C-Reactive Protein Levels Are Associated with Complement C4 Deposits and Interstitial Arteritis in ANCA-Associated Renal Vasculitis

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis in case of kidney involvement, representing a major denominator of AAV mortality. Innate immunity with complement system activation is increasingly recognized in the pathogenesis of AAV and as an attractive therapeutic target. Although C-reactive protein (CRP) was thought to be a passive, nonspecific marker of inflammation, recent studies indicate that CRP plays a key role in the innate immune system by recognizing pathogens and altered self-determinants. Elevated baseline CRP at disease onset of AAV has already been described as a determinant of poor long-term outcomes. However, its clinical implications at disease onset of AAV, with respect to vasculitis manifestations and complement system activation that might also affect long-term outcomes, remain elusive. CRP levels were retrospectively analyzed in 53 kidney-biopsy-confirmed cases of ANCA-associated renal vasculitis; a total of 138 disease controls were also evaluated. Univariate and multivariate regression analysis was performed on clinicopathological parameters associated with CRP levels in ANCA-associated renal vasculitis. Results: Compared to disease controls, CRP elevation was common in ANCA-associated renal vasculitis and associated with de novo disease (p = 0.0169), critical illness (p = 0.0346), and severe deterioration of kidney function (p = 0.0167), independent of extrarenal disease manifestations. As confirmed by multiple regression analysis, CRP levels were correlated with active lesions predominated by interstitial arteritis in renal vasculitis, specifically with MPO-ANCA seropositivity (p = 0.0017). Based on analysis of systemic complement system activation and intrarenal complement deposits, CRP elevation was correlated specifically with complement C4 deposits in interstitial arteries in the subgroup with myeloperoxidase (MPO)-ANCA seropositivity (p = 0.039). Finally, this association was independent of systemic complement system activation, as reflected by the consumption of respective complement components. Here, we expand our current understanding of CRP in ANCA-associated renal vasculitis not only as an inflammatory marker, but potentially also as being involved in the pathogenesis of kidney injury by interaction with the complement system.

Serum Uric Acid Associates with Systemic Complement C3 Activation in Severe ANCA-Associated Renal Vasculitides

“…We have shown that complement C3 deposition in the glomerular tuft is associated with impaired kidney function in ANCA-associated renal vasculitis [12,40]. Independent of consumption of systemic complement components, CRP levels correlated with active renal lesions and intrarenal C4 deposition in interstitial arteries in MPO-ANCA renal vasculitis [41]. We saw an implication for CRP engaging in intrarenal complement synthesis.…”

“…Nuclear counterstaining was performed using Mayer's Hematoxylin Solution (Sigma, St. Louis, MO, USA). C3c and C4d deposits in the glomerular tuft, interlobular arteries, peritubular capillaries, and venules were evaluated for presence, as recently described [12,41].…”

Clinical Characteristics of EGPA Patients in Comparison to GPA Subgroup with Increased Blood Eosinophilia from POLVAS Registry

“…Interestingly, a similar pattern can be observed in the case of renal manifestations, even though the difference between subsets of GPA is on the border of significance ( p = 0.05). As CRP is not only a nonspecific biomarker of inflammation but also contributes to forming complement C4 deposits, which play a pivotal role in developing renal manifestations [ 38 ], it can partially explain these findings.…”

C-Reactive Protein: Pathophysiology, Diagnosis, False Test Results and a Novel Diagnostic Algorithm for Clinicians

“…The literature data conclude that CRP could be of prognostic value in evaluating Chagas autoimmune myocarditis progression, and cardiac dysfunction and remodeling [ 661 , 662 ]. Despite its diagnostic utility, individuals with giant cell arteritis can show disparate CRP results—and there exist reports with normal values—whereas CRP can be increased in autoimmune thrombocytopenia; systemic vasculitis; leukocytoclastic vasculitis; other IgG4-related vascular diseases; polyarteritis nodosa in which it can predict poor outcomes if complications are present; and Henoch–Schönlein purpura, in which it can act as a possible biomarker for gastrointestinal involvement; and it was also reported as a marker in anti-neutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis with interstitial arteritis [ 663 , 664 , 665 , 666 , 667 ]. CRP has been reported to be elevated in both antineutrophil cytoplasmic antibody-negative and -positive eosinophilic granulomatosis with polyangiitis.…”