A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection.

BACKGROUND: Antibody-mediated rejection is a leading cause of kidney-transplant failure. The targeting of CD38 to inhibit graft injury caused by alloantibodies and natural killer (NK) cells may be a therapeutic option. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with antibody-mediated rejection that had occurred at least 180 days after transplantation to receive nine infusions of the CD38 monoclonal antibody felzartamab (at a dose of 16 mg per kilogram of body weight) or placebo for 6 months, followed by a 6-month observation period. The primary outcome was the safety and side-effect profile of felzartamab. Key secondary outcomes were renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels. RESULTS: A total of 22 patients underwent randomization (11 to receive felzartamab and 11 to receive placebo). The median time from transplantation until trial inclusion was 9 years. Mild or moderate infusion reactions occurred in 8 patients in the felzartamab group. Serious adverse events occurred in 1 patient in the felzartamab group and in 4 patients in the placebo group; graft loss occurred in 1 patient in the placebo group. At week 24, resolution of morphologic antibody-mediated rejection was more frequent with felzartamab (in 9 of 11 patients [82%]) than with placebo (in 2 of 10 patients [20%]), for a difference of 62 percentage points (95% confidence interval [CI], 19 to 100) and a risk ratio of 0.23 (95% confidence interval [CI], 0.06 to 0.83). The median microvascular inflammation score was lower in the felzartamab group than in the placebo group (0 vs. 2.5), for a mean difference of -1.95 (95% CI, -2.97 to -0.92). Also lower was a molecular score reflecting the probability of antibody-mediated rejection (0.17 vs. 0.77) and the level of donor-derived cell-free DNA (0.31% vs. 0.82%). At week 52, the recurrence of antibody-mediated rejection was reported in 3 of 9 patients who had a response to felzartamab, with an increase in molecular activity and biomarker levels toward baseline levels. CONCLUSIONS: Felzartamab had acceptable safety and side-effect profiles in patients with antibody-mediated rejection. (Funded by MorphoSys and Human Immunology Biosciences; ClinicalTrials.gov number, NCT05021484; and EUDRACT number, 2021-000545-40.).

Continuous glucose monitoring for the prediction of posttransplant diabetes mellitus and impaired glucose tolerance on day 90 after kidney transplantation-A prospective proof-of-concept study.

Posttransplant diabetes mellitus (PTDM) and prediabetes represent serious complications after kidney transplantation and are associated with increased cardiovascular morbidity and mortality. We assessed the predictive performance of continuous glucose monitoring (CGM) compared with plasma glucose and hemoglobin A1c in 46 kidney transplant recipients (KTRs) without known preexisting diabetes mellitus. CGM (14-day recording duration) was performed on days 8, 30, 45, 60, 90, and 180 posttransplant. Eight patients (17%) developed PTDM and nine (20%) impaired glucose tolerance (IGT), as diagnosed by oral glucose tolerance test (oGTT)-derived 2-hour plasma glucose (2hPG) or glucose-lowering therapy on day 90. CGM-readouts percent of time >140 mg/dL (%TAR (140 mg/dL)) and percent of time >180 mg/dL (%TAR (180 mg/dL)) showed excellent in-sample test characteristics regarding PTDM from day 8 onward (days 8-90 receiver operating characteristic area under the curve: 0.88-0.99) and regarding PTDM/IGT with the commencement of maintenance immunosuppression from day 30 onward (days 30-90 receiver operating characteristic area under the curve: 0.88-0.91). Exploratory CGM-%TAR (140 mg/dL)-screening thresholds of 31.8% on day 8 and 13.2% on day 30 yielded sensitivities/specificities of 88%/83% for PTDM and 94%/78% for PTDM/IGT on day 90, respectively. Although our findings need to be replicated in studies with larger sample sizes, CGM bears promising potential to facilitate clinical practice and research regarding PTDM.

The Banff 2022 Kidney Meeting Work Plan: Data-driven refinement of the Banff Classification for renal allografts.

The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell-mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.

Subthreshold rejection activity in many kidney transplants currently classified as having no rejection.

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (4170 patients). An updated archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower eGFR, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR respectively diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.

Office or home versus 24-hour blood pressure measurement in stable kidney transplant recipients.

BACKGROUND AND HYPOTHESIS: The aim of this study was to quantify hypertension control and evaluate concordance between all commonly available blood pressure modalities in kidney transplant recipients (KTR). METHODS: For this prospective cross-sectional study 89 stable KTR were recruited at the Charité Transplant Outpatient Clinic. For each study participant office (manual office blood pressure 'MOBP' and automated office blood pressure 'AOBP'), 7-day home (HBPM) and 24-hour ambulatory blood pressure measurement (24h-ABPM) were performed. RESULTS: 80 of the 89 patients recruited had sufficient blood pressure recordings. Mean blood pressure for MOBP, AOBP, HBPM and 24h-ABPM was 129/73, 126/71, 131/85 and 130/81 mmHg, respectively. Uncontrolled hypertension, as defined by 24h-ABPM (mean ≥ 130/80 mmHg), was present in 53 (66%) patients. MOBP, AOBP and HBPM classified 19 (24%), 22 (28%) and 41 (51%) patients respectively as 'uncontrolled hypertensive'. The Bland-Altman plot showed good agreement between systolic MOBP, AOBP, HBPM and Daytime-ABPM (mean bias ± SD: -1 ± 13 mmHg, -4 ± 13 mmHg, 1 ± 10 mmHg, respectively). Uncontrolled nighttime hypertension was present in 74 (93%) KTR, with 71 (89%) patients showing a non-physiological dipping pattern. Moderate positive correlation between Daytime-ABPM/HBPM and Nighttime-ABPM (Pearson Correlation Coefficients: 0.62-0.73), followed by MOBP/AOBP (Pearson Correlation Coefficients: 0.49-0.59) was noted. eGFR and proteinuria displayed weak correlation with 24h-, Daytime- and Nighttime-ABPM (absolute values of Pearson Correlation Coefficients: 0.04-0.41). No robust association with either 24h-, Daytime- or Nighttime-ABPM was observed for volume status exams. CONCLUSIONS: Masked hypertension is highly prevalent in KTR, especially due to high rates of uncontrolled nighttime hypertension. HBPM shows the narrowest limits of agreement with Daytime-ABPM. Daytime-ABPM and HBPM show the highest, albeit clinically insufficient, correlation with Nighttime-ABPM. Systematic integration of 24h-ABPM into clinical practice, as proposed by the '2023 ESH Guidelines for the Management of arterial hypertension', should not be withheld for the KTR population. Clinical trials evaluating treatment of hypertension in KTR are urgently needed.

Plasma NGAL levels in stable kidney transplant recipients and the risk of allograft loss.

BACKGROUND: The objective of this study was to investigate the utility of neutrophil gelatinase-associated lipocalin (NGAL) and calprotectin (CPT) to predict long-term graft survival in stable kidney transplant recipients (KTR). METHODS: A total of 709 stable outpatient KTR were enrolled >2 months post-transplant. The utility of plasma and urinary NGAL (pNGAL, uNGAL) and plasma and urinary CPT at enrollment to predict death-censored graft loss was evaluated during a 58-month follow-up. RESULTS: Among biomarkers, pNGAL showed the best predictive ability for graft loss and was the only biomarker with an area under the curve (AUC) > 0.7 for graft loss within 5 years. Patients with graft loss within 5 years (n = 49) had a median pNGAL of 304 [interquartile range (IQR) 235-358] versus 182 (IQR 128-246) ng/mL with surviving grafts (P < .001). Time-dependent receiver operating characteristic analyses at 58 months indicated an AUC for pNGAL of 0.795, serum creatinine-based Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) had an AUC of 0.866. pNGAL added to a model based on conventional risk factors for graft loss with death as competing risk (age, transplant age, presence of donor-specific antibodies, presence of proteinuria, history of delayed graft function) had a strong independent association with graft loss {subdistribution hazard ratio (sHR) for binary log-transformed pNGAL [log2(pNGAL)] 3.4, 95% confidence interval (CI) 2.24-5.15, P < .0001}. This association was substantially attenuated when eGFR was added to the model [sHR for log2(pNGAL) 1.63, 95% CI 0.92-2.88, P = .095]. Category-free net reclassification improvement of a risk model including log2(pNGAL) in addition to conventional risk factors and eGFR was 54.3% (95% CI 9.2%-99.3%) but C-statistic did not improve significantly. CONCLUSIONS: pNGAL was an independent predictor of renal allograft loss in stable KTR from one transplant center but did not show consistent added value when compared with baseline predictors including the conventional marker eGFR. Future studies in larger cohorts are warranted.

Old for young kidney transplantation: a responsible option for our patients to reduce waiting time?

PURPOSE: The Eurotransplant Senior program allocating grafts from donors ≥ 65 years to recipients aged ≥ 65 years has proven good results within the last 20 years. However, "old" grafts are also allocated to younger recipients < 65 years, and this outcome of "old for young" kidney transplantations (KT) still lacks detailed investigations. METHODS: All "old for young" KT performed at four tertiary referral centers were retrospectively compared including a recent follow-up, stratifying for "old for young" (donor ≥ 65 years to recipient < 65 years) vs. "very old for young" KT (donor ≥ 70 years to recipient < 65 years). RESULTS: Overall, 99 patients were included with 56 (56.6%) "old for young" and 43 (43.4%) "very old for young" KT. The median waiting time did not differ (60.7 vs. 45.8 months, respectively) at comparable living donation rates (57.1% vs. 44.2%) as well as intra- and postoperative results. At a median follow-up of 44 months (range 1; 133), the 3-year graft survival of 91% vs. 87% did not significantly vary. In subgroup analyses assessing living donation or donation after brain death (DBD) KT only, the graft survival was significantly longer for "old for young" KT within the living donation subgroup. In multivariate Cox regression analyses, the presence of panel-reactive antibodies was the only significant impact factor on graft survival (HR 8.32, p = 0.001). CONCLUSION: This analysis clearly demonstrates the effectiveness of the "old for young" approach, enabling favorable perioperative results as well as comparable data of graft- and overall survival, while reducing waiting time for eligible patients.

Retrospective analysis of the perioperative outcome in living donor kidney transplantation with multiple renal arteries: does accessory vessel ligation affect the outcome?

PURPOSE: Accurate surgical reconstruction of arterial vascular supply is a crucial part of living kidney transplantation (LDKT). The presence of multiple renal arteries (MRA) in grafts can be challenging. In the present study, we investigated the impact of ligation versus anastomosis of small accessory graft arteries on the perioperative outcome. METHODS: Clinical and radiological outcomes of 51 patients with MRA out of a total of 308 patients who underwent LDKT with MRA between 2011 and 2020 were stratified in two groups and analyzed. In group 1 (20 patients), ligation of accessory arteries (ARAs) and group 2 (31 patients) anastomosis of ARAs was performed. RESULTS: Significant differences were observed in the anastomosis-, surgery-, and warm ischemia time (WIT) in favor of group 1. Students t-test showed comparable serum creatinine levels of 2.33 (± 1.75) to 1.68 (± 0.83) mg/dL in group 1 and 2.63 (± 2.47) to 1.50 (± 0.41) mg/dL in group 2, were seen from 1 week to 1 year after transplant. No increased rates of Delayed graft function (DGF), primary transplant dysfunction and transplant rejection were seen, but graft loss and revision rates were slightly higher when the ARAs were ligated. Analysis of Doppler sonography revealed that segmental perfusion deficits tend to regenerate during the clinical course. CONCLUSION: Ligation of smaller accessory renal arteries may not affect the outcome of living kidney transplantation, except for a minor increase in the reoperation rate. Segmental perfusion deficits of the graft seem to regenerate in most cases as seen in Doppler sonography.

Transplant nephrectomy: indication, surgical approach and complications-experiences from a single transplantation center.

PURPOSE: Management of a failed kidney allograft, and the question whether it should be removed is a challenging task for clinicians. The reported risks for transplant nephrectomy (TN) vary, and there is no clear recommendation on indications or surgical approach that should be used. This study gives an overview of indications, compares surgical techniques, and identifies risk factors for higher morbidity. METHODS: Retrospective analysis was conducted on all transplant nephrectomies performed between 2005 and 2020 at Charité Hospital Berlin, Department of Urology. Patient demographics, laboratory parameters, graft survival data, indication for TN, and surgical complications were extracted from medical reports. RESULTS: A total of 195 TN were performed, with graft intolerance syndrome being the most common indication in 52 patients (26.7%), acute rejection in 36 (18.5%), acute infection in 30 (15.4%), and other reasons to stop immunosuppression in 26 patients (13.3%). Rare indications were vascular complications in 16 (8.2%) and malignancies in the allograft in six (3.1%) cases. Extracapsular surgical approach was significantly more often used in cases of vascular complications and earlier allograft removal, but there was no difference in complication rates between extra- and intracapsular approach. Acute infection was identified as an independent risk factor for a complication grade IIIb or higher according to Clavien-Dindo classification, with a HR of 12.3 (CI 2.2-67.7; p = 0.004). CONCLUSION: Transplant nephrectomy should only be performed when there is a good indication, and non-elective surgery should be avoided, when possible, as it increases morbidity.

Validation of risk scores for prediction of severe pneumonia in kidney transplant recipients hospitalized with community-acquired pneumonia.

PURPOSE: Risk scores for community-acquired pneumonia (CAP) are widely used for standardized assessment in immunocompetent patients and to identify patients at risk for severe pneumonia and death. In immunocompromised patients, the prognostic value of pneumonia-specific risk scores seems to be reduced, but evidence is limited. The value of different pneumonia risk scores in kidney transplant recipients (KTR) is not known. METHODS: Therefore, we retrospectively analyzed 310 first CAP episodes after kidney transplantation in 310 KTR. We assessed clinical outcomes and validated eight different risk scores (CRB-65, CURB-65, DS-CRB-65, qSOFA, SOFA, PSI, IDSA/ATS minor criteria, NEWS-2) for the prognosis of severe pneumonia and in-hospital mortality. Risk scores were assessed up to 48 h after admission, but always before an endpoint occurred. Multiple imputation was performed to handle missing values. RESULTS: In total, 16 out of 310 patients (5.2%) died, and 48 (15.5%) developed severe pneumonia. Based on ROC analysis, sequential organ failure assessment (SOFA) and national early warning score 2 (NEWS-2) performed best, predicting severe pneumonia with AUC of 0.823 (0.747-0.880) and 0.784 (0.691-0.855), respectively. CONCLUSION: SOFA and NEWS-2 are best suited to identify KTR at risk for the development of severe CAP. In contrast to immunocompetent patients, CRB-65 should not be used to guide outpatient treatment in KTR, since there is a 7% risk for the development of severe pneumonia even in patients with a score of zero.

European Consensus on the Management of Sensitized Kidney Transplant Recipients: A Delphi Study.

An increasing number of sensitized patients awaiting transplantation face limited options, leading to fatalities during dialysis and higher costs. The absence of established evidence highlights the need for collaborative consensus. Donor-specific antibodies (DSA)-triggered antibody-mediated rejection (AMR) significantly contributes to kidney graft failure, especially in sensitized patients. The European Society for Organ Transplantation (ESOT) launched the ENGAGE initiative, categorizing sensitized candidates by AMR risk to improve patient care. A systematic review assessed induction and maintenance regimens as well as antibody removal strategies, with statements subjected to the Delphi methodology. A Likert-scale survey was distributed to 53 European experts (Nephrologists, Transplant surgeons and Immunologists) with experience in kidney transplant recipient care. A rate ≥75% with the same answer was considered consensus. Consensus was achieved in 95.3% of statements. While most recommendations aligned, two statements related to complement inhibitors for AMR prophylaxis lacked consensus. The ENGAGE consensus presents contemporary recommendations for desensitization and immunomodulation strategies, grounded in predefined risk categories. The adoption of tailored, patient-specific measures is anticipated to streamline the care of sensitized recipients undergoing renal allografts. While this approach holds the promise of enhancing transplant accessibility and fostering long-term success in transplantation outcomes, its efficacy will need to be assessed through dedicated studies.

Antibody Mediated Rejection and T-cell Mediated Rejection Molecular Signatures Using Next-Generation Sequencing in Kidney Transplant Biopsies.

Recently, interest in transcriptomic assessment of kidney biopsies has been growing. This study investigates the use of NGS to identify gene expression changes and analyse the pathways involved in rejection. An Illumina bulk RNA sequencing on the polyadenylated RNA of 770 kidney biopsies was conducted. Differentially-expressed genes (DEGs) were determined for AMR and TCMR using DESeq2. Genes were segregated according to their previous descriptions in known panels (microarray or the Banff Human Organ Transplant (B-HOT) panel) to obtain NGS-specific genes. Pathway enrichment analysis was performed using the Reactome and Kyoto Encyclopaedia of Genes and Genomes (KEGG) public repositories. The differential gene expression using NGS analysis identified 6,141 and 8,478 transcripts associated with AMR and TCMR. While most of the genes identified were included in the microarray and the B-HOT panels, NGS analysis identified 603 (9.8%) and 1,186 (14%) new specific genes. Pathways analysis showed that the B-HOT panel was associated with the main immunological processes involved during AMR and TCMR. The microarrays specifically integrated metabolic functions and cell cycle progression processes. Novel NGS-specific based transcripts associated with AMR and TCMR were discovered, which might represent a novel source of targets for drug designing and repurposing.

[The German Transplant Registry - An Analysis of Legacy Data 2006-2016]. / Das Deutsche Transplantationsregister ­ eine Analyse der Altdaten 2006­2016.

INTRODUCTION: In 2018, medical transplant data from three institutions were merged to create a German transplant registry. Since June 2021, access to data of the registry has been available. It was planned to analyze the registry data in order to compare special allocation rules with regular allocation for heart, liver, lung, and kidney transplantation. Our approach led to a quality analysis of the registry. METHODS: Upon request, legacy data (2006-2016) of the registry was provided, divided into 61 elements. From these elements, the user had to compile the required dataset. Data checks were performed for completeness, correct allocation of information, and consistency among different sources. Software used for these tasks included R, SQL, and Excel. RESULTS: The initial elements ("waiting list" elements) of the four types of transplantations contained data from a total of 80,259 originally listed patients. However, these patients were only partially present in other elements resulting in complete datasets reflecting waiting time in only 23%, 30%, 50%, and 96%, and for post-transplantation outcomes in 14%, 11%, 38%, and 13% (heart, liver, lung, and kidney transplantation, respectively). The linking of urgency information with clinical data was successful in only a small proportion, with only 6% for heart transplantation. Incorrect and thus implausible allocations in the case of special allocation rules indicated incorrect entries in the registry. Data from different data providers were inconsistent. DISCUSSION: The incompleteness and incorrect data allocation raise doubts about the reliability of scientific studies based on the transplant registry. The complex structure also hinders the compilation of a reliable dataset, which is uncommon internationally. New data (acquisition since 2017) has only been available since December 2023. CONCLUSION: The transplant registry urgently needs restructuring. Competent clinical data management, involving transplant medical expertise, and continuous quality controls are essential in this process.

Positive Long-Term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients.

Introduction: Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation. Methods: This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0-5%; PRA-0) and intermediately sensitized (PRA 6-84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System. Results: Estimated 10-year overall graft survival between the PRA-0 and AM cohorts was similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody-mediated rejection rates was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of de novo donor-specific antibody (dnDSA) was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival, and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup. Discussion: The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival, and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help reduce dnDSA formation, particularly in high-risk AM patients.

Successful Desensitization with Imlifidase and Daratumumab in a Highly Immunized, Crossmatch Positive, Blood Group-Incompatible Living-Donor Re-Transplant Recipient with Systemic Lupus Erythematosus and Antiphospholipid Syndrome.

Introduction: The transplantation of highly sensitized patients remains a major obstacle. Immunized patients wait longer for a transplant if not prioritized, and if transplanted, their transplant outcome is worse. Case Presentation: We report a successful AB0- and HLA-incompatible living donor kidney transplantation in a 35-year-old female patient with systemic lupus erythematosus (SLE) and antiphospholipid syndrome. The patient had a positive T- and B-cell complement-dependent cytotoxicity (CDC) crossmatch and previous graft loss due to renal vein thrombosis. We treated the patient with intravenous immunoglobulins, rituximab, horse anti-thymocyte globulin, daratumumab, and imlifidase, besides standard immunosuppression. All IgG antibodies were sensitive to imlifidase treatment. Besides donor-specific HLA antibodies, anti-dsDNA antibodies and antiphospholipid antibodies were cleaved. The patient initially had delayed graft function. Two kidney biopsies (day 7 and day 14) revealed acute tubular necrosis without signs of HLA antibody-mediated rejection. On posttransplant day 30, hemodialysis was stopped, and creatinine levels declined over the next weeks to a baseline creatinine of about 1.7 mg/dL after 12 months. Conclusion: In this case, a novel multimodal treatment strategy including daratumumab and imlifidase enabled successful kidney transplantation for a highly immunized patient with antiphospholipid antibodies.

A first small step toward personalized immunosuppression.

Lloberas et al. provide further evidence for the benefits of an individualized tacrolimus dosing algorithm based on population pharmacokinetics and pharmacogenetics. Better tacrolimus dosing could prevent underexposure and overexposure and potentially save costs. Most important, this could be the start of precision medicine in kidney transplantation, incorporating improved immunologic and donor quality assessments, advanced biopsy readouts, innovative pharmacogenomics for drug safety, and novel diagnostic and outcome algorithms to guide a truly personalized therapy.

Challenges in the management of the kidney allograft: from decline to failure: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

In March 2022, Kidney Disease: Improving Global Outcomes (KDIGO) held a virtual Controversies Conference to address the important but rarely examined phase during which the kidney transplant is failing or has failed. In addition to discussing the definition of a failing allograft, 4 broad areas were considered in the context of a declining functioning graft: prognosis and kidney failure trajectory; immunosuppression strategies; management of medical and psychological complications, and patient factors; and choice of kidney replacement therapy or supportive care following graft loss. Identifying and paying special attention to individuals with failing allografts was felt to be important in order to prepare patients psychologically, manage immunosuppression, address complications, prepare for dialysis and/or retransplantation, and transition to supportive care. Accurate prognostication tools, although not yet widely available, were embraced as necessary to define allograft survival trajectories and the likelihood of allograft failure. The decision of whether to withdraw or continue immunosuppression after allograft failure was deemed to be based most appropriately on risk-benefit analysis and likelihood of retransplantation within a few months. Psychological preparation and support was identified as a critical factor in patient adjustment to graft failure, as was early communication. Several models of care were noted that enabled a medically supportive transition back to dialysis or retransplantation. Emphasis was placed on the importance of dialysis-access readiness before initiation of dialysis, in order to avoid use of central venous catheters. The centrality of the patient to all management decisions and discussions was deemed to be paramount. Patient "activation," which can be defined as engaged agency, was seen as the most effective way to achieve success. Unresolved controversies, gaps in knowledge, and areas for research were also stressed in the conference deliberations.

A paired-kidney allocation study found superior survival with HLA-DR compatible kidney transplants in the Eurotransplant Senior Program.

The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLA-DR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.53-0.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation.

A single centre in-depth analysis of death with a functioning kidney graft and reasons for overall graft failure.

BACKGROUND: High numbers of unknown classifications and inconsistent methodologies in previous studies make the interpretation of causes leading to graft loss difficult. In addition, data on a holistic view looking at both death with a functioning graft (DWFG) and death-censored graft failure (DCGF) are sparse. METHODS: In this single-centre study we included 1477 adult kidney transplants performed between 1997 and 2017, of which all 286 DWFGs until the end of observation were analysed and causes for death assigned. Additionally, the results were compared with the causes of 303 DCGFs of the same cohort to evaluate the impact of causes for overall graft loss. RESULTS: The most frequent causes for DWFG were cardiovascular disease (CVD) in 30.8%, malignancy in 28.3% and infections in 21%. Only 9.4% of reasons for DWFG were unknown. Sudden death occurred in 40% (35/88) of patients classified as DWFG due to CVD. Overall graft loss was related to the effect of immunosuppression in 36.2% [infection 20.9% (123/589), malignancy 15.3% (90/589)] and CVD in 22.4% (132/589). In 27.4% (161/589), graft failure was associated with underimmunosuppression (rejection). For infections (60 DWFG, 63 DCGF) and CVD (88 DWFG, 44 DCGF), a considerable overlap was observed between DWFG and DCGF. For patients >70 years of age at transplantation, medical events accounted for 78% of overall graft losses and only 6.5% were associated with rejection. CONCLUSIONS: DWFG and DCGF share more causes for graft loss than previously reported and sudden death plays an underestimated role in death with a functioning graft.

Predictors of graft failure after first detection of de novo donor-specific HLA antibodies in kidney transplant recipients.

BACKGROUND: De novo donor-specific antibodies (dnDSAs) may cause antibody-mediated rejection and graft dysfunction. Little is known about the clinical course after first detection of dnDSAs during screening in asymptomatic patients. We aimed to assess the value of estimated glomerular filtration rate (eGFR) and proteinuria to predict graft failure in patients with dnDSAs and their potential utility as surrogate endpoints. METHODS: All 400 kidney transplant recipients with dnDSAs at our centre (1 March 2000-31 May 2021) were included in this retrospective study. The dates of graft loss, rejection, doubling of creatinine, ≥30% eGFR decline, proteinuria ≥500 mg/g and ≥1000 mg/g were registered from the first dnDSA appearance. RESULTS: During 8.3 years of follow-up, graft failure occurred in 33.3% of patients. Baseline eGFR and proteinuria correlated with 5-year graft loss (area under the receiver operating characteristics curve 0.75 and 0.80, P < .001). Creatinine doubled after a median of 2.8 years [interquartile range (IQR) 1.5-5.0] from dnDSA and the time from doubling creatinine to graft failure was 1.0 year (IQR 0.4-2.9). Analysing eGFR reduction ≥30% as a surrogate endpoint (148/400), the time from dnDSA to this event was 2.0 years (IQR 0.6-4.2), with a positive predictive value (PPV) of 45.9% to predict graft loss, which occurred after 2.0 years (IQR 0.8-3.2). The median time from proteinuria ≥500 mg/g and ≥1000 mg/g to graft failure was identical, 1.8 years, with a PPV of 43.8% and 49.0%, respectively. Composite endpoints did not improve PPV. Multivariable analysis showed that rejection was the most important independent risk factor for all renal endpoints and graft loss. CONCLUSIONS: Renal function, proteinuria and rejection are strongly associated with graft failure in patients with dnDSA and may serve as surrogate endpoints.