Pneumococcal carriage and serotype distribution in children with nephrotic syndrome.

BACKGROUND: Patients with nephrotic syndrome (NS) are at a higher risk of developing invasive pneumococcal disease (IPD). Pneumococcal carriage studies are helpful tools for detecting potentially infectious serotypes and guiding immunization efforts. Pneumococcal nasopharyngeal colonization is common, and IPD can easily occur in an immunosuppressed state. Limited information is available regarding the frequency of pneumococcal carriage in individuals with NS. The aim of this study was to evaluate pneumococcal carriage and serotype distribution in children with NS. METHODS: Pneumococcal carriage was detected by real-time PCR assays from nasopharyngeal swab samples from 98 children with NS, and 100 healthy controls. Isolates were serotyped by real-time PCR. RESULTS: The pneumococcal carriage rate was 44.9% in children with NS. Regarding the recommendation about pneumococcal immunization in children with NS, the vaccination rate was low. Also, non-PCV13 serotypes have been detected in at least 25% of PCV13-vaccinated children. There is no statistically significant difference in total pneumococcal carriage rate, PCV13 serotype carriage rate, or non-PCV13 serotype carriage rate between children with NS and healthy controls (p > 0.05 for all). CONCLUSIONS: The pneumococcal carriage rate was similar between children with NS and healthy controls. However, because children with NS have an increased risk for IPD, the serotype distribution of children with NS can demonstrate the improved protection offered by new pneumococcal vaccines. Regular monitoring for IPD is crucial for assessing the evolving sero-epidemiology of pneumococcal infections and evaluating the effectiveness of vaccines for children with NS.

Comprehensive mapping of saliva by multiomics in children with idiopathic nephrotic syndrome.

AIM: Saliva can reflect an individual's physiological status or susceptibility to systemic disease. However, little attention has been given to salivary analysis in children with idiopathic nephrotic syndrome (INS). We aimed to perform a comprehensive analysis of saliva from INS children. METHODS: A total of 18 children (9 children with INS and 9 normal controls) were recruited. Saliva was collected from each INS patient in the acute and remission phases. 16S rRNA gene sequencing, widely targeted metabolomics, and 4D-DIA proteomics were performed. RESULTS: Actinobacteria and Firmicutes were significantly enriched in the pretreatment group compared with the normal control group, while Bacteroidota and Proteobacteria were significantly decreased. A total of 146 metabolites were identified as significantly different between INS children before treatment and normal controls, which covers 17 of 23 categories. KEGG enrichment analysis revealed three significantly enriched pathways, including ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and terpenoid backbone biosynthesis (P < 0.05). A total of 389 differentially expressed proteins were selected between INS children before treatment and normal controls. According to the KEGG and GO enrichment analyses of the KOGs, abnormal ribosome structure and function and humoral immune disorders were the most prominent differences between INS patients and normal controls in the proteomic analysis. CONCLUSION: Oral microbiota dysbiosis may modulate the metabolic profile of saliva in children with INS. It is hypothesized that children with INS might have "abnormal ribosome structure and function" and "humoral immune disorders".

A Novel Model for Nephrotic Syndrome Reveals Associated Dysbiosis of the Gut Microbiome and Extramedullary Hematopoiesis.

Glomerular kidney disease causing nephrotic syndrome is a complex systemic disorder and is associated with significant morbidity in affected patient populations. Despite its clinical relevance, well-established models are largely missing to further elucidate the implications of uncontrolled urinary protein loss. To overcome this limitation, we generated a novel, inducible, podocyte-specific transgenic mouse model (Epb41l5fl/fl*Nphs1-rtTA-3G*tetOCre), developing nephrotic syndrome in adult mice. Animals were comprehensively characterized, including microbiome analysis and multiplexed immunofluorescence imaging. Induced knockout mice developed a phenotype consistent with focal segmental glomerular sclerosis (FSGS). Although these mice showed hallmark features of severe nephrotic syndrome (including proteinuria, hypoalbuminemia and dyslipidemia), they did not exhibit overt chronic kidney disease (CKD) phenotypes. Analysis of the gut microbiome demonstrated distinct dysbiosis and highly significant enrichment of the Alistipes genus. Moreover, Epb41l5-deficient mice developed marked organ pathologies, including extramedullary hematopoiesis of the spleen. Multiplex immunofluorescence imaging demonstrated red pulp macrophage proliferation and mTOR activation as driving factors of hematopoietic niche expansion. Thus, this novel mouse model for adult-onset nephrotic syndrome reveals the significant impact of proteinuria on extra-renal manifestations, demonstrating the versatility of this model for nephrotic syndrome-related research.

Immunological Impact of a Gluten-Free Dairy-Free Diet in Children With Kidney Disease: A Feasibility Study.

Kidney disease affects 10% of the world population and is associated with increased mortality. Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children, often failing standard immunosuppression. Here, we report the results of a prospective study to investigate the immunological impact and safety of a gluten-free and dairy-free (GF/DF) diet in children with SRNS. The study was organized as a four-week summer camp implementing a strict GF/DF diet with prospective collection of blood, urine and stool in addition to whole exome sequencing WES of DNA of participants. Using flow cytometry, proteomic assays and microbiome metagenomics, we show that GF/DF diet had a major anti-inflammatory effect in all participants both at the protein and cellular level with 4-fold increase in T regulatory/T helper 17 cells ratio and the promotion of a favorable regulatory gut microbiota. Overall, GF/DF can have a significant anti-inflammatory effect in children with SRNS and further trials are warranted to investigate this potential dietary intervention in children with SRNS.

Gut Microbiota Profile in Adult Patients with Idiopathic Nephrotic Syndrome.

BACKGROUND: Increasing evidences have reported gut microbiota dysbiosis in many diseases, including chronic kidney disease and pediatric idiopathic nephrotic syndrome (INS). There is lack evidence of intestinal microbiota dysbiosis in adults with INS, however. Here, we to address the association between the gut microbiome and INS. METHODS: Stool samples of 35 adult INS patients and 35 healthy volunteers were collected. Total bacterial DNA was extracted, and the V4 regions of the bacterial 16S ribosomal RNA gene were sequenced. The fecal microbiome was analyzed using bioinformatics. The correlation analysis between altered taxa and clinical parameters was also included. RESULTS: We found that microbial diversity in the gut was reduced in adult patients with INS. Acidobacteria, Negativicutes, Selenomonadales, Veillonellaceae, Clostridiaceae, Dialister, Rombousia, Ruminiclostridium, Lachnospira, Alloprevotella, Clostridium sensu stricto, Megamonas, and Phascolarctobacterium were significantly reduced, while Pasteurellales, Parabacteroides, Bilophila, Enterococcus, Eubacterium ventriosum, and Lachnoclostridium were markedly increased in patients with INS. In addition, Burkholderiales, Alcaligenaceae, and Barnesiella were negatively correlated with serum creatinine. Blood urea nitrogen levels were positively correlated with Christensenellaceae, Bacteroidales_S24.7, Ruminococcaceae, Ruminococcus, and Lachnospiraceae_NK4A136, but were negatively correlated with Flavonifractor_plautii and Erysipelatoclostridium_ramosum. Enterobacteriales, Enterobacteriaceae, Porphyromonadaceae, Escherichia/Shigella, Parabacteroides, and Escherichia_coli were positively correlated with albumin. Proteinuria was positively correlated with Verrucomicrobia, Coriobacteriia, Thermoleophilia, Ignavibacteria, Coriobacteriales, Nitrosomonadales, Coriobacteriaceae, and Blautia, but was negatively correlated with Betaproteobacteria, Burkholderiales, and Alcaligenaceae. CONCLUSION: Our findings show compositional alterations of intestinal microbiota in adult patients with INS and correlations between significantly altered taxa and clinical parameters, which points out the direction for the development of new diagnostics and therapeutic approaches targeted intestinal microbiota.

Idiopathic nephrotic syndrome in children: role of regulatory T cells and gut microbiota.

BACKGROUND: We investigated whether an association exists between regulatory T cells (Tregs) during initial presentation in children with idiopathic nephrotic syndrome (INS) and later development of frequently relapsing INS. METHODS: Blood samples were obtained at onset and at remission from 25 patients (median age, 4.0 years) with INS; eight did not show relapse after initial response (non-relapsing [NR]), whereas 17 showed frequent relapses (frequently relapsing [FR]). Tregs were measured by flow cytometry; increases were compared between groups. Fecal samples were obtained at onset from 20 patients with INS, as well as from 20 age-matched healthy children. Gut microbiota composition was assessed using 16S ribosomal RNA (rRNA) sequencing (ion PGM). RESULTS: The rate of increase in Tregs from onset to remission was significantly lower in the FR group (124.78%) than in the NR group (879.16%; P < 0.001). Additionally, 16S rRNA sequencing of gut microbiota showed that the proportion of butyric acid-producing bacteria was significantly lower in the FR group (7.08%) than in the healthy children (17.45%; P < 0.001). CONCLUSIONS: In children with INS, small increases in Tregs in response to steroid treatment were associated with subsequent increased risk of frequent relapses. In addition, the FR group had a greater degree of dysbiosis at onset. IMPACT: A low rate of Tregs increase is associated with subsequent frequent relapses of INS. The increase in Tregs in response to steroid treatment was small when dysbiosis was present in patients with INS, particularly when the proportion of butyrate-producing bacteria was considerably reduced We presume that improvement of dysbiosis by administration of probiotics and prebiotics may enhance the rate of Tregs' increase, thus preventing frequent relapse.

Cholestatic hepatitis with concomitant nephrotic syndrome due to late syphilis in an immunocompetent 32-year-old man.

A 32-year-old man was referred to our clinic for evaluation of abnormal liver function tests and concurrent proteinuria. Physical examination revealed a maculopapular rash, involving the trunk and palms, and multiple 'moth-eaten' patches of alopecia. After a prolonged diagnostic work-up a hepatitis with concomitant nephrotic syndrome due to secondary syphilis was diagnosed. Treatment with benzylpenicillin led to complete clinical recovery. Syphilis is a re-emerging infectious disease with heterogeneous clinical presentation that should be considered in the differential diagnosis of inexplicable simultaneous liver and kidney dysfunction in patients with high-risk sexual behaviour.Syphilis is a re-emerging infectious disease with heterogeneous clinical presentation that should be considered in the differential diagnosis of inexplicable simultaneous liver and kidney dysfunction in patients with high-risk sexual behaviour.

Urinary tract infection in children with nephrotic syndrome: A systematic review and meta-analysis.

OBJECTIVE: Urinary tract infection (UTI) is among the most common infection diseases in children with nephrotic syndrome (NS), resulting in treatment failure and relapse. No systematic reviews have estimated the prevalence of UTI in children with NS on a global scale, therefore, did the first systematic review and meta-analysis study to estimate the prevalence of UTI in children with NS in different geographical regions and different countries. METHODS: PubMed, EMBASE, Scopus, Web of Science and Google Scholar databases were systematically searched up to 20 February 2019, for studies assessing the prevalence of UTI in children with NS. Pooled prevalence of UTI was calculated using the random effects model. Data were stratified based on WHO geographical regions and individual countries. Subgroup analysis regarding the gender and socio-demographic variables were also performed. RESULTS: Thirty studies involving 6314 children with NS were included. The pooled prevalence of UTI was 21.6% (95%CI, 17.1-26.5%), with the highest prevalence in the African region (34.8%, 95%CI: 4.7-73.9%), and lowest prevalence in the region of the Americas (7.4%, 95% CI: 1.7-16.2%). With respect to countries, the lowest and highest prevalence rates were reported from USA (3.3%) and Indonesia (45.9%). In subgroup analyses, a higher prevalence was observed in females, and in countries with lower levels of income and human development index. The most common isolated bacteria were Escherichia coli (28%), and Klebsiella spp. (22.4%). CONCLUSIONS: The high prevalence of UTI in children with NS reported in this study is a significant health threat for these patients. These results call for intervention strategies and preventive measures for children with NS to reduce the burden of UTI.

Infection associated relapses in children with nephrotic syndrome: A short-term outcome study.

Children with nephrotic syndrome (NS) encounter multiple episodes of relapses associated/triggered by an episode of infection. The primary objective of this study was to find the proportion of infection associated relapses that resolve on the treatment of acute infection over an observation period of two weeks in children with NS. This prospective observational study enrolled 45 children with steroid-sensitive NS presenting with an infection associated relapse during the study period (February 2015 to February 2016). Baseline information and examination findings of all children were recorded. Biochemical and other investigations were performed according to the site of infection for all patients and were treated appropriately. None of the patients received daily 2 mg/kg of prednisolone during the observation period. All children were followed for two weeks for resolution of relapse and subsequently every month for another three months. The 45 patients (median age 66 months) enrolled in the study had 64 episodes of infections, of which upper respiratory tract infections (45%) were the commonest, followed by peritonitis (18.5%) and diarrhea in 12%. Twenty-seven (60%) patients achieved remission on symptomatic treatment of infection with/without the use of stress doses of prednisolone. Most (77.8%) patients who achieved remission without the use of daily 2 mg/kg of prednisolone did so within the 1st week and a majority of patients were still in remission at three months follow-up. We conclude that most infection associated relapses can be managed with treatment of underlying infection alone and use of stress doses of steroids for inducing remission without increasing the prednisolone doses to 2 mg/kg/d and thus reducing the cumulative steroid doses.

Gut Microbiota Dysbiosis in Children with Relapsing Idiopathic Nephrotic Syndrome.

BACKGROUND: While the etiology of idiopathic nephrotic syndrome (idiopathic nephrotic syndrome [INS]; characterized by repeated relapses and comorbid allergic conditions) remains unknown, recent evidence suggests that dysfunction in regulatory T cells (Tregs) plays an important role in the development of INS as well as allergic diseases. We hypothesized that dysbiosis involving decreased butyric acid-producing gut microbiota leads to defective induction and differentiation of peripherally induced Tregs, resulting in INS relapse. METHODS: Study subjects were 12 children with INS, 8 classified as relapsing (R group; median age: 3.0 years) and 4 as non-relapsing (NR group; median age: 4.3 years), and 11 healthy children (HC group; median age: 5.1 years) serving as normal controls. Measurement of microbiota was performed using 16S ribosomal RNA metagenomic analysis, and fecal butyric acid was measured using high performance liquid chromatography. Flow-cytometric analysis of Tregs and CD4-positive (CD4+) cells in peripheral blood was also performed. RESULTS: Metagenomic analysis of gut microbiota using feces showed that the proportion of butyric acid-producing bacteria was significantly lower in R (median 6.36%) than HC (median 18.84%; p = 0.0013), but no different between NR (median 16.71%) and HC (p = 0.29). Fecal organic acid analysis revealed significantly lower butyric acid quantities in R than HC (medians: 0.48 vs. 0.99 mg/g, p = 0.042). Circulating Tregs as a proportion of CD4+ cells were decreased in 75% of R and NR. CONCLUSION: Pediatric relapsing INS patients show gut microbiota dysbiosis, characterized by a decreased proportion of butyric acid-producing bacteria and lower fecal butyric acid quantities, concomitant with reduced circulatory Tregs.

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.

Role of gut microbiota in idiopathic nephrotic syndrome in children.

Nephrotic syndrome characterized by heavy proteinuria and edema is the most common chronic kidney disease in children. It is classified into three categories, of which the idiopathic type accounts for the vast majority of cases. As indicated by the name, the etiology of idiopathic nephrotic syndrome remains unknown though it has been suggested that impaired T cell function is involved. Recently, evidence has mounted to suggest that dysfunction in regulatory T cells plays an important role in the development of allergic disease, a recognized comorbid condition for children with idiopathic nephrotic syndrome. It is known that regulatory T cells are mainly induced by short chain fatty acids produced by gut microbiota and that children with allergy are reported to have aberrant gut microbiota. On this basis, we hypothesize that an aberrant microbiota, i.e., dysbiosis in the gut resulting in defective induction of regulatory T cells, is also involved in the etiology of idiopathic nephrotic syndrome in children. Our hypothesis can be directly tested by metagenome analysis using bacterial DNA extracted from the feces of patients with idiopathic nephrotic syndrome. Indirect evidence could be obtained by epidemiological survey, such as a comparative study of the environmental factors influencing the initial colonization of gut microbiota between patients with idiopathic nephrotic syndrome and age-matched healthy children. Factors that may disrupt this colonization include a cesarean delivery, formula feeding, excessive use of antibiotics, or the introduction of inappropriate solid foods containing a high amount of saturated fat. Based on this hypothesis, we suggest it would be clinically worthwhile to study whether administration of probiotics composed of commensal bacteria known to efficiently induce regulatory T cells in vitro could control the exacerbation or relapse of INS.

Enzymatic Activity of Candida spp. from Oral Cavity and Urine in Children with Nephrotic Syndrome.

Oral colonization with Candida spp. is not synonymous with a systemic active infection. The aim of the study was to evaluate enzymatic activity of Candida strains isolated from the oral cavity in patients with nephrotic syndrome (NS) and to compare it with the activity determined in urine. We studied 32 children with NS and 26 control healthy children. Children with NS were treated with glucocorticosteroids, cyclosporin A, mycophenolate mofetil or azathioprine. In all children, API-ZYM enzymatic tests were performed to evaluate hydrolytic enzymes of Candida isolated from the oral cavity and in urine. Candida spp. were isolated from the oral cavity in 11 patients with NS (34.4%), all receiving immunosuppressive treatment. All strains produced valine arylamidase, 9 alpha-glucosidase (E16), and 9 N-acetyl-beta-glucosaminidase (E18). A positive correlation between the presence of Candida in the oral cavity and E16 and E18 enzymatic activity in both oral cavity and urine was found. A dose of cyclosporin A had an effect on the enzymatic activity (p < 0.05). We conclude that immunosuppressive treatment of NS in children may predispose to systemic Candida invasion. The results of this study suggest that oral candida infection should be monitored in children with nephrotic syndrome, particularly those treated with immunosuppressive agents.

Clinical characteristics and risk factors of severe infections in hospitalized adult patients with primary nephrotic syndrome.

Objective Infection is a common condition in patients with nephrotic syndrome. The objective of the present study is to investigate the clinical characteristics and risk factors of infections in adult patients with primary nephrotic syndrome (PNS). Methods Medical charts of 138 consecutive patients with PNS and infections who were admitted to hospital from April 2013 to April 2016 were systematically reviewed. Results Patients were divided into three groups according to the degree of infections: mild infection group (n = 45), moderate infection group (n = 60), and severe infection group (n = 33). In the severe infection group, most patients (96.9%) had pulmonary infections with opportunistic pathogens. There were significant differences in cumulative prednisone dose, immunosuppressor use, and CD4+ T cell count among the three groups. A lower CD4+ T cell count (<300 cells/mm3) (odds ratio = 4.25 [95% confidence interval 1.680-10.98]) and higher cumulative dose of prednisone (odds ratio = 1.38 [95% confidence interval 1.05-3.26]) were risk factors for severe infections in adult patients with PNS. Conclusions CD4+ T cell count (<300 cells/mm3) and a higher cumulative dose of prednisone are important risk factors for severe infections in adult patients with PNS.

Renal amyloidosis in leprosy, an infrequent cause of nephrotic syndrome in Europe.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae The main clinical manifestations involve the skin and the peripheral nervous system. Several types of nephropathy have been described in leprosy. One frequent form of renal involvement is amyloidosis, especially in patients with lepromatous leprosy. In these patients, end-stage renal disease is an important contributor to morbidity and mortality. Here, we present the case of a patient with nephrotic syndrome caused by secondary amyloidosis, chronic peripheral neuropathy and a history of leprosy. The patient was correctly treated in her youth, which is the best way to avoid renal pathology, but she developed a nephrotic syndrome years later.

Optimizing seroprotection against pneumococcus in children with nephrotic syndrome using the 13-valent pneumococcal conjugate vaccine.

BACKGROUND: Infections are among the main life-threatening complications in patients with nephrotic syndrome (NS), in particular with Streptococcus pneumoniae, the first cause of bacterial peritonitis and sepsis in these patients. This study aims to evaluate the baseline seroprotection of NS patients against S. pneumoniae, and immunize them with the 13-valent pneumococcal conjugate vaccine (PCV13) regardless of disease activity and previous immunization history, in order to evaluate the immunogenicity, safety profile, and effect of NS treatment on vaccine responses. METHODS: This multicentre prospective interventional study enrolled 42 children with NS at disease onset or during a regular follow-up appointment. PCV13 was administered at inclusion. Serotype-specific S. pneumoniae IgG titer were assessed at baseline, after immunization, and at 1year follow-up. Vaccine safety was evaluated clinically and by urinary tests. RESULTS: PCV13 induced high serotype-specific IgG titers that were maintained at high levels one year after vaccination, even in children previously immunized. No serious adverse event occurred and relapse frequency was unchanged. CONCLUSION: Given that high IgG titers were achieved and maintained after PCV13 vaccination, and considering the high morbidity related to S. pneumoniae, we propose PCV13 (re-)vaccination for all NS patients, irrespective of their previous immunization history, treatment and disease activity.

Streptococcal Infection-related Nephritis (SIRN) Manifesting Membranoproliferative Glomerulonephritis Type I.

We herein report the case of an 18-year-old boy who developed nephrotic syndrome and hypertension after upper airway inflammation. Post-streptococcal acute glomerulonephritis was diagnosed on the basis of a high antistreptolysin O titer, hypocomplementemia, proteinuria, and microscopic hematuria. A renal biopsy was performed due to persistent proteinuria, and the pathological diagnosis was membranoproliferative glomerulonephritis (MPGN) type I. Glomeruli showed positive staining for nephritis-associated plasmin receptor (NAPlr), a nephritogenic group A streptococcal antigen, and plasmin activity was found in a similar distribution as NAPlr deposition. This rare case of streptococcal infection-related nephritis (SIRN) manifesting MPGN type I supports the histological diversity of SIRN.

[Syphilitic glomerulonephritis: case report and review of the literature]. / Veseérintettség syphilises fertozésben: esetismertetés és a szakirodalom áttekintése.

The authors report the history of a patient with syphilitic glomerulonephritis, a rare complication of syphilis. The patient was admitted to the hospital with clinical symptoms of neurosyphilis. During his hospital stay urine analysis revealed an extremely high proteinuria, that had not been known before. Intravenous penicillin treatment improved the renal protein loss, but it took a total of six months until complete resolution was achieved. The serology that confirmed the syphilis, the concomitant nephrotic syndrome and the improvement after penicillin therapy met the criteria of syphilitic glomerulonephritis. This case prompted the authors to review the literature about this rare complication of syphilis that has a great clinical significance.