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Access to kidney transplantation is limited by HLA-specific sensitization. Desensitization strategies enable crossmatch-positive kidney transplantation. In this review, we describe clinical experience gained over the last 20 y using desensitization strategies before kidney transplantation and describe the different tools used (both drugs and apheresis options), including IVIg, rituximab, apheresis techniques, interleukin-6 interference, proteasome inhibition, enzymatic degradation of HLA antibodies, complement inhibition, and B cytokine interference. Although access to transplantation for highly sensitized kidney transplantation candidates has been vastly improved by desensitization strategies, it remains, however, limited by the recurrence of HLA antibodies after transplantation and the occurrence of antibody-mediated rejection.

Kidney transplant candidates (KTCs) who are HLA highly sensitized (calculated panel-reactive alloantibodies >95%) have poor access to deceased kidney transplantation. In this single-center prospective study, 13 highly sensitized desensitization-naive KTCs received IV tocilizumab (8 mg/kg) every 4 weeks. We evaluated tolerability as well as immune responses, that is, T cell, B cell, T follicular helper (Tfh) subsets, blood cytokines (IL-6, soluble IL-6 receptor-sIL-6R-, IL-21), blood chemokines (CXCL10, CXCL13), and anti-HLA alloantibodies. Tocilizumab treatment was well-tolerated except in one patient who presented spondylodiscitis, raising a note of caution. Regarding immune parameters, there were no significant changes of percentages of lymphocyte subsets, that is, CD3+ , CD3+ /CD4+ , CD3+ /CD8+ T cells, and NK cells. This was also the case for Tfh cell subsets, B cells, mature B cells, plasma cells, pre-germinal center (GC) B cells, and post-GC B cells, whereas we observed a significant increase in naive B cells (p = .02) and a significant decrease in plasmablasts (p = .046) over the tocilizumab treatment course. CXCL10, CXCL13, IL-21, total IgG, IgA, and IgM levels did not significantly change during tocilizumab therapy; conversely, there was a significant increase in IL-6 levels (p = .03) and a huge increase in sIL-6R (p = .00004). There was a marginal effect on anti-HLA alloantibodies (class I and class II). To conclude in highly sensitized KTCs, tocilizumab as a monotherapy limited B cell maturation; however, it had almost no effect on anti-HLA alloantibodies.

Background A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts. Methods Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed. Results In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of –0.6 and –3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males. Conclusion In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study.

International audience; Multiple days assessments are frequent for the evaluation of candidates to living kidney donation, combined with an early GFR estimation (eGFR). Living kidney donation is questionable when eGFR is 55 years) in a population of 1825 French living kidney donors with a median follow-up of 5.9 years. In donors younger than 45, postdonation eGFR, absolute- and relative-eGFR variation were not different between the three groups. For older donors, postdonation eGFR was higher in S90 than in S80 or Sage but other comparators were identical. Postdonation eGFR slope was comparable between all groups. Our results are in favour of in-depth screening for all candidates to donation with a normal eGFR for age.

BACKGROUND Plasmapheresis can deplete pathogenic antibodies and allow ABO- and/or HLA-incompatible transplantation. AIM To determine the impacts of three modalities of plasmapheresis (centrifugal plasmapheresis [cTPE], single-filtration plasmapheresis [mTPE], double-filtration plasmapheresis [DFPP]) on hemostasis parameters and thrombin generation. MATERIALS/METHODS Prospective, comparative study on 21 patients that received three modalities of plasmapheresis (7 patients/group). Hemostasis (prothrombin time [PT], activated partial thromboplastin time [aPTT], procoagulant factors and natural anticoagulants) were measured before and after the first plasmapheresis session. Thrombin generation was also assessed in platelet-poor plasma using an STA-Genesia (Stago) analyzer and Thromboscreen reagents (Stago) in 4-5 patients from each group. RESULTS Both cTPE and mTPE resulted in high decreases in proteins, whatever their molecular weights. Median post/pre ratios were 0.27 to 0.55 for cTPE for most proteins (except FVIII [0.64] and VWF [0.57]). Median post/pre-ratios of mTPE were 0.28 to 0.56 for all proteins. DFPP decreased high-molecular-weight proteins (fibrinogen, FV, FVIII, FXI, VWF) and proteins strongly bound to large molecules (protein SandTFPI). Median post/pre ratios with cTPE and mTPE were similar to DFPP for fibrinogen and FXIII. Regarding thrombin generation, cTPE and mTPE did not significantly modify endogenous thrombin potential (ETP) and DFPP induced a slight decrease in ETP (median post/pre ratio at 0.73) in the absence of thrombomodulin. ETP inhibition by thrombomodulin was decreased for all procedures. CONCLUSIONS DFPP depleted high molecular-weight proteins in contrast to cTPE and mTPE, which significantly decreased all proteins. Regarding thrombin generation, depletion of procoagulant factors was counterbalanced by a decrease in some natural anticoagulants whatever plasmapheresis method used; with all methods, fibrinogen and FXIII were highly depleted.

Kidney transplant recipients (KTRs) are frequently infected with chronic hepatitis C virus (HCV), which can increase the risk of graft loss. Active HCV infections among KTRs are associated with shorter survival times. The emergence of very efficient interferon-free treatments (direct-acting antivirals [DAAs]) has revolutionized prognoses for chronic viral hepatitis. We performed a multicenter study where HCV (+)/RNA (+) KTRs were followed up and either received DAAs (group A) or not (group B) according to the transplant center. The aim was to assess, in a real-life setting, the impact of DAA therapy and to compare these results with those from HCV RNA (+) KTRs where HCV infection was not treated during the same period.This study included 66 patients from 11 centers: 44 patients (66.7%; group A) received DAAs, whereas 22 patients did not (group B); the 2 groups were comparable according to baseline data. Most patients (88.6%) received sofosbuvir, 50% received ledipasvir, and 34.7% received daclatasvir. The duration of treatments ranged from 8 to 24 weeks.HCV RNA clearance (ie, a sustained virologic response) was observed in 95.4% of treated patients. Eradication of HCV led to a significant decrease in liver enzymes (50% reduction for alanine aminotransferase [P ≤ .001] and 41% for gamma glutamyl transpeptidase [P .001]). Conversely, liver enzymes did not decrease in group B. Death occurred significantly more frequently in nontreated than treated patients (3 in group B vs none in group A, P = .003). Of the 10 treated patients with severe renal impairment before DAA therapy, 6 experienced graft loss.DAAs are very effective at treating chronic HCV and have an excellent tolerance profile.

The European Society for Organ Transplantation (ESOT) submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) in 2018, to explore whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research, thereby improving long-term outcomes for allograft recipients. The request was refined collaboratively by the EMA and ESOT, with the EMA issuing a final response in December 2020. This Transplant International special issue explores the topics that were the focus of these interactions between the EMA and ESOT. Articles explore the current issues and dilemmas in kidney transplantation, primarily relating to unclear or outdated risk stratification and markers of transplantation success, although several potential improvements for outcomes assessment are also suggested. Discussions between the EMA and ESOT and recommendations are summarized, in the hope that this project will generate further discussion eventually generating a consensus on clinical trial endpoints and risk stratification, increase the quality of research in transplantation medicine, and improve long-term outcomes for kidney transplant recipients. ispartof: TRANSPLANT INTERNATIONAL vol:35 ispartof: location:Switzerland status: published

Patient-reported outcomes (PROs) that assess individuals' perceptions of life participation, medication adherence, disease symptoms, and therapy side effects are extremely relevant in the context of kidney transplantation. All PROs are potentially suitable as primary or secondary endpoints in interventional trials that aim to improve outcomes for transplant recipients. Using PRO measures (PROMs) in clinical trials facilitates assessment of the patient's perspective of their health, but few measures have been developed and evaluated in kidney transplant recipients; robust methodologies, which use validated instruments and established frameworks for reporting, are essential. Establishing a core PROM for life participation in kidney transplant recipients is a critically important need, which is being developed and validated by the Standardized Outcomes in Nephrology (SONG)-Tx Initiative. Measures involving electronic medication packaging and smart technologies are gaining traction for monitoring adherence, and could provide more robust information than questionnaires, interviews, and scales. This article summarizes information on PROs and PROMs that was included in a Broad Scientific Advice request on clinical trial design and endpoints in kidney transplantation. This request was submitted to the European Medicines Agency (EMA) by the European Society for Organ Transplantation in 2016. Following modifications, the EMA provided its recommendations in late 2020. ispartof: TRANSPLANT INTERNATIONAL vol:35 ispartof: location:Switzerland status: published

BACKGROUND AND AIMS Chronic antibody-mediated rejection (cAMR) has very few effective therapeutic options. Interleukin-6 is an attractive target because it is involved in inflammation and humoral immunity. Therefore, the use of tocilizumab (anti-IL6 receptor, TCZ) is a potential valuable therapeutic option to treat cABMR in kidney-transplant (KT) recipients METHOD This single-centre retrospective study included all KT recipients that received monthly TCZ infusions in the setting of cABMR, between August 2018 and July 2021. We assessed 12-month renal function and KT histology during follow-up. RESULTS Forty patients were included. At 12-months, eGFR was not significantly different, 41.6 ± 17 versus 43 ± 17 mL/min/1.73 m2 (P = .102) in patients with functional graft. Six patients (15%) lost their grafts: Their condition was clinically more severe at the time of the first TCZ infusion. Histological follow-up showed no statistical difference in the scores of glomerulitis, peritubular capillaritis, and interstitial fibrosis/tubular atrophy (IFTA). However, the chronic glomerulopathy score, increased significantly over time, and conversely, arteritis and inflammation in IFTA ares improved in follow-up biopsies. CONCLUSION In our study, the addition of TCZ prevented clinical and histological worsening of cABMR in KT recipients, except for more severely ill patients. Randomized studies are needed to clarify the risk/benefit of TCZ in cABMR.

BACKGROUND AND AIMS Current Glomerular filtration rate (GFR) estimating equations based on serum creatinine are facing increased criticism due to the inclusion of a race correction in black Americans with the CKD-EPI equation (CKD-EPIASR, A = Age, S = Sex, R = Race). A new equation without race (CKD-EPIAS) has been proposed. However, this equation was developed mainly from US cohorts. The performance of this new equation has been poorly compared with current European-developed creatinine-based equations, i.e. the Lund-Malmö Revised (LMR), and the new European Kidney Function Consortium (EKFC) METHOD Data from subjects over 18 years, representing 11 cohorts from Europe (previously described as the EKFC dataset, n = 13 856), and enhanced with data from Brazil (n = 100), France (n = 4429) and Africa [Democratic Republic of Congo (DRC) and Côte d'Ivoire, n = 508] were considered (n = 18 893 for the whole cohort). The EKFC cohort was considered as non-black population. All data from Africa derived from black individuals. From France, 964 subjects were self-reported as black (=Blacks from Paris). Measured GFR as a reference method and IDMS creatinine results were available. Median bias (eGFR—mGFR) with 95% confidence intervals (CI), imprecision (interquartile range: IQR), and P30 accuracy (percentage of eGFR-values within ± 30% of mGFR) with 95% CI were calculated. RESULTS Results are summarized in Table. CONCLUSION The new CKD-EPIAS has been launched in the USA for societal reasons and is now recommended by US guidelines. However, in Europe and Africa, its performance was suboptimal. The EKFC equation, using the usual Q values, or population-specific Q values (when available), displays the best performance over the whole age range for populations in Europe and Africa.

Background: Tacrolimus is the calcineurin inhibitor of choice for preventing acute rejection episodes in kidney transplant patients. However, tacrolimus has a narrow therapeutic range that requires regular monitoring of blood concentrations to minimize toxicity. A new once-daily tacrolimus formulation, LCP-tacrolimus (LCPT), has been developed, which uses MeltDose™ drug-delivery technology to control drug release and enhance overall bioavailability. Our study compared dosing of LCPT with current standard-of-care tacrolimus [immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac)] during the 6 months following de novo kidney transplantation. Comparisons of graft function, clinical outcomes, safety, and tolerability for LCPT versus IR-Tac/PR-Tac were also performed.Methods: Standard immunological risk patients with end-stage renal disease who had received a de novo kidney transplant were randomized (1:1) to LCPT (N = 200) or IR-Tac/PR-Tac (N = 201).Results: Least squares (LS) mean tacrolimus total daily dose from Week 3 to Month 6 was significantly lower for LCPT than for IR-Tac/PR-Tac. Although LS mean tacrolimus trough levels were significantly higher for LCPT than IR-Tac/PR-Tac, tacrolimus trough levels remained within the standard reference range for most patients. There were no differences between the groups in treatment failure measures or safety profile.Conclusion: LCPT can achieve similar clinical outcomes to other tacrolimus formulations, with a lower daily dose.Clinical Trial Registration:https://clinicaltrials.gov/, identifier NCT02432833.

Background This study aimed to identify transplantation characteristics and biomarkers that predict outcomes for kidney transplant (KT) patients from donors after circulatory death (DCDs). Methods Consecutive patients receiving a KT from a DCD in our center between 2014 and 2016 were included; the reference population was recipients with a living donor KT. The urinary tubular injury biomarker-to-creatinine ratio and serum lactate dehydrogenase (LDH) were measured at post-transplant days 1 and 3. The primary outcome was the occurrence of delayed graft function (DGF). Descriptive and receiver operating characteristic analyses were performed. Results Forty-one patients were included in the analysis: 15 (36.59%) DCD KTs (9 of which suffered from DGF) and 26 (63.41%) living donor KTs. For the primary endpoint, neutrophil gelatinase-associated lipocalin, N-acetyl-beta-D-glucosaminidase, urinary tubular injury biomarker-to-creatinine ratio, and LDH areas under the curve were 1 and 0.96 (95% confidence interval: 0.84-1.0), 1 and 0.92 (95% confidence interval: 0.73-1.0), respectively. Among the transplant characteristics, only the 30-minute resistive index on the perfusion machine was significantly higher in DCD KTs with DGF vs those without DGF (0.26 mm Hg/mL/min [0.20; 0.32] vs 0.14 mm Hg/mL/min [0.12; 0.16], P = .05). Median 3-month creatinine clearance among DGF DCD KTs was 49 mL/min/1.73 m2 [IQR: 42; 65] and 65 mL/min/1.73 m2 [IQR: 62; 66] among DCD KTs without DGF (P = .22). Conclusion In the DCD KT population, clinical and biological markers were identified that provided predictive tools for DGF. Thus, systematic measurement of these biomarkers, particularly LDH, could improve the management of kidney graft recipients’ immunosuppressive therapy.

Objectives Chronic antibody-mediated rejection is the main cause of late kidney graft loss. The presence of donor-specific antibodies in the serum is the main criterion for this diagnosis. Single antigen Luminex assays can identify donor-specific antibodies, and semiquantitative estimates of antibodies can be assessed using mean fluorescence intensity. Recent data have shown that patients whose donor-specific antibodies fix C3d have worse clinical outcomes, implying that C3d-specific Luminex assays may provide useful prognostic data. Materials and methods We compared C3d donor-specific antibodies with standard immunoglobulin G donor-specific antibody mean fluorescence intensities in a cohort of patients with de novo class II donor-specific antibodies and analyzed subsequent graft survival. The included kidney graft recipients received transplants between 2005 and 2015 and had developed de novo class II donor-specific antibodies. Serum was tested using the standard single antigen Luminex technique and the C3d-fixing antibody-detection system (Immucor, Herentals, Belgium). Results In our patient cohort, 41/924 patients (4.4%) developed class II donor-specific antibodies, and 65 serum samples were analyzed (at baseline and follow-up). Among these samples, 43 (66%) were negative for C3d donor-specific antibodies. A mean fluorescence intensity threshold of 9000 in the single antigen Luminex assay discerned all negative (from positive) C3d donor-specific antibodies, even when all single-bead results were taken into account. Sixteen patients (39%) had poor outcomes (ie, either creatinine levels had doubled or they had lost their graft) over the median follow-up of 5 years. C3d results were significantly associated with graft survival (P = .04). We found a strong correlation between C3d-fixing antibody positivity and mean fluorescence intensity strength in the setting of de novo class II donor-specific antibodies. Conclusions These results further reinforce the paradigm that the higher the mean fluorescence intensity, the more complement activation occurs. Routine C3d testing is thus unnecessary in this setting.

BACKGROUND The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age. MATERIAL AND METHODS Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 -post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years). RESULTS Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus. CONCLUSIONS Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.

Background and Aims Studies of healthy individuals or candidates for living kidney donation, in various geographical areas and ethnic groups, describe a decline of glomerular filtration rate (GFR) with age. Most data on GFR are obtained from subjects in the general population or from candidates for kidney donation who are younger than 65 years. It is currently unknown whether the definition of normal GFR in subjects older than 65 years is similar to the definition in those younger than 65 years. Because the age of candidates for living kidney donation is increasing worldwide, lack of GFR references for older donors complicates the selection process. Moreover, older individuals are most likely to have a mildly decreased GFR that may be misinterpreted as chronic kidney disease. In this study, we calculated percentiles of measured GFR (mGFR) from a large cohort of effective kidney donors (EKD) younger than 65 years, and extrapolated them to subjects older than 65 years. Additionnaly, we collected mGFR data from different centers within Europe from EKD and/or healthy people (HP) from the general population older than 65 years. We tested if the distribution of mGFR of these older subjects fitted with the extrapolated percentiles. Method In this retrospective, observational, multi-center study, percentiles of mGFR in EKD were calculated from a development cohort of French and Belgian EKD younger than 65 years (n=1983). From the French kidney donor study, 147 EKD older than 65 years were considered as the internal validation cohort. In an external validation cohort, data on mGFR of subjects older than 65 years, either EKD or HP from the general population (from Germany, Sweden (2), Norway, Netherlands and France, n=2459) were included. Data were fully anonymized and this retrospective study was approved by the respective ethics committees. Percentiles were derived for the development database, using quantiles modeled as cubic splines with two linear parts joining at one age-knot of 40 years. The median quantile had a constant first part (slope of zero) and a second part with a negative slope of -0.88235 mL/min/1.73m² per year. To maintain consistency, all quantiles were adjusted to show the same shape as the medium quantile. Above 65 years, the percentile values were extrapolated using the same mathematical model. We then calculated the percentage of results from the internal and external validation cohorts that were within the 5th extrapolated percentile (P5) and 95th percentile (P95). A sensitivity analysis including the EKD only was performed. Results Individuals in the development cohort were younger than in the internal or external validation cohort (47.3±10.5 years vs. 68.8±2.9 years and 71.4±6.4 years; respectively, both p Conclusion We demonstrate that extrapolated percentiles of mGFR (calculated in individuals younger than 65) fits well with the distribution of mGFR in individuals older than 65. Extrapolation of percentiles to individuals older than 65 is useful to define age-adapted GFR thresholds for older individuals.

Background Long-term studies have demonstrated a slight increased risk for end-stage renal disease (ESRD) for living kidney donors (LKD). In France, living kidney donation doubled within the past 10 years. We investigated the change in characteristics of LKD between 2007 and 2017 and the adequacy of follow-up. Methods Data were obtained from the national registry for LKD. We compared characteristics of LKD between two study periods: 2007–11 and 2012–17, and stratified donors by age and relation to recipient. We aggregated four characteristics associated with higher ESRD risk [young age, first-degree relation to recipient, obesity, low glomerular filtration rate (GFR) for age] in a single risk indicator ranging from 0 to 4. Results We included 3483 donors. The proportion of unrelated donors >56 years of age increased significantly. The proportion of related donors Conclusions An increase in living kidney donation in France does not seem to be associated with the selection of donors at higher risk of ESRD and the proportion of donors with adequate annual follow-up significantly increased.

Background Resistance to the action of rituximab (RTX) has been documented in several diseases. More recently, obinutuzumab (OBZ) has shown promise where RTX has failed in oncology and lupus nephritis. Unlike RTX, OBZ is a weak activator of complement, which may avoid the false-positive complement-dependent cytotoxicity (CDC) crossmatch tests after RTX infusions. Methods The aim of this study was to explore the effect of OBZ on B-cell depletion in kidney-transplant candidates and its impact on crossmatch test results. We included 12 patients: who were either highly sensitized kidney-transplant candidates or kidney-transplant recipients presenting with antibody-mediated rejection. Six received OBZ and 6 received RTX. CD-19 counts, flow cytometry and CDC crossmatch tests were run immediately before and at 2 weeks after drug infusion. Results OBZ reduced CD-19 counts: median reduction was 98%. B-cell CDC crossmatch test results became positive following RTX infusion but were not affected by OBZ infusion. Conclusions OBZ effectively depleted B-cell counts in sensitized kidney-transplant candidates and, unlike RTX, had no effect on CDC crossmatch results.

Background Highly HLA-sensitized kidney transplant candidates are difficult to desensitize, which reduces their chances of receiving a transplant. Methods We administered tocilizumab as a monotherapy (8 mg/kg once a mo) to 14 highly sensitized kidney transplant candidates. Highest mean fluorescence intensities of anti-HLA antibodies obtained before and after tocilizumab administration were compared from raw and diluted sera. Results The administration of tocilizumab significantly reduced dominant anti-HLA antibody sensitization. However, this decrease in mean fluorescence intensities was minor compared with the initial values. Conclusions Tocilizumab as a monotherapy was not sufficient to allow highly sensitized kidney-transplant candidates to undergo transplantation and, therefore, was not an effective desensitization method.

Summary Due to the Covid‐19 pandemic caused by SARS‐CoV‐2, transplant programs worldwide have been severely impacted with dwindling numbers of transplantations performed and a complete halt in several areas. In this review we examine whether SARS‐CoV‐2 infection presents differently in transplant recipients, whom and how we should test, how susceptible the transplant population is to overt infection and describe the range of outcomes. From retrieved published reports on SARS‐CoV‐2infections in 389solid organ transplant recipients reported in the literature, the overall mortality rate was 16.7% (n = 65); however for those with mild or moderate Covid‐19 disease this was 2.9% and 2.3% respectively; conversely, for those with severe infection the mortality rate was 52.2%.We then address questions regarding halting transplantation programs during this pandemic, whether all human tissues being considered for transplantation are capable of transmitting the infection, and if we should alter immunosuppressive medications during the pandemic.

Background New-onset diabetes after transplantation (NODAT) is a serious complication after kidney transplantation because of worse graft survival and increased risk of cardiovascular events. It is partly induced by immunosuppressive therapies such as corticosteroids. This study aimed to assess whether early corticosteroid withdrawal on day 4 (early steroid withdrawal [ESW] group) could prevent the development of NODAT within 2 years posttransplantation while maintaining good graft and patient survival rates. Methods This was an observational, single-center, retrospective study. All patients received an induction therapy of antithymocyte globulin or basiliximab and maintenance therapy of tacrolimus/mycophenolate mofetil/corticosteroids. Patients were either weaned off corticosteroids on day 4 (ESW group) or were maintained on corticosteroids for at least 3 months (standard group). NODAT was defined as the initiation of any oral hypoglycemic agent or insulin at 3 months and up to 2 years posttransplantation in previously nondiabetic recipients. Results Between January, 1, 2010, and December 14, 2014, 492 recipients were included in this study; 88 received the ESW strategy, and 404 received the standard strategy. Age and body mass index (BMI) were significantly higher in the ESW group. The incidence of NODAT was 36.8% in the ESW group and 8.8% in the standard group (odds ratio [OR], 47.5; P 25 kg/m2, the ESW strategy significantly decreased the risk of NODAT compared with the standard strategy (OR, 0.07; P = .013). Safety endpoints (eg, acute rejection, de novo–specific antibodies, graft function/survival) did not differ between groups. Conclusion Despite a reassuring safety profile, ESW on day 4 after kidney transplantation only had a marginal effect on the incidence of NODAT.

Background The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved. Methods In a cross-sectional analysis covering the years 2003–17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund–Malmö revised equation (LMR) and the Full Age Spectrum equation. Results 7In patients aged 18–39 years old, CKD-EPI overestimated GFR with 5.0–16 mL/min/1.73 m2 in median in both cohort types at mGFR levels Conclusions None of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated.

Background and Aims Great progression in treating hepatitis C infection has been made with the new Interferon-free regimens. Reports about developing hepatocellular carcinoma after DAAs have been spotlighted. Kidney transplantation and hemodialysis are considered risk factors for developing malignancies. Here we are evaluating the prevalence of HCC after DAAs treatment in high risk population. Method This cross-sectional study was held in Urology and Nephrology Center, Mansoura University, Egypt including. Total number of 165 patients received DAAs included in this study in 2 phases. The first phase included 50 patients (12 hemodialysis and 38 kidney transplant recipients). All patients completed DAAs course as treatment for hepatitis C infection (HCV) 24 months ago. Alfa feto protein and liver ultrasound (Use of both modalities combined yielded sensitivity (99.2%) and specificity (68.3%)) was used to screening of HCC for all patients. Triphasic CT liver with 86% to 94% sensitivity was done for all hemodialysis patients and KTRs with suspicious lesions or high alfa-feto protein. Results Our patients mean age was 52.32±3.2 years with male predominance. Mean Hemodialysis duration was 48.21±12.3 months and mean kidney transplantation duration was 36.21±6.7 months. Baseline laboratory investigations: ALT: 39.17±16.3 iu/l, Albumin: 3.6±1.32 g/dl, Bilirubin: 0.54±0.21, Hemoglobin: 10.57±1.9 g/dl, AFP: 5.3±2.4 ng/ml. Baseline liver US: normal (49%), enlarged (42%) and cirrhotic (9%) (No focal lesions). Fibro scan: F0 (26%), F1 (31%), F2 (32%) and F3 (11%). None of them experienced hepatic encephalopathy attacks or bleeding varices. All hemodialysis patients received Ombitasvir/Paritaprevir/Ritonavir (OMV/PTV/RTV) regimen (3 months). Only 2 KTRs received OMV/PTV/RTV regimen (3 months), the remaining 36 KTRs received Sofosbuvir/Daclatasvir regimen (6 months). Only 1 case reported relapse within 3 month after completing treatment. The rest achieved 12-week and 24-week SVR successfully. After 2 years from completing treatment, there was significant improvement in ALT levels. Four KTRs passed to graft failure due to accelerated immunologic response (rejection episodes) and 7 KTRs showed rise of serum creatinine (biopsy-proven rejection). Mean AFP rose up to 7.6±2.4 ng/ml with no statistical difference. Three hemodialysis patients and 4 KTRs showed rise in alfa-feto protein above normal values (10ng/dl). Four out of them exceeded 500ng/ml (1 HD and 3 KTRs). Abdominal US revealed: no change (39 patients), enlargement (6 patients) and cirrhosis (5 patients). Suspicious mass was found in 11 patients. Triphasic CT then was done for all hemodialysis patients and 9 KTRs. Regarding hemodialysis, 1 patient was diagnosed as HCC based on increased enhancement by Triphasic CT and alfa-fetoprotein was >500 ng/ml. Regarding KTRs, HCC was diagnosed in 2 patients and liver metastasis secondary to lymphoma was diagnosed in 1 case. The other patients with suspicious lesions (5 patients) showed uniform enhancement by Triphasic CT suggesting benign lesions. So, we have 3 (6%) out of 50 patients has been diagnosed as HCC after DAAs. By retrieval of their data, HCV duration was over 10 years and the liver was cirrhotic or enlarged with cirrhotic changes by ultrasound. Baseline ALT was slightly high without significant improvement after treatment. Also, baseline alfa-feto protein was high. The 3 patients were F2 or F3. Conclusion Hepatocellular carcinoma incidence after Direct-acting anti-virals is related mostly to the poor condition of the patients at baseline not to the drug itself and HCC in such cases could be considered as a part of disease progression not a drug complication.

Background and Aims With the advance of new direct acting antiviral, treatment of HCV became safer and easier. Renal impairment makes treatment of HCV more difficult due to poor drug tolerability. Anemia is a common side effect occurring in renal patients. Effect of anemia on the efficacy and safety of these drugs in those particular populations is a point of interest. Method This is a single center cohort study was held in Urology and Nephrology Center, Mansoura, Egypt, including 235 renal patients who were divided into 2 groups according to presence/absence of anemia; hemoglobin below 10.5 g/dL is considered cut-off value: 70 chronic kidney disease patients (CKD) (42 anemic and 28 non-anemic), 40 hemodialysis patients (HD) (24 anemic and 16 non-anemic) and 125 kidney-transplant recipients (KTRs) (40 anemic and 85 non-anemic). Hemodialysis patients received ritonavir-boosted paritaprevir and ombitasvir±ribavirin (OMV/PTV/RTV), KTRs received sofosbuvir and daclatasvir. CKD with eGFR >30 ml/min/1.73m2 received sofosbuvir and daclatasvir. CKD with eGFR Results: Demographics: Mean age was 49.17y for CKD, 43.2y for HD and 45.2y for KTRs. Most of them were males with body mass index around 23.8. Out of 235, 22 patients had been previously treated with interferon-IFN- (14 patients showed relapse after primary response on IFN and 8 patients could not tolerate IFN due to severe anemia, leucopenia and recurrent infection) and 7 patients had been co-infected with hepatitis B virus (all patients were cleared from the virus prior to HCV treatment). Efficacy: Rapid virologic response was achieved in all groups. 12-week sustained viral response (SVR-12) among CKD patients was 92.86% in anemic group and 96.42% in no-anemic group (p=91%). SVR-24 was lower in both groups. There were 16 relapse cases among CKD patients (11 in anemic group and 5 in non-anemic group; p value=0.69). Relative Risk for relapse incidence among anemic CKD patients was 1.4 with 95% CI 3.58 to 8.58 (p value: 0.42). Among HD patients, there was only 1 relapse case and it was in anemic group. All KTRs achieved SVR-12 and SVR-24. Safety: Deterioration of kidney function within 1 month from starting DAAs was the major side effect in both groups among CKD patients but it was more profound in anemic group (59.5%) (p value: 0.024). Deterioration of creatinine clearance was more obvious in anemic group (26.7±11.8mL/min, 21.28±12.97mL/min; p value: 0.014). More cases needed hemodialysis either temporary (3 cases) or permanently (13 cases) in anemic group (p value: 0.03 for temporary hemodialysis and 0.005 for permanent hemodialysis). Relative Risk for A/CKD incidence with anemia among CKD patients was 1.85 with 95% CI from 22.94 to 1.98 (p value: 0.04). Anemia was associated with rise of serum creatinine among kidney transplant recipient also. Graft impairment among anemia group was 30% (12 out of 40 patients) in comparison to 3.5% in no-anemia group (3 out of 85 patients); p value: 0.0002. Relative Risk for graft impairment with anemia among KTRs was 8.5 with 95% CI 6.95 to 2.64. Subsequently, drug interruption was more frequent among anemia group in both CKD and KTRS as treatment was suspended during AKI period. Regarding hemodialysis patients, the only difference was that worsening of anemia was more frequent among no-anemia group (p value: 0.0002). Ribavirin resulted in this this difference as no-anemia group received ribavirin while the other group did not receive it. Conclusion Direct-acting anti viral drugs are considered advance in treatment of hepatitis C infection and it is well tolerated by kidney disease patients. However, this particular population needs special care. Correction of anemia before starting DAAs may improve the outcome. Hemoglobin levels below 10.5 g/dL prior to DAAs are associated with rise of serum creatinine among KTRs and CKD patients.

After solid organ transplantation the cornerstone of immunosuppression is based on calcineurin inhibitors (CNIs), mostly tacrolimus. However, CNIs have a very narrow therapeutic window. The most important and serious side-effects of CNIs are nephrotoxicity, high blood pressure, post-transplant diabetes mellitus (PTMD), i.e., new-onset diabetes after transplantation (NODAT), dyslipidemia, and modification to the cardiovascular-risk profile. In this review, we will focus on tacrolimus-related toxicities in the setting of liver transplantation.

Background: Inconsistencies in outcome reporting and frequent omission of patient-centered outcomes can diminish the value of trials in treatment decision-making. We identified critically important outcome domains in kidney transplantation based on the shared priorities of patients/caregivers and health professionals. Methods: In a 3-round Delphi survey, patients/caregivers and health professionals rated the importance of outcome domains for trials in kidney transplantation on a 9-point Likert scale and provided comments. During Round 2 and 3, participants re-rated the outcomes after reviewing their own score, the distribution of the respondents’ scores, and comments. We calculated the median, mean, and proportion rating 7-9 (critically important), and analyzed comments thematically. Results: 1018 participants (461 [45%] patients/caregivers and 557 [55%] health professionals) from 79 countries completed Round 1, and 779 (77%) completed Round 3. The top eight outcomes that met the consensus criteria in Round 3 (mean ≥7.5, median ≥8 and proportion >85%) in both groups were graft loss, graft function, chronic rejection, acute rejection, mortality, infection, cancer (excluding skin) and cardiovascular disease. Compared with health professionals, patients/caregivers gave higher priority to six outcomes (mean difference of 0.5 or more): skin cancer, surgical complications, cognition, blood pressure, depression, and ability to work. We identified five themes: capacity to control and inevitability, personal relevance, debilitating repercussions, gaining awareness of risks, and addressing knowledge gaps. Conclusions: Graft complications and severe comorbidities were critically important for both stakeholder groups. These stakeholder-prioritized outcomes will inform the core outcome set to improve the consistency and relevance of trials in kidney transplantation.

International audience; BACKGROUND: Treatment decisions in kidney transplantation requires patients and clinicians to weigh the benefits and harms of a broad range of medical and surgical interventions, but the heterogeneity and lack of patient-relevant outcomes across trials in transplantation makes these trade-offs uncertain, thus, the need for a core outcome set that reflects stakeholder priorities. METHODS: We convened 2 international Standardized Outcomes in Nephrology-Kidney Transplantation stakeholder consensus workshops in Boston (17 patients/caregivers; 52 health professionals) and Hong Kong (10 patients/caregivers; 45 health professionals). In facilitated breakout groups, participants discussed the development and implementation of core outcome domains for trials in kidney transplantation. RESULTS: Seven themes were identified. Reinforcing the paramount importance of graft outcomes encompassed the prevailing dread of dialysis, distilling the meaning of graft function, and acknowledging the terrifying and ambiguous terminology of rejection. Reflecting critical trade-offs between graft health and medical comorbidities was fundamental. Contextualizing mortality explained discrepancies in the prioritization of death among stakeholders-inevitability of death (patients), preventing premature death (clinicians), and ensuring safety (regulators). Imperative to capture patient-reported outcomes was driven by making explicit patient priorities, fulfilling regulatory requirements, and addressing life participation. Specificity to transplant; feasibility and pragmatism (long-term impacts and responsiveness to interventions); and recognizing gradients of severity within outcome domains were raised as considerations. CONCLUSIONS: Stakeholders support the inclusion of graft health, mortality, cardiovascular disease, infection, cancer, and patient-reported outcomes (ie, life participation) in a core outcomes set. Addressing ambiguous terminology and feasibility is needed in establishing these core outcome domains for trials in kidney transplantation.

Recent data from the World Population Prospects projects that, by 2050, nearly all regions in the world will have a quarter or more of the population aged 60 and above. Chronic kidney disease (CKD) has a high global prevalence (~13%) worldwide, and the prevalence of chronic kidney disease and end-stage kidney disease increase with age. Kidney transplantation remains the best therapeutic option for end-stage kidney disease, offering a survival benefit in comparison with dialysis maintenance for most patients. This review focuses on immunological aspects of kidney transplantation in older patients and marginal donors, i.e., 60 years or older deceased kidney donors or 50–59 years old deceased kidney donors with comorbidities. Clinical outcomes of kidney recipients in terms of renal and patient survival are more than acceptable even for patients over 70. In this population, the first cause of graft loss is death with a functional graft. However, the inherent issues of these transplantations are the acceptance or refusal of frail kidney from an old donor and the increased immunogenicity of these organs in balance with potential frail and immunosenescent recipients. Finally, the immunosuppressive regimen itself is a challenge for the future of the transplant, to prevent adverse effects such as nephrotoxicity and higher risk of infections or cancer in a population already at risk. Belatacept may have a good place in the immunosuppressive strategy to improve efficacy and the safety posttransplantation.

Contains fulltext : 226016.pdf (Publisher’s version ) (Closed access) In several deceased donor kidney allocation systems, organs from elderly donors are allocated primarily to elderly recipients. The Eurotransplant Senior Program (ESP) was implemented in 1999, and since then, especially in Europe, the use of organs from elderly donors has steadily increased. The proportion of ≥60-year-old donors reported to the Collaborative Transplant Study (CTS) by European centers has doubled, from 21% in 2000-2001 to 42% in 2016-2017. Therefore, in the era of organ shortage it is a matter of debate whether kidney organs from elderly donors should only be allocated to elderly recipients or whether

Background The 2 main objectives regarding living kidney transplant are to provide optimal graft function and to ensure the safety of donation. Our study hypothesized that the glomerular filtration rate of a single kidney (skGFR), when transplanted, might predict graft function and that the skGFR of the remaining kidney could predict donor functional gain. Methods A prospective monocentric study was conducted at Grenoble-Alpes University Hospital. Twenty couples of donors and recipients were included. Dimercaptosuccinic acid renal scintigraphy and 51Cr-ethylene-diamine tetra-acetic acid clearance were evaluated predonation to calculate skGFR. All patients had renal function according to 51Cr-ethylene-diamine tetra-acetic acid clearance at 1 year post transplant to assess graft function and donor functional gain. All donors had normal renal function predonation. Results At 1 year post transplant, median glomerular filtration rate of the graft was 50 mL/min/1.73 m2 (range, 46-56 mL/min/1.73 m2) and donor median glomerular filtration rate was 59 mL/min/1.73 m2 (range, 55-74 mL/min/1.73 m2). Median functional gain was 20 mL/min/1.73 m2 (range, 12-22 mL/min/1.73 m2). No statistical correlation was found between skGFR of the transplanted kidney and graft function at 1 year (R2 = 0.096, P = .7). For the donor, functional gain was not associated with predonation skGFR of the remaining kidney (R2 = 0.17, P = .5). A statistical difference was found between donor functional gain (18 [SD, 10] mL/min) and recipient gain (delta between skGFR before and after transplant, 7 [SD, 16] mL/min; P = .02). Conclusion Predonation skGFR of the transplanted kidney had no influence on renal allograft function at 1 year post transplant. Similarly, there was no association between measured skGFR of the remaining kidney and donor functional gain at 1 year.

Background. Calcineurin inhibitors (CNIs) and steroids are strongly associated with new-onset diabetes after transplantation, worsening of pre-existing diabetes, and cardiovascular events. We assessed the benefit of conversion from CNI-based to belatacept-based immunosuppression in diabetic kidney-transplant (KT) recipients on glucose control and cardiovascular risk factors. Methods. In this retrospective, noncontrolled single-study conducted between May 2016 and October 26, 2018, we recruited KT recipients converted from CNIs to belatacept at least 6 months after KT. The primary endpoint was the evolution of hemoglobin A1c (HbA1c) between baseline and after 6 months of treatment. Secondary endpoints included modifications to antidiabetic drugs, other cardiovascular risk factors, and renal function. Results. One hundred and three KT recipients were included. Of these, 26 (25%) had type 2 diabetes. The patients were either receiving oral antidiabetic drugs (n = 21; 75%) or insulin therapy (n = 14; 54%). Overall HbA1c decreased significantly from 6.2 ± 1 to 5.8 ± 1%, P < 0.001. In diabetic patients, HbA1c decreased from 7.2 ± 1 to 6.5 ± 1%, P = 0.001. HbA1c significantly decreased in the subgroup of patients with new-onset diabetes after transplantation and whether diabetes was controlled at inclusion or not (ie, HA1c ≤7% or >7%). Moreover, no diabetic patient increased the number of oral antidiabetic drugs and the dose of basal insulin was not statistically different from baseline to 6 months (16 international unit at baseline and 16 international unit at 6 mo, P = 1). One patient had to start treatment by insulin pump. During follow-up, the renal function, body mass index, and hemoglobin level of all 103 patients remained stable, 2 patients presented acute cellular rejection, and no patient suffered from graft loss. Conclusions. A late switch from CNI to belatacept was a valuable therapeutic option for diabetic kidney recipients and substantially improved glycemic parameters.

BACKGROUND Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS). METHODS We performed a retrospective study on 1029 kidney transplant patients (2004-2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti-human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate). RESULTS Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P < 0.001) in a univariate model, on the full analysis set comprising 1029 patients. In the multivariate time-varying model, based on 666 patients with available cytochrome P450 3A5 genotypes, the effect of the C/D ratio remained significant (HR, 2.26; P = 0.015); even when glomerular filtration rate at month 3 < 30 mL/min/1.73 m (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P < 0.001) and continued steroid prescription (HR=2.08, P = 0.014) were taken into account (other covariates, including tacrolimus trough concentrations, were nonsignificant). In the same multivariate model, the effect of early C/D ratio (median at mo 3 and mo 6) remained significantly associated with DCGS (HR, 2.25; P = 0.041). CONCLUSIONS C/D ratio is an independent and early predictor of DCGS. Identification of fast metabolizers could be a strategy to improve graft survival, for example, by optimizing tacrolimus formulation. Mechanistic studies to understand the C/D ratio effect are required.

International audience; The complement system has been implicated in several kidney diseases, such as antibody-mediated rejection after kidney transplantation. Antibody-depletion techniques allow successful ABO- and/or HLA-incompatible transplantation. Considering the IgG removal, the use of semi-selective immunoadsorption (IA) has been advocated. However, because of results on incomplete IgM depletion, the adjunctive use of membrane filtration (MF) has been proposed to enhance the removal of macromolecules and to interfere with complement activation. This secondary endpoint analysis of a recently published randomized, controlled, cross-over trial was designed to investigate the effect of combined treatment IA + MF compared to IA alone on complement depletion. Two treatment sequences, a single session of IA + MF followed by IA (and vice versa), were analyzed with regard to C5b-9, properdin, and mannose-binding lectin (MBL) levels. Neither IA alone nor IA + MF provoked complement activation as demonstrated by stable low levels of C5b-9 after the procedure as compared to the previous. The combined treatment substantially lowered properdin (77% vs. 26% reduction, P

Ganciclovir (GCV) is the cornerstone of cytomegalovirus prevention and treatment in transplant patients. It is associated with problematic adverse hematological effects in this population of immunosuppressed patients, which may lead to dose reduction thus favoring resistance. GCV crosses the membranes of cells, is activated by phosphorylation, and then stops the replication of viral DNA. Its intracellular accumulation might favor host DNA polymerase inhibition, hence toxicity. Following this hypothesis, we investigated the association between a selected panel of membrane transporter polymorphisms and the evolution of neutrophil counts in n=174 renal transplant recipients. An independent population of n=96 renal transplants served as a replication and experiments using HEK293T-transfected cells were performed to validate the clinical findings. In both cohorts, we found a variant in ABCC4 (rs11568658) associated with decreased neutrophil counts following valganciclovir (GCV prodrug) administration (exploratory cohort: β±SD=-0.68±0.28, p=0.029; replication cohort: β±SD=-0.84±0.29, p=0.0078). MRP4-expressing cells showed decreased GCV accumulation as compared to negative control cells (transfected with an empty vector) (-61%; p

Background Patients with HNF1B mutations develop progressive chronic renal failure, diabetes mellitus (40-50%), and liver tests abnormalities (40-70%). In HNF1B patients who reach end-stage renal disease, single kidney transplantation (SKT) or combined kidney-pancreas transplantation can be considered. Methods A retrospective multicenter study including 18 HNF1B patients receiving SKT or kidney-pancreas transplantation, and in vitro experiments including the characterization of the HNF1B expression after calcineurin inhibitor (CNI) exposure. Results After SKT, 50% of the HNF1B patients develop early posttransplantation diabetes mellitus, whereas 40% experience new-onset or severe worsening of preexisting abnormalities of liver tests, including severe cholestasis. In liver biopsies, disorders of the cholangiocytes primary cilium and various degrees of bile duct paucity and dysplasia were identified. In vitro studies combining CNI exposure and siRNA-mediated inhibition of NFATc revealed that calcineurin inhibition decreases HNF1B expression in epithelial cells but independent of NFATc. Conclusions Because HNF1B-related disease is a heterozygous condition, CNIs used to prevent rejection may induce reduced expression of the nonmutated allele of HNF1B leading to a superimposed defect of HNF-1β transcriptional activity. Taking into account the specific risk of posttransplantation diabetes mellitus and liver disorders in HNF1B patients, these findings advocate for in-depth characterization of pathways that regulate HNF1B and plead for considering individually tailored graft management that may include a CNI-free immunosuppressive regimen. Interventional studies will have to confirm this individualized approach.

International audience; Little is known about the impact of posttransplant blood transfusion on the sensitization of anti-HLA antibodies and the formation of donor-specific antibodies (DSAs). The aims of our study were to determine the 1-year incidence of DSAs (assessed using a solid-phase assay) and antibody-mediated rejection (AMR) in kidney transplant patients who had or had not received a blood transfusion during the first year after transplantation. Included were 390 non– HLA-sensitized patients who had received an ABOcompatible kidney transplant and had not previously or simultaneously received a nonkidney transplant. Overall, 64% of patients received a red blood cell transfusion within the first year after transplantation, most within the first month. The overall 1-year incidence of DSAs was significantly higher in patients that had undergone transfusion (7.2% vs. 0.7% in patients with no transfusion, p < 0.0001). AMR occurred more often in the transfusion group (n = 15, 6%) compared with the nontransfusion group (n = 2, 1.4%; p = 0.04). Blood transfusion was an independent predictive factor for de novo DSA formation butnot for AMR. Patients who had a transfusion and developed DSAs were more often treated with cyclosporin A (n = 10, 55.5%) rather than tacrolimus (n = 45, 19.4%; p = 0.0001). In conclusion, early posttransplant blood transfusion may increase immunological risk, especially in underimmunosuppressed patients.

In the Belatacept Evaluation of Nephroprotection and Efficacy as First‐Line Immunosuppression Trial–Extended Criteria Donors (BENEFIT‐EXT), extended criteria donor kidney recipients were randomized to receive belatacept‐based (more intense [MI] or less intense [LI]) or cyclosporine‐based immunosuppression. In prior analyses, belatacept was associated with significantly better renal function compared with cyclosporine. In this prospective analysis of the intent‐to‐treat population, efficacy and safety were compared across regimens at 7 years after transplant. Overall, 128 of 184 belatacept MI–treated, 138 of 175 belatacept LI–treated and 108 of 184 cyclosporine‐treated patients contributed data to these analyses. Hazard ratios (HRs) comparing time to death or graft loss were 0.915 (95% confidence interval [CI] 0.625–1.339; p = 0.65) for belatacept MI versus cyclosporine and 0.927 (95% CI 0.634–1.356; p = 0.70) for belatacept LI versus cyclosporine. Mean estimated GFR (eGFR) plus or minus standard error at 7 years was 53.9 ± 1.9, 54.2 ± 1.9, and 35.3 ± 2.0 mL/min per 1.73 m2 for belatacept MI, belatacept LI and cyclosporine, respectively (p < 0.001 for overall treatment effect). HRs comparing freedom from death, graft loss or eGFR, In patients transplanted with an extended donation criteria kidney, belatacept‐based immunosuppression is associated with a similar death/graft loss and improved renal function at 7 years posttransplant as a cyclosporine‐based immunosuppression, with a safety profile consistent with previous reports.

Few studies have assessed the outcomes of ABOi/HLAi living-kidney transplantation. We report a single-center experience of 12 ABOi/HLAi living-kidney recipients. Twenty-seven donor-specific alloantibodies (DSAs) (1-6 per patient) were found with fluorescence intensities of 1500-15 000. Desensitization was based on IVIg, two doses of rituximab (375 mg/m2 ), tacrolimus-based (0.2 mg/kg) immunosuppression (started on day-10 pretransplant), and 11 (6-27) pretransplant apheresis sessions (plasmapheresis, specific or semi-specific immunoadsorption). By day 0, 17 of the 27 DSAs had become undetectable. After 19 (3-51) months, patient- and graft-survival rates were 100% and 91.6%, respectively. One patient had an acute humoral rejection whereas three had a chronic antibody-mediated rejection (CAMR). At the last follow-up, kidney biopsies were nearly normal in seven cases (58.3%) and renal function was excellent except for the three cases of CAMR. Four patients had a BK virus infection. We conclude that ABOi/HLAi living-kidney transplantation is a reasonable option for highly sensitized patients.

Aim: To investigate the potential influence of variants in genes involved in the calcineurin pathway on the efficacy and toxicity of calcineurin inhibitors in renal transplantation. Materials & methods: Twenty-three polymorphisms in thirteen genes were tested in 381 renal transplant recipients receiving ciclosporin (n = 221) or tacrolimus (n = 160) and mycophenolate mofetil. Data were collected prospectively over the first year post-transplantation. Results: Multivariate survival analyses revealed no genetic associations with biopsy proven acute graft rejection and serious infections. Donor–recipient Cytomegalovirus mismatch was the only variable associated with serious infection. Conclusion: This large exploratory study casts doubts on the potential interest of genetic biomarkers related to CNI pharmacodynamics but associations with other phenotypes in transplantation deserve further studies.

Background Informing kidney transplant recipients of their prognosis and disease progression is of primary importance in a patient-centred vision of care. By participating in decisions from the outset, transplant recipients may be more adherent to complex medical regimens due to their enhanced understanding. Methods We proposed to include repeated measurements of serum creatinine (SCr), in addition to baseline characteristics, in order to obtain dynamic predictions of the graft failure risk that could be updated continuously during patient follow-up. Adult recipients from the French Données Informatisées et VAlidées en Transplantation (DIVAT) cohort transplanted for the first or second time from a heart-beating or living donor and alive with a functioning graft at 1 year post-transplantation were included. Results The model was composed of six baseline parameters, in addition to the SCr evolution. We validated the dynamic predictions by evaluating both discrimination and calibration accuracy. The area under the receiver operating characteristic curve varied from 0.72 to 0.76 for prediction times at 1 and 6 years post-transplantation, respectively, while calibration plots showed correct accuracy. We also provided an online application tool (https://shiny.idbc.fr/DynPG). Conclusion We have created a tool that, for the first time in kidney transplantation, predicts graft failure risk both at an individual patient level and dynamically. We believe that this tool would encourage willing patients into participative medicine.

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation (KT), but its use is complicated by a narrow therapeutic index and high inter- and intra-patient pharmacokinetic variability. There are three available oral formulations of tacrolimus: immediate-release tacrolimus (IR-Tac), extended-release tacrolimus (ER-Tac) and a MeltDose® (LCPT) formulation, the latter favoring a prolonged drug release and increased bioavailability. The time-concentration curves of these formulations are different. Compared with IR-Tac and ER-Tac, LCPT has a relatively flat pharmacokinetic profile with less fluctuation between trough and peak exposures, and a delayed peak concentration. This translates to a more stable delivery of tacrolimus and may alleviate the risk of underexposure and allograft rejection or overexposure and toxicity. The once-daily formulation of both ER-TAC and LCPT may also offer a potential advantage on patient adherence. Fast metabolizers of tacrolimus, the elderly, and human leukocyte antigen-sensitized patients are at risk of poorer outcomes after KT, possibly associated with a different exhibited pharmacokinetics of tacrolimus or different requirements in terms of exposure. Simple, practical strategies are needed to identify patients at risk of suboptimal KT outcomes and those who would benefit from a more proactively personalized approach to tacrolimus treatment. This review aims to increase awareness of the link between the pharmacokinetics of oral tacrolimus formulations and the clinical needs of patients after KT, particularly among those who have clinically significant pharmacokinetic variation of tacrolimus.

Accumulating evidence suggests that detection of human leukocyte antigen (HLA) antibodies by solid phase Luminex assays predicts renal allograft outcomes. However, several controversies exist regarding the interpretation, reproducibility, impact and financial feasibility of global utilization of this assay in pretransplant assessment.We studied short-term patient-centered outcomes, medical standards of care, and financial plausibility of using Luminex-based screening for HLA antibodies in renal allograft recipients compared to outcomes in nontested patients.We included 1808 patients assessed for transplantation from 2011 to 2018. Luminex-tested patients had lower rates of rejection in the first post-transplant week (OR 0.36, P .001) and lower odds of antibody-mediated rejection in the first 6 months (OR 0.4, P = .004). Forty-four patients with preformed, donor-specific antibodies were transplanted, and everolimus was introduced into our protocols for low-risk patients based on risk stratification by Luminex results. The number of tests needed to be performed to prevent 1 episode of antibody-mediated rejection in the first 6 months was 28 (P = .004), which was financially plausible.Routine pre-transplant assessment of HLA antibodies using Luminex assays may allow for better patient-centered, short-term graft outcomes and objective tailoring of immunosuppression at a financially plausible, cost-effective rate.

There are an estimated 14,000 randomized trials published in chronic kidney disease. The most frequently reported outcomes are biochemical endpoints, rather than clinical and patient-reported outcomes including cardiovascular disease, mortality, and quality of life. While many trials have focused on optimizing kidney health, the heterogeneity and uncertain relevance of outcomes reported across trials may limit their policy and practice impact. The international Standardized Outcomes in Nephrology (SONG) Initiative was formed to identify core outcomes that are critically important to patients and health professionals, to be reported consistently across trials. We convened a SONG Implementation Workshop to discuss the implementation of core outcomes. Eighty-two patients/caregivers and health professionals participated in plenary and breakout discussions. In this report, we summarize the findings of the workshop in two main themes: socializing the concept of core outcomes, and demonstrating feasibility and usability. We outline implementation strategies and pathways to be established through partnership with stakeholders, which may bolster acceptance and reporting of core outcomes in trials, and encourage their use by end-users such as guideline producers and policymakers to help improve patient-important outcomes. ispartof: pages:1053-1068 ispartof: Kidney Int vol:94 issue:6 pages:1053-1068 ispartof: location:United States status: published

Supplemental digital content is available in the text., Background End-stage renal failure occurs in a substantial number of patients having received a nonrenal transplantation (NRT), for whom a kidney transplantation is needed. The medical strategy regarding the use of immunosuppression (IS) for a kidney graft in patients after an NRT is not well established. The prekidney grafts long-term IS advocates for a mild induction, such as using anti-IL-2R antibodies, whereas addition of new incompatibilities and anti-HLA preimmunization may suggest using stronger IS such as induction by polyclonal antithymocyte globulins (ATG). Methods We performed Cox multivariate and propensity score analysis of our validated transplant database to study the impact of the type of induction therapy on kidney graft survival of recipients of a kidney graft after NRT. Results We report here that kidney transplantation after NRT treated with an ATG induction has a poorer outcome (kidney and recipient survival) than that with an anti–IL-2R induction. After accounting for potential baseline differences with a multivariate Cox model, or by adjusting on a propensity score, we found that despite patients having received ATG cumulate more risk factors, ATG appears independently involved. As animal-derived biotherapeutics induce antiglycan antibodies and particularly anti–N-glycolylneuraminic acid (Neu5Gc) IgGs which may activate endothelial cells in patients and grafts, we also investigated the magnitude and the nature of the anti-Neu5Gc elicited by the induction and showed that induction was associated with a shift in anti-Neu5Gc IgG repertoire. Possible reasons and mechanisms of a deleterious ATG usage in these patients are discussed. Conclusions Our study suggests that ATG induction after a kidney transplantation in recipients already under maintenance IS for a NRT should be used cautiously.

It is widely accepted that HLA donor-specific antibodies (DSA) are associated with antibody-mediated rejection and graft loss. However, in many transplant programs, preformed anti-HLA-Cw and anti-HLA-DP DSA are not considered in organ allocation policies because their clinical relevance is still uncertain.We analyzed the clinical impact of Cw/DP DSA through a retrospective study, comparing 48 patients transplanted with isolated preformed Cw/DP DSA (Cw/DP DSA group) with (i) 104 matched HLA-sensitized kidney transplant recipients with No DSA at D0 (No DSA group) and (ii) 47 kidney transplant recipients with preformed A, -B, -DR, -DQ DSA (A/B/DR/DQ DSA group).A positive flow cytometry crossmatch in the Cw/DP DSA group was more frequent than in the No DSA group and as frequent as in the A/B/DR/DQDSA group. Two years after transplantation, the biopsy-proven acute rejection-free survival was worse in the Cw/DP and A/B/DR/DQ DSA groups than in the No DSA group (65%, 84%, 93%, P = 0.001 and P = 0.05, respectively). Accordingly, graft survival was lower in the Cw/DP and the A/B/DR/DQ DSA groups than in the No DSA group (87%, 89%, 95%, P = 0.02 and P = 0.1, respectively).These results suggest that preformed anti-HLA-Cw and anti-HLA-DP DSA are as deleterious as anti-HLA A/B/DR/DQ DSA. It justifies their inclusion in kidney allocation programs and in immunological risk stratification algorithms.