Subepithelial Immune Deposits Research Articles

Glomerulus-Targeted ROS-Responsive Polymeric Nanoparticles for Effective Membranous Nephropathy Therapy.

Membranous nephropathy (MN) is a common immune-mediated glomerular disease that requires the development of safe and highly effective therapies. Celastrol (CLT) has shown promise as a therapeutic molecule candidate, but its clinical use is currently limited due to off-target toxicity. Given that excess levels of reactive oxygen species (ROS) contributing to podocyte damage is a key driver of MN progression to end-stage renal disease, we rationally designed ROS-responsive cationic polymeric nanoparticles (PPS-CPNs) with a well-defined particle size and surface charge by employing poly(propylene sulfide)-polyethylene glycol (PPS-PEG) and poly(propylene sulfide)-polyethylenimine (PPS-PEI) to selectively deliver CLT to the damaged glomerulus for MN therapy. Experimental results show that PPS-CPNs successfully crossed the fenestrated endothelium, accumulated in the glomerular basement membrane (GBM), and were internalized by podocytes where rapid drug release was triggered by the overproduction of ROS, thereby outperforming nonresponsive CLT nanotherapy to alleviate subepithelial immune deposits, podocyte foot process effacement, and GBM expansion in a rat MN model. Moreover, the ROS-responsive CLT nanotherapy was associated with significantly lower toxicity to major organs than free CLT. These results suggest that encapsulating CLT into PPS-CPNs can improve efficacy and reduce toxicity as a promising treatment option for MN.

The Mayo Clinic consensus report on membranous nephropathy; a promising step toward better treating the disease

Membranous nephropathy is an immune complex disease caused by subepithelial deposits. The pathological manifestations of membranous nephropathy are considered by the creation of immune complexes in the epithelial cells of the glomerular basement membrane. The established pathologic features of primary membranous nephropathy include subepithelial immune deposits, thickening of the glomerular basement membrane, and podocyte foot process effacement. The clinical implications of pathological features of primary membranous nephropathy include male gender, age, persistent heavy proteinuria, decreased glomerular filtration rate on presentation, and tubulointerstitial fibrosis. Membranous nephropathy is diagnosed through a kidney biopsy, confirming subepithelial immune deposits, thickening of the glomerular basement membrane, and podocyte foot process effacement.

Characterization of Membranous Nephropathy with Microspherular Deposits

Introduction: Membranous nephropathy (MN) is a common cause of adult nephrotic syndrome in the USA. The typical ultrastructural finding is of global uniformly dense subepithelial electron-dense immune complex deposits along glomerular basement membranes. However, early reports described deposits with a unique microspherular substructure. There was variability in what was identified as microspherular, sometimes overlapping with other entities such as podocyte infolding glomerulopathy. Currently, the nature, composition, and clinical significance of these microspherular deposits (MSDs) remain unknown. Method: We report the clinicopathologic features of a series of MN cases with MSD, with detailed ultrastructural characterization as well as PLA2R and THSD7A immunohistochemical and IgG subclass-staining characteristics. The proportion of MSD to overall deposits is segregated into two groups: global MSD with >50% MSD (n = 14) and segmental MSD with <50% (n = 5). Results: The size and appearance of the microspherules were nearly identical in global and segmental MSD groups (mean diameter of 77.9 nm and 77.2 nm, respectively), with subepithelial (n = 19) or intramembranous (n = 12) distributions in all cases. Mesangial MSDs (n = 5) were only found in the global MSD group. The majority of biopsies (86% of global MSD and 100% of segmental MSD) were Ehrenreich-Churg stage 2 or above; early stage 1 was only observed in the global MSD group. All but 3 cases were PLA2R/THSD7A double negative; 1 THSD7A positive in global MSD and 2 PLA2R positive in segmental MSD. IgG1 was the dominant subclass in the global MSD group, and IgG4 was dominant in the segmental MSD group, including the 2 PLA2R-positive cases. Conclusion: The findings suggest that MSDs are more commonly associated with secondary MN. This case series is the largest to date, and the findings may yield etiologic and prognostic information on this rare but unique subset of MN and provide a well-characterized cohort of cases for future studies.

One antigen closer to understanding membranous nephropathy

Membranous nephropathy is an immune-mediated kidney disease characterized by subepithelial immune deposits. Through the utilization of advanced proteomic techniques, multiple target antigens have been identified, including those associated with primary and secondary etiologies. Nonsteroidal anti-inflammatory drugs represent an important secondary cause of membranous nephropathy. In this study by Sethi etal., advanced proteomic techniques identify proprotein convertase subtilisin/kexin type 6 as a target antigen in nonsteroidal anti-inflammatory drug-associated membranous nephropathy.

#2627 IGA-DOMINANT POSTINFECTIOUS GLOMERULONEPHRITIS, “THE OTHER SIDE OF THE COIN”: A CASE REPORT

Abstract Background and Aims Postinfectious glomerulonephritis (PIGN) is a disease presented as nephritic syndrome with hypocomplementemia usually secondary to a skin or throat infection by beta hemolytic Streptococcus and with histopathological findings of endocapillary proliferation, C3 deposits along the capillary wall and mesangium, subepithelial immune complex deposits and IF positive for IgG. There are other unusual presentations of PIGN with IgA dominance or C3-IgA codominance. Method A 58-year-old Guatemalan male, with history of one-week duration pain in the right upper quadrant associated with jaundice, diagnosed with cholangitis and intravenous antibiotics use. History of consumption of 10 beers a month for 40 years. No other medical history. During hospitalization, presented a lower-limb cellulitis, for which clindamycin was started. Blood cultures were taken and were positive for S. epidermidis and AKI (Cr 2.84 mg/dl) was observed, associated with de novo appearance of hematuria (80% acanthocytes), proteinuria (580mg/day) and hypertension. Diagnostic approach for nephritic syndrome was performed obtaining: C3 0.592 (low) ANA, ANCAs, HIV-HCV-HBV negative, total cholesterol 184 mg/dl, albumin 2.78 g/dl. Results Renal biopsy was performed and reported: PIGN with IgA dominance with extra capillary proliferation. Reason why pulses of methylprednisolone were given for 3 days and then oral prednisone (1 mg/kg/day), progressively decreasing it until it was discontinued. Resolved the soft tissue infection and was discharged. At 1-month follow-up as outpatient, was evidence of a 50% decrease in proteinuria compared to baseline, disappearance of hematuria but with persistent of high Cr (2.09 mg/dl). Conclusion IgA-dominant PIGN is characterized by usually presenting in patients &amp;gt;60 years with DM, alcohol consumption and staphylococcal skin infections. It can present hypocomplementemia and histopathological findings are characterized by IgA dominance over C3 and no IgG in IF. Elevated serum IgA levels may be involved in the pathogenesis. Treatment is based on eradication of the infection with antibiotics and in some cases the use of steroids is suggested depending on the aggressiveness of the lesion and the presence of crescents in the renal biopsy. It has worse prognosis than the traditional PIGN.

#6227 SPONTANEOUS REMISSION OF MEMBRANOUS VARIANT OF PGNMID WITH MONOCLONAL IGG2κ

Abstract Background and Aims The clinical significance of the morphological patterns of glomerular injury and of each IgG subclass in proliferative glomerulonephritis (GN) with monoclonal immunoglobulin deposits (PGNMID) is not well understood. Literature suggests that PGNMID with certain histological features such as membranous or mesangio-proliferative features or non-IgG3 subclass staining may be associated with a more favourable renal prognosis. We present a patient with membranous variant of PGNMID with monoclonal IgG2κ who had spontaneous remission without recurrence over a 2-year follow-up. Method Not applicable Results A 62-year-old Malay gentleman presented with new onset nephrotic range proteinuria, on a background of type 2 diabetes mellitus with diabetic duration of 5 years, hypertension and hyperlipidemia. He was mildly hypertensive (blood pressure 148/87) and non-edematous at presentation. Investigations revealed preserved kidney function [serum creatinine (sCr) 66µmol/L], bland urinalysis, and 24-hour urinary total protein (UTP) of 3.74g/day. Serum albumin (sAlb) was 35g/L. Serum complements were not low. Autoimmune markers inclusive of anti-double stranded DNA antibodies, anti-neutrophil cytoplasmic antibodies, and anti-phospholipase A2 receptor (PLA2R) antibodies were negative. Viral serologies were also unremarkable. No monoclonal band was detected on serum electrophoresis, while serum immunofixation was not performed. Kidneys were normal sized. Renal biopsy performed demonstrated 28 glomeruli, of which only 1 was globally sclerosed. Glomeruli capillary walls were diffusely thickened by vacuolations. Capillary loops were mostly single contoured although occasional focal double contouring was seen. Masson trichome stain revealed fuchsinophilic subepithelial immune deposits while periodic acid methenamine silver stain showed argyrophilic basement membrane spikes. Variable mesangial expansion and hypercellularity was observed, as well as mesangiolysis. Focal leukocyte margination was present, but significant endocapillary proliferation was not seen. There were no Kimmelstiel-Wilson lesions. Tubular atrophy with interstitial fibrosis was overall mild (10% of parenchymal area) and there were no tubulointerstitial infiltrates. Immunofluoresence showed granular staining of IgG (1-2+), C3 (2-3+) along glomerular capillary walls, as well as presence of kappa light chain restriction (κ 1-2+; λ negative in glomeruli). Immunostaining for PLA2R was negative. IgG subclass analysis performed in view of kappa restriction revealed isolated deposition of IgG2. Electron microscopy was not available. Overall findings were most consistent with membranous variant of PGNMID with monoclonal IgG2κ. Age-appropriate and symptom-directed malignancy screening did not reveal significant abnormalities. Given that the patient was minimally symptomatic, a trial of conservative therapy was initiated with optimized non-immunosuppressive anti-proteinuric therapy using renin-angiotensin-aldosterone and sodium-glucose co-transporter-2 inhibitors. Gradual spontaneous remission was observed without recurrence over 2 years of follow-up (sCr 77µmol/L; sAlb 40g/L; 24-hour UTP 0.22g/day). Conclusion Our case adds to the literature that a membranous variant of PGNMID with monoclonal IgG2κ may be associated with better renal outcomes. Despite the lack of proliferative changes, it is possible that membranous variants may share similar underlying disease mechanisms as the other proliferative variants. Large international registries to allow the correlation of morphological features and IgG subclasses with clinical outcomes are required to confirm our observation.

#5430 ANTI-PLA2R ASSOCIATED MEMBRANOUS NEPHROPATHY AND CHRONIC LYMPHOCYTIC LEUKAEMIA, IS THERE A LINK?

Abstract Background and Aims The spectrum of glomerular lesion that occurs in the context of plasma cell dyscrasias (PCD) is wide, including type I and type II membranoproliferative glomerulonephritis (MPGN), focal proliferative GN, membranous nephropathy (MN), minimal change disease and amyloidosis. A clear-cut link between hematological dyscrasias and glomerulopathy is often offered by the finding of paraproteins in the kidney or by kidney leucocytic infiltration and, in these scenarios, malignancy treatment is often found to be also effective towards the glomerulopathy. In the context of PCD in which proliferation of the B-cell clone does not lead to plasma-cell terminal differentiation such as chronic lymphocytic leukemia (LLC) the physiopathological link with glomerulonephritis is not well established and it's hard to determine whether the combination of these two disorders is fortuitous. With regarding to MN, it's now well established that this histopathological pattern must be related to the presence of circulating autoantibodies, where anti-PLA2R auto-antibodies usually been associated with primary MN. To our knowledge association between LLC and anti-PLA2R associated MN has not been described. Case report We report the case of a 76-year-old man who was admitted in February 2022 with anasarca and acute kidney injury. He had recently been evaluated by a hematologist in the context of suspected chronic lymphocytic leukemia (CLL). Laboratory findings, along with typical CLL white blood cell count, showed decreased kidney function from baseline and were compatible with nephrotic syndrome, with proteinuria progressively increasing up to 27 gr/24 h in the following weeks. CLL was confirmed by lymphocyte typing. A total body CT scan showed mediastinal, abdominal and inguinal lymphadenopathies, but no suspected neoplastic lesions. Screening for autoimmunity tested completely negative, as well as infectious screening for common hepatic viruses (HBV, HAV, HCV), EBV, CMV, HIV, Parvovirus B19. Lymph node biopsy showed no aspects of aggressive lymphoproliferative disease and hematological consultation only indicated clinical and laboratory follow-up of LLC, with no further indication to specific therapies. A kidney biopsy was performed showing diffuse thickening of the basement membrane (Fig. 1) with granular deposition of IgG (+++) and C3 (++) along the glomerular capillary walls at immunofluorescence. Electron microscopy revealed subepithelial immune deposits (Fig. 2) with initial incorporation from the glomerular basement membrane (GBM). Anti PLA2R antibodies, found negative at first determination, subsequently tested positive at high titre (ELISA 1356.4 U/ml). A diagnosis of stage two membranous nephropathy was made, and the patient was treated with Rituximab 375 mg/m2 every week for four weeks. Clinical stability was obtained with repeated intravenous administration of diuretics (furosemide 60 mg + canrenone 200 mg) along with albumin. Nevertheless, nephrotic syndrome persisted, and kidney function progressively decreased with serum creatinine up to 2.8 mg/dL. Immunophenotype, which showed reduction but no suppression of CD19+ lymphocytes, was again repeated on November 2022 and showed typical LLC findings (CD 19+, CD 20+, CD 23+, CD 5+) with repopulation of CD19+ lymphocytes. Anti PLA2R antibodies gradually decreased instead, reaching a value of ELISA 1.8 U/ml in November 2022 and persisted negative until present. The patient recovered from nephrotic syndrome in Autumn 2022 and is currently on stage G3B chronic kidney disease with persistent sub-nephrotic proteinuria in supportive treatment. Conclusion Simultaneous diagnosis of primary MN and LLC led us to ask ourselves whether this patient could benefit from LLC-specific chemotherapy, even though there were no signs of aggressive hematological disease and no clear link with the nephropathy. We think that further investigations are required to deeply understand the connection between hematological and renal disorders, in order to identify whether there are two diseases to treat separately or two sides of the same disease to treat as one.

German Shorthaired Pointer dogs with exfoliative cutaneous lupus erythematosus develop immune-complex membranous glomerulonephropathy.

German Shorthaired Pointer (GSHP) dogs with a UNC93B1 gene mutation develop exfoliative cutaneous lupus erythematosus (ECLE) and kidney disease resembling lupus nephritis in humans. The objective of this study was to characterize the kidney disease by light microscopy, immunofluorescence, and electron microscopy in a population of GSHP dogs with ECLE. Medical records were reviewed, and light microscopy of kidneys from 7 GSHP dogs with a previous histologic diagnosis of ECLE was performed. Immunofluorescence of fresh-frozen kidney from 1 dog and transmission electron microscopy of kidney from that dog and 2 additional dogs were performed. Five of 7 dogs had proteinuria diagnosed by urinalysis or urine protein-to-creatinine ratio. Two of 7 dogs were intermittently hypoalbuminemic, and none were azotemic. Histologic findings included early (2 dogs) to late (5 dogs) membranous glomerulonephropathy characterized by mild-to-severe glomerular capillary loop thickening and tubular proteinosis. In all 7 cases, trichrome staining revealed red granular immune deposits on the subepithelial surface of the glomerular basement membrane. Immunofluorescence revealed strong granular labeling for immunoglobulins and complement protein C3. Electron microscopy demonstrated subepithelial electron-dense immune deposits encircled by the remodeled glomerular basement membrane. These findings are diagnostic of immune-complex membranous glomerulonephropathy and are similar to class V lupus in humans. This cohort of GSHP dogs with ECLE developed immune-complex membranous glomerulonephropathy, which we hypothesize is a manifestation of systemic lupus erythematosus. GSHP dogs with ECLE should undergo clinical evaluation of renal function for early identification and treatment.

Paraneoplastic Nephropathy with Peculiar Immunofluorescence Pattern: Report of a Rare Case

Abstract Introduction/Objective Hematolymphoid neoplasms are commonly associated with medical renal disease; however, association of renal cell carcinoma and nephrotic/nephritic syndrome is exceedingly rare. Paraneoplastic nephropathy in setting of renal cell carcinoma can manifest as membranous nephropathy, IgA nephropathy, or minimal change disease. The purpose of this report is to describe a rare case of clear cell renal cell carcinoma with associated membranous nephropathy with concurrent glomerular IgG and IgA deposition. Methods/Case Report A 68-year-old male presented with a penile mass. Diagnostic work up reveled an 11cm renal mass. Urinalysis demonstrated nephrotic range proteinuria (&amp;gt;5 g/d). Subsequently, the patient underwent nephrectomy and penectomy. Pathologic evaluation showed clear cell renal carcinoma with sarcomatoid component and metastasis to penis. Nonneoplastic kidney workup revealed membranous glomerulopathy, with 3+ granular IgG predominantly within glomerular capillaries and 2+ IgA and 1+ C3 in a similar pattern. Electron microscopy demonstrated numerous subepithelial and intramembranous immune deposits, and few small mesangial deposits. Concurrent membranous and IgA nephropathy has been reported, but the IgA in that case is typically mesangial. The peculiar pattern of IgG and IgA deposition in this case can be seen with membranous nephropathy secondary to lupus or neoplasia. Lupus was excluded based on patient’s history, serology, and absence of significant C1q staining. Therefore, the findings were consistent with membranous glomerulopathy secondary to patient’s cancer. Patient’s proteinuria improved after nephrectomy. He is alive and disease-free 10months after nephrectomy, with proteinuria in 0.1-0.6 g/d range. Results (if a Case Study enter NA) NA Conclusion This case highlights the importance of thorough evaluation of non-neoplastic kidney in nephrectomy specimens for cancer, thus guiding the type of surgical intervention. Non-orthodox presentation of immunoglobulin deposition may be the herald of neoplasia in select cases.

A Case of ALECT2 Renal Amyloidosis Associated with IgG4 Related Kidney Disease, Membranous Nephropathy and Early Diabetic Kidney Injury

Abstract Introduction/Objective ALECT-2 amyloidosis is a rare type of amyloidosis that mostly involves kidneys with other organs rarely affected. It has a high prevalence among patients of Hispanic descent. Membranous nephropathy is one of the most common causes of proteinuria in adults. IgG4-related disease is a systemic disease, which commonly involves the pancreas, but occasionally affects the kidney and manifests as chronic renal insufficiency. Here we describe a very unusual case of concurrence of membranous nephropathy, IgG4 disease involving the kidney, ALECT2 amyloidosis, and early diabetic kidney injury. Methods/Case Report A 49-year-old Hispanic male patient with a history of diabetes and IgG4-related autoimmune pancreatitis and primary sclerosing cholangitis presented with abrupt onset of proteinuria and hypoalbuminemia. A kidney biopsy was performed and showed severe interstitial plasma cell-rich inflammatory infiltrates and interstitial fibrosis which had a storiform pattern. The glomerular basement membranes (GBM) showed focal pinpoint holes but no spikes by silver stain. Immunofluorescence microscopy (IF) showed diffuse and finely granular capillary loop staining for IgG, with Kappa and lambda light chains of equal intensity. IF for Anti-phospholipase A2 receptor (PLA2R) was negative. Immunohistochemical (IHC) stain showed IgG4 positivity in about 60% of IgG-positive plasma cells. Congo red was positive for birefringent deposits predominantly in the interstitium and arteriolar walls with focal deposits in the glomerular mesangium and capillary wall. IHC stain for Amyloid AA and DNAJB9 were negative. Electron microscopy showed scattered subepithelial immune complex-type electron dense deposits consistent with membranous nephropathy, randomly oriented fibrils in interstitium, mesangium and GBM, consistent with amyloidosis, and thickening of GBM (average 559 nm), consistent with early diabetic kidney change. The tissue was sent for mass spectrometry which showed a peptide profile consistent with ALECT-2 (Leukocyte chemotactic factor 2) type amyloidosis. Results (if a Case Study enter NA) NA Conclusion In up to a third of cases reported in the literature, a concomitant renal pathology was present. Diabetic nephropathy was the most common concurrent pathology, to be followed by IgA nephropathy and membranous nephropathy. However, the concurrence of membranous nephropathy, IgG4 disease involving the kidney, ALECT2 amyloidosis, and early diabetic kidney injury has never been described before.

Netrin G1 Is a Novel Target Antigen in Primary Membranous Nephropathy.

Primary membranous nephropathy (MN) is caused by circulating autoantibodies binding to antigens on the podocyte surface. PLA2R1 is the main target antigen in 70%-80% of cases, but the pathogenesis is unresolved in 10%-15% of patients. We used native western blotting to identify IgG4 autoantibodies, which bind an antigen endogenously expressed on podocyte membranes, in the serum of the index patient with MN. These IgG4 autoantibodies were used to immunoprecipitate the target antigen, and mass spectrometry was used to identify Netrin G1 (NTNG1). Using native western blot and ELISA, NTNG1 autoantibodies were analyzed in cohorts of 888 patients with MN or other glomerular diseases. NTNG1 was identified as a novel target antigen in MN. It is a membrane protein expressed in healthy podocytes. Immunohistochemistry confirmed granular NTNG1 positivity in subepithelial glomerular immune deposits. In prospective and retrospective MN cohorts, we identified three patients with NTNG1-associated MN who showed IgG4-dominant circulating NTNG1 autoantibodies, enhanced NTNG1 expression in the kidney, and glomerular IgG4 deposits. No NTNG1 autoantibodies were identified in 561 PLA2R1 autoantibodies-positive patients, 27 THSD7A autoantibodies-positive patients, and 77 patients with other glomerular diseases. In two patients with available follow-up of 2 and 4 years, both NTNG1 autoantibodies and proteinuria persisted. NTNG1 expands the repertoire of target antigens in patients with MN. The clinical role of NTNG1 autoantibodies remains to be defined.

POS-032 Human PLA2R-antibodies induce membranous nephropathy in minipigs and activate complement

POS-032 Human PLA2R-antibodies induce membranous nephropathy in minipigs and activate complement

Retraction Note: 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.

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

BackgroundLupus 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.MethodologyA 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).ResultsEighty-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.ConclusionsLP is a spectrum of p-SLE, not an association as it is related to disease activity and its initial presentation.

Rituximab Treatment of Membranous Nephropathy after Failure of other Therapies- A Case report

Membranous Nephropathy (MN) also known as membranous glomerulonephritis is a slowly progressive kidney disease characterized of subepithelial immune complex deposits and subsequent thickening of glomerular basement membrane. MN is a common cause of proteinuria that may progress to ERDS. The decision to treat MN with immunosuppressive medications is complicated by the well-known natural history of disease and it depends on patient presentation and disease progression. Herein, we present a case of a 48-year-old male patient with weight gain, lower extremity edema, arterial hypertension, and nephrotic range proteinuria (13.5 gr).

The clinicopathologic spectrum of segmental membranous glomerulopathy

Membranous glomerulopathy (MGN) is characterized by global subepithelial immune deposits that stain most intensely by immunofluorescence for IgG. Here we describe the clinical and pathologic findings in a cohort of patients with MGN in which, by definition, only segmental immune deposits are present. This rare variant, termed segmental MGN (sMGN), is poorly characterized. We retrospectively identified all patients with sMGN diagnosed at Columbia University from January 2010 to October 2018, excluding those with systemic lupus erythematosus. Data on presenting features, pathologic findings, and outcomes were collected. Fifty cases of sMGN were identified, representing 2.5% of MGN. In 21 of 50 biopsies, there was an alternative, predominant disease process. The remaining 29 patients with isolated sMGN had a median creatinine of 0.97 mg/dl, median 24-hour urine protein 3.1 g/day, and 32% had nephrotic syndrome. Staining for NELL-1 (a protein kinase C binding protein) was positive in five of 17 cases. Staining for PLA2R, THSD7A, and exostosin 1 (autoantigens in primary MGN) was negative in all biopsies evaluated. Ultrastructural evaluation revealed predominantly early stage sMGN (stage 1 or 1-2 in 14/29). Follow-up was available for 21 of the 29 patients with isolated sMGN (median 12 months), including seven who received immunosuppression (primarily glucocorticoids). During follow-up, 86% had stable/improved kidney function and 45% achieved complete while 15% achieved partial remission. Among the 15 patients with isolated sMGN without full nephrotic syndrome, only two received immunosuppression; nonetheless, 50% achieved complete while 21% achieved partial remission. Thus, sMGN is a rare PLA2R-negative variant of MGN with 29% NELL-1 positivity and favorable prognosis, even in the absence of immunosuppressive treatment.

Anti-LRP2 nephropathy with concurrent kidney infiltration by lymphoma.

Anti-low-density lipoprotein receptor-related lipoprotein 2 (LRP2) nephropathy/anti-brush border antibody disease is rare and characterized by tubular basement membrane, Bowman’s capsule and glomerular subepithelial immune deposits on kidney biopsy. No reported cases have occurred in patients with lymphoproliferative disorders or monoclonal gammopathies. We present two cases of anti-LRP2 nephropathy that occurred in patients with progressive low-grade B-cell lymphoma and had concurrent kidney infiltration by lymphoma on biopsy. We speculate that underlying immune dysregulation related to lymphoma may contribute to the development of this rare autoimmune kidney disease in some patients.

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.

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.