Clinical Predictive Value of Phospholipase A2 Receptor Gene Polymorphism Combined with Subclass of Immunoglobulin G in Renal Tissues for Membranous Nephropathy.

Context: Idiopathic membranous nephropathy (IMN) is a common pathologic type of nephrotic syndrome, and the level of the M-type phospholipase A2 receptor (PLA2R) antibody can serve as one index for predicting its progression and prognosis. However, patients with the same level can show great differences in their responses and prognoses. Objectives: The study aimed to explore the relationship between a PLA2R gene polymorphism combined with an immunoglobulin G (IgG) subclass in renal tissues and patients' responses to immunosuppressive therapy, to determine the clinical prognosis for IMN patients. Design: This is a prospective study. Patients with new onset membranous nephropathy who need treatment were selected and grouped according to the curative effect after 6 months of treatment. Setting: The study took place at the First Affiliated Hospital of Ningbo University, Ningbo, China. Participants: Participants were 60 patients with IMN, who had been admitted in the hospital between January 1, 2021 and June 30, 2022. Intervention: Participants first received standard immunosuppressive therapy for six months. The research team then clinically divided participants into two groups: (1) a remission group with 32 participants and (2) a nonremission group with 28 participants. Outcome Measures: The research team: (1) compared the groups, summarizing the demographic and clinical differences between the groups, (2) compared the PLA2R antibody titers at baseline and postintervention between the groups, (3) analyzed the genotyping of the PLA2R single nucleotide polymorphisms (SNPs) rs35771982 and rs4664308 loci as well as the human leukocyte antigen (HLA)-DQA1 SNP rs2187668 locus, and (4) compared the subclass IgG and PLA2R depositions in the renal tissues between the groups. Results: Compared with the remission group, the nonremission group included significantly more males (P < .05), was significantly older (P < .05), had significantly more participants with a BMI of >25 (P < .05), and included significantly more participants with a positive IgG3 (P < .01) than the remission group. The remission group's PLA2R antibody titers at baseline and postintervention weren't significantly different from those of the nonremission group. Postintervention, 24 participants in the remission group had a negative conversion of PLA2R antibodies, and 22 in the nonremission group had a negative conversion. The genotyping of the PLA2R SNP rs4664308 and the HLA-DQA1 SNP rs2187668 loci showed no relationship to the remission rate. The GC genotype on the PLA2R SNPrs35771982 locus may be a risk factor for a poor prognosis for IMN patients. Moreover, the patients with a positive IgG3 in the renal tissues and the GC genotype on the PLA2R SNPrs35771982 locus exhibited a poor response to immunosuppressive therapy and could need intensive treatment. Conclusions: The PLA2R gene polymorphism combined with the IgG subclass can predict the sensitivity of IMN patients to immunosuppressive therapy.

Clinicopathological features and long-term prognosis of glomerular diseases associated with mercury-containing cosmetics.

OBJECTIVE: The pathological types and long-term prognosis of glomerular diseases related to mercury exposure are unclear. This study retrospectively examined 41 cases of glomerulonephropathy caused by mercury-containing cosmetics. METHODOLOGY: Forty-one subjects with glomerular diseases presumably caused by mercury-containing cosmetics were selected. Clinical features, kidney biopsy, treatment, and follow-up data were collected. RESULTS: All patients were female with an average age of 39.4 ± 6.6 years at diagnosis. Median time of exposure to mercury-containing cosmetics was six months, and average urine mercury level was 66.80 ± 38.55ug/(g·Cr). Most patients presented with nephrotic syndrome. Renal histopathology showed membranous nephropathy in 22 patients (53.65%), minimal change disease in 13 patients (31.71%), IgA nephropathy with minimal change disease in 5 patients (12.20%), and focal segmental glomerulosclerosis in 1 patient. Median time of exposure to mercury was longer and the proportion of patients with autoantibodies (mainly antinuclear antibodies) was higher in patients with membranous nephropathy. Both blood phospholipase A2 receptor -Ab and kidney tissue phospholipase A2 receptor were negative. Thirty-six patients received glucocorticosteroids and/or immunosuppressants. Five patients were treated with an angiotensin receptor blocker, and nine patients were treated with chelation therapy. The median follow-up time was 40 months (range 27-94). All patients achieved complete remission, and the median time to complete remission was one month. They all successfully discontinued the drugs without relapsing; withdrawal time was 26 months. CONCLUSION: Membranous nephropathy was the most common pathological type in mercury-induced glomerular disease. Patients were sensitive to glucocorticosteroids and immunosuppressants and achieved complete remission quickly. Contrary to primary glomerulonephritides, patients with mercury-induced glomerular diseases had no relapses after withdrawal of the mercury containing cosmetics.

[Clinical Significance of IgG4 Level in Predicting the Activity and Outcome of Phospholipase A2 Receptor-associated Membranous Nephropathy].

Objective To investigate the feasibility of IgG4 as a biomarker of the activity and outcome of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (PLA2R-MN). Methods Serum and urine samples were collected from 56 patients with PLA2R-MN,13 patients with secondary membranous nephropathy (SMN),and 10 patients with primary IgA nephropathy (IgAN) when kidney biopsy was performed in the Department of Nephrology,Hangzhou Hospital of Traditional Chinese Medicine from April 2017 to January 2018.Sandwich enzyme-linked immunosorbent assay was employed to measure the serum and urinary IgG4 levels. Results The PLA2R-MN group had higher median serum IgG4/IgG ratio than the SMN group (P=0.009) and the IgAN group (P<0.001) and higher median urinary IgG4/creatinine ratio than the SMN group (P=0.008).In the patients with PLA2R-MN,the median serum IgG4/IgG ratio and urinary IgG4/creatinine ratio were significantly higher in the renal insufficiency group than in the normal renal function group (P=0.049,P=0.015).Moreover,the median serum IgG4/IgG ratio was higher in those with a serum albumin level<30 g/L than in those with a serum albumin level ≥30 g/L (P=0.005).Fifty-three patients with PLA2R-MN were followed up for at least 1 year,and the serum IgG4/IgG ratios of the patients in remission were lower than those of the patients without remission (P=0.005).The median serum IgG4/IgG ratio of 23 patients in remission decreased from 5.82% (4.54%,10.20%)(at initial enrollment) to 2.91% (2.11%,5.37%)(after 1-year follow up) in remission patients (P<0.001).The receiver operating characteristic curve showed that the patients with a serum IgG4/IgG ratio<10.24% had a higher possibility of remission (P=0.005). Conclusion Serum and urinary IgG4 levels may be an indicator of the activity in PLA2R-MN patients and thus may be a predictive biomarker of the outcomes.

Calcineurin inhibitor therapy in combination with Tripterygium wilfordii polyglycoside tablets for idiopathic membranous nephropathy: A retrospective clinical observation.

ABSTRACT: To compare the efficacy and safety of calcineurin inhibitor (CNI) and Tripterygium wilfordii polyglycoside tablets (TWPs) in treating idiopathic membranous nephropathy (IMN) with CNI and glucocorticoids (GCs).Data of patients with IMN who were treated with CNI+TWPs (TWP group) or CNI+GCs (GC group) and followed up for more than 12 months at the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from 2017 to 2020 were retrospectively analyzed. The 24-h urine protein (24hUP), serum albumin (ALB), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), serum creatinine, alanine aminotransferase, and aspartate transaminase levels on the third, sixth, ninth, and twelfth months of treatment and phospholipase A2 receptor (PLA2R) level before and after treatment were compared in both groups.We recruited 64 patients who were assigned to either the GC group (n = 31) or TWP group (n = 33). No difference in baseline indicators between the two groups were observed (P > .05). After 12 months, the 24hUP levels of both groups significantly decreased compared with that at baseline (P < .01). At the end of the sixth month, 24hUP of the TWP group were less and reduced more quickly than those in the GC group (P < .05), but there is no difference at the other time point (P > .05). After treatment, the number of patients who up to the standard of TG and the ALB levels in both groups increased (P < .05), the LDL-C levels and the number of patients positive for PLA2R in both groups were reduced (P < .05), and no significant difference was observed in the overall changes of 24hUP, ALB and LDL-C levels, TG compliance rate, and PLA2R positive rate between both groups (P > .05). During treatment, no patient in either group had hepatorenal dysfunction, one case in the TWP group and two cases in the GC group experienced side effects, but no apparent difference in the side effects were observed between both groups (P > .05).Two therapeutic schemes have the advantage of reducing urinary protein excretion in patients with IMN. Compared with CNI+GCs, CNI+TWPs have high efficiency and is widely applied, which might be considered as an optimum therapy in the future.

Retrospective analysis of Tripterygium wilfordii polyglycoside combined with angiotensin receptor blockers for the treatment of primary membranous nephropathy with sub-nephrotic proteinuria.

INTRODUCTION: Primary membranous nephropathy (PMN) is one common cause of end-stage kidney disease. There is no optimal treatment for PMN patients with sub-nephrotic proteinuria currently. Tripterygium wilfordii polyglycoside (TWG) is a widely used traditional medicine in China and has been used to treat nephropathy for decades. OBJECTIVE: To investigate the effect of TWG combined with angiotensin receptor blocker (ARB) on the treatment of PMN with sub-nephrotic proteinuria. METHODS: Biopsy-proven sub-nephrotic PMN patients with normal kidney function and treated with TWG combined with ARB or ARB alone were retrospectively analyzed. The primary outcome was remission rate (complete or partial remission), and the secondary outcomes included proteinuria, serum albumin levels, estimated glomerular filtration rate (eGFR), relapse rate, and adverse events. RESULTS: The clinical trial included 55 patients. The overall remission rates for the TWG + ARB and ARB groups after 9 months of treatment were 74.3% and 35%, respectively (p = 0.004). Moreover, the complete remission (CR) rate for the TWG + ARB and ARB groups in the 9th month were 45.7% and 15%, respectively (p = 0.044). Treatment with TWG + ARB was the independent predictor of complete remission of proteinuria (p = 0.048). Besides, the remission rate was higher in the TWG + ARB group than in the ARB group among patients who were positive for anti-phospholipase A2 receptor (PLA2R) antibodies (65.4% vs. 21.4%, p = 0.02). CONCLUSIONS: These data demonstrate that TWG may be a promising treatment for PMN patients with sub-nephrotic proteinuria, whether anti-PLA2R antibody is positive or negative.

Treatment of idiopathic membranous nephropathy.

Immunosuppressive treatment of patients with idiopathic membranous nephropathy (iMN) is heavily debated. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40-50% of patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of iMN. The guideline suggests that immunosuppressive therapy should be restricted to patients with nephrotic syndrome and persistent proteinuria, deteriorating renal function or severe symptoms. Alkylating agents are the preferred therapy because of their proven efficacy in preventing end-stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data on hard renal end points are limited. In this Review, we summarize the KDIGO guideline and address remaining areas of uncertainty. Better risk prediction is needed to identify patients who will benefit from immunosuppressive therapy, and the optimal timing and duration of this therapy is unknown because most of the randomized controlled trials were performed in low-risk or medium-risk patients. Alternative therapies, directed at B cells, are under study. The discovery of anti-M type phospholipase A2 receptor-antibodies is a major breakthrough and we envisage that in the near future, antibody-driven therapy will enable more individualized treatment of patients with iMN.

Enhancement of mast cell survival: a novel function of some secretory phospholipase A(2) isotypes.

This study tested the hypothesis that certain secretory phospholipase A(2) (sPLA(2)) isotypes act in a cytokine-like fashion through cell surface receptors to influence mast cell survival. Initial experiments revealed that sPLA(2) activity and sPLA(2) receptor expression are increased, and mast cells lost their capacity to maintain membrane asymmetry upon cytokine depletion. Groups IB and III, but not group IIA PLA(2), prevented the loss of membrane asymmetry. Similarly, group IB prevented nucleosomal DNA fragmentation in mast cells. Providing putative products of sPLA(2) hydrolysis to cytokine-depleted mast cells did not influence survival. Furthermore, catalytic inactivation of sPLA(2) did not alter its capacity to prevent apoptosis. Inhibition of protein synthesis using cycloheximide or actinomycin reversed the antiapoptotic effect of sPLA(2). Additionally, both wild-type and catalytically inactive group IB PLA(2) induced IL-3 synthesis in mast cells. However, adding IL-3-neutralizing Ab did not change Annexin V(FITC) binding and only partially inhibited thymidine incorporation in sPLA(2)-supplemented mast cells. In contrast, IL-3-neutralizing Ab inhibited both Annexin V(FITC) binding and thymidine incorporation in mast cells maintained with IL-3. sPLA(2) enhanced phosphoinositide 3'-kinase activity, and a specific inhibitor of phosphoinositide 3'-kinase reversed the antiapoptotic effects of sPLA(2). Likewise, sPLA(2) increased the degradation of I-kappaBalpha, and specific inhibitors of nuclear factor kappa activation (NF-kappaB) reversed the antiapoptotic effects of sPLA(2). Together, these experiments reveal that certain isotypes of sPLA(2) enhance the survival of mast cells in a cytokine-like fashion by activating antiapoptotic signaling pathways independent of IL-3 and probably via sPLA(2) receptors rather than sPLA(2) catalytic products.