B cell-mediated pathogenesis of ANCA-mediated vasculitis

B cells and their progeny that produce and release anti-neutrophil cytoplasmic autoantibodies (ANCA) are the primary cause for an aggressive form of necrotizing small vessel vasculitis. Cytoplasmic ANCA antigens are released at the surface and in the microenvironment of cytokine-primed neutrophils. Binding of ANCA to ANCA antigens activates neutrophils by both Fc receptor engagement and direct Fab’2 binding to antigen on the cell surface. ANCA-activated neutrophils release factors that induce alternative complement pathway activation, which establishes a potent inflammatory amplification loop that causes severe necrotizing vascular inflammation. The origin of the ANCA autoimmune response is unknown but appears to involve genetically determined HLA specificities that allow the autoimmune response to develop. One putative immunogenic mechanisms begins with an immune response to a peptide that is complementary to the autoantigen and evolves through an anti-idiotypic network to produce autoantibodies to the autoantigen. Another putative immunogenic mechanism begins with an immune response to a microbe-derived molecular mimic of the autoantigen resulting in antibodies that cross-react with the autoantigen. Release of neutrophil extracellular traps, apoptosis and increased granule protein expression of ANCA antigens may facilitate the initiation of an ANCA autoimmune response, augment established pathogenic ANCA production, or both. The ANCA B cell autoimmune response is facilitated by quantitatively and qualitatively impaired T cell and B cell suppression, and by release from activated neutrophils of B cell activating factors that enhance B cell proliferation and retard B cell apoptosis

Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells

Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Anti-myeloperoxidase autoantibodies are found in association with idiopathic necrotizing glomerulonephritis and systemic vasculitis. It is not known if their presence is an epiphenomen or an integral part of the pathogenic process. To further delineate their hypothesized pathogenicity, we studied their ability to stimulate neutrophils to damage human umbilical vein endothelial cells in vitro. Anti-myeloperoxidase antibodies from human, rabbit and mouse sources were utilized. These antibodies stimulated neutrophils to damage endothelial cells as determined by 51Cr release. The effect was dependent on priming the neutrophils with tumor necrosis factor-α, and further enhanced with the addition of endotoxin. The amount of endothelial cell damage was dependent on the dose of anti-myeloperoxidase, the source of the neutrophils, the concentration of TNF, and the presence of endotoxin. Under identical conditions, control antibodies did not stimulate neutrophils to damage endothelial cells. The effect was confirmed by labeling the endothelial cells with 3H-adenine which yielded the same results. These results provide further in vitro evidence that anti-myeloperoxidase autoantibodies may play a significant role in the pathogenesis of idiopathic pauci-immune glomerulonephritis and vasculitis

Pathogenesis of antineutrophil cytoplasmic autoantibody vasculitis

Anti-neutrophil cytoplasmic autoantibodies (ANCA) are associated with vasculitis. Current therapy involves administration of toxic therapy that is not optimally effective. The review will summarize evidence for the pathogenicity of ANCA, which will suggest possible strategies for improving treatment

Collapsing glomerulopathy: A clinically and pathologically distinct variant of focal segmental glomerulosclerosis

Collapsing glomerulopathy: A clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Sixteen patients with renal biopsy findings of extensive focal glomerular capillary collapse, visceral epithelial cell hypertrophy and hyperplasia, and variable degrees of tubulointerstitial injury in the absence of evidence for human immunodeficiency virus (HIV) infection or intravenous drug abuse were prospectively identified by renal biopsy. The pathologic process was designated collapsing glomerulopathy to distinguish it from other patterns of focal glomerular sclerosis. The clinical and pathologic characteristics of these 16 patients were analyzed and compared to a group of 25 patients with noncollapsing focal segmental glomerulosclerosis (FSGS). Thirteen of 16 patients with collapsing glomerulopathy were black as compared with 11 of 25 with FSGS (P = 0.018). The most common findings at presentation were hypertension and manifestations of the nephrotic syndrome. Although the duration of symptoms prior to presentation was no longer in the collapsing glomerulopathy group, the presenting mean serum creatinine was higher in patients with collapsing glomerulopathy than in those with noncollapsing FSGS (3.5 ± 3.4 mg/dl vs. 1.3 0.6 mg/dl, P = 0.001). Twenty-four-hour urine protein excretion was also higher in the collapsing glomerulopathy group (13.2 ± 7.7 g/day vs. 4.6 ± 4.5 g/day FSGS, P = 0.005). The collapsing glomerulopathy patients had a mean age of 41.4 ± 19.1 (range 19 to 81), a male-to-female ratio of 11:5 and a black-to-white ratio of 13:3. Renal survival, evaluated by life-table analysis, was markedly worse in collapsing glomerulopathy patients than in FSGS patients (P = 0.0004). It is proposed that collapsing glomerulopathy is a distinct entity characterized by black racial predominance, massive proteinuria, relatively rapidly progressive renal insufficiency, and distinctive pathologic findings. The data suggest that collapsing glomerulopathy is clinically, pathologically, and epidemiologically different from noncollapsing FSGS. Although collapsing glomerulopathy resembles HIV-nephropathy both pathologically and clinically, it differs clinically by having no evidence for associated HIV infection and differs pathologically by lacking endothelial tubuloreticular inclusions

Temporal and Demographic Trends in Glomerular Disease Epidemiology in the Southeastern United States, 1986–2015

BACKGROUND AND OBJECTIVES: Large-scale, contemporary studies exploring glomerular disease epidemiology in the United States are lacking. We aimed to determine 30-year temporal and demographic trends in renal biopsy glomerular disease diagnosis frequencies in the southeastern United States. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this cross-sectional, observational study, we identified all patients with a native kidney biopsy specimen showing one of 18 widely recognized glomerular disease diagnoses referred to the University of North Carolina Chapel Hill Division of Nephropathology between 1986 and 2015. Biopsy era (1986-1995, 1996-2005, and 2006-2015) and demographics (age, sex, and race) were our primary and secondary predictors, respectively, and the relative frequency of each glomerular disease diagnosis was our primary outcome. RESULTS: Among 21,374 patients (mean age =48.3±18.3 years old; 50.8% men; 56.8% white; 38.3% black; 2.8% Latino; 1.4% Asian; 0.8% other), the frequency of diabetic glomerulosclerosis in renal biopsy specimens increased dramatically over the three decades (5.5%, 11.4%, and 19.1% of diagnoses, respectively; P for trend <0.001). The frequency of FSGS initially increased but then declined (22.6%, 27.2%, and 24.7%, respectively; P for trend =0.64). The frequencies of other common glomerular disease subtypes remained stable (IgA nephropathy and ANCA/pauci-immune GN) or declined (minimal change disease, membranous nephropathy, membranoproliferative GN, and lupus nephritis). These temporal trends were largely preserved within all demographic subgroups, although cross-sectional frequency distributions differed according to age, sex, and race. CONCLUSIONS: 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

Predictors of 30-Day Hospital Readmission among Maintenance Hemodialysis Patients: A Hospitals Perspective

Over 35% of patients on maintenance dialysis are readmitted to the hospital within 30 days of hospital discharge. Outpatient dialysis facilities often assume responsibility for readmission prevention. Hospital care and discharge practices may increase readmission risk. We undertook this study to elucidate risk factors identifiable from hospital-derived data for 30-day readmission among patients on hemodialysis

Antineutrophil cytoplasmic antibodies and associated diseases: A review of the clinical and laboratory features

Antineutrophil cytoplasmic antibodies and associated diseases: A review of the clinical and laboratory features. There have been a number of recent advances in this field. First, the "International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA)" has been developed to optimize ANCA testing. It requires that all sera are tested by indirect immunofluorescent (IIF) examination of normal peripheral blood neutrophils and, where there is positive fluorescence, in enzyme-linked immunosorbent assays (ELISAs) for antibodies against both proteinase 3 (PR3) and myeloperoxidase (MPO). Testing will be further improved when international standards and common ELISA units are available. Second, new diagnostic criteria for the small vessel vasculitides that take into account ANCA-positivity and target antigen specificity as well as histologic features are currently being produced. Third, we understand that the complications associated with treatment of the ANCA-associated vasculitides are often more hazardous than the underlying disease, and regimens that use effective but less toxic agents are being evaluated. The factors associated with increased risk of relapse, however, remain incompletely understood. Finally, ANCA with specificities other than PR3 and MPO are present in many nonvasculitic autoimmune diseases. Their clinical significance is still largely unclear, and some of the target antigens are present in other cells as well as neutrophils and thus are not strictly "ANCA.

Treatment with Glucocorticoids or Calcineurin Inhibitors in Primary FSGS

In primary FSGS, calcineurin inhibitors have primarily been studied in patients deemed resistant to glucocorticoid therapy. Few data are available about their use early in the treatment of FSGS. We sought to estimate the association between choice of therapy and ESRD in primary FSGS

Longitudinal studies of patients with ANCA vasculitis demonstrate concurrent reactivity to complementary PR3 protein segments cPR3m and cPR3C and with no reactivity to cPR3N

Antibodies recognizing the complement of the middle of PR3 (cPR3m) occur in ~30% of PR3-ANCA-vasculitis patients and immunization of animals with a peptide complementary to the middle of PR3 (cPR3m) induces not only anti-complementary PR3 antibodies, but also anti-PR3 antibodies derived through an anti-idiotypic response. PR3 epitopes recognized by patient ANCA however, are not restricted to the middle of PR3. This prompted us to test for antibodies that react with proteins complementary to the terminal regions of PR3 (cPR3C and cPR3N) in PR3-ANCA patients. Anti-cPR3C reactivity was detected in 28% of patients but anti-cPR3N reactivity in only 15%. Ranked anti-cPR3C and anti-cPR3m reactivity correlated in the cohort, whereas there was no significant relationship between cPR3C and cPR3N reactivity. Serial samples from three patients’ revealed that anti-cPR3C and anti-cPR3m reactivity followed a similar pattern over time. Serial samples from a fourth patient demonstrated an anti-cPR3N response without concurrent cPR3m or cPR3C reactivity. Epitope determination by mass spectrometry identified a thirteen amino acid sequence on cPR3C that contained a common binding site recognized by antibodies from three patients. This peptide sequence contains a “PHQ” motif which was reported to be the basis for cross-reactivity of anti-cPR3m antibodies with plasminogen. Why these antibodies are detected in only ~30% of the patients remains unclear. The data reveal it is not due to lack of inclusion of flanking regions of complementary PR3 during screening. Instead, quite unexpectedly, the data demonstrate that patients’ antibodies react with a restricted epitope that exists in both cPR3m and cPR3C

Amelioration of immune complex-mediated glomerulonephritis by synthetic protease inhibitors.

Proteases are involved in the pathogenesis of inflammatory diseases by participating in the activation of mediator systems and by producing proteolytic tissue injury. Homeostatic control of inflammation is accomplished in part by physiologic protease inhibitors. The authors investigated the effectiveness of a number of synthetic protease inhibitors in ameliorating the glomerular injury induced by immune complex-mediated glomerulonephritis in mice. Two amidine-type protease inhibitors, bis (5-amidino-2-benzimidazolyl)methane and 1,2-bis (5-amidino-2-benzimidazolyl)ethane, had the greatest effects. They caused a marked reduction in glomerular necrosis (P < 0.001) but did not affect the amount or site of immune complex localization or leukocyte influx. The inhibition constants of the protease inhibitors against nine purified physiologic proteases were determined. These results were discussed in relation to the effectiveness of the protease inhibitors in reducing glomerular injury. This investigation indicates that the administration of synthetic protease inhibitors can have a beneficial effect on immune-mediated inflammatory injury