An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10(−5) to 10(−3). Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD

Hypereosinophilia in a Home HD Patient

Parallel Session 17: Clinical Case Discussions: Home HD Wednesday, November 29, 2023, 02:00PM-02:20PM, Level 4 ‘Hypereosinophilia in a Home HD Patient’ Inès Dufour Fellow in Nephrology UCLouvain Abstract: We described the case of a 55-year-old woman with kidney failure due to primary focal segmental glomerulosclerosis (FSGS) who received a kidney transplant in 1989. Chronic allograft dysfunction required kidney replacement therapy and the patient was started on home hemodialysis in October 2020. In February 2022, she presented with isolated total macroscopic hematuria for three consecutive days. Urinalysis ruled out urinary tract infection. Computed tomography scan of the abdomen showed uncomplicated kidney allograft atrophy. Cystoscopy and gynecologic examination were normal. In April 2022, routine monthly biology revealed severe hypereosinophilia (peak eosinophil count: 3,33× 109/L (normal, <0.5 × 109/L)), total white blood cells: 12,1 x 109/L (normal, 4-10× 109/L) and systemic inflammation (C-reactive protein: 41 mg/L, normal <5 mg/L). No new medication had recently been introduced. Stool ova and parasite test, and anti-neutrophil cytoplasmic antibody were both negative; and lymphocyte immunophenotyping and IgE concentration were normal. A18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) was performed and showed intense hyperactivity of the kidney allograft cortex. Graft nephrectomy was subsequently performed. Histopathology showed significant interstitial inflammation with lymphocytes and eosinophils infiltration, signs of glomerulitis (g3), peritubular capillaritis (ptc3) and glomerular basement membrane double contours (cg1). The C4d staining was positive in peritubular capillaries. These findings were all consistent with the diagnosis of eosinophil-rich acute antibody mediated rejection (ABMR) on chronic allograft nephropathy. Blood eosinophils count normalized two weeks after surgery. Association between peripheral blood eosinophilia and episodes of graft rejection were initially reported in the 1980s. More recent studies have confirmed those findings, proposing eosinophilia as a biomarker for acute rejection1. Rise of blood eosinophils in early post-transplant months has even been proposed as a hallmark of graft rejection2. Eosinophils are now considered true immunoregulatory cells having some roles in antigen presentation, T-cell regulation, B-cell priming, as well as regulation of dendritic and mast cells, basophils and neutrophils. Eosinophils have been linked to acute allograft rejection induced by Th2-type CD4+ cells, which are effector cells in the alternative pathway implicated in acute rejection3. Cytokines, like IL-5, released by activated T lymphocytes are responsible for the eosinophils recruitment in acute rejection. In experimental mouse heart transplant, acute rejection mediated by Th2 cells was characterized by a marked eosinophils infiltrate in the allograft.In summary, this case reminds that antibody-mediated rejection should be considered in the differential diagnosis of hypereosinophilia in a transplanted patient, even after kidney graft failure and hemodialysis resumption. References: 1. Wang GY, Li H, Liu W, Zhang J, Zhu HB, Wang GS, Zhang Q, Yang Y, Chen GH. Elevated blood eosinophil count is a valuable biomarker for predicting late acute cellular rejection after liver transplantation. Transplant Proc. 2013 Apr;45(3):1198-200. 2. Almirall J, Campistol JM, Sole M, Andreu J, Revert L. Blood and graft eosinophilia as a rejection index in kidney transplant. Nephron. 1993;65(2):304-9. 3. Goldman M, Le Moine A, Braun M, Flamand V, Abramowicz D. A role for eosinophils in transplant rejection. Trends Immunol. 2001 May;22(5):247-51

mTORC Pathway Activation and Effect of Sirolimus on Native Kidney Antiphospholipid Syndrome Nephropathy: A Case Report.

Despite optimal anticoagulation and blood pressure control, patients with antiphospholipid syndrome (APS) nephropathy frequently progress to kidney failure, and recurrence after transplantation is common. The mTORC (mechanistic target of rapamycin complex) pathway was recently identified as a potential intermediate and a therapeutic target in vascular lesions associated with APS nephropathy. However, these results were derived from the retrospective analysis of a small cohort of patients receiving sirolimus after kidney transplantation. Therefore, they warranted external validation and the demonstration of the potential benefit of sirolimus in native kidney APS nephropathy. We report a patient with active APS nephropathy lesions occurring on native kidneys, in which endothelial mTORC activation was substantiated at the molecular level. Treatment with sirolimus was shown on a repeat kidney biopsy to successfully inhibit the AKT/mTORC pathway and was associated with significant improvement in kidney function and lesions of vasculopathy. Drug tolerance was excellent during the entire follow-up. This case validates and extends previous observations in kidney transplant recipients and demonstrates that endothelial activation of the AKT/mTORC pathway occurs in the damaged renal vasculature of native kidneys in APS nephropathy. These findings further support the potential of precision medicine and the use of mTORC activation as a biomarker of disease activity and as therapeutic target in patients with APS nephropathy

Ventral Primary Hernia with Liver Content

Background. Herniation of the liver through the anterior abdominal wall is an extremely rare phenomenon. Most cases occur within an incisional hernia (mostly upper abdomen surgery or cardiac surgery). Only two reports mentioned liver herniation without previous abdominal incision. Case Presentation. We report the case of a 70-year-old woman presenting an epigastric swelling. Radiological findings showed a liver herniation in a primary ventral hernia. This case is the first to have been described requiring semiurgent hernia repair associated with partial liver resection. Conclusion. This case is, to the best of our knowledge, the first case of primary ventral hernia with liver content necessitating wedge resection of the left liver lobe

COVID-19 et maladies du sang

La pandémie liée au SARS-CoV-2, représente un défi sans précédent pour la communauté médicale. Le COVID-19 se révèle potentiellement dévastateur pour les patients âgés ou présentant des comorbidités, et aussi pour ceux atteints de pathologies hématologiques chroniques. Des mesures exceptionnelles ont été mises en place par les centres hospitaliers de manière à éviter la dissémination du virus et garantir à chacun un accès optimal aux soins, en n’impactant pas les chances de guérison de ceux porteurs de pathologies curables. Les sociétés internationales ont émis des lignes de conduites que nous répercutons ici pour les pathologies les plus fréquemment prises en charge dans notre centre, à la lumière de notre expérience.[COVID-19 and blood diseases] The SARS-CoV-2 pandemic poses an unprecedented challenge to the medical community. COVID-19 is potentially devastating for elderly patients, those who have comorbidities, as well as those with chronic hematological conditions. Exceptional measures have been implemented by hospitals to prevent the spread of the virus and ensure optimal access to care for everyone, without jeopardizing the chances of recovery for patients with curable diseases. The hematological societies have issued guidelines that we summarize in this article for the diseases most commonly treated in our center, in the light of our experience