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Abstract: FR-PO828

Antibodies to Plasminogen and a Pathogenic Myeloperoxidase (MPO) Epitope Precede MPO- and Proteinase 3-ANCA in Patients with ANCA Vasculitis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Mendoza, Carmen E., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Bunch, Donna O., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Kennedy, Kristin Brock, UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Hogan, Susan L., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Hu, Yichun, UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Little, Dustin J., AstraZeneca, Gaithersburg, Maryland, United States
  • Poulton, Caroline J., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Henderson, Candace Dione, UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Jennette, J. Charles, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Falk, Ronald J., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Olson, Stephen W., Walter Reed National Military Medical Center, Bethesda, Maryland, United States
Background

The preclinical immunopathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis has not been elucidated. Antibodies to plasminogen (anti-PLG) and a specific epitope of myeloperoxidase (MPO447-459, anti-KIV) are associated with active disease. The presence of these antibodies has not been examined prior to diagnosis. We hypothesized that anti-PLG and anti-KIV precede detectable MPO-ANCA and proteinase 3 (PR3)-ANCA.

Methods

Up to 4 serum samples collected before clinical diagnosis were available from 64 patients with ANCA vasculitis (50 PR3, 12 MPO, 2 unknown) and 63 healthy controls (HC) matched for age, gender, ethnicity, and timing of sample through the Department of Defense Biorepository. Anti-PLG, anti-KIV, MPO- and PR3-ANCA were measured by ELISA. Analyses accounted for matched pairs using McNemar tests and odds ratios and 95% confidence intervals from stratified exact conditional logistic regression.

Results

Anti-PLG was detected in 17/64 (27%) of cases prior to diagnosis (median = -8.8 years [IQR -13.1, -2.0]). Anti-PLG was positive before ANCA in 76% (13/17) of cases where both were positive.

Anti-KIV was detected in 21/64 (33%) of cases prior to diagnosis (-6.6 years [-15.0, -4.1]), was elevated before ANCA in 71% (15/21) cases, and elevated when MPO-ANCA was negative in 33% (4/12) of MPO-ANCA patients.

ANCA patients were more likely to have elevated anti-PLG and anti-KIV than matched controls (Table). Limiting analysis to PR3-ANCA patients, the odds ratio for anti-PLG remained statistically significant; the odds ratio for anti-KIV was the same albeit not statistically significant.

Conclusion

Anti-KIV and anti-PLG antibodies are present years before diagnosis and prediagnostic ANCA seropositivity. Thus, anti-KIV and anti-PLG may participate in the initial genesis of the ANCA autoimmune response and be part of a multi-hit immunopathogenic mechanism.

The views expressed are those of the author and do not reflect the official policy of the Department of Army, Department of Defense, or U.S. Government.

Paired GroupVariablesExact odds ratio (CI)P
All ANCA with matched-pair controls (n=63)Anti-PLG6.5 (1.47,59.33)0.007
Anti-KIV3.0 (1.14,9.23)0.023
Limited to PR3-ANCA with matched-pair controls (n=50)Anti-PLG5.0 (1.07,46.93)0.039
Anti-KIV3.0 (0.91,12.76)0.077

Funding

  • NIDDK Support