Living-donor kidney transplantation (KT) offers the best outcomes for patients with kidney failure (KF). However, recurrence of primary kidney disease in the allograft remains a major concern and represents 1 of the leading causes of graft loss, significantly influencing donor and recipient selection. The recurrence risk varies substantially among kidney diseases and must be carefully assessed during pretransplant evaluation. For diseases associated with low-to-intermediate recurrence risk, such as lupus nephritis, antineutrophil cytoplasmic antibodies-associated vasculitis, or IgA nephropathy, living-donor KT is generally safe, although appropriate counseling remains essential. In contrast, diseases such as membranous nephropathy (MN), primary focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), primary hyperoxaluria (PH), and amyloid light-chain (AL) amyloidosis are associated with higher recurrence rates and often require complex, individualized assessment. Recent advances have significantly transformed this field. Biomarkers such as anti-phospholipase A2 receptor (anti-PLA2R) antibodies in MN and antinephrin antibodies in FSGS enable refined risk stratification and tailored pre- and post-transplant strategies. Complement gene analysis and targeted therapies, including eculizumab, have markedly improved outcomes in aHUS, whereas novel complement inhibitors show promise for recurrent C3G. RNA interference therapy has expanded kidney-alone transplantation options in PH, and modern hematologic therapies have improved post-transplant prognosis in AL amyloidosis. These developments are reshaping the decision-making landscape for living-donor KT in diseases with a high risk of recurrence, highlighting the need for multidisciplinary evaluation, individualized strategies, and transparent donor-recipient communication to optimize transplant outcomes.

Introduction In kidney transplantation, immunosuppressive therapy is essential to control alloimmune reactions, prevent graft rejection and improve patient survival rates. However, commonly used drugs like tacrolimus (TAC) and mycophenolate mofetil (MMF) have a narrow therapeutic window and exhibit significant inter- and intra-individual variability in pharmacokinetics (PK) and dose-response relationships. Recent pilot studies suggest that the gut microbiome may influence this variability.Methods and analysis ElucidatiNg Immunosuppressant pharmacokinetic variabilities by investigating Gut Microbiome modulations After kidney transplantation (ENIGMA) is a prospective, low-interventional, naturalistic longitudinal trial designed to identify biomarkers of TAC and MMF PK variability by examining gut microbiome changes and modulations after kidney transplantation and their link with TAC and MMF PK. Biological samples from 50 patients will be collected at nine specific timepoints pre- and post-transplantation using a rich PK and biological sampling strategy. This approach will enable the derivation of PK parameters for the investigated drugs and the creation of a biobank for future hypothesis testing.Ethics and dissemination The ENIGMA trial has received ethical approval from the European Medicines Agency (EMA). The reference number of our project is R&D/1325226 and is registered on the Clinical Trial Information System (CTIS) platform with European Union Clinical Trial number 2023–5 08 335-31-00. Results of the trial will be published in scientific journals and presented at different (inter)national conferences.Trial registration number 2023–5 08 335-31-00 EMA.

Mechanical dysfunction remains a frequent cause of peritoneal dialysis (PD) catheter failure. Fallopian tube entrapment is an uncommon and probably underrecognized mechanism. A 78-year-old woman with end-stage kidney disease secondary to ANCA-associated vasculitis presented early peritoneal dialysis catheter dysfunction after uncomplicated laparoscopic insertion of a Di Paolo catheter. Peritoneal dialysis was successfully initiated 30 days after PD catheter placement and functioned well for 16 days. The patient subsequently experienced slow and incomplete effluent drainage. Clinical examination was normal. Imaging assessment, including abdominal X-ray and CT scan, showed a normally positioned catheter in the right iliac fossa, with the tip positioned in the Douglas pouch. Laparoscopic exploration revealed wrapping of the right Fallopian tube around the catheter tip as primary cause of catheter dysfunction. Following adhesiolysis of the right Fallopian tube, intraoperative functional testing demonstrated persistent catheter dysfunction due to intraluminal fibrin deposits. As these deposits could not be removed by flushing, the catheter was laparoscopically replaced with a new Swan-neck pigtail PD catheter, and the Di Paolo catheter was removed. Postoperative course was uneventful, and PD function was successfully restored three weeks later. This case highlights that normal PD catheter positioning on conventional imaging does not exclude mechanical obstruction. In women presenting with persistent PD catheter dysfunction despite reassuring imaging, uncommon causes, including Fallopian tube entrapment, should be considered, and early diagnostic laparoscopy may provide both diagnosis and definitive treatment.

Mortality in patients with kidney failure on maintenance haemodialysis (HD) is higher after the long inter-dialytic interval, probably from fluid overload and electrolyte disturbances. In HD patients, the optimal timing of a HD session before surgery is unknown. Surgery induces cardiovascular stress and may trigger cardiac events in fluid overloaded or hyperkalemic patients if the interval between the last HD and the intervention is too long. However, a shorter interval might on the contrary increase bleeding risk due to recent anticoagulation. Whether a shorter or longer interval between the last HD session and surgery impacts early post-transplant outcomes has not been investigated yet. In this study, we evaluate the effect of the timing of the last HD session on the occurrence of delayed graft function and the need for early surgical revision in chronic haemodialysis patients receiving a kidney allograft. In this retrospective monocentric study, we included all adult patients on maintenance HD who received a deceased donor kidney transplant in our centre between 01/01/2015 and 31/12/2022. Patients with no retrievable information regarding the last HD session and multiorgan transplants were excluded. Baseline characteristics (Table 1), data regarding the last dialysis session before transplant surgery (anticoagulation regimen, ultrafiltration volume, haemodialysis modality, dry weight) and transplantation data (date of transplantation, ischemia time, induction therapy) were collected. The timing between the last dialysis and transplantation was defined as the time between the start of the last HD session and anaesthetic induction for kidney transplant. Patients were divided into a “short” (<24h) and “long" (≥24h) interval based on this delay. The primary outcome was a composite of the occurrence of delayed graft function (as defined by the need for dialysis within the first 7 days after kidney transplantation) or surgical revision within the same hospital stay. 202 patients were included, 87 in the “short” and 115 in the “long” group. Baseline characteristics were similar with a median age at transplantation of 55 y. Data regarding transplantation (cold ischemia time (11.4 vs 12.5 hours), donor type (DBD = 71 vs 72%), induction regimen (including plasmapheresis = 21% in both groups), mean peak historic virtual PRA, cardiovascular (25% vs 31%) and diabetes history (20 vs 22%) were similar between the two groups. The median time between the last HD session and transplant surgery was 9 and 35 hours in the “short” and “long” group respectively. In the “short” group, anticoagulation regimen consisted mainly of unfractionated heparin (57%) while some patients did not receive any anticoagulant (13%). Low molecular weight heparin was used in the majority of patients in the “long” group (87%). There was no primary non function in both groups. The primary outcome occurred in 38% of patients in the “short" versus 23% in the “long” group (p-value = 0.02). This was mainly driven by the need for surgical revision (18% vs 8%; p-value = 0.03). The difference in DGF between the two groups was not significant (28% vs 20%; p-value = 0.18) (Fig. 1). In maintenance HD patients, the timing between the last HD session and transplant surgery may impact postoperative outcomes. Patients dialyzed within the last 24 hours were at an increased risk of surgical revision compared to those dialyzed ≥24h before surgery, despite similar characteristics and the use of unfractionated heparin.

BACKGROUND:Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to the progressive loss of pancreatic beta cells. Interferons (IFNs) contribute to the initiation and amplification of beta cell autoimmunity. STAT1 is the main mediator of IFN signalling but little is known about its complex activation processes and role in the progression of beta cell failure. METHODS:We investigated the IFN-α-stimulated STAT1 pathway from three human beta cell models: EndoC-βH1 cells, iPSC-derived islet-like cells and human islets by directly targeting two T1D candidate genes, namely PTPN2 and BACH2. FINDINGS:We presently show that PTPN2 and BACH2 modulate STAT1 activation via two different pathways, namely the JAK/STAT, involved in the phosphorylation of its tyrosine residue (Y701), and the MAPKs pathway, involved in the phosphorylation of its serine residue (S727). Each STAT1 phosphorylation type can independently induce expression of CXCL10, but both residues are necessary for the expression of MHC class I molecules. IFN-α-induced STAT1 activation is dynamic and residue-dependent, being STAT1-Y701 fast but transitory, while STAT1-S727 increases slowly and is associated with the long-term effects of IFN-α exposure. INTERPRETATION:The present findings provide a better understanding of the dynamics of STAT1 activation in human beta cells and will be useful to develop new and targeted (i.e. favouring individuals with particular polymorphisms) therapies for T1D and other autoimmune diseases. FUNDING:EFSD and Sanofi European Diabetes Research Programme on autoimmunity in type 1 diabetes; Breakthrough T1D, HIRN-CBDS, NIDDK, Fondation Saint-Luc, Programme d'Investissement d'Avenir' to European Genomic Institute for Diabetes, and Fondation de la Recherche Médicale.

Remission of type 2 diabetes (T2D) can occur after hypocaloric diet, bariatric surgery, or pharmacological treatments and associates with improved β cell function. Here, we studied islets from nondiabetic ( n = 15) and T2D ( n = 21) donors. We examined whether T2D β cell dysfunction can be rescued, charted the underlying molecular mechanisms by RNA sequencing, and mined transcriptomes for drug targets. Glucose responsiveness of T2D β cells improved in 60% of preparations after 3-day culture in euglycemic conditions. This was accompanied by changes in expression of >400 genes involved in functional or inflammatory pathways. Drug repurposing and target identification analyses predicted chemical and genetic hits, including JAK inhibitors, which were validated in a β cell line, human islets, and db/db mice. Therefore, defective β cell glucose responsiveness in T2D can recover, demonstrating β cell functional plasticity. The recovery associates with transcriptomic traits, pointing to targetable defects to induce T2D remission.

Autoimmune diseases, such as type 1 diabetes (T1D) and Hashimoto's thyroiditis (HT), are often studied from an immune perspective with less focus on the target tissue responses. Target tissues, however, are key to disease and engage in a harmful crosstalk with the immune system contributing to their own destruction. We presently integrated transcriptomic data from the target tissues of six autoimmune/inflammatory diseases affecting β-cells (T1D and type 2 diabetes), thyroid (HT), brain (multiple sclerosis and Alzheimer's disease) or the joints (rheumatoid arthritis), using both bulk and single-cell/nucleus RNA-sequencing (sc/snRNA-seq) approaches. Common upregulated pathways were associated with innate/adaptive immunity, antigen presentation and interferon (IFN) signaling. The role of IFNs was confirmed by RNA-seq in human insulin-producing EndoC-βH1 cells and stem cell-derived thyroid follicle cells exposed to IFNα or IFNγ. Commonly upregulated inflammatory gene signatures were explored, and fibroblast growth factor receptor (FGFR) inhibitors emerged as a potential strategy to counteract these inflammatory transcriptional signatures. The effects of the FGFR1 inhibitor PD173074 on IFN-induced immune related genes were evaluated in EndoC-βH1 cells, stem cell-derived islets and adult human islets. We validated the FGFR inhibitor PD173074 as a promising drug for preserving expression of β-cell protective genes (PDL1 and HLA-E) while reducing HLA class I expression and β-cell recognition by diabetogenic pre-proinsulin-specific CD8+ T-cells. In conclusion, we integrated transcriptomic data from the target tissues of autoimmune and inflammatory/degenerative diseases and departing from these data identified the potential beneficial effects of FGFR inhibitors in T1D.

Kidney transplantation (KT) is the best treatment for patients with kidney failure, associated with improved survival and quality of life compared with maintenance dialysis. However, despite constant improvements in the assessment and management of the alloimmune response, KT patients frequently demonstrate a reduced estimated glomerular filtration rate. Therefore, the usual complications of chronic kidney disease (CKD), such as anemia, hypertension, metabolic acidosis, hyperkalemia, or persistent secondary hyperparathyroidism, are highly prevalent after KT. However, their underlying mechanisms are different in the transplant setting (compared with the nontransplanted CKD population), and management recommendations are based on relatively poor-quality data. In recent years, new therapies have emerged, significantly improving kidney and cardiovascular outcomes of non-KT patients with CKD. Whether those new drugs could improve the outcomes of KT patients has largely been under investigated so far. In this review, we will address the challenges of the management of a KT patient with a reduced estimated glomerular filtration rate, cover the published evidence, and highlight the critical knowledge gaps.

Highly sensitized (HS) kidney transplant (KTx) candidates, that is, typically considered internationally as those with panel-reactive antibody levels of >85%, remain a substantial subpopulation of patients with low chance of receiving a compatible organ. Among its many objectives, Eurotransplant-an international transplant organ allocation network serving 8 European countries-aims to improve the management of HS KTx candidates through its prioritized "acceptable mismatch" (AM) program. However, despite this program, some HS patients within the Eurotransplant network who have panel-reactive antibodies >85% still cannot access donor kidneys. For patients who remain in the AM program for ≥3 y without undergoing transplantation, an additional prioritization strategy has been implemented. This involves defining further AMs to allow for desensitization with imlifidase within the AM program. While the AM desensitization program was being developed, the Belgian Imlifidase Scientific Expert Group within the Eurotransplant network independently recognized the need for guidelines on imlifidase desensitization for real-world use in HS KTx candidates (including both AM and Eurotransplant Kidney Allocation System patients). This article describes the consensus guidelines they subsequently developed, which represent a model that any center within the Eurotransplant region could adapt or apply in clinical practice when treating HS KTx candidates who require imlifidase desensitization. The consensus guidelines include patient eligibility criteria for imlifidase treatment that align with Eurotransplant allocation rules and incorporate posttransplant management strategies for HS patients. These guidelines are dynamic and will be reviewed and updated regularly as Eurotransplant rules change and imlifidase experience grows.

Introduction: Etelcalcetide is an i.v. calcimimetic agent, effectively reducing parathyroid hormone levels in patients on maintenance hemodialysis (HD). The clinical impact of discontinuing etelcalcetide at the time of kidney transplantation is unknown. Methods: We retrospectively reviewed all patients on HD meeting prede fi ned criteria who received a kidney transplant at our institution between January 1, 2015, and December 12, 2022. The incidence of parathyroidectomy and the evolution of calcium, phosphate, and intact parathyroid hormone (iPTH) levels after transplantation was analyzed according to the type of calcimimetic treatment before transplantation (cinacalcet vs. etelcalcetide vs. none). Results: Overall, 372 patients (aged 53 years; interquartile range [IQR]: 42 - 62 years) were included. At the time of transplantation, 35, 75, and 262 patients were under etelcalcetide, cinacalcet, or no calcimimetic, respectively. After 1064 (IQR: 367 - 1658) days, the incidences of parathyroidectomy in the etelcalcetide, cinacalcet, no calcimimetic groups were 29%, 12%, and 1%, respectively ( P < 0.001). Etelcalcetide was associated with an increased incidence of parathyroidectomy after adjustment for age, sex, and HD vintage (hazard ratio [HR]: 97.0, 95% con fi dence interval [CI]: 19.1 - 493.9, P < 0.001). The incidence of parathyroidectomy was related to etelcalcetide dosage (6/11 [54.6%] in patients with >= 10 mg vs. 4/24 [16.7%] in patients with < 10 mg, P 1 / 4 0.02). Moreover, peak calcium levels were higher ( P < 0.001) and parathyroidectomy was performed earlier (median 80 vs. 480 days, P < 0.001) in the etelcalcetide compared with the cinacalcet group. Long-term graft function, graft loss, and mortality were similar. Conclusion: Etelcalcetide use during maintenance HD is associated with an increased incidence of early parathyroidectomy after transplantation compared to cinacalcet or no calcimimetic.

Background and aimsHuman islet preparations designated for research exhibit diverse insulin-secretory profiles. This study aims to assess the impact of donor- and isolation-related factors on in vitro islet secretory function.MethodsA retrospective analysis of 46 isolations from 23 pancreata discarded for clinical transplantation was conducted. In vitro islet secretory function tests were performed on Day 1 and Day 7 of culture. Linear mixed-effects models (LMMs) were employed to investigate the relationships between various predictors characterizing the patient and donor characteristics as well as the isolation effectiveness and two functional outcomes including the islet stimulation index (SI) and area under the insulin curve (AUC). Fixed effects were introduced to represent the main effects of each predictor, and backward elimination was utilized to select the most significant fixed effects for the final model. Interaction effects between the timepoint (Day 7 vs. Day 1) and the predictors were also evaluated to assess whether predictors were associated with the temporal evolution of SI and AUC. Fold-change (Fc) values associated with each predictor were obtained by exponentiating the corresponding coefficients of the models, which were built on log-transformed outcomes.ResultsAnalysis using LMMs revealed that donor body mass index (BMI) (Fc = 0.961, 95% CI = 0.927–0.996, p = 0.05), donor gender (female vs. male, Fc = 0.702, 95% CI = 0.524–0.942, p = 0.04), and donor hypertension (Fc = 0.623, 95% CI = 0.466–0.832, p= <0.01) were significantly and independently associated with SI. Moreover, donor gender (Fc = 0.512, 95% CI = 0.302–0.864, p = 0.02), donor cause of death (cerebrovascular accident vs. cardiac arrest, Fc = 2.129, 95% CI = 0.915–4.946, p = 0.09; trauma vs. cardiac arrest, Fc = 2.129, 95% CI = 1.112–7.106, p = 0.04), pancreas weight (Fc = 1.01, 95% CI = 1.001–1.019, p = 0.03), and islet equivalent (IEQ)/mg (Fc = 1.277, 95% CI = 1.088–1.510, p ≤ 0.01) were significantly and independently associated with AUC. There was no predictor significantly associated with the temporal evolution between Day 1 and Day 7 for both SI and AUC outcomes.ConclusionThis study identified donor- and isolation-related factors influencing in vitro islet secretory function. Further investigations are essential to validate the applicability of these results in clinical practice.

Background: Induction therapy with basiliximab is recommended in kidney transplant (KT) recipients with a low immunological risk (LIR) profile. Whether basiliximab is associated with a decreased risk of acute rejection (AR) and graft loss is controversial. Methods: In our institution, LIR patients (absence of anti-HLA antibodies before KT) are inducted with basiliximab in case of living-donor KT, while deceased-donor KT recipients receive no induction. Maintenance immunosuppression is similar, including a combination of tacrolimus (Tac), mycophenolate (MPA) and steroids. In this single-center retrospective study, we included all adult LIR patients who underwent KT between 1 January 2015 and 31 December 2022. Results: Of the 471 patients included, 354 received no induction and 117 received basiliximab. The median (IQR) number of HLA A-B-DR mismatches was 3 (2-3) and 2 (2-4) in the no induction group and the basiliximab group, respectively. The cumulative incidences in the no induction group vs. the basiliximab group of acute rejection and graft loss over 5 years post-KT were similar at 8.9% vs. 7.8% (p = 0.8) and 8.5% vs. 4.2% (p = 0.063), respectively. In multivariable Cox regression analysis, delayed graft function emerged as an independent risk factor for acute rejection (hazard ratio [HR] 2.75, 95% confidence interval [CI] 1.23-6.13, p = 0.014) and graft loss (HR 9.32, CI 4.10-21.1, p < 0.001). Conclusions: Basiliximab did not provide any advantage in terms of rate of acute rejection and graft survival within 5 years post KT compared with a strategy without induction therapy in patients with a low immunological risk profile receiving triple maintenance immunosuppression Tac/MPA/steroids.

Abstract Background and Aims Cardiovascular diseases are traditionally considered as the leading cause of death in kidney transplant recipients. Significant improvements in immunosuppressive strategies but also in the prevention and management of cardiovascular diseases have been made over the last decades. Therefore, we aimed to explore the evolution over time of the causes of death with a functioning graft in kidney transplant recipients. Method We performed a retrospective study including all patients transplanted with a kidney between January 1995 and December 2009 at Cliniques Universitaires Saint-Luc in Brussels who died with a functioning graft. Patients younger than 18 years old and those who received bone marrow or other solid organ transplant were excluded. Clinical data were collected by electronic medical chart review. Differences in causes of death were assessed between two eras of transplantation (first era [1995-2001] vs second era [2002-2009]). Results A total of 256 patients (aged 56 ± 11.18 years, 164 (64.9%) man) were included. Among those patients, 65 (25.39%) died from infectious causes, 64 (25%) from neoplastic causes, 62 (24.22%) from cardiovascular causes and 24 (9.38%) from other causes. The cause of death was unknown for 42 (16.41%) patients. Patients who received a kidney graft during the first era mostly died from cardiovascular causes (33%), while those who received a graft during the second era mostly died from infectious causes (31%). Death from neoplastic causes remained similar across eras (32 (26%) versus 32 (24%), p-value &gt; 0.1). Patients grafted in the more recent era have threefold higher odds of dying from infectious than cardiovascular causes compared to those grafted in the former graft era (OR 3.1, p=0.002). Infectious causes of death were the most prevalent early cause of death in both eras i.e. 3 patients (60%) in the first era and 6 patients (50%) in the second era. Conclusion We observed a significant shift from cardiovascular deaths to infectious deaths between the former and the more recent transplantation era. Neoplastic causes of death remained stable over time.