Jin-Soon Suh

A Polymorphism of Interleukin-22 Receptor Alpha-1 Is Associated with the Development of Childhood IgA Nephropathy

Recent studies suggest that dysregulated innate immunity plays an important role in the pathogenesis of immunoglobulin A nephropathy (IgAN). The interleukin-20 subfamily and its receptor, interleukin-22 receptor alpha-1 (IL-22R1), were recently identified as immunomodulators in human diseases, acting as mediators of mucosal host defense. However, the potential role of IL-22R1 in the pathogenesis of IgAN has not been explored. In the current study, 194 patients with IgAN and 287 normal controls were genotyped for coding polymorphisms of the IL-22R1 gene and the association between the polymorphisms and IgAN was investigated. Local expression of IL-22R1 was examined in patients with IgAN and healthy controls using immunohistochemistry. Our case-control analysis showed that genotypes of rs3795299 were associated with childhood IgAN. Individuals with the CC genotype of rs3795299 had about 3-fold reduced risk of IgAN compared with those with the GG genotype in the codominant model (P=0.0028) and those with the genotypes containing the G allele (GG or GC) in the recessive model (P=0.002). After Bonferroni correction, the association between the rs3795299 CC genotype and reduced risk of developing IgAN remained significant. Furthermore, the renal expression of IL-22R1 was significantly higher in healthy controls compared with subjects with IgAN. Our data suggest that the CC genotype of rs3795299 polymorphism in the IL-22R1 gene is associated with the reduced risk of IgAN, and this genetic association was supported by the higher renal expression of IL-22R1 in healthy controls compared with patients with IgAN.

Recent Advances of Oral Rehydration Therapy (ORT)

Diarrheal disease is one of the leading causes of worldwide morbidity and mortality, especially in children. It causes loss of body fluid, which may lead to severe dehydration, electrolyte imbalance, shock and even to death. The mortality rate from acute diarrhea has decreased over the last few decades. This decline, especially in developing countries is largely due to the implantation of the standard World Health Organization-oral rehydration solution (WHO-ORS). However, the use of standard ORS has been limited by its inability to reduce fecal volume or diarrhea duration. Subsequently, this has led to various attempts to modify its compositions. And these modifications include the use of reduced osmolarity ORS, polymer-based ORS and zinc supplementation. Some of these variations have been successful and others are still under investigation. Therefore, further trials are needed to progress toward the ideal ORS. In this article, we briefly reviewed the pathophysiologic basis of the ORS, followed by the standard WHO-ORS and several modifications to improve the ORS.

Mean platelet volume in pediatric chronic kidney diseases

To the editor Mean platelet volume (MPV) is the most commonly used measure of platelet size and a useful platelet function index that can show platelet activation and its production rate in bone marrow [1, 2]. MPV has been studied in various disease groups other than hematologic disease, and we have reported this platelet index in hepatic diseases and acute ischemic stroke [1, 2]. It has been suggested that high-grade systemic inflammatory diseases, such as rheumatoid arthritis, present with low levels of MPV [3]. However, there were some needs to evaluate MPV in low-grade or localized inflammatory diseases. Therefore, to investigate MPV in chronic localized inflammation such as glomerulonephritis, we planned to investigate MPV in Korean pediatric patients with chronic kidney diseases (CKD). This study was done at Kyung Hee University Hospital, a tertiary teaching hospital, between January 2011 and February 2012. The study included total 200 individuals for patients group, which were subdivided into 71 with IgA nephropathy (IgAN), 52 with mesangeal proliferative glomerulonephritis (MesPGN), and 77 with nephrotic syndrome (NS). The diagnosis and classification of CKD were based on renal biopsy results and clinical criteria. Since it was not easy to recruit normal pediatric patients from those who visited the pediatric department of our hospital, we had to compare MPVs with a disease control that had inflammatory signs in the upper respiratory tract (URT). Seventy pediatric patients with acute inflammatory symptoms in regions of URT were enrolled for age-matched disease controls (Table 1). Mean age of patient group was 11.64 (range 2–20 years), and male to female ratio was 75:125. Blood sampling was performed through venepuncture and MPV was measured using EDTA-containing tubes in Advia 2120 (Bayer Diagnostics, Tarrytown, NY, USA) within 2 hours. ANOVA followed by post-hoc analysis were used to compare means in our study. The statistical analyses were performed with MedCalc v11.6 (MedCalc Software, Mariakerke, Belgium) and Excel 2007 (Microsoft corporation, Redmond, WA). Statistical significance was set at p< 0.05. Based on the comparison of MPV between one disease control and three CKD groups, a significant difference was observed (Figure 1): MPV was markedly increased in IgAN and MesPGN than the other two groups (p1⁄4 0.01). Several cytokines, inflammatory mediators and growth factors may affect MPV, with subsequent production of larger and more reactive platelets [1, 3–6]. Because bone marrow might be exposed longer in chronic inflammation than acute conditions, inflammatory mediators have more time to make an impact upon platelet size. In this study, we were able to compare the change in MPVs between chronic and acute inflammation types by designating a patient group that showed acute inflammatory symptom and signs in the URT as the control group. Also, we confirmed whether there are meaningful differences in MPVs at IgAN and MesPGN that are known to show more frequent inflammatory findings such as cell proliferations, based on pathologic findings in renal biopsy. In such circumstances, MPV showed increased levels in IgAN and MesPGN than NS and acute diseases like upper respiratory infection. Therefore, we carefully suggest that the type, duration or degree of inflammation may affect the levels of MPV. However, we also note that there were some limitations to our study. First, subjects in the control

The Clinical Significance of Serum Cystatin Cin Critically Ill Newborns With Normal Serum Creatinine

The aim of this study is to evaluate the clinical significance of cystatin C(CysC) in the newborns who show normal serum creatinine (Cr) and who are in an intensive care unit.

Linkage and association study of neurotrophins and their receptors as novel susceptibility genes for childhood IgA nephropathy.

Neurotrophins (NTs) and their receptors (NTRs) are known to be important for pathogenesis of various inflammatory diseases that occur in not only neuronal but also nonneuronal tissues, including kidney. Here, we investigated association between childhood IgA nephropathy (IgAN) and single nucleotide polymorphisms (SNPs) of genes encoding NTs [nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)] and NTRs [nerve growth factor receptor (NGFR) and neurotrophic tyrosine kinase receptor 1–3 (NTRK1–3)]. The genotyping data of 197 patients and 289 control subjects revealed significant association between NGF SNP rs11102930 and presence of IgAN. Patient subgroup analysis revealed that that the presence of nephrotic range proteinuria (>40 mg/m2/h) was associated with rs6334 of NTRK1 and rs11030104, rs7103411, rs7103873, and rs6484320 of BDNF. Significant genotype differences were observed in podocyte foot process effacement for rs1187321 and rs1187323 of NTRK2. Furthermore, some SNPs showed significantly different genotype distribution between patients with or without pathologically advanced disease markers, specifically in rs6334 of NTRK1. Our results suggest that SNPs of NTs and NTRs are associated with susceptibility, pathological advancement, podocyte foot process effacement, and development of proteinuria in childhood IgAN.

Polymorphisms of insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) contribute to pathologic progression in childhood IgA nephropathy

Previous studies have suggested that insulin-like growth factor-1 (IGF-1) signaling might play an important role in renal fibrosis and regulation of the proliferation of mesangial cells and podocytes. We conducted the present study to investigate association between single nucleotide polymorphisms (SNPs) of IGF-1 (IGF-1) and IGF-1 receptor (IGF-1R) genes and childhood immunoglobulin (Ig) A nephropathy (IgAN). We analyzed five SNPs of IGF-1 and IGF-1R in 188 pediatric IgAN patients and in 263 healthy controls. We compared variations in SNPs in several sets of IgAN subgroups that were designated based on the presence of nephrotic range proteinuria (>40 mg/m2 per h), podocyte foot process effacement, and pathological progression. Genotyping of IgAN patients and controls revealed differences in IGF-1R rs2229765. Moreover, the rs2195239, rs978458, and rs1520220 SNPs of IGF-1 showed significant association with pathological progression. Thus, in the present study, we observed associations between the IGF-1/1R pathway, susceptibility to IgAN, and the pathologic progression of IgAN.

Polymorphisms of signal transducers and activators of transcription 1 and 4 (STAT1 and STAT4) contribute to progression of childhood IgA nephropathy

BACKGROUND Several experimental studies have suggested that signal transducers and activators of transcription 1 and 4 (STAT1 and STAT4) play important roles in the regulation of mesangial proliferation and renal fibrosis, and in the development of inflammation in several types of glomerulonephritis. METHODS The present study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) of the STAT1 and STAT4 genes and childhood IgA nephropathy (IgAN). RESULTS Genotyping of 170 childhood IgAN patients and 442 controls showed no significant differences in allele frequency. However, patient subgroup analysis revealed that development of proteinuria ( and >4mg/m(2)/h) was associated with STAT1 rs10199181 (dominant model, P=0.035) and high serum level of IgA with STAT1 rs6718902 (dominant model, P=0.035) and STAT1 rs2280232 (codominant model, P=0.014; dominant model, P=0.022). Furthermore, some SNP frequencies were significantly different between patients with pathologically mild and advanced disease; STAT1 rs6718902 (overdominant model, P=0.030), STAT1 rs10199181 (codominant model, P=0.023; dominant model, P=0.012; overdominant model, P=0.018), and STAT4 rs7561832 (dominant model, P=0.026; overdominant model, P=0.029). CONCLUSIONS Our results suggest that polymorphisms of STAT1 and STAT4 are associated with increased susceptibility, pathological advancement, and development of proteinuria in childhood IgAN.

Association Between Lymphotoxin Beta Receptor Gene Polymorphisms and IgA Nephropathy in Korean Children

Lymphotoxin beta receptor (LTBR) is essential for development and organization of the secondary lymphoid tissues. To investigate whether LTBR polymorphisms are associated with IgA nephropathy (IgAN) in Korean children, One hundred ninety nine patients with IgAN and 289 controls were recruited. Two promoter single nucleotide polymorphisms (SNPs) (rs3759333, -1387C/T and rs3759334, -1326A/G) and one coding SNP (rs2364480, Ala172Ala) in LTBR gene were selected and genotyped by direct sequencing. For analysis of data, SNPStats, SPSS 18.0, and Haploview version 4.2 were used. Multiple logistic regression models (codominant 1, codominant 2, dominant, and recessive models) were performed for odds ratio (OR), 95% confidence interval (CI), and p value. The rs3759334 was significantly associated with IgAN in codominant 1 (G/G vs. A/G, p = 0.025) and dominant (p = 0.017) models. The A alleles of rs3759334 and rs2364480 were related to risk of developing IgAN, respectively (rs3759334, p = 0.015; rs2364480, p = 0.041). Haplotypes CGC and TAA in LTBR gene were also associated with IgAN, respectively (CGC, p = 0.032 in codominant; TAA, p = 0.008 in codominant, p = 0.009 in dominant models). In conclusion, results suggest that LTBR gene polymorphisms may be associated with risk of IgAN in Korean children.

Polymorphisms of CXCL8 and Its Receptor CXCR2 Contribute to the Development and Progression of Childhood IgA Nephropathy

Many studies have suggested that CXCL8 and CXCR2 play an important role in the pathogenesis of several types of renal diseases. However, there is no prior study on the association between polymorphisms of these genes and IgA nephropathy (IgAN), especially in children. The genotyping data from 192 patients with childhood IgAN and 397 controls showed significant differences in the frequencies of the CXCL8 gene with rs2227306 (dominant, P = 0.019; overdominant, P = 0.009), rs2227543 (dominant, P = 0.01; overdominant, P = 0.0057), and rs4073 (codominant, P = 0.034; dominant, P = 0.011; overdominant, P = 0.022). In addition, 2 single-nucleotide polymorphism frequencies of the CXCR2 gene (rs4674257 and rs4674259) significantly differed between the patients with pathologically mild and patients with advanced disease. Further, 5 single-nucleotide polymorphisms of the CXCL8 and CXCR2 genes significantly differed in the patients with infiltration of inflammatory cells on the renal biopsy samples. The results of this study suggest that polymorphisms of CXCL8 are associated with increased susceptibility to IgAN, and polymorphisms of CXCR2 with the pathological progression of childhood IgAN. These genetic variations might provide insight into novel individualized antichemokine regimens for treatment.

The enabled homolog gene polymorphisms are associated with susceptibility and progression of childhood IgA nephropathy.

The enabled homolog gene (ENAH, hMena) is abundantly expressed in mesangial tissue, and might play an important role in inflammatory processes of IgA nephropathy (IgAN). The present study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) of the ENAH and childhood IgAN. We analyzed 12 SNPs of ENAH in 176 patients with childhood IgAN and 397 healthy controls. In addition, IgAN patients were dichotomized and compared with respect to several clinical and pathological parameters. Genotyping data showed significant differences between IgAN patients and controls in the frequency of rs2039620, rs12034829, and rs3795443. On comparison of patients with proteinuria to those without proteinuria (≤ or > 4 mg/m2/h), rs12043633 was significantly different between the two groups. With regard to maximum proteinuria (≤ or > 4 mg/m2/h), rs3795443, rs4653643, rs6751, rs10799319, rs7555139, rs576861, and rs487591 showed significant allele frequency differences. For patients with and without gross hematuria, rs4653643, rs6751, rs10799319, rs7555139, rs576861, and rs487591 showed significant allele frequency differences. The rs3795443 was found to be associated with progression of pathological findings. Our results suggest that ENAH polymorphisms are associated with increased susceptibility, development of proteinuria and gross hematuria, and pathological progression of childhood IgAN.