Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation

Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis(ICGN).However,an in-depth study on this topic is currently lacking.Herein,we report an ICGN model to address this gap.ICGN was induced via the intravenous injection of cationized bovine serum albumin(c-BSA)into Sprague-Dawley(SD)rats for two weeks,after which mycophenolate mofetil(MMF)and losartan were administered orally.Two and six weeks after ICGN establishment,fecal samples were collected and 16S ribosomal DNA(rDNA)sequencing and untargeted metabolomic were conducted.Fecal microbiota transplantation(FMT)was conducted to determine whether gut normali-zation caused by MMF and losartan contributed to their renal protective effects.A gradual decline in microbial diversity and richness was accompanied by a loss of renal function.Approximately 18 genera were found to have significantly different relative abundances between the early and later stages,and Marvinbryantia and Allobaculum were markedly upregulated in both stages.Untargeted metabolomics indicated that the tryptophan metabolism was enhanced in ICGN,characterized by the overproduction of indole and kynurenic acid,while the serotonin pathway was reduced.Administration of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in feces.FMT using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes(F/B)ratio but did not improve renal function.These findings indicate that ICGN induces serous gut dysbiosis,wherein an altered tryptophan metabolism may contribute to its pro-gression.MMF and losartan significantly reversed the gut microbial and metabolomic dysbiosis,which partially contributed to their renoprotective effects.

Echerichia coli Infection—Associated Glomerulonephritis in a Kidney Transplant Patient: A Case Report

Post infectious Glomerulonephritis (PIGN) in renal allograft is a rare entity. Only a few Cases have been described in the literature. The post streptococcal glomerulonephritis is the classic example in native kidney. A wide variety of organism has been associated with PIGN in renal allograft such as Staphylococcus, Cytomegalovirus and Polyomavirus. We describe one case of Infection associated glomerulonephritis due to Echericha Coli, developed 5 years after kidney transplantation, in 47 years old female patient. The Clinical presentation was characterized by a peripheral edema and high blood pressure, and biological tests showed a nephrotic syndrome, an acute kidney injury, a consumption of Complement fractions. The renal biopsy revealed a diffuse endocapillary cell proliferation with preponderant deposits of C3. Total recovery was achieved 4 months after Methyprednisolone pulse and Cyclophasphamid with antimicrobial treatment.

Short-term renal and patient outcomes of primary immunoglobulinassociated mesangiocapillary glomerulonephritis:Insights from a developing country

BACKGROUND Primary immunoglobulin(Ig)-associated mesangiocapillary glomerulonephritis(Ig-MCGN)is an immune complex glomerulonephritis of unknown etiology.It is a common cause of chronic kidney disease in developing countries.There is limited data available on renal and patient outcomes of this disease from developing countries.AIM To determine the short-term renal and patient outcomes of adults with a tissueconfirmed diagnosis of primary Ig-MCGN at a single center in Pakistan.METHODS A retrospective cohort study of adult patients was conducted on biopsy-proven Ig-MCGN cases diagnosed between 1998 and 2019 at the Sindh Institute of Urology and Transplantation,Karachi,Pakistan.Secondary causes were excluded.The primary endpoint was renal survival without end-stage kidney disease(ESKD)or mortality.The secondary endpoint was the rate of remission during the 2-year follow-up period.Survival curves were made with the use of Kaplan-Meier estimates.RESULTS A total of 163 patients were included in the study and their mean follow-up duration was 29.45 months±21.28 months.Among baseline characteristics,young age,lower estimated glomerular filtration rate,requirement of kidney replacement therapy,presence of crescents,and severity of interstitial fibrosis and tubular atrophy were found to have a significant association with renal outcomes.The renal outcomes were negatively correlated with the presence of hypertension,level of complements,and degree of proteinuria.In all,63(37.4%)patients were treated with steroids and 21(13%)received combination therapy(cyclophosphamide with steroids).At 2 years,124(76.07%)patients were in complete remission or partial remission[56(34.3%)and 68(41.71%),respectively],while 32(19.63%)patients progressed to ESKD and 7(4.29%)patients died.CONCLUSION The outcomes of primary Ig-MCGN are guarded in Pakistan and require further prospective studies to improve our understanding of this relatively common disease so that more personalized treatment approaches can be developed.

Renal Vein Thrombosis Suggestive of Extramembranous Glomerulonephritis Associated with Sjögren’s Syndrome (Case Report)

Introduction: Glomerular damage during Gougerot-Sjgren syndrome is much rarer than interstitial damage, and is essentially extra-membranous and membrano-proliferative glomerulonephritis. Observation: We report the case of a 44-year-old woman with primary Sjgrens syndrome, confirmed by clinical dryness syndrome, positive anti-SSA and anti-SSB antibodies, and a salivary gland biopsy revealing grade 4 lymphocytic sialadenitis according to CHISHOLMs classification. Later, the patient developed nephrotic syndrome, along with hypertension. Renal function remained normal with a creatinine level of 9.3 mg/l, and hematuria was absent. Only antinuclear antibodies tested positive, while anti-PLA2R antibodies were negative. A renal biopsy was performed, which was complicated on the same day by hemodynamic instability with hematuria. Renal CT scan with contrast injection revealed a posterior perirenal hematoma without contrast extravasation. Additionally, bilateral renal vein thrombosis was incidentally discovered, suggesting extramembranous glomerulonephritis. The patients hemodynamic status stabilized after fluid resuscitation with isotonic saline solution (0.9%), without the need for blood transfusion. Renal biopsy confirmed extramembranous glomerulonephritis with interstitial fibrosis and minimal tubular atrophy. The initial etiological assessment was negative. The patient was started on oral corticosteroids, angiotensin-converting enzyme inhibitors, and therapeutic anticoagulation for renal vein thrombosis. The patients condition improved, with the disappearance of the syndrome and spontaneous regression of the hematoma. Discussion: The association of nephrotic syndrome and renal vein thrombosis primarily suggests glomerulopathy, in particular extra-membranous glomerulonephritis. Sjgrens syndrome can be associated with extra-membranous glomerulonephritis without being its direct cause. Like, it is possible that it is a cause of glomerulonephritis, essentially extra membranous and membrano-proliferative. Conclusion: Sjgrens syndrome is generally underestimated cause of glomerulonephritis, which should be considered in cases of extra-membranous glomerulonephritis.

肾复康Ⅱ号联合氯沙坦钾对IgAN伴肾小管间质纤维化患者尿蛋白定量与中医证候积分的影响

目的:探讨肾复康Ⅱ号胶囊联合氯沙坦钾片对免疫球蛋白A肾病(immunoglobulin A nephropathy,IgAN)伴肾小管间质纤维化患者尿蛋白定量与中医证候积分的影响及其相关性。方法:将80例IgAN伴肾小管间质纤维化患者分为对照组和试验组各40例,对照组予氯沙坦钾片治疗,试验组在对照组基础上予肾复康Ⅱ号胶囊,观察两组患者治疗12、24周后尿蛋白定量及治疗前后中医证候积分。结果:与治疗前比较,试验组治疗12、24周后尿蛋白定量下降(P<0.05),对照组治疗24周尿蛋白定量下降(P<0.05);与对照组比较,试验组治疗12、24周尿蛋白定量降低(P<0.05);治疗24周后试验组中医证候积分较治疗前降低(P<0.05)。结论:IgAN伴肾小管间质纤维化患者尿蛋白定量与中医证候积分之间存在相关性,尿蛋白定量及预后与中医证候、总有效率具有一致性。

国际IgAN预测模型对内蒙古地区IgAN患者预后评估的适用性

目的:探究国际IgAN预测工具在IgAN预后评估中的可行性。方法:以多因素Logistic回归分析影响患者预后的危险因素,将分析后的危险因素作为预测因素构建预测模型,检验构建模型的总体性能,并选取308例IgAN患者作为验证对象进行模型效能验证。回顾性分析内蒙古地区308例IgAN患者临床预后情况,根据患者的预后情况分为生存组、死亡组,分别应用国际IgAN预测工具与牛津病理分型模型评估预后的预测价值,对比国际IgAN预测工具与牛津病理分型模型评估检查情况及ROC曲线准确率AUC、特异度以及敏感度。结果:纳入的308例IgAN患者的预后不良比例为42.60%;国际IgA预后预测模型的检出准确率明显高于牛津分型(χ^(2)=18.422,P=0.001);对比牛津分型,国际IgA预后预测模型的AUC、敏感度、特异度均明显升高且差异具有统计学意义(P<0.05)。结论:IgAN患者存在年龄、高血压疾病史、SBP、Pro、Scr、NLR、eGFR等多项影响预后因素,应为存在以上危险因素的患者制定针对性护理预防方案,基于IgAN患者预后影响因素建立的预测模型具有较高的临床敏感度、特异度,并且整体预测效能优于牛津分型,值得临床推广应用。

PAI-1、VEGF及其受体flk-1与IgAN患者肾小管间质损害程度相关性分析

目的 分析纤溶酶原激活物抑制物-1(PAI-1)、血管内皮细胞生长因子(VEGF)及其受体VEGF-R2(flk-1)与IgA肾病(IgAN)患者肾小管间质损害(TIL)程度相关性。方法 选取2019年6月至2021年6月我院收治的IgAN患者86例,作为IgAN组,以同期因疑似肾脏恶性肿瘤而进行病理活检且结果正常的85例对象作为对照组。对比不同患者PAI-1、VEGF及flk-1差异,以散点图分析各指标与Katafuchi半定量积分的相关性。结果 IgAN组PAI-1、VEGF及flk-1表达均高于对照组(P<0.05)。三组中,重度TIL损伤组PAI-1、VEGF及flk-1最高,轻度TIL损伤组PAI-1、VEGF及flk-1最低,各组间PAI-1、VEGF及flk-1表达比较差异有显著性(P<0.05)。PAI-1、VEGF及flk-1均与肾小管间质损害程度呈正相关性(P<0.05)。结论 PAI-1、VEGF及其受体flk-1与IgAN患者肾小管间质损害程度显著相关,监测各指标水平有利于判断肾小管病理损伤程度。

三种细胞生长因子在IgAN肾组织分布及临床意义的研究

目的 探讨TGFβ2、PDGF、bFGF在人类IgA肾病 (IgAN)中的表达及临床意义。 方法 采用sABC法检测I gAN肾活检组织中的TGFβ2、PDGF、bFGF的表达。 结果 ①TGFβ2在IgAN肾组织内 73%强阳性表达于皮质区肾小管上皮细胞内 ,损伤脱落的上皮细胞内可见聚集成较大的强阳性颗粒 ,45 %的肾小球系膜区可见表达 ,间质淋巴细胞浸润区强阳性。②PDGF在 2 7%的IgAN肾组织内的肾小球系膜区呈弱阳性表达。③bFGF在IgAN肾组织内表达与TGFβ2相似 ,另外在Bowman囊壁层上皮细胞可见阳性表达。结论 TGFβ2、PDGF、bFGF的高表达在IgAN系膜增生、肾小管间质病变发挥重要作用 。

Infection related membranoproliferative glomerulonephritis secondary to anaplasmosis:A case

BACKGROUND Anaplasmosis is a tick-borne disease with a range of clinical manifestations,from a flu-like illness with fever and myalgias to a severe systemic disease with multisystem organ failure.Although renal involvement is not a common presentation,there have been few cases reporting acute kidney injury from Anaplasmosis.CASE SUMMARY We present a 55-year-old female with anaplasmosis who developed acute kidney injury due to membranoproliferative glomerulonephritis(MPGN).The patient originally presented with cough and shortness of breath.She was admitted to the hospital with a diagnosis of community acquired pneumonia and received antibiotics.During the hospital course she developed severe acute renal failure.Initial serological work up didn’t provide any conclusive diagnosis.Hence,she underwent kidney biopsy which showed MPGN pattern suggesting autoimmune,multiple myeloma or infectious etiology.Extensive work up was undertaken which was negative for autoimmune diseases,vasculitis panel,paraproteinemias but tested positive for IgG anaplasma with high titers indicating Anaplasmosis.CONCLUSION Our case shows a unique presentation of severe acute renal failure from MPGN from tick borne illness.MPGN is usually seen with autoimmune diseases,hepatitis C virus infections,paraproteinemias.Hence,we suggest that tick borne illness should also be considered when evaluating acute renal failure cases in tick borne prevalent regions.

Exploring the Protective Effect of the Ethanolic Extract of Rosa laevigata Michx.Fruit on Rats with Mesangial Proliferative Glomerulonephritis Based on NLRP3 Inflammasome Pathway

Objective:To investigate the effect of the ethanolic extract of Rosa laevigata Michx.fruit on rats with mesangial proliferative glomerulonephritis based on the NLRP3 inflammasome pathway.Methods:Thirty Wistar rats were divided into three groups,a blank control group,a diabetic nephropathy(DN)model group,and an ethanolic extract intervention group,according to the random number table method,with 10 rats in each group.One day before the experiment,basic feeding was initiated for all the rats;the changes in activity and weight of each group of rats were observed and recorded after 7 d,and a rat model of renal function injury was established after 1 d.Results:Compared with the control group,the model group had significantly higher kidney/body ratio,24 h urine protein,serum creatinine(SCr),blood urea nitrogen(BUN),glomerular mesangial cell(GMC)count,and extracellular matrix(ECM)positive area ratio(P<0.05);the same indicators were significantly lower in the intervention group than in the model group(P<0.05).The NLRP3 inflammasome pathway in renal intrinsic cells was activated in the intervention group.The overactivation of NLRP3 inflammasome is known to promote interleukin(IL)-1βrelease,which was inhibited in the intervention group.Conclusion:The ethanolic extract of Rosa laevigata Michx.fruit has a protective effect on renal intrinsic cells and may be related to NLRP3 inflammasome pathway,suggesting that the fruit of Rosa laevigata Michx.has a potential role in protecting renal intrinsic cells from inflammatory damage.NLRP3 inflammasomes are involved in the development of various chronic inflammatory diseases,such as acute and chronic glomerulonephritis and renal fibrosis.

吸烟对IgA肾病(IgAN)患者肾功能和肾小管间质及血管病变的影响

目的探讨吸烟在IgA肾病患者肾功能减退和肾小管间质及血管病变中的作用。方法纳入2011年3月至2012年7月间113例经肾活检诊断为原发性IgA肾病的患者,分析其吸烟状态与估算肾小球滤过滤(estimated glomerular filtration rate,eGFR)及病理指标的关系。结果 113例IgA肾病患者中吸烟者38例,其中既往吸烟者12例、目前吸烟者26例。吸烟者eGFR显著低于非吸烟者(P=0.000)。多重线性回归分析显示,吸烟与eGFR(β=-0.220,P=0.031)呈负相关。吸烟者肾小管间质及血管病变更重,表现为间质炎细胞浸润积分(P=0.023)、间质纤维化积分(P=0.000)、肾小管萎缩积分(P=0.003)和血管壁增厚积分(P=0.004)显著高于非吸烟者。多因素二元Logistic回归分析提示吸烟增加患者肾间质纤维化的风险(OR=4.874,P=0.020)。进一步采用有序Logistic回归分析,发现吸烟与肾间质纤维化积分呈正相关(6=1.747,P=0.004)。Pearson和Spearman单因素相关分析显示,吸烟量与eGFR呈显著负相关(r=-0.308,P=0.001),与肾间质纤维化积分(r_s=0.428,P=0.000)、小管萎缩积分(r_s=0.284,P=0.003)、炎细胞浸润积分(r_s=0.232,P=0.016)、血管壁增厚积分(r_s=0.264,P=0.006)呈显著正相关。结论吸烟是IgA肾病患者肾功能减退程度及肾间质纤维化的独立危险因素,且随着吸烟量增大,可能会增加IgA肾病患者肾功能减退及病理损伤的程度。

多种细胞因子在IgAN小管间质中作用及相关性研究

目的探讨7种细胞因子在IgAN(IgA nephropathy)小管间质中的作用以及与IgAN小管间质损伤的相关性。方法经光镜、免疫荧光和电镜诊断为IgAN的肾活检组织86例,采用Katafuchi半定量积分标准和免疫组织化学技术,对86例IgAN进行了病理学分级和检测TGFβ1、TGFβ2、BMP-7、CTGF、bFGF、ICAM-1、PDGF等7种细胞因子的表达。结果①IgAN间质增生及炎细胞浸润达51.16%及82.56%;肾小管肿胀及小动脉壁增厚达41.86%、39.53%及39.53%;肾小球的系膜细胞不同程度的增生占50%;②TGFβ1,TGFβ2,BMP-7在IgAN肾组织中表达率最高;其次为bFGF,CTGF;再次为ICAM-1,PDGF;③细胞因子主要表达在肾小管、炎细胞浸润区域以及肾小管的系膜区。结论IgAN小管间质的损伤程度早于或重于肾小球的损伤。TGFβ1、TGFβ2、BMP-7、CTGF、bFGF可作为判断IgAN进展和预后的重要检测指标。

90例IgAN临床与病理相关因素分析

目的 观察IgAN患者血清IgA、C3水平与病理Lee氏分级的相关性,探讨影响IgAN预后的临床及病理因素.方法 该院肾脏内科经肾活检穿刺病理检查确诊为原发性IgAN 90例与非IgAN原发性肾小球肾炎患者84例,检测两组患者的血清IgA、C3水平、血压、24 h尿蛋白、血浆白蛋白及血肌酐,同时按Lee氏分级标准评估IgAN病理分级及分析Katafuchi 积分与病情严重程度的相关性.结果 （1）原发性IgAN患者与非IgAN原发性肾小球肾炎患者血清IgA水平分别为[（3.04±0.78）vs（2.45±1.73）g·L-1,P〈0.05];血清C3水平分别为[（0.96±0.32）vs（1.16±0.37）g·L-1,P〉0.05];（2）Lee氏分级为Ⅰ～Ⅲ级与Lee氏分级为Ⅳ～Ⅴ级的IgAN患者血清IgA水平分别为[（3.13±0.93）vs（2.97±0.65）g·L-1,P〉0.05];血清C3水平分别为[（1.07±0.28）vs（0.89±0.33）g·L-1,P〈0.01].结论 IgAN是一种免疫复合物性肾小球肾炎,血清IgA水平可作为IgAN与非IgAN的诊断参考指标;C3水平、Katafuchi 积分与IgAN患者病理严重程度密切相关.

IL-1α在IgAN肾组织中的表达与疾病进展的关系

目的：探讨IL－1α在IgAN肾组织中的表达与疾病进展的关系，方法：对36例经光镜，免疫荧光，电镜等病理诊断为IgAN的肾组织进行了IL－1α免疫组织化学检测，结果：IL－1α主要表达于肾小管上皮细胞内（近曲小管31／36，远曲小管25／36），在肾小球的毛细血管腔内侧（15／36）和肾小球囊壁的肾小囊腔（10／36）亦可见IL－1α的表达，在肾小于系膜区无明显增宽时，IL－1α的表达率高，结论：IL－1α在IgAN肾组织内主要位于肾小管上皮细胞内，在IgAN的进展过程中，IL－1α的表达率增强，此期如选用IL－1α受体拮抗剂进行治疗，可控制IgAN的进展。

IgAN肾病理的中医微观辨证

IgA肾病（IgAN）是世界范围最常见的肾小球疾病,我院近15年来的肾病理资料显示：IgAN占6312例慢性原发性肾小球疾病的53.25%。众所周知IgAN诊断有赖于肾病理检查,且其结果对治疗及预后具有重要意义,这在现代医学已成共识。

金葡菌、葡聚糖和大肠杆菌外膜蛋白诱导IgAN模型病理学分析

研究疾病模型的建立,遵循的原则是与所研究的疾病从临床指标到病理指标必须相一致,而且还不能给其他组织和器官造成损伤。本研究是从多数研究者曾使用的模型和在前辈模型的基础上有所创新的模型进行了对比研究,提出了金葡菌诱导的IgAN模型是当今最理想的IgAN模型。

Reclassification of membranoproliferative glomerulonephritis:Identification of a new GN:C3GN

This review revises the reclassification of the mem-branoproliferative glomerulonephritis （MPGN） after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and patho-genesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized： The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecifc treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in fnding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies.

Triple hit to the kidney-dual pathological crescentic glomerulonephritis and diffuse proliferative immune complexmediated glomerulonephritis: A case report

BACKGROUND Anti-glomerular basement membrane(GBM)disease is a rare rapidly progressive glomerulonephritis,frequently associated with alveolar hemorrhage in the lungs and involving the kidney by crescentic glomerulonephritis.It has been described in association with other glomerulonephritides[such as anti-neutrophilic antibody(ANCA)-glomerulonephritis,membranous nephropathy,and immunoglobulin(Ig)A nephropathy].CASE SUMMARY Herein we present an unusual case of concurrent anti-GBM disease,ANCAassociated crescentic glomerulonephritis and diffuse proliferative immune complex mediated glomerulonephritis with predominant staining for IgA and C3 by immunofluorescence.The patient is a 46-year-old Caucasian male who presented to the emergency department with acute onset of flank pain and was found to have high serum creatinine levels of 15 mg/dL,proteinuria,and hematuria.He rapidly deteriorated and became anuric.He was found to have high anti-GBM antibodies titers(151 units)and high anti-neutrophil cytoplasmic-ANCA.Despite prompt and early treatment,the patient’s condition worsened,and he succumbed to his illness.CONCLUSION Our case emphasizes the importance of a renal biopsy in anti-GBM disease,even in the presence of positive serum anti-GBM antibodies,to identify other potential causes of rapidly progressive glomerulonephritis.The challenge in treating such cases lies in the different therapy modalities.

IgA1 O-糖基化异常及其在IgAN中致病机制

IgA肾病（IgAN）又称Berger病，是以肾小球系膜区IgA沉积为特征的免疫复合物性肾小球肾炎，其发病机制尚不清楚，治疗上也无特异性方案。研究发现IgA1分子铰链区O-连接糖基化异常是其重要致病因素。本文主要对IgA1 O-糖基化异常及其在IgAN中致病机制的研究进展作一综述。