Aggressive treatment may be needed for idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions.

OBJECTIVE: The purpose of this study was to analyze the clinical, pathological, prognostic features and treatment response of the coexistence of focal segmental glomerulosclerosis lesions with idiopathic membranous nephropathy. METHODS: This is a two-center retrospective cohort study. Patients of idiopathic membranous nephropathy were enrolled and divided into two groups with or without focal segmental glomerulosclerosis lesions according to the renal biopsy. Laboratory data and pathological manifestation were compared. Renal phospholipase A2 receptor was detected by immunofluorescence. During the follow-up, the effects of different therapies and renal function were estimated. RESULTS: A total of 236 patients were finally enrolled in this study, of which 60 and 176 idiopathic membranous nephropathy patients were enrolled in the FSGS+ and FSGS- groups, respectively. The FSGS+ group showed a higher percentage of hypertension history (38.3 vs. 20.0%, p=0.004), with a significantly higher level of systolic pressure [137 (120, 160) mmHg vs. 130 (120, 140) mmHg, p=0.009]. Main laboratory findings, including serial albumin (20.4±7.8 g/L vs. 24.5±6.7 g/L, p<0.001), 24-h proteinuria [5.61 (3.10, 7.87) g/day vs. 3.82 (2.31, 5.79) g/day, p=0.002], serial creatinine [80.8 (65.8, 97.9) µmol/L vs. 72.0 (58.7, 84.9) µmol/L, p=0.003], and estimated glomerular filtration rate [86 (66, 101) mL/min/1.73 m2 vs. 95 (81, 108) mL/min/1.73 m2, p=0.007] showed significant differences between the two groups. Pathologically, patients with focal segmental glomerulosclerosis lesions appeared with a higher percentage of crescents, a more severe degree of interstitial fibrosis, and a higher level of membranous nephropathy stage. Renal phospholipase A2 receptor showed a relatively lower positive rate of only 75.0% in the FSGS+ group in comparison with the positive rate of 90.3% in the FSGS- group (p=0.031). The prognosis was generally similar between the two groups. Among patients who were given non-immunosuppression treatment, those with focal segmental glomerulosclerosis lesions took a relatively longer period of time to achieve complete remission (29.3±7.0 m vs. 15.4±8.9 m, p=0.025) and experienced a higher rate of renal function deterioration (37.5 vs. 5.4%, p=0.033) compared with the other ones. While among those receiving immunosuppression treatment, both groups received similar remission rates. CONCLUSION: Compared with FSGS- group, idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions represented more severe nephrotic syndrome and worse renal function. In view of the renal function decline during the follow-up, more aggressive treatment with the use of immunosuppressants should be considered for idiopathic membranous nephropathy patients with focal segmental glomerulosclerosis lesions.

Correlation analysis of lipid metabolism genes with the immune microenvironment in gastric cancer and the construction of a novel gene signature.

BACKGROUND: Lipid metabolism reprogramming plays an important role in cell growth, proliferation, angiogenesis and invasion of cancer. However, the prognostic value of lipid metabolism during gastric cancer (GC) progression and the relationship with the immune microenvironment are still unclear. The aim of this study was to clarify the correlation between lipid metabolism genes and GC immunity. METHOD: We obtained 350 patients from The Cancer Genome Atlas (TCGA) and 355 patients from Gene Expression Omnibus (GEO) databases. Lipid metabolism-related gene datasets were obtained from the Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Molecular subtypes were obtained by Consensus clustering, and subtype immune status was analyzed using ESTIMATE, TIMER and microenvironmental cell population counter (MCP Counter) algorithm for immune analysis. Functional analyses included the application of Gene Set Enrichment Analysis (GSEA), KEGG, gene ontology (GO), and Protein-Protein Interaction Networks (PPI) to evaluate the molecular mechanisms of different subtypes. Weighted gene co-expression network analysis (WGCNA) was used to identify genes associated with immunity. The LASSO algorithm and multivariate Cox regression analysis were used to construct prognostic risk models. RESULT: Based on the lipid metabolism genes found in GC, patients with GC can be divided into two subgroups with significantly different survival. The subgroup with a better prognosis presented higher immune scores and immune infiltrating cell abundance. 1170 immune-related genes were screened by WGCNA, and further screening by PPI network analysis revealed that PTPRC, CD4, ITGB2 and LCP2 were closely associated with immune cells. Combined with the TIDE score results, it was found that the population with high expression of the above genes might be more sensitive to immunotherapy. In addition, a survival prediction model for GC was developed based on five survival-related lipid metabolism genes, PIAS4, PLA2R1, PRKACA, SLCO1A2 and STARD4. The ROC analysis over time showed that the risk prediction score model had good stability. CONCLUSION: Lipid metabolism gene expression is correlated with the immune microenvironment in GC patients and can accurately predict their prognosis. Studies on lipid metabolism and GC immunity can help to screen the population for immunotherapy benefits.

[Phospholipase A2 receptor antigen antibodies in serum and renal biopsies of patients with membranous nephropathy]. / 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.

Takayasu's arteritis and secondary membranous nephropathy: an exceptional association.

The association between Takayasu's arteritis and membranous nephropathy is uncommon. We present the case of a 46-year-old man with Takayasu's arteritis treated over 10 years by a multidisciplinary medical team. He had an atrophic left kidney due to arterial stenosis, with a basal creatinine of 1.59 mg/dL (140.55 µmol/l). Three years ago, he presented with full nephrotic syndrome, uncontrolled blood pressure, creatinine increases to 4.5 mg/dL (basal: 1.59 mg/dL), severe hypoalbuminaemia (1.4 g/dL) and albuminuria of 24.6 g per day. He underwent percutaneous biopsy of the right kidney that showed membranous nephropathy with negative PLA2R1 and positive IgG 1, 3 and 4 subclasses. After therapy with oral prednisone and cyclophosphamide, the patient's kidney function improved, without recurrence of disease after 3 years of follow-up. Here, we present this extremely uncommon association of Takayasu's arteritis and membranous nephropathy.

Prevalencia del anticuerpo anti receptor de fosfolipasa A2 sérico e histológico en pacientes con nefropatía membranosa en un Centro Universitario / Phospholipase A2 receptor antigen antibodies in serum and renal biopsies of patients with membranous nephropathy

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.

Autoantibodies against phospholipase A2 receptor in Brazilian patients with glomerular diseases.

BACKGROUND: Recently, great progress has been made in understanding the pathogenesis of membranous nephropathy (MN) with the discovery of autoantibodies (Abs) to M-type phospholipase A2 receptor (PLA2R) in serum and in immunocomplexes deposited in glomerulus in most adult patients with primary MN. OBJECTIVE: To evaluate the diagnostic performance of anti-PLA2R in Brazilian patients with MN, as well as to verify the possible association of anti-PLA2R serum levels with disease activity. METHODS: 117 patients with glomerular diseases confirmed by renal biopsy underwent routinely clinical and laboratory evaluation (serum creatinine and albumin, 24-h proteinuria, urinalysis, tests for etiological investigation) and determination of serum anti-PLA2R by ELISA. RESULTS: 67.5% of the patients had MN, 9.4% focal segmental glomerulosclerosis, 7.7% lupus nephritis class V and 15.4%, other proteinuric glomerular diseases. The mean level of glomerular filtration rate (estimated by the CKD-EPI formula) was 79.43 mL/min (12.00-151.20 mL/min), 24 h proteinuria of 2.89 g (0-14.90 g), serum albumin of 3.79 g/dL (1.20-4.80 g/dL). Anti-PLA2R was detected in 27 patients, all with active MN, being 26 primary and 1 secondary MN. Sensitivity and specificity rates for the test were 60.5-94.7%, and positive (PPV) and negative (NPV) predictive values were 92.9 and 67.9%, respectively. CONCLUSIONS: Anti-PLA2R showed high specificity and PPV for the diagnosis of primary MN in Brazilian patients. There was a strong correlation between disease activity and positive anti-PLA2R. This biomarker represents an important diagnostic tool for primary MN and may contribute to the monitoring of disease activity in such patients.

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.

A rare case of PLA2R- and THSD7A-positive idiopathic membranous nephropathy.

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.

Biochemical characterization of a phospholipase A2 homologue from the venom of the social wasp Polybia occidentalis

Wasp venoms constitute a molecular reservoir of new pharmacological substances such as peptides and proteins, biological property holders, many of which are yet to be identified. Exploring these sources may lead to the discovery of molecules hitherto unknown. This study describes, for the first time in hymenopteran venoms, the identification of an enzymatically inactive phospholipase A2 (PLA2) from the venom of the social wasp Polybia occidentalis. Methods: P. occidentalis venom was fractioned by molecular exclusion and reverse phase chromatography. For the biochemical characterization of the protein, 1D and 2D SDS-PAGE were performed, along with phospholipase activity assays on synthetic substrates, MALDI-TOF mass spectrometry and sequencing by Edman degradation. Results: The protein, called PocTX, was isolated using two chromatographic steps. Based on the phospholipase activity assay, electrophoresis and mass spectrometry, the protein presented a high degree of purity, with a mass of 13,896. 47 Da and a basic pI. After sequencing by the Edman degradation method, it was found that the protein showed a high identity with snake venom PLA2 homologues. Conclusion: This is the first report of an enzymatically inactive PLA2 isolated from wasp venom, similar to snake PLA2 homologues.(AU)

Age-related changes in the response of intestinal cells to 1α,25(OH)2-vitamin D3.

The hormonally active form of vitamin D(3), 1α,25(OH)(2)-vitamin D(3), acts in intestine, its major target tissue, where its actions are of regulatory and developmental importance: regulation of intracellular calcium through modulation of second messengers and activation of mitogenic cascades leading to cell proliferation. Several causes have been postulated to modify the hormone response in intestinal cells with ageing, among them, alterations of vitamin D receptor (VDR) levels and binding sites, reduced expression of G-proteins and hormone signal transduction changes. The current review summarizes the actual knowledge regarding the molecular and biochemical basis of age-impaired 1α,25(OH)(2)-vitamin D(3) receptor-mediated signaling in intestinal cells. A fundamental understanding why the hormone functions are impaired with age will enhance our knowledge of its importance in intestinal cell physiology.

Efficacy of tannins from Mimosa pudica and tannic acid in neutralizing cobra (Naja kaouthia) venom

In the present study, the effectiveness of Mimosa pudica tannins (MPT) in neutralizing the lethality of Naja kaouthia venom was compared with commercially derived tannins. Preincubation of MPT with N. kaouthia venom maintained 100 percent survival of mice after 24 hours. The mouse group in which there was no preincubation, no protection against the effects of the venom was observed. M. pudica tannin was found to be more effective in neutralizing the lethality of N. kaouthia venom when compared to commercial tannic acid. Two protein spots were missing in the two-dimensional gel electrophoresis (2-DE) of the MPT treated mouse indicating the down-regulation of venom proteins. The results from this study indicated that tannins obtained from M. pudica are better than tannic acid in neutralizing the lethality of N. kaouthia venom in vitro. However, further investigations are required to establish that M. pudica has potential for treating N. kaouthia snakebites.(AU)

Factores circulantes de injuria endotelial y procesos subendoteliales en mujeres postmenopáusicas sanas / Endothelial injuring factors and subendothelial events in healthy postmenopausal women

La concentración elevada de lipoproteínas aterogénicas con apo B en mujeres posmenopáusicas (MPM), es un componente importante del mecanismo multifactorial causante de la enfermedad coronaria. En MPM sanas (n=30) en comparación con premenopáusicas (MpreM) (n=28), se evaluó el perfil lipoproteico incluyendo apoproteínas A-I y B, LDL pequeña y densa, composición y oxidabilidad de LDL, proteína transportadora de colesterol esterificado y lipasa hepática. Se determinaron los siguientes factores emergentes: homocisteína, fosfolipasa A2, ferritina, PCR-hs (alta sensibilidad) y fibronectina proveniente de la matriz extracelular. La insulino-resistencia fue evaluada por la circunferencia de cintura, el índice HOMA y el índice triglicéridos/colesterol-HDL. El índice de riesgo apo B/apoA-I fue significativamente mayor en MPM (p<0,0001). MPM presentaron mayor proporción de LDL pequeña y densa, la cual correlacionó con el aumento de actividad de lipasa hepática (p<0,005), y con marcadores de insulino-resistencia (p<0,05). Fosfolipasa A2 (p<0,05), homocisteína (p<0,005), ferritina (p<0,0001), PCR-hs (p<0,005) y fibronectina (p<0,05)) fueron mayores en MPM. La oxidabilidad de LDL no mostró diferencias significativas pero correlacionó positivamente con LDL pequeña y densa (p<0,01), fosfolipasa A2 (p<0,05), homocisteína (p<0,05), PCR-hs (p<0,04), fibronectina (p<0,05) y cintura (p<0,02). Luego de ajustar por la condición menopáusica, edad y cintura, la oxidabilidad de LDL permaneció asociada con LDL pequeña y densa (b:0,36, p=0,027), homocisteína (b:0,36, p<0,038), fibronectina (b:0,41 p=0,05) y cintura (b:0,35, p=0,047). En este estudio, la interacción de factores de riesgo aterogénico clásicos y no tradicionales sugiere una secuencia de eventos que comienzan con la injuria endotelial causada por homocisteína y LDL pequeña y densa, que penetra en subendotelio donde su oxidación es favorecida por la homocisteína. Se produciría un proceso inflamatorio, que cursa con aumento de PCR y ferritina. La fosfolipasa A2, proveniente de macrófagos, atravesaría el endotelio unida a la LDL modificada, y promueve la liberación de fibronectina desde la matriz extracelular. La estrecha interacción entre la injuria endotelial, inflamación e insulino-resistencia se observaría desde estadíos subclínicos de aterosclerosis en MPM sanas.

In postmenopausal women (PMW), high concentrations of atherogenic apoB lipoproteins is an important component of the multifactorial mechanism underlying a higher risk of coronary artery disease, as compared with premenopausal women (PreMW). Lipoprotein pattern, including apopoproteins A-I and B, LDL chemical composition and small dense LDL (sdLDL), hepatic lipase activity, circulating cholesterol transfer protein and LDL oxidability were assessed in PMW (n=30) in comparison to PreMW (n=28). The following endothelial injuring factors were measured: homocysteine, lipoprotein binding phospholipase A2 (LpPLA2), ferritin, hs-CRP and fibronectin coming from extracellular vascular matrix. Insulin-resistance was evaluated by waist circumference, HOMA and triglyceride/HDL-cholesterol. PMW showed higher apoB/apoA-I (p<0.0001) and a higher proportion of sdLDL which showed significant correlations with the increase in hepatic lipase activity (p<0.005) and insulin-resistance markers (p<0.05). LpPLA2 (p<0.05), homocysteine (p<0.005), hs-CRP (p<0.005), fibronectin (p<0.05) and ferritin (p<0.0001) were elevated in PMW. LDL oxidability showed no differences between groups, but was positively correlated with waist (p<0.02), homocysteine (p<0.05), fibronectin (p<0.05), hs-CRP (p<0.04), LpPLA2 (p<0.05) and sdLDL (p<0.01). After adjusting by age, menopausal condition and waist, LDL oxidability remained associated with homocysteine (b: 0,36) p<0,038), sdLDL (b: 0.36, p=0.027), waist (b: 0.35, p=0.047) and fibronectin (b: 0,41 p=0.05). In this study, the interaction of classic and emerging atherogenic risk factors would suggest a sequence of events starting with endothelial damage caused by homocysteine and sdLDL, promoting its passage into the subendothelial space where it is oxidatively modified, enhanced by homocysteine. The above mentioned inflammatory process takes place with an increase in circulating hs-CRP and ferritin. LpPLA2, coming from macrophages, passes through the endothelium bound to modified LDL, promoting a release of fibronectin from the subendothelial extracellular matrix. Results suggest that the close interaction among endothelial injury, inflammation and insulin resistance can be observed since subclinical atherosclerosis states in healthy PMW.