Evidence from mendelian randomization identifies several causal relationships between primary membranous nephropathy and gut microbiota.

BACKGROUND: Research has showcased a correlation between disruptions in gut microbiota and primary membranous nephropathy (pMN), giving rise to the concept of the 'gut-kidney axis'. However, the precise relationship between gut microbiota and pMN remains elusive. Hence, this study endeavors to investigate whether a causal relationship exists between gut microbiota and pMN utilizing Mendelian randomization (MR) analysis. METHODS: The primary method employed for MR analysis is the inverse variance weighting method, supplemented by MR-Egger and the weighted median method, to infer causality. This approach was validated within the pMN cohort across two distinct populations. RESULTS: At the species level, the abundance of Bifidobacterium bifidum and Alistipes indistinctus was negatively correlated with the risk of pMN. Conversely, pMN was positively associated with Bacilli abundance at the class level, Lachnospiraceae abundance at the family level, and Dialister abundance at the genus level. Specifically, at the species level, pMN was positively correlated with the abundance of Ruminococcus lactaris, Dialister invisus, and Coprococcus_sp_ART55_1. CONCLUSION: These findings lay the groundwork for future research exploring the interplay between pMN and the gut microbiota, with substantial implications for the prevention and treatment of pMN and its associated complications.

The gut microbiome in differential diagnosis of diabetic kidney disease and membranous nephropathy.

BACKGROUND: Diabetic kidney disease (DKD) and membranous nephropathy (MN) are the two major causes of end-stage renal disease (ESRD). Increasing evidence has shown that intestinal dysbiosis is associated with many diseases. The aim of this study was to explore the composition of the gut microbiome in DKD and MN patients. METHODS: 16S rRNA gene sequencing was performed on 271 fecal samples (DKD = 129 and MN = 142), and taxonomic annotation of microbial composition and function was completed. RESULTS: We observed distinct microbial communities between the two groups, with MN samples exhibiting more severe dysbiosis than DKD samples. Relative increases in genera producing short-chain fatty acids (SCFAs) in DKD and a higher proportion of potential pathogens in MN were the main contributors to the microbiome alterations in the two groups. Five-fold cross-validation was performed on a random forest model, and four operational taxonomic unit (OTU)-based microbial markers were selected to distinguish DKD from MN. The results showed 92.42% accuracy in the training set and 94.52% accuracy in the testing set, indicating high potential for these microbiome-based markers in separating MN from DKD. Overexpression of several amino acid metabolic pathways, carbohydrate metabolism and lipid metabolism was found in DKD, while interconversion of pentose/glucoronate and membrane transport in relation to ABC transporters and the phosphotransferase system were increased in MN. CONCLUSION: The composition of the gut microbiome appears to differ considerably between patients with DKD and those with MN. Thus, microbiome-based markers could be used as an alternative tool to distinguish DKD and MN.

Genetic determinants of the development and course of membranous nephropathy.

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults and is classified as either primary (idiopatic) or secondary MN according to underlying etiology (the later result from some known disease such as systemic autoimmune diseases, infections, malignancies, drugs, etc). In recent years, phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) were identified as two major podocytic antigens involved in the pathogenesis of idiopatic MN (IMN). And the discovery of circulating antibodies specific for these target antigens has transformed the diagnostic workup and significally improved management of IMN. However why do such antibodies develop is not conclusively established. The role of underlying genetic factors is discussed. The review presents the results of recent studies, that have shown significant associations of specific genetic factors (particularly human leucocyte antigen class II and PLA2R1 genes) with IMN.

The causal association of specific gut microbiota on the risk of membranous nephropathy: a Mendelian randomization study.

PURPOSE: Gut microbiota transplantation has been reported to improve the renal function of membranous nephropathy (MN). However, whether there is a causal effect of gut microbiota on MN remained unclear. METHODS: We performed two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was used as the main approach to evaluate the causal relationship between gut microbiota and MN. Additional methods including MR-Egger regression, weighted median, and MR-weighted mode were also conducted. Cochrane's Q test, MR-Egger regression, and MR-PRESSO were employed to detect heterogeneity and pleiotropy, respectively. RESULTS: A total of 196 gut microbiota were examined. After IVW and sensitivity analysis, eight gut bacteria taxa were observed causal effects on the risk of MN. Specifically, Genus. Oscillibacter was a protective factor (OR: 0.57; 95% CI 0.328-0.979; P = 0.042), while Class. Melainabacteria (OR: 1.51; 95% CI 1.004-2.277; P = 0.048), Genus. Butyricicoccus (OR: 2.16; 95% CI 1.005-4.621; P = 0.048), Genus. Catenibacterium (OR: 1.49; 95% CI 1.043-2.134; P = 0.028), Genus.Ruminiclostridium5 (OR: 1.74; 95% CI 1.053-2.862; P = 0.030), Genus. Ruminococcaceae UCG-003 (OR: 1.73; 95% CI 1.110-2.692; P = 0.015), Order. Bacillales (OR: 1.52; 95% CI 1.135-2.025; P = 0.0048) and Order. Gastranaerophilales (OR: 1.45; 95% CI 1.010-2.085; P = 0.044) were risk factors. Heterogeneity was not significant for most single-nucleotide polymorphisms, and no statistical difference in pleiotropy. CONCLUSIONS: This study first indicated the causal association between specific gut microbiota and MN, which would be of great significance to guide clinical prevention and treatment in MN.

Lactobacillus species ameliorate membranous nephropathy through inhibiting the aryl hydrocarbon receptor pathway via tryptophan-produced indole metabolites.

BACKGROUND AND PURPOSE: Membranous nephropathy (MN) is an immune-mediated glomerular disease in adults. Antibody- and antigen-bonding mechanisms have been largely clarified, but the subepithelium immune complex deposition-mediated downstream molecular mechanisms are currently unresolved. Increasing evidence has suggested that gut microbiota contribute to MN pathogenesis. EXPERIMENTAL APPROACH: In this study, we identified alterations in faecal gut microbiota and serum metabolites that mediate an aryl hydrocarbon receptor (AhR) mechanism in cationic bovine serum albumin (CBSA)-induced MN rats and in patients with idiopathic MN (IMN). KEY RESULTS: Impaired renal function correlated with the relative abundance of reduced faecal probiotics, Lactobacillus and Bifidobacterium, and altered serum levels of tryptophan-produced indole derivatives (TPIDs) in MN rats. Further results showed that reduced relative abundance of five probiotics, namely Lactobacillus johnsonii, Lactobacillus murinus, Lactobacillus vaginalis, Lactobacillus reuteri and Bifidobacterium animalis, positively correlated with decreased levels of indole-3-pyruvic acid, indole-3-aldehyde and tryptamine and negatively correlated with increased levels of indole-3-lactic acid and indole-3-acetic acid in serum of MN rats. Altered five probiotics and five TPIDs also were observed in patients with IMN. Further studies showed that MN rats exhibited a significant increase in intrarenal mRNA expression of AhR and its target genes CYP1A1, CYP1A2 and CYP1B1, which were accompanied by protein expression of down-regulated cytoplasmic AhR, but up-regulated nuclear AhR, in MN rats and IMN patients. CONCLUSION AND IMPLICATIONS: Activation of the intrarenal AhR signalling pathway may involve five TPIDs. These data suggest that gut microbiota could influence MN through TPIDs that engage host receptors.

Oral bacteriome and mycobiome of patients with idiopathic membranous nephropathy with different tongue coatings treated with a Chinese herbal formula.

ETHNOPHARMACOLOGICAL RELEVANCE: Moshen Fuyuan Formula (MSFY) is one of the representative Chinese medicine compound for Idiopathic membranous nephropathy (IMN), that originate from Fang Ji Huang Qi decoction in the Han dynasty. IMN is usually accompanied by different tongue coatings in traditional Chinese medicine (TCM), and tongue microorganisms are important factors affecting the formation of the tongue coating. Recently, oral microbiomes, including bacteria and fungi, have been identified as pivotal factors that contribute to disease development. However, the regulation of oral microbiomes by MSFY has not been defined. AIM OF THE STUDY: In this work, we explore the characteristics of oral bacteria and fungi in IMN patients with different tongue coatings, and clarify the therapeutic effect of MSFY based on oral microbiome. MATERIALS AND METHODS: We enrolled 24 patients with IMN, including 11 with white tongue (IMN-W) and 13 with yellow tongue (IMN-Y), and recruited an additional 10 healthy individuals. Patients with IMN were treated with the MSFY. The oral bacteriome and fungi before and after treatment were detected using full-length 16S rRNA and internal transcribed spacer gene sequencing. RESULTS: The therapeutic effect of MSFY on patients with yellow tongue coating was more significant than that on patients with white tongue coating. In terms of oral bacteriome, Campylobacter bacteria were enriched in patients with yellow tongue and could be a promising biomarker for yellow coating. Enrichment of Veillonella parvula_A may partially account for the therapeutic effect of MSFY. As for oral fungi, Malassezia globosa was enhanced in patients with IMN-W and reduced in patients with IMN-Y. Notably, it was reduced by MSFY. We also found that mycobiome-bacteriome interactions were highly complex and dynamic in patients with IMN. CONCLUSION: The regulation of the dynamic balance between oral fungi and bacteria by MSFY contributes to the treatment of IMN. This study determined the oral bacteriome and mycobiome of patients with IMN with different tongue coatings before and after MSFY treatment, which aids in promoting personalized treatment in clinical TCM and provides direction for investigating the mechanism of Chinese herbal medicines.

Structural modulation of gut microbiota during alleviation of experimental passive Heymann nephritis in rats by a traditional Chinese herbal formula.

BACKGROUND: Jianpi-Qushi-Heluo formula (JQHF) has been used to treat idiopathic membranous nephropathy (IMN) in hospitals for many years. PURPOSE: Elucidating the protective effect and exploring the potential mechanism of JQHF against IMN. METHODS: Passive Heymann nephritis (PHN) was induced in rats by a single tail vein injection of anti-Fx1A antiserum. Then, the animals were treated with JQHF at 16.2 g/kg or 32.4 g/kg, with benzepril (10 mg/kg) as a positive control. Renal function was evaluated by biochemical measurements and pathological testing. Fecal samples were collected before and after treatment to analyze the gut microbiota composition by shotgun whole metagenome sequencing. RESULTS: JQHF exhibited potent efficacy in ameliorating PHN at both doses, as revealed by decreasing the deposition of IgG and C5b-9, relieving podocyte injury, and reducing glomerular and tubular cell apoptosis. The lower dose was corresponding to the clinical dosage and showed better therapeutic effects than the higher dose. Metagenomic analysis showed that gavage with 16.2 g/kg of JQHF shifted the structure of the gut microbiota in PHN rats and significantly increased the relative abundances of Prevotella copri, Lactobacillus vaginalis and Subdoligranulum variabile. Particularly, S. variabile was strongly negatively correlated with serum levels of TC and TG, the deposition of IgG and C5b-9, and apoptosis of glomerular cells. CONCLUSIONS: The JQHF is an effective agent for the treatment of experimental PHN. The PHN-allevating effect of JQHF is associated with specific alternation of gut microbiota.

Clinicopathological features of atypical nephrotic syndrome in Jamaican children.

OBJECTIVES: To document the histopathological spectrum of atypical nephrotic syndrome in Jamaican children and to make clinicopathological correlations which will assist physicians in identifying patients needing nephrology consultation. METHODS: This was a retrospective review of renal biopsy data of Jamaican children who were referred to the University Hospital of the West Indies and the Bustamante Hospital for Children between January 1985 and December 2008. The study population consisted of children < 12 years old with atypical nephrotic syndrome. RESULTS: Biopsies were done in 157 children--85 males and 72 females (mean age 8.91 +/- 3.44 years). Indications for biopsy were steroid resistance (35%), frequent relapses (8.9%) and other atypical presentations (56.1%). Overall, mesangial proliferative glomerulonephritis (MesGN) was the commonest histology (49/157, 31.2%), followed by minimal change disease (MCD) (36/157, 22.9%) and diffuse proliferative glomerulonephritis (DPGN) (26/157, 16.6%). Infection was present in 38/157 (24%) cases. Diffuse proliferative glomerulonephritis was the predominant type associated with streptococcal infection (52.9%) while Hepatitis B was seen in 83% of cases of membranous nephropathy. CONCLUSION: Mesangial proliferative glomerulonephritis is the commonest histology seen in Jamaican children with atypical nephrotic syndrome. Most membranous nephropathy is Hepatitis B related. Hypertension with hypocomplementaemia, renal failure and anaemia are features of more serious renal disease (eg membranoproliferative glomerulonephritis and crescentic nephritis) rather than MCNS and should warrant urgent nephrology consultation for renal biopsy.

Membranous Glomerulonephritis as an Uncommon Presentation of Secondary Syphilis: A Reminder on Therapeutic Decision-Making in Clinical Practice.

Membranous glomerulonephritis is one of the common causes of nephrotic syndrome in the adult population. It is idiopathic in the majority of patients, but the secondary forms can be seen in the setting of autoimmune disease, cancer, infection, and following exposure to certain medications. However, subclinical syphilis-related membranous nephropathy remains a particularly rare clinicopathologic entity in modern times. In this article, we chronicle an interesting case of latent syphilis masquerading as membranous glomerulonephritis, which resolved with benzathine penicillin without requiring immunosuppressive treatment. We further supplement this paper with a concise review of the relevant literature that delineates the utility of appropriate antibiotic therapy in the management of luetic membranous nephropathy. Clinicians should remain cognizant of secondary syphilis while evaluating patients for possible glomerulonephritis or those presenting with proteinuria. Additionally, patients with hepatitis B, hepatitis C, and human immunodeficiency virus infections are not infrequently coinfected with Treponema pallidum. Therefore, a high index of suspicion for systemic manifestations of syphilis such as nephrotic syndrome is warranted in the setting of a coinfection. Prompt diagnosis and treatment of syphilis may result in resolution of proteinuria, without the need for standard immunosuppressive therapy commonly used in clinical practice.

Tuberculosis as a microbiologically proven etiology of membranous nephropathy and interstitial nephritis.

Secondary causes of membranous glomerulonephritis (GN) include systemic lupus erythematosus, other autoimmune diseases, neoplasms, and infections such as hepatitis B and C viruses, syphilis, and parasites. The association of tuberculosis (TB) with membranous GN is rare. We report the first case of microbiologically proven tubercular interstitial nephritis and membranous nephropathy (MN) occurring concurrently in the same patient. The patient improved with the use of antitubercular therapy alone. TB should be recognized as a potentially treatable infectious cause of secondary MN.

Secondary Syphilis Associated with Membranous Nephropathy and Acute Hepatitis in a Patient with HIV: A Case Report.

INTRODUCTION: We present a case of membranous nephropathy associated with a secondary syphilis infection in a patient with HIV. CASE PRESENTATION: A 37-year-old white man with HIV who was receiving highly active antiretroviral therapy presented to the Emergency Department with 6 weeks of rectal pain. He had a CD3-CD4 count of 656 cells/mm3 and an undetectable viral load. On admission, he was found to have an anal ulcer, a serum creatinine of 1.4 mg/dL (baseline 0.7 to 1.0 mg/dL), elevated transaminases, positive rapid plasmin reagin, and a urine protein/creatinine ratio revealing nephrotic-range proteinuria. Renal biopsy demonstrated membranous nephropathy with features suggestive of a secondary cause. Our patient was treated with penicillin for secondary syphilis, with normalization of renal function, resolution of the nephrotic syndrome, and improvement of his elevated transaminases. DISCUSSION: This case is a reminder that patients with HIV are not infrequently coinfected with Treponema pallidum and that secondary syphilis can have systemic manifestations, including elevated transaminases and nephrotic syndrome. Prompt diagnosis and treatment will result in resolution of these problems.

AIDS presenting as focal segmental membranous glomerulopathy.

The case of a young, heterosexual man who was investigated for proteinuria is reported. A renal biopsy specimen showed a focal and segmental membranous glomerulopathy. He was later found to be HIV positive and died from cerebral infarction associated with HIV vasculitis 16 months after his initial presentation. Unusual forms of immune complex mediated glomerulopathies should alert the pathologist to the possibility of HIV associated disease.

Hepatitis B virus associated membranous glomerulonephritis in children--experience in Hong Kong.

A retrospective review was undertaken on all renal biopsies performed in Chinese children under 13 years of age in Queen Mary Hospital, Hong Kong from 1980 to 1990. Of 172 renal biopsies, 18 cases were diagnosed to be membranous glomerulonephritis. All were associated with hepatitis B virus infection. Fourteen patients presented with, and 3 others developed later nephrotic syndrome. Hematuria was a common feature (83%). Complement C3 was low in 5 cases and they became normal later. At last observation, 10 patients (59%) remitted, usually within 3 years. One had persistent proteinuria and 5 had nephrotic syndrome. One patient developed end-stage renal failure 12 years after onset of illness. All three female patients completely remitted. Of the 15 boys, 50% remitted whether they received steroid treatment or not. Two patients received interferon alpha-2a therapy. One achieved remission but HBsAg and HBeAg persisted. The other had transient seroconversion and clinical improvement but nephrotic syndrome returned after stopping treatment.

[Clinical and histological observation of HBV glomerulonephritis treated with interferon-beta].

Hepatitis B virus carriers, a 30-year-old man (case 1) and a 31-year-old man (case 2), associated with nephrotic syndrome were treated with interferon-beta. The nephrotic syndrome did not respond to corticosteroid therapy. Their HBs-Ag, HBe-Ag and HBc-Ab were positive. Renal biopsies revealed membranous glomerulonephritis in case 1 and mixed membranous and proliferative glomerulonephritis in case 2. Direct immunofluorescence studies showed strong granular staining of the GBM with IgG and using sandwich technique with anti-HBe antiserum, granular deposits were seen throughout the GBM. Patients were administrated mainly 3-6 x 10(6) IU/day interferon-beta intravenously for four weeks. After transitory elevation of serum transaminase, HBe-Ag and DNA-polymerase have disappeared with development of HBe-Ab (seroconversion) about six months after the end of interferon-beta administration. Then nephrotic syndrome has recovered in incomplete remission after a year and a half follow-up. The secondary renal biopsy in case 1 showed less intense deposits of HBe-Ag along GBM. These facts suggest that the improvement of proteinuria is associated with the decrease in HBV replication due to interferon therapy.

An unusual cause of membranous glomerulonephritis in a patient with HIV.

A 68-year old Caucasian male with a past medical history of human immunodeficiency virus (HIV) infection presented with acute oliguric renal failure and maculopapular rash. Renal biopsy demonstrated extensive foot process effacement as well as confluent small subepithelial electron-dense deposits, which is diagnostic of membranous glomerulonephritis. Subsequent serological tests showed venereal disease research laboratory test was positive in both serum and cerebral spinal fluid. Following penicillin treatment, the patient's creatinine returned to baseline 4 weeks later. Secondary membranous glomerulonephritis caused by syphilis in patients with HIV is discussed.

Clinicopathological features of atypical nephrotic syndrome in jamaican children / Características clínico-patológicas del síndrome nefrótico atípico en los niños jamaicanos

OBJECTIVES: To document the histopathological spectrum of atypical nephrotic syndrome in Jamaican children and to make clinicopathological correlations which will assist physicians in identifying patients needing nephrology consultation. METHODS: This was a retrospective review of renal biopsy data of Jamaican children who were referred to the University Hospital of the West Indies and the Bustamante Hospital for Children between January 1985 and December 2008. The study population consisted of children < 12 years old with atypical nephrotic syndrome. RESULTS: Biopsies were done in 157 children - 85 males and 72 females (mean age 8.91 ± 3.44 years). Indications for biopsy were steroid resistance (35%), frequent relapses (8.9%) and other atypical presentations (56.1%). Overall, mesangial proliferative glomerulonephritis (MesGN) was the commonest histology (49/157, 31.2%), followed by minimal change disease (MCD) (36/157, 22.9%) and diffuse proliferative glomerulonephritis (DPGN) (26/157, 16.6%). Infection was present in 38/157 (24%) cases. Diffuse proli ferative glomerulonephritis was the predominant type associated with streptococcal infection (52.9%) while Hepatitis B was seen in 83% ofcases ofmembranous nephropathy. CONCLUSION: Mesangial proliferative glomerulonephritis is the commonest histology seen in Jamaican children with atypical nephrotic syndrome. Most membranous nephropathy is Hepatitis B related. Hypertension with hypocomplementaemia, renal failure and anaemia are features ofmore serious renal disease (eg membranoproliferative glomerulonephritis and crescentic nephritis) rather than MCNS and should warrant urgent nephrology consultation for renal biopsy.

OBJETIVOS: Documentar el espectro histopatológico del síndrome nefrótico atípico en los niños jamaicanos y hacer correlaciones clínico-patológicas que ayuden a los médicos a identificar pacientes que necesitan la consulta de nefrología.. MÉTODOS: Se trata de un estudio retrospectivo de datos de biopsias renales de niños jamaicanos remitidos al Hospital Universitario de West Indies y al Hospital Pediátrico Bustamante, entre enero de 1985 y diciembre de 2008. La población del estudio consistió en niños < 12 años de edad que padecían el síndrome nefrótico atípico. RESULTADOS: Se realizaron biopsias a 157 niños - 85 varones y 72 hembras (edad promedio 8.91 + 3.44 años). Las indicaciones para la biopsia se debieron a resistencia a los esteroides (35%), recaídas frecuentes (8.9%) y otras manifestaciones atípicas (56.1%). En general, la glomerulonefritis proliferativa mesangial (GNMes) fue la histología más común con 49/157 (31.2%), seguida por la enfermedad de cambio mínimo (ECM) con 36/157(22.9%) y la glomerulonefritis proliferativa difusa (GNPD) con 26/157 (16.6%). La infección estuvo presente en 38/157 (24%) de los casos. La glomerulonefritis proliferativa difusa fue el tipo predominante asociado con la infección estreptocóccica (52.9%), mientras que Hepatitis B fue observada en el 83% de los casos de nefropatía membranosa. CONCLUSIÓN: La glomerulonefritis proliferativa mesangial es la histología que con mayor frecuencia se observa en los niños jamaicanos que padecen el síndrome nefrótico atípico. La mayoría de los casos de nefropatía membranosa guardan relación con la hepatitis B. La hipertensión con hipocomplementemia, la insuficiencia renal y la anemia son rasgos más bien de enfermedades renales más serias (p.ej, glomerulonefritis membranoproliferativa, nefritis crescéntica) que del síndrome nefrótico de cambios mínimos (SNCM) y debe asegurarse la consulta urgente con el nefrólogo para se realice una biopsia renal.

Hepatitis B virus-associated membranous glomerulonephropathy.

A variety of extrahepatic abnormalities have been described in patients with hepatitis B viral infection, including the prodromal arthritis (serum sickness-like) syndrome, polyarteritis nodosa, and glomerulonephropathy. Five patients with hepatitis B virus (HBV)-associated membranous glomerulonephropathy (MGN) were persistent carriers of HBsAg. The deposition of HBsAg in the renal lesions of these patients was proved by using monospecific antibody and immunofluorescence technique. These findings support the hypothesis of an etiological correlation of hepatitis B viral infection with some cases of MGN. HBV-associated MGN may be much more frequent in the world than previously reported, and more cases must be collected for the understanding of this unique entity.