ANCA-Negative Pauci-immune Necrotizing Glomerulonephritis: A Case Series and a New Clinical Classification

Rationale & ObjectivePauci-immune necrotizing glomerulonephritis (PING) is usually associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). However, a minority (2%-3%) of patients with PING do not have detectable ANCA. We assessed the clinical spectrum and outcome of patients with ANCA-negative PING.Study DesignCase series.Setting & Participants74 patients with ANCA-negative PING diagnosed in 19 French nephrology centers between August 2006 and December 2018 were included in the series. Patients' medical files were reviewed, and kidney biopsies were centrally reexamined by pathologists who were masked to the diagnosis.FindingsMedian age at diagnosis was 69 (IQR, 61-76) years. The clinical and pathological features were remarkable for a high frequency of extrarenal manifestations (54%), nephrotic syndrome (32%), and endocapillary hypercellularity (31%). Three main subtypes of ANCA-negative PING were observed: infection-associated (n = 9 [12%]), malignancy-associated (n = 6 [8%]), and primary (n = 57 [77%]). For patients with primary PING, induction treatment included mainly corticosteroids (n = 56 [98%]), cyclophosphamide (n = 37 [65%]), and rituximab (n = 5 [9%]). Maintenance treatment consisted mainly of corticosteroids (n = 42 [74%]), azathioprine (n = 18 [32%]), and mycophenolate mofetil (n = 11 [19%]). After a median follow-up period of 28 months, 28 (38%) patients had died and 20 (27%) developed kidney failure (estimated glomerular filtration rate < 15 mL/min/1.73 m2). Eleven (21%) patients (9 with primary and 2 with malignancy-associated PING) relapsed.LimitationsRetrospective study and limited number of patients; electron microscopy was not performed to confirm the absence of glomerular immune deposits.ConclusionsWithin the spectrum of ANCA-negative PING, infection and malignancy-associated forms represent a distinct clinical subset. This new clinical classification may inform the management of ANCA-negative PING, which remains a severe form of vasculitis with high morbidity and mortality rates despite immunosuppressive treatments. Pauci-immune necrotizing glomerulonephritis (PING) is usually associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). However, a minority (2%-3%) of patients with PING do not have detectable ANCA. We assessed the clinical spectrum and outcome of patients with ANCA-negative PING. Case series. 74 patients with ANCA-negative PING diagnosed in 19 French nephrology centers between August 2006 and December 2018 were included in the series. Patients' medical files were reviewed, and kidney biopsies were centrally reexamined by pathologists who were masked to the diagnosis. Median age at diagnosis was 69 (IQR, 61-76) years. The clinical and pathological features were remarkable for a high frequency of extrarenal manifestations (54%), nephrotic syndrome (32%), and endocapillary hypercellularity (31%). Three main subtypes of ANCA-negative PING were observed: infection-associated (n = 9 [12%]), malignancy-associated (n = 6 [8%]), and primary (n = 57 [77%]). For patients with primary PING, induction treatment included mainly corticosteroids (n = 56 [98%]), cyclophosphamide (n = 37 [65%]), and rituximab (n = 5 [9%]). Maintenance treatment consisted mainly of corticosteroids (n = 42 [74%]), azathioprine (n = 18 [32%]), and mycophenolate mofetil (n = 11 [19%]). After a median follow-up period of 28 months, 28 (38%) patients had died and 20 (27%) developed kidney failure (estimated glomerular filtration rate < 15 mL/min/1.73 m2). Eleven (21%) patients (9 with primary and 2 with malignancy-associated PING) relapsed. Retrospective study and limited number of patients; electron microscopy was not performed to confirm the absence of glomerular immune deposits. Within the spectrum of ANCA-negative PING, infection and malignancy-associated forms represent a distinct clinical subset. This new clinical classification may inform the management of ANCA-negative PING, which remains a severe form of vasculitis with high morbidity and mortality rates despite immunosuppressive treatments.