Association of BH3 interacting domain death agonist (BID) gene polymorphisms with proteinuria of immunoglobulin A nephropathy.

BACKGROUND: Apoptosis plays an important role in the mechanism regulating the development of glomerulonephritis. We investigated whether polymorphisms of apoptotic genes such as B-cell CLL/lymphoma 2 (BCL2), BH3-interacting domain death agonist (BID), and caspase 8 (CASP8) were associated with immunoglobulin A nephropathy (IgAN) and with the clinical phenotypes of IgAN patients. METHODS: We genotyped promoter and coding region single nucleotide polymorphisms (SNPs) (rs2279115 and rs1801018 for BCL2; rs8190315 and rs2072392 for BID; and rs6747918 and rs1045487 for CASP8) using direct sequencing in 195 IgAN patients and 289 control subjects. RESULTS: No SNPs were associated with IgAN. However, in analysis of clinical phenotypes, we found that rs8190315 and rs2072392 of BID were associated with proteinuria levels of IgAN patients in additive (AG vs. GG vs. AA, p = 0.0008 for rs8190315; TC vs. CC vs. TT, p = 0.0012 for rs2072392) and dominant models (AG/GG vs. AA, p = 0.0014 for rs8190315; TC/CC vs. TT, p = 0.0031 for rs2072392). In particular, the frequencies of genotypes containing minor alleles of rs8190315 (G allele) and rs2072392 (C allele) were increased in IgAN patients with higher protienuria levels (> 40 mg/m(2)/h). CONCLUSION: These results suggest that BID may play a role in severe IgAN.

Association of FOS-like antigen 1 promoter polymorphism with podocyte foot process effacement in immunoglobulin A nephropathy patients.

BACKGROUND: FOS has been implicated in the progression of renal disease including IgAN. In this study, we investigated whether polymorphisms of FOS family genes [FOS, FOSB, FOS-like antigen 1 (FOSL1), and FOSL2] were associated with immunoglobulin A nephropathy (IgAN) and the clinical phenotypes of IgAN patients. METHODS: We genotyped single nucleotide polymorphisms (SNPs) of FOS family genes (rs2239615 and rs7101 for FOS, rs12373539 and rs2282695 for FOSB, rs637571 for FOSL1, and rs925255 for FOSL2) using direct sequencing in 198 IgAN patients and 290 control subjects. RESULTS: No SNPs were associated with IgAN; however, in the analysis of clinical phenotypes, we found that rs637571 of FOSL1 was associated with podocyte foot process effacement of IgAN in additive (CT vs. TT vs. CC, P = 0.0031, OR = 2.08, 95% CI = 1.27-3.40) and dominant models (CT/TT vs. CC, P = 0.0034, OR = 2.50, 95% CI = 1.35-4.64). The frequency of genotypes containing the T allele was increased in IgAN patients with podocyte foot process effacement, compared to those without podocyte foot process effacement. CONCLUSION: These results suggest that FOSL1 may be related to IgAN severity.

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.

A nationwide study of mass urine screening tests on Korean school children and implications for chronic kidney disease management.

BACKGROUND: Since 1998, urine screening tests have been performed on school children in Korea. We report the findings of the screening program that analyzed patients with proteinuria and/or hematuria. METHODS: Between 1999 and 2008, 5,114 children were referred to pediatric nephrologists at seven nationwide hospitals. Renal biopsies were performed on 1,478 children [28.79 % of total subjects; 26.77 % for isolated hematuria (IH), 9.09 % for isolated proteinuria (IP), and 51.19 % for combined hematuria and proteinuria (CHP)] who showed abnormal renal function, persistent hematuria and/or proteinuria for more than 6 months, nephrotic-range proteinuria, or those with underlying systemic diseases. RESULTS: Chronic glomerulonephritis (GN) was detected in 25 % of all visiting subjects. The most common findings in renal biopsies were immunoglobulin A (IgA) nephropathy in 38.97 %, mesangial proliferative GN in 24.29 %, and thin basement membrane nephropathy in 13.13 %. Compared with the relative frequency of renal diseases associated with urinary abnormalities, CHP (46.90 %) and nephrotic-range proteinuria (69.96 %) groups had more frequent GN than the others. Abnormal findings on renal ultrasound with or without Doppler scan were noted in 462 cases (suspected nutcracker phenomenon, 159; increased parenchymal echogenicity, 92; hydronephrosis, 75; simple cyst, 47). CONCLUSION: Mass urine screening tests could detect asymptomatic GN in its early stages. Initial aggressive diagnosis and treatment for CHP and nephrotic-range groups may prove helpful as interventions that delay chronic kidney disease progression. These findings may assist in the development of diagnostic and management guidelines for relatively mild urinary abnormalities, such as IH or low-grade IP.

Relationship between glomerulomegaly and clinicopathologic findings in IgA nephropathy.

BACKGROUND: Large glomeruli are a common finding in the early stages of progressive renal disease. We studied the relationship between glomerular surface area (GSA) and clinicopathologic features of IgA nephropathy (IgAN), including renal outcome, to better understand the role of GSA in IgAN. METHODS: We analyzed renal biopsy specimens and clinical information from 34 patients with IgAN. Mean and maximal GSA were determined using a computed imaging analyzer. RESULTS: Mean GSA was 16,811 ± 4,671 µ2 in IgAN patients (n = 34). When we analyzed various clinical parameters of IgAN patients, there were significant correlations between mean or maximal GSA and age, body mass index (BMI), systolic and diastolic blood pressure, estimated glomerular filtration rate (eGFR), and pathologic findings including H.S. Lee' grades, interstitial fibrosis, and tubular atrophy. GSA did not show any relationship with the degree of hematuria and proteinuria. By multivariate regression analysis of age, BMI, blood pressure, H.S. Lee' grades, and eGFR as independent variables, mean GSA was associated with H.S Lee' grades and initial eGFR. The results for maximal GSA were the same as those for mean GSA. When we divided IgAN patients according to their mean levels of GSA, the group with larger GSA had higher blood pressure and H.S. Lee' grades and lower initial and final eGFR. More patients in the larger GSA group showed the decline in eGFR of more than 15 ml/min/1.73 m2 during the followup period compared with the smaller group. CONCLUSION: These results suggest that glomerular size, estimated by measuring GSA, is related to pathologic findings and renal function in IgAN. However, further investigation is required to determine if GSA can be used as a prognostic indicator of IgAN.

The clinical significance of serum cystatin C in critically ill newborns with normal serum creatinine.

BACKGROUND: 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. METHODS: From July 2009 to May 2010, a total of 106 patients (53 male and 53 female newborns) in a neonatal intensive care unit at Kyung Hee Medical Center were enrolled in this study. When clinicians ordered CysC, it was tested using HiSens Cystatin-C LTIA(HBi, An-yang, Korea) on a Toshiba chemical analyzer (Toshiba, Nasushiobara, Japan). RESULTS: The range of serum Cr and CysCwas from 0.1 to 0.8 mg/dL and from 1.0 to 2.3 mg/L, respectively. CysCpresented the wider amplitude of the changes in acute renal failure. CONCLUSION: In this study, CysCwithout an increased Cr showed only a mild increase. However, CysCreflected more delicate changes in newborns than the serum Cr. This characteristic of CysCcould make it very appropriate for a pediatric population, especially for critically ill newborns.

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.

Association between toll-like receptor 10 (TLR10) gene polymorphisms and childhood IgA nephropathy.

Toll-like receptors (TLRs) play an important role in the induction and regulation of the innate immune system and adaptive immune responses. TLR10 gene polymorphisms have been reported to be associated with a range of immune-related diseases. In this study, we investigated the association of TLR10 gene polymorphisms with immunoglobulin A nephropathy (IgAN) in Korean children. To examine the association, we genotyped one promoter single nucleotide polymorphisms (SNP) [rs10004195 (-113T/A)] and three missense SNPs [rs11096957 (Asn241His), rs11096955 (Ile369Leu), and rs4129009 (Ile775Val)] using direct sequencing in 199 IgAN patients and 289 control subjects. Our case-control analysis showed that rs10004195 was associated with IgAN (codominant model, p = 0.016 in TT vs. TA; p = 0.044 in TT vs. AA; dominant model, p = 0.0068). In addition, when comparing the proteinuria level of IgAN patients according to the genotypes of each SNP, we found that in dominant model of rs1004195, the level of proteinuria of patients with TA or AA genotypes (median, 4.01 mg/m(2)/h) was higher than that of patients with TT genotype (2.00 mg/m²/h, p = 0.033). In conclusion, these results suggest that TLR10 gene may be associated with susceptibility to IgAN in Korean children.

Coding polymorphisms of bone morphogenetic protein 2 contribute to the development of childhood IgA nephropathy.

Bone morphogenetic proteins (BMPs) are multi-functional growth factors belonging to the transforming growth factor ß (TGFB) superfamily and are important in both preservation of kidney function and resistance to injury. BMP2 is highly regulated in the kidney, and high affinity binding sites for BMP2 have been identified in kidney epithelial cells. BMP2 has been demonstrated to play various roles in the pathogenesis of renal diseases. However, the role of the BMP2 gene in glomerulonephritis has not been previously investigated. We aimed to evaluate the association of BMP2 gene polymorphisms with immunoglobulin A nephropathy (IgAN) in children. We evaluated 187 pediatric patients with biopsy-confimed IgAN and 262 healthy controls. Two coding single nucleotide polymorphisms (cSNPs) in the BMP2 gene [rs235768 (missense, Arg190Ser) and rs1049007 (synonymous, Ser87Ser)] were selected and genotyped by direct sequencing. Genotypes of rs1049007 were associated with childhood IgAN in the codominant model II (GG vs. AA) [p=0.02; OR (95% CI), 0.16 (0.04-0.70)] and in the recessive model [p=0.0023; OR (95% CI), 0.16 (0.04-0.69)]. We also found an association between rs235768 and IgAN in the codominant model II (TT vs. AA) [p=0.01; OR (95% CI), 0.08 (0.01-0.57)] and in the recessive model [p=0.0002; OR (95% CI), 0.07 (0.01-0.55)]. After Bonferroni correction, these associations of rs235768 and rs1049007 with IgAN risk remained significant. In the haplotype analysis, the TG haplotype [p=0.01; OR (95% CI), 6.76 (1.55-29.50) in the dominant model] and AA haplotype [p=0.01; OR (95% CI), 0.08 (0.01-0.59) in the recessive model] showed associations with IgAN. The BMP2 gene may contribute to susceptibility to IgAN in Korean children.

Interleukin 7 receptor gene polymorphisms and haplotypes are associated with susceptibility to IgA nephropathy in Korean children.

An abnormal T-cell response is involved in the pathogenesis of various renal diseases. Survival of naïve T cells is dependent on interleukin 7 (IL7) and its receptor (IL7R). Thus, we investigated the association between IL7R single nucleotide polymorphisms (SNPs) and childhood IgA nephropathy (IgAN). We analyzed the genotypic distributions of two missense SNPs of IL7R, rs1494558 (Ile66Thr) and rs1494555 (Val138Ile), among 198 pediatric IgAN patients and 288 healthy controls. Haplotype analysis and measurement of pair-wise linkage disequilibrium were performed. In addition, the genotypes of patient subgroups, determined by the presence of nephrotic range proteinuria (>40 mg/m(2)/h) and pathological advancement, were analyzed. The genotyping data of IgAN patients and controls showed significant differences in rs1494558 (codominant, P=0.0003; dominant, P=0.0003) and rs1494555 (codominant, P=0.0038; dominant, P=0.0099). In the haplotype analysis, AC (codominant, P=0.0066) and GT (codominant, P=0.0005; dominant, P=0.0006) were significantly associated with susceptibility to IgAN. Furthermore, in the analysis of clinical subgroups of IgAN patients, rs1494558 was associated with nephrotic range proteinuria (codominant, P=0.027; recessive, P=0.023). Our results suggest that IL7R may be associated with disease susceptibility and proteinuria in childhood IgAN.

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/m/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.

Clinical and histologic response to methylprednisolone pulse therapy in glomerulonephritis.

We retrospectively analyzed the data of the first and second renal biopsies to investigate the adverse effects as well as the clinical and histologic responses of methylprednisolone pulse therapy in patients with chronic glomerulonephritis. At the time of the second renal biopsy, the activity index had decreased significantly and the chronicity index was well preserved. The activity index and interstitial fibrosis were improved in the complete and partial remission groups, but not in the nonresponse group. These findings indicate that methylprednisolone pulse therapy is effective in patients with chronic glomerulonephritis and has an acceptably low risk of side effects.

Phosphodiesterase-5 gene (PDE5A) polymorphisms are associated with progression of childhood IgA nephropathy.

The phosphodiesterase-5 (PDE-5) gene is highly specific to cyclic GMP (cGMP) and several experimental studies have shown that the nitric oxide/cGMP pathway plays an important role in the pathogenesis of glomerulonephritis, including IgA nephropathy (IgAN). The present study was conducted to investigate the association among 16 single nucleotide polymorphisms (SNPs) of PDE5A and childhood IgAN. The genotyping data from 160 patients with childhood IgAN and 454 controls showed a significant difference in rs13124532 (codominant, P = 0.005; dominant, P = 0.005). Furthermore, patient subgroup analysis revealed an association between the development of proteinuria (>4 and 40 mg/m(2)/h) and rs11734241 (dominant, P = 0.035), rs12510138 (dominant, P = 0.028), rs13134665 (dominant, P = 0.025), rs3822192 (dominant, P = 0.027), rs10013305 (dominant, P = 0.020), rs1480940 (dominant, P = 0.020), rs1480936 (dominant, P = 0.019), rs11947234 (dominant, P = 0.019), and rs2127823 (dominant, P = 0.026). The pathological findings showed that rs13124532 had an association with podocyte foot process effacement (codominant, P = 0.035; dominant, P = 0.044) and with pathological progression (codominant, P = 0.046). Our results suggest that PDE5A is associated with increased disease susceptibility, pathological progression, and development of proteinuria in childhood IgAN.