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.

Is podocytopathy another image of renal affection in p-SLE?

Background Lupus podocytopathy (LP) is a renal affection described in systemic lupus erythematosus (SLE) patients with nephrotic range proteinuria, characterized by diffuse foot process effacement without immune deposits and glomerular proliferation. This study describes LP, its pathological features and outcomes of pediatric (p-SLE) patients in comparison to the usual lupus nephritis (LN) cases. Methodology A retrospective cohort study conducted on a 10-year registration (2010–2019) of 140 p-SLE patients at the Pediatric Department, Tanta University. Histopathological analysis with light microscopy (LM) and immunofluorescence (IF) of all renal biopsies were evaluated according to the International Society of Nephrology Renal Pathology Society (ISN/RPS) grading system. In addition, some biopsies were examined with electron microscopy (EM). Results Eighty-six p-SLE cases (61.4%) had renal involvement; seventy-nine biopsies (91.86%) of them met the classification criteria of LN as defined by ISN/RPS system. Five biopsies were normal (MCD) and two showed focal segmental sclerosis (FSGN) that did not meet any known classification of LN. Hence, they were reevaluated using EM that revealed diffuse effaced podocytes without glomerular sub-epithelial, endocapillary or basement membrane immune deposits, and were classified as having lupus podocytopathy, representing (8.14%) of all LN biopsies. Those seven cases showed good response to steroids with a complete remission duration of 3.40 ± 1.95 weeks. However, some case had 1–3 relapses during the duration of follow up. Conclusions LP is a spectrum of p-SLE, not an association as it is related to disease activity and its initial presentation.

Glomerular Immune Deposition in MPO-ANCA Associated Glomerulonephritis Is Associated With Poor Renal Survival

BackgroundRapidly progressive glomerulonephritis caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is typically characterized as pauci-immune glomerulonephritis. However, immune complex (IC) deposition in the glomerulus has been reported in a growing number of studies. Here, we assess the presence of glomerular immune deposits alongside renal outcome in myeloperoxidase (MPO)-ANCA associated glomerulonephritis (MPO-ANCA GN).MethodsClinical and histopathologic characteristics of 97 patients with MPO-ANCA GN classified by renal biopsy from January 2008 to December 2019 were extracted retrospectively from electronic medical records. The extent of immune deposits in the kidney (C3, C4, C1q, IgA, IgG, IgM) at diagnosis were analyzed by immunofluorescence (IF). Patients were followed up for a median period of 15 months. The response to treatment and outcomes of renal and histological lesion changes were also assessed.ResultsIn our study, 41% (40/97) of patients showed positive IF (≥2+) for at least one of the six immunoglobulin or complement components tested. Patients with IC deposits showed higher levels of serum creatinine (p=0.025), lower platelet counts (p=0.009), lower serum complement C3 (sC3) (≤790 ml/L) (p=0.013) and serum IgG (p=0.018) than patients with pauci-immune (PI) deposition at diagnosis. End-stage renal disease was negatively associated with eGFR (HR 0.885, 95% CI 0.837 to 0.935, p<0.0001), platelet count (HR 0.996, 95% CI 0.992 to 1.000, p=0.046) and serum globulin (HR 0.905, 95% CI 0.854 to 0.959, p=0.001). Patients with lower sC3 levels showed a worse renal outcome than the patients with normal sC3 at diagnosis (p=0.003). Analysis of the components of the renal deposits found that patients with IgG deposits exhibited a poorer renal outcome compared to patients that were IgG negative (p=0.028). Moreover, Bowman’s capsule rupture occurred less frequently in patients with IgM deposition compared with IgM negative counterparts (p=0.028). Vascular lesions and granuloma-like lesions had been seen more frequently in cases with IgA deposition than those without IgA deposition (p=0.03 and 0.015, respectively).ConclusionIn conclusion, patients with immune complex deposits in the kidney showed less platelet count, lower sC3 and sIgG levels, and higher serum creatinine levels. Patients with low sC3 at initial and with continued low sC3 during the treatment displayed a trend toward poorer kidney survival. Moreover, the IC group showed a worse renal outcome than the PI group, further enforcing the present strategy of introducing complement targeted therapies in AAV.

Identification of Lupus Podocytopathy with Coexistent Glomerular Diseases – A Case Report

Introduction/Objective Lupus podocytopathy (LP), featured by nephrotic syndrome, is a unique subtype of lupus nephritis that mimics minimal change disease or primary focal segmental glomerulosclerosis (FSGS) on renal biopsy with diffuse podocyte foot process effacement and no capillary-loop immune deposits. LP usually presents on a background of ISN/RPS class I or class II lupus nephritis, and very rarely may present without immune deposits. Diagnosis of LP, when confounded by other glomerular diseases associated with nephrotic syndrome, can be very challenging and requires thorough clinical and pathology correlations. Methods Here we report a case of LP in a patient with nephrotic syndrome and multiple comorbidities affecting kidneys. A 24-year-old female with type-I diabetes, psoriasis, and intermittent arthritis/rash of unknown etiology, presented with abrupt onset of nephrotic proteinuria attributed to recent low dose prednisone therapy, and renal insufficiency. A renal biopsy showed nodular glomerulosclerosis and FSGS. No immune deposits were identified by immunofluorescence or electron microscopy. Ultrastructurally there was also diffuse glomerular basement membrane thickening and over 90% podocyte foot process effacement. With no established systemic lupus erythematosus (SLE), the case was initially diagnosed as diabetic nephropathy with coexistent FSGS as the etiologies for nephrotic proteinuria, and the patient was put on ACEI and diuretics. However, massive proteinuria persisted, and the patient also developed pancytopenia. Serology concurrent with the biopsy came out later showing positive autoantibodies against dsDNA, Smith, and Histone. With continued worsening of creatinine, a renal biopsy was repeated revealing essentially similar findings to the first biopsy. Results Integrating the serology results and clinical presentation, SLE was favored. The pathology findings were re- evaluated and considered to be most consistent with LP and coexistent diabetic nephropathy, with FSGS either a component of LP or an independent lesion secondary to diabetes or hypertension. The patient was started with high dose prednisone at 60 mg/day. One month later, her proteinuria, serum creatinine, pancytopenia, skin rash, and arthritis were all significantly improved. Conclusion LP can be easily masked by coexistent glomerular diseases. Sufficient awareness of the entity is necessary for the appropriate diagnosis and treatment.

Correlation Between Serological Makers and Immunofluorescence Deposits i n Kidney Tissue of Patients with Lupus Nephritis

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease. Few biomarkers for SLE have been validated and widely accepted for the laboratory follow-up of inflammatory activity. In SLE patients, with lupus nephritis (LN), complement activation leads to fluctuation of serum C3 and C4 that are frequently used as clinicalm biomarker of disease activity in SLE. Patients and Methods: In this study the number of patients were 37, seven patients were excluded for incomplete data collection, 28 were females ,2 were males. The duration of the study is two years from 2015 to 2017. Patients were considered to have SLE and LN according to American College of Rheumatology (ACR) criteria, and International Society of Nephrology/ Renal Pathology Society (ISN/RPS). All patients were evaluated withm clinical presentation, laboratory investigations. Our patients underwent kidney biopsy according to standard procedure by Kerstin Amann, and their tissue specimens were studied in the laboratory with light microscope (LM) and immunofluorescence microscope reagents. The relationship between the serological markers and immunofluorescence deposits in kidney biopsy of all patients were studied using the statistical analysis of Pearson correlation and single table student's T test. A P value 0.05 was considered statistically significant. Results: The granular pattern of IF deposits was present in all LN patients, and in more than two third of patients these IF deposits presented in glomerular, tubular, and mesangium sites. While less than one third of patients had IF deposits in the mesangium only. There was no statistically significant correlation between serum ANA, anti-dsDNA, and IF deposits of different types. There was significant correlation between serum C3 and C4 hypocomplementemia and IgG immune deposits in kidney biopsy, and there was significant relationship between serum C3 hypocomplementemia and full house immunofluorescence (FHIF) deposits inm kidney biopsy.Conclusions:Immunofluorescence deposits is mainly granular pattern in LN patients. There was no significant association between serum ANA, anti-dsDNA, and immune deposits in kidney tissue. Immunofluorescence deposits of IgG type correlates significantly with serum C3 and C4 hypocomplemetemia, and these immune deposits in association with low complement levels correlates with LN flare. There was significant correlation between C3 hypocomplementemia and FHIF.

Successful management of proliferative glomerulonephritis with monoclonal immune deposits with combined immunosuppressive therapy

Proliferative glomerulonephritis with monoclonal immune deposits (PGNMID) is a newly described entity characterised by monoclonal IgG deposits consisting of single light chain isotype and single heavy chain subtype (IgG1-4) in the kidneys. We are presenting two cases of patients who presented with acute kidney injury and worsening proteinuria. Kidney biopsy showed membranoproliferative pattern. Special staining for subclass of IgG showed monoclonal IgG3-kappa (case 1) and IgG1-kappa deposits (case 2) suggestive of PGNMID. Workup for underlying infection, malignancy, monoclonal gammopathy was negative. Since pathogenesis of PGNMID involves clonal proliferation of B-cells, we treated both patients with rituximab along with steroids that led to improvement of proteinuria and renal function. We also reviewed current literature to assess efficacy of rituximab in treatment of PGNMID. However, a larger pool of patients and a longer follow-up period is required to establish a role of rituximab and steroids in the treatment of this disease entity.