Caracterización de enfermedades glomerulares: análisis de 22 años de biopsias renales / Frequency of glomerular diseases in an analysis of 550 kidney biopsies

BACKGROUND: The frequency of glomerular diseases is dynamic and varies according to geographic area. AIM: To evaluate the frequency of primary and secondary glomerulopathies, their demographic profile and main clinical characteristics. MATERIAL AND METHODS: Renal biopsies from native kidneys performed between 1999 and 2020 were retrospectively reviewed. Demographic characteristics, clinical presentation, most relevant laboratory tests, frequency of primary and secondary glomerulopathies were analyzed. RESULTS: We analyzed 550 kidney biopsies from patients with a median age of 48 years (64% females). Nephrotic syndrome was the main indication for renal biopsy. Primary and secondary glomerulopathies occurred with similar frequency. Within the primary glomerulopathies, membranous nephropathy (34.1%) was the most common, followed by IgA nephropathy (31.1%) and focal segmental glomerulosclerosis (14.1%). Among the secondary glomerulopathies, lupus nephropathy was the most common (41.7%), followed by pauciimmune glomerulonephritis (27.1%) and diabetic nephropathy (6.4%). When comparing the results with other regions, significant differences were observed with reported frequencies in United States, Europe, Asia and the rest of Latin America. CONCLUSIONS: The most common primary glomerulopathies were membranous nephropathy and IgA nephropathy. Among the secondary glomerulopathies lupus nephropathy and pauci-immune glomerulonephritis were the most common. Compared to international registries, we observed a high proportion of membranous nephropathy and pauci-immune glomerulonephritis.

Comparison of efficacy and safety of rituximab at different doses in the treatment of idiopathic membranous nephropathy / 中华肾脏病杂志

It was a retrospective cohort study. Patients diagnosed with idiopathic membranous nephropathy (IMN) and received rituximab (RTX) alone for one course of treatment during hospitalization in the Department of Nephrology of the First Hospital of Jilin University from March 2020 to March 2022 were enrolled. The patients were divided into 1 g standard treatment group (once 1 g every 2 weeks for twice) and 375 mg/m 2 experimental treatment group (375 mg/m 2 once a week for 4 weeks) according to the different methods of drug administration, and the efficacy and safety of different doses of RTX in the treatment of IMN were compared between the two groups to provide a reference for optimizing the clinical treatment protocol. The patients were followed up regularly for more than 9 months after treatment and the data were complete. A total of 69 patients were included with age of (51.7±11.8) years old, and 46 males (66.7%). There were 31 patients in the 1 g standard treatment group and 38 patients in the 375 mg/m 2 experimental treatment group. The proportion of first-treatment patients in the 1 g standard treatment group was higher than that in the 375 mg/m 2 experimental treatment group (87.1% vs. 65.8%, χ2=4.174, P=0.041). There were no statistically significant differences in the general data, clinical characteristics and baseline laboratory parameters between the two groups (all P>0.05). At the end of 3 months of treatment, 22 patients (31.9%) experienced remission, including 9 patients (29.0%) in the 1 g standard treatment group and 13 patients (34.2%) in the 375 mg/m 2 experimental treatment group ( χ2=0.211, P=0.646). At 6 months, 30 patients (43.5%) experienced remission, including 12 patients (38.7%) in the 1 g standard treatment group and 18 patients (47.4%) in the 375 mg/m 2 experimental treatment group ( χ2=0.521, P=0.470). At 9 months, 38 patients (55.1%) achieved remission, including 18 patients (58.1%) in the 1 g standard treatment group and 20 patients (52.6%) in the 375 mg/m 2 experimental treatment group ( χ2=0.204, P=0.652). At 9 months, the 24 h urine protein of 1 g standard treatment group and 375 mg/m 2 experimental treatment group decreased by 7.93 (6.24, 8.46) g and 7.45 (5.66, 8.67) g (both P<0.05), respectively, and serum albumin increased by 16.4 (15.5, 17.5) g/L and 15.5 (9.0, 15.8) g/L (both P<0.05), respectively, from the baseline value. Kaplan-Meier survival analysis result showed that there was no significant difference in the time of phospholipase A2 receptor titer decreasing to <5 RU/ml between the two groups (Log-rank χ2=3.653, P=0.056). Twenty-three non-serious adverse events occurred in the 1 g standard treatment group, involving 16 patients, and 10 non-serious adverse events occurred in the 375 mg/m 2 experimental treatment group, involving 10 patients. There was better safety in the 375 mg/m 2 experimental treatment group than that in the 1 g standard treatment group ( Fisher value=8.593, P=0.015). Both 375 mg/m 2 regimen and 1 g regimen of RTX in IMN patients are effective in relieving proteinuria and elevating serum albumin. The 375 mg/m 2 regimen of RTX has a lower incidence of adverse events compared with the 1 g regimen.

IgG4-related kidney disease complicated with membranous nephropathy in one patient with multiple metastatic lung malignancies / 中华肾脏病杂志

Here we report the diagnosis and treatment of a rare IgG4-related kidney disease with nephrotic syndrome as the first manifestation. A 62-year-old male patient, presented with edema in both lower limbs and foam urine, had a history of "lung malignant tumor with brain and lymph node metastasis". The increase of IgG4 and decrease of glomerular filtration rate were detected at admission, and the pathological consideration of renal biopsy was membranous nephropathy with IgG4-related tubulointerstitial nephritis. After the combination of low-dose glucocorticoids therapy and rituximab treatment, the patient showed good prognosis in a 9 month follow-up.

Three cases of obinutuzumab treatment for rituximab-resistant phospholipase A 2 receptor- associated membranous nephropathy / 中华肾脏病杂志

Rituximab is currently used as a first-line therapy for phospholipase A 2 receptor-associated membranous nephropathy due to its good efficacy and safety. Although the remission rate after rituximab treatment is more than 60%, nearly 40% patients still do not respond to treatment. We used obinutuzumab to treat 3 cases of rituximab resistant PLA 2R-associated membranous nephropathy. After the first dose of 1 000 mg with or without additional dose, the amount of anti-PLA 2R antibody and urinary protein decreased significantly and the adverse reactions were mild. The results show that obinutuzumab has a certain therapeutic effect on rituximab resistant PLA 2R-associated membranous nephropathy, but the time of follow-up observation is short and can only be used as individual cases, which needs to be confirmed by a large sample and high-quality prospective cohort study.

Influencing factors of early non-remission of proteinuria in patients with idiopathic membranous nephropathy / 中华肾脏病杂志

Objective:To investigate the influencing factors of non-remission of proteinuria in patients with nephrotic syndrome (NS) and idiopathic membranous nephropathy (IMN).Methods:The study was a retrospective observational study. The clinical data of patients with NS who were diagnosed as IMN by renal biopsy and serum albumin recovered normal after six months of treatment were collected from Beijing Anzhen Hospital, Capital Medical University from June 1, 2010 to January 31, 2022. Patients were divided into proteinuria remission group and non-proteinuria remission group according to whether urinary protein < 3.5 g/24 h and decreased 50% from the onset. The differences of clinical and pathological characteristics between the two groups at baseline were compared. The logistic regression model was used to analyze the influencing factors of non-remission of proteinuria.Results:Ninety-five NS patients with renal pathology of IMN were included in this study, with age of 57(43, 65) years old and 50 males (52.6%). There were 75 patients in the proteinuria remission group and 20 patients in the non-proteinuria remission group. Compared with the proteinuria remission group, the non-proteinuria remission group had higher baseline body mass index [(26.83±4.03) kg/m 2vs. (24.68±3.97) m 2, t=-2.149, P=0.034] and proportion of overweight (85.0% vs. 58.7%, χ2=4.765, P=0.029), and larger waist circumference [88.5(85.3, 101.5) cm vs. 87.0(77.5, 92.0) cm, Z=2.362, P=0.018]. Renal pathological results showed that the proportions of diabetes nephropathy (10.0% vs. 0, P=0.043) and glomerular hypertrophy (45.0% vs. 20.0%, χ2=5.227, P=0.022) were higher, and the average diameter of hypertrophic glomeruli was longer [(197.96±6.37) μm vs. (193.51±8.50) μm, t=2.029, P=0.041] in the proteinuria remission group than those in the non-proteinuria remission group. Multivariate logistic regression analysis results showed that waist circumference was an independent influencing factor of non-proteinuria remission in patients with IMN under waist circumference > 90 cm in men and >85 cm in women ( OR=1.083, 95% CI 1.005-1.168, P=0.037). Conclusion:Abdominal obesity is an independent risk factor of non-remission of proteinuria in NS patients with IMN after early treatment.

Neural epidermal growth factor-like 1 protein-related membranous nephropathy complicated with moyamoya syndrome: a case report and literature review / 中华肾脏病杂志

Except for IgA nephropathy, membranous nephropathy (MN) is the most common primary glomerulonephritis in China. Neural epidermal growth factor-like 1 protein (NELL-1) has been currently considered as one of the target antigens for diagnosis of primary MN. Moyamoya syndrome is a syndrome with clinical and imaging manifestations of moyamoya disease and possible vascular stenosis. By far, primary MN complicated with moyamoya syndrome has not been reported internationally. The paper reports a case of NELL-1-related MN complicated with moyamoya syndrome and reviews relevant literature to provide evidence for clinical diagnosis and treatment.

Clinicopathological characteristics and prognosis of idiopathic membranous nephropathy with or without C3 deposition / 中华全科医师杂志

Objective:To investigate the clinicopathological characteristics and prognosis of idiopathic membranous nephropathy (IMN) with or without C3 deposition.Methods:Clinical and pathological data of 576 patients with IMN diagnosed in Affiliated Hospital of Qingdao University from January 2017 to January 2021 were retrospectively analyzed. The patients were divided into C3 deposition group and non-C3 deposition group according to the immunofluorescence staining of C3. The clinical and pathological characteristics were compared between the two groups. Kaplan-Meier survival curve was used to compare the prognosis of the two groups.Results:A total of 576 IMN patients (male 364 (63.20%)) were enrolled, including 400 patients (69.44%) with C3 deposition and 176 patients (30.56%) without C3 deposition. Compared with the non-C3 deposition group, the levels of total blood cholesterol ( t=0.94, P=0.002) and the proportion of phospholipase A2 receptor ( χ2=9.99, P=0.002), IgG ( χ2=10.67, P=0.001), IgM ( χ2=7.00, P=0.008), IgA ( χ2=7.87, P=0.005) and C1q ( χ2=8.28, P=0.004) depositions in renal tissues was higher in C3 deposition group, while the levels of serum C3 ( t=2.87, P=0.004), albumin ( t=3.57, P<0.001) and IgG ( Z=3.55, P<0.001) were lower in C3 deposition group. There were no significant differences in other clinicopathological indicators between the two groups. The survival analysis was performed in 460 patients who were followed for>6 months, including 319 cases (69.35%) of C3 deposition and 141 cases (30.65%) of non-C3 deposition. The end point event was defined as an eGFR decline>30% or entry into end stage renal disease (ESRD). There was no statistically significant difference in treatment method between the two groups ( P>0.05). The median follow-up time was 22 (13,32) months, 327 (71.09%) patients achieved remission, and 22 patients had renal end-point events. Compared with the non-C3 deposition group, the proportion of urinary protein remission was lower ( χ2=10.85, P<0.05), the incidence of renal end-point events was higher ( χ2=5.05, P<0.05). Kaplan-Meier survival analysis showed that patients with C3 deposition had a lower cumulative remission rate (Log-rank χ2=6.68, P=0.010), and a lower cumulative renal survival than those without C3 deposition had ( χ2=5.42, P=0.020). Conclusions:Compared with patients without C3 deposition, IMN patients with C3 deposition have more severe clinical and pathological changes, lower renal cumulative remission rate, and are more likely to have poor prognosis.

Analysis of the characteristics of IgG4-related membranous nephropathy with literature review / 中华风湿病学杂志

Objective:By retrospectively analyzing 6 cases of IgG4-related membranous nephropathy (IgG4-MN), combined with literature review, to explore the clinical and renal pathological characteristics of the disease, and improve clinicians' understanding of the disease.Methods:The data of six patients with biopsy-proven IgG4-MN in the nephrology center of our hospital during April 2017 to January 2021 were collected. At the same time, we reviewed the literature systematically and summarized the clinicopathological characteristics.Results:Six male patients with the age ranged fom 55 to 75 years old were described. Urine protein level was (3.1±2.1) g/24 h, 3 cases (50%) showed nephrotic syndrome and 4 cases (67%) had elevated serum creatinine. The median creatinine level was (103±24) μmol/L. Six cases (100%) had elevated serum immunoglobulin (Ig)E level, and 4 cases (67%) had elevated IgG4. M-type phospholipase A2 receptor (PLA2R) was positive in 1 case (17%) and tubulointerstitial nephritis (TIN) was present in 6 cases. The review of the literature suggested that a total of 49 cases with IgG4-MN were reported, including 6 cases in this report. There were 40 males (40/46, 87%), with a age range of (61±12) years old, 32 cases (32/49, 65%) showed nephrotic syndrome range proteinuria, and the proportion of serum IgG and IgG4 increase was 61%(20/33) and 88% (36/41), respectively, 13 cases (13/15, 87%) had elevated serum IgE level, 47% (14/30) had low-complement C3 and 44%(12/27) had low-complement C4 level. The main organs involved were pancreas (15/37) and lymph nodes (16/37). Renal pathology showed TIN in 74%(36/49). Electron dense deposition was mainly subepithelial deposits. 7%(2/28) were positive for anti-PLA2R antibody in serum, 17%(3/18) were positive for PLA2R in kidney tissue, 6%(1/18) were suspected positive for PLA2R in kidney tissue, and 8%(1/12) were dual positive in blood and kidney tissue.Conclusion:IgG4-MN usually presents with nephrotic range proteinuria or nephrotic syndrome in middle-aged and elderly patients. Most of them are complicated with TIN and other organ involvement. A certain proportion of patients are PLA2R positive in IgG4-MN, and whether it is primary or secondary MN needs further study.

Analysis of treatment responses and kidney prognosis of atypical membranous nephropathy / 中华肾脏病杂志

Objective:To analyze the clinicopathological characteristics, treatment responses and kidney outcomes of patients with atypical membranous nephropathy (MN), and to provide information for the clinical practice.Methods:The clinical data of patients with atypical MN and synchronous primary MN who were diagnosed, treated and followed up in Peking University First Hospital from January 2008 to June 2020 were retrospectively collected and analyzed. Clinicopathological features, treatment responses and kidney prognosis were compared between the two groups. The expression of phospholipase A2 receptor (PLA2R) in kidney tissues was detected by immunofluorescence. Serum anti-PLA2R antibody was detected by enzyme-linked immunosorbent assay. Clinicopathological indexes were compared between PLA2R-related MN group and non-PLA2R-related MN group. Kaplan-Meier (Log-rank test) survival curve and multivariate Cox regression analysis methods were used to analyze the influencing factors of kidney prognosis in patients with atypical MN. The primary endpoint of renal adverse outcome was renal insufficiency, defined as end-stage renal disease or estimated glomerular filtration rate (eGFR) decline>30% baseline and<60 ml·min -1·(1.73 m 2) -1. Results:A total of 65 atypical MN patients were enrolled in this study. Compared with primary MN ( n=324), patients with atypical MN had younger age ( Z=-4.229, P<0.001), higher proportion of hematuria ( χ2=5.555, P=0.018), higher level of urinary protein ( Z=2.228, P=0.026) and lower level of eGFR ( t=-5.108, P<0.001); the proportion of IgG4 deposition in kidneys was lower ( χ2=8.081, P=0.004), and the proportions of IgA ( χ2=16.969, P<0.001) and IgM ( χ2=9.281, P=0.002) deposition were higher. There was no significant difference on gender, serum albumin, positive proportion of anti-PLA2R antibody, anti-PLA2R antibody level and kidney C3/C1q deposition between the two groups (all P>0.05). The proportions of atypical MN patients receiving renin-angiotensin aldosterone system inhibitors (49.3% vs 57.1%), calcineurin inhibitors (27.7% vs 19.1%) and cyclophosphamide (21.5% vs 23.8%) were comparable to those of primary MN patients (all P>0.05). The rates of clinical remission (80.0% vs 77.2%), partial remission (44.6% vs 44.1%), complete remission (35.4% vs 33.1%), spontaneous remission (36.9% vs 42.6%), response to cyclophosphamide (85.7% vs 81.8%), response to calcineurin inhibitor (88.9% vs 79.0%), and relapse (30.8% vs 26.8%) in atypical MN patients were comparable to those in primary MN patients (all P>0.05). During the follow-up 30.0(21.5, 61.5) months, 15 atypical MN patients (23.1%) had eGFR reduction>30%, among whom 7 patients (10.8%) had eGFR reduction>50% and 3 patients (4.6%) had end-stage kidney disease. There was no significant difference on poor kidney prognosis between the two groups (all P>0.05). Kaplan-Meier survival curve showed that patients with age>39 years old ( χ2=10.092, P=0.001), eGFR≤100 ml·min -1·(1.73 m 2) -1( χ2=5.491, P=0.019), tubular interstitial lesion ( χ2=6.999, P=0.008) and no nephropathy remission ( χ2=22.952, P<0.001) had earlier poor renal prognosis. Multivariate Cox regression analysis showed that no nephropathy remission ( HR=12.604, 95% CI 2.691-59.037, P=0.001) was an independent influencing factor for poor renal prognosis in atypical MN patients. Conclusion:No significant difference is found between atypical MN and primary MN on treatment responses and kidney prognosis, which implies that clinical practice of atypical MN can be performed by referring to the guidelines and experience of primary MN.

The correlation between the level of PLA 2R and the condition and prognosis of patients with primary membranous nephropathy / 中国医师杂志

Objective:To investigate the correlation between serum anti phospholipase A2 receptor (PLA 2R) antibody level and the condition and prognosis of patients with primary membranous nephropathy (PMN).Methods:61 patients who were diagnosed as PMN in the laboratory department of Jiangsu Province Hospital of Chinese Medicine from January 2017 to August 2019 were selected and divided into PLA 2R positive group (41 cases) and PLA 2R negative group (20 cases) according to the level of PLA 2R antibody. The gender, age and other general data of the two groups were collected, and the clinical pathological characteristics and prognosis of the two groups were analyzed. Spearman correlation was used to analyze the correlation between the level of PLA 2R antibody and the disease condition and treatment prognosis.Results:The levels of estimate glomerular filtration rate (eGFR), total protein (TP) and albumin (ALB) in PLA 2R positive group were lower than those in PLA 2R negative group, while the levels of 24-h urinary protein and IgG4 were higher in PLA 2R positive group than that in PLA 2R negative group ( P<0.05); Multivariate logistic regression analysis showed that 24-hour urinary protein was an independent risk factor for PLA 2R antibody level ( OR=2.242, P<0.05), while TP and ALB levels were protective factors ( OR=0.840, 0.674, P<0.05); The patients in both groups were followed up for one year by rechecking serological indexes. The complete remission rate and total remission rate of PLA 2R positive group were lower than those of PLA 2R negative group ( P<0.05); Spearman correlation analysis showed that the level of PLA 2R antibody was negatively correlated with the levels of TP, ALB, and prognosis of patients ( r=-0.642, -0.547, -0.357, P<0.05), and positively correlated with the level of 24-hour urinary protein ( r=0.347, P<0.05). PLA 2R in renal tissue of 61 patients was found to be positive in 63.93% (39/61). Conclusions:The level of PLA 2R antibody is closely related to serum albumin, TP, 24 h urinary protein and prognosis of patients with PMN.

Effect of Moshen Decoction for the patients with idiopathic membranous nephropathy and spleen-kidney qi deficiency syndrome / 国际中医中药杂志

Objective:To evaluate the curative effect of Moshen Decoction combined with routine western medicine on idiopathic membranous nephropathy (IMN) of spleen-kidney qi deficiency syndrome and explore its influences on renal function, C1q, PLA2R and E-cadherin levels.Methods:A total of 62 patients with IMN meeting inclusion criteria in the hospital were enrolled between January 2018 and January 2021. According to simple random grouping method, they were divided into control group (hormones combined with cyclophosphamide) and observation group (Moshen Decoction on basis of control group), 31 in each group. Both groups were treated continuously for 6 months. Before and after treatment, TCM syndromes were scored. The levels of blood urea nitrogen (BUN), serum creatinine (SCr), cystatin C (Cys-C), anti-phospholipase A2 receptor (PLA2R) and E-cadherin (EC) were detected by ELISA. The level of serum complement C1q was detected by immunoturbidimetry. The 24 h urine was collected for quantitative determination by full-automatic biochemical analyzer. The adverse events during treatment were observed and recorded. And clinical curative effect was evaluated.Results:The differences in total response rate between observation group and control group were statistically significant [93.55% (29/31) vs. 74.19% (23/31); χ2=4.29, P=0.038]. After treatment, scores of TCM syndromes (edema of lower limbs, fatigue and poor appetite, lusterless complexion) in observation group were significantly lower than those in the control group ( t=10.07, 10.80, 4.34, 4.57, P<0.001). After treatment, levels of serum Cys-C [(0.51±0.05) mg/L vs. (0.55±0.06) mg/L, t=2.85], 24 h urine protein quantification [(0.95±0.19) g vs. (1.38±0.23) g, t=13.32] in observation group were lower than those in the control group ( P<0.01), and levels of serum PLA2R [(17.53±1.84) Ru/ml vs. (19.62±2.05) Ru/ml, t=4.22], EC [(2.74±0.26) μg/L vs. (3.05±0.37) μg/L, t=3.82] and complement C1q [(152.34±15.62) mg/L vs. (169.33±16.77) mg/L, t=4.13] in observation group were significantly lower than those in the control group ( P<0.01). During treatment, there was no significant difference in incidence of adverse events between observation group and control group [12.90% (4/31) vs. 16.13% (5/31); χ2=0.13, P=0.781]. Conclusion:Moshen Decoction combined with routine western medicine can improve renal function and clinical curative effect in patients with IMN of spleen-kidney qi deficiency syndrome. Its mechanism of action may be related to reducing urine protein, complement C1q, PLA2R and EC.

Prevalencia del anticuerpo anti receptor de fosfolipasa A2 sérico e histológico en pacientes con nefropatía membranosa en un Centro Universitario

Background: The discovery of the phospholipase A2 receptor antigen and its highly specific autoantibody (anti-PLA2R Ab) was useful for the diagnosis and follow-up of patients with membranous nephropathy (MN). Thus, some international guidelines recommend not performing renal biopsy in patients with positive serum anti-PLA2R Ab. Aim: To evaluate the prevalence of anti-PLA2R Ab in serum and renal tissue samples from Chilean patients with primary MN. Material and Methods: Twenty-eight patients aged 50 ± 14 years (20 males) with biopsy-proven primary MN plus a negative workup for secondary causes were included. Measurements of serum and renal histologic anti-PLA2R Ab were performed. The relationship between the findings of serum and tissue anti-PLA2R Ab was evaluated. Results: Fifteen patients (54 %) had anti-PLA2R Ab presence in serum and 19 patients (68%) had positive anti-PLA2R Ab in the renal biopsy. All patients with positive serum anti-PLA2R Ab had positive antibodies on immunohistochemistry. Conclusions: Serum anti-PLA2R Ab is potentially useful in the diagnosis of patients with suspected primary MN in Chilean population.

Changes in serum C3d and C5b-9 levels in elderly patients with idiopathic membranous nephropathy and their clinical significance / 中华老年医学杂志

Objective:To investigate changes in serum C3d and C5b-9 levels in elderly patients with idiopathic membranous nephropathy(IMN)and their correlations with prognosis.Methods:Two hundred thirty-one elderly patients with IMN and 96 non-elderly patients with IMN confirmed by kidney biopsy at the First Affiliated Hospital of Zhengzhou University from January 2015 to May 2017 were enrolled.During the same period, 118 healthy individuals receiving health checkups were included as controls.Patients were divided into the low C3d group( n=112)and the high C3d group( n=113)according to the median level of serum C3d.Serum C3d and C5b-9 levels were measured by enzyme-linked immunosorbent assays. Results:Serum C3d and C5b-9 levels in elderly IMN patients were 0.23(0.15, 0.45)mg/L and 0.28(0.20, 1.23)mg/L, respectively, which were higher than those in healthy controls[0.18(0.13, 0.22)mg/L, 0.22(0.16, 0.26)mg/L, respectively]( Z=-4.261 and -6.213, P<0.001). Serum C3d levels in elderly and non-elderly IMN patients were correlated negatively with the estimated glomerular filtration rate( r=-0.155 and -0.426, P=0.019 and 0.000), but positively with serum creatinine, anti-phospholipase A2 receptor(PLA2R)antibody levels and 24 h urinary protein( r=0.184, 0.326, 0.407, 0.321 and 0.145, P=0.005, 0.001, 0.000, 0.001 and 0.027). Kaplan-Meier survival analysis showed that the cumulative renal survival rate in elderly IMN patients was lower in the high C3d group than in the low C3d group(47.8% vs.70.8%, Log Rank χ2=7.399, P=0.007). Multivariate Cox regression analysis showed that high C3d levels were an independent risk factor for poor renal outcomes in elderly IMN patients( HR=2.288, 95% CI: 1.082-4.839, P=0.030). Conclusions:High serum C3d levels are associated with increases in urinary protein excretion and anti-PLA2R antibody levels, renal function decline, and poor renal outcomes in elderly IMN patients.

Progress in the treatment of elderly patients with primary membranous nephropathy / 中华老年医学杂志

Membranous nephropathy(MN)is the most common cause of nephrotic syndrome in the elderly.In recent years, the prevalence of MN has been increasing every year.The diagnosis and treatment of MN has entered the new era of molecular medicine with the identification of autoantibodies against the phospholipase A2 receptor(PLA2R). This review focuses on recent advances in the treatment and diagnosis of MN based on the 2020 Kidney Disease: Improving Global Outcomes(KDIGO)guidelines.

A rare case of PLA2R- and THSD7A-positive idiopathic membranous nephropathy / Positividade tecidual dupla para PLA2R e THSD7A em nefropatia membranosa idiopática: raro relato de caso

ABSTRACT Idiopathic membranous nephropathy (IMN) is a frequent cause of nephrotic syndrome in adults. In terms of etiology, the condition may be categorized as primary/idiopathic or secondary. Literature on the pathophysiology of IMN has indicated the presence of autoantibodies (PLA2R and THSD7A) directed against podocyte antigens. The detection of antibodies against a domain favors IMN. The presence of autoantibodies against one of the domains would in theory exclude the possibility of there being autoantibodies against the other domain. However, cases of patients with PLA2R- and THSD7A-positive disease have been recently reported, showing that antibodies against two targets may be concomitantly produced via yet unknown pathophysiological mechanisms. This study reports the case of a 46-year-old male patient with nephrotic-range proteinuria, hematuria, hypoalbuminemia, and hypercholesterolemia submitted to biopsy and histopathology examination (LM, IF, IHC, and EM) eventually diagnosed with PLA2R- and THSD7A-positive IMN associated with IgA nephropathy, stressing our experience with the use of IgG subclasses, PLA2R, and THSD7A in the workup for MN and the relevance of adopting a broad and adequate approach to elucidating and acquiring knowledge of the pathophysiology of IMN.

RESUMO A Nefropatia Membranosa Idiopática (NMi) é uma frequente causa de síndrome nefrótica em adultos e sua etiologia pode ser estratificada em primária/idiopática ou secundária. O conhecimento da fisiopatologia da NMi sugeriu a presença de autoanticorpos (PLA2R e a THSD7A) direcionados contra antígenos existentes nos podócitos. A detecção de anticorpos contra um domínio favorece NMi. A presença de autoanticorpos contra um desses domínios autoexcluiria a possibilidade de autoanticorpos contra o outro domínio; no entanto, recentemente foram descritos casos que apresentaram dupla positividade para PLA2R e THSD7A, comprovando que, por mecanismos fisiopatológicos ainda não conhecidos, raramente pode existir produção concomitante de anticorpos contra os dois alvos. O presente estudo tem por objetivo relatar o caso de um paciente de 46 anos de idade, do sexo masculino, que apresentou quadro de proteinúria nefrótica, hematúria, hipoalbuminemia e hipercolesterolemia submetido a biópsia e exame histopatológico (ML, IF, IHQ e ME), confirmando um caso raro de NMi com positividade dupla para os anticorpos anti-PLA2R e anti-THSD7A e associação à nefropatia por IgA, mostrando nossa experiência com a utilização de subclasses de IgG, PLA2R e THSD7A na rotina laboratorial para a investigação da GNM e enfatizando a importância de uma abordagem ampla para adequada elucidação e conhecimento dos mecanismos fisiopatológicos na NMi.

Focal and Segmental Glomerulosclerosis and Membranous Nephropathy overlapping in a patient with Nephrotic Syndrome: a case report / Glomeruloesclerose Segmentar e Focal e Nefropatia Membranosa sobrepostas em paciente com Síndrome Nefrótica: relato de caso

Abstract Introduction: Some cases of membranous nephropathy (MGN) present focal segmental glomerulosclerosis (FSGS) typically associated with disease progression. However, we report a case of a patient who seemed to have MGN and FSGS, both primary. Case presentation: A 17-year-old female, Caucasian, presenting lower extremity edema associated with episodes of foamy urine and high blood pressure, had physical and laboratorial exams indicating nephrotic syndrome. A renal biopsy was performed and focal and segmental glomerulosclerosis were observed under light microscopy in some glomeruli presented as tip lesion, and in others it was accompanied by podocyte hypertrophy and podocyte detachment in urinary space, compatible with podocytopathy FSGS. Besides, there were thickened capillary loops with basement membrane irregularities due to "spikes" compatible with MGN stage II. Immunofluorescence showed finely granular IgG, IgG4, and PLA2R deposits in capillary loops and, in electron microscopy, subepithelial deposits and foot process effacement. These morphological findings are compatible with FSGS and MGN stage II. Conclusions: In the present case, clinical and morphological characteristics showed a possible overlap of primary FSGS and MGN as focal and segmental glomerulosclerosis does not seem to be related with MGN progression but with the podocytopathy FSGS.

Resumo Introdução: Alguns casos de nefropatia membranosa (NM) apresentam glomeruloesclerose segmentar e focal (GESF) tipicamente associada a progressão da doença. Contudo, relatamos o caso de uma paciente que parece ter NM e GESF, ambas primárias. Apresentação do caso: Uma jovem branca de 17 anos de idade com edema de membros inferiores associado a episódios de urina espumosa e hipertensão apresentou-se com achados físicos e laboratoriais sugestivos de síndrome nefrótica. Foi realizada biópsia renal. GESF foi observada por microscopia de luz em alguns glomérulos que apresentavam lesões de ponta, enquanto em outros o achado era acompanhado por hipertrofia podocitária e descolamento de podócitos no espaço urinário, compatíveis com podocitopatia GESF. Além disso, as alças capilares estavam espessadas com irregularidades na membrana basal devido a "espículas" compatíveis com NM estágio II. Imunofluorescência revelou depósitos finamente granulares de IgG, IgG4 e PLA2R nas alças capilares. Microscopia eletrônica exibiu depósitos subepiteliais e apagamento de pedicelos. Tais achados morfológicos são compatíveis com GESF e NM estágio II. Conclusões: No presente caso, as características clínicas e morfológicas revelaram uma possível sobreposição de GESF primária e NM, uma vez que a glomeruloesclerose segmentar e focal não parece estar relacionada com a progressão da NM, mas com a podocitopatia GESF.

Clinical significance of glomerular IgG4 deposition in primary membranous nephropathy / 中华肾脏病杂志

Objective@#To analyze the distribution of glomerular immunofluorescence IgG4 subtypes in primary membranous nephropathy, and to explore the relationship between IgG4 deposit intensity and renal pathology, clinical manifestations and prognosis.@*Methods@#All the patients of biopsy-proven primary membranous nephropathy with IgG staining and at least one IgG subtype staining 1+ or higher on capillary loops from September 2015 to April 2017 were retrospectively enrolled. The distribution of IgG4 deposits were analyzed, and the relationship between IgG4 positive intensity and clinical manifestations, pathological indexes and clinical remission was investigated.@*Results@#A total of 250 cases were enrolled, including 157 males (62.8%) and 93 females (37.2%), and age was (54.4 ± 14.6) years. There were 40 patients in IgG4-negative group, and 210 patients in IgG4-positive group. The IgG4-positive group was divided into subgroups as 114 cases of the mild positive subgroup (1+) and 62 cases of the moderate positive subgroup (2+), and 34 cases of the strong positive subgroup (3+, 4+). The IgG4-positive group had higher 24-hour urine protein and higher positive rate of phospholipase A2 receptor staining than those in the negative group (both P<0.05), while the strong positive subgroup had lower serum albumin and higher IgG1 staining than those in the mild positive subgroup (both P<0.05). There was no difference in the ratio of glomerular sclerosis, tubular atrophy, IgG2, IgG3 or other immunofluorescence between the groups. After a median follow-up of 180(122, 209) days, 32 individuals were lost to follow-up. Among the rest 218 patients, 45 patients (20.6%) got complete remission, 104 patients (47.7%) got partial remission, and 69 patients (31.7%) showed no response. For no response as the outcome event, multivariate Cox regression analysis showed that higher IgG4 staining intensity (HR=1.371, 95%CI 1.068-1.759, P=0.013), male (HR=1.818, 95%CI 1.028-3.214, P=0.040), higher 24-hour urine protein level (HR=1.108, 95%CI 1.003-1.225, P=0.043) were independent risk factors for disease remission.@*Conclusions@#The glomerular IgG4 positivity and intensity are related to the severity of primary membranous nephropathy. The glomerular IgG4 deposit degree may be an effective prognostic marker for the treatment response of primary membranous nephropathy.

Effects of steroids-free immunosuppressive treatment for membranous nephropathy combining with type 2 diabetes mellitus / 中华肾脏病杂志

Objective@#To evaluate the efficacy and safety of steroids-free immunosuppressive therapy including tacrolimus, cyclosporin A, tripterygium glycosides or intravenous cyclophosphamide in membranous nephropathy (MN) patients combined with type 2 diabetes mellitus (T2DM).@*Methods@#This study was a retrospective analysis of patients with T2DM complicated with biopsy proved MN in the First Affiliated Hospital, College of Medicine, Zhejiang University from January 2009 to January 2017. The patients were divided into steroids-free group and control group. The patients in steroids-free group were treated with one or two immunosuppressive agents except glucocorticoids. The patients in control group were treated with glucocorticoid combining with immunosuppressive agents.@*Results@#A total of 64 patients were enrolled in this study. There were 26 cases in steroids-free group and 38 cases in control group. The total remission rate was 69.24% in steroids-free group and 73.68% in control group at 12 months. In a median follow up of 33(12-106) months, two patients in control group entered hemodialysis and one of them died after 1 year of dialysis. One patient in steroids-free group died of accidental death and no patient entered dialysis. All patients in control group had elevated blood glucose level, whereas only 5 patients in steroids-free group had elevated blood glucose and all these 5 patients used tacrolimus.@*Conclusion@#Immunosuppressive regimen without glucocorticoid treatment can reduce side effects on blood glucose level in MN patients with type 2 diabetes, with a certain rate of treatment response.

Effect of Danhong injection on expression of nephrin and podocin in podocyte of renal tissue in rats with membranous nephropathy / 国际中医中药杂志

Objective To observe the effect of Danhong injection on the expression of nephrin podocin protein and gene in the kidney of membranous nephropathy rats.Methods A total of 34 male clean level SD rats were divided at random into the normal control group (8 rats),model group (26 rates).The model group were injected the C-BSA into caudal vein to establish the model of the membranous nephropathy.After four week of succession of the models,two model rats were taken to confirm the success of the model.Another 24 models divided at random into model group,Losartan potassium treatment group and Danhong injection treatment group,8 in each group.In the losartan group,the losartan 40 mg/kg was administered,and the Danhong group was injected with 4 ml/kg of Danhong injection in the tail vein for 4 weeks.The rat urine was collected after the last administration,and 24 h urine protein was determined by spectrophotometer.The serum total protein,albumin,TC and TG levels were determined by automatic biochemical analyzer.The renal pathological changes were observed by HE staining.The expressions of nephrin,podocin and WT1 labeled podocytes were detected by immunohistochemical staining.The expressions of nephrin and podocin in renal tissue were detected by real-time quantitative PCR and Western blot,and the results were correlated.Results Compared with the model group,the content of serum albumin increased in the Danhong group (P＜0.01),24 h urine protein quantitation,TC,TG significantly decreased (P＜0.01).The expression of nephrin protein (1.12 ± 0.03 vs.0.57 ± 0.09),podocin protein (0.99 ± 0.04 vs.0.53 ± 0.08),nephrin mRNA (0.49 ± 0.08 vs.0.14 ± 0.02),podocin mRNA (0.50 ± 0.11 vs.1.18 ± 0.05) in Danhong group significantly increased (P＜0.01),and the number of podocytes labeled with WT1 (14.88％ ± 1.73％ vs.9.63％ ± 1.69％) significantly increased (P＜0.05).Correlation analysis showed that 24 h urine protein quantitation and expression of nephrin protein (r=-0.908),podocin protein (r=-0.916),nephrin mRNA (r=-0.930),podocin mRNA (r=-0.923).There was a negative correlation between serum albumin (r=-0.934) and podocyte count (r=-0.778) (P＜0.01),and positive correlation with TC (r=0.814) and TG (r=0.870) (P＜0.01).Conclusions The Danhong injection may reduce the urine protein of membranous nephropathy rats by up-regulating the expression of nephrin,podocin mRNA and protein in renal cells of membranous nephropathy.

Effects of steroids-free immunosuppressive treatment for membranous nephropathy combining with type 2 diabetes mellitus / 中华肾脏病杂志

Objective To evaluate the efficacy and safety of steroids-free immunosuppressive therapy including tacrolimus, cyclosporin A, tripterygium glycosides or intravenous cyclophosphamide in membranous nephropathy (MN) patients combined with type 2 diabetes mellitus (T2DM). Methods This study was a retrospective analysis of patients with T2DM complicated with biopsy proved MN in the First Affiliated Hospital, College of Medicine, Zhejiang University from January 2009 to January 2017. The patients were divided into steroids-free group and control group. The patients in steroids-free group were treated with one or two immunosuppressive agents except glucocorticoids. The patients in control group were treated with glucocorticoid combining with immunosuppressive agents. Results A total of 64 patients were enrolled in this study. There were 26 cases in steroids-free group and 38 cases in control group. The total remission rate was 69.24％ in steroids-free group and 73.68％ in control group at 12 months. In a median follow up of 33(12-106) months, two patients in control group entered hemodialysis and one of them died after 1 year of dialysis. One patient in steroids-free group died of accidental death and no patient entered dialysis. All patients in control group had elevated blood glucose level, whereas only 5 patients in steroids-free group had elevated blood glucose and all these 5 patients used tacrolimus. Conclusion Immunosuppressive regimen without glucocorticoid treatment can reduce side effects on blood glucose level in MN patients with type 2 diabetes, with a certain rate of treatment response.