Autosomal Dominant Tubulointerstitial Kidney Disease-Uromodulin (ADTKD-UMOD) is classically due to missense variants displaying a dominant negative effect.Here we describe a family with high clinical suspicion of ADTKD-UMOD for which no molecular diagnosis was obtained through standard techniques including extensive panel sequencing.Whole genome and long read sequencing in multiple affected family members uncovered a large deletion (1313 bp) encompassing part of exon 3, the entire intron 3 and exon 4, and part of intron 4, conserved regions of UMOD where most known pathogenic variants are found. The pathogenic effect of the variant was validated through multimodal analysis of the urinary protein composition. Instead of loss-of-function, our data suggest that it may result in an altered protein.This is the first large deletion demonstrated by functional assessment as responsible for ADTKD-UMOD, and importantly it was undetected by conventional variant calling on short read exome sequencing. Our result suggest that copy number variant may also be responsible for ADTKD-UMOD. We propose that when ADTKD is suspected but not explained by massive parallel sequencing and MUC-1 analysis, additional sequencing techniques might unravel other types of genetic alteration, notably copy number variants, and thereby address unsolved ADTKD cases.

Autosomal dominant tubulointerstitial kidney disease-uromodulin (ADTKD-UMOD) is classically due to missense variants in UMOD that display a dominant-negative effect. Here, we describe a family with high clinical suspicion for ADTKD-UMOD for which no molecular diagnosis was obtained through standard techniques including extensive panel sequencing. Whole genome and long-read sequencing in multiple affected family members uncovered a large deletion (1,313 bp) encompassing part of exon 3, the entire intron 3 and exon 4, and part of intron 4, conserved regions of UMOD in which most known pathogenic variants are found. The pathogenic effect of the variant was validated through multimodal analysis of the urinary protein composition. Instead of loss of function, our data suggest that this deletion may result in an altered protein. This is the first large deletion demonstrated by functional assessment as responsible for ADTKD-UMOD, and importantly, it was undetected by conventional variant calling on short-read exome sequencing. Our results suggest that copy number variants may also be responsible for ADTKD-UMOD. We propose that when ADTKD is suspected but not explained by massive parallel sequencing and MUC1 analysis, additional sequencing techniques might unravel other types of genetic alteration, notably copy number variants, and thereby address unsolved ADTKD cases.

Donor Specific Antibodies (DSAs) are associated with a higher risk of Antibody Mediated Rejection (AMR). However, not all DSAs are pathogenic, and patients that raise DSAs have a wide spectrum of outcomes ranging from the complete absence of graft injury to severe AMR. Hence, characterization of both the qualitative features and titer of DSAs has the potential to predict AMR risk and treatment outcome for sensitized patients. Here, using HLA-A2+ cell-based assays, we investigate the qualitative features of immunoglobulin G (IgG) alloantibodies including Fc receptor binding properties and Fc-mediated effector function over time. Compared to seronegative controls, reactive antibodies in seropositive participants were predominantly IgG1, and exhibited elevated levels of binding to the receptors involved in Antibody Dependent Cellular Phagocytosis (ADCP) and Antibody Dependent Cellular Cytotoxicity (ADCC) activity. Further analysis of seropositive individuals revealed that these activities were predictive ofAMR status. Collectively, these results suggest a role for phagocytic and cytotoxic antibody effector functions of DSA in contributing to graft injury.

Obesity is an increasing health concern among kidney transplant candidates. While transplantation should be encouraged to treat advanced chronic kidney disease (CKD), obesity often hinders access to transplant due to the higher rate of post-operative complications. Pre-transplant bariatric surgery provides significant weight loss but is not free of risk. ‘Glucagon Like Peptide-1’analogues (GLP-1Ras) demonstrated efficacy to treat obesity in the general population but data in renal transplant candidates are poor. This study aims to determine whether treatment with semaglutide enabled waitlisting and transplantation of otherwise unlisted obese renal transplant candidates. Between 01/01/2021 and 30/10/2023, patients recused from renal transplantation due to obesity received pre-transplant subcutaneous semaglutide up to 1 mg/week. Of the 23 patients included, initial mean body weight, BMI and waist circumference were 106 Kg, 35.6 and 119 cm respectively. After a median of 13 months on semaglutide, decreased by 11 kg (P = 0.001), 3.8 points (P = 0.001) and 9.6 cm (P = 0.001) respectively. Total weight loss (TWL%) and excess weight loss (EWL) were 10.8% and 10.7% respectively. 56.5% of patients initially rejected for transplant were wait-listed within a median of 6.7 months, and 61.5% of them were transplanted within a median of 3.9 months. No major side effects of the treatment were reported. Treatment with semaglutide enabled waitlisting and transplantation of otherwise unlisted obese renal transplant candidates and should be included in the stepwise management of obesity in renal transplant candidates.

Although transplantation remains the treatment of choice for end-stage renal disease, patients suffering from severe obesity are too often unlisted for this reason. Pre-transplant bariatric surgery is not free of risk and the use of ‘Glucagon Like Peptide-1’analogues in these patients is limited. Our study aims to determine whether semaglutide administration enabled waitlisting and transplantation of otherwise ineligible obese renal transplant candidates. Between 01/01/2021 and 10/30/2023, patients rejected from renal transplantation because of obesity received pre-transplant subcutaneous semaglutide up to 1 mg/week. Of the 23 patients included, initial mean body weight, BMI and waist circumference were 102.9 Kg, 35.6 and 119.5 cm respectively. After a median of 12.2 months on semaglutide, these parameters decreased by 11.4 Kg (p ≤ 0.001), 3.9 points (p ≤ 0.001) and 9.6 cm (p ≤ 0.001) respectively. 56.5% of patients initially rejected for transplantation were listed within a median of 5.4 months, and 61.5% of them were transplanted. No major side effects were reported. In summary semaglutide administration enabled waitlisting and transplantation of otherwise ineligible obese renal transplant candidates. This treatment should be an integral part of the pre-transplant management of obesity.

BACKGROUND:Despite the burden of pyelonephritis after kidney transplantation, there is no consensus on initial empirical antibiotic management. METHODS:We surveyed clinicians throughout the world on their practice and opinions about the initial empirical therapy of post-transplant pyelonephritis, using clinical vignettes. A panel of experts from 19 countries on six continents designed this survey, and invited 2145 clinicians to participate. RESULTS:A total of 721 clinicians completed the survey (response rate: 34%). In the hypothetical case of a kidney transplant recipient admitted with pyelonephritis but not requiring intensive care, most respondents reported initiating either a 3rd-generation cephalosporin (37%) or piperacillin-tazobactam (21%) monotherapy. Several patient-level factors dictated the selection of broader-spectrum antibiotics, including having a recent urine culture showing growth of a resistant organism (85% for extended-spectrum ß-lactamase-producing organisms, 90% for carbapenemase-producing organisms, and 94% for Pseudomonas aeruginosa). Respondents attributed high importance to the appropriateness of empirical therapy, which 87% judged important to prevent mortality. Significant practice and opinion variations were observed between and within countries. CONCLUSION:High-quality studies are needed to guide the empirical management of post-transplant pyelonephritis. In particular, whether prior urine culture results should systematically be reviewed and considered remains to be determined. Studies are also needed to clarify the relationship between the appropriateness of initial empirical therapy and outcomes of post-transplant pyelonephritis.

Abstract Nodal/paranodal IgG4-related chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) rarely involves anticontactin (CNTN1) subtype and exceptionally complicates with nephrotic syndrome. A 65-year-old man developed weakness, facial palsy, and balance impairment; after spontaneous recovery, he severely relapsed 1 month later. Electroneuromyography confirmed CIDP. Proteinorachy (462 mg/dL; N < 45), proteinuria (3.5 g/g creatine), and biopsy-proven membranous nephropathy were identified. Intravenous immunoglobulins, corticosteroids, and plasmaphereses did not allow recovery. Anti-CNTN1 immunoglobulin G4 (IgG4) assay was positive. Rituximab (375 mg/m2/week, 4 weeks) provided obvious improvement. Relapsing–remitting anti–CNTN1-CIDP co-occurring with nephrotic syndrome is exceptional, and its identification is essential because efficient therapies such as rituximab are available for this severe condition.

Antibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSAs) are associated with a higher risk of AMR, not all patients with DSAs develop rejection, suggesting that the characteristics of alloantibodies determining their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we apply systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and FcγR-binding properties. Levels of afucosylated anti-A2 antibodies are elevated in seropositive patients, especially those with AMR, suggesting potential cytotoxicity via FcγRIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 drives potentiated binding to, slower dissociation from, and enhanced signaling through FcγRIII, a receptor widely expressed on innate effector cells, and greater cytotoxicity against HLA-A2+ cells mediated by natural killer (NK) cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and contribute to pathogenesis.

DOI: 10.1097/TP.0000000000003942 Preemptive Antibody Therapy for Vaccine Breakthrough SARS-CoV-2 Infection in Immunocompromised Patients Concetta Catalano, MD, Sophie Servais, MD, PhD, Catherine Bonvoisin, MD, Bruno Couturier, MD, Marc Hildebrand, MD, Isabelle Etienne, MD, Christelle Meuris, MD, Jean-Christophe Goffard, MD, PhD, Martin Wissing, MD, PhD, Michel Goldman, MD, PhD, and Alain Le Moine, MD, PhD

Background: Ciliopathies are rare diseases causing renal and extrarenal manifestations. Here, we report the case of a ciliopathy induced by a homozygous pathogenic variant in the TTC21B gene. Case Description: A 47-year-old patient started hemodialysis for chronic kidney disease (CKD) of unknown origin. She presented with early onset of hypertension, pre-eclampsia, myopia and cirrhosis. Renal biopsy showed mild interstitial fibrosis, tubular atrophy, and moderate arteriosclerosis while liver pathology demonstrates grade B biliary cirrhosis. Family history revealed several cases of early-onset severe hypertension and one case of end-stage renal disease (ESRD) needing kidney transplantation at twenty years of age. Clinical exome sequencing showed homozygosis for the pathogenic variant c.626C>T (p.Pro209Leu) in the TTC21B gene. The patient underwent combined liver-renal transplantation with an excellent renal and hepatic graft outcome. Conclusions:TTC21B gene mutations can lead heterogeneous to clinical manifestations and represent an underappreciated cause of ESRD. The paradigm in diagnosis of CKD of early onset and/or of unknown origin is changing and genetic counseling should be performed in all patients and families that meet those criteria. Renal or combined liver-renal transplantation represents the best option for patients suffering from those diseases in terms of prognosis and quality of life.

Background The efficacy and cost-effectiveness of prophylactic thrombolytic locks in hemodialysis patients at high-risk of thrombotic dialysis catheter dysfunction is uncertain. We investigated this question in a double-blinded randomized controlled study. Methods Prevalent hemodialysis patients from 8 Belgian hemodialysis units, with ≥2 separate episodes of thrombotic dysfunction of their tunneled cuffed catheter during the 6 months before inclusion, were randomized to either: taurolidine heparin locks thrice weekly (control arm) or the same locks twice a week combined with taurolidine urokinase locks once a week before the longest interval without HD (TaurolockU arm). The primary efficacy outcome was the incidence rate of catheter thrombotic dysfunction requiring thrombolytic locks to restore function. Results 68 hemodialysis patients (32 controls, 36 urokinase) were followed during 9875 catheter days between May 2015 and June 2017. Incidence rate of thrombotic catheter dysfunction was 4.8 in TaurolockU vs 12.1/1000 catheter days in control group (rate ratio 0.39; 95%CI 0.23–0.64). 15/36 (42%) catheters in the treatment group required at least one therapeutic urokinase lock vs 23/32 (72%) in the control group (P = 0.012). The two groups did not differ significantly in catheter-related bloodstream infection and combined cost of prophylactic and therapeutic catheter locks. The TaurolockU group had a numerically higher number of episodes of refractory thrombosis. Conclusions Prophylactic use of urokinase locks is highly effective in reducing the number of thrombotic catheter dysfunctions in catheters with a history of recurring dysfunction. Prophylactic use of urokinase locks did not reduce the overall costs associated with catheter locks and was associated with a numerically higher number of episodes of refractory thrombosis. Trial registration ClinicalTrials.gov Identifier: NCT02036255.

Primary membranous nephropathy (MN) is an autoimmune glomerular disease in which autoantibodies are directed against podocyte proteins. In about 80% of cases the main targeted antigen is the phospholipase A2 receptor 1 (PLA2R1). Anti-PLA2R1 antibodies are mainly immunoglobulin G type 4 (IgG4). However, the antigenic target remains to be defined in 20% of cases. MN can be associated with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system where a common antigenic target has yet to be identified. To ascertain a possible novel target antigen, we analyzed kidney biopsies from five patients positive for anti-contactin 1 antibodies and presenting with MN combined with chronic inflammatory demyelinating polyneuropathy. Eluted IgG from biopsy sections against contactin 1 and nerve tissue were screened. Western blot revealed contactin 1 expression in normal kidney glomeruli. Confocal microscopic analysis showed the presence and colocalization of contactin 1 and IgG4 on the glomerular basement membrane of these patients. Glomerular contactin 1 was absent in patients with anti-PLA2R1-associated MN or membranous lupus nephritis or a healthy control. The eluted IgG from contactin 1-positive biopsy sections but not the IgG eluted from patients with PLA2R1 MN bound contactin 1 with the main eluted subclass IgG4. Eluted IgG could bind paranodal tissue (myelinated axon) and colocalized with commercial anti-contactin 1 antibody. Thus, contactin 1 is a novel common antigenic target in MN associated with chronic inflammatory demyelinating polyneuropathy. However, the precise pathophysiology remains to be elucidated.

OBJECTIVES:Many transplant physicians screen for and treat asymptomatic bacteriuria (ASB) during post-kidney-transplant surveillance. We investigated whether antibiotics are effective in reducing the occurrence of symptomatic urinary tract infection (UTI) in kidney transplant recipients with ASB. METHODS:We performed this multicentre, randomized, open-label trial in kidney transplant recipients who had ASB and were ≥2 months post-transplantation. We randomly assigned participants to receive antibiotics or no therapy. The primary outcome was the incidence of symptomatic UTI over the subsequent 12 months. RESULTS:One hundred and ninety-nine kidney transplant recipients with ASB were randomly assigned to antibiotics (100 participants) or no therapy (99 participants). There was no significant difference in the occurrence of symptomatic UTI between the antibiotic and no-therapy groups (27%, 27/100 versus 31%, 31/99; univariate Cox model: hazard ratio 0.83, 95%CI: 0.50-1.40; log-rank test: p 0.49). Over the 1-year study period, antibiotic use was five times higher in the antibiotic group than in the no-therapy group (30 antibiotic days/participant, interquartile range 20-41, versus 6, interquartile range 0-15, p < 0.001). Overall, 155/199 participants (78%) had at least one further episode of bacteriuria during the follow-up. Compared with the participant's baseline episode of ASB, the second episode of bacteriuria was more frequently caused by bacteria resistant to clinically relevant antibiotics (ciprofloxacin, cotrimoxazole, third-generation cephalosporin) in the antibiotic group than in the no-therapy group (18%, 13/72 versus 4%, 3/83, p 0.003). CONCLUSIONS:Applying a screen-and-treat strategy for ASB does not reduce the occurrence of symptomatic UTI in kidney transplant recipients who are more than 2 months post-transplantation. Furthermore, this strategy increases antibiotic use and promotes the emergence of resistant organisms.

BackgroundDuring routine post-kidney transplant care, most European transplant physicians screen patients for asymptomatic bacteriuria. The usefulness of this strategy is debated. To make screening cost-effective, asymptomatic bacteriuria should be prevalent enough to justify the expense, and antibiotics should improve patient outcomes significantly if asymptomatic bacteriuria is detected. Regrettably, the prevalence of asymptomatic bacteriuria among kidney transplant recipients is not well defined.MethodsTo determine the prevalence of asymptomatic bacteriuria among kidney transplant recipients, we did a cross-sectional study among kidney transplant recipients undergoing routine surveillance in three outpatient transplant clinics in Belgium and France. We excluded patients who were in the first two months post-transplantation and/or had a urinary catheter. Asymptomatic participants who had a urine culture with one organism isolated at ≥ 105 CFU/mL were asked to provide a confirmatory urine specimen. Asymptomatic bacteriuria was defined per Infectious Diseases Society of America guidelines.ResultsWe screened 500 consecutive kidney transplant recipients. Overall, the prevalence of asymptomatic bacteriuria was 3.4% (17/500 patients). It was similarly low among kidney transplant recipients who were between 2 and 12 months after transplantation (1.3%, 1/76 patients) and those who were farther after transplantation (3.8%, 16/424 patients: p = 0.49). Asymptomatic bacteriuria was significantly associated with female gender (risk ratio 3.7, 95% CI 1.3-10.3, p = 0.007) and older age (mean age: 61 ± 12 years [bacteriuric participants], versus 53 ± 15 years [non-bacteriuric participants], p = 0.03). One participant's colistin-resistant Escherichia coli isolate carried the globally disseminated mcr-1 gene.ConclusionsAmong kidney transplant recipients who are beyond the second month post-transplant, the prevalence of asymptomatic bacteriuria is low. Further studies are needed to ascertain the cost-effectiveness of a screen-and-treat strategy for asymptomatic bacteriuria in this population.

L’hypothèse selon laquelle l’administration prophylactique d’un verrou fibrinolytique (composé de 25,000 unités d’urokinase, de taurolidine et de citrate) une fois par semaine permet de réduire les dysfonctions thrombotiques de 50 % chez des patients avec antécédents de dysfonctions thrombotiques de leurs hémocathéters a été testée dans cette étude multicentrique randomisée contrôlée en double aveugle. Les patients de 8 centres de dialyse en Belgique ayant présenté au minimum 2 dysfonctions thrombotiques de leurs hémocathéters dans les 6 mois précédant l’inclusion et consentants à participer furent randomisés en double aveugle en 2 groupes : le groupe recevant le verrou fibrinolytique une fois par semaine (et un verrou standard de taurolidine, citrate et héparine lors des deux autres sessions d’hémodialyse) et le groupe contrôle recevant une poudre placebo une fois par semaine diluée dans le verrou standard de taurolidine (administré après chaque hémodialyse). Les ampoules contenant la poudre d’urokinase et le placebo étaient indistinguables l’une de l’autre. Chaque patient était suivi pendant 6 mois après la randomisation. Le premier objectif était de comparer l’incidence de dysfonctions thrombotiques définies par le recours à de l’urokinase (instillée dans la lumière de l’hémocathéter) dans les 2 groupes. Le second objectif était de comparer le nombre d’échecs de fibrinolyse locale par urokinase menant au retrait du cathéter ou à la fibrinolyse systémique. Soixante-huit patients ont été randomisés (32 dans le groupe contrôle et 36 dans le groupe recevant le verrou fibrinolytique prophylactique) et suivis pendant 9821 cathéter jours. Quinze sur trente-six patients (42 %) du groupe recevant le verrou fibrinolytique a nécessité au minimum d’une administration thérapeutique d’urokinase contre 23/32 (72 %) dans le groupe contrôle (p = 0,012). Au total, 24 administrations d’urokinase (incidence de thromboses 4,8/1000 cathéter jours) ont été relevées dans le groupe bénéficiant du verrou fibrinolytique prophylactique comparé à 59 (incidence de thromboses 12,3/10 000 cathéter jours) dans le groupe contrôle (Rate ratio 0,39 ; IC 95 % 0,23 à 0,63 ; p < 0,0001). Il n’y avait pas de différence statistiquement significative dans le nombre de dysfonctions thrombotiques réfractaires dans les 2 groupes. Aucune complication hémorragique ne fut observée durant l’étude. L’utilisation prophylactique d’un verrou à base d’urokinase une fois par semaine permet de réduire de manière significative et sûre le recours thérapeutique à de l’urokinase dans une population à risque de patients hémodialysés mais ne permet pas de réduire la survenue de complications thrombotiques plus sévères responsables de la perte du cathéter.

La glomérulonéphrite extramembraneuse (GEM) idiopathique se caractérise par la présence d’anticorps (Ac) anti-PLA2R dans le sérum dans ± 70 % des cas. En immunofluorescence (IF), une fixation granulaire et diffuse d’IgG et C3 le long des membranes basales glomérulaires est classique. Un immunomarquage positif avec toutes les classes des Ig (pattern « full house ») peut être retrouvé et erronément interprété. Nous présentons une série de 3 cas de syndrome néphrotique floride dont le diagnostic histologique de GEM lupique a été proposé sur base de ce pattern. En absence de tout tableau clinicobiologique évocateur de lupus, la présence d’Ac anti-PLA2R a rectifié le diagnostic. Le Tableau 1 reprend les principales caractéristiques des patients. Un pattern « full house » à l’IF peut erronément conduire à un diagnostic de GEM lupique. La recherche d’Ac anti-PLA2R sur sérum et l’expression des PLA2Recepteurs sur tissu rénal permettent d’orienter le diagnostic vers une GEM idiopathique. À notre connaissance, un seul cas de GEM idiopathique associant Ac anti-PLA2R et pattern « full house » à l’IF a été décrit. La recherche et la description d’une telle association est utile au diagnostic et permet d’affiner au mieux le traitement immunosuppresseur. Dans notre expérience, le développement d’un lupus n’a pas été observé et le pronostic rénal est médiocre. La positivité des Ac anti-PLA2R dans une GEM avec pattern « full house » à l’IF confirme le diagnostic de GEM idiopathique.

Introduction The prophylactic use of recombinant tissue plasminogen activator once weekly reduces the incidence rate of tunneled cuffed catheter (TCC) malfunction and bacteremia as compared to the exclusive use of heparin as locking solution. Restricting the use of prophylactic thrombolytic agents to patients with a history of thrombotic TCC malfunction could be more cost effective. We conduct a multicenter, double-blind, randomized controlled trial and test the hypothesis that weekly use of urokinase lock will reduce the incidence of thrombotic malfunction by 50% in prevalent hemodialysis patients with a history of thrombotic malfunction. Methods Patients with a history of at least two separate TCC thrombotic dysfunctions treated with urokinase lock during the 6 months preceding inclusion are recruited in eight Belgian dialysis units. Patients are randomized in two groups: the control group receiving Taurolock™-HEP500 (heparin 500 IU/mL, taurolidine, citrate 4%) after each hemodialysis session and the treatment group receiving Taurolock-U 25,000 (urokinase 25,000, taurolidine, citrate 4%) once a week and the standard Taurolock-HEP500 at the end of the two others sessions. The primary outcome is the incidence rate of TCC thrombotic dysfunction defined by the use of urokinase. The secondary outcomes are the incidence rate of TCC removal and systemic thrombolysis. For the study, both patients and healthcare staff are blinded to treatment allocation. Conclusions The present trial is the first to investigate the effect of Taurolock-U 25,000 catheter lock once a week as secondary prevention in hemodialysis patients with the highest risk of TCC-related thrombotic dysfunction. Trial Registration ClinicalTrials.gov Identifier: NCT02036255