Glomerular IgG4 Research Articles

Malignancy-associated membranous nephropathy: focus on diagnosis and treatment.

The clinicopathological features of malignancy-associated membranous nephropathy have been described previously, but information about diagnosis and treatment remains limited. Patients with malignancy-associated membranous nephropathy in a tertiary hospital in China between June 2012 and October 2021 were retrospectively reviewed. Forty-two patients with malignancy-associated membranous nephropathy were identified. Compared to patients with idiopathic membranous nephropathy, patients with malignancy-associated membranous nephropathy were older and less frequently showed glomerular phospholipase A2 receptor staining (37.9% vs 85.0%) and IgG4 predominant deposition (66.7% vs 95.0%). At diagnosis of membranous nephropathy, themalignancy was unknown in 67% (28/42) of patients and was detected only by tumor screening. Among the 19 patients with concurrent diagnosis of cancer and biopsy-proven membranous nephropathy, 15 received anticancer treatment alone initially. Six of the 10 patients who attained cancer remission achieved remission of membranous nephropathy, while none of the 5 patients without remission of cancer did, suggesting a causal relationship between the two diseases. Some patients with persistent or relapsing membranous nephropathy following cancerremissionachieved remission of membranous nephropathy after immunosuppressive therapy. Over a median follow-up of 24months, 25% (10/40) of patients died, mainly due to neoplasia. Tumor screening is important in patients with membranous nephropathy, especially in elderly patients and patients with negative phospholipase A2 receptor or non-IgG4 predominant deposition. Remission of membranous nephropathy can be observed following remission of cancer in some cases. Immunosuppressive therapy may be considered if membranous nephropathy does not remit after remission of cancer.

Clinicopathological features and outcome in elderly patients with idiopathic membranous nephropathy

Background Idiopathic membranous nephropathy (IMN) is the leading cause of nephrotic syndrome in the elderly. The treatment of idiopathic membranous nephropathy is quite challenging due to the particularity of elderly patients. This study intends to investigate the clinicopathological characteristics and initial therapeutic effect of idiopathic membranous nephropathy among elderly patients. Methods A retrospective study of 67 elderly patients (58.2% male, median age 69.0 years, range, 65–83 years) with biopsy-proven membranous nephropathy was conducted at Guangdong Provincial People’s Hospital from 2016 to 2020. Data on clinicopathological characteristics and initial therapeutic effects were analyzed. Results Of the 67 patients, the mean eGFR of overall patients was 66.49 mL/min/1.73m2 while the median urine protein-to-creatinine ratio (uPCR) and urine albumin-to-creatinine ratio (uACR) was 5676.73 mg/g and 2951.56 mg/g, respectively. Pathological data revealed that the membranous Churg’s stage II was the most frequent (71.64%). Moreover, glomerular PLA2R antigen fluorescence intensity of (+) and IgG4 antigen fluorescence intensity of (++) were detected in 63.6% and 86.4% of all patients, respectively. Overall, 44 patients, accounting for 65.7%, achieved remission including complete remission and partial remission within 1 year after renal biopsy. Compared with a non-remission group, the levels of uPCR (6274.6 vs. 3235.6 mg/g, p = 0.007) and uACR (3433.6 vs. 1773.2 mg/g, p = 0.017) were significantly higher in remission group. The proportion of immunosuppressive therapy in the remission group was also higher (86.4% vs. 30.4%, p < 0.01). Compared with conservative treatment, patients with combined treatment with glucocorticoid and cyclophosphamide (CTX) or glucocorticoid and calcineurin inhibitor (CNIs) achieved higher remission rate (glucocorticoid plus cyclophosphamide vs. conservative treatment, 84.6% vs. 27.3%, p = 0.001; glucocorticoid plus calcineurin inhibitor vs. conservative treatment, 88.0% vs. 27.3%, p < 0.001). Further analysis showed that compared with patients who underwent conservative treatment, the proportion of males, the levels of uPCR, uACR, BUN, Scr, CysC and PLA2R antigen-positive staining rate in kidney biopsy were higher in those who underwent combined treatment with glucocorticoid and CTX, while the levels of eGFR, TP and ALB were lower (p < 0.05). In addition, patients who received combined treatment with glucocorticoid and CNIs had higher levels of uPCR, uACR, TC and lower levels of TP, ALB than those who received conservative treatment (p < 0.05). Moreover, there were no statistically significant differences in the 1-year progression rate in eGFR between the immunosuppressive treatment group and conservative treatment group (3.3 vs. 0.2 ml/min/1.73m2, p = 0.852). Conclusions Most elderly patients diagnosed with IMN had multiple comorbidities, and the membranous Churg’s stage II was most common. The glomerular PLA2R and IgG4 antigen deposition were frequently detected accompanied by glomerulosclerosis and severe tubulointerstitial injury. For high-risk elderly patients with severe proteinuria, early initial immunosuppressive therapy could achieve a higher urinary protein remission rate. Therefore, it is crucial for clinicians to balance the risks and benefits of immunosuppressive therapy based on clinical and pathological characteristics and develop individualized treatment regimens for elderly patients with IMN.

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.

Characteristics and renal survival of patients with lupus nephritis with glomerular immunoglobulin G4 deposition: a single-centre retrospective analysis

ObjectiveRenal injury is common in SLE. Immune complex deposition plays an important role in the development of lupus nephritis (LN), while little is known about glomerular IgG4 deposition in patients...

Clinicopathological features in membranous nephropathy with cancer: A retrospective single-center study and literature review.

Membranous nephropathy is the most common glomerular disease related to malignancy. However, it is difficult to distinguish between true malignancy-related membranous nephropathy and idiopathic membranous nephropathy coincident with cancer. It has been reported that phospholipase A2 receptor (PLA2R) is the first autoantigen involved in idiopathic membranous nephropathy and thrombospondin type-1 domain-containing 7A (THSD7A) may have a close relationship with malignancy-related membranous nephropathy. Therefore, the aim of this study was to compare the clinicopathological characteristics between membranous nephropathy patients with cancer and idiopathic membranous nephropathy patients without cancer to better detect malignancy-related membranous nephropathy, including glomerular PLA2R and THSD7A depositions and their circulating antibodies, together with glomerular IgG4 deposition. Twelve membranous nephropathy patients with cancer and 257 idiopathic membranous nephropathy patients without cancer were included in this study and had been followed up for more than 1 year. The glomerular expression of PLA2R, THSD7A, and IgG4 was analyzed by immunohistochemistry. Circulating anti-PLA2R and anti-THSD7A antibodies were assessed by enzyme-linked immunosorbent assay and indirect immunofluorescence testing, respectively. Membranous nephropathy patients with cancer were significantly older and had higher serum creatinine and a lower estimated glomerular filtration rate than idiopathic membranous nephropathy patients (P<0.05). The positive rates of glomerular PLA2R and IgG4 depositions and circulating anti-PLA2R antibodies in membranous nephropathy patients with cancer were significantly lower than those in idiopathic membranous nephropathy patients without cancer (P<0.01). The absence of glomerular PLA2R deposition and negative circulating anti-PLA2R antibodies, along with negative glomerular IgG4 staining, may be useful clues to more accurately screen underlying malignancies in membranous nephropathy patients.

FP146The diagnostic value of glomerular PLA2R and IgG4 between idiopathic and secondary membranous nephropathy

FP146The diagnostic value of glomerular PLA2R and IgG4 between idiopathic and secondary membranous nephropathy

Clinicopathological and long-term prognostic features of membranous nephropathy with crescents: a Japanese single-center experience.

Three recent studies from the United States and China reported the clinicopathological features and short-term prognosis in patients with membranous nephropathy (MN) and crescents in the absence of secondary MN, anti-glomerular basement membrane (GBM) antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA). We compared clinicopathological and prognostic features in 16 MN patients with crescents (crescent group) and 38 MN patients without crescents (control group), in the absence of secondary MN, anti-GBM antibodies, and ANCA. Median follow-up periods in the crescent and control groups were 79 and 50months, respectively. Decreased estimated glomerular filtration rates (<50mL/min/1.73m2), glomerulosclerosis, and moderate-to-severe interstitial fibrosis were more frequently observed in the crescent group than in the control group (P=0.043, P=0.004, and P=0.035, respectively). Positive staining rates for glomerular IgG2 and IgG4 were significantly different between the 2 groups (P=0.032, P=0.006, respectively). Doubling of serum creatinine during follow-up was more frequently observed in the crescent group than in the control group (P=0.002), although approximately two-thirds of patients in the crescent group were treated with immunosuppressive therapy. Crescent formation and interstitial fibrosis were risks for doubling of serum creatinine [hazard ratio (HR)=10.506, P=0.012; HR=1.140, P=0.009, respectively]. This is the first Japanese study demonstrating significant differences in clinicopathological and prognostic features between the 2 groups. Most patients in the crescent group may develop a long-term decline in renal function despite immunosuppressive therapy.

Patients With Combined Membranous Nephropathy and Focal Segmental Glomerulosclerosis Have Comparable Clinical and Autoantibody Profiles With Primary Membranous Nephropathy: A Retrospective Observational Study.

Patients with combined membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS) have been reported with different clinical significance. Investigations on the possible mechanisms of the combined glomerular lesions are necessary but scarce. Twenty patients with both MN and FSGS lesions were enrolled in the study. Sixty-five patients with primary MN and 56 patients with primary FSGS were used as disease controls. Clinical data on renal biopsy and during follow-up were collected. Circulating anti-phospholipase A2 receptor (PLA2R) antibody, glomerular PLA2R expression, IgG4 deposition, and soluble urokinase receptor (suPAR) levels were detected. We found that patients with combined lesions presented with older age, less proteinuria, higher albumin, and better renal function on biopsy. These were comparable to the patients with primary MN, but differed from the patients with primary FSGS. Patients with combined lesions showed higher stages of MN, no cellular variant on FSGS classification, and more common (100.0%) tubulointerstitial injury than both primary MN and primary FSGS patients. In the patients with combined lesions, 80.0% had circulating anti-PLA2R antibody and 68.4% had IgG4 predominant deposition in glomeruli, which were comparable to primary MN. The patients with combined lesions had significantly lower urinary suPAR concentrations, than the primary FSGS patients (315.6 ± 151.0 vs 752.1 ± 633.9 pg/μmol; P = 0.002), but similar to the primary MN patients (267.9 ± 147.5 pg/μmol). We conclude that patients with combined MN and FSGS may share the same underlying pathogenesis with primary MN. The FSGS lesion might be secondary to primary MN.

Glomerular IgG subclasses in idiopathic and malignancy-associated membranous nephropathy.

BackgroundIn idiopathic membranous nephropathy (MN), antibodies directed towards the glomerular phospholipase A2 receptor (PLA2R) have mainly been reported to be of IgG4 subclass. However, the role of the different IgG subclasses in the pathogenesis of MN, both in idiopathic MN and in secondary cases, is still unclear. In this retrospective study, we test the hypothesis that the absence of glomerular IgG4 and PLA2R in patients with MN indicates malignant disease.MethodsThe distribution pattern of glomerular IgG subclasses and PLA2R was studied in 69 patients with idiopathic MN and 16 patients with malignancy-associated MN who were followed up for a mean of 83 months.ResultsA significant correlation between the absence of IgG4 and PLA2R and malignancy-associated MN was found. Thus, IgG4 was positive in 45 of 69 patients (65%) with idiopathic MN but only in 5 of 16 patients (31%) with malignancy-associated MN. The other IgG subclasses did not differ statistically between the groups, IgG2-positivity being present in more than 94% of patients in both groups. Thirty-five of 63 patients (56%) with idiopathic MN and 3 of 16 (19%) patients with malignancy-associated MN had glomerular deposits of PLA2R.ConclusionsWe have found that the absence of glomerular IgG4 and PLA2R is common in patients with malignancy-associated MN. In our material, IgG2 could not be used as a marker of underlying malignant disease. Finally, neither IgG1 nor IgG3 seems to be involved in the pathogenesis of MN.

IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression

Recent breakthrough findings revealed that most patients with idiopathic (primary) membranous glomerulonephritis have IgG4 antibodies to the phospholipase A2 receptor (PLA2R). These IgG4 antibodies can be detected in the glomerular immune complexes and they colocalize with PLA2R. In secondary forms of membranous glomerulonephritis, such IgG4 antibodies are absent or less prevalent. There are no studies addressing the IgG subclass distribution across different stages of membranous glomerulonephritis. During a 25-month period, we identified 157 consecutive biopsies with membranous glomerulonephritis with adequate tissue for light, immunofluorescence and electron microscopy. Of the 157 membranous glomerulonephritis cases, 114 were primary membranous glomerulonephritis and 43 were secondary membranous glomerulonephritis. We compared the intensity of IgG subclass staining (on a semiquantitative scale of 0 to 3+) and the IgG subclass dominance between primary and secondary membranous glomerulonephritis and between the different stages of membranous glomerulonephritis. In primary membranous glomerulonephritis most (76% of cases) were IgG4 dominant. In contrast, in secondary membranous glomerulonephritis IgG1 was dominant in 60% of biopsies (P=0.0018). Interestingly, in early stage (stage 1) primary membranous glomerulonephritis, IgG1 was the dominant IgG subclass (64% of cases); in all later stages IgG4 dominated (P=0.0493). It appears that there is an inverse relationship between the intensity of glomerular capillary IgG4 and C1q staining. In secondary forms of membranous glomerulonephritis (heterogeneous group with low case numbers), we did not find such associations. Our data indicate that in early stage membranous glomerulonephritis, antibody response is different from later stages, with IgG1 dominant deposits. It is possible that early on, antigens other than PLA2R have an important role, Alternately, there may be an IgG subclass switch in the antibody response with IgG4 taking over later as the dominant immunoglobulin.

Membranous nephropathy associated with type 1 autoimmune pancreatitis and dominant glomerular IgG4 deposit.

We report a case of membranous nephropathy associated with type 1 autoimmune pancreatitis. A 58-year-old man presented with anorexia. Work-up revealed a mass in the pancreatic head, which was subsequently resected. Pathological examination showed diffuse infiltration of immunoglobulin (Ig) G4-positive plasma cells, which was compatible with the diagnosis of type 1 autoimmune pancreatitis. Serum IgG4 was elevated. He developed nephrotic syndrome around the time of the surgery. Kidney biopsy confirmed the diagnosis of membranous nephropathy. Immunofluorescent staining showed predominant glomerular IgG4 deposit among IgG subclasses. Tubulointerstitial nephritis, which is usually a dominant feature of renal involvement in IgG4-related disease, was not observed. The patient was treated with prednisolone and several immunosuppressants. During the course, the degree of proteinuria was associated with the serum IgG4 level. Serum antibody against phospholipase A2 receptor was negative. These findings together with IgG4-dominant glomerular deposit suggest that IgG4 may play a unique role in the pathogenesis of secondary membranous nephropathy caused by IgG4-related diseases.

Absence of glomerular IgG4 deposition in patients with membranous nephropathy may indicate malignancy

The renal pathological manifestations of malignancy-associated membranous nephropathy (M-MN) and idiopathic membranous nephropathy (I-MN) are similar. It has been suggested that glomerular IgG4 deposition may play an important role in the pathogenesis of I-MN. In the present study, we compared the IgG subclass of immune complex deposition, clinical data and pathological data of patients with M-MN and I-MN. Eight patients with M-MN and 42 patients with I-MN diagnosed between 1997 and 2009 in our hospital were enrolled. The clinical and pathological data were retrospectively collected, and glomerular IgG subclass deposition was detected by immunohistochemistry. Patients with M-MN were older (P = 0.003), with lower serum albumin (P = 0.034) and higher serum C-reactive protein (CRP) level (P = 0.003) than patients with I-MN. The majority of patients with M-MN had earlier pathological stages (P = 0.003) and less IgG deposition in glomeruli (P = 0.029). Absence of IgG4 deposition in glomeruli was notably observed in patients with M-MN (7/8 in M-MN versus 6/42 in I-MN, P < 0.001) and it was an independent predictor for occurrence of malignancy (hazard ratio 0.065, 95% confidence intervals 0.007-0.571, P = 0.014). Absence of glomerular IgG4 deposition, together with older age, severe hypoalbuminemia and high serum CRP level could be useful clues to differentiate M-MN from I-MN.

Distribution of glomerular IgG subclass deposits in patients with membranous nephropathy and anti-U1 ribonucleoprotein antibody

It is known that a predominant glomerular deposition of IgG4 is characteristic of idiopathic membranous nephropathy (MN) and that significant deposition of other IgG subclasses is also observed in lupus MN. However, there is no report focusing on the distribution of glomerular IgG subclass deposits in MN patients with anti-U1 ribonucleoprotein (RNP) antibody. We evaluated clinicopathological features and the distribution patterns of glomerular IgG subclass deposits in seven MN patients with positive anti-RNP antibody and negative antibodies to double-stranded DNA (dsDNA) and Smith antigen (Sm) (RNP-MN group) and in seven age- and sex-matched lupus MN patients with positive anti-dsDNA antibody and negative antibodies to RNP and Sm (L-MN group). Mixed connective tissue disease was diagnosed in four patients in the RNP-MN group. Two patients in the RNP-MN group and three patients in the L-MN group developed nephrotic syndrome. Renal insufficiency was not present in all patients in both groups. Hypocomplementemia was found in two patients in the RNP-MN group and six patients in the L-MN group. In the RNP-MN group, positive stainings for glomerular IgG1, IgG2, IgG3 and IgG4 were observed in one, seven, zero and five patients, respectively. On the contrary, in the L-MN group, positive stainings for glomerular IgG1, IgG2, IgG3 and IgG4 were observed in seven, seven, seven, and six patients, respectively. This is the first study showing striking differences in the distribution of glomerular IgG subclass deposits between RNP-MN and L-MN groups. RNP-MN and L-MN may result from different immunological mechanisms.

Predominant tubulointerstitial nephritis in a patient with systemic lupus erythematosus: phenotype of infiltrating cells

A 63-year-old man with systemic lupus erythematosus developed tubular proteinuria. All subclasses of serum IgG increased, and the largest IgG subclass increase was IgG4. A renal biopsy showed lupus nephritis (Class II) with severe tubulointerstitial nephritis (so-called predominant tubulointerstitial lupus nephritis, an unusual form of lupus nephritis). Immunofluorescence microscopy revealed positive granular staining for IgG, C3 and C1q in the mesangium and peritubular interstitium, and along the tubular basement membranes (TBM). Electron microscopy also showed electron-dense deposits in the mesangium and TBM. Immunophenotyping of interstitial infiltrating cells disclosed a predominance of T cells. CD8-positive cytotoxic T cells infiltrated the peritubular interstitium, and some of these cells infiltrated the tubules. B cell-rich lymphoid follicles were also observed. IgG subclass analyses showed glomerular IgG1, IgG2 and IgG4 deposition, positive staining of IgG4 in the peritubular interstitium and along the TBM, and abundant IgG1-, IgG3- and IgG4-positive plasma cells in the interstitium. The patient responded well to moderate-dose steroid therapy. This is the first report of immunophenotyping of interstitial infiltrates in predominant tubulointerstitial lupus nephritis. The results suggest CD8-positive cytotoxic T cell-mediated tubular injury. Furthermore, immune complexes containing IgG4 might be one of etiologic factors.

Evaluation of T helper-1/-2 balance on the basis of IgG subclasses and serum cytokines in children with glomerulonephritis

Background:To clarify the mechanism of deposition of immunoglobulin G (IgG) subclasses in glomerulonephritis in children, we investigated IgG subclasses in glomerular deposits and T helper subtype 1 (TH1)/TH2 cytokine balance in pediatric patients with glomerulonephritis. Methods:We enrolled 95 children in whom glomerulonephritis had been diagnosed in our hospital between 1993 and 2000. Patients were divided into 5 groups according to histological diagnosis: 31 patients with lupus nephritis (LN), 22 patients with membranoproliferative glomerulonephritis (MPGN), 7 patients with membranous glomerulonephritis (MGN), 20 patients with Henoch-Schönlein purpura nephritis, and 20 patients with IgA nephropathy. We compared serum IgG subclass values, serum cytokine (interleukin-2 [IL-2] receptor [IL-2R], IL-2, IL-4) values, and immunofluorescence evidence of glomerular IgG subclasses in the kidney among groups. Results:(1) High serum IgG1 and IgG2 values and glomerular IgG1 and IgG2 deposits were found frequently in the LN group. (2) High serum IgG3 values and glomerular IgG3 deposits were found frequently in the MPGN group. (3) High serum IgG4 values and glomerular IgG4 deposits were found frequently in the MGN group. (4) Conversely, cytokine measurements showed high serum IL-2 and IL-2R values in the LN and MPGN groups, and serum IL-4 values were high in the MGN group. Conclusion:These findings suggest that the pathogenetic mechanism of LN may involve both the TH1 and TH2 pattern, the pathogenetic mechanism of MPGN may involve the TH1 pattern, and the pathogenetic mechanism of MGN may involve the TH2 pattern.