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Abstract Background True population-based clinical and outcomes data are lacking for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAGN). Therefore we aimed to estimate the incidence, prevalence and mortality of AAGN, as well as the relationship between the grade of chronic renal damage at presentation and renal and non-renal outcomes. Methods Patients with AAGN were identified among a population-based incident cohort of 57 Olmsted County residents diagnosed with ANCA-associated vasculitis (AAV) in 1996–2015. Incidence rates were age and sex adjusted to the 2010 US white population. Age- and sex-adjusted prevalence was calculated for 1 January 2015. Survival rates were compared with expected rates in the Minnesota population. Chronic renal damage was assessed by chronicity score (CS) on biopsies performed at diagnosis. Results Thirty-four (60%) patients had AAGN. Of these, 65% had microscopic polyangiitis (MPA) and 74% were myeloperoxidase (MPO)-ANCA positive. The annual incidence of AAGN was 2.0/100 000 population [95% confidence interval (CI) 1.3–2.7] and the overall prevalence was 35/100 000 (95% CI 24–47). Mortality for AAGN was increased (P < 0.001), whereas mortality for AAV without glomerulonephritis did not differ from the general population. Minimal to mild CS predicted recovery of renal function at 1 year; clinical diagnosis (granulomatosis with polyangiitis versus MPA) and ANCA specificity (proteinase 3 versus MPO) did not. This observation was replicated in an independent cohort of 38 newly diagnosed AAGN patients seen at our centre over the 1999–2014 period. Conclusions The annual incidence and prevalence of AAGN in Minnesota are 2.0/100 000 and 35/100 000, respectively. Mortality is worse compared with AAV patients without glomerulonephritis. More advanced renal damage at diagnosis predicts less renal recovery.

FSGS describes a renal histologic lesion with diverse causes and pathogenicities that are linked by podocyte injury and depletion. Subclasses of FSGS include primary, genetic, and secondary forms, the latter comprising maladaptive, viral, and drug-induced FSGS. Despite sharing certain clinical and histologic features, these subclasses differ noticeably in management and prognosis. Without an accepted nongenetic biomarker that discriminates among these FSGS types, classification of patients is often challenging. This review summarizes the clinical and histologic features, including the onset and severity of proteinuria as well as the presence of nephrotic syndrome, that may aid in identifying the specific FSGS subtype. The FSGS lesion is characterized by segmental sclerosis and must be differentiated from nonspecific focal global glomerulosclerosis. No light microscopic features are pathognomonic for a particular FSGS subcategory. The characteristics of podocyte foot process effacement on electron microscopy, while helpful in discriminating between primary and maladaptive FSGS, may be of little utility in detecting genetic forms of FSGS. When FSGS cannot be classified by clinicopathologic assessment, genetic analysis should be offered. Next generation DNA sequencing enables cost-effective screening of multiple genes simultaneously, but determining the pathogenicity of a detected genetic variant may be challenging. A more systematic evaluation of patients, as suggested herein, will likely improve therapeutic outcomes and the design of future trials in FSGS.

Summary Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3–ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.

IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody–producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy–proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin–converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR<90 ml/min per 1.73 m 2 , to receive standard therapy or rituximab with standard therapy. Primary outcome measures included change in proteinuria and change in eGFR. Median baseline serum creatinine level (range) was 1.4 (0.8–2.4) mg/dl, and proteinuria was 2.1 (0.6–5.3) g/d. Treatment with rituximab depleted B cells and was well tolerated. eGFR did not change in either group. Rituximab did not alter the level of proteinuria compared with that at baseline or in the control group; three patients in each group had ≥50% reduction in level of proteinuria. Serum levels of galactose-deficient IgA1 or antibodies against galactose-deficient IgA1 did not change. In this trial, rituximab therapy did not significantly improve renal function or proteinuria assessed over 1 year. Although rituximab effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 and antigalactose–deficient IgA1 antibodies. Lack of efficacy of rituximab, at least at this stage and severity of IgA nephropathy, may reflect a failure of rituximab to reduce levels of specific antibodies assigned salient pathogenetic roles in IgA nephropathy.

Primary membranous nephropathy (MN) is an autoimmune disease mainly caused by autoantibodies against the recently discovered podocyte antigens: the M-type phospholipase A2 receptor 1 (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A). Assays for quantitative assessment of anti-PLA2R antibodies are commercially available, but a semiquantitative test to detect anti-THSD7A antibodies has been only recently developed. The presence or absence of anti-PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN. Levels of anti-PLA2R antibodies and possibly, anti-THSD7A antibodies tightly correlate with disease activity. Low baseline and decreasing anti-PLA2R antibody levels strongly predict spontaneous remission, thus favoring conservative therapy. Conversely, high baseline or increasing anti-PLA2R antibody levels associate with nephrotic syndrome and progressive loss of kidney function, thereby encouraging prompt initiation of immunosuppressive therapy. Serum anti-PLA2R antibody profiles reliably predict response to therapy, and levels at completion of therapy may forecast long-term outcome. Re-emergence of or increase in antibody titers precedes a clinical relapse. Persistence or reappearance of anti-PLA2R antibodies after kidney transplant predicts development of recurrent disease. We propose that an individualized serology-based approach to MN, used to complement and refine the traditional proteinuria-driven approach, will improve the outcome in this disease.