Glomerular Disease Education Experience across Nephrology Fellowship Programs: An International Survey

Introduction: Glomerular disease (GN) education is an important, albeit a challenging component of nephrology fellowship training. We hypothesized that trainee experience varies widely across programs, leading to differences in self-reported comfort levels in the diagnosis and management of glomerular diseases. Methods: The Glomerular Disease Study & Trial Consortium (GlomCon) conducted an anonymous online survey to determine the educational experience of nephrology trainees. We used multiple-choice questions to obtain data about a) curriculum-based education, b) dedicated specialty clinic, and c) exposure to pathology. We leveraged a visual analogue scale of 1-100 (with a higher number indicating a higher comfort level) to assess self-reported levels of clinical comfort. The survey was disseminated via email to the subscribing members of GlomCon, and through Twitter. Results: In total, there were 109 respondents to our survey, and 56% were from training programs in the United States. Exposure to a specialized GN clinic was reported by 45%, while 77% reported the presence of an onsite nephropathologist at their training program. Self-reported comfort scores were 59±25 and 52±25 for diagnosis and treatment of glomerular diseases respectively. Days spent in GN clinic per year, years of fellowship and dedicated nephropathology didactics were associated with higher diagnosis and treatment comfort scores. Conclusion: Trainees report a wide variation in glomerular disease education across fellowship programs. A lack of nephropathology exposure and a dedicated GN curriculum were associated with lower scores in self-reported clinical comfort in caring for patients with glomerular disease.

IgA nephropathy and atypical anti GBM disease: A rare dual pathology in a pediatric RPGN

Introduction: Anti-GBM nephritis in the pediatric age group is exceedingly rare with concurrent additional pathologies being even rarer. Tissue diagnosis requires a combination of crescentic histomorphology, immunofluorescence showing “Paint brush stroke” pattern of linear IgG or rarely IgA and serum anti-GBM antibodies subject to the disease course and treatment. The authors describe one such case with a dual pathology involving IgA nephropathy and atypical anti-GBM disease. Case presentation: A thirteen-year-old girl presenting with features of rapidly progressive glomerulonephritis underwent a renal biopsy showing a mesangioproliferative histology with crescents and an immunofluorescence pattern indicating a dual pathology of IgA Nephropathy and Anti GBM Nephritis. Additional ancillary testing including staining for IgG subclasses and galactose deficient IgA (KM55) helped to confirm the diagnosis. She responded to steroid pulses and plasma exchange therapy, was off dialysis after 8 weeks with serum creatinine of 1.5 mg/dl however remains proteinuric at last follow up. Conclusion: Concurrent Anti-GBM nephritis and IgA nephropathy is a rare occurrence and possibly arises from a complex interaction between the anti-GBM antibodies and the basement membrane unmasking the antigens for IgA antibodies. Additional newer techniques like immunofluorescence for KM 55 are helpful in establishing the dual pathology.

IgA nephropathy: a tale of 3 continents

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Experimentally induced anti-myeloperoxidase vasculitis is not attenuated in factor B or VISTA deficient mice

Background: Anti-neutrophil cytoplasmic antibody vasculitis is characterised by antibodies to myeloperoxidase or proteinase 3. Previous work in murine anti-myeloperoxidase vasculitis has shown a role for the alternative pathway complement component factor B and the anaphylotoxin C5a. However, mice deficient in properdin, which stabilizes the alternative pathway convertase, were not protected. VISTA-deficient mice were protected in the nephrotoxic nephritis model but the role of VISTA in anti-myeloperoxidase vasculitis is unknown. Objectives: This study had two aims. Firstly, we attempted to reproduce previous findings on the role of factor B in anti-myeloperoxidase vasculitis. Secondly, we examined the role of VISTA in this model, in order to see if the protection in the nephrotoxic nephritis model extended to anti-myeloperoxidase vasculitis. Methods: Anti-myeloperoxidase vasculitis was induced in wildtype, factor B, or VISTA deficient mice. Disease was assessed by quanitfying glomerular crescents and macrophages, in addition to albuminuria and serum creatinine. Results: When wild type and factor B deficient mice were compared, there were no differences in any of the histological or biochemical parameters of disease assessed. Similarly, when wild type or VISTA defiicent mice were compared, there were no differences. Conclusions: Factor B deficient mice were not protected which is in contrast to previous studies. Therefore alternative pathway activation is not essential in this model, under the conditions used in this study. VISTA deficient mice were not protected, suggesting that therapies targetting VISTA may not be effective in vasculitis.

KM55 in the evaluation of IgA containing glomerular diseases

Introduction: Mucosal derived galactose deficient IgA is central to the pathogenesis of primary IgA nephropathy. Recent reports suggest similar pathogenesis in Henoch Schonlein purpura and secondary IgA nephropathy. Its role in other IgA containing glomerular diseases is still under investigation. It can be detected in glomeruli with the recently described antibody, KM55. We aimed to evaluate the role of KM55 by immunostaining a wide spectrum of IgA containing glomerular diseases. Methods: After standardization and co localization in a case of IgA nephropathy, a spectrum of 60 cases including IgA nephropathy, Henoch Schonlein purpura, chronic liver disease related IgA nephropathy, other secondary IgA Nephropathy, IgA dominant/co dominant membranoproliferative glomerulonephritis and lupus nephritis were subjected to immunofluorescence with KM55. KM55 was used to resolve diagnostic dilemma in cases of IgA deposition with confounding histology. Results: The group of primary IgA Nephropathy (17 cases), Henoch Schonlein purpura (4 cases) and secondary IgA nephropathy (19 cases) including chronic liver disease showed 2 -3+ granular staining with KM55 suggesting mucosal derived IgA. In contrast, cases of IgA dominant/co dominant membranoproliferative glomerulonephritis (8 cases) and lupus nephritis (12 cases) were negative for KM55, suggesting systemic derivation of IgA. In cases of IgA deposition with confounding histology such as membranoproliferative or diffuse endocapillary proliferative pattern, KM55 helped to resolve the diagnosis. Discussion/Conclusion: This cross-sectional study concludes that KM55 is useful in the evaluation of IgA containing glomerular diseases from a pathogenetic perspective, and is a practical tool in resolving differential diagnosis in cases with overlapping histopathologic features.

Anti-phospholipase A2 receptor in Non-lupus Patients with Membranous Nephropathy and Crescents

Introduction: Anti-phospholipase A2 receptor (PLA2R) is detected in approximately 70% of biopsies of “primary” membranous nephropathy (MN). Crescents in MN in non-lupus patients suggest additional injury, such as antineutrophil cytoplasmic antibody (ANCA) or anti-glomerular basement membrane (anti-GBM)-associated glomerulonephritis and is postulated to reflect injury by a mechanism that unmasks cryptic epitopes leading to the second autoantibody. Methods: We studied PLA2R staining in non-lupus patients with MN and crescents. Native renal biopsies in 16 non-lupus patients with MN and crescents were stained for PLA2R. Results: The patients included 5 women and 11 men, with mean age 61 yrs and elevated serum creatinine (mean 4.68 mg/dL). Hematuria and proteinuria (mean 4.97 g/d) were documented in 13 patients. Two patients had positive serum anti-GBM antibody. Nine of eleven patients tested for ANCA were positive, with p-ANCA (n=4), c-ANCA (n=2), or both (n=1), with two not specified. On average, 27% of glomeruli had crescents. One patient had an initial biopsy with MN, 4 years later had MN with crescent, and 7 years later had rebiopsy with persistent MN with crescents. One patient had ANCA-associated vasculitis, and 5 years later had MN and crescent. The remaining 14 patients had concurrent diagnoses of MN and crescents. PLA2R was positive in 5 cases, 3 with ANCA positivity, 2 with unknown ANCA status, and none with anti-GBM disease. The patient with initial MN preceding crescent was PLA2R positive; the patient with initial ANCA-associated vasculitis preceding MN was PLA2R negative. Conclusions: Most patients (64%) presented with concomitant MN and crescents, with rare occurrence of an initial disease process followed later by the second injury. PLA2R was positive in 31% of patients, suggesting most are secondary MN. Further study to determine the cryptic epitopes may shed light on the triggering mechanisms for these rare but unlikely coincidental glomerular injuries.