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Kidney Week

Abstract: TH-PO573

A Vexing Case

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Dave, Dhara, Yale School of Medicine, New Haven, Connecticut, United States
  • Malvar, Grace Landayan, Yale School of Medicine, New Haven, Connecticut, United States
  • Moeckel, Gilbert W., Yale School of Medicine, New Haven, Connecticut, United States
  • Shirali, Anushree C., Yale School of Medicine, New Haven, Connecticut, United States
Introduction

In 2020, somatic mutations in UBA1, an X-linked gene that encodes enzyme E1 necessary for ubiquitination, were described in patients with an adult-onset inflammatory syndrome called VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, and Somatic). It has diverse systemic presentations and kidney manifestations are not well-characterized. We describe a patient who developed proliferative crescentic glomerulonephritis (GN) with deposits coincident with diagnosis of VEXAS.

Case Description

A 75-year-old male with hypertension and alcohol use disorder was admitted for worsening pancytopenia and acute kidney injury. 2 months prior he reported otitis externa and biopsy-proven atopic dermatitis responsive to steroids. Workup for pancytopenia including prior bone marrow biopsy (BM) was negative. Physical exam: BP 142/88 mmHg, normal heart, lung, abdomen and skin exam. Labs on admission: WBC 5200/μL, Hb 6.9g/dL, Platelets 133000/μL, Cr 1.96 mg/dL (baseline 0.8 mg/dL). Urinalysis: 2+ protein, 3+ blood, pyuria. Urine protein creatinine ratio 3.77. Serologies for complement, cryoglobulins, and ANCA were negative. Kidney biopsy displayed proliferative necrotizing and crescentic GN with subendothelial deposits and lymphoplasmacytic infiltrate. IF staining: 3+ IgM, 3+ IgA, 1+ IgG, 1+ lambda. Review of prior BM biopsy showed cytoplasmic vacuoles in erythroid and myeloid precursors. Genetic screen positive for somatic UBA1c mutation. He was treated with steroids, mycophelonate and tocilizumab with partial response of declining creatinine and proteinuria.

Discussion

Limited data on kidney manifestations in VEXAS include MPO-positive necrotizing and crescentic GN, acute tubulointerstitial nephritis, and isolated interstitial infiltrate with MPO-positive and CD68+ myeloid cells. The present case adds to this data in describing a serology-negative necrotizing and crescentic GN. VEXAS syndrome represents dysregulated immune activation that leads to auto-immune organ injury. The kidney-specific pathological mechanisms of VEXAS syndrome are unknown but proposed theories include: cytokine-mediated tubular injury activating endothelial cells, recruitment of myeloid cells leading to further inflammation, and dysregulated neutrophil extracellular traps. Further research into how VEXAS syndrome involves the kidney is critical to targeted therapies for kidney disease in patients with this multi-system inflammatory syndrome.