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Concept: IgA nephropathy

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Kawasaki disease (KD) is a systemic vasculitis and affects many organ systems. It often presents sterile pyuria, microscopic hematuria, and proteinuria due to renal involvement. The aims of this study were to define clinical characteristics of acute KD patients with pyuria and to analyze meaning of pyuria in KD.

Concepts: Nephrology, Vasculitis, Nephrotic syndrome, Arthralgia, Glomerulonephritis, Kawasaki disease, Urinalysis, IgA nephropathy

139

Immunoglobulin A vasculitis (IgAV), also referred to as Henoch-Schönlein purpura, is the most common form of childhood vasculitis. The pathogenesis of IgAV is still largely unknown. The disease is characterized by IgA1-immune deposits, complement factors and neutrophil infiltration, which is accompanied with vascular inflammation. Incidence of IgAV is twice as high during fall and winter, suggesting an environmental trigger associated to climate. Symptoms can resolve without intervention, but some patients develop glomerulonephritis with features similar to IgA nephropathy that include hematuria, proteinuria and IgA deposition in the glomerulus. Ultimately, this can lead to end-stage renal disease. In IgA nephropathy immune complexes containing galactose-deficient (Gd-)IgA1 are found and thought to play a role in pathogenesis. Although Gd-IgA1 complexes are also present in patients with IgAV with nephritis, their role in IgAV is disputed. Alternatively, it is has been proposed that in IgAV IgA1 antibodies are generated against endothelial cells. We anticipate that such IgA complexes can activate neutrophils via the IgA Fc receptor FcαRI (CD89), thereby inducing neutrophil migration and activation, which ultimately causes tissue damage in IgAV. In this Review, we discuss the putative role of IgA, IgA receptors, neutrophils and other factors such as infections, genetics and the complement system in the pathogenesis of IgA vasculitis.

Concepts: Immune system, Inflammation, Kidney, Immunoglobulin A, Glomerulonephritis, Phagocyte, Kidney diseases, IgA nephropathy

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Background: A multicenter case-control study on IgA nephropathy (IgAN) was conducted to develop an evidence-based clinicopathologic classification of IgAN for predicting long-term renal outcome. Methods: Two hundred and eighty-seven patients including those with isolated hematuria or very mild proteinuria were enrolled. During a median follow-up of 9.3 years after biopsy, 49 patients (17%) progressed to end stage renal disease (ESRD). The associations between pathological variables and the need for chronic dialysis was examined by multivariate logistic regression analysis separately in patients who required dialysis earlier than 5 years (Early Progressors) and those who required dialysis within 5 to 10 years (Late Progressors) after biopsy. Results: Independent pathological variables predicting progression to ESRD were global sclerosis, segmental sclerosis and fibrous crescents for Early Progressors, and global sclerosis and cellular/fibrocellular crescents for Late Progressors. Four histological grades, HG 1, HG 2, HG 3 and HG 4, were established corresponding to <25%, 25-49%, 50-74% and =75% of glomeruli exhibiting cellular or fibrocellular crescents, global sclerosis, segmental sclerosis or fibrous crescents. Eleven (7%) patients in HG 1, 12 (16%) in HG 2, 13 (31%) in HG 3 and 13 (68%) in HG 4 progressed to ESRD. Multivariate logistic analysis revealed that the risk of progression to ESRD was significantly higher in HG 2, 3 and 4 than in HG 1 (odds ratio, 2.4, 5.7 and 27.6 vs. 1.0). Conclusions: Our evidence-based histologic classification can identify the magnitude of the risk of progression to ESRD and is useful for predicting long-term renal outcome in IgAN.

Concepts: Regression analysis, Logistic regression, Renal failure, Chronic kidney disease, Nephrology, Cancer, Glomerulonephritis, IgA nephropathy

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Renal involvement with significant organ damage is common in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). As a result, it is independently referred to ANCA-associated renal vasculitis. Clinically, ANCA-associated renal vasculitis is characterized by rapidly progressive glomerulonephritis. Pathologically, it is defined by pauci-immune type necrotizing and crescentic glomerulonephritis. According to previous reports from all over the world, the etiology, prevalence, and prognosis of RPGN including ANCA-associated renal vasculitis varies among races and periods. To elucidate the clinical characteristics of Japanese RPGN patients, a registry derived from a questionnaire survey was established in 1999 and maintained until 2006. As a result, 1,772 cases were collected, analyzed, and reported previously. In this mini-review, we outline the characteristic clinical findings of Japanese patients (Asian) with ANCA-associated renal vasculitis, based on the registry data.

Concepts: Inflammation, Kidney, Glomerulonephritis, Windows Registry, Kidney diseases, Rapidly progressive glomerulonephritis, Real estate, IgA nephropathy

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Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterized by mesangial deposits of IgM. IgM nephropathy presenting with proteinuria, especially nephrotic syndrome, frequently is steroid-dependent or steroidresistant and associated with reaching endstage renal disease after a 15-year follow-up. Because no long-term effective treatment is known for patients with IgM nephropathy, there is a clear need for therapeutic alternatives. We describe a patient with IgM nephropathy represented by recurrence of nephrotic syndrome who achieved longterm remission with interferon-α sustained treatment.

Concepts: Immune system, Kidney, Nephrotic syndrome, Glomerulonephritis, Proteinuria, Nephritic syndrome, Minimal change disease, IgA nephropathy

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Objective: To investigate the therapeutic efficacy of tonsillectomy for patients with recurrence of IgA nephropathy (IgAN) after kidney transplantation. Methods: From May 2014, tonsillectomy was performed in 11 renal transplant patients with biopsy-proved recurrent IgAN. In a median follow-up of 14 (4-38) months, data of proteinuria, hematuria, estimated glomerular filtration rate (eGFR), and serum levels of IgA in these patients were compared before and after tonsillectomy.Patient’s survival and renal graft survival were also summarized. Results: A remission of proteinuria was observed in 8 patients after tonsillectomy, and this status maintained well in the subsequent follow-up.Three patients had no or minimal reduction of proteinuria after tonsillectomy and returned to dialysis within 1 year after tonsillectomy.Possible causes could be severe primary IgAN of crescentric glomerulonephritis, IgAN recurrence in kidney retransplantation, and late tonsillectomy after IgAN recurrence.Serum levels of IgA significant decreased and no patients developed acute rejection or infection after tonsillectomy.In the 1-year follow-up, no patients died and grafts survived well in 8 out of 11 patients. Conclusions: Tonsillectomy may represent an effective and reliable way to treat recurrence IgAN after kidney transplantation, and may be applied widely in the future clinical management. However, early intervention is critical and effects may depend on the pathological features of primary IgAN.

Concepts: Renal failure, Chronic kidney disease, Kidney, Nephrology, Organ transplant, Kidney transplantation, Glomerulonephritis, IgA nephropathy

2

To review major organizational guidelines on the evaluation and management of asymptomatic microscopic haematuria (AMH).

Concepts: Hematuria, IgA nephropathy, Microscopic hematuria

2

Complement-mediated glomerulonephritis, which includes C3 glomerulopathy, is characterized by dominant staining of C3 with minimal or no immunoglobulin deposits on immunofluorescence studies. We describe a new entity of complement-mediated glomerulonephritis that is characterized by bright C4d staining but with no or minimal C3 or immunoglobulin deposits on immunofluorescence studies. We label this entity as C4 glomerulopathy. C4 glomerulopathy includes C4 dense deposit disease and C4 glomerulonephritis. C4 dense deposit disease is characterized by bright C4d staining and dense deposits along glomerular basement membranes. C4 glomerulonephritis is characterized by bright C4d staining and many mesangial electron-dense deposits, with or without rare intramembranous electron-dense deposits. We describe clinical features and kidney biopsy results in a short series of 3 patients to highlight these findings. All 3 patients presented with proteinuria, and 2 patients also had hematuria. Kidney function was preserved in 2 patients, whereas 1 patient presented with declining kidney function. Evaluation for autoimmune disease, infection, and paraprotein yielded negative results in all patients. Complement levels were normal, although 1 patient had borderline low C4 levels. Kidney biopsy showed mesangial proliferative or membranoproliferative glomerulonephritis with bright C4d staining and absent or minimal C1q, C3, and immunoglobulin. Laser microdissection and mass spectrometry of glomeruli in all 3 patients showed large to moderate numbers of spectra matching C4. Furthermore, analysis of amino acid sequences showed that they were localized to the C4d portion of C4, consistent with immunofluorescence findings. Further studies are required to determine the underlying cause. In summary, we describe a novel complement-mediated glomerulonephritis that is characterized by bright glomerular C4d staining with minimal or absent staining for C1q, C3, and immunoglobulin.

Concepts: Kidney, Nephrology, Amino acid, Glomerulus, Nephrotic syndrome, Glomerulonephritis, IgA nephropathy, Membranous glomerulonephritis

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The significance of persistent hematuria or proteinuria in patients with ANCA-associated vasculitis who are otherwise in clinical remission is unclear.

Concepts: Nephrology, Urine, Glomerulonephritis, Hematuria, IgA nephropathy

1

Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury.

Concepts: DNA, Gene, Genetics, Chromosome, Cell cycle, Cyclin-dependent kinase, Rapidly progressive glomerulonephritis, IgA nephropathy