Weakened IgG4 Staining and Positive PLA2R staining Indicate Resolving Primary Membranous Glomerulopathy (MGN)

Introduction/Objective IgG4 related disease, a systemic autoimmune inflammatory disorders, can be identified by high% of IgG4 positive plasma cells, thus IgG4 staining in paraffin embedded tissue is widely available in the most of pathology labs. IgG4 staining has been found useful to identify primary MGN (PLA2R and/or THSD7A positive) by others and us. This study was to scrutinize the findings of primary vs secondary MGN needed for IgG4 staining as a screening tool in our renal pathology practice over pasts 5 years Methods/Case Report IgG4 staining in paraffin embedded tissue was performed in 45 primary MGN and 43 secondary MGN after the clinical history was reviewed and a possibility of primary MGN cannot be excluded. In addition, both groups of cases were also stained for PLA2R. Detail correlation with clinical history was analyzed. Results (if a Case Study enter NA) Totally 82 % (37/45) of primary MGN was found diffuse positive for IgG4 staining at 2+ intensity in the glomeruli. Seven out of eight remaining primary MGN cases with either negative or weak IgG4 stained MGN were found to have diffuse resolving features by electron microscopy but there was still positive PLA2R staining in the glomeruli. All secondary MGN were stained negatively for both IgG4 and PLA2R and we found that etiologies of the secondary MGN included membranous lupus nephritis, infection, GVHD, or variants of cancers. Conclusion Our data indicate that IgG4 staining along (without IgG1-3 staining) is a reliable screening tool to confirm the majority of primary MGN vs secondary MGN in paraffin embedded tissue. As both PLA2R+ and THSD7A+ primary MGN are both IgG4 related, the IgG4 staining may potentially represent a wider range of scope in identifying primary MGN. In addition, negative/weak IgG4 staining in PLA2R-positive MGN most likely represents a primary MGN with resolving features.

Transforming growth factor beta receptor 3 (TGFBR3)-associated membranous nephropathy

Background: Membranous lupus nephritis (MLN) comprises 10-15 percent of lupus nephritis and increases morbidity and mortality of patients with systemic lupus erythematosus (SLE) through complications of nephrotic syndrome and chronic kidney failure. Identification of the target antigens in MLN may enable non-invasive monitoring of disease activity, inform treatment decisions, and aid in prognostication, as is now possible for idiopathic MN caused by antibodies against the phospholipase A2 receptor. Here, we show evidence for type III transforming growth factor-beta receptor (TGFBR3) as a novel biomarker expressed in a subset of patients with membranous lupus nephritis. Methods: We utilized mass spectrometry for protein discovery through enrichment of glomerular proteins by laser capture microdissection and through elution of immune complexes within MLN biopsies. Co-localization with IgG within glomerular immune deposits from patients and disease controls was evaluated by confocal microscopy. Immunostaining of consecutive case series was used to determine the overall frequency in MN and MLN. Results: TGFBR3 was found to be enriched in glomeruli and co-immunoprecipitated with IgG within a subset of MLN biopsies by mass spectrometry. Staining of consecutive MN cases without clinical evidence of SLE did not show TGFBR3 expression (0/104), but showed a 5.5% prevalence in MLN (11/199 cases). TGFBR3 co-localized with IgG along the glomerular basement membranes in TGFBR3-associated MN, but not in control cases. Conclusions: Positive staining for TGFBR3 within glomerular immune deposits represents a distinct form of membranous nephropathy, substantially enriched in membranous lupus nephritis. A diagnosis of TGFBR3-associated MN can alert the clinician to search for an underlying autoimmune disease.

In Patients with Membranous Lupus Nephritis, Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes

BackgroundIn patients with secondary (autoimmune) membranous nephropathy, two novel proteins, Exostosin 1 and Exostosin 2 (EXT1/EXT2), are potential disease antigens, biomarkers, or both. In this study, we validate the EXT1/EXT2 findings in a large cohort of membranous lupus nephritis.MethodsWe conducted a retrospective cohort study of patients with membranous lupus nephritis, and performed immunohistochemistry studies on the kidney biopsy specimens against EXT1 and EXT2. Clinicopathologic features and outcomes of EXT1/EXT2-positive versus EXT1/EXT2-negative patients were compared.ResultsOur study cohort included 374 biopsy-proven membranous lupus nephritis cases, of which 122 (32.6%) were EXT1/EXT2-positive and 252 (67.4%) were EXT1/EXT2-negative. EXT1/EXT2-positive patients were significantly younger (P=0.01), had significantly lower serum creatinine levels (P=0.02), were significantly more likely to present with proteinuria ≥3.5 g/24 h (P=0.009), and had significantly less chronicity features (glomerulosclerosis, P=0.001 or interstitial fibrosis and tubular atrophy, P<0.001) on kidney biopsy. Clinical follow-up data were available for 160 patients, of which 64 (40%) biopsy results were EXT1/EXT2-positive and 96 (60%) were EXT1/EXT2-negative. The proportion of patients with class 3/4 lupus nephritis coexisting with membranous lupus nephritis was not different between the EXT1/EXT2-positive and EXT1/EXT2-negative groups (25.0% versus 32.3%; P=0.32). The patients who were EXT1/EXT2-negative evolved to ESKD faster and more frequently compared with EXT1/EXT2-positive patients (18.8% versus 3.1%; P=0.003).ConclusionsThe prevalence of EXT1/EXT2 positivity was 32.6% in our cohort of membranous lupus nephritis. Compared with EXT1/EXT2-negative membranous lupus nephritis, EXT1/EXT2-positive disease appears to represent a subgroup with favorable kidney biopsy findings with respect to chronicity indices. Cases of membranous lupus nephritis that are EXT1/EXT2-negative are more likely to progress to ESKD compared with those that are EXT1/EXT2-positive.

A 4-year old presenting with fever and achiness

In children under the age of 5 who have abnormalities in history, physical examination, and laboratory studies indicating multi-system disease, uncovering the correct diagnosis is challenging. Here, we report the course of a 4-year-old girl who presented with a change in behavior, fever, arthralgia, arthritis, and hematuria following three recent hospitalizations for pneumonia and impetigo. Serologic findings were suggestive of a rheumatologic etiology and a renal biopsy was consistent with Membranous Lupus Nephritis Class V which helped secure the diagnosis of pediatric systemic lupus erythematosus. We review the clinical features and diagnostic criteria of early-onset systemic lupus erythematosus and discuss diagnostic considerations and prognosis.

The emergence of bladder dysfunction secondary to lupus cystitis in a patient with established lupus nephritis: the first case from Pakistan

Lupus cystitis is an uncommon manifestation of systemic lupus erythematosus (SLE). We describe the case of a 23-year-old woman with lupus that complained of abdominal pain, vomiting, and diarrhea for one week. Two years back, she was brought with an affirmative history that satisfied the clinical criteria of SLE which was renal biopsy-proven (class V membranous lupus nephritis). On radiologic workup, she was found to have bilateral hydronephrosis and a thick-walled bladder with diverticula. Immunosuppressive therapy was commenced however augmentation cystoplasty had to be opted for as the symptoms did not subside with medical therapy alone.