Long-term Kidney Allograft Survival Research Articles

Improving long-term kidney allograft survival by rethinking HLA compatibility: from molecular matching to non-HLA genes

Optimizing immunologic compatibility in organ transplantation extends beyond the conventional approach of Human Leukocyte Antigen (HLA) antigen matching, which exhibits significant limitations. A broader comprehension of the roles of classical and non-classical HLA genes in transplantation is imperative for enhancing long-term graft survival. High-resolution molecular HLA genotyping, despite its inherent challenges, has emerged as the cornerstone for precise patient-donor compatibility assessment. Leveraging understanding of eplet biology and indirect immune activation, eplet mismatch calculators and the PIRCHE-II algorithm surpass traditional methods in predicting allograft rejection. Understanding minor histocompatibility antigens may also present an opportunity to personalize the compatibility process. While the application of molecular matching in deceased donor organ allocation presents multiple technical, logistical, and conceptual barriers, rendering it premature for mainstream use, several other areas of donor-recipient matching and post-transplant management are ready to incorporate molecular matching. Provision of molecular mismatch scores to physicians during potential organ offer evaluations could potentially amplify long-term outcomes. The implementation of molecular matching in living organ donation and kidney paired exchange programs is similarly viable. This article will explore the current understanding of immunologic matching in transplantation and the potential applications of epitope and non-epitope molecular biology and genetics in clinical transplantation.

Clinical Value of Peripheral Blood Gene Expression Profile and dd-cfDNA for Identifying Persistent Rejection.

Persistent rejection is an increasingly recognized barrier to long-term kidney allograft survival. A noninvasive method to help identify patients with persistent rejection in need of biopsy would be valuable. This was a post-hoc analysis of a multicenter observational study. Subjects that had a biopsy-proven acute rejection and had another biopsy within 9 months (270 days) and had a biopsy-paired biomarker sample were included. A total of 64 "index" rejections in 58 subjects with repeat biopsies were identified with a median time to repeat biopsy of 100 days. Persistent rejection was present in 61%; 69% of follow-up biopsies were performed in clinically stable patients. Peripheral blood gene expression profile (GEP) demonstrated 59% sensitivity, 76% specificity, PPV of 79%, and NPV of 54%. Donor-derived cell-free DNA (dd-cfDNA) demonstrated sensitivity of 62%, specificity of 86%, PPV of 88%, and NPV of 56%. For repeat biopsies within 90 days of rejection in clinically stable patients (63% of repeat biopsies), both GEP and dd-cfDNA had specificities and PPVs of 100%. GEP was more likely to be positive in TCMR, while dd-cfDNA was more likely to be positive in AMR. Both GEP and dd-cfDNA may have utility at identifying clinically stable patients with persistent rejection in need of biopsy, however they identify different types of rejection.

Effect of Spironolactone on Kidney Function in Kidney Transplant Recipients (the SPIREN trial): A Randomized Placebo-Controlled Clinical Trial.

Long-term kidney allograft survival is hampered by progressive interstitial fibrosis and tubular atrophy. The SPIREN trial tested the hypothesis that the mineralocorticoid receptor antagonist spironolactone stabilizes kidney function and attenuates glomerular barrier injury in kidney transplant patients treated with calcineurin inhibitors. Randomized, placebo-controlled, double blind clinical trial including 188 prevalent kidney transplant patients. Patients were randomized to spironolactone or placebo for three years. Glomerular filtration rate was measured along with proteinuria and kidney fibrosis. The primary endpoint was change in measured glomerular filtration rate. Secondary outcomes were 24h proteinuria, kidney allograft fibrosis and cardiovascular events. Measured glomerular filtration rates, 24h proteinuria and blood pressure were determined yearly. Kidney biopsies were collected at baseline and after two years (n=48). Fibrosis was evaluated by quantitative stereology and classified according to Banff. The groups were comparable at baseline except for slightly older allografts in the spironolactone group. Spironolactone reduced measured glomerular filtration rates (up to -7.6 (95% CI -10.9;-4.3) ml/min compared to placebo) independently of time since transplantation and blood pressure with no impact on the kidney function curve over time and reduced 24h proteinuria after one year. There was no significant effect of spironolactone on the development of interstitial fibrosis. Spironolactone added to standard therapy for three years in kidney transplant patients did not improve kidney function, long-term proteinuria or interstitial fibrosis.

A non-muscle myosin heavy chain 9 genetic variant is associated with graft failure following kidney transplantation.

Despite current matching efforts to identify optimal donor-recipient pairs for kidney transplantation, alloimmunity remains a major source of late transplant failure. Additional genetic parameters in donor-recipient matching could help improve longterm outcomes. Here, we studied the impact of a non-muscle myosin heavy chain 9 gene (MYH9) polymorphism on allograft failure. We conducted an observational cohort study, analyzing the DNA of 1,271 kidney donor-recipient transplant pairs from a single academic hospital for the MYH9 rs11089788 C>A polymorphism. The associations of the MYH9 genotype with risk of graft failure, biopsy-proven acute rejection (BPAR), and delayed graft function (DGF) were estimated. A trend was seen in the association between the MYH9 polymorphism in the recipient and graft failure (recessive model, p = 0.056), but not for the MYH9 polymorphism in the donor. The AA-genotype MYH9 polymorphism in recipients was associated with higher risk of DGF (p = 0.03) and BPAR (p = 0.021), although significance was lost after adjusting for covariates (p = 0.15 and p = 0.10, respectively). The combined presence of the MYH9 polymorphism in donor-recipient pairs was associated with poor long-term kidney allograft survival (p = 0.04), in which recipients with an AA genotype receiving a graft with an AA genotype had the worst outcomes. After adjustment, this combined genotype remained significantly associated with 15-year death-censored kidney graft survival (hazard ratio, 1.68; 95% confidence interval, 1.05-2.70; p = 0.03). Our results reveal that recipients with an AA-genotype MYH9 polymorphism receiving a donor kidney with an AA genotype have significantly elevated risk of graft failure after kidney transplantation.

Application of the iBox prognostication system as a surrogate endpoint in the TRANSFORM randomised controlled trial: proof-of-concept study

ObjectivesDevelopment of pharmaceutical agents in transplantation is currently limited by long waits for hard endpoints. We applied a validated integrative risk-prognostication system integrative Box (iBox) as a surrogate endpoint to...

Beyond the Biopsy: Monitoring Immune Status in Kidney Recipients.

Improved long-term kidney allograft survival is largely related to better outcomes at 12 months, in association with declining acute rejection rates and more efficacious immunosuppression. Finding the right balance between under- and overimmunosuppression or rejection versus immunosuppression toxicity remains one of transplant's holy grails. In the absence of precise measures of immunosuppression burden, transplant clinicians rely on nonspecific, noninvasive tests and kidney allograft biopsy generally performed for cause. This review appraises recent advances of conventional monitoring strategies and critically examines the plethora of emerging tests utilizing tissue, urine, and blood samples to improve upon the diagnostic precision of allograft surveillance.

Chronic Kidney Allograft Disease: New Concepts and Opportunities.

Chronic kidney disease (CKD) is increasing in most countries and kidney transplantation is the best option for those patients requiring renal replacement therapy. Therefore, there is a significant number of patients living with a functioning kidney allograft. However, progressive kidney allograft functional deterioration remains unchanged despite of major advances in the field. After the first post-transplant year, it has been estimated that this chronic allograft damage may cause a 5% graft loss per year. Most studies focused on mechanisms of kidney graft damage, especially on ischemia-reperfusion injury, alloimmunity, nephrotoxicity, infection and disease recurrence. Thus, therapeutic interventions focus on those modifiable factors associated with chronic kidney allograft disease (CKaD). There are strategies to reduce ischemia-reperfusion injury, to improve the immunologic risk stratification and monitoring, to reduce calcineurin-inhibitor exposure and to identify recurrence of primary renal disease early. On the other hand, control of risk factors for chronic disease progression are particularly relevant as kidney transplantation is inherently associated with renal mass reduction. However, despite progress in pathophysiology and interventions, clinical advances in terms of long-term kidney allograft survival have been subtle. New approaches are needed and probably a holistic view can help. Chronic kidney allograft deterioration is probably the consequence of damage from various etiologies but can be attenuated by kidney repair mechanisms. Thus, besides immunological and other mechanisms of damage, the intrinsic repair kidney graft capacity should be considered to generate new hypothesis and potential therapeutic targets. In this review, the critical risk factors that define CKaD will be discussed but also how the renal mechanisms of regeneration could contribute to a change chronic kidney allograft disease paradigm.

Optimization of isolation protocol and characterization of urinary extracellular vesicles as biomarkers of kidney allograft injury.

Long-term kidney allograft survival requires a personalized approach to allograft injury recognition in a timely and reliable manner. Kidney biopsy is invasive and unsuitable for continuous function assessment. Alternatively, in urine, we find extracellular vesicles (uEVs), stable carriers of kidney pathology signals. Analysis of uEVs and their cargo could allow for more frequent and non-invasive assessment of allograft function. We aimed to optimize the uEVs isolation method applicable for kidney allograft injury biomarker studies. To this end, we optimized several steps of size-exclusion chromatography (SEC)-based method for uEVs isolation from second morning urine of kidney allograft recipients. uEVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), western analysis, and quantitative PCR. According to TEM and NTA, SEC isolated high concentrations (8.64 × 108 EVs/mL of urine) of EVs that showed typical morphology and mean size (171 nm), but addition of EDTA and filtration step were needed to remove impurities. Additionally, typical EV proteins Hsc70, CD63, flotillin, tubulin, GAPDH, and miR hsa-let-7i were detected in isolated uEVs, further confirming their identity. Optimized method based on SEC was effective and adequate in isolating pure EVs from urine of kidney allograft recipients and could be used in future biomarker studies.

Belatacept-based immunosuppressive regimen in HIV-positive kidney transplant recipients.

BackgroundKidney allograft survival in human immunodeficiency virus (HIV)-positive patients is lower than that in the general population. Belatacept increases long-term patient and allograft survival rates when compared with calcineurin inhibitors (CNIs). Its use in HIV-positive recipients remains poorly documented. MethodsWe retrospectively report a French cohort of HIV-positive kidney allograft recipients who were switched from CNI to belatacept, between June 2012 and December 2018. Patient and allograft survival rates, HIV immunovirological and clinical outcomes, acute rejection, opportunistic infections (OIs) and HLA donor-specific antibodies (DSAs) were analysed at 3 and 12 months, and at the end of follow-up (last clinical visit attended after transplantation). Results were compared with HIV-positive recipients group treated with CNI.ResultsTwelve patients were switched to belatacept 10 (2–25) months after transplantation. One year after belatacept therapy, patient and allograft survival rates scored 92% for both, two (17%) HIV virological rebounds occurred due to antiretroviral therapy non-compliance, and CD4+ and CD8+ T-cell counts remained stable over time. Serious adverse events included two (17%) acute steroid-resistant T-cell-mediated rejections and three (25%) OIs. Kidney allograft function significantly increased over the 12 post-switch months (P = 0.009), and DSAs remained stable at 12 months after treatment. The control group showed similar results in terms of patient and kidney allograft survival rates, DSA characteristics and proteinuriaConclusionsSwitch from CNI to belatacept can be considered safe and may increase long-term kidney allograft survival in HIV-positive kidney allograft recipients. These results need to be confirmed in a larger cohort.

Tolerance induction with donor hematopoietic stem cell infusion in kidney transplantation: a single-center experience in China with a 10-year follow-up.

BackgroundImmunosuppressive therapy after life-saving kidney transplantation increases the risk of infection, cardiovascular diseases, metabolic diseases, and cancer. To date, four centers (three in the USA and one in South Korea) have reported clinical tolerance trials in kidney transplantation. We performed the first Chinese clinical trial in which kidney transplantation was combined with donor hematopoietic stem cell (DHSC) infusion to induce tolerance. This study summarizes the 10-year follow-up results.MethodsFrom 2009 to 2017, 11 donor/recipient pairs underwent living-related kidney transplantation combined with DHSC infusion. Two of the pairs were human leukocyte antigen (HLA)-matched, and nine were HLA-mismatched. DHSCs were mobilized using granulocyte colony-stimulating factor (G-CSF) and harvested 1 day before transplantation. The recipients received consecutive total lymphoid irradiation (TLI) for 3 days before kidney transplantation. The induction drug was anti-thymocyte globulin (ATG). DHSCs were infused on days 2, 4, and 6 post surgery. All patients were followed-up until Dec 2019. Routine laboratory examinations, chimerism, biopsies, and mixed lymphocyte reactions were performed.ResultsOne HLA-matched recipient had 30–50% chimerism, while the other patients had less than 1% chimerism. Recipients had donor-specific hyporesponsiveness (DSH) while sustaining normal reactivity to non-donors in mixed lymphocyte reactions. All recipients were followed up for 717–3,918 days. One recipient lost allograft function, and 10 recipients had stable renal function. None of the 11 recipients developed myelosuppression or graft-versus-host disease (GVHD) post transplantation. Our protocol did not increase the risk of infection. Allograft biopsy confirmed that one patient had mild rejection with Banff grade IA, while the other ten recipients did not develop rejection. Five patients were able to reduce the dose of their immunosuppressive therapy.ConclusionsOur immune tolerance induction protocol, which used DHSC infusion and TLI, achieved low dose immunosuppression with long-term stable kidney allograft survival in Chinese patients.

Low Hydrophobic Mismatch Scores Calculated for HLA-A/B/DR/DQ Loci Improve Kidney Allograft Survival.

We evaluated the impact of human leukocyte antigen (HLA) disparity (immunogenicity; IM) on long-term kidney allograft survival. The IM was quantified based on physicochemical properties of the polymorphic linear donor/recipient HLA amino acids (the Cambridge algorithm) as a hydrophobic, electrostatic, amino acid mismatch scores (HMS\\AMS\\EMS) or eplet mismatch (EpMM) load. High-resolution HLA-A/B/DRB1/DQB1 types were imputed to calculate HMS for primary/re-transplant recipients of deceased donor transplants. The multiple Cox regression showed the association of HMS with graft survival and other confounders. The HMS integer 0–10 scale showed the most survival benefit between HMS 0 and 3. The Kaplan–Meier analysis showed that: the HMS=0 group had 18.1-year median graft survival, a 5-year benefit over HMS>0 group; HMS ≤ 3.0 had 16.7-year graft survival, a 3.8-year better than HMS>3.0 group; and, HMS ≤ 7.8 had 14.3-year grafts survival, a 1.8-year improvement over HMS>7.8 group. Stratification based on EMS, AMS or EpMM produced similar results. Additionally, the importance of HLA-DR with/without -DQ IM for graft survival was shown. In our simulation of 1,000 random donor/recipient pairs, 75% with HMS>3.0 were re-matched into HMS ≤ 3.0 and the remaining 25% into HMS≥7.8: after re-matching, the 13.5 years graft survival would increase to 16.3 years. This approach matches donors to recipients with low/medium IM donors thus preventing transplants with high IM donors.

Carbamylated erythropoietin regulates immune responses and promotes long-term kidney allograft survival through activation of PI3K/AKT signaling

Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival. To determine mechanisms by which a nonhematopoietic erythropoietin (EPO) derivative, carbamylated EPO (CEPO), regulates innate and adaptive immune cells and affects renal allograft survival, we utilized a rat model of fully MHC-mismatched kidney transplantation. CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group. This therapeutic effect was inhibited when the recipients were given LY294002, a selective inhibitor of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway or anti-EPO receptor (EPOR) antibody, in addition to CEPO. In vitro, CEPO inhibited the differentiation and function of dendritic cells and modulated their production of pro-inflammatory and anti-inflammatory cytokines, along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells. Moreover, after CD4+ T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell (Treg)/Th17 ratio increased. These effects were abolished by LY294002 or anti-EPOR antibody, suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner. The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.

IMMUNOSUPPRESSIVE OPTION WITH BELATACEPT IN HIV-POSITIVE KIDNEY TRANSPLANT RECIPIENTS

Kidney allograft survival in HIV-infected patients is lower than in the general population. Belatacept increases long-term patients and allografts survival compare to anticalcineurins (CNI). Its use in HIV-positive recipients is poorly documented. We retrospectively reported a French cohort of HIV-positive kidney allograft recipients treated with belatacept. Patient and allograft survivals, HIV immunovirological and clinical evolution, acute rejection, opportunistic infections (OI), and donor-specific anti-HLA antibodies (DSA) were analyzed and compared to an historical CNI control group. Fourteen patients were treated with belatacept: 2 (16%) de novo and 12 (84%) switches 10 [2-30] months after transplantation. One year after belatacept therapy patients’ and allografts survival were 91% and 92% respectively with two (17%) HIV viral rebound linked to antiretroviral therapy non-compliance while CD4+ and CD8+ T cell count remained over time. Serious adverse events included 2 (17%) acute steroid-resistant T-cell mediated rejections and 2 (17%) OI. Kidney allograft function increased significantly 12-months after switch (P=0.009) whereas proteinuria remained comparable. DSAs remained stable 12 months after treatment. Results were similar in control group. Belatacept can be used safely and could increase long-term kidney allograft survival in HIV+ kidney allograft recipients. These results need to be confirmed in a larger cohort.

Machine learning for predicting long-term kidney allograft survival: a scoping review.

Supervised machine learning (ML) is a class of algorithms that "learn" from existing input-output pairs, which is gaining popularity in pattern recognition for classification and prediction problems. In this scoping review, we examined the use of supervised ML algorithms for the prediction of long-term allograft survival in kidney transplant recipients. Data sources included PubMed, the Cumulative Index to Nursing and Allied Health Literature, and the Institute for Electrical and Electronics Engineers (IEEE) Xplore libraries from inception to November 2019. We screened titles and abstracts and potentially eligible full-text reports to select studies and subsequently abstracted the data. Eleven studies were identified. Decision trees were the most commonly used method (n = 8), followed by artificial neural networks (ANN) (n = 4) and Bayesian belief networks (n = 2). The area under receiver operating curve (AUC) was the most common measure of discrimination (n = 7), followed by sensitivity (n = 5) and specificity (n = 4). Model calibration examining the reliability in risk prediction was performed using either the Pearson r or the Hosmer-Lemeshow test in four studies. One study showed that logistic regression had comparable performance to ANN, while another study demonstrated that ANN performed better in terms of sensitivity, specificity, and accuracy, as compared with a Cox proportional hazards model. We synthesized the evidence related to the comparison of ML techniques with traditional statistical approaches for prediction of long-term allograft survival in patients with a kidney transplant. The methodological and reporting quality of included studies was poor. Our study also demonstrated mixed results in terms of the predictive potential of the models.

Reduced Recurrence of Primary IgA Nephropathy in Kidney Transplant Recipients Receiving Everolimus With Corticosteroid: A Retrospective, Single-Center Study of 135 Transplant Patients

BackgroundLong-term kidney allograft survival remains a major clinical challenge. Recurrent glomerulonephritis disease, including recurrence of IgA nephropathy (IgAN), is a significant barrier to long-term kidney allograft survival. We performed a retrospective, observational study to evaluate the role of everolimus (EVR) in the risk of recurrent IgAN. MethodsThe study included data from 135 patients aged ≥16 years with biopsy-proven IgAN on native kidneys who underwent a kidney transplant (KT) between December 2002 and December 2018. ResultsPatients who underwent de novo KT received mycophenolate mofetil (MMF) (n = 107) or EVR (n = 28). The mean recipient age in the MMF and EVR groups was 44.9 ± 13.7 and 41.1 ± 10.1, respectively. The median (interquartile range) follow-up period was 90.9 (64.9-115.3) and 21.2 (11.4-30.6) months, respectively (< .0001). All patients received continuous corticosteroid and tacrolimus therapy. The death-censored graft survival rate after KT and the recurrence-free survival rate did not differ significantly between the groups. Univariate and multivariate Cox regression analyses identified EVR for de novo KT as an independent predictive factor for recurrence-free survival (P = .024). ConclusionsOur findings suggest that EVR-based regimens with tacrolimus and corticosteroid therapy for de novo KT reduce the recurrence of IgAN compared with MMF-based regimens with tacrolimus and corticosteroid therapy.

Long-Term (≥25 Years) Kidney Allograft Survivors: Retrospective Analysis at a Single Center

IntroductionDespite great improvements in the short-term patient and kidney graft survival, the long-term morbidity and mortality in kidney transplant recipients still remains a significant problem. The aim of the study was to evaluate the impact of both donor and transplant recipient factors, as well as renal function indices on the very long-term (>25 years) kidney allograft survival. Material and MethodsRetrospective analysis was performed on the data of 41 kidney transplant recipients (KTR), group A: follow-up = 25 years, 20 KTR, 10 male, mean age (mean [M] ± standard deviation [SD]): 34.6 ± 12.6 years, 14 living donors (LD), 6 cadaveric donors (CD); group B: follow-up > 25 years, 21 KTR, 16 male, mean age (M ± SD): 30.86 ± 12.37 years, 14 LD, 7 CD). Kidney graft origin, post-kidney transplantation diabetes mellitus, HLA compatibility, delayed graft function, and acute rejection episodes were also analyzed retrospectively. Statistical analysis with Mann-Whitney test and Kaplan-Meier survival analysis was performed (SPSS 20.0 for Windows). ResultsThe mean age of CDs was lower than that of LDs: CD mean age (M ± SD): 23.84 ± 16.26 years vs LD mean age: 52.75 ± 12.42 years (P < .001). Cadaveric kidney graft was associated with better renal allograft function 10, 15, and 25 years post kidney transplant. None of the other factors analyzed reached statistical significance between the 2 groups. ConclusionThe age of the donor and the kidney graft origin are important co-factors of the very long-term kidney allograft survival.

Imbalance favoring follicular helper T cells over IL10+ regulatory B cells is detrimental for the kidney allograft

A high frequency of regulatory B (Breg) cells, generally transitional B cells, has been associated with long-term kidney allograft survival and operational tolerance. However, circulating follicular helper T cells (cTfh) correlate with graft rejection. In order to better understand the interplay between these cell subsets and to determine their association with graft outcome we studied transitional and IL10+ Breg cells, as well as cTfh, pre- and post-transplantation in a prospective cohort of 200 kidney transplant recipients and in healthy volunteers. Patients with end-stage kidney disease had higher frequencies of transitional and IL10+ Breg cells compared to controls, and these subsets decreased during the one-year post-transplant follow-up. Higher frequencies of pre-transplant IL10+ Breg cells, and a larger reduction in these cells early post-transplantation, predicted acute rejection and graft failure. Moreover, IL10+ Breg cells correlated with cTfh pre-transplantation, and a post-transplant increase in the cTfh/IL10+Breg ratio preceded acute rejection. Thus, evaluation of pre-transplant IL10+ Breg cells and the regular monitoring of the cTfh/IL10+Breg ratio may be useful to assess post-transplant risk. Hence, our observations suggest the need to develop therapeutic strategies aimed at preserving regulatory B cells, and depleting Tfh, post-transplantation.

One-year Outcome of Everolimus With Standard-dose Tacrolimus Immunosuppression in De Novo ABO-incompatible Living Donor Kidney Transplantation: A Retrospective, Single-center, Propensity Score Matching Comparison With Mycophenolate in 42 Transplants.

Background.Despite improvement in immunosuppressive therapy, long-term kidney allograft survival remains a major challenge. The outcomes of therapy with everolimus (EVR) and standard-dose tacrolimus (Tac) have not been compared with those of mycophenolate mofetil (MMF) and standard-dose Tac in recipients of de novo ABO-incompatible (ABOi) living donor kidney transplantation (LDKT).Methods.This retrospective, observational, single-center, propensity score matching (PSM) study compared the outcomes of EVR and standard-dose Tac with those of MMF and standard-dose Tac following de novo ABOi LDKT. In total, 153 recipients of ABOi LDKT between January 2008 and March 2018 were screened for inclusion in the study. The variables considered for PSM were: recipient age/sex, duration of dialysis, cytomegalovirus mismatch (seronegative recipient and seropositive donor), cause of kidney disease, donor age/sex, and numbers of mismatches (HLA-A, HLA-B, and HLA-DR). After PSM, there were 21 patients in each group (n = 42 overall).Results.Four patients in the EVR group and 1 patient in the MMF group were withdrawn because of adverse effects. There were no significant differences between the 2 groups in 1-year outcomes regarding patient death, graft loss, delayed graft function, biopsy-proven acute rejection, infection requiring hospital admission, or estimated glomerular filtration rate. The 1-year protocol biopsy showed that the severity of interstitial fibrosis/tubular atrophy was significantly milder in the EVR group than in the MMF group.Conclusions.The findings suggest that the renal efficacy and safety of EVR and standard-dose Tac in recipients of de novo ABOi LDKT are comparable with those of MMF and standard-dose Tac.

Novel insights into non-HLA alloimmunity in kidney transplantation.

SummaryRecognition of non‐self structures on donor cells represents the main immunological barrier in solid organ transplantation. The human leukocyte antigens (HLA) are considered the most important non‐self (allo)antigens in transplantation. Long‐term graft attrition is mainly caused by the formation of alloreactive antibodies that are directed against non‐self structures (i.e., epitopes) on cell surface proteins. Recently published data provided evidence for a similar importance of non‐HLA mismatches between donors and recipients in acute rejection as well as long‐term kidney allograft survival. These data suggest a broader concept of immunological non‐self that goes beyond HLA incompatibility and expands the current concept of polymorphic non‐self epitopes on cell surface molecules from HLA to non‐HLA targets. Amino acid substitutions caused by single nucleotide variants in protein‐coding genes or complete loss of gene expression represent the basis for polymorphic residues in both HLA and non‐HLA molecules. To better understand these novel insights in non‐HLA alloimmunity, we will first review basic principles of the alloimmune response with a focus on the HLA epitope concept in donor‐specific antibody formation before discussing key publications on non‐HLA antibodies.

Steroid pretreatment of organ donors does not impact on early rejection and long-term kidney allograft survival: Results from a multicenter randomized, controlled trial.

Steroid pretreatment of deceased donors reduces inflammation in allografts and is recommended by organ procurement guidelines. The impact on long‐term graft outcome, however, remains elusive. In this multicenter randomized controlled trial, 306 deceased donors providing organs for 455 renal transplant recipients were randomized to 1000 mg of methylprednisolone or placebo prior to organ procurement (ISRCTN78828338). The incidence of biopsy‐confirmed rejection (Banff>1) at 3 months was 23 (10%) in the steroid group and 26 (12%) in the placebo group (P = .468). Five‐year functional graft survival was 84% and 82% for the steroid group and placebo group, respectively (P‐value = .941). The hazard ratio of functional graft loss was 0.90 (95% confidence interval 0.57‐1.42, P = .638) for steroid vs placebo in a multivariate Cox model. We did not observe effect modification by any of the predictors of graft survival and treatment modality. A robust sandwich estimate was used to account for paired grafts of some donors. The mean estimated GFR at 5 years was 47 mL/min per 1.73 m2 in the steroid group and 48 mL/min per 1.73 m2 in the placebo group (P = .756). We conclude that steroid pretreatment does not impact on long‐term graft survival. In a donor population with higher risk of delayed graft function, however, repetitive and higher doses of steroid treatment may result in different findings.