Morphofunctional Effects of C5 Convertase Blockade in Immune Complex-Mediated Membranoproliferative Glomerulonephritis: Report of Two Cases with Evidence of Terminal Complement Activation.

Abstract

A membranoproliferative pattern of glomerular injury is frequently observed in patients with complement-mediated disorders, such as C3 glomerulopathies (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). The outcomes of C3G and -IC-MPGN are poor, independently of immunosuppressive therapy. However, two 48-week treatment periods with the anti-C5 monoclonal antibody eculizumab, divided by a -12-week washout period, achieved remission of proteinuria and stabilization/improvement of the glomerular filtration rate (GFR), measured through iohexol plasma clearance, in 3 of 10 patients with biopsy-proven MPGN, nephrotic syndrome and terminal complement complex sC5b-9 plasma levels >1,000 mg/mL, at inclusion. Baseline and end-of-study kidney biopsies were available for 2 patients with IC-MPGN, and their baseline characteristics were similar. However, in 1 patient proteinuria and GFR did not improve during the study, whereas in the other proteinuria decreased from 4.84 to 2.12 g/24-h and GFR increased from 91.5 to 142.7 mL/min/1.73 m2. Glomerular inflammation improved and median (interquartile range) glomerular staining for C5b-9 decreased in both cases: from 23.6 to 18.2% (p = 0.021) in the patient who achieved remission and from 15.8 to 10.7% (p = 0.019) in the patient with persistent proteinuria. Chronic glomerular lesions progressed and C3 glomerular staining and electron-dense deposits did not change appreciably in either case. However, in the patient who achieved remission, ultrastructural evaluation revealed features of glomerular microangiopathy at inclusion, which fully recovered posttreatment. Podocyte foot process effacement was observed in both patients at inclusion, but recovered only in the patient with microangiopathy. Thus, in 2 patients with -IC-MPGN, chronic glomerular changes progressed despite eculizumab-induced amelioration of glomerular inflammation and inhibition of sC5b-9 deposition, and independently of treatment effects on proteinuria and podocytes. The finding that the regression of microangiopathic changes was associated with improved clinical outcomes suggests that C5 blockade might have a therapeutic role in patients with IC-MPGN displaying microangiopathic endothelial injury.

• Authors: Camillo Carrara, Manuel Alfredo Podestà, Mauro Abbate, Paola Rizzo, Rossella Piras, Marta Alberti, Erica Daina, Piero Ruggenenti, Giuseppe Remuzzi, on behalf of the EAGLE Study Group
• Journal: Nephron (Nephron) Vol. 144 Issue 4 Pg. 195-203 ( 2020) ISSN: 2235-3186 [Electronic] Switzerland
• PMID: 32050203 (Publication Type: Case Reports, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 S. Karger AG, Basel.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antigen-Antibody Complex
• Complement Membrane Attack Complex
• eculizumab
• Complement C3-C5 Convertases

Topics

• Adolescent
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antigen-Antibody Complex (immunology)
• Complement Activation
• Complement C3-C5 Convertases (analysis, antagonists & inhibitors)
• Complement Membrane Attack Complex (immunology)
• Female
• Glomerular Filtration Rate
• Glomerulonephritis, Membranoproliferative (drug therapy, immunology, pathology)
• Humans
• Male