Prevalence of Different Clinical Variants of Nephrotic Syndrome in Children 1–18 Years of Age in Tertiary Care Hospital of North India

Introduction: Childhood nephrotic syndrome has an incidence of 90–100 per million population of India. This study was conducted with the primary objective of studying the prevalence of different clinical variants of childhood nephrotic syndrome (new-onset steroid-sensitive nephrotic syndrome/infrequent relapsing nephrotic syndrome [IFRNS]/frequently relapsing nephrotic syndrome [FRNS]/steroid-dependent nephrotic syndrome [SDNS]/steroid-resistant nephrotic syndrome [SRNS]), while the secondary objectives were to estimate the prevalence of use of steroid-sparing drugs in those with FRNS and SDNS. Materials and Methods: A retrospective study of all patients referred to renal diseases clinic at Government Medical College, Jammu, was done. Records of 61 children of 1–18 years of age fulfilling the International Study of Kidney Disease in Children criteria for nephrotic syndrome attending to our nephrology clinic were reviewed over 1 year period. Standard definitions for new-onset nephrotic syndrome, IFRNS, FRNS, SDNS, and SRNS were used. Steroid-sparing drugs used were levamisole in FRNS and low-dose SDNS whereas cyclophosphamide, mycophenolate mofetil (MMF), and tacrolimus in high-dose SDNS. Results: Among nephrotic syndrome, patients mean age of presentation was 5.95 years, with M: F ratio of 1.77:1. Infrequent relapsers (27.9%) were the most prevalent clinical variant followed by steroid-dependent nephrotic syndrome (24.6%) and new-onset nephrotic syndrome (21.3%). Prednisolone alone was successful in achieving remission in 50.8% of total cases and less commonly involving use of other immunosuppressants with prednisolone such as levamisole (23%), cyclophosphamide (9.8%), and tacrolimus in (3.3%). However, prednisolone in combination with cyclophosphamide and then MMF was used in 14 (23%) in an aim to achieve full remission, but full remission was achieved in 48 (78.7%). Conclusion: In the present study, clinical profile of children with nephrotic syndrome was concordant with typical nephrotic syndrome in children. Pattern of nephrotic syndrome differs in our population in terms of increased number with SDNS and response to treatment did not differ significantly from other studies.

The metabolomics signature associated with responsiveness to steroid therapy in focal segmental glomerulosclerosis: a pilot study

Abstract Background Focal segmental glomerulosclerosis (FSGS) is considered one of the most severe glomerular diseases and around 80% of cases are resistant to steroid treatment. Since a large proportion of steroid-resistant (SR) FSGS patients progress to end-stage renal disease, other therapeutic strategies may benefit this population. However, identification of non-invasive biomarkers to predict this high-risk population is needed. Objective We aimed to identify the biomarker candidates to distinguish SR from steroid-sensitive (SS) patients using metabolomics approach and to identify the possible molecular mechanism of resistance. Methods Urine was collected from biopsy-proven FSGS patients eligible for monotherapy with prednisolone. Patients were followed for 6-8 weeks and categorized as SS or SR. Metabolite profile of urine samples was analyzed by one-dimensional 1H-nuclear magnetic resonance (1H-NMR). Predictive biomarker candidates and their diagnostic importance impaired molecular pathways in SR patients, and the common target molecules between biomarker candidates and drug were predicted. Results Homovanillic acid, 4-methylcatechol, and tyrosine were suggested as the significant predictive biomarker candidates, while L-3,4-dihydroxyphenylalanine, norepinephrine, and gentisic acid had high accuracy as well. Tyrosine metabolism was the most important pathway that is perturbed in SR patients. Common targets of the action of biomarker candidates and prednisolone were molecules that contributed in apoptosis. Conclusion Urine metabolites including homovanillic acid, 4-methylcatechol, and tyrosine may serve as potential non-invasive predictive biomarkers for evaluating the responsiveness of FSGS patients.

Clinical analysis of renal biopsy in 172 cases with steroid-resistant nephrotic syndrome / 中华实用儿科临床杂志

Objective To analyze the pathologic constitution,repeated renal biopsy,treatment,prognosis and focal segmental glomerulosclerosis (FSGS) risk factors of children with steroid-resistant nephrotic syndrome (SRNS).Methods A retrospective analysis was made of 172 SRNS cases of renal biopsy in the Pediatric Nephrology Center,the First Affiliated Hospital of Sun Yat-Sen University from September 1,2006 to August 31,2016.Results The main pathological types of 172 children with SRNS were FSGS in 72 cases (41.9％),minimal change disease (MCD) in 52 cases (30.2％),and mesangial proliferative glomerulonephritis (MsPGN) in 31 cases (18.0％).There were 11 cases (6.4％) with repeated renal biopsy,5 cases of 6 children with MCD changed to FSGS;3 cases of FSGS whose repeated renal biopsy were still FSGS,but the subtype had changed;2 cases of MsPGN changed to FSGS in repeated renal biopsy.Compared to non-FSGS,the age of onset of FSGS was smaller [3.0(1.7,6.0) years old vs.5.8 (3.4,8.9) years old],the plasma albumin of FSGS was lower [18.0 (14.0,22.9) g/L vs.20.0 (15.1,29.1) g/L],the 24 hours urine protein level was higher [136.0(76.0,200.0) mg/(kg · d) vs.93.0(55.3,150.0) mg/(kg · d)],and the differences were all significant(all P ＜ 0.05).Logistic regression analysis showed that the smaller the age(P =0.007),the higher the 24-hour urine protein(P =0.028),the greater the risk of FSGS.The receiver operating characteristic (ROC) curve analysis showed that the optimal critical value of 24 hour urine protein was 131 mg/(kg · d).The effective rate of Cycloposphamide (CTX) treatment in MCD children (10/12 cases) was higher than that of FSGS (1/5 cases) and MsPGN (1/2 cases),and the differences were statistically significant (all P ＜0.05).There was no significant difference in the curative effect of Tacrolimas (TAC) and Ciclosporin A (CsA) in children with FSGS,MCD and MsPGN (all P ＞ 0.05).In 62 cases of FSGS,25 cases (56.4％) were effective,and 37 cases (84.1％) were effective in 44 cases of MCD,15 cases (60.0％) were effective in 25 cases of MsPGN,and the difference of prognosis between different pathological types was statistically significant (P ＜ 0.05).Conclusions The most common pathological types of children with SRNS are FSGS,MCD,and MsPGN,but the pathological types can be converted to each other.The smaller the age is,the higher the 24-hour urine protein level is,and the greater the risk of FSGS of the pathological type.When the quantity of 24-hours urine protein was more than 131 mg/ (kg · d),it should be alert to the possibility of pathological type of FSGS.In children with MCD,the effective rate of CTX is higher than that of children with FSGS and MsPGN.The prognosis of FSGS is the worst but the prognosis of MCD is better.

Clinical analysis of gene mutation in children with steroid-resistant nephrotic syndrome in a single center / 中华实用儿科临床杂志

Objective To analyze the podocyte gene mutation in children with steroid -resistant nephrotic syndrome (SRNS),and to explore the clinical manifestations and prognosis of children with gene mutation,so as to pro-vide a theoretical basis for the diagnosis and treatment of SRNS gene mutation in children. Methods Twenty-four pa-tients with SRNS diagnosis and ages less than 14 years old were selected from the Pediatric Nephrology Center of First Affiliated Hospital of Sun Yat-Sen University during August 31,2014 to September 1,2016. The gene detection was performed through PCR amplification and second DNA general sequencing,in which the target genes were detected in 23 cases with nephrotic panel,and 1 case was sequenced with the exon gene. Results There were 14 cases of male and 10 cases of female in 24 cases of genetic testing. The median age of onset was 4. 7 years old. There were 9 cases of sim-ple type,15 cases of nephritis type. And all the cases were primary steroid-resistant. Within the 20 cases of renal biop-sy,there were 5 cases of minimal change disease (MCD),11 cases of focal segmental glomerulosclerosis(FSGS),and 4 cases of mesangial proliferative glomerulonephritis (MsPGN). In the 24 cases,there were 8 cases of gene mutation. Their age was (3. 97 ± 3. 61)years old. The ratio of male and female was 1. 67:1. 00. The main clinical classification was nephritis type (6/8 cases). The major genes were NPHS2(3 cases),NPHS1(2 cases),INF2(2 cases),MYO1E(1 case). And FSGS was the main pathological type (4 cases). Most of them were no remission or end stage renal disease (ESRD)(6/8 cases),including 2 cases of renal transplantation. The 24 hour urine protein level in the gene mutation group was significantly higher than that in the non-mutation group [195. 4 (166. 0,262. 4)mg/(kg·d)vs. 85. 4 (74. 5,101. 3 ) mg/(kg·d )],and the difference was statistically significant (Z ＝ -3. 674,P ＜ 0. 001 ). Conclusion The main mutation genes of children with SRNS were NPHS2,NPHS1 and so on. FSGS was the main pathological type. Most of them were no remission or ESRD. The higher of the 24 hour urine protein level,the more pos-sibility of genetic mutation.

The bioinformatics analysis of gene methylation for children steroid resistance nephrotic syndrome / 中华肾脏病杂志

Objective Through selecting abnormal DNA methylation of children steroid resistance nephrotic syndrome and bioinformatics analysis to find the pathogenesis of steroid resistance nephrotic syndrome and provide new targets for therapy. Methods We use illumine 450K methylation chip to detected blood gene DNA methylation of 9 cases of children primary nephrotic syndrome. 9 cases were divided into 2 groups: G1 is the group of steroid sensitive nephritic syndrome, a total of 4 cases; G2 is the group of steroid resistance nephrotic syndrome, a total of 5 cases. Selected the abnormal DNA methylation in children steroid resistant nephritic syndrome, clarified the function of those genes through using functional annotation of gene GO, enrichment analysis and KEGG pathway analysis, conducted the preliminary analysis on children with steroid resistant nephrotic syndrome of gene methylation. Results Compared with the control group, G2 has a number of genes that were extensively methylated. According to the results of bioinformatics analysis, the abnormal DNA methylation in G2 is the components of the various kinds of organelles and cell membrane. They also regulated the polymerization and composition of cytoskeleton and actin, as well as involved in the process of metabolism of many amino acids and drug. Conclusions The abnormal DNA methylation in the group 2 have extensive role, offering possibility of clinical prediction and provided potential therapeutic targets.

The mechanisms of steroid resistance of children′s idiopathic nephrotic syndrome / 国际儿科学杂志

The resistance to steroid remains a major trouble in the treatment of idiopathic nephrotic syn-drome,and the mechanisms are complicated. Recent studys have shown that multidrug resistance gene l and P-glycoprotein170,glucocorticoid receptor,renal pathology,gene mutation and complications are all closely related to the resistance to steroid. This review is focused on the mechanisms of steroid resistance of children′s idiopath-ic nephrotic syndrome.

Children with Steroid-resistant Nephrotic Syndrome: Long-term Outcomes of Sequential Steroid Therapy / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>This study aimed to investigate the long-term outcomes in children with steroid-resistant nephrotic syndrome (SRNS), who received methylprednisolone pulse therapy (MPT)-based sequential steroid therapy. In particular, we aimed to observe whether these patients had a high risk of adverse events.</p><p><b>METHODS</b>We conducted a retrospective study over a 5-year period. The long-term outcomes for children with SRNS receiving sequential therapy were observed.</p><p><b>RESULTS</b>Sixty-three children were diagnosed with SRNS and underwent MPT-based sequential steroid therapy. Thirty-five (55.6%) achieved complete or partial remission, 19 (30.2%) of whom were in remission even after treatment cessation at last review. The mean time to initial remission after MPT was 24.3±13.1 days. Forty-nine children (77.8%) experienced relapses, of whom 31 (49.2%) demonstrated a frequent relapsing course. Adverse effects relevant to MPT were generally mild and infrequent. Five patients (7.9%) complained of vomiting or nausea during MPT infusion; 25 (39.7%) experienced excessive weight gain and developed an obvious Cushingoid appearance; and 26 (41.3%) had poor growth associated with long-term steroid use. Twenty-eight patients (44.4%) failed to respond to MPT, of whom 21 (33.3%) achieved complete or partial remission with immunosuppressive agents.</p><p><b>CONCLUSION</b>MPT-based sequential steroid therapy appears to be a safe and effective method for inducing rapid remission in childhood SRNS. Further clinical studies are needed to comprehensively evaluate this therapy.</p>

Endoplasmic Reticulum Stress and the Related Signaling Networks in Severe Asthma

The endoplasmic reticulum (ER) is a specialized organelle that plays a central role in biosynthesis, correct protein folding, and posttranslational modifications of secretory and membrane proteins. Loss of homeostasis in ER functions triggers the ER stress response, resulting in activation of unfolded protein response (UPR), a hallmark of many inflammatory diseases. These pathways have been reported as critical players in the pathogenesis of various pulmonary disorders, including pulmonary fibrosis, lung injury, and chronic airway disorders. More interestingly, ER stress and the related signaling networks are emerging as important modulators of inflammatory and immune responses in the development of allergen-induced bronchial asthma, especially severe asthma.

Clinical Features and Long-Term outcomes of Patients with Late Steroid Resistant/Sensitive Nephrotic Syndrome: A Single Center Study

OBJECTIVE: To find out clinical features and long-term outcomes of idiopathic childhood nephrotic syndrome(NS) patients with late steroid resistance(LSR)/late steroid sensitiveness(LSS). PATIENTS AND METHODS: A retrospective chart review was performed on 480 patients diagnosed with idiopathic childhood NS at Asan Medical Center Children's Hospital from 1990 to 2013. Twenty-four patients whose responsiveness to steroids changed over a minimum 2 year follow-up period (2-17.5 years) were investigated. All patients had undergone a renal biopsy. RESULTS: Among 480 nephrotic children, 428 (89%) were sensitive to the first steroid course. Of those who initially responded, 11 (2.5%) developed resistance to steroid therapy after relapses. LSR mostly developed between 1 month and 1 year after the initial episode. Six patients showed a minimal change and five showed focal segmental glomerulosclerosis (FSGS). Nine (82%) responded to cyclosporine or methylprednisolone pulse therapy. Of these, two had no further relapse, whereas the other seven experienced several relapses that ranged in length from 1.1 to 13.9 years. Three of the nine who initially responded to immunosuppression went on to experience several changes in steroid responsiveness. Two (18%) with resistance to immunosuppressants, including steroids, eventually progressed to end stage renal disease. Among the 52 patients (11%) who were initially steroid resistant, 13 (23%) were converted to steroid sensitive at relapses. Among these, 9 showed minimal change and 4 showed FSGS. Two had no further relapse and the other 11 responded to steroids on subsequent relapses ranging in length from 1.3 to 9.4 years. All these patients have had no further changes in steroid responsiveness with normal renal function. CONCLUSIONS: In this study, 2.5% of initial steroid responders and 25% of initial steroid non-responders changed their responsiveness to steroids at subsequent relapses. Eighteen percent of LSR patients developed end stage renal disease. All of the LSS patients showed preserved normal renal function. Responsiveness to immunosuppressants seemed to be the most important factor determining longterm outcomes in LSR/LSS patients.

NPHS2 Mutations in Indian Children with Sporadic Early Steroid Resistant Nephrotic Syndrome.

We examined the frequency and spectrum of podocin NPHS2 mutations in Indian children with sporadic steroid resistant nephrotic syndrome (SRNS). Of 25 children screened, only one (4%) had a pathogenic mutation resulting in a stop codon. The allele and genotype frequencies of the four known single nucleotide polymorphisms detected in the cohort were similar to that of controls. This finding emphasizes the need to screen for mutations in other genes involved in the pathogenesis of SRNS.

Corticosteroid Sparing Effect of Hachimijiogan in Mikulicz's Disease : A Case Report / 日本東洋医学雑誌

A 65-year-old woman suffered from swollen parotid and submandibular glands in July 2005, and sicca of the eyes and oral cavity arose in October 2005. We diagnosed her as having Mikulicz's disease based on magnetic resonance imaging of the head, gallium scintigraphy, and a lip biopsy in June 2006. After prednisolone 10 mg/day was commenced, her salivary glands shrank slightly. Although the amount of prednisolone had been tapered to 7 mg/day by May 2007, her serum IgG rebounded. In January 2008, hachimijiogan extract granules 7.5 g/day were introduced. Swelling of the salivary glands disappeared and her serum IgG level decreased. In May 2008, the amount of prednisolone was tapered successfully to 6 mg/day. Mikulicz's disease is a corticosteroid-sensitive disease, but in this case steroid resistance made treatment difficult. Based on this case, we performed functional assays of P-glycoprotein with calcein-AM, which demonstrated that hachimijiogan can reverse drug resistance.

Multidrug resistance gene (MDR-1) expression in the colonic mucosa of patients with refractory ulcerative colitis / Expresión del gen de multirresistencia a drogas (MDR-1) en la mucosa colónica de pacientes con colitis ulcerosa refractaria

BACKGROUND: P-Glycoprotein (P-gp), a product of the MDR-1 gene, is a transmembrane efflux pump involved in drug transport, first described in cancer refractoriness. In the normal bowel P-gp is detectable on superficial epithelial cells, but has not been described in crypt epithelium. The role of P-gp and its intestinal expression in steroid-refractory ulcerative colitis (UC) are controversial. AIM: to compare P-gp immunostaining pattern in colonic epithelial cells of steroid-refractory versus steroid-responder UC patients. METHODS: P-gp was assessed by immunohistochemistry in rectal biopsies obtained from 19 patients with active UC, including pre-surgical samples from 11 refractory patients who underwent colectomy, and 8 responders. We devised a 5-point (0-4) score, according to the percentage of epithelial surface with positive immunostaining in the superficial and crypt epithelium (apical, lateral and cytoplasmic areas). RESULTS: Compared with responders, steroid-refractory patients had significantly higher immunostaining scores in the superficial epithelium, both in apical (2.8+/-0.5 versus 1.1+/-0.5, p=0.023) and cytoplasmic cellular areas (2.7+/-0.5 versus 1.2+/-0.5, p=0.032). Positive immunostaining of the superficial epithelium was frequently detected in refractory patients (apical: 9/11 cases, cytoplasmic: 10/11 cases) but was only observed in 4/8 responders. P-gp was also detected in similar areas of the crypt epithelium in 6/11 refractory patients, while it was infrequent in the group of 8 responders (1 apical 1 case, cytoplasmic 2 cases). Samples from the mucosa of normal ileal pouch-anal anastomoses obtained several years after the surgical procedure had a P-gp immunostaining pattern which was similar to that of rectal samples from patients with refractory UC. CONCLUSIONS: These results suggest a critical role of P-gp overexpression in steroid-refractory UC.

Antecedentes. La glicoproteína P (P-gp), un producto del gen MDR-1, es una bomba de eflujo transmembranainvolucrada en el transporte de drogas, descripta por primera vez en el cáncer refractario. En el intestino normal, P-gp se detecta sobre las célulasepiteliales superficiales, pero no se la ha descripto en el epitelio de las criptas. El papel de P-gp y su expresiónintestinal en la colitis ulcerosa (CU) refractaria a esteroides es controvertido. Objetivo. Comparar elpatrón de inmunotinción de P-gp en células epiteliales colónicas de pacientes con CU refractaria vs.respondedora a esteroides. Métodos. Se estudió P-gp por inmunohistoquímica en biopsias rectales obtenidasde 19 pacientes con CU activa, incluyendo muestras prequirúrgicas de 11 pacientes refractarios que fueronsometidos a una colectomía y muestras de 8 respondedores. Ideamos un score de 5 puntos (0-4), según elporcentaje de superficie epitelial con inmunotinción positiva en el epitelio superficial y críptico (áreas apical,lateral y citoplásmica). Resultados. Comparados con los respondedores, los pacientes refractarios a esteroides tenían scores de inmunotinción significativamente mayores en el epitelio superficial, tanto en lasáreas celulares apical (2.8+0.5 vs. 1.1+0.5, p=0.023) como citoplásmica (2.7+0.5 vs. 1.2+0.5, p=0.032). Se detectó frecuentemente inmunotinción positiva en el epitelio superficial en los pacientes refractarios (apical: 9/11 casos, citoplásmica: 10/11 casos), pero la misma se observó sólo en 4/8 respondedores. P-gp también sedetectó en áreas similares del epitelio de las criptas en 6/11 pacientes refractarios, en tanto que fue infrecuenteen el grupo de los 8 respondedores (1 caso en el área apical y 2 en la citoplásmica). Fuerón estudiadasbiopsias de la mucosa de la anastomosis pouch ileal - anal, obtenidas varios años después del procedimeinto quirúrgico, observándose un patrón de...

Expression of glucocorticoid receptor beta in peripheral blood mononuclear cells of asthmatics experiencing exacerbation after upper respiratory infection / 천식및알레르기

BACKGROUND AND OBJECTIVES: Glucocorticoids have demonstrated excellent efficacy in decreasing airway inflammation and controlling bronchial asthma symptoms. However, exacerbations of asthma are frequently observed even during treatment with inhaled glucocorticoids, and most of these episodes occur following viral upper respiratory infections (URI). Recently, it has been suggested that transient resistance to glucocorticoid developed after URI and this resistance to glucocorticoid in asthmatics was related to the increased expression of glucocorticoid receptor beta (GCRbeta). The aim of this study is to evaluate the expression of GCRbeta in asthmatics experiencing exacerbation after an episode of URI. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from asthmatics experiencing exacerbation after URI (n=15), stable asthmatics (n=23), and normal controls (n= 12). Exacerbated asthmatics were started on systemic glucocorticoids upto two weeks and PBMCs were obtained again after the treatment. The degree of expression of GCRbeta mRNA and ratio of GCRbeta/GCRalpha mRNA were calculated using the semi-quantitative RT-PCR. RESULTS: Compared with stable asthmatics and normal control, exacerbated asthmatics showed significantly higher expression of GCRbeta mRNA and ratio of GCRbeta/GCRalpha mRNA. However, comparing exacerbated asthmatics before and after treatment, we found no significant difference but trends of reduction in expression of GCRbeta mRNA and ratio of GCRbeta/GCRalpha mRNA after treatment. CONCLUSION: These findings suggest that transient resistance to corticosteroid in asthmatics experiencing exacerbation after an episode of URI may be related to increased expression of GCRbeta.

Prediction of Steroid Responsiveness in Adult Minimal Change Nephrotic Syndrome Using Urinary beta2-Microglobulin / 대한신장학회잡지

Urinary protein per se causes renal tubular injury and stimulates immunologic reaction. The extent of proximal tubular injury can be estimated by measuring the amount of 24 hours urinary beta2-microglobulin (U beta2-MG). The aim of this study was whether U beta2-MG level could predict the response to the initial steroid treatment for the patients with minimal change nephrotic syndrome (MCNS). We analyzed 58 adult patients (33 M, 25 F), aged 33+/-15 years (range 16-76), with biopsy-proven MCNS treated with 40 to 60mg of oral prednisolone daily up to 16 weeks. The responsiveness (44 cases) inculded complete and partial remission or steroid resistance (14 cases). No difference was found between the steroid responsive and resistant group with regard to age, BUN, serum creatinine, albumin, cholesterol, and urinary protein. The levels of U beta2- MG (microgram/g creatinine) were 250808+/-478917 and 1648+/-2386 in resistan ia Kwang-Yul Chang, et al.:Prediction of Steroid Responsiveness in Adult Minimal Change Nephrotic. Syndrome Using Urinary beta2-Microglobulint group and responsive group, respectively (P<0.05). The cut off value was 400microgram/ g creatinine with 78% of sensitivity and 48% of specificity. The likelihood ratio for the resistance was 2.5 to 2.8 with the U beta2-MG levels over 400 ug/g creatinine and was 0.2 to 0.3 below that value. Multivariate analysis confirmed that higher U beta2- MG level was associated with a lower likelihood of steroid responsiveness, independent of age, sex, creatinine, serum protein, and urinary protein. This study showed that the pretreatment U beta2- MG level may be used to identify subgroup of patients with MCNS who are more likely to be responsive to initial steroid treatment.

Ethical Research on Treatment of Steroid-resistant Nephritic Syndrome / 中国医学伦理学

Some questions like the hardship of treatment and lacking of standard on diagnosis are existing in steroid-resistant nephritic syndrome(SRNS).This article make an ethical analysis on these questions and assumes that we should persist in treating the patients carefully with humanism,carry on informed consent principle,implement the optimal treatment and perfect the standard of diagnosis and treatment,carry on clinical ethics education and promote the judgment level of clinical ethics.