenocyte stimulation in tolerant LT recipients, whereas an overall hyperresponsiveness was observed in alloreactive terminally differentiated effector memory CD4+ T cells. In addition, elevated percentages of circulating activated T helper cells were observed in these recipients. Lastly, tolerant and control LT recipients did not differ in donor-specific antibody formation. In conclusion, a combination of circulating hyperresponsive highly differentiated alloreactive CD4+ T cells and circulating activated T helper cells could discriminate tolerant recipients from a larger group of LT recipients.

T-Cell Epitopes Shared Between Immunizing HLA and Donor HLA Associate With Graft Failure After Kidney Transplantation.

CD4+ T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4+ memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4+ memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4+ memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4+ memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation.