Proliferative glomerulonephritis with monoclonal IgM deposits without Waldenström's macroglobulinemia: case report and review of the literature

A 38-year-old man was presented with nephrotic syndrome associated with hematuria and mild hypocomplementemia. Renal biopsy revealed lobular mesangial proliferation, thickened capillary walls, and intraluminal protein thrombi. Immunofluorescence showed marked and mild depositions of immunoglobulin (Ig) M heavy chains and complement C3, respectively, in a peripheral lobular pattern. On light chain staining, only kappa (κ) light and IgM heavy chains showed a similar pattern. Electron microscopy showed fine granular electrondense deposits in subendothelial areas and numerous globular deposits (varying size and density) in glomerular capillary lumens. Serum levels of Ig κ, but not of free κ, light chains were significantly increased. Bone marrow aspiration revealed a normocellular marrow. Waldenstr?m's macroglobulinemia and cryoglobulinemia were ruled out. Clinically, steroid therapy was ineffective and proteinuria persisted. This report demonstrates that glomerular deposition of monoclonal IgM-κ can produce membranoproliferative- like changes in the glomeruli. This condition may be recognized as proliferative glomerulonephritis with monoclonal IgM deposits similar to the recently recognized proliferative glomerulonephritis with monoclonal IgG deposits.     

Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathologic features

BACKGROUND: Controversy surrounds the relatedness of fibrillary glomerulonephritis (FGN) and immunotactoid glomerulonephritis (IT). METHODS: To better define their clinicopathologic features and outcome, we report the largest single center series of 67 cases biopsied from 1980 to 2001, including 61 FGN and 6 IT. FGN was defined by glomerular immune deposition of Congo red-negative randomly oriented fibrils of < 30 nm (mean, 20.1 +/- 0.4 nm). IT was defined by glomerular deposition of hollow, stacked microtubules of > or = 30 nm (mean, 38.2 +/- 5.7 nm). RESULTS: FGN comprised 0.6% of total native kidney biopsies and IT was tenfold more rare (0.06%). Deposits in FGN were immunoglobulin G (IgG) dominant and polyclonal in 96%. IgG subtype analysis in 19 FGN cases showed monotypic deposits in four (two IgG1 and two IgG4) and oligotypic deposits in 15 (all combined IgG1 and IgG4). In IT, deposits were IgG dominant in 83% and monoclonal in 67% (three IgG1 kappa and one IgG1 lambda). FGN patients were a mean age of 57 years, 92% were Caucasian, and 39% were male. At biopsy, FGN patients had the following clinical characteristics (mean, range): creatinine 3.1 mg/dL (0.5 to 14), proteinuria 6.5 g/day (0.8 to 25), 60% microhematuria, and 59% hypertension. Histologic patterns of FGN were diverse, including diffuse proliferative glomerulonephritis (DPGN) (nine cases), membranoproliferative glomerulonephritis (MPGN) (27 cases), mesangial proliferative/sclerosing (MES) (13), membranous glomerulonephritis (MGN) (four), and diffuse sclerosing (DS) (eight). The more proliferative (MPGN and DPGN) and sclerosing (DS) forms presented with a higher creatinine and greater proteinuria compared to MES and MGN. Median time to end-stage renal disease (ESRD) was 24.4 months for FGN and mean time to ESRD varied by histologic subtype: DS 7 months, DPGN 20 months, MPGN 44 months, compared to MES 80 months and MGN 87 months. There was no statistically significant effect of immunosuppressive therapy (given to 36% of FGN patients). By Cox regression (hazard ratio, confidence interval, P value), independent predictors of progression to ESRD were creatinine at biopsy [2.05 (1.55 to 2.72) P < 0.001] and severity of interstitial fibrosis [2.01 (1.05 to 3.85) P = 0.034]. Although IT had similar presentation, histologic patterns, and outcome compared to FGN, it had a greater association with monoclonal gammopathy (P = 0.014), underlying lymphoproliferative disease (P = 0.020), and hypocomplementemia (P = 0.032). CONCLUSION: FGN is an idiopathic condition characterized by polyclonal immune deposits with restricted gamma isotypes. Most patients present with significant renal insufficiency and have a poor outcome despite immunosuppressive therapy, and outcome correlates with histologic subtype. By contrast, IT often contains monoclonal IgG deposits and has a significant association with underlying dysproteinemia and hypocomplementemia. Differentiation of FGN from the much more rare entity IT appears justified on immunopathologic, ultrastructural, and clinical grounds.     

Fibrillary glomerulonephritis: an entity with unusual immunofluorescence features

We describe seven patients with renal biopsy findings of mild glomerular abnormalities on light microscopy but with prominent accumulation of randomly-arranged fibrillar material in the mesangium and capillary walls on electron microscopy. This material differed from amyloid in that fibrils were thicker (diameter range 10 to 19.5 nm) and did not stain with Congo Red. In six of seven cases fluorescence microscopy showed prominent staining for IgG and kappa light chain in mesangium and glomerular capillary walls; in three cases weak lambda chain staining was also present. Stains for IgA, IgM, and lambda chain were otherwise negative. One biopsy showed equal staining for kappa and lambda light chains, but not for heavy chain components. Clinical findings were heterogeneous. Patients presented with features of nephritis and/or nephrotic syndrome. No patient had an associated lymphoplasmacytic disorder, paraproteinemia, or other evidence of systemic disease. On follow-up ranging from five months to 12 years, all patients are still alive; six progressed to end-stage renal disease requiring dialysis. One patient developed recurrent disease in a renal allograft five years after transplantation. Non-amyloidotic fibrillary glomerulonephritis is an ultrastructurally distinct entity of undetermined etiology. The apparent association with monoclonal IgG and kappa light chain deposition observed in this series deserves further study.     

Double monoclonal cryoglobulinemia, glomerulonephritis and lymphoma.

We present a case of monoclonal cryoglobulinemia with double monoclonal component IgA lambda-IgG lambda, without complement activation, membranoproliferative glomerulonephritis (MPGN) with deposits of IgA, IgG and lambda chains and lymphocytic IgA-lambda-chain-secreting lymphoma. This case emphasizes the possibility that double monoclonal cryoglobulins could behave differently compared to type I cryoglobulins, determining a MPGN-like type II cryoglobulins do, but without activating the complement cascade.     

Rapidly progressive glomerulonephritis in IgA/IgG cryoglobulinemia

Mixed IgA/IgG cryoglobulins were found in the serum of a 48-year-old man suffering from rapidly progressive glomerulonephritis (RPGN) with crescent formation. The type-II cryoglobulins were composed of monoclonal IgA1-kappa and polyclonal IgG, with the IgA possessing antibody activity against the IgG. The RPGN was of the immune complex type with granular deposits of IgA, IgG, and C3 on immunofluorescence microscopy and preponderant subendothelial deposits on electron microscopy. Occluding protein thrombi could be demonstrated in several glomerular capillary loops. Removal of the cryoglobulins from the patient's serum by plasmapheresis and immunosuppression was paralleled by a remarkable improvement in renal function with fall of serum creatinine values from 13.6 mg/dl (1,202.2 mumol/l) to 2.8 mg/dl (247.5 mumol/l), a resolution of the glomerular lesions, and clinical improvement as well. Our observations suggest that the crescentic glomerulonephritis may be due to an immune complex-like deposition of the cryoproteins. We conclude that crescentic glomerulonephritis in IgA/IgG cryoglobulinemia has to be considered as an autoimmune form of RPGN.     

IgA antiglomerular basement membrane disease associated with bronchial carcinoma and monoclonal gammopathy

Antiglomerular basement membrane (anti-GBM) disease is characterized by a linear deposition of immunoglobulins along the glomerular basement membrane. A 67-year-old man with a recently discovered monoclonal gammopathy of unknown significance (MGUS) presented with microscopic hematuria, nephrotic-range proteinuria, and rapidly deteriorating renal function after a pneumonia. Renal histology showed a crescentic glomerulonephritis; immunohistology showed intense linear staining of the GBM with immunoglobulin A (IgA) and moderate linear staining with kappa and lambda light chains. Screening for systemic disease, including diabetes mellitus, lupus erythematodes disseminatus, cryoglobulinemia, was negative. Serological tests for detection of anti-GBM antibodies were positive for IgA class and negative for IgG. Further examination indicated a bronchial carcinoma T2N2M0. This clinical report adds new information to the spectrum of anti-GBM disease and suggests that neoplasia may be associated with unusual exposure of and/or immune response to epitopes in the GBM.     

Proliferative Glomerulonephritis with Monoclonal IgG Deposits

Dysproteinemias that result in monoclonal glomerular deposits of IgG are relatively uncommon. Here, we report the largest series of proliferative glomerulonephritis with monoclonal IgG deposits, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. We retrospectively identified 37 patients, most of whom were white (81%), female (62%), or older than 50 yr (65%). At presentation, 49% had nephrotic syndrome, 68% had renal insufficiency, and 77% had hematuria. In 30% of the patients, we identified a monoclonal serum protein with the same heavy- and light-chain isotypes as the glomerular deposits (mostly IgG1 or IgG2), but only one patient had myeloma. Histologic patterns were predominantly membranoproliferative (57%) or endocapillary proliferative (35%) with membranous features. Electron microscopy revealed granular, nonorganized deposits, and immunofluorescence demonstrated glomerular deposits that stained for a single light-chain isotype and a single heavy-chain subtype, most commonly IgG3κ (53%). During an average of 30.3 mo of follow-up for 32 patients with available data, 38% had complete or partial recovery, 38% had persistent renal dysfunction, and 22% progressed to ESRD. Correlates of ESRD on univariate analysis were higher creatinine at biopsy, percentage of glomerulosclerosis, and degree of interstitial fibrosis but not immunomodulatory treatment or presence of a monoclonal spike. On multivariate analysis, higher percentage of glomerulosclerosis was the only independent predictor of ESRD. Only one patient lacking a monoclonal spike at presentation subsequently developed a monoclonal spike and no patient with a monoclonal spike at presentation subsequently developed a hematologic malignancy. We conclude that proliferative glomerulonephritis with monoclonal IgG deposits does not seem to be a precursor of myeloma in the vast majority of patients.Among dysproteinemia-related renal diseases, those manifesting monoclonal glomerular deposits of IgG are relatively uncommon. Renal diseases caused by monoclonal IgG deposition include light- and heavy-chain deposition disease (LHCDD),¹ type 1 cryoglobulinemic glomerulonephritis,² immunotactoid glomerulonephritis (IT),³ light- and heavy-chain amyloidosis,⁴ and rarely fibrillary glomerulonephritis (FGN).³ LHCDD is characterized by the presence of nodular sclerosing glomerulopathy by light microscopy (LM); diffuse, linear staining of glomerular basement membranes (GBMs) and tubular basement membranes (TBMs) for a single heavy chain and a single light chain by immunofluorescence (IF); and nonfibrillar, “powdery” electron-dense deposits in GBMs and TBMs by electron microscopy (EM).¹ Type 1 cryoglobulinemic glomerulonephritis exhibits a membranoproliferative or diffuse proliferative glomerulonephritis pattern on LM, usually with prominent intracapillary infiltrating monocytes and large, glassy intraluminal immune deposits.² Ultrastructurally, the deposits commonly show an annular-tubular or fibrillar substructure. The glomerular deposits in IT are composed of microtubular structures with a diameter of 30 to 50 nm and a tendency for parallel alignment, whereas in FGN they are composed of Congo red–negative, randomly oriented fibrils measuring 16 to 24 nm in diameter.³ Light- and heavy-chain amyloidosis is extremely rare and, similar to light chain amyloidosis, is characterized by the presence of Congo red–positive deposits composed of haphazardly oriented fibrils that measure 8 to 14 nm in diameter.⁴In 2004, we reported 10 patients with a novel form of glomerular injury related to monoclonal IgG deposition that could not be assigned to any of these conditions, which we termed “proliferative glomerulonephritis with monoclonal IgG deposits” (PGNMID).⁵ On IF, the glomerular deposits were monoclonal, staining for a single light-chain isotype and a single γ heavy-chain subclass. LM exhibited endocapillary proliferative or membranoproliferative glomerulonephritis, and EM revealed granular electron-dense deposits, mimicking ordinary immune-complex glomerulonephritis. Clinical presentations included proteinuria in 100% of patients (mean 24-h urine protein 5.8 g/d), renal insufficiency in 80% (mean serum creatinine 2.8 mg/dl), and micohematuria in 60%. A monoclonal serum or urine protein was identified in 50% of patients, although none of them had evidence of multiple myeloma (MM) or B cell lymphoproliferative disorder.⁵ The follow-up on these 10 patients was of short duration, and the treatment details were limited.This report enlarges our experience with PGNMID to 37 cases, representing the largest series to date. Our aim was to define better the natural history, presenting features, treatment, and outcome of this enigmatic disease.     

Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features

BACKGROUND: The clinical relevance of distinguishing two types of glomerulonephritis (GN) with non-amyloid organized immunoglobulin (Ig) deposits-fibrillary GN (FGN) and immunotactoid (microtubular) GN (IT/MTGN)-on the basis of ultrastructural organization, is debated. METHODS: Twenty-three patients with organized glomerular Ig deposits were classified into two groups based on the fibrillar or microtubular ultrastructural appearance of the deposits. Kidney biopsy samples were studied by immunofluorescence microscopy, using anti-light chain conjugates (all cases) and anti-IgG subclass conjugates (13 patients). In each group, we studied clinicopathological features, associated monoclonal gammapathy (detected by immunoelectrophoresis and/or immunoblot) or B-cell lymphoproliferative disease, effects of chemotherapy and long-term renal outcome. RESULTS: In 14 IT/MTGN and 9 FGN patients, clinical symptoms [hypertension, nephrotic syndrome (NS) and hematuria] and the mean diameters of the substructures were similar. In 13 IT/MTGN patients, glomerular (IgG1, 2 or 3) deposits were monotypic (kappa, 7 cases; lambda, 6 cases). Glomerular deposits were associated with a monoclonal Ig of the same isotype in eight patients, detected in the serum (5 cases), and/or in the cytoplasm of lymphocytes (4 cases), and with lymphoproliferative disease in seven patients. The ultrastructural features of monoclonal Ig inclusions in lymphocytes were similar to those of glomerular microtubular deposits. In contrast, none of the FGN patients presented lymphoplasmocytic proliferation or paraproteinemia. Glomerular Ig deposits were polyclonal in eight cases and contained IgG4 in all three cases studied. Although patient and renal survival did not differ significantly between the two groups, chemotherapy led to remission of NS in ten IT/MTGN patients, with parallel improvement in hematological parameters. CONCLUSIONS: The identification of ultrastructural patterns in these nephropathies is important. GN with organized microtubular monoclonal deposits (GOMMID) probably accounts for a large proportion of immunotactoid (microtubular) GN cases.     

透射电镜检查在冷球蛋白血症肾损害诊断中的作用

目的 探讨透射电镜检查在冷球蛋白血症肾损害诊断中的作用。方法 我院近6年来接受的肾活检病例中,透射电镜观察发现肾组织内有类似冷球蛋白沉积形成的特殊有形结构的病例共16例,对其临床、病理特征及超微结构改变进行分析。结果 4例血冷球蛋白检测阳性,诊断为冷球蛋白血症肾损害;其余12例未进行血冷球蛋白的检测,诊断为可疑的冷球蛋白血症肾损害。临床上表现为蛋白尿及镜下血尿,部分病例有肾病综合征、高血压及轻至中度肾功能不全。病理改变以膜增生性肾小球肾炎为主要病理类型,伴有毛细血管内细胞增生及单核细胞浸润,可见肾小球内皮细胞下及毛细血管腔内的嗜复红蛋白沉积形成白金耳或微血栓样结构。透射电镜检查可见肾小球内皮细胞下及毛细血管腔内的沉积物形成特殊的有形结构,表现为微管状、纤维样、晶格样或颗粒样等结构。大部分病例是通过电镜检查首先观察到肾组织内的特殊结构后才提示冷球蛋白血症肾损害的存在。结论 透射电镜检查发现肾组织内特殊结构的沉积物是诊断冷球蛋白血症肾损害的重要依据。     

Nodular glomerulosclerosis with deposition of monoclonal immunoglobulin heavy chains lacking C(H)1

The objective of this study was to further characterize the clinical and immunopathologic features of heavy chain deposition disease (HCDD), a recently described entity. Four patients were diagnosed as having HCDD on a kidney biopsy. All presented with nodular glomerulosclerosis with deposition of gamma1 heavy chains lacking CH1 epitopes, but without light chains. Two different patterns were observed in the serum. First, patients 1 and 2 had a circulating monoclonal IgGlambda containing a short gamma1 heavy chain lacking CH1 epitopes, with an apparent molecular weight of 40 kD consistent with a complete CH1 deletion. Biosynthetic experiments also showed that the deleted heavy chain was produced in excess compared with light chains, and was secreted in vitro together with half Ig molecules, although these abnormal components were not detected by Western blot analysis of whole serum. Second, patients 3 and 4 had a circulating monoclonal IgG1lambda with an apparently normal, nondeleted heavy chain subunit, but serum fractionation followed by immunoblotting revealed an isolated monoclonal gamma1 chain lacking CH1 epitopes. These data strongly suggest that renal deposition of a CH1-deleted heavy chain circulating in low amounts in the serum as a free unassembled subunit is a major feature of HCDD. The CH1 deletion is most likely responsible for the premature secretion in blood of the heavy chain by a clone of plasma cells.     

Morphologic variants of light-chain deposition disease in the kidney

A variety of histologic changes have been observed in the kidneys of patients with light-chain deposition disease. We report 3 cases with kappa light chain deposition who presented with diverse clinical, histological, and ultrastructural features. All the cases were diagnosed by the presence of monoclonal kappa light chain deposits by immunohistochemical methods. Based on the present study and review of literature, four basic patterns of glomerular lesions are identified: (1) minimal glomerular changes without glomerular deposits, but with extensive tubular involvement; (2) mild glomerular changes with glomerular deposits; (3) focal or diffuse proliferative glomerulonephritis with or without crescents, and (4) nodular glomerulosclerosis resembling diabetic glomerulosclerosis. This pathological and clinical variability can cause diagnostic problems at initial presentation. A high index of suspicion is necessary along with appropriate laboratory data and routine staining for light chains.     

A case of monoclonal immunoglobulin light- and heavy-chain deposition disease exhibiting atypical deposition with fibrillary structures, successfully treated with chemotherapy

We report a case of light and heavy chain deposition disease (LHCDD), a rather rare monoclonal immunoglobulin deposition disease (MIDD) with successful therapeutic effect. A 58-year-old woman suffered from proteinuria and renal insufficiency (serum creatinine 1.0 mg/dl, creatinine clearance 49.2 ml/min) in February 2003. In serum and urine samples, monoclonal IgG-kappa was detected. A bone marrow aspiration showed a slightly hypocellular marrow and plasma cell population was increased to 7.0%. Renal histological findings revealed lobulated glomeruli with nodular lesions on light microscopy, characteristic findings of MIDD. Intense deposition of IgG heavy chains in the linear pattern in the glomerular and tubular basement membranes was observed. Immunohistochemistry revealed both kappa and lambda light chain depositions in glomeruli. Electron-microscopic examination revealed fine granular electron-dense deposits accompanied by microfibrils. Based on these findings, this patient was diagnosed as LHCDD. She received three courses of melphalan and prednisone chemotherapy, resulting in disappearance of proteinuria, prevention of renal functional deterioration and the decrease of monoclonal immunoglobulin. This case clearly demonstrates that the earlier and accurate diagnosis and initiation of chemotherapy at the early stage with serum creatinine level below 4.0 mg/dl are necessary to improve renal and patient outcome.     

Pathology of glomerular deposition diseases and fibrillary glomerulopathies associated with paraproteinemia and haematopoietic disorder

SUMMARY:   The primary glomerulopathies with a deposit of ultrastructural fibrillary structure, which are negative for Congo-red stain but positive for immunoglobulins, include fibrillary glomerulonephritis and immunotactoid glomerulopathy. Several paraproteinemias, including cryoglobulinemia, monoclonal gammopathy and light chain deposition disease as well as haematopoietic disorders including plasmacytoma, plasma cell dyscrasia and B cell lymphoproliferative disorders involve glomerulopathy with an ultrastructural fibrillary structure. A rare glomerulopathy with fibrillary structure showing negative stain for Congo-red and for immunoglobulins has been also reported. The pathological diagnoses of these glomerulopathies with ultrastructural fibrillary deposits can include either glomerular diseases, or paraproteinemic diseases, or haematopoietic diseases. The terminology is still confusing when glomerular diseases can be combined with paraproteinemic diseases and/or haematopoietic diseases. Therefore, the generic term, 'glomerular deposition disease', has been proposed by pathologists with a requirement for clinicians to detect autoantibodies, paraproteins and to carry out a bone marrow check. An attempt has been made to elucidate the correlation among the glomerular deposition disease, paraproteinemia and haematopoietic disorder.     

Association of overt glomerulonephritis and liver disease: a study of 34 patients.

Thirty-four patients with overt glomerulonephritis and chronic liver disease were studied. Kidney specimens were examined by light, electron and immunofluorescence microscopy. Plasma C3 levels were measured and a search for cryoglobulinemia was carried out in all patients. Twenty-six out of the thirty-four patients had an immune complex type glomerulonephritis (membrano-proliferative glomerulonephritis or glomerulosclerosis with mesangial deposits) suggestive of hepatic glomerulonephritis. The glomerular deposits almost always contained IgA and very frequently other immunoglobulins as well as C3. The membrano-proliferative glomerulonephritis was characterized by severe renal symptoms, mixed cryoglobulinemia and the frequent finding of low C3 levels. These data suggest that there is a linkage between liver disease and glomerulonephritis. The immunomorphological type of glomerulonephritis and the cryoglobulinemia are both suggestive of an immune complex disease. The lowering of the C3 levels could be due to activation of complement components by immune complexes, to hepatic hyposynthesis, or to a combination of the two.     

Hypocomplementemic proliferative glomerulonephritis with C3 nephritic-factor-like activity in multiple myeloma

Advanced renal failure, nephrotic-range proteinuria due to proliferative glomerulonephritis and multiple myeloma with circulating IgG2 lambda and free lambda light-chain paraproteins occurred in a 31-year-old male. Commonly established causes of renal failure in multiple myeloma were excluded. Immunofluorescence revealed heavy granular glomerular deposition of C3. Serum C3 was decreased, and C3c was increased. C3 nephritic-factor (C3 NeF)-like activity was demonstrated in the serum. Plasmapheresis and chemotherapy resulted in a decrease in paraprotein concentration up to 90%, a decrease in C3 NeF-like activity to negligible, normal serum complement levels and a marked improvement in both renal function and proteinuria. With reference to the literature, the possibility of a syndrome of paraproteinemia, C3 NeF-like activity and glomerulonephritis is forwarded.     

Antineutrophil cytoplasmic antibody-associated glomerulonephritis with immunoglobulin deposition

Background

Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis is commonly classified as pauci-immune glomerulonephritis; however, some cases have granular immunoglobulin deposition along the glomerular capillary. The pathogenesis of immune deposits is poorly studied.

Methods

Of 66 patients diagnosed with ANCA-associated glomerulonephritis on renal biopsy, cases with immunoglobulin deposition along the glomerular capillary were identified and their clinicopathological characteristics were analyzed. We also performed myeloperoxidase (MPO) and double immunofluorescence (IF) stainings to determine the presence of immune complex antigens.

Results

Granular IgG deposition, IgG plus IgM deposition, and IgM deposition were observed in 15 (22.1%), 8 (11.2%), and 17 (25.0%) cases, respectively. In cases with granular IgG deposition, MPO-IgG double IF staining revealed co-localization of MPO and IgG. In cases with granular IgM deposition, MPO-IgM double IF staining did not co-localize. By electron microscopy, subepithelial deposition as well as intramembranous, subendothelial, and mesangial deposition was detected in the patients with IgG deposition. In addition, renal survival curves were not significantly different between the immunoglobulin deposition and non-deposition groups.

Conclusions

Granular IgG and/or IgM deposition was observed in 60.6% of patients with ANCA-associated glomerulonephritis. In cases with IgG deposition, electron-dense deposits (EDDs) were observed at various sites in the glomerulus, and MPO and IgG immunocomplex deposition was frequently observed along the glomerular capillary. With IgM deposition, EDDs were not obvious in the glomerular basement membrane, and MPO and IgM immunocomplex was not detected. These data suggest differential mechanism between IgG deposition and IgM deposition.

     

Successful treatment with steroid and cyclosporine A in a patient with immunoglobulin A–proliferative glomerulonephritis with monoclonal immunoglobulin deposits

We report a case of glomerulonephritis with monoclonal immunoglobulin (Ig) A deposits as a form of monoclonal gammopathy of renal significance (MGRS) caused by monoclonal immunoglobulins without blood disorders in a 41‐year‐old woman. She developed lower leg oedema and was hospitalized because of nephrotic syndrome. Serum and urine were negative for M protein, and the free light chain κ/λ ratio was within the normal range. Renal histopathological findings included mesangial proliferation, endocapillary cell proliferation, and a double‐contour appearance of the capillary walls. Immunofluorescent staining indicated IgA and C3 deposits on the mesangium and capillary walls. Only λ chain and IgA1 deposits were noted. Fine granular sub‐endothelial deposits with no specific structure were observed under electron microscopy. The patient was diagnosed with IgA–proliferative glomerulonephritis with monoclonal immunoglobulin deposits (IgA‐PGNMID). The patient had decreased urine protein and sediment erythrocytes after she underwent two rounds of steroid pulse therapy and oral steroid therapy, but proteinuria and haematuria still remained. Four months later, the patient was administered 50 mg/day cyclosporine (CsA), and proteinuria and haematuria dramatically decreased. Only a few case reports have been published on IgA‐PGNMID. This case is rare in that the patient achieved successful treatment using a combination of steroids and CsA.     

Glomerulonephritis, B monoclonal small lymphocytic lymphoma and mixed cryoglobulinemia

A novel association in the same patient with small lymphocytic lymphoma, type II cryoglobulinemia and glomerulonephritis is reported. This case is also characterized by a quite unusual sequence of glomerular alterations. A first renal biopsy showed severe endocapillary proliferative glomerulonephritis due to monocytic infiltration without any evidence of deposition of immune reactants. The immune deposits associated with type II cryoglobulinemia were only observed at a second renal biopsy performed five months later. This case shows that mononuclear cells can be responsible in and of themselves for severe glomerular damage, without deposition of immune material, and suggests that monocytic infiltration might be the first stage of type II cryoglobulinemia associated glomerulonephritis.     

Primary antiphospholipid antibody syndrome and mesangial IgA glomerulonephritis

The antiphospholipid antibody syndrome (APS) is characterized by recurrent thrombosis, fetal loss, multiorgan involvement, and the presence of lupus anticoagulant and/or anticardiolipin antibody. When not associated with systemic lupus erythematosus, other collagen diseases, or ingestion of medications, the condition is called primary APS. The kidney may be involved in the APS syndrome with acute nephritis and renal failure. The cases with renal biopsy studies have shown variable glomerular morphology, ranging from mild mesangial changes to a diffuse endocapillary proliferative glomerulonephritis. The most frequent lesion is thrombotic microangiopathy or features seen in the hemolytic uremic syndrome. Apart from fibrin thrombus deposition, only a few cases have shown focal and segmental deposits of IgG and/or IgM and/or C3. We describe a patient with primary APS who had thrombosis with lower limb amputation and acute renal failure. The renal biopsy specimen showed a focal proliferative glomerulonephritis with endothelial proliferation and damage, with diffuse heavy mesangial deposits of IgA and fibrinogen. This case with diabetes mellitus, but without diabetic nephropathy, represents the occurrence of primary APS and mesangial IgA nephropathy which potentiated the renal injury, leading to acute renal failure. The relationship to the Henoch-Sch?nlein syndrome is discussed.     

Lenalidomide plus dexamethasone for proliferative glomerulonephritis with monoclonal immunoglobulin deposits

Objective To evaluate the efficacy and safety of lenalidomide plus dexamethasone (LD) in patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Methods The clinicopathological data of PGNMID patients who were treated with LD protocol from January 2010 to October 2019 were retrospectively analyzed. Results All of 6 patients received LD treatment for≥3 months after renal biopsy in Jinling Hospital. During the follow-up period of 6 to 19 months, 3 patients achieved renal remission, and the renal remission rate was 50%(3/6). Light microscopy showed membranoproliferative glomerulonephritis and immunofluorescence showed single kappa type IgG3 was deposited in the mesangial region and the vascular loop. Before taking LD scheme, the median urinary protein were 7.76(1.27, 14.57) g/24 h, the median serum creatinine was 118.5(70.7, 289.1) μmol/L, and the median albumin was 34.5(22.4, 37.5) g/L. The concentration of serum free kappa and lambda light chain was increased in 5 patients, but the serum free light chain ratio was normal. Hypocomplementemia was detected in two cases. Six patients underwent bone marrow flow cytometry, and 2 patients had elevated monoclonal plasma cells, accounting for 0.7% and 0.5%, respectively. Immunofixation electrophoresis suggested that 1 patient had positive serum M protein for kappa type IgG3. At the last follow-up, median urine protein was 3.33(0.33, 11.23) g/24 h, median serum creatinine was 108.7(80.4, 160.9) μmol/L, and median albumin was 35.9(24.5, 45.6) g/L. The concentration of serum free light chain in 4 patients from 5 patients with elevated serum free light chain was lower than that before taking the drug. Decreased level of serum complement in two cases returned to normal after treatment. The M spike did not turn negative during the follow-up in one patient. Adverse events included anemia, neutropenia, limb numbness and upper respiratory tract infection. Conclusion This study reports for the first time that LD protocol may be effective in treating PGNMID, but more attention should be paid to the hematological adverse events of lenalidomide.