Proliferative Glomerulonephritis With Monoclonal IgG Deposits Research Articles

Proliferative glomerulonephritis with monoclonal IgG deposits in an adolescent successfully treated with daratumumab

AbstractThere is no specific treatment for proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID), a disease that is very rare in the pediatric population. We report the case of a 15-year-old boy who presented with mildly reduced kidney function and nephrotic syndrome. Kidney biopsy revealed PGNMID with monoclonal deposits of IgG3 with kappa light chain restriction. Flow cytometry showed a significant CD38 plasma cell population in the peripheral blood in the absence of other signs of hematological malignancy. The patient was treated with a 6-month course of daratumumab, a monoclonal antibody targeting CD38. There was a significant reduction in proteinuria and normalization of kidney function. Based on positive experience with adults, daratumumab should also be studied in children with PGNMID.

Overexpression of Plasmalemmal Vesicle-Associated Protein-1 Reflects Glomerular Endothelial Injury in Cases of Proliferative Glomerulonephritis with Monoclonal IgG Deposits

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) occasionally presents refractory nephrotic syndrome resulting in poor renal prognosis, but its etiology is not fully elucidated. Given that glomerular endothelial cell (GEC) stress or damage may lead to podocytopathy and subsequent proteinuria, as in thrombotic microangiopathy (TMA), diabetic kidney disease, and focal segmental glomerulosclerosis, we investigated the evidence of glomerular endothelial injury by evaluating the expression of plasmalemmal vesicle-associated protein-1 (PV-1), a component of caveolae in the cases of PGNMID. We measured the immunofluorescent PV-1 intensities of 23 PGNMID cases and compared with those of primary membranoproliferative glomerulonephritis (MPGN) (n= 5) and IgA nephropathy (IgAN) (n= 54) cases. PV-1 localization was evaluated with Caveolin-1, and CD31 staining, and the ultrastructural analysis was performed using a low-vacuum scanning electron microscope (LVSEM). To check the association of podocyte injury, we also conducted 8-oxoguanine and Wilms tumor 1 (WT1) double stain. We then evaluated PV-1 expression in other glomerulitis and glomerulopathy such as lupus nephritis and minimal change disease. The intensity of glomerular PV-1 expression in PGNMID is significantly higher than that in the other glomerular diseases, although the intensity is not associated with clinical outcomes such as urinary protein levels or renal prognosis. Immunostaining and LVSEM analysis revealed that glomerular PV-1 expression is localized in GECs in PGNMID. 8-oxoguanine accumulation was detected in WT1-positive podocytes but not in PV-1-expressing GECs, suggesting GEC-derived podocyte injury in PGNMID. PV-1 overexpression reflects glomerular endothelial injury, which could be associated with podocyte oxidative stress in PGNMID cases.

POS-126 PROLIFERATIVE GLOMERULONEPHRITIS WITH MONOCLONAL IgG DEPOSITS; A NOVEL PATHOLOGIC PRESENTATION

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a rare form of PGN that mimics immune-complex (IC) GN by light microscopy (LM), but shows monoclonal IgG deposits by immunofluorescence (IF). PGNMID often presents with membranoproliferative (MPGN) pattern or endocapillary hypercellularity. Focal crescents are not uncommon in PGNMID, but diffuse crescentic involvement is very rare.

Progression of proliferative glomerulonephritis with monoclonal IgG deposits in pediatric patients.

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a glomerular disease defined by non-organized glomerular deposits of heavy and light chain-restricted immunoglobulin and israrely reported in children. We characterized a series of nine pediatric patients from two academic centers with biopsy-proven PGNMID and additionally describe two patients with monotypic IgG in the setting of IgM deposition. Each patient presented with hematuria and/or proteinuria; however, only five had elevated serum creatinine. Prodromal or concurrent infection was identified in six patients, low C3 in five, and alternate complement pathway gene variants in two. No monoclonal serum proteins were identified in five tested patients. Seven patients had monotypic deposits composed of IgG3-λ, two showed IgG3-κ, and one each IgG1 and IgG3 with lambda dominance in the setting of IgM deposition. The glomerular pattern was predominantly mesangial proliferative or membranoproliferative glomerulonephritis (MPGN). Treatment and outcomes were variable; four patients have recent PGNMID diagnoses and therefore minimal follow up, one had relatively stable kidney function for over a decade, and six experienced kidney failure, with four receiving transplants. Recurrent deposits of the same isotype were identified in five of six transplanted kidneys, corresponding to three of four transplanted patients. One of these patients developed PGNMID recurrences in three separate kidney allografts over a 20-year disease course. Our study emphasizes the need for upfront IgG subclass investigation in pediatric mesangial or MPGN with IgG deposition and monotypic or biased light-chain staining. Furthermore, this pediatric experience suggests expanded pathogenic considerations in PGNMID. Graphical abstract.

Monoclonal Immunoglobulin Deposition Disease and Related Diseases.

Abnormal proliferation of plasma cells and some monoclonal B cells frequently cause the secretion of monoclonal immunoglobulins or immunoglobulin fragments into the serum, causing monoclonal gammopathy, which leads to various diseases including renal diseases. Therefore, monoclonal gammopathy is frequently associated with kidney diseases, including glomerular and tubulointerstitial diseases. Glomerular disease, with the deposition of monoclonal immunoglobulins or their components, includes monoclonal immunoglobulin deposition disease (MIDD), AL or AH amyloidosis, type I cryoglobulinemia, proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID), immunotactoid glomerulopathy, and fibrillary glomerulonephritis. In addition, tubulointerstitial diseases with the deposition of monoclonal immunoglobulins or their components are constituted by light chain (myeloma) cast nephropathy, light chain associated Fanconi's syndrome (light chain proximal [crystal] tubulopathy), and crystal-storing histiocytosis. In the present review article, we demonstrate the clinicopathological characteristics of MIDD, which is one of the representative diseases of plasma cell dyscrasias, and discuss various renal diseases with the deposition of monoclonal immunoglobulins or their components in glomeruli and the tubulointerstitium. We recommend that these renal diseases are arranged as one disease category, "renal diseases with deposition of monoclonal immunoglobulins or their components", in order to simplify the understanding of complicated diseases in plasma cell dysplasia.

Clinicopathological analysis of proliferative glomerulonephritis with monoclonal IgG deposits in 5 renal allografts

BackgroundWe present a case series of 5 patients with proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) of renal allografts to better define its natural history, presenting characteristics, pathological features and treatment outcome.ResultsThese 5 patients presented 5 to 19 months post-kidney transplantation for complaints of serum creatinine (Scr) elevation, proteinuria or hematuria. Membranoproliferative glomerulonephritis (MPGN) pattern was the most frequently observed histological manifestation. Immunofluorescence showed monoclonal IgG3κin 3 patients and IgG3λ in the other 2 cases. Immunofluorescence staining helped to establish PGNMID in the absence of conspicuous microscopic changes in one case. Rituximab and bortezomib were effective in alleviating proteinuria in all 4 treated patients and decreasing Scr in 2 cases. Plasmapheresis treatment in another patient was not effective in preventing Scr elevation. At last-follow-up, 2 patients were in dialysis and 2 had improved kidney function with almost normal Scr and no proteinuria. The remaining one patient died of pulmonary infections.ConclusionsWe conclude that PGNMID occurs early after kidney transplant. PGNMID should be included in the differential diagnoses of recurrent MPGN in renal allografts. Rituximab and bortezomib are helpful to decrease proteinuria and Scr in a subset of patients. Larger studies are needed to conclusively establish best treatment strategies for PGNMID in renal allografts.

Proliferative glomerulonephritis with monoclonal IgG deposits in children and young adults.

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) has been recognized as a distinct entity in recent years. To the best of our knowledge, all patients with PGNMID reported thus far were older than 20years of age. We now report five cases of PGNMID in patients under 20years of age. The clinical database was searched for patients with native kidney biopsies from 9/2011 to 8/2017, and cases with a diagnosis of PGNMID were retrieved. Light microscopy specimens and immunofluorescence and electron microscopy images were revisited. Clinical data and kidney biopsy findings for patients under the age of 20 were recorded. Five (0.78%) of a total of 637 patients younger than 20 with native renal biopsies had a diagnosis of PGNMID, including three males and two females with an average age of 14years old (range 10-19). All five patients presented with microscopic hematuria and proteinuria. Three patients were nephrotic and their C3 levels were low. All five cases showed a membranoproliferative pattern with abundant mesangial and subendothelial monoclonal IgG3 deposits (3 κ and 2 λ light chain, respectively). The patients were followed up to 56months. Two patients had re-biopsies 28 and 18months after initial diagnosis and both showed similar morphologic changes. Various treatments were attempted including prednisone, mycophenolate mofetil, tacrolimus, rituximab, and eculizmab, with mixed responses. PGNMID does occur in children and young adults. Membranoproliferative glomerulonephritis pattern with monoclonal IgG3 deposits is a common feature. Despite various immunosuppressive treatments, the disease appears slowly progressive.

Proliferative Glomerulonephritis with Monoclonal IgG Deposits Associated with Membrano-Proliferative Features: Case Report

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a recently described entity. It is featured by glomerular nonorganized monoclonal immunoglobulin G deposits. Monoclonal IgG deposits are associated with glomerular proliferative lesions, mimicking different types of immune-complex glomerulonephritis. We report two classic cases of PGNMID which fulfilled all criteria of this disease. We conclude that recognition of proliferative glomerulonephritis with monoclonal IgG deposits requires routine immunostaining for light chain and IgG isotype.

Proliferative Glomerulonephritis With Monoclonal IgG Deposits in a Young Patient: A Case Report

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a newly described entity that belongs to the class of disorders known as monoclonal gammopathy of renal significance (MGRS). The renal deposit in PGNMID is composed of monoclonal immunoglobulin (Ig). Microscopic findings typically show a non-fibrillar or non-microtubular pattern of Ig deposit without any organized structure. This entity affects adults and most patients present with nephrotic-range proteinuria and hematuria with or without renal failure. We report a unique case of PGNMID occurring in a young patient following a viral infection. The patient had significant proteinuria. There were no monoclonal proteins found in the serum. The renal biopsy was consistent with proliferative glomerulonephritis (GN) with monoclonal immune deposits. PGNMID is a novel form of GN that mimics immune-complex type GN on light and electron microscopy; thus, renal biopsy with careful attention to light-chain and IgG isotype staining is essential for diagnosis. J Med Cases. 2016;7(5):191-194 doi: http://dx.doi.org/10.14740/jmc2444w

Proliferative glomerulonephritis with monoclonal immunoglobulin deposition disease: The utility of routine staining with immunoglobulin light chains.

Proliferative glomerulonephritis occurring as a consequence of monoclonal glomerular deposits of IgG is uncommon. It is a form of renal involvement in monoclonal gammopathy that mimics immune complex glomerulonephritis. Here, we report the first series of proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) from the Indian subcontinent highlighting use of light chain immunofluorescence (IF) in routine renal biopsy interpretation. We retrieved 6 patients diagnosed as proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) out of 160 biopsies (3.7%) with membranoproliferative patterns over 5 1/2 years (2009–2014), one of whom had recurrence 6 months post-renal transplant. Four (67%) patients presented with rapidly progressive renal failure and two (33%) with nephrotic syndrome. None of these patients had overt multiple myeloma. The predominant histologic pattern was membranoproliferative with all the biopsies showing IgG3 Kappa deposits on IF. The deposits were primarily subendothelial on electron microscopy.

Proliferative glomerulonephritis with monoclonal IgG deposits in a patient with autoimmune hemolytic anemia

A 25-year-old woman was admitted because of proteinuria. A renal biopsy showed mesangial/endocapillary proliferative glomerulonephritis with IgG2-κ deposits. Electron microscopy showed immune complex-type deposits. She also had Coombs-positive hemolytic anemia, anticardiolipin antibodies, and antinuclear antibodies. Middle-dose steroid therapy led to improvement of proteinuria and hemolytic anemia. Six years later, she developed crescentic glomerulonephritis with IgG2-κ deposits during pregnancy. Middle-dose steroid therapy improved renal dysfunction. This is an exceptional case of proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID), a recently described rare dysproteinemia-related glomerulonephritis, associated with autoimmune disease. This case also suggests that crescentic glomerulonephritis can be superimposed on PGNMID.

Proliferative glomerulonephritis with monoclonal IGG deposits on a background of chronic lithium nephrotoxicity – a case report

Aims To document a previously unreported association of chronic lithium nephrotoxicity and proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID). Methods A 70-year-old female with a long-term history of lithium treatment for bipolar disorder presented with the nephrotic syndrome. A renal biopsy was performed. Results A chronic tubulo-interstitial nephritis with microcysts was present, typical of lithium toxicity. The glomeruli showed a membranoproliferative glomerulonephritis with mesangial and granular capillary loop reactivity for C3, IgG and kappa (but not lambda) light chain. Electron microscopy confirmed mesangial and subendothelial deposits which lacked microtubular and fibril-lary features. Cryoglobulins were not detected. Discussion Lithium treatment can cause the nephrotic syndrome, but usually due to minimal change nephropathy or focal segmen-tal glomerulosclerosis. An association with PGNMID has not been described in the literature, and is probably coincidental.

Proliferative glomerulonephritis with monoclonal IgG deposits secondary to chronic lymphocytic leukemia. Report of two cases

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a recently described entity that is only rarely associated with a hematological or lymphoproliferative malignancy. We describe the cases of two men with preexisting chronic lymphocytic leukemia (CLL) who developed endocapillary proliferative glomerulonephritis with nonorganized monoclonal IgG(1) deposits. One biopsy also showed CLL infiltration of the cortex. Both patients were treated with rituximab in addition to cyclophosphamide in one case and fludarabine in the other with significant improvement of their renal disease and CLL. This report provides additional evidence to support the use of rituximab in the therapy of CLL-associated PGNMID.

Characteristics of proliferative glomerulo-nephritis with monoclonal IgG deposits associated with membranoproliferative features

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) associated with membranoproliferative features is an extremely rare entity. Information on clinicopathological features and prognosis in this entity is limited. We reviewed 5,443 renal biopsies processed at our department, and identified 4 patients with PGNMID associated with membranoproliferative features. We evaluated clinicopathological features and outcomes in these patients, and characterized paraprotein deposits by immunofluorescence studies. Three out of 4 patients had nephrotic syndrome with renal insufficiency at presentation. Cryoglobulin or monoclonal protein in serum and urine was not detected. Renal biopsy showed membranoproliferative features with or without nodular formation. Tubulointerstitial and vascular alterations were mild in three patients. All patients had glomerular IgG-kappa deposits. Heavy chain subclass analysis performed in 3 patients showed IgG3 deposits. Immunofluorescence studies using antibodies specific for gamma-heavy chain C(H)1, C(H)2, and C(H)3 domains and gamma3 hinge did not show any apparent deletion. Confocal microscopy revealed glomerular colocalization of light and heavy chains. On electron microscopy, granular deposits were predominantly mesangial and subendothelial. All patients were treated with steroids and cytotoxic agents, but no effect on proteinuria was observed. The renal outcome was progressive in all patients. Early death was observed in two elder patients. No patient had overt myeloma or lymphoma at presentation or over the course of follow-up (mean 43 months). Our study suggests a predominance of IgG3-kappa glomerular deposits of nondeleted whole immunoglobulin molecules in PGNMID associated with membranoproliferative features. The clinical outcome in patients with this entity appears to be poor.