Complement Components C3 and C4 Indicate Vasculitis Manifestations to Distinct Renal Compartments in ANCA-Associated Glomerulonephritis

Abstract

Background: Acute kidney injury (AKI) is a common and severe complication of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) causing progressive chronic kidney disease (CKD), end-stage renal disease (ESRD) or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN), a common manifestation of glomerular injury in AAV. However, there is growing evidence that activation of the complement pathway contributes to the pathogenesis and progression of AAV. We here aimed to compare glomerular and tubulointerstitial lesions in ANCA GN and extrarenal manifestation of AAV in association with levels of circulating complement components C3c and C4. Methods: Plasma levels of C3c and C4 in a total number of 53 kidney biopsies with ANCA GN were retrospectively included between 2015 and 2020. Glomerular and tubulointerstitial lesions were evaluated according to established scoring systems for ANCA GN and analogous to the Banff classification. Results: We here show that circulating levels of C3c and C4 in ANCA GN were comparable to the majority of other renal pathologies. Furthermore, hypocomplementemia was only detectable in a minor subset of ANCA GN and not correlated with renal or extrarenal AAV manifestations. However, low levels of circulating C3c correlated with AKI severity in ANCA GN independent of systemic disease activity or extrarenal AAV manifestation. By systematic scoring of glomerular and tubulointerstitial lesions, we provide evidence that low levels of circulating C3c and C4 correlated with vasculitis manifestations to distinct renal compartments in ANCA GN. Conclusions: We here expand our current knowledge about distinct complement components in association with vasculitis manifestations to different renal compartments in ANCA GN. While low levels of C4 correlated with glomerulitis, our observation that low levels of circulating complement component C3c is associated with interstitial vasculitis manifestation reflected by intimal arteritis implicates that C3c contributes to tubulointerstitial injury in ANCA GN.

Comparative Histological Subtyping of Immune Cell Infiltrates in MPO-ANCA and PR3-ANCA Glomerulonephritis

“…A total number of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively included between 2015 till 2020; the patient cohort has previously been described (16)(17)(18)(19)(20)(21). While no formal approval was required for the use of routine clinical data, a favorable ethical opinion was granted by the local Ethics committee (no.…”

Comprehensive Analysis of Sex Differences at Disease Manifestation in ANCA-Associated Glomerulonephritis

“…A total of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively included between 2015 and 2020, the patient cohort was previously described (19)(20)(21)(22)(23)(24)(25). While no formal approval was required to use routine clinical data, a favorable ethical opinion was granted by the local Ethics committee (protocol no.…”

“…(15-20.5). The median (IQR) SAPS II at admission was 24(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), and 24/53 (45.3%) of patients required ICU supportive care. There were 44/53 patients (83%) with some extrarenal manifestation of AAV (31 with lung, 9 with sinus, 12 with joint, 4 with ear, 3 with eye, 6 with peripheral nerve, and 9 with skin involvement), and 7/53(13.2%) had alveolar hemorrhage.…”

Low Serum Levels of Complement C3c at Diagnosis Indicate Poor Outcome in Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis

“… 1 We herein share our own experience with regard of low serum levels of complement C3c at diagnosis of ANCA glomerulonephritis. 2 Although only 5 of 38 patients (13.2%) had hypocomplementemia with C3c levels below the normal range (<0.82 g/l), patients who will experience requirement of kidney replacement therapy (13 of 38) or death (1 of 38) had significantly lower C3c levels ( P = 0.0265; Figure 1 a). According to median serum levels of C3c (1.295 g/l), low levels of C3c were associated with worse renal function reflected by median glomerular filtration rate (9.8 vs. 24.1 ml/min, P = 0.0121), higher urinary protein-to-creatinine ratio (1492 vs. 754 mg/g, P = 0.0344), and higher ANCA renal risk score ( Figure 1 b).…”