Internal medicine

Pathology

Disease

Rituximab

Antibody

Immunology

Anti-neutrophil cytoplasmic antibody

Rapidly progressive glomerulonephritis

Vasculitis

Kidney

Glomerulonephritis

Fibrinoid necrosis

Medicine

Kidney International Reports

We thank you for the opportunity to respond to the letter by Pr Jean-François Augusto. Low serum complement pauci-immune glomerulonephritis (PIGN) is increasingly being recognized as an entity with distinct characteristics, in terms of its clinical picture and response to currently used immunosuppressive regimens.S1,1Brilland B. Wacrenier S. Henry N. et al.Low complement C3 levels at diagnosis of ANCA-associated glomerulonephritis, a specific subset of patients to target with anti-C5aR therapy?.Kidney Int Rep. 2021; 6: 2931-2933Abstract Full Text Full Text PDF Scopus (1) Google Scholar,2Lionaki S. Marinaki S. Liapis G. et al.Hypocomplementemia at diagnosis of pauci-immune glomerulonephritis is associated with advanced histopathological activity index and high probability of treatment resistance.Kidney Int Rep. 2021; 6: 2425-2435Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Patients with low serum complement were shown to have highly active glomerular and tubulointerstitial lesions (i.e., crescents, interstitial leukocyte infiltration, and fibrinoid necrosis in vessel walls).3Hogan S.L. Falk R.J. Chin H. et al.Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis.Ann Intern Med. 2005; 143: 621-631Crossref PubMed Scopus (352) Google Scholar Low complement PIGN was shown to be more frequently resistant to therapy with high-dose glucocorticoids and either cyclophosphamide or rituximab.S1,1Brilland B. Wacrenier S. Henry N. et al.Low complement C3 levels at diagnosis of ANCA-associated glomerulonephritis, a specific subset of patients to target with anti-C5aR therapy?.Kidney Int Rep. 2021; 6: 2931-2933Abstract Full Text Full Text PDF Scopus (1) Google Scholar,2Lionaki S. Marinaki S. Liapis G. et al.Hypocomplementemia at diagnosis of pauci-immune glomerulonephritis is associated with advanced histopathological activity index and high probability of treatment resistance.Kidney Int Rep. 2021; 6: 2425-2435Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar In general, although referring to fewer than one-fourth of patients,3Hogan S.L. Falk R.J. Chin H. et al.Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis.Ann Intern Med. 2005; 143: 621-631Crossref PubMed Scopus (352) Google Scholar treatment resistance remains problematic, as it is associated with end-stage kidney disease and death. Classic risk factors associated with this outcome include advanced age, female gender, black ethnicity, and severe renal disease.4Jayne D.R.W. Merkel P.A. Schall T.J. Bekker P. Avacopan for the treatment of ANCA- associated vasculitis.N Engl J Med. 2021; 384: 599-609Crossref PubMed Scopus (126) Google Scholar However, these dataS1,1Brilland B. Wacrenier S. Henry N. et al.Low complement C3 levels at diagnosis of ANCA-associated glomerulonephritis, a specific subset of patients to target with anti-C5aR therapy?.Kidney Int Rep. 2021; 6: 2931-2933Abstract Full Text Full Text PDF Scopus (1) Google Scholar,2Lionaki S. Marinaki S. Liapis G. et al.Hypocomplementemia at diagnosis of pauci-immune glomerulonephritis is associated with advanced histopathological activity index and high probability of treatment resistance.Kidney Int Rep. 2021; 6: 2425-2435Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar clearly suggest that hypocomplementemia per se defines a noteworthy subset of patients with a high probability for nonresponsiveness to immunosuppressive treatment. Clinically, this is important from 3 aspects: first, it would be reasonable to know what proportion of those patients who experience treatment resistance overall correspond to patients with hypocomplementemia at diagnosis; second, as the renal lesions are highly active in low serum C3 PIGN, one might postulate that they represent relatively new and theoretically reversible kidney injury if appropriate therapy is given; and third, the fact is that standard of care is not effective in this particular setting. Therefore, additional and/or targeted therapeutic intervention(s) are required to regulate the complement system and avoid organ or life-threatening disease. Glucocorticoids, the traditional nonselective anticomplement medication and the targeted antagonist of C5a receptor, avacopan, are both able to restrain complement. The anaphylatoxin C5a, produced by the final complement pathway, is determinant to drive the disease in animal models. The potential of avacopan to reduce the need of glucocorticoids was demonstrated in the CLEAR study,4Jayne D.R.W. Merkel P.A. Schall T.J. Bekker P. Avacopan for the treatment of ANCA- associated vasculitis.N Engl J Med. 2021; 384: 599-609Crossref PubMed Scopus (126) Google Scholar and the CLASSIC trialS2 provided a positive assessment regarding safety and tolerability, when administered in addition to the standard therapy. Hence, avacopan seems likely to play a principal role in the management of patients with low serum C3 PIGN, but it remains to be elucidated if it should be given as an add-on therapy or as a substitute to glucocorticoids, initially or subsequently, or in both occasions and indefinitely. Download .docx (.02 MB) Help with docx files Supplementary File (Word) Supplementary References Low Complement C3 Levels at Diagnosis of ANCA-Associated Glomerulonephritis, a Specific Subset of Patients to Target With Anti-C5aR Therapy?: In response to: Hypocomplementemia at Diagnosis of Pauci-immune Glomerulonephritis Is Associated with Advanced Histopathological Activity Index and High Probability of Treatment Resistance (Lionaki ., , June 2021, DOI: 10.1016/j.ekir.2021.05.043)Kidney International ReportsVol. 6Issue 11PreviewAvacopan, an anti-C5aR, recently showed comparable efficacy to corticosteroid therapy in antineutrophil cytoplasmic antibodies-associated vasculitis (AAV). Patients who would benefit most from this treatment are not yet well defined. Thus, complement-based prognostic biomarkers could be used for guiding therapy and improving outcomes. We therefore read with much interest the study by Lionaki et al.1 regarding the value of low serum C3 as an independent predictor of poor prognosis in patients with pauci-immune glomerulonephritis (ANCA-GN). Full-Text PDF Open Access

Low Serum C3 Pauci-Immune Glomerulonephritis: High Histopathological Activity and Lower Rates of Response to Standard Therapies