Primary Mn Research Articles

Mannose-Binding Lectin Deposition in Membranous Nephropathy and Differentiation of Primary from Secondary Forms.

We investigated the lack of mannose-binding lectin (MBL) deposition in patients with secondary MNs (sMNs) with the presence of IgG4 deposition in relation to the presence of MBL deposition in patients with primary MNs (pMNs). We also established a connection between the stage of MN and MBL deposition. Materials from 72 renal biopsies with proven MN were used for immunohistochemistry staining (IHC) for the phospholipase A2 receptor (PLA2R), immunoglobulin subtype IgG4, and MBL. Patients were separated into one of the following three groups: primary MN (pMN), idiopathic MN (iMN), and secondary MN (sMN). Serum antibodies for PLA2R and thrombospondin type-I-domain-containing 7A (THSD7A) were also used for the precise evaluation of the type of MN, as well as for detecting positivity for PLA2R using IHC. Which stage of MN was present in relation to the deposition of MBL was evaluated. In total, 50 patients were positive for IgG4, 34 with pMN, 12 with iMN, and 4 with sMN. A total of 20 patients were positive for MBL, 14 with pMN and 6 with iMN; no MBL deposits were found in patients with sMN. MBL positivity was predominantly present in the first two stages of MN, with a gradual reduction in the later stages. The activation of the lectin-complement pathway occurs in the early stages of the disease and is associated with the deposition of IgG4; IgG4 deposition is present in sMN, but there is no MBL deposition. IgG4 cannot be used for the differentiation of primary from secondary MNs, but the lack of MBL can be used as a marker for sMN in the early stages of the disease.

Microbial contribution to the formation of the Carboniferous sedimentary manganese deposits in northwestern China

There is an increasing consensus that microbes play a critical role in the genesis of sedimentary manganese (Mn) carbonate deposits. However, compelling evidence for the microbial involvement during sedimentary Mn metallogenesis remains insufficient, and the specific effects of microbial mediation need to be further elucidated. To advance our understanding of the microbial Mn metallogenesis, multi-scale petrographic observations and high-resolution mineralogical analyses (mainly based on Fourier transform infrared spectrometer and Raman spectroscopy) were conducted on the Carboniferous black shale-hosted Malkansu and limestone-hosted Zhaosu Mn ore deposits in northwestern China. Results show that the Mn ore samples are characterized by finely laminated texture with μm-scale cyclic variations of microbe-associated minerals including rhodochrosite, apatite, quartz, and organic matter as well. These features indicate the ubiquity of microbial mats during Mn mineralization. Microbial involvement is also supported by Mn carbonate aggregates with variable morphologies (filamentous with pearl necklace-like inner forms resembling vermiform morphologies and spheroidal, coccoid-like forms), as well as the annular organic matter that resembles bacterial cells. The cyclic occurrence of trace amounts of remnant Mn oxides verify that primary Mn accumulation took place under oxic bottom waters. The negative co-variation between Mn carbonates and organic matter on Raman profiles suggests that the former was formed during diagenesis via organic matter decomposition coupled with Mn oxide reduction. Combined with previous experimental simulations and natural observations, a two-step microbially mediated Mn metallogenic model is tentatively proposed for the studied Mn deposits: (1) Mn(II)-oxidizing bacteria effectively catalyzed the deposition of considerable Mn oxides under oxygenated bottom water columns, a process that was simultaneously sustained by oxygenic microbial mats such as cyanobacteria; (2) Buried Mn oxides were reduced by highly reactive organic matter sourced from dead biomats of Mn(II)-oxidizing bacteria and benthic phototrophs, a process mediated by Mn(IV)-reducing bacteria which not only promoted the reaction rate but also served as nucleation sites for Mn carbonate minerals. This model can also help to explain the occurrence of diverse authigenic accessory minerals (e.g., quartz, apatite, and talc) and remarkable enrichments of several specific elements (e.g., Co, Ce, and Mo) in the studied Mn ores, which were closely linked to the decomposed cells and extracellular polymeric substance (EPS). By comparing with previous microbial investigations on Mn deposits over geological history, we further highlight the fundamental role of microorganisms in regulating the formation of economic Mn carbonate deposits.

Evidence for and against manganese deficiency as causal for congenital joint deficiency disease or death in fetal and neonatal cattle.

Measures of manganese (Mn) status in cattle vary among studies, and no single criterion accurately predicts or diagnoses Mn deficiency and pathologic outcomes. Mn deficiency causes congenital joint laxity and dwarfism (CJLD) when total dietary intake is <20 ppm Mn dry matter (DM) for most of the pregnancy. However, the recommended dietary intake of 40 ppm DM can also result in clinical Mn deficiency. Some studies have found that CJLD occurs in calves from cows fed red clover or silage but not in calves from cows fed hay. The concentration of Mn in the liver is the best indicator of Mn status in neonates and adults but cannot be interpreted in fetuses. Serum, plasma, and whole blood concentrations of Mn are unreliable indicators of bovine Mn status. The primary objective of our report is to present evidence linking CJLD to a primary or secondary Mn deficiency. To predict and diagnose Mn deficiency in cattle, we propose using a combination of clinical signs, dietary Mn, liver Mn at birth and beyond, positive response to Mn supplementation or the replacement of silage with other forages, and ruling out other causes of malformations. By following these recommendations, we expect that CJLD and gestational death will decrease as hepatic Mn concentrations increase at birth. Many publications we reviewed are not statistically sound, and future research should include a statistician from the initial discussions of the study through the final publication.

Patient and caregiver characteristics associated with differential use of primary care for children and young people in the UK: a scoping review

ObjectiveTo systematically map evidence to answer the research question: What is the relationship between the characteristics of children and young people (CYP) or their caregivers and primary care service use...

Effect of manganese and vanadium additions on the microstructures and two-body abrasive wear behaviors of Fe–B hardfacing alloys

Fe–B wear-resistant alloys often exhibit brittleness and suboptimal wear resistance, making them unsuitable for severe operational conditions. In this study, we incorporated ferromanganese powder and ferrovanadium powder were compounded into the Fe–B wear-resistant alloy by plasma cladding technology. The results indicate that the addition of a minor percentage of vanadium, such as about 2 wt%, does not induce any changes in the phase composition. The alloy layer primarily consists of (Mn,Fe)2B and γ-Fe, with vanadium predominantly dissolving in the primary (Mn,Fe)2B phase. This dissolution enhances the toughness of the hard phase and refines the grain structure. At around 4 wt% vanadium, a spherical VB phase precipitates. This inclusion elevates the impact toughness of the alloy layer. The impact toughness of the high manganese content with 4.69 wt% vanadium is the highest, up to 39.11 J/cm2, which is about 30 %higher than that of the sample without vanadium. As vanadium content rises, both the hardness and wear resistance of the alloy layer improve. The most optimal performance was observed with a manganese content of 20.15 wt% and vanadium at 4.69 wt%, achieving a hardness of 65.5 HRC and wear amounts of 48.1 mg (24 N load) and 85.0 mg (48 N load).

Characteristics and Outcomes of NELL1 Membranous Nephropathy in Lipoic Acid Users and Nonusers

Neural epidermal growth factor like 1 membranous nephropathy (NELL1 MN) is associated with various secondary etiologies. However, previous studies on the frequency of these associations and their impact on outcomes are limited. We report a large multiinstitutional series of patients with NELL1 MN with a focus on secondary associations, pathology findings, and their impact on outcome. We retrospectively reviewed clinicopathologic features of NELL1 MN from 3 institutions and analyzed clinical and histologic associations with outcome. Of 70 patients, 53% were male with a median age of 66 years; median proteinuria was 5.9 g/d. NELL1 MN was associated with lipoic acid (36%), heavy nonsteroidal antiinflammatory drug (NSAID) use (27%), autoimmune disease (23%), malignancy (10% recent, 23% any), mercury exposure (1%), and 11% had no known secondary association. At median follow-up of 11 months, 72% achieved complete or partial remission. Remission rate was 91% in patients with lipoic acid-associated NELL1 MN and≥6 months of follow-up. On multivariable analyses, patients with primary NELL1 MN (adjusted odds ratio [OR]: 19.7, P= 0.01) and increasing degree of tubular atrophy and interstitial fibrosis (IFTA) (adjusted OR 1.1, P= 0.01) were less likely to achieve any remission, whereas complete remission (CR) was associated with lipoic acid use (adjusted OR: 10.9, P= 0.04, 95% confidence interval [CI]: 1.2-100) and lesser degrees of IFTA (adjusted OR: 0.79, P= 0.16, 95% CI: 0.66-0.96). Our findings strengthen the association between lipoic acid and NELL1 MN. Furthermore, our findings suggest that discontinuation of lipoic acid without immunosuppression should be considered as the first-line treatment.

Potassium permanganate oxidation enhanced by infrared light and its application to natural water

Photocoupled permanganate (PM) is an effective way to enhance the oxidation efficiency of PM, however, the activation of PM by infrared has received little attention. This study aimed to investigate the ability of infrared light to activate PM. When coupled with infrared, the degradation rate of 4-chlorophenol (4-CP) is increased to 3.54 times of PM oxidation alone. The accelerated reaction was due to the formation of vibrationally excited PM by absorbing 3.1 kJ mol-1 infrared energy, which also leads to the primary reactive intermediates Mn(V/IV) in the reaction system. The infrared coupled PM system also showed 1.14–2.34 times promotion effect on other organic pollutants. Furthermore, solar composed of 45% infrared, coupled PM system showed excellent degradation performance, where the degradation of 4-CP in 10 L of tap water and river water was 68 and 23 times faster than in ultrapure water, respectively. The faster-increased degradation rate in natural waters is mainly due to the abundant inorganic ions, which can stabilize the manganese species, and then has a positive effect on 4-CP degradation. In summary, this work develops a energy-efficient photoactivated PM technology that utilizes infrared and provides new insights into the design of novel sunlight-powered oxidation processes for water treatment.

Material flow analysis on the critical resources from spent power lithium-ion batteries under the framework of China's recycling policies

With the rapid growth of electric vehicles in China, the number of spent power lithium-ion batteries is dramatically increased. Considering the environmental risk, security risk, and potential resource value, China has issued a series of laws and regulations to manage the spent power lithium-ion batteries. This work employs the material flow analysis method to evaluate the material flows of Li, Ni, Co, and Mn during the life cycle of power lithium-ion batteries under the framework of China's recycling policy system. The results show that the demand for primary Li, Ni, Co, and Mn can achieve 26.9, 68.1, 20.4, and 21.9 kt in 2021, and a lot of primary critical resources will inburst the in-use stage. Moreover, the number of secondary Li, Ni, Co, and Mn can achieve 6.1, 15.4, 4.6, and 5 kt in 2021, accounting for 22.7%, 22.6%, 22.5%, and 22.8% of their corresponding demand. Based on the economic evaluation under the framework of China's recycling policy system, it is found that the potential recycling values of Li, Ni, Co, and Mn are approximately 966, 523, 414, and 43 million RMB yuan, which are 66.4%, 71%, 59.6%, and 66.4% higher than those in the absence of China's recycling policy system. It is implied that China's recycling policy system could markedly improve the collection rate by reducing losses and indirectly enhancing the recycling and reuse of spent power lithium-ion batteries. This work is expected to provide guidance for policymakers to improve the management of spent power lithium-ion batteries in China.

Use of Chinese Herbal Medicine to Inhibit Podocyte Damage as Therapeutic Strategy for Membranous Nephropathy

ABSTRACT Membranous nephropathy (MN), one of the most common glomerular diseases, is a noninflammatory autoimmune podocyte disease. In the body, podocytes play an important role in maintaining the stability of the glomerular filtration barrier, and the degree of podocyte damage is a major determinant of MN prognosis because of the limited ability of podocytes to repair and regenerate. Although several therapeutic modalities for inhibiting podocyte damage are currently available, most lead to adverse, nonspecific systemic effects; therefore, newer drugs are necessary to target podocyte damage in MN. Traditional Chinese medicine (TCM) plays an important role in the treatment of primary MN in China. This study reviews the role of podocytes and the mechanisms of podocyte injury in MN glomeruli and summarizes the current status of complement-mediated therapy, the clinical efficacy of TCM in the treatment of primary MN, and the potential mechanisms regulating podocyte injury to support the development of new therapeutic strategies.

Mineralogy of the 1.45 Ga Wafangzi manganese deposit in North China: Implications for pulsed Mesoproterozoic oxygenation events

Abstract Ancient manganese (Mn) deposits are primarily characterized by the presence of Mn(II) carbonates that likely formed by the diagenetic reduction of precursor Mn(IV) oxides. As such, Precambrian sedimentary Mn deposits have been used as a line of evidence for the evolution of oxygen in Earth’s surface environments. However, recent studies have shown that these Mn(II)-carbonates have the ability to directly accumulate within anoxic water columns, where free oxygen does not play a role in their formation. This alternative pathway casts uncertainty on the robustness of using ancient Mn deposits to constrain the redox fabric of the past marine water columns. Here, we investigate the Wafangzi Mn and Fe ore deposit from the 1.45 billion-year-old Tieling Formation, North China. The deposit contains Mn(II, III) mineral phases (hausmannite, braunite) as inclusions, or unreacted residues, trapped within Mn(II) carbonate (Ca-rhodochrosite). Some nodules and oolites of Mn(II) and Fe(II)-carbonate phases are also present and display a banded structure with concentric rings. Mn(III) oxide (manganite) is present in a paragenetic assemblage along with hematite and replacement textures with braunite. The negative carbon isotope composition (δ13C, –7‰ to –4‰) from Mn(II) carbonate samples in the Wafangzi Mn deposit which are distinct from that of contemporaneous seawater (~0‰), along with petrographic and speciation analyses, collectively suggest that the Mn(II, III)- and Fe(II)-bearing mineral phases formed through the diagenetic reduction of primary Mn(IV)/Fe(III) minerals coupled to the oxidation of organic matter. Therefore, the Wafangzi Mn deposit suggests the presence of sufficiently oxygenated marine waters, overlying anoxic ferruginous deeper waters with a transitional manganous water layer that could have driven the redox cycling of Mn, Fe, and C. Given the contemporaneous economic Mn deposits in the 1.45 Ga Ullawarra Formation in Western Australia, our findings imply the existence of a transient, and perhaps widespread, pulsed oxygenation event in the mid-Proterozoic oceans.

Spatial and temporal variability of dissolved metal(loid)s in water of the karst ecosystem: consequences of long-term exposure to wastewaters

The metal(loid) variability in the sensitive karst ecosystem was addressed as possible indicator of short- and long-term exposure to the wastewaters, recognized as the main metal contamination sources. Industrial and municipal wastewaters are released without proper purification only 2 km upstream from the Krka National Park (KNP) in Croatia. The variability of dissolved metal(loid)s was studied in four seasons and eight locations: Krka River source (reference site, KRS), municipal wastewaters from the Town of Knin (KRK), industrial wastewaters from the screw factory (IWW), Brljan Lake in the KNP (KBL), and the tributaries Krčić (TKR), Kosovčica (TKO), Orašnica (TOR) and Butišnica (TBU). Water taken directly from IWW had several times higher concentrations of all elements than other locations and indicated industrial wastewater as the primary Mn, Zn, Co, Cs, and Fe source. Tributary Orašnica, flowing by IWW, was the most affected site, although higher metal concentrations were also found at other locations compared to KRS. Overall, spatial metal contamination followed the order: TOR>KRK>TKO>TBU>KBL>KRS. Seasonality was not pronounced, although the highest levels for most metals were observed in summer, dry season when the self-purification processes are reduced. Almost all elements had low tendency to bind with particles, therefore showing high presence in dissolved fraction and confirming their bioavailability and potential toxicity. Although metal concentrations increased over time, they were still low compared to metal-contaminated rivers. However, observed metal exposure and inter-site differences present a warning and indicate the need for the targeted continuous monitoring of potential hotspots to protect this karst ecosystem.

#6502 ETIOLOGICAL SPECTRUM OF MEMBRANOUS NEPHROPATHY

Abstract Background and Aims Primary MN includes forms of MN in which there is a humoral autoimmune response to a normal podocyte antigen in the absence of secondary features or etiologies of disease. Antigens implicated in primary MN include PLA2R, thrombospondin type-1 domain-containing 7A (THSD7A), neural epidermal growth factor-like 1 (NELL1), semaphorin 3B (Sema3B), the serine protease high-temperature requirement A1 (HTRA1), protocadherin 7 (PCDH7), and others. PLA2R associated MN is most common MN among primary MN. Nowadays, a significant number of newer antigens implicating MN are being discovered. Research is ongoing for a better understanding of the role of these antigens in pathophysiology, and targeted therapeutic implications in future if possible. We aim to analyze the etiological spectrum associated with different antigens in patients with Membranous Nephropathy. We assessed the renal tissue staining of autoantigens PLA2R, THSD7A, and NELL-1 in patients with biopsy-proven Membranous Nephropathy. Method This was a single center ambispective observational study. The study was performed up till September 2022 for prospective data, and retrospective data from January 2018 to March 2021 was retrieved from the medical records department of the institute. The study included patients with biopsy-proven Membranous Nephropathy (Primary and secondary). The primary outcome was to study the etiological spectrum of Membranous Nephropathy. Results A total of 90 patients were included in the study of membranous nephropathy over the period of 4 years. 72 cases had primary MN whereas 18 cases had secondary MN. The mean age was 42.01 ± 14.6 years. Among 18 cases of Secondary MN, the majority of the cases were of lupus nephritis 14 (78%), while other etiologies of secondary MN were malignancy related (11%), rheumatoid arthritis (5.5%) and HCV (5.5%). PLA2R renal tissue positivity was found in 44 (61.1%) cases of primary MN, whereas in 4 (22.2%) cases of Secondary MN. The THSD7A was found in 4 (5.6%) cases of primary MN. One patient of MN was dual PLA2R and NELL1 positive. Two cases of MN were dual PLA2R and THSD7A positive. Renal tissue staining for NELL-1 was found in 8 (11.1%) cases of primary MN whereas it was found in 1 (5.6%) case of secondary MN. In terms of clinical presentation, proteinuria is the most common clinical finding present in nearly all the patients (80%). Most of the cases with nephrotic syndrome (60%) belonged to primary MN. Conclusion PLA2R is the most common etiology of Primary membranous nephropathy. None of the antigens was exclusive to primary membranous nephropathy.

#3418 DISAPPEARANCE OF GLOMERULAR C3 DEPOSITION MIGHT BE A PROGNOSTIC MARKER IN MEMBRANOUS NEPHROPATHY AFTER TREATMENT

Abstract Background and Aims Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults. In about 80% is primary and remaining 20% are secondary due to medications or other diseases. Treatment of primary MN remains controversial, and the prognosis is still difficult to predict despite the introduction of anti phospholipase A2 receptor (PLA2R) antibody. We evaluated pathological changes for predicting prognosis in patients of MN after methyprednisolone (MPD) pulse therapy. Method We performed 1,649 renal biopsies at the OPD during last 9 years, of which 31 subjects were MN. We performed follow up biopsy who showed normal urinary findings after treatment with MPD pulse therapy in 11 subjects of MN. Indications of the initial biopsy in MN were oral steroid resistant NS (9 subjects), massive proteinuria associated with hematuria (2 subjects). Among the 11 subjects of MN, 3 subjects were lupus nephritis (LN), 8 subjects were primary MN. One cycle of MPD consist of 10-20 mg/kg (max 1.0 g)/day for 3 consecutive days, performing every 10 to 14 days. Mean MPD pulse therapy were done 13 cycles Results Among the 11 cases of MN, male to female ratio was 6 to 5. Age distribution from 1 year old to 61years old (mean 40.8 y/o), Mean spot urine protein to creatinine before treatment was 4,182.5 mg/g and 189.4 mg/g after treatment. 9 subjects showed glomerular C3 deposition were noted at the initial biopsy and 2 subjects showed no C3 deposition. After treatment glomerular C3 deposition were disappeared in 8 subjects, and showed no relapse during 5.3 years follow up. However, 3 subjects who showed glomerular C3 deposition were lupus nephritis, relapsed during follow up period. Conclusion MPD pulse therapy might be still promising therapeutic modality in conventional oral steroid resistant MN. Although further larger number of studies are mandatory, disappearance of glomerular C3 deposition might be a prognostic marker for treatment response, instead of disappearance of proteinuria in MN.

#6905 PREVALENCE OF ANTIPLA2R ANTIBODIES IN EGYPTIAN PATIENTS WITH NEPHROTIC SYNDROME

Abstract Background and Aims Primary membranous nephropathy (PMN), a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Autoimmunity is driven by circulating autoantibodies that bind to one or more antigens on the surface of glomerular podocytes. PLA2R antigen is the most common and prevalent one among these antigens. Anti-PLA2R antibodies are measured in serum and detected within biopsies of primary membranous nephropathy patients. Up to the moment, no clear data about the prevalence of AntiPLA2R antibodies associated PMN in Egyptian patients. The aim of this work was to study the prevalence of antiPLA2R antibodies in Egyptian patients with nephrotic syndrome underwent renal biopsy. Method In this cross-sectional study we recruited 70 adult patients presented with nephrotic range proteinuria to Ain-shams university hospital and a private nephrology center in Cairo during a period of 20 months (from March 2020 to October 2021). All patients first presentation for whom laboratory investigations including serum anti-PLA2R antibodies titer by indirect immunofluorescence and kidney biopsy were done. Anti-PLA2R antibodies were measured in serum, checked in biopsies and correlated with biopsy findings. Results Membranous nephropathy (primary and secondary) was found by biopsy finding in 25 of 70 patients (35.7%) presenting with nephrotic range proteinuria. 21 patients (84%) of the cases of membranous nephropathy had been diagnosed with primary membranous nephropathy and 4 (16%) had been diagnosed with secondary membranous nephropathy. Circulating anti-PLA2R antibodies were detected within serum in 9 (42.85%) of primary MN cases while detection of anti-PLA2R antibodies within the glomerular extracts of primary MN cases was much higher; 17 patients (80.95%). There was positive correlation between serum AntiPLA2R Antibodies titer and U PCR (r = 0.839, P = 0.005) (Fig. 1). Conclusion A we may conclude that, most patients with primary membranous nephropathy have anti-PLA2R antibodies. Detection of anti-PLA2R antibodies within the biopsy has higher sensitivity than serum (80.95% versus 42.85%). Specificity of PLA2R to primary membranous nephropathy is 100%. Patients with high anti-PLA2R titer had higher baseline proteinuria than patients with lower anti-PLA2R titer.

Episodic ventilation of euxinic bottom waters triggers the formation of black shale-hosted Mn carbonate deposits

Many manganese (Mn) carbonate deposits over geologic history are often closely associated with black shales. However, the mechanism(s) by which the Mn entered the sediments remains controversial because on one hand oxygenated waters are required for primary Mn(IV) oxide formation but on the other hand black shales generally form under reducing conditions. China hosts some of the world’s largest black shale-hosted Mn deposits, for example, the Carboniferous Ortokarnash and Malkantu Mn deposits in the Malkansu region, offering a good opportunity to revisit the genesis of black shale-hosted Mn carbonate deposits. Here, we present the first coupled, systematic paleoredox and hydrographic reconstruction of those deposits with the aim of elucidating the redox-state of the depositional basin at the time of their initial deposition. The Mn ore beds in this region are hosted within laminated, organic-rich mudstones (i.e., black shales) reflective of a relatively deep-water depositional environment. The Mn ores are comprised of the Mn(II) carbonate minerals (rhodochrosite and Ca-rhodochrosite), with minor alabandite, pyrite, and monazite. Multiple independent lines of evidence, including positive shale-normalized Ce anomalies (average 3.0), negative δ13CVPDB values (average −11.55 ‰), and negative δ98MoNIST+0.25 values (average −1.07 ‰), indicate that the Mn(II) carbonate ores were formed during diagenesis via the coupled oxidation of organic matter and reduction of Mn(IV) oxides originally deposited from an oxygenated water column. However, in apparent contradiction, highly reactive iron to total iron (FeHR/FeT; average 0.66) and pyrite iron to highly reactive iron (FePy/FeHR; average 0.71) ratios, combined with a high abundance of small framboidal pyrites (mean diameter ∼5 μm) with narrow size ranges (standard deviations <2 μm), suggest that the associated black shales were deposited in euxinic (H2S-bearing) bottom waters. Euxinia resulted from sluggish water mass circulation, with sedimentary Mo/TOC ratios indicating a relatively strong hydrologic restriction. During this stage, dissolved Mn(II) would have accumulated in euxinic waters but not become permanently fixed into sediments, as indicated by higher degrees of enrichment for Mo over U and lower Mo isotope values than coeval seawater recorded in the black shales. These reveal an active Mn(IV) oxide shuttle across a redox-stratified water column. Combined, the Mn ore intervals document sharp benthic oxygenation of euxinic bottom waters, a process that might be induced by the periodic incursions of oxic seawater associated with eustatic sea level rises. This model is supported by the Mo isotopic characteristics of the Mn carbonate ores, which indicate original Mn oxide precipitation from an overlying water with Mo isotopic composition close to coeval open seawater (minimum δ98MoNIST+0.25 of 1.9 ‰). In contrast to the generalized “bathtub ring” model envisaging that the black shale-hosted Mn deposits were formed at shallow basin margins, our results highlight that they were more likely formed by in-situ ventilation of anoxic (especially euxinic) deep waters of basin center settings. In this regard, we suggest that the ventilation model better explains the close association of Mn carbonate ores with black shales, and has profound implications for understanding the paleoredox framework of otherwise Mn-rich black shale successions.

Primary membranous nephropathy: an endless story.

Primary membranous nephropathy (PMN) is an autoimmune disease caused by the attack of autoantibodies against podocyte antigens leading to the in situ production of immune complexes. However, the etiology is unknown and the pathogenesis is still far from being completely elucidated. MN is prevalently idiopathic or primary, but in about 20-30% of cases it is secondary to chronic infections, systemic diseases, exposure to drugs, or malignancy. The differentiation between primary and secondary MN may be difficult, particularly when MN precedes signs and symptoms of the original disease, as in some cases of cancer or systemic lupus erythematosus. The natural course of PMN is variable, but in the long term 40-60% of patients with nephrotic syndrome progress to end-stage renal disease (ESRD) or die from thrombotic or cardiovascular events. PMN is a treatable disease. Patients with asymptomatic proteinuria should receive supportive care. Immunosuppressive treatments should be given to patients with nephrotic syndrome or risk of progression. The most frequently adopted treatments rely on cyclical therapy alternating steroids with a cytotoxic agent every other month, i.e., rituximab at different doses, or calcineurin inhibitors plus low-dose steroids. A good rate of response may be obtained but relapses can occur. Randomized controlled trials, with adequate size, long-term follow-up, and fair definition of endpoints are needed to identify treatment with the best therapeutic index.

Matched Paired Primary and Recurrent Meningiomas Points to Cell-Death Program Contributions to Genomic and Epigenomic Instability along Tumor Progression.

Simple SummaryMeningioma (MN) is the most frequent primary brain tumor with a high frequency of recurrences and a lack of objective tools for predicting their prognosis. In this study, we analyzed a careful selection of patients in which both the primary tumor and at least one recurrence were available, allowing us to extend the changes that occur during tumor progression. We developed a histological, genetic, and epigenetic analysis of the samples. Thus, we identified markers of quick recurrence, increased tumor instability by copy number alterations, and the accumulation of epigenetic changes during tumor progression. Interestingly, the genes involved seemed to be randomly distributed along the genome but eventually suggest a common impact on cell-death programs such as apoptosis and autophagy.Meningioma (MN) is an important cause of disability, and predictive tools for estimating the risk of recurrence are still scarce. The need for objective and cost-effective techniques addressed to this purpose is well known. In this study, we present methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a friendly method for deepening the understanding of the mechanisms underlying meningioma progression. A large follow-up allowed us to obtain 50 samples, which included the primary tumor of 20 patients in which half of them are suffering one recurrence and the other half are suffering more than one. We histologically characterized the samples and performed MS-MLPA assays validated by FISH to assess their copy number alterations (CNA) and epigenetic status. Interestingly, we determined the increase in tumor instability with higher values of CNA during the progression accompanied by an increase in epigenetic damage. We also found a loss of HIC1 and the hypermethylation of CDKN2B and PTEN as independent prognostic markers. Comparison between grade 1 and higher primary MN’s self-evolution pointed to a central role of GSTP1 in the first stages of the disease. Finally, a high rate of alterations in genes that are related to apoptosis and autophagy, such as DAPK1, PARK2, BCL2, FHIT, or VHL, underlines an important influence on cell-death programs through different pathways.

MO105: Study of 45 Cases of Membranous Nephropathy from a Kidney Biopsy Record at the Level of the Nephrology Department in Marrakech

Abstract BACKGROUND AND AIMS Membranous nephropathy is the most common cause of nephrotic syndrome in adults. However, the epidemiological data of this disease are not yet sufficiently known in our country. The aim of our study was to determine the clinical, biological and histological profile of MN and to evaluate its therapeutic approaches and evolutive aspects. METHOD We conducted a single-centre retrospective study in the nephrology department of the University Hospital Center Mohammed VI, over a period of 3 years (2016–2019) including 45 cases of MN confirmed by renal biopsy, with a minimum follow-up of 6 months. All patients were started on supportive therapy and then reassessed at 6 months. The nature of the next treatment was determined on an individual basis according to the risk of progression of each patient. The primary endpoint of the study was to obtain a remission of nephrotic syndrome. Complete remission was defined as proteinuria &amp;lt;0.3 g/day, and normal renal function partial remission was defined as proteinuria of 0.3–3 g /day and a stabilization of creatininemia. RESULTS The mean age of the patients was 45.24 ± 10.98 years. The clinical presentation was dominated by edematous syndrome found in 75.8% of cases. Systemic manifestations were found in 50% of cases. Nephrotic syndrome was objectified in 66.67% of cases. The histological study showed a predominance of the stage 3 in 56.7% of cases. Membranous lupus nephritis was found in 20.1% of cases, viral hepatitis B in 3% of cases, secondary syphilis in 3% of cases and primary MN in 73.9% of cases. Anti-PLA2R antibodies were positive in four patients with primary MN. After a minimal 6-month follow-up, we achieved remission in 74% of patients. Eighteen patients received aetiopathogenic treatment. Total remission was found in 48% of patients, partial in 39.4% of patients and an aggravation was noted in 15.1% of the cases progressing towards end-stage renal failure. CONCLUSION The evolution of membranous nephropathy is highly variable, but it remains a considerable cause of end-stage renal failure; hence, the need for rapid and continuous management is high in order to achieve remission and reduce the morbimortality related to membranous nephropathy.

MO240: The Evolution and Epidemiology of Membranous Nephropathy at a Single Centre Over Two Decades

Abstract BACKGROUND AND AIMS Membranous nephropathy (MN) commonly presents with nephrotic syndrome and carries significant risk of progression to end-stage kidney disease (ESKD) (33% without treatment, 10%–20% with). Patients may spontaneously remit (up to 40%), but are also at risk of relapse. A total of 80% of cases are primary (kidney-specific) and the majority of these are associated with antibodies to the M-type phospholipase A2 receptor (anti-PLA2R) or thrombospondin type 1 domain containing 7A antibodies (THS7DA). Treatment ranges from supportive care with renin–angiotensin system (RAS) blockade through to immunosuppression. Here we assessed the epidemiology of MN over 20 years at our centre (Salford Royal Hospital, UK) with particular reference to treatment administered and key clinical outcomes. METHOD A total of 238 patients with kidney biopsy-proven MN were identified from the local database between January 2000 and December 2020. Twenty-one were excluded (see Fig. 1) resulting in a total of 217 patients in whom demographic data, co-morbidities, remission and relapse rates, baseline laboratory values, treatment given, and outcomes were collected. Analyses compared effects of (i) immunosuppressed versus non-immunosuppressed, (ii) effect of modified Ponticelli versus other forms of immunosuppression and (iii) rates of remission. Univariate and multivariate cox regression determined factors that were associated with increased risk of renal replacement therapy (RRT) or death. RESULTS A total of 63.6% of the cohort were male, 88% Caucasian, 10.1% diabetic, 50.2% hypertensive and 15.2% had coexisting cardiovascular disease (Table 1). A total of 82.0% had primary MN. Median baseline eGFR was 72.7 mL/min/1.73 m2 and median baseline uPCR was 664 g/mol. A total of 157 patients (72.4%) went into remission (either spontaneous—75 (47.8%) or with treatment—85 (52.2%)), and of these 41.4% subsequently relapsed. A total of 89.4% received RAS blockade and 48.8% received immunosuppression. The median follow-up period was 56 months; 9.7% progressed to ESKD and 32.3% died. Patients who received immunosuppression had significantly more proteinuria than those who did not (765 g/mol versus 514 g/mol, P ≤ 0.001), were more likely to relapse (53.7% versus 28.0%, p ≤0.001) and were more likely to require RRT (15.1% versus 4.9%, P = .028). Those who received modified Ponticelli were less likely to relapse than those who received other forms of immunosuppression (34% versus 46%, P = .019), less likely to require RRT (3% versus 22%, P = .018) and less likely to die (11% versus 38%). Multivariate cox regression showed that pre-existing cardiovascular disease was a risk factor for death (HR 2.47, P &amp;lt; .001) and higher baseline eGFR and use of RAS blockade was associated with reduced risk of death (HR 0.98, P &amp;lt; .001 and HR 0.34, P = .012, respectively). CONCLUSION Despite advances in knowledge of underlying pathogenesis and increased treatment options, MN continues to pose a significant risk of progression to ESKD and death. This real-world study suggests that immunosuppression with modified Ponticelli is associated with lower rates of progressive CKD compared with MMF and calcineurin-inhibitor based therapy. Whilst many patients respond to treatment and can achieve remission, a significant proportion of these subsequently relapse. Identifying these patients early with judicial use of appropriate immunosuppression is key.

Mineral paragenesis in Paleozoic manganese ore deposits: Depositional versus post-depositional formation processes

Unlike modern Mn(IV)-dominated manganese nodules, ancient manganese deposits primarily contain Mn(II) (manganous) mineral phases. The general assumption is that these manganous minerals formed post-depositionally from a Mn(IV) precursor phase during diagenesis and metamorphism. However, recent studies have shown that aqueous Mn(II) may combine with either CO32–(aq) or H4SiO4(aq) to nucleate and precipitate as primary manganous phases within anoxic waters. These findings thus make it difficult to assess what comprised the primary mineral assemblage of ancient Mn deposits, which in turn, has implications for understanding the redox fabric of the past marine water column. Here, we investigate the paragenesis and oxidation state of various Mn minerals (oxides, carbonates, and silicates) from the late Devonian Xialei and middle to late Permian Zunyi manganese deposits in South China. Through characterization of the micro-scale distribution, composition, and speciation of different Mn-bearing mineral phases, we provide evidence to support an oxidative mechanism during Mn cycling at the time of deposition. We document the presence of a residual oxide phase (hausmannite; Mn3O4) that represents a primary to early formed Mn(III)-bearing oxide preserved in Mn(II)-carbonate nodules. Additionally, we observe spherulitic textures comprised of mixed-valence Mn(II,III,IV)-silicates enclosed in diagenetic Mn(II)-carbonate laminations. Our results allow for the construction of a paragenetic model for these deposits beginning with the reduction of a primary Mn(IV) phase and the subsequent precipitation of intermediate Mn(III)-oxide or -silicate mineral phases. Following continued exposure to reducing conditions during early diagenesis, Mn(III)-oxides were then replaced by Mn(II)-carbonates. Similarly, Mn(III)-silicates were transformed into various Mn(II)-silicates during late-stage diagenesis and metamorphism. This model suggests that the accumulation of various divalent Mn mineral phases in ancient sediments may, therefore, be indicative of deposition under a water column with a sufficient oxidizing potential to induce Mn(II) oxidation.