Prediction of steroid resistance and steroid dependence in nephrotic syndrome children

Zaorska, Katarzyna; Zawierucha, Piotr; Świerczewska, Monika; Ostalska‐Nowicka, Danuta; Zachwieja, Jacek; Nowicki, Michał

doi:10.1186/s12967-021-02790-w

Cited by 17 publications

(13 citation statements)

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“…Recently, growing studies focus on the association between MIF -794 CATT 5−8 or -173 G>C polymorphism and INS susceptibility as well as steroid treatment response. At present, a total of two studies investigated the association between MIF -794 CATT 5−8 polymorphism and INS, and both reported that a higher CATT number was not associated with increased risk of INS and steroid resistance (3,6). However, studies related to the association between MIF -173 G>C polymorphism and INS presented conflicting results, so we conducted a meta-analysis to clarify the association between the MIF -173 G>C polymorphism and INS.…”

Section: Introductionmentioning

confidence: 97%

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Association Between Macrophage Migration Inhibitory Factor -173 G>C Gene Polymorphism and Childhood Idiopathic Nephrotic Syndrome: A Meta-Analysis

et al. 2021

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Background: Studies have identified that MIF -173 G>C gene polymorphism is associated with idiopathic nephrotic syndrome (INS) susceptibility and steroid resistance, but the results remain inconclusive.Methods: We searched PubMed, Embase, and Web of Science for relevant studies published before 31 March 2021. Pooled data were reported as odds ratio (OR) with 95% confidence interval (CI). Noteworthiness of significant OR was estimated by the false positive report probability (FPRP) test. Trial sequential analysis (TSA) was used to control type I and type II errors.Results: We selected seven case-control studies that included 1,026 INS children (362 were steroid-resistant NS and 564 were steroid-sensitive NS) and 870 controls. The results showed that MIF -173 G>C polymorphism was significantly associated with INS susceptibility in allelic, heterozygous and dominant genetic models (C vs. G: OR = 1.325, 95% CI: 1.011-1.738; GC vs. GG: OR = 1.540, 95% CI: 1.249-1.899; CC + GC vs. GG: OR = 1.507, 95% CI: 1.231-1.845), and FPRP test and TSA indicated that the associations were true in heterozygous and dominant models. The pooled results also revealed that MIF -173 G>C polymorphism was significantly associated with steroid resistance in allelic, homozygous and recessive models (C vs. G: OR = 1.707, 95% CI: 1.013-2.876; CC vs. GG: OR = 4.789, 95% CI: 2.109-10.877; CC vs. GC + GG: OR = 4.188, 95% CI: 1.831-9.578), but FPRP test indicated that all these associations were not noteworthy. Furthermore, TSA revealed that the non-significant associations between MIF -173 G>C polymorphism and steroid resistance in heterozygous and dominant models were potential false negative.Conclusions: This meta-analysis could draw a firm conclusion that MIF -173 G>C polymorphism was significantly associated with increased INS risk in heterozygous and dominant genetic models. MIF -173 G>C polymorphism was not likely to affect steroid responsiveness, but more studies were needed to confirm.

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Section: Introductionmentioning

confidence: 97%

“…The exact pathogenesis of INS and the precise mechanism of the difference in steroid response remain unknown. Current evidence indicates that genetic polymorphisms can affect INS susceptibility and predict steroid treatment response (2,3).…”

Section: Introductionmentioning

confidence: 99%

Association Between Macrophage Migration Inhibitory Factor -173 G>C Gene Polymorphism and Childhood Idiopathic Nephrotic Syndrome: A Meta-Analysis

et al. 2021

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“…Moreover, a literature review of different gene variations related to steroid therapy response resulted in discordant conclusions. Not only cytokine genes, but also steroid-metabolism-related genes, displayed contradictory results in various ethnic groups [33,34].…”

Section: Introductionmentioning

confidence: 99%

Genetic Variants of Interleukin-4 in Romanian Patients with Idiopathic Nephrotic Syndrome

Ţieranu

Tieranu

Dutescu³

et al. 2022

Medicina

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Background and objectives: One of the most frequent glomerular diseases in the pediatric population is represented by the idiopathic nephrotic syndrome (INS). The exact mechanisms mediating the disease are still unknown, but several genetic factors have been studied for possible implications. Cytokines are considered to play a pivotal role in mediating INS disease progression, interleukin-4 (IL-4) exhibiting particular interest. The objective of this research project was to investigate the association between two IL-4 gene single-nucleotide polymorphisms (SNPs) and INS susceptibility as well as response to steroid therapy, in a group of Romanian children. Materials and Methods: In total, 75 patients with INS and 160 healthy controls of Romanian origin were genotyped for IL-4 rs2243250/−590C/T and rs2070874/−34C/T using real-time polymerase chain reaction. Association tests were performed using the DeFinetti program and Plink 1.07 software and p-values < 0.05 were considered statistically significant. Results: The analysis of INS patients and controls revealed a similar genotype distribution of the studied SNPs. The minor T alleles were less frequent in the INS group, but not statistically significant (p = 0.1, OR = 0.68 and p = 0.2, OR = 0.74). Regarding the response to steroids, a low frequency of 590*T allele in steroid-resistant patients (7.7%), compared with steroid-sensitive patients (14%) and controls (17.5%), was obtained, but the difference did not reach the statistical significance threshold. The same result was obtained for −34C/T SNP. Conclusions: This is the first study examining the relationship between the IL-4 gene and INS susceptibility conducted in a European population, and particularly in Romania. The investigated SNPs were found to not be associated with disease susceptibility or response to the steroid treatment of pediatric INS.

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“…Steroid-resistant nephrotic syndrome is not a single entity [4]. Different factors discussed in term of steroid-resistance formation, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Different factors discussed in term of steroid-resistance formation, i.e. pathomorphological type of disease (the most dominant lesion is focal segmental glomerulosclerosis (FSGS) [4,5], genetic markers [6], metabolic factors [7].…”

Section: Introductionmentioning

confidence: 99%

Clinical and Apoptotic Factors Defining and Predicting Steroid Resistance in Nephrotic Syndrome in Children

Burlaka¹,

Mitiuriaeva-Korniyko²,

Багдасарова³

2021

Preprint

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Background. Nephrotic syndrome (NS) is a kidney disease characterized by albuminuria, hyperlipidemia, edema, and hypoalbuminemia. Recent data shown that more than 80% of children with nephrotic syndrome respond to steroid treatment, remain steroid-sensitive during subsequent relapses, and consequently have a favorable long-term prognosis. However, above 20 % of nephrotic children do not show response to steroid treatment. Steroid resistance is believed to be associated with a high risk of developing chronic renal failure. Recent reports suggest different clinical, genetic and molecular markers to be accompanied with phenomenon of steroid resistance. However, molecular markers controlling apoptosis have not been studied as a predictors of steroid resistant NS (SRNS) and steroid sensitive NS (SSNS).Aim of the study. To identify clinical and molecular markers which define and predict the steroid-resistance phenomenon in children with NS.Methods. We analyzed 56 clinical cases of children hospitalized in Pediatric Hospital №7 (Kyiv, Ukraine) with NS (26 SSNS and 30 SRNS). Clinical data (age, gender, disease duration, blood pressure), conventional laboratory markers (serum creatinine, serum urea, serum cholesterol, GFR, proteinuria, blood WBC, PLT, RBC), markers of apoptosis (Bax, BcL-xL, caspase-3, caspase-8), transcriptional factors (NF-kB, HIF-1alfa, Mn-SOD) analyzed. Stepwise logistic regression models use to identify candidates with the potential to be related to have influence of steroid resistance in children with NS. Data processed using GraphPad Prism 9.0 Software for Windows (USA, San Diego, CA).Results. Stepwise logistic regression models identified arterial hypertension as a candidate among clinical characteristics (β - 0,31, SE 0.15, 95% CI -0.6 to -0.007, p<0.05) as a candidate predictive of SRNS. Among basic laboratory factors WBC level (OR: 1.4; OR 95% CI: 1.12–1.85) and RBC level (OR: 1.14; OR 95% CI: 0.38–3.48), serum creatinine (OR: 1.04; OR 95% CI: 0.92–1.14), serum urea (OR: 1.14; OR 95% CI: 0.89–1.49), serum cholesterol (OR: 1.97; OR 95% CI: 1.37–3.18) were found to be a factors defining SRNS.Apoptosis regulating BcL-xL (OR: 1.4; OR 95% CI: 1.17–1.91), Bax (OR: 1.15; OR 95% CI: 1.04–1.37), caspase-3 (OR: 1.66; OR 95% CI: 1.27–2.68) but not caspase-8 (OR: 0.95; OR 95% CI: 0.84–1.05) (AUC: 0.93; SE: 0.03; 95% CI: 0.87-0.99; p<0.001) found to be those defining SRNS. Finally, in group of transcriptional factors HIF-1alfa selected as a factor defining steroid resistance phenomenon (OR: 1.02; OR 95% CI: 0.98–1.07).For SSNS group significant negative correlation was observed between BcL-xL and Bax, BcL-xL and caspase-3, significant positive correlation was observed between marker of cellular hypoxia HIF-1alfa and proapoptotic factor caspase-3.For SRNS group significant negative correlation was observed between BcL-xL and Bax, BcL-xL and caspase-3 level, significant positive correlation was observed between HIF-1alfa and proapoptotic factor caspase-3.Conclusion. Arterial hypertension, serum creatinine level, serum urea level, serum cholesterol level, WBC and RBC count, BcL-xL, Bax, caspase-3 and HIF-1alfa indentified as candidate biomarkers to predict and define SRNS in pediatric NS.

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Prediction of steroid resistance and steroid dependence in nephrotic syndrome children

Cited by 17 publications

References 55 publications

Association Between Macrophage Migration Inhibitory Factor -173 G>C Gene Polymorphism and Childhood Idiopathic Nephrotic Syndrome: A Meta-Analysis

Association Between Macrophage Migration Inhibitory Factor -173 G>C Gene Polymorphism and Childhood Idiopathic Nephrotic Syndrome: A Meta-Analysis

Genetic Variants of Interleukin-4 in Romanian Patients with Idiopathic Nephrotic Syndrome

Clinical and Apoptotic Factors Defining and Predicting Steroid Resistance in Nephrotic Syndrome in Children

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