Anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCAnegative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.

We identified significant changes in relative renal biopsy frequencies of many glomerular disease subtypes over three decades. Temporal trends were consistently observed within all major demographic groups, although relative predominance of individual glomerular disease subtypes differed according to patient age, sex, and race. We propose that exploration of behavioral and environmental exposures that likely underlie these findings should be the focus of future hypothesis-driven research.

Background and objectives In ANCA-associated GN, severe renal dysfunction portends a poor prognosis for renal recovery and patient survival. This study evaluated the prognostic factors affecting renal and patient outcomes in patients presenting with severe kidney failure to guide immunosuppressive therapy.Design, setting, participants, & measurements This study retrospectively evaluated clinical and histopathologic characteristics of 155 patients who underwent biopsy between October 1985 and February 2011 (median eGFR at presentation, 7.1 ml/min per 1.73 m 2 ; 87% required hemodialysis), all treated with immunosuppressive medications. Three outcomes of interest were measured: patient survival, renal survival, and treatment response (defined as dialysis-free survival without active vasculitis by 4 months after biopsy). Competing risk, Cox, and logistic regression analyses were conducted for each outcome measure.Results Within 4 months after biopsy, treatment response was attained in 51% of patients, 35% remained on dialysis, and 14% died. In a competing risk analysis, estimated cumulative incidence rates of ESRD and diseaserelated mortality were 26% and 17% at 1 year and 32% and 28% at 5 years, respectively. Cyclophosphamide therapy and treatment response by 4 months were independently associated with patient and renal survival, adjusting for the percentage of normal glomeruli, histopathologic chronicity index score, and baseline clinical characteristics. Only 5% of patients still dialysis dependent at 4 months subsequently recovered renal function. Low chronicity index score (odds ratio [OR], 1.16; 95% confidence interval [95% CI], 1.04 to 1.30, per unit decrease) and baseline eGFR.10 ml/min per 1.73 m 2 (OR, 2.77; 95% CI, 1.09 to 7.01) were significantly associated with treatment response by 4 months. Among cyclophosphamide-treated patients, the likelihood of treatment response was .14% even with highest chronicity index score and eGFR,10 ml/min per 1.73 m 2 .Conclusions Although low baseline renal function and severe renal scarring are associated with lower treatment response rate, no "futility" threshold could be identified. Conversely, continued immunosuppressive therapy beyond 4 months is unlikely to benefit patients who remain dialysis dependent.Clin J Am Soc Nephrol 9: 905-913, 2014.

Objective How advances in the management of ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis (AAV) have impacted long-term outcomes is still unclear. We examined temporal changes over 25 years in long-term clinical outcomes, including the impact of renal function at diagnosis (a potential marker of time to disease detection) and duration of cyclophosphamide use in AAV patients with renal involvement. Methods ANCA-positive, biopsy-proven patients with AAV diagnosed in 1985–2009 followed in the Glomerular Disease Collaborative Network inception cohort were included. Outcomes included the composite outcome of end-stage renal disease (ESRD) or death as well as relapse. Cox proportional hazard or competing risk regression models were adjusted for potential baseline confounders. Results Data from 544 patients were included in the analysis. There was a decreasing 5-year risk of ESRD or death over time (log rank test for trend: p < 0.001). After adjustment for baseline characteristics, the risk of relapse was similar across the time periods (test for trend: p = 0.45). Serum creatinine at baseline was the only significant predictor of an increased risk of ESRD or death (HR 1.11 per 1 mg/dL of serum creatinine [95% CI 1.04–1.18], p = 0.002). Conclusion In patients with renal disease secondary to AAV, over 25 years the risk of ESRD or death has decreased but the risk of relapse has not changed. A higher serum creatinine at diagnosis is associated with a higher risk of ESRD or death, suggesting that earlier disease detection is potentially an important measure to improve outcomes in AAV.

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_11_21_CJASNPodcast_18_1_v.mp3.