Subepithelial Deposits Research Articles

Serum amyloid P deposition is a sensitive and specific feature of membranous-like glomerulopathy with masked IgG kappa deposits

Membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) is a recently described pattern of glomerulonephritis with a unique histopathology. The pattern is characterized by subepithelial and/or mesangial immune deposits that are “masked”, to immunoglobulin staining by routine immunofluorescence but strongly stain for IgG and kappa light chain after protease digestion. Patients with this pattern of glomerulonephritis are most commonly young females presenting with proteinuria and a vague history of autoimmune disease such as low titer antinuclear antibodies. Here we compared the mass spectrometry profile of laser capture microdissected glomeruli from nine MGMID renal biopsies with eight biopsies showing other patterns of membranous glomerulopathy. The protein most significantly increased in MGMID was serum amyloid P. Immunostaining showed serum amyloid P colocalized with IgG in the glomeruli of MGMID but not with PLA2R-associated membranous glomerulopathy. Serum amyloid P was positive in the glomeruli of all 32 MGMID biopsies but negative in biopsies of other types of membranous glomerulopathies such as those associated with PLA2R and THSD7A. There were four biopsies with glomerular serum amyloid P staining among the 173 biopsies that did not fulfill criteria for MGMID or amyloidosis. All four of these biopsies with positive serum amyloid P staining had a membranous pattern of glomerulopathy with IgG kappa deposits that only differed from MGMID by the lack of “masking”. Thus, positive staining within glomerular deposits for serum amyloid P identifies a unique form of glomerulonephritis likely sharing a common pathophysiologic mechanism of disease.

RETRACTED ARTICLE: Transplantation of Mouse Induced Pluripotent Stem Cell-Derived Podocytes in a Mouse Model of Membranous Nephropathy Attenuates Proteinuria

Injury to podocytes is a principle cause of initiation and progression of both immune and non-immune mediated glomerular diseases that result in proteinuria and decreased function of the kidney. Current advances in regenerative medicine shed light on the therapeutic potential of cell-based strategies for treatment of such disorders. Thus, there is hope that generation and transplantation of podocytes from induced pluripotent stem cells (iPSCs), could potentially be used as a curative treatment for glomerulonephritis caused by podocytes injury and loss. Despite several reports on the generation of iPSC-derived podocytes, there are rare reports about successful use of these cells in animal models. In this study, we first generated a model of anti-podocyte antibody-induced heavy proteinuria that resembled human membranous nephropathy and was characterized by the presence of sub-epithelial immune deposits and podocytes loss. Thereafter, we showed that transplantation of functional iPSC-derived podocytes following podocytes depletion results in recruitment of iPSC-derived podocytes within the damaged glomerulus, and leads to attenuation of proteinuria and histological alterations. These results provided evidence that application of iPSCs-derived renal cells could be a possible therapeutic strategy to favorably influence glomerular diseases outcomes.

Sensitivity and Specificity of Pathologic Findings to Diagnose Lupus Nephritis.

In 2012, the Systemic Lupus International Collaborating Clinics proposed that lupus nephritis, in the presence of positive ANA or anti-dsDNA antibody, is sufficient to diagnose SLE. However, this "stand-alone" kidney biopsy criterion is problematic because the ISN/RPS classification does not specifically define lupus nephritis. We investigated the combination of pathologic features with optimal sensitivity and specificity for the diagnosis of lupus nephritis. Three hundred consecutive biopsies with lupus nephritis and 560 contemporaneous biopsies with nonlupus glomerulopathies were compared. Lupus nephritis was diagnosed if there was a clinical diagnosis of SLE and kidney biopsy revealed findings compatible with lupus nephritis. The control group consisted of consecutives biopsies showing diverse glomerulopathies from patients without SLE, including IgA nephropathy, membranous glomerulopathy, pauci-immune glomerulonephritis, membranoproliferative glomerulonephritis (excluding C3 GN), and infection-related glomerulonephritis. Sensitivity and specificity of individual pathologic features and combinations of features were computed. Five characteristic features of lupus nephritis were identified: "full-house" staining by immunofluorescence, intense C1q staining, extraglomerular deposits, combined subendothelial and subepithelial deposits, and endothelial tubuloreticular inclusions, each with sensitivity ranging from 0.68 to 0.80 and specificity from 0.8 to 0.96. The presence of at least two, three, or four of the five criteria had a sensitivity of 0.92, 0.8, and 0.66 for the diagnosis of lupus nephritis, and a specificity of 0.89, 0.95, and 0.98. In conclusion, combinations of pathologic features can distinguish lupus nephritis from nonlupus glomerulopathies with high specificity and varying sensitivity. Even with stringent criteria, however, rare examples of nonlupus glomerulopathies may exhibit characteristic features of lupus nephritis.

3221 A Rare Case of Collagenous Sprue

INTRODUCTION: Collagenous Sprue (CS) is a rare clinicopathological malabsorptive disorder characterized by mucosal villi atrophy and sub-epithelial collagen deposition. It is very important to consider the possibility of CS in patients diagnosed with celiac disease not improving on the gluten-free diet. CASE DESCRIPTION/METHODS: We present an elderly caucasian male with clinicopathological manifestations of Collagenous Sprue, as well as the successful treatment course that he underwent. DISCUSSION: Collagenous Sprue (CS) is a rare clinicopathological malabsorptive disorder characterized by mucosal villi atrophy which was first described in 1947. Approximately 60 cases have been reported so far in the medical literature. Replacement of the crypts with subepithelial collagen deposition in the small intestine made some experts believe CS to be a histopathologic variant of celiac disease with a poorer outcome. Although it's not true in all patients, diagnosis of CS should be considered in a patient whose symptoms are not getting better despite a gluten-free diet. Unlike in celiac disease, the collagenous deposits in CS doesn't regress with a gluten-free diet. Thus far, the etiology of CS is not clearly understood and it is very essential to initiate treatment at an early stage of the sprue to prevent fibrotic progression. Multiple treatment strategies were advised in the past but there is no standard therapy.

2760 A Case of Collagenous Gastritis: A Rare Entity

INTRODUCTION: Collagenous gastritis (CG) is a rare histopathologic entity that involves marked subepithelial collagen deposition in the gastric mucosa. Endoscopic findings can be diverse such as mucosal erythema, nodularity and ulceration. The presentation is very diverse such as abdominal pain, weight loss, gastrointestinal bleeding and dyspepsia. Its treatment remains unclear. CASE DESCRIPTION/METHODS: 71-year-old with long history of dyspepsia was referred to our institution due to a 6-month history of epigastric discomfort, profound weight loss (50 lb) and early satiety. Symptoms were mildly improved with sucralfate and smaller and more frequent meals. Tissue transglutaminase antibody was negative. Endoscopy at other institution suggested collagenous gastritis but biopsies were not conclusive. Endoscopic ultrasound at our institution was done for further characterization of the stomach layers and revealed a tubular J-shape stomach deformity with diffuse atrophic mucosa in the gastric body. Localized submucosal wall thickening was visualized endosonographically in the entire body of the stomach which measure up to 5 mm in thickness in the gastric wall. Random gastric biopsies could not confirm CG diagnosis. Persistent symptoms led to further work up including MRI enterography and gastric emptying study, all negative. Eight months later, “well type” biopsies were taken from the gastric body and antrum. Pathology report revealed antral glands atrophy with pyloric hyperplasia, prominent smooth muscle hyperplasia in the lamina propia, along with gastric corpus and antrum with thickened subepithelial collagen layer on hematoxylin and eosin, confirmed on trichrome stain. These features were consistent with a diagnosis of collagenous gastritis. Although limited evidence on the treatment of this disease, patient was started on budesonide therapy (9 mg/day). Future endoscopic surveillance and clinical follow up is planned to assess symptomatic improvement. DISCUSSION: Collagenous gastritis is a rare entity as only 60 cases have been reported in the literature. We need more awareness of this disease for early recognition and reduction of unnecessary work up. Clinical presentation is very diverse and endoscopic findings can be very subtle. High clinical suspicion is necessary to allow proper biopsy techniques. The well technique permits deep tissue sampling by taking multiple samples from the same site and has been advocated for use in subepithelial lesions, avoiding the need for full thickness biopsy or surgery.

1545 Drug-Induced Colitis With Nintedanib Therapy

INTRODUCTION: Nintedanib has emerged as an important treatment agent for Idiopathic Pulmonary Fibrosis (IPF). Gastrointestinal side effects, such as diarrhea and nausea, have been reported. However, Nintedanib-Induced Colitis, as described in the following cases, is a rare finding. CASE DESCRIPTION/METHODS: Case 1: 65 year-old man with a history of IPF on Nintedanib for three years presented with diarrhea. He reported two watery, non-bloody bowel movements daily with urgency, despite taking four tablets of loperamide daily. He had lower abdominal pain and an eighty-pound weight loss. A colonoscopy revealed mild edema, loss of vascular markings throughout the colon, and significant patches of submucosal hemorrhage/petechiae in the right colon. Biopsies revealed subepithelial deposition of amorphous eosinophilic material, prominently filling the subepithelial capillaries (Figure 1). Masson trichrome stain highlights dense blue staining, indicating collagen. The patient's symptoms resolved within a few days of discontinuing Nintedanib, and returned with rechallenge. Case 2: 76 year-old man with IPF on Nintedanib for three years presented with four loose, non-bloody bowel movements daily. He had bowel urgency, abdominal pain, and ten-pound weight loss despite loperamide use. Colonoscopy showed diffuse villous clubbing and erythema in the ileum. The entire colon revealed erythema and loss of vascular markings without ulcers (Figure 2). Histopathology revealed a paucicellular area of eosinophilic change in the lamina propria of the colon (Figure 3). There was no definite collagen deposition in this case. Nintedanib was discontinued and the patient's diarrhea resolved within two days; it returned with rechallenge. DISCUSSION: Nintedanib is a tyrosine kinase inhibitor, which is associated with diarrhea in about half of patients. Diarrhea is usually reported in the first three months of treatment and is generally adequately treated with anti-diarrheal medications. However, the specific entity of Nintedanib-induced colitis is a rare finding. There have only been two cases reported in the literature, neither of which described any particular pathologic findings. Our two cases demonstrate that symptoms resolve rapidly with drug withdrawal, recur rapidly upon rechallenge, and resolve again on withdrawal, suggesting a hypersensitivity reaction. Both cases demonstrate deposition of subepithelial eosinophilic material, which may offer a diagnostic clue to this drug induced diarrhea.

2686 Collagenous Gastritis: A Rare Entity

INTRODUCTION: Collagenous gastritis is a rare entity characterized by subepithelial deposition of collagen bands thicker than 10 μm and the infiltration of inflammatory mononuclear cells in the lamnia propia. While collagenous colitis has become more common in clinical practice, collagenous gastritis is rare. These two entities generally present differently. Collagenous colitis presents more commonly with diarrhea, while collagenous gastritis presents more commonly with abdominal pain. Since the disease was reported in 1989, only 60 cases have been documented in English literature. We present a case of collagenous gastritis in a pediatric patient. CASE DESCRIPTION/METHODS: A 17-year-old male patient presents to our office with a three month history of epigastric pain with no changes in bowel habits. He denies any previous past medical or surgical history. He immigrated to the United States from China. Physical examination was unremarkable aside from mild epigastric tenderness. A CMP, CBC and celiac serologies were unremarkable. Upper endoscopy was performed which revealed moderate erythematous mucosa in the gastric antrum (Figures 1 and 2). Biopsies of the antrum yielded mild chronic gastritis with sub-epithelial collagenous gastritis in the antrum (Figure 3). Helicobacter Pylori was negative. Patient symptoms gradually responded to a proton pump inhibitor. DISCUSSION: Collagenous gastritis is a rare condition with limited data in the literature. Most patients are young, abdominal pain and anemia occur secondary to stomach-specific infiltration. The etiology is mostly unknown and hypothesized. The endoscopic findings that are commonly reported include nodular changes in the mucosa, due to chronic inflammatory infiltration, mucosal atrophy and deposition of bands of collagen. Compared with the diffuse and continuous deposition seen in collagenous colitis, the changes in collagenous gastritis are heterogenous. Collagenous gastritis as a rare entity should be in the differential in younger patients who present with epigastric pain.

A case of denosumab-associated membranous nephropathy in a patient with rheumatoid arthritis.

We herein report a case of anti-RANKL monoclonal antibody-associated membranous nephropathy (MN). A 67-year-old woman with a history of rheumatoid arthritis treated with prednisolone and methotrexate for more than 30years and osteoporosis treated with eldecalcitol and teriparatide for 4years had achieved a stable disease condition. Her kidney function was normal and her urinalysis was negative for hematuria and proteinuria. An anti-RANKL monoclonal antibody (denosumab) was administered for the treatment of osteoporosis. Four months later, proteinuria appeared (2.3g/g creatinine) and remained positive for about 6months, therefore, she was admitted to our hospital. An immunofluorescence study revealed fine granular deposits of immunoglobulin G (IgG) and C3 along the capillary walls. Staining for IgG subclasses showed positive staining for IgG1 (3+), IgG2 (1+), IgG3 (1+), and IgG4 (1+); phospholipase A2 receptor was negative. Electron microscopy showed partial subepithelial and intramembranous deposits and focal thickening of the glomerular basement membrane. No evidence of malignancy or infectious disease was seen. After cessation of denosumab, the proteinuria gradually improved. Based on the renal biopsy results and clinical course (development of marked proteinuria in the presence of denosumab with subsequent amelioration in the absence of the drug), we diagnosed the patient with secondary MN due to denosumab. This is the first reported case of denosumab-associated MN.

High-Output (HO) Ostomy With Histopathologic Abnormality: Examination of 78 Stoma Specimens

Abstract Background HO (>2,000 mL output/day) is a serious complication following ostomy procedure. HO may be associated with variable underlying conditions or idiopathic. We encountered an ileostomy case with diffuse subepithelial collagen deposits resembling collagenous colitis from a patient with history of HO without underlying cause. A subset of idiopathic HO may be associated with histopathologic abnormalities of the bowel. Methods Resected stomas from ostomy malfunction were searched using ICD-9 and CPT codes (2003-2018). Archived pathology materials were reviewed and activity, villous blunting, pyloric metaplasia (PM), and subepithelial collagen deposits were assessed. Trichrome stain was performed when necessary. Clinical history was obtained from medical records. Results Sixty-one ileostomies and 17 colostomies were retrieved from 69 patients. Types of ostomy malfunction were stricture/obstruction (n = 21), hernia (n = 10), ischemia/necrosis (n = 4), leak (n = 4), abscess/adhesion (n = 3), skin breakdown (n = 3), prolapse (n = 3), retraction (n = 2), reepithelialization (n = 1), and unclear/not specified (n = 15). Thirty-two patients had inflammatory bowel disease (IBD; 19 Crohn disease [CD], 13 ulcerative colitis [UC]). All HOs were from ileostomy, and 16 had risk factors for HO, including IBD (n = 9 [56%]; 7 CD, 2 UC), short bowel (n = 6, 3 with CD), pelvic/intra-abdominal abscess (n = 2), sepsis (n = 2), and prokinetic (n = 1). Five ileostomies from CD showed PM, while 11 lacked significant histologic abnormalities. Among 5 (24%) idiopathic HOs, 1 was the index case with diffuse subepithelial collagen deposits with subtotal villous blunting, 1 showed PM, and 1 had focal activity. Remaining 2 ileostomies from idiopathic HO were unremarkable. Stomas from patients with other types of ostomy malfunction showed compatible histologic changes. Fifteen cases without ostomy malfunction did not show histologic abnormality. Conclusion Most HO represents functional abnormality without histopathologic abnormality except in IBD. However, idiopathic HO may be associated with histopathologic abnormalities in the stoma suggestive of acute/chronic enteritis and scarring, which may be underrecognized and treatable.

Membranous Lupus Nephritis: A Clinical Review.

Membranous lupus nephritis (MLN) (Class V lupus nephritis [LN]) is a distinct form of LN defined by the presence of subepithelial immune complex deposits seen on kidney biopsy. MLN is often associated with the nephrotic syndrome. The histology of MLN closely resembles that of idiopathic (primary) membranous nephropathy (pMN). However, MLN typically has abundant mesangial deposits that are absent in primary membranous nephropathy. The clinical presentation, management, and prognosis of MLN differ from that of the proliferative forms of LN (Class III, IV, or Mixed III/IV+V). Although immunosuppressive therapy is often warranted in MLN, the optimal treatment regimen remains unclear. Here we describe the clinical presentation, histologic features, and natural history of MLN. We also review the role of supportive treatment and discuss when to deploy immunosuppressive management in MLN.

Lupus Podocytopathy: An Overview.

In systemic lupus erythematosus, nephrotic-range proteinuria typically signals the presence of a proliferative lupus nephritis (class III/IV) and/or membranous lupus nephritis (class V, with or without concomitant class III or IV lesions). However, in rare instances, systemic lupus erythematosus patients with nephrotic syndrome have kidney biopsy findings of normal glomeruli or focal segmental glomerulosclerosis lesions, with or without mesangial proliferation, on light microscopy; the absence of subepithelial or subendothelial deposits on immunofluorescence and electron microscopy; and diffuse foot process effacement on electron microscopy. This pattern, termed lupus podocytopathy, is a unique form of lupus nephritis that mimics minimal change disease or primary focal segmental glomerulosclerosis and represents approximately 1% of lupus nephritis biopsies. Here we review the clinical features, histological manifestations, diagnostic criteria and classification, pathogenesis, treatment, and prognosis of lupus podocytopathy.

Complement activation products in the circulation and urine of primary membranous nephropathy

BackgroundComplement activation plays a substantial role in the pathogenesis of primary membranous nephropathy (pMN). C5b-9, C3c, MBL, and factor B have been documented in the subepithelial immune deposits. However, the changing of complement activation products in circulation and urine is not clear.MethodsWe measured the circulating and urinary levels of C1q, MBL, C4d, Bb, properdin, C3a, C5a, and sC5b-9, in 134 patients with biopsy-proven pMN, by enzyme-linked immunosorbent assay. All the plasma values were corrected by eGFR and all the urinary values were corrected by urinary creatinine and urinary protein excretion. Anti-PLA2R antibodies were measured in all patients.ResultsThe plasma complement activation products were elevated both in the patients with and without anti-PLA2R antibodies. C3a levels were remarkably increased in the circulation and urine, much higher than the elevated levels of C5a. C5b-9 was in normal range in plasma, but significantly higher in urine. The urinary C5a had a positive correlation with anti-PLA2R antibody levels and urinary protein. The plasma level of C4d was elevated, but C1q and MBL were comparable to healthy controls. Positive correlations were observed between plasma C4d/MBL and urinary protein, only in the patients with positive anti-PLA2R antibodies but not in those without. The plasma level of Bb was elevated and had positive correlation with urinary protein only in the patients without anti-PLA2R antibodies.ConclusionComplement activation products were remarkable increased in pMN and may serve as sensitive biomarkers of disease activity. The complement may be activated through lectin pathway with the existence of anti-PLA2R antibodies, while through alternative pathway in the absence of antibody.

MON-028 PATHOLOGICALLY PROVEN COMPLETE CURE OF IDIOPATHIC MEMBRANOUS GLOMERULONEPHRITIS BY METHYLPREDNISOLONE PULSE THERAPY

MGN is the second most common cause of nephrotic syndrome in adults, with FSGS recently becoming the most common, however there is no cure for idiopathic MGN and treatment focus on conservative methods such as salt restriction, blood thinning agents, ARB etc. Sometimes corticosteroids, cyclophosphamide, chlorambucil, cyclosporine-A, tacrolimus, MMF, Rituximab etc are tried with mixed results. Recently we have tried methylprednisolone pulse therapy in 7 cases and follow up renal biopsy were performed after 1 year of therapy. Age distribution from 1 to 61 (mean37) year old. Methylprednisolone pulse were tried by Cho’s method (Andreucci; New Therap Strat Nephrol, Kluwer Acad.Pub 1990). One cycle of MP pulse consist of methylprednisolone 20-30mg/kg (max1,000mg)/day mixed at 250ml amino acids solution for 3 consecutive days at 2 weeks interval. We tried 10 cycles. Between pulse therapy we tried deflazacort 0.5mg/kg/day and ARB were given every day. All 7 cases showed complete response clinically and complete dissolution of subepithelial deposits although sclerotic lesions were persisted pathologically. Two pediatric cases ages 1 and 7 showed completely cured clinically and pathologically. No major side effects were noted except one case developed cataract although minor side effects such as moon face, mild abdominal striae were noted. No relapses during 3 years follow up. In conclusion, further studies are needed. However methylprednisolone pulse therapy might be a promising initial treatment method in idiopathic MGN without noticeable side effects before considering secondary drugs such as alkylating agents, calcineurin inhibitors, Rituximab etc. Follow up renal biopsy is mandatory when deciding to stop oral steroid therapy.

<p>Salzmann nodular degeneration: prevalence, impact, and management strategies</p>

PurposeThis review will summarize the clinical and histological presentation of Salzmann nodular degeneration (SND), its prevalence and risk factors, potential underlying mechanisms, diagnostic tools, management options, and impact on cataract surgery and co-morbid ocular surface diseases.MethodPubMed review of 44 articles published between 1976 and 2018.ResultsSND is a corneal disease characterized by whitish gray or bluish nodules on the peripheral or central cornea. The clinical presentation of SND is variable and the nodules can be asymptomatic or cause foreign body sensation and/or blurred vision. Histologically, SND appears as subepithelial nodules with thin overlying epithelium, disrupted or absent Bowman’s layer, and activated fibroblasts within the nodule. SND pathogenesis is not fully understood but is thought to involve poor epithelial protection and disruption of the epithelial–stromal interface, allowing for penetration of epithelially derived growth factors into the stroma and subsequent activation of stromal fibroblasts, eventually leading to sub-epithelial deposition of disorganized extracellular membrane components. SND most commonly occurs in Caucasian females in a bimodal distribution, occurring in the fifth or eighth and ninth decades of life. Risk factors for SND include ocular surface diseases and surgery. Surgical intervention is recommended in individuals with symptomatic nodules – primarily superficial keratectomy performed with or without intraoperative mitomycin C, photokeratectomy, and/or amniotic membrane transplantation. These procedures have been successful in removing the lesion and reducing corneal irregularity, but have variable recurrence rates (0–31%).ConclusionThe pathogenesis of SND is complex and multifactorial. Advances in diagnostic and treatment modalities have allowed for earlier and more accurate diagnosis and effective treatment of SND.

SUN-011 ISOLATED MEMBRANOUS NEPHROPATHY OCCURRING IN A PATIENT WITH MPO-ANCA RELATED ARTHRITIS WITH ABSENCE OF MYELOPEROXIDASE IN MEMBRANOUS DEPOSITS

The co-occurrence of membranous nephropathy (MN) with MPO-ANCA related crescentic glomerulonephritis (MPO-rCGN) has been well described. Recent reports identified the myeloperoxidase (MPO) in membranous deposits in these cases, suggesting a role for MPO-ANCA in the pathogenesis of the membranous lesion in these patients. For the first time, we report a case of isolated MN (i.e. without concurrent MPO-rCGN) occurring in a patient with MPO-ANCA related arthritis, without MPO in membranous deposits. Case report A 69 year old male presented with a 5 month history of migratory polyarthralgias. Past history included localised prostate cancer and paroxysmal atrial fibrillation. ESR 69mm/hr. Haemoglobin 118 g/L. pANCA positive on immunofluorescence; MPO-ANCA titre 88 U/ml (normal < 20U/ml) on ELISA. Rheumatoid factor negative. ANA 1:80, with negative dsDNA and normal complement studies. Hepatitis B and C, and HIV serology negative. A diagnosis of MPO-ANCA related arthritis was made. He was noted to have microscopic haematuria (74 X 106 erythrocytes/L) and significant proteinuria – urinary protein excretion 5.5g/day. Renal function was normal – serum creatinine 75 umol/L, eGFR 89 ml/min/1.73m2. Serum albumin 29g/L. Blood pressure 127/74mmHg. No oedema. A renal biopsy demonstrated extensive basement membrane spikes along capillary loops, with intervening subepithelial deposits, consistent with stage 2 MN. Immunohistochemistry revealed moderate to strong capillary loop staining for IgG, IgG4, C3c and C1q. IHC staining with anti-MPO antibody was negative. PLA2R-antibody negative. Screening for malignancy revealed a new L1 vertebral lesion consistent with a metastasis from his known prostate cancer. Prednisolone 15mg daily was commenced which rapidly improved the joint symptoms and inflammatory markers. Methotrexate 10mg weekly was added 1 month later, and prednisolone weaned to 2.5mg over 6 months. Proteinuria improved rapidly, with protein excretion falling to 1.5g/day after 1 month of prednisolone. Complete remission of proteinuria occurred within 6 months. MPO-ANCA remained positive with no significant change in titre. Initial reports of concurrent MN and MPO-rCGN proposed that the lesions occurred together by chance. Recent reports have challenged this idea by demonstrating the presence of MPO in membranous deposits in these patients. Furthermore, the IgG subclasses in deposits have been shown to be IgG1 and IgG4, the subtypes which comprise most MPO-ANCA antibodies in the serum in ANCA vasculitis. It has thus been proposed that MPO/MPO-ANCA antibody complexes are pathogenic in forming the membranous deposits. The current case is the first report of isolated MN occurring in a patient with active MPO-ANCA related disease without concurrent MPO-rCGN. MPO was not identifiable in membranous deposits in this case, suggesting an alternative mechanism of injury. While it is possible the MN occurred secondary to prostate cancer, the strong IgG4 staining is atypical for malignancy associated MN. Additionally, the temporal relationship and parallel courses of activity of the MN and ANCA-related arthritis in response to treatment favours a pathogenetic link between the conditions. This case calls into question the role of MPO/MPO-ANCA antibody complexes in the pathogenesis of MN in patients with MPO-ANCA vasculitis.

Correlation between corneal involvement and anterior chamber flare in epidemic keratoconjunctivitis.

To investigate the correlation between corneal involvement and anterior chamber flare using a laser flare meter in eyes with epidemic keratoconjunctivitis. A total of 82 eyes of 50 (32 female and 18 male) consecutive patients with epidemic keratoconjuctivitis were evaluated. Besides complete opthalmic examination, anterior chamber flare measurements with laser flare meter (FM 600, Kowa, Kowa Company Ltd., Nagoya, Japan) were performed. The relationship between corneal involvement, subepithelial deposits, and anterior chamber flare was assessed. The mean age of the patients was 36.32 ± 18.77 (range 4-75) years and the mean duration of complaints was 5.28 ± 2.65 (range 1-12) days. The biomicroscopic findings were conjunctival hyperemia in 82 (100%), follicular reaction in 66 (80.5%), eyelid edema in 56 (68.3%), punctate epitheliopathy in 38 (46.3%), and subepithelial deposits in 36 (43.9%) eyes. The mean flare value was 17.35 ± 12.62 (range 2.0-45.0) photons/ms. Flare measurements were significantly higher in eyes with subepithelial deposits (p < 0.001). Subepithelial deposits seem to occur in eyes with higher anterior chamber inflammation in epidemic keratoconjunctivitis. The laser flare meter might be a useful tool to predict subepithelial deposit development in these patients.

Multiple airborne allergen-induced eosinophilic chronic rhinosinusitis murine model.

Several murine models have been established to mimic human eosinophilic chronic rhinosinusitis (ECRS). However, in most of these models, ECRS was induced using ovalbumin, which does not cause sinusitis in humans. Thus, we aimed to develop a more clinically relevant murine model of ECRS using multiple airborne allergens. We also investigated the effects of exposure duration of the allergens on ECRS development. C57BL/6 mice were intranasally administered multiple airborne allergens (house dust mite, Aspergillus fumigatus, Alternaria alternata, and protease from Staphylococcus aureus) three times weekly for 4, 8, 12, and 16 consecutive weeks. Histopathological changes, the levels of cytokines and chemokines in the nasal lavage fluid, and immune cells of the blood and spleen were analyzed. The mice administered multiple allergens showed significantly increased eosinophil infiltration, epithelial thickening and disruption, and subepithelial collagen deposition from 8weeks compared to the control group. Goblet cell hyperplasia, polyp-like lesions, and blood eosinophils, as well as the levels of interleukin-5 and eotaxin in the nasal lavage fluid were considerably increased in the ECRS group from 12weeks compared to those of controls. Instillation of allergens for 16weeks exacerbated the eosinophil infiltration and eotaxin increase in the nasal lavage fluid. We successfully established a new murine model of ECRS using more clinically relevant multiple airborne allergens. Prolonged exposure to airborne allergens for 12weeks or more, corresponding to the definition of human ECRS, strongly induced eosinophil infiltration as well as epithelial remodeling.

Inyección intraestromal combinada con ganciclovir y betametasona de depósito para el manejo de la queratitis numular: serie de casos

Nummular keratitis is an inflammatory process of the cornea that is characterised by multiple sub-epithelial deposits, for which a variety of therapeutic approaches have been proposed. A retrospective review was performed using the medical records of patients diagnosed with nummular keratitis and treated with a combined intrastromal injection of ganciclovir and depot betamethasone between the years 2009 and 2017. A total of 21 eyes of 16 patients were finally included. Upon termination of the treatment, 18 eyes (85.71%) were asymptomatic. This improvement was maintained during a mean follow-up time of 22.90 months. Depot betamethasone mixed with ganciclovir by intrastromal application is a good alternative for the treatment of nummular keratitis.

Significance of subepithelial deposits in patients diagnosed with IgA nephropathy

Subepithelial deposits are observed in rare adult IgA nephropathy (IgAN) cases and are a key diagnostic finding in IgA-dominant infection-related glomerulonephritis (IgA-IRGN). Sometimes, it is difficult to distinguish IgA-IRGN from IgAN without a precise clinical history. We hypothesized that some IgA-IRGN cases might be diagnosed as IgAN with subepithelial deposits (IgAN-SD) and aimed to clarify the significance of subepithelial deposits in patients diagnosed with IgAN. We examined 464 patients diagnosed with IgAN at Nagasaki University Hospital and affiliated hospitals between 1996 and 2013. The differences in clinicopathological findings between IgAN-SD and IgAN with no subepithelial deposits (IgAN-NSD) were investigated. In addition to clinical data and typical IgAN pathological features, we analyzed complement levels, immunoglobulin localization, light chain staining patterns, and intramembranous deposits. There were 214 men and 250 women with a mean age of 38.8 ± 18.3 years. Subepithelial deposition was observed in 51 patients (11%). Compared to patients with IgAN-NSD, those with IgAN-SD had significantly lower mean serum protein (6.4 g/dL vs. 6.7 g/dL; p = 0.02), albumin (3.7 g/dL vs. 3.9 g/dL; p = 0.02), and complement (C3) (94 mg/dL vs. 103 mg/dL; p = 0.02) levels. Diffuse mesangial hypercellularity (M) (65% vs. 45%; p<0.01), endocapillary hypercellularity: (E) (43% vs. 28%; p = 0.03), and IgA staining in the glomerular capillary wall (22% vs. 8%; p<0.01) were more common in patients with IgAN-SD. The incidence of light chain lambda predominance was lower in patients with IgAN-SD (47% vs. 63%; p = 0.03). Hump-shaped subepithelial deposits and intramembranous deposits were observed in nine and 17 patients with IgAN-SD, respectively. Patients with IgAN-SD tended to have the characteristics of IgA-IRGN rather than IgAN-NSD. Since the therapeutic strategies for IgA-IRGN differ from those for IgAN, we should review the clinical history and pay careful attention to the clinical course in cases with atypical findings, such as subepithelial deposits.

Upregulated microRNAs in membranous glomerulonephropathy are associated with significant downregulation of IL6 and MYC mRNAs.

Membranous glomerulonephropathy (MGN) is a glomerulopathy characterized by subepithelial deposits of immune complexes on the extracapillary side of the glomerular basement membrane. Insertion of C5b-9 (complement membrane-attack complex) into the membrane leads to functional impairment of the glomerular capillary wall. Knowledge of the molecular pathogenesis of MGN is actually scanty. MicroRNA (miRNA) profiling in MGN and unaffected tissues was performed by TaqMan Low-Density Arrays. Expression of miRNAs and miRNA targets was evaluated in Real-Time polymerase chain reaction (PCR). In vitro transient silencing of miRNAs was achieved through transfection with miRNA inhibitors. Ten miRNAs (let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, miR-107, miR-129-3p, miR-423-5p, miR-516-3p, miR-532-3p, and miR-1275) were differentially expressed (DE) in MGN biopsies compared to unaffected controls. Interleukin 6 (IL6) and MYC messenger RNAs (mRNAs; targets of DE miRNAs) were significantly downregulated in biopsies from MGN patients, and upregulated in A498 cells following let-7a-5p or let-7c-5p transient silencing. Gene ontology analysis showed that DE miRNAs regulate pathways associated with MGN pathogenesis, including cell cycle, proliferation, and apoptosis. A significant correlation between DE miRNAs and mRNAs and clinical parameters (i.e., antiphospholipid antibodies, serum creatinine, estimated glomerular filtration, proteinuria, and serum cholesterol) has been detected. Based on our data, we propose that DE miRNAs and their downstream network may be involved in MGN pathogenesis and could be considered as potential diagnostic biomarkers of MGN.