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Abstract: SA-OR021

Clonal Hematopoiesis in ANCA-Associated Vasculitis

Session Information

  • ANCA It Is
    November 09, 2019 | Location: 207, Walter E. Washington Convention Center
    Abstract Time: 04:30 PM - 04:42 PM

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Weiss, Marlene, Charité Berlin, Germany, Berlin, Germany
  • Rousselle, Anthony, ECRC, Berlin, Germany
  • Bullinger, Lars, Charité University Medicine, Berlin, Germany
  • Eckardt, Kai-Uwe, Charité – Universitätsmedizin Berlin, Berlin, Germany
  • Kettritz, Ralph, Universitatsmedizin Berlin, Berlin, Germany
  • Damm, Frederik, Charité Universitätsmedizin Berlin, Berlin, Germany
  • Schreiber, Adrian, Charite Berlin, Berlin, Germany
Background

Antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides (AAV) are induced by binding of ANCA IgG to myeloid cells and their subsequent activation. Autoantigen expression has been described to be dysregulated on both molecular and protein expression level in AAV patients. Recently, clonal hematopoiesis of indeterminate potential (CHIP), which is defined by the presence of a somatic mutation in the peripheral blood of individuals without evidence of hematologic neoplasms, has been linked with increased risk of hematologic cancer and cardiovascular disease. Here we aimed to characterize CHIP in patients with AAV.

Methods

112 patients with AAV (median age 64, range 18-84) were screened for CHIP using targeted sequencing. mRNA expression of PR3 and MPO in peripheral blood leukocytes was quantified by qPCR, ANCA autoantigen expression and neutrophil reactive oxygen generation were measured by flow-cytometry.

Results

CHIP was discovered in 34 out of 112 AAV patients (in total of 46 somatic mutations), which is a higher prevalence than expected in age-matched healthy controls (30.4% vs. 13.5%, p<0.001). The overall frequency of CHIP increased with age, however, 18.2% of patients <55 years had CHIP. The most frequently mutated genes were DNMT3A (19/46=39.1%), TET2 (7/46=15.2%), and ASXL1 (4/46=8.7%). CHIP was not associated with disease activity, ANCA subtype, or therapy. No differences in blood counts, creatinine levels, comorbidities, the development of malignancies, disease activity status, and AAV relapse risk were observed. However, disease manifestation patterns differed: CHIPpositive GPA patients showed less renal (68.2% vs. 88.5%, p=0.049) and nervous system involvements (0% vs. 19.2%, p=0.028). Longitudinal analysis of 23 CHIP clones in 19 selected patients revealed that more than 25% of patients showed an increase in clone size over time. Finally, a downregulation of both PR3 and MPO mRNA in peripheral blood leukocytes and significant less ROS production after ANCA IgG stimulation of neutrophils from CHIPpositive AAV patients compared to CHIPnegative patients (stimulation-index aMPO 7.8±5.4 vs. 15.5±9.3 and aPR3 6.8±3.1 vs. 13.2±7.7) was found.

Conclusion

Our findings provide novel experimental evidence of CHIP in AAV patients. Additionally, we found a functional impact of CHIP on ANCA-related neutrophil functions.