Reappraisal of Renal Arteritis in ANCA-associated Vasculitis: Clinical Characteristics, Pathology, and Outcome.

BACKGROUND: Renal involvement in ANCA-associated vasculitis (AAV) is associated with poor outcomes. The clinical significance of arteritis of the small kidney arteries has not been evaluated in detail. METHODS: In a multicenter cohort of patients with AAV and renal involvement, we sought to describe the clinicopathologic characteristics of patients with AAV who had renal arteritis at diagnosis, and to retrospectively analyze their prognostic value. RESULTS: We included 251 patients diagnosed with AAV and renal involvement between 2000 and 2019, including 34 patients (13.5%) with arteritis. Patients with AAV-associated arteritis were older, and had a more pronounced inflammatory syndrome compared with patients without arteritis; they also had significantly lower renal survival (P=0.01). In multivariable analysis, the ANCA renal risk score, age at diagnosis, history of diabetes mellitus, and arteritis on index kidney biopsy were independently associated with ESKD. The addition of the arteritis status significantly improved the discrimination of the ANCA renal risk score, with a concordance index (C-index) of 0.77 for the ANCA renal risk score alone, versus a C-index of 0.80 for the ANCA renal risk score plus arteritis status (P=0.008); ESKD-free survival was significantly worse for patients with an arteritis involving small arteries who were classified as having low or moderate risk, according to the ANCA renal risk score. In two external validation cohorts, we confirmed the incidence and phenotype of this AAV subtype. CONCLUSIONS: Our findings suggest AAV with renal arteritis represents a different subtype of AAV with specific clinical and histologic characteristics. The prognostic contribution of the arteritis status remains to be prospectively confirmed.

Developments in the Histopathological Classification of ANCA-Associated Glomerulonephritis.

BACKGROUND AND OBJECTIVES: The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes were ordered by severity of kidney function loss as follows: focal, crescentic, mixed, and sclerotic. Subsequent validation studies disagreed on outcomes in the crescentic and mixed classes. This study, driven by the original investigators, provides several analyses in order to determine the current position of the histopathologic classification of ANCA-associated GN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A validation study was performed with newly collected data from 145 patients from ten centers worldwide, including an analysis of interobserver agreement on the histopathologic evaluation of the kidney biopsies. This study also included a meta-analysis on previous validation studies and a validation of the recently proposed ANCA kidney risk score. RESULTS: The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes (P<0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class (P=0.98). In the meta-analysis, no significant difference in kidney failure was also observed when crescentic class was compared with mixed class (relative risk, 1.15; 95% confidence interval, 0.94 to 1.41). When we applied the ANCA kidney risk score to our cohort, kidney survival at 3 years was 100%, 96%, and 77% in the low-, medium-, and high-risk groups, respectively (P<0.001). These survival percentages are higher compared with the percentages in the original study. CONCLUSIONS: The crescentic and mixed classes seem to have a similar prognosis, also after adjusting for differences in patient populations, treatment, and interobserver agreement. However, at this stage, we are not inclined to merge the crescentic and mixed classes because the reported confidence intervals do not exclude important differences in prognosis and because an important histopathologic distinction would be lost.

Renal relapse in antineutrophil cytoplasmic autoantibody-associated vasculitis: unpredictable, but predictive of renal outcome.

Objectives: To determine predictors of renal relapse and end-stage renal failure (ESRF) in patients with ANCA-associated vasculitis. Methods: Data from four European Vasculitis Society randomized controlled trials, conducted roughly simultaneously between 15 March 1995 and 30 September 2002, was pooled to determine predictors of long-term renal outcome. The respective trial inclusion criteria covered the entire spectrum of disease severity. Baseline predictors of time to first renal relapse and time to ESRF were assessed by competing events analysis and Cox proportional hazards regression. The effect of renal relapse on time to ESRF was assessed by adding renal relapses to the competing events analysis as a time-varying covariate. Results: The number of patients participating was 535; mean serum creatinine (±s.d.) at entry was 341 ± 321 µmol/l and 19.7% developed ESRF. One or more renal relapse(s) was experienced by 101 patients. Multivariable regression analysis demonstrated that, in addition to impaired baseline renal function, developing ⩾1 renal relapse was an independent risk factor for ESRF (subhazard ratio 9; 95% CI 4, 19; P < 0.001). No predictive factors for renal relapse were found. Conclusion: In addition to baseline renal function, the occurrence of renal relapses is an important determinant of ESRF in patients with ANCA-associated vasculitis. We did not find any clinical predictors for renal relapse itself, including disease activity elsewhere. In light of the silent nature of renal relapse in ANCA-associated vasculitis, we stress the need for long-term vigilant monitoring for early signs of renal relapse and propose performing 3-monthly urinalysis. This will enable timely treatment and help further improve renal outcome.

The role of complement in antineutrophil cytoplasmic antibody-associated vasculitis.

PURPOSE OF REVIEW: To provide a comprehensive overview of the current insight into the role of complement activation in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). In addition, the therapeutic options targeting the complement system in AAV are discussed. RECENT FINDINGS: It has become increasingly clear that complement, and more specifically signalling through the C5a receptor, contributes to the immunopathology of AAV. This has led to the design of clinical trials with a C5a receptor blocker. The first results show a reduction in tissue damage and a favourable safety profile, as other parts of the complement defence system are left intact. SUMMARY: Although AAV was initially regarded as a pauci-immune disease, it is now well established that, in addition to autoantibodies, complement plays an essential role in the disease process. Animal models delivered the first insight, but the effective therapeutic interventions using complement inhibitors provided the proof that indeed complement activation contributes to disease activity and tissue damage in human AAV.

Investigations in systemic vasculitis - The role of renal pathology.

ANCA-associated vasculitis (AAV) describes a group of small-vessel vasculitides with frequent renal involvement. The first description of these conditions can be traced back to the 19th-century paper on necrotizing vasculitis by Kussmaul and Maier. Since then, our understanding of the pathogenesis has improved and the histopathological lesions have been described in detail. Characteristic histologic lesions in ANCA-associated glomerulonephritis (AAGN) are fibrinoid necrosis and crescents, often accompanied by tubulointerstitial inflammation. The discovery of ANCAs has not rendered renal biopsies obsolete in the diagnostic process. Currently, renal biopsies remain the gold standard for the diagnosis of AAV in conjunction with ANCA serology. In addition to diagnosis, renal biopsies are useful for patient prognosis. The evaluation of renal histological samples from patients with new-onset AAV who participated in clinical trials led to the proposal of the histopathological classification for AAGN. The prognostic value of this classification continues to be validated and an update is expected soon.

Antineutrophil cytoplasmic antibody-associated vasculitis and malignancy.

PURPOSE OF REVIEW: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have an increased malignancy risk compared with the general population. This review aims to evaluate recent evidence for changes in the incidence of malignancy in patients with AAV and to examine explanations for the association between AAV and malignancy. RECENT FINDINGS: The overall malignancy risk in patients with AAV has decreased, most likely as a result of recent changes in therapeutic regimen, that is, a decrease in the exposure to cyclophosphamide. The risk of nonmelanoma skin cancer (NMSC), however, remains increased, which is probably attributable to treatment with azathioprine. Malignancy risk in patients with AAV treated with rituximab was found to be lower than in cyclophosphamide-treated patients. The incidence of malignancy prior to AAV is not increased compared with the general population. SUMMARY: Continuing efforts to reduce the exposure to cyclophosphamide have led to a decrease in malignancy risk in patients with AAV, except for NMSC. Rituximab could be a well tolerated alternative for cyclophosphamide regarding the development of malignancies.