SOCS3 is epigenetically up-regulated in steroid resistant nephrotic children.

The mechanism of steroid resistance in children with the nephrotic syndrome is yet unknown. About 20% of patients demonstrate steroid unresponsiveness and progress to end stage renal disease. Aberrant SOCS3 and SOCS5 expression in steroid resistant and sensitive patients has previously been demonstrated. Here, we investigate genetic and epigenetic mechanisms of regulation of SOCS3 and SOCS5 transcription in nephrotic children. 76 patients with the nephrotic syndrome (40 steroid resistant and 36 steroid sensitive) and 33 matched controls were included in this study. We performed genotyping of a total of 34 single nucleotide polymorphisms for SOCS3 and SOCS5 promoters and evaluated their methylation status using MS-PCR and QMSP methods. Steroid resistant patients had a significantly lower methylation of one region of SOCS3 promoter in comparison with steroid sensitive patients and controls (p < 0.0001). However, the relative methylation level in the steroid sensitive patients and controls differed significantly even before the first steroid dose (p = 0.001758). Other SOCS3 and SOCS5 promoter regions displayed no differences in methylation or were fully methylated/unmethylated in all study groups, showing site-specific methylation. The allele and genotype distribution for SOCS3 and SOCS5 markers did not differ statistically between the groups. We demonstrate an epigenetic mechanism of SOCS3 up-regulation in steroid resistant children with the nephrotic syndrome. The assessment of methylation/unmethylation of SOCS3 promoter might be an early marker for steroid responsiveness in NS patients.

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Molecular factors predicting steroid resistance in pediatric nephrotic syndrome

Ukrainian Journal of Nephrology and Dialysis ◽

10.31450/ukrjnd.2(70).2021.04 ◽

2021 ◽

pp. 32-37

Author(s):

Ie. A. Burlaka ◽

I. V. Bagdasarova

Keyword(s):

Nephrotic Syndrome ◽

Steroid Resistance ◽

Control Group ◽

Activation Markers ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Steroid Sensitive Nephrotic Syndrome ◽

Cellular Hypoxia ◽

Steroid Sensitive ◽

Nephrotic Children

Objectives: the objective of this paper was to study the levels of cellular hypoxia, apoptosis controlling factors in children with steroid-sensitive and steroid-resistant nephrotic syndrome. Background: patients with steroid-resistant nephrotic syndrome (SRNS) represent a challenging subset of patients with nephrotic syndrome who often fail standard immunosuppression and have a higher likelihood of progressing to end-stage renal disease. The search of the biochemical markers undergoing the steroid-resistance is under urgent need. Methods: an examination of kidney biopsies and blood of 56 patients (aged 10 to 15 years) with nephrotic syndrome was done. Conventional clinical investigations, immunohistochemistry, immunoblotting were used in this study. Results: patients with steroid-resistant nephrotic syndrome show an increased level of HIF-1 alfa (a marker of cellular hypoxia) as compared to the control group and children with steroid-sensitive nephrotic syndrome. Patients with steroid-resistant nephrotic syndrome show a down-regulation of anti-apoptotic marker BcL-xL as compared to the control group and children with steroid-sensitive nephrotic syndrome. Conclusion: hypoxia-induces disorders and apoptosis activation markers are considered to be included in the complex scheme predicting steroid-resistance in nephrotic children.

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A genetic study of steroid-resistant nephrotic syndrome: relationship between polymorphism -173 G to C in the MIF gene and serum level MIF in children

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174415007850 ◽

2015 ◽

Vol 7 (1) ◽

pp. 102-107 ◽

Cited By ~ 4

Author(s):

O. R. Ramayani ◽

N. Sekarwana ◽

P. P. Trihono ◽

A. H. Sadewa ◽

A. Lelo

Keyword(s):

Nephrotic Syndrome ◽

Steroid Resistance ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Children ◽

Single Nucleotide ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Increased Risk ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive

There is no satisfactory explanation as to why some nephrotic syndrome (NS) patients respond to glucocorticoids and others do not. The aim of this study was to investigate an association between single nucleotide polymorphism of the MIF gene -rs755622 and serum MIF concentrations in NS patients. During a period between November 2011 and September 2012, 120 consecutive children divided into three groups [healthy children, steroid-resistant nephrotic syndrome (SRNS) and steroid-sensitive nephrotic syndrome (SSNS)] were examined. Children were defined as healthy when they had a normal estimated glomerular filtration rate and spot urinary albumin creatinine ratio <150 μg/mg creatinine. SRNS was diagnosed in children who did not respond to the usual doses of steroids within 4 weeks of initiating treatment. SSNS patients were defined as those who had remission after usual doses of steroids. The genotype of -173 G to C polymorphism of the MIF gene was determined using polymerase chain reaction restriction fragment length polymorphism methods. Serum MIF concentration was measured using sandwich enzyme-linked immunosorbent assay. The allele frequency of the C allele was higher in SRNS compared with that of SSNS patients (P=0.025). There was a trend toward an association between genotypes and serum MIF disturbances. In conclusion, this study noted elevated circulating serum MIF levels and higher frequency of the C allele of the MIF gene in SRNS patients. The presence of the C allele implies an increased risk for steroid resistance.

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Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome

Journal of Clinical Medicine ◽

10.3390/jcm10030523 ◽

2021 ◽

Vol 10 (3) ◽

pp. 523

Author(s):

Shipra Agrawal ◽

Richard Ransom ◽

Saras Saraswathi ◽

Esperanza Garcia-Gonzalo ◽

Amy Webb ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Experimental Studies ◽

Protective Role ◽

Binding Activity ◽

Steroid Resistance ◽

Blood Leukocytes ◽

Steroid Resistant ◽

Biologically Relevant ◽

Steroid Sensitive ◽

In Silico Algorithm

Glucocorticoid (GC) resistance complicates the treatment of ~10–20% of children with nephrotic syndrome (NS), yet the molecular basis for resistance remains unclear. We used RNAseq analysis and in silico algorithm-based approaches on peripheral blood leukocytes from 12 children both at initial NS presentation and after ~7 weeks of GC therapy to identify a 12-gene panel able to differentiate steroid resistant NS (SRNS) from steroid-sensitive NS (SSNS). Among this panel, subsequent validation and analyses of one biologically relevant candidate, sulfatase 2 (SULF2), in up to a total of 66 children, revealed that both SULF2 leukocyte expression and plasma arylsulfatase activity Post/Pre therapy ratios were greater in SSNS vs. SRNS. However, neither plasma SULF2 endosulfatase activity (measured by VEGF binding activity) nor plasma VEGF levels, distinguished SSNS from SRNS, despite VEGF’s reported role as a downstream mediator of SULF2’s effects in glomeruli. Experimental studies of NS-related injury in both rat glomeruli and cultured podocytes also revealed decreased SULF2 expression, which were partially reversible by GC treatment of podocytes. These findings together suggest that SULF2 levels and activity are associated with GC resistance in NS, and that SULF2 may play a protective role in NS via the modulation of downstream mediators distinct from VEGF.

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Comparison of clinical and lab profile between steroid sensitive and steroid resistant nephrotic syndrome at onset of disease and evaluating predictors for developing steroid resistance in nephrotic syndrome

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20202138 ◽

2020 ◽

Vol 7 (6) ◽

pp. 1304

Author(s):

Anitha Palaniyandi ◽

Subramani Palaniyandi

Keyword(s):

Nephrotic Syndrome ◽

Age At Onset ◽

Steroid Resistance ◽

First Episode ◽

Observation Study ◽

Serum Triglycerides ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive

Background: Nephrotic syndrome is a notable chronic disease in children. The objective of this study was to compare the clinical and lab profile between steroid sensitive nephrotic syndrome and steroid resistant nephrotic syndrome at the onset of disease. Certain parameters were tested if they could be significate predictors of developing steroid resistance at the onset of first episode of nephrotic syndrome.Methods: Retrospective observation study done children 1-12 years diagnosed with nephrotic syndrome in Sri Ramachandra Medical College and Hospital, Department of Paediatrics, Chennai. Sample size 150. Period of study Jan 2013- Dec 2015. Variables considered were age at onset, sex, parental consanguinity with essential lab parameters done at the onset of nephrotic syndrome proteinuria, pyuria, microscopic hematuria, urine protein creatinine ratio, serum creatinine, serum triglycerides and serum albumin. Children less than 1 year of age, cases with secondary causes of nephrotic syndrome and steroid dependant nephrotic syndrome, children with incomplete records were not included in this study. 150 cases who fulfilled the study criteria were included in this study.Results: 75 cases of steroid sensitive nephrotic syndrome (SSNS) were compared with an equal number of steroid resistant nephrotic syndrome (SRNS). 85 children had onset of disease before 3 years of age and majority had 3+ proteinuria and males predominated in both the groups. The overall consanguinity rates were higher among SRNS group. Triglyceride level >300 mg/dl predominated in SRNS group along with a higher severity of hypoalbuminemia when compared to SSNS group. None of the parameters tested were significant predictors of developing SRNS subsequently.Conclusions: Comparing steroid sensitive with steroid resistance nephrotic syndrome, no lab parameter could identify the risk of a child developing steroid resistance subsequently. This could be a field of interest in future studies that could predict the development of steroid resistance at the onset of first episode of nephrotic syndrome itself.

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MO248P-GLYCOPROTEIN EXPRESSING IL-17A+IFN-GAMA+ TH17/1 CELLS ARE REFRACTORY TO GLUCOCORTICOID IN NEPHROTIC SYNDROME*

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab104.006 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Akhilesh Kumar Jaiswal ◽

Narayan Prasad ◽

Vikas Agarwal

Keyword(s):

Nephrotic Syndrome ◽

Th17 Cells ◽

Steroid Resistance ◽

Glycoprotein P ◽

Steroid Resistant ◽

P Glycoprotein ◽

Cellular Source ◽

Steroid Sensitive ◽

Ifn Γ

Abstract Background and Aims Th17 cells are critical effectors mediating the autoimmunity in nephrotic syndrome (NS). Elevated IFN-γ has also been involved in NS; however, it remains unclear to what extent Th1 cells contribute to glucocorticoids resistance in NS. P-glycoprotein (P-gp) effluxes glucocorticoids outside the cells and selectively expressed differentially on T cell subtypes. In this study, we investigated the role of P-gp and cellular source of IFN-γ and assessed its contribution to glucocorticoids resistance in NS. Method We analyzed the frequency of pathogenic IL-17A+IFN-γ+ Th17/1 lymphocytes and P-gp expression on their surface by flow cytometry in SSNS (n = 32; mean age: 9.06 ± 5.84) and SRNS (n = 28; mean age: 11.29 ± 3.73) patients. We also included 15 age- and sex-matched healthy controls. All patients were of biopsy proven minimal change disease and all patients were treated with steroids. All patients were recruited as per the criteria of ISKDC. Results We found a significant IL-17A+IFN-γ+ Th17/1 population (P < 0.001) in steroid resistant NS (SRNS) as compared to steroid sensitive NS (SSNS) patients. IL-12 and IL-23 are significantly higher in SRNS as compared to SSNS patients which are require for transition of pathogenic Th17 cells to IFN-γ producers. Of the IL-17A+IFN-γ+ Th17/1 population 95.8% cells were expressed P-gp on their surface in SRNS; however only 30.1% cells expressed P-gp in SSNS group (Figure 1). We also observed that P-gp expression correlate positively with IL-17A+IFN-γ+ Th17/1 population (r= 0.739, p< 0.001) significantly. Conclusion The above findings clearly show that higher expression of P-gp on IL-17A+IFN-γ+ Th17/1 cells associated with steroid resistance in nephrotic syndrome through both IL-17A and IFN-γ.

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Therapies for Glomerular Diseases in Children

Annals of the National Academy of Medical Sciences (India) ◽

10.1055/s-0040-1712821 ◽

2018 ◽

Vol 54 (01) ◽

pp. 043-053

Author(s):

Arvind Bagga

Keyword(s):

Nephrotic Syndrome ◽

Immunosuppressive Agents ◽

Calcineurin Inhibitors ◽

Steroid Resistance ◽

Glomerular Diseases ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Steroid Dependence ◽

Frequent Relapses ◽

Steroid Sensitive

AbstractNephrotic syndrome is an important chronic disease of childhood, with a steroid sensitive course in most patients. Research on pathogenesis has emphasized the importance of T-lymphocyte dysregulation and vascular permeability factors that alter podocyte function and glomerular permselectivity. Mutations in genes that encode important podocyte proteins and therapeutic targets within podocytes have been identified. A hypothesis unifying available evidence on pathogenesis is yet to be proposed. An important proportion of patients have difficult disease course, characterized by frequent relapses, steroid dependence or steroid resistance, requiring therapy with alternative immunosuppressive agents. Clinical studies support the use of levamisole, cyclophosphamide, mycophenolate mofetil, calcineurin inhibitors (CNIs) and rituximab in patients with frequent relapses or steroid dependence. The management of steroid-resistant nephrotic syndrome is difficult and patients failing to achieve remission show progressive renal damage. Prospective studies in patients with steroid sensitive and steroid resistant nephrotic syndrome are the basis of current guidelines while ongoing studies will help identify and formulate effective and safe therapies.

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Predictive value of platelet indices in children with idiopathic nephrotic syndrome

Immunopathologia Persa ◽

10.15171/ipp.2020.04 ◽

2019 ◽

Vol 6 (1) ◽

pp. e04-e04

Author(s):

Azar Nickavar ◽

Sahar Sadr Moharerpour ◽

Ehsan Abiry

Keyword(s):

Nephrotic Syndrome ◽

Idiopathic Nephrotic Syndrome ◽

Steroid Resistance ◽

Platelet Volume ◽

Distribution Width ◽

Steroid Resistant ◽

Qualitative And Quantitative ◽

Platelet Counts ◽

Steroid Sensitive ◽

Quantitative Changes

Introduction: Different biomarkers have been investigated for prognosis of patients with nephrotic syndrome. Qualitative and quantitative changes have been reported in platelets in these patients. Objectives: The aim of this study was to identify platelet abnormalities and their prognostic value of steroid response in children with idiopathic nephrotic syndrome. Patients and Methods: Platelet counts and indices (mean platelet volume [MPV], platelet distribution width [PDW] and platelet larger cell ratio [PLCR]) were evaluated and compared in 122 children with active nephrotic syndrome (64%; steroid resistant and 36%; steroid sensitive). Results: Mean age at diagnosis was 55 months (6 to169 months), and males outnumbered females (1.7/1). Steroid resistant patients had significantly higher platelet counts and lower PLCR, compared to steroid sensitive group. Regarding area under the ROC curve, low MPV, high PDW and low PLCR showed relatively acceptable correlation with steroid resistance. Conclusion: Increased platelet counts in addition to low PLCR are the suggestive indicators of steroid resistance in children with idiopathic nephrotic syndrome.

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ASSOTIATIONS OF PECULIARITIES OF HLA-PHENOTYPE AND THE SENSIBILITY TO THE CORTICOSTEROID TREATMENT IN PATIENTS WITH CHRONIC GLOMERULONEPHRITIS WITH NEPHROTIC SYNDROME

Ukrainian Journal of Nephrology and Dialysis ◽

10.31450/ukrjnd.1(37).2013.07 ◽

2017 ◽

pp. 37-44

Author(s):

M. Kolesnyk ◽

G. Drannik ◽

V. Driyanska ◽

O. Petrina ◽

M. Velychko

Keyword(s):

Nephrotic Syndrome ◽

Hla Antigens ◽

Corticosteroid Treatment ◽

Steroid Resistance ◽

Control Group ◽

Chronic Glomerulonephritis ◽

Healthy Donors ◽

Steroid Sensitive ◽

Steroid Sensitivity ◽

Hla Phenotype

The purpose of study was determination of HLA -antigens I and II classes as predictors of ineffectiveness of initial steroid therapy, and according prognozonegative markers of chronic glomerulonephritis with nephrotic syndrome. Methods. In 59 chronic glomerulonephritis with nephrotic syndrome patients (steroid sensitive n=33 (1 gr.) and steroid resistant’s n= 26 (2 gr.)) and 350 healthy donors( control group) studied HLA antigens I and II classes of the special anti- HLA-antigens panel (20 antigens of locus A, 31 – of locus B and 9- of locus DR). Result. In patients with chronic glomerulonephritis, nephrotic syndrome with hormone sensitivity relative risk is high at the presents of A28 (RR=8,5, r р <0,001), it made attributive risk (=0,37). In comparison with a control group, RR>2 for antigens A11 (RR=2,23), A23 (RR=4,28), A24 (RR=3,3), A29 (RR=10,78) that A30 (RR=11,23); attributive risk more than 0,1 for the antigen A11 (=0,16) ; A24 (=0,13), other did not differ from control. Subzero connection is exposed for the antigens of A2 (р<0,001), А9 (р=0,007). In locus antigen B14 (RR=5,65, р =0,001) are exposed, B44 (RR=48,25, р =0,004), B51(RR=12,32, р =0,006) and attributive risk of development of disease (according =0,24, 0,12 ; 0,14); and antigens B38 and B41 (RR=11,57, р=0,05). The steroid sensitivity was associated with the antigens B5 (p=0,033), B12 (p=0,005) and B35 (p=0,021). In locus DR made etiologic faction antigens DR4 (RR=7,0 and =0,24) DRw52 (RR=7,0 and =0,25). Conclusions. For patients with chronic glomerulonephritis with a nephrotic syndrome antigens of HLA-B14,B38, B51, DRw52 are associated with steroid sensitivity. The attributive risk of steroid resistance is high for split A19+31+32, antigens B8, B55.

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Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.06060519 ◽

2019 ◽

Vol 15 (1) ◽

pp. 89-100 ◽

Cited By ~ 15

Author(s):

Samuela Landini ◽

Benedetta Mazzinghi ◽

Francesca Becherucci ◽

Marco Allinovi ◽

Aldesia Provenzano ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Signs ◽

Long Term Outcome ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Pathogenic Variants ◽

Whole Exome ◽

Steroid Sensitive

Background and objectivesNephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients.Design, setting, participants, & measurementsAll patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and in silico filtering of 298 genes related to CKD were combined with subsequent reverse phenotyping in patients and families. Pathogenic variants were defined according to current guidelines of the American College of Medical Genetics.ResultsA total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies.ConclusionsReverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.

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