Sung-Do Kim

Susceptibility for ischemic stroke in Korean population is associated with polymorphisms of the interleukin-1 receptor antagonist and tumor necrosis factor-α genes, but not the interleukin-1β gene

Enhanced release of proinflammatory cytokines may contribute to the pathogenesis of ischemic stroke. Interleukin-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine, and tumor necrosis factor (TNF)-alpha and IL-1beta are proinflammatory cytokine. To determine the role of cytokines in genetic susceptibility to ischemic stroke, we genotyped ischemic stroke patients (n = 152) and the healthy control subjects (n = 165) for IL-1Ra, TNF-alpha and IL-1beta polymorphism by polymerase chain reaction-restriction fragment length polymorphism methods. The analysis shown the association of IL1RN*1, IL1RN*2 allele (IL1RN*1, OR=0.44, P = 0.0206 IL1RN*2, OR=2.90, P = 0.0141) and TNF1, TNF2 allele (TNF1, OR=2.16, P = 0.0225; TNF2, OR=2.16, P = 0.0225) to ischemic stroke. However, the genetic polymorphism of IL-1beta was not associated with ischemic stroke. Our results suggest that IL-1Ra and TNF-alpha gene polymorphism is associated with the susceptibility to ischemic stroke.

School urinalysis screening in Korea: prevalence of chronic renal disease.

Abstract. Since 1998, mass urine screening tests have been performed on Korean school children. We have analyzed those patients who showed abnormal urinary findings in the school screening program. Between January 1998 and January 2000, 452 children with abnormal urinary findings visited the Pediatric Kidney Center, Kyung-Hee University Hospital. Sex, age, 24-h urine creatinine clearance, ultrasonography, Doppler scans and renal biopsies were reviewed retrospectively. Results of initial urinalysis are divided into three groups: solely hematuria group (228 cases, 50.4%), solely proteinuria group (98 cases, 21.7%), and combined hematuria and proteinuria group (79 cases, 17.5%). Among the biopsied cases, the proportions representing renal parenchymal diseases were as follows: IgA nephropathy 11.3%, mesangial proliferative glomerulonephritis 21.9%, others 3.8%. Among the three groups, the combined hematuria and proteinuria group had more frequent chronic renal disease (57.7%) than the other groups. Chronic renal disease was detected in 36.9% of all visiting subjects. In the school screening program a significant number of patients showed abnormal urinary findings, which were associated with chronic renal diseases especially in the combined hematuria and proteinuria group. In conclusion, mass urine screening tests should be mandatory to detect asymptomatic chronic renal disease in school children.

Activation of hypoxia-inducible factor-1 regulates human histidine decarboxylase expression

Abstract.Histidine decarboxylase (HDC) catalyzes the formation of histamine from histidine. Histamine has various effects in physiological and pathological reactions, such as inflammation, cell growth, and neuro-transmission. We investigated the role of hypoxia-inducible factor (HIF)-1 on hypoxia-induced HDC expression in human mast cell line, HMC-1 cells and mouse bone marrow-derived mast cells (BMMCs). Hypoxia significantly increased histamine production. HDC expression and activity were induced by hypoxia. Additionally, when cells were transfected with a native form of HIF-1α, hypoxia could induce higher HDC expression than in the nontransfected cell. HIF-1 binding activity for HDC 5’ flanking region (HFR) was similar to that for the hypoxia-responsive element. Using HDC promoter deletion analysis, we also demonstrated that HFR was regulated by HIF-1 activation. In addition, depletion of HIF-1α prevents hypoxic induction of HDC in BMMCs. In conclusion, these results demonstrate that hypoxia induces HDC expression by transcriptional mechanisms dependent upon HIF-1.

Renoprotective effect of Tanshinone IIA, an active component of Salvia miltiorrhiza, on rats with chronic kidney disease.

Chronic kidney disease (CKD) is a common cause of end‐stage renal disease. Antihypertensive agents are used clinically to inhibit the progression of CKD, but cannot prevent eventual renal failure. This study investigated the effect of Tanshinone IIA, an active component of Salvia miltiorrhiza, in rats suffering from CKD induced by 5/6 nephrectomy. After development of renal insufficiency, the rats were treated with Tanshinone IIA (10 mg/kg) for 8 weeks. Serum creatinine, angiotensin II (Ang II), transforming growth factor β1 (TGF‐β1) and collagen IV levels were significantly reduced in Tanshinone IIA treated rats compared with a control group. In addition, Tanshinone IIA suppressed increases in urinary protein excretion in CKD rats. These findings suggest that chronic oral administration of Tanshinone IIA can improve renal dysfunction associated with CKD. Copyright

Pamidronate Therapy for Preventing Steroid-Induced Osteoporosis in Children with Nephropathy

Background: Steroid-induced osteoporosis (SIO) is a serious complication of long-term steroid therapy and is of particular concern in growing children. Recently bisphosphonates have been applied in the treatment or prevention of SIO. We investigated the efficacy of pamidronate on SIO in childhood nephropathy patients receiving long-term corticosteroid therapy. Methods: Forty-four children receiving high doses of steroids were enrolled in the study. There was no history of bone, liver, or endocrine disease. Patients were randomly classified into two groups, the control group and the study group. All patients received corticosteroids for 3 months. Control group took oral calcium supplements (500 mg/day) only, and the study group oral calcium and pamidronate (125 mg) for 3 months. Biochemical tests, long bone radiography, and bone mineral density (BMD) were performed in the first month and 3 months later in all patients. Results: The differences in the results of biochemical tests such as serum calcium, BUN, and cre atinine level obtained in the first month and three months later were not of statistical significance in both the control and the study groups. However, the mean BMD of the lumbar spine decreased from 0.654 ± 0.069 (g/cm2) to 0.631 ± 0.070 (g/cm2) in the control group (p = 0.0017), while it did not in the study group from 0.644 ± 0.189 (g/cm2) to 0.647 ± 0.214 (g/cm2). Conclusions: Pamidronate appears to be effective in preventing SIO in children with nephropathy requiring long-term steroid therapy. Further long-term follow-up studies regarding the efficacy and side effects appear to be necessary to set a more solid basis for such pediatric uses of bisphosphonates such as pamidronate.

School urinalysis screening in Korea

SUMMARY:  Since 1998, by law, all school children in Korea must have an annual urinalysis. The first early morning urine specimen is examined by a simple dipstick method for the detection of proteinuria, haematuria and glucose. If a urine test is positive, a second test is performed by paediatric nephrologists. We analysed urinalysis data of school urinalysis screening. We also analysed the results of clinical data and the renal biopsy findings of patients referred to our medical centre due to abnormal urinalysis result. To date, about five million students have been screened since annual school urinalysis started in January 1998. Among them, isolated proteinuria was about 0.2%, occult blood was about 0.8%, and glucosuria was about 0.07% from January 1998 to December 2004. Among referred patients, renal biopsy was taken in 63.1% of isolated haematuria, 10.5% of isolated proteinuria and 69.9% of haematuria combined with proteinuria. Histopathological findings are IgA nephropathy in 43.8%, mesangial proliferative glomerulonephritis in 38.4%, Henoch–Schönlein nephritis in 2.7%, membranoproliferative glomerulonephritis in 1.6% and lupus nephritis in 0.5%. Alport disease showed 0.6% as a hereditary disease. In conclusion, the school urinalysis screening could detect chronic renal disease in its early stage. Early detection using school urinalysis screening and confirmatory diagnosis by renal biopsy seems to be helpful for assessment of prognosis and intervention of chronic renal disease progression.

Association of IL-1β, IL-1ra, and TNF-α gene polymorphisms in childhood nephrotic syndrome

We investigated the association between IL-1β, IL-1ra, and TNF-α gene polymorphisms and childhood nephrotic syndrome (NS). We analyzed the genetic polymorphism of IL-1β, IL-1ra, and TNF-α genes in 152 patients with childhood NS and 292 healthy adult controls. The C to T exchange at position −511 of IL-1β and the G to A at −308 of the TNF-α gene were genotyped. Five alleles of the IL-1ra gene were identified and designated as IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5, according to the variable number of tandem repeats in intron 2. The allele frequencies of IL-1β1 (-511C), IL-1β2 (-511T), TNF1 (-308G), and TNF2 (-308A) were 53.0, 47.0, 92.1, and 7.9%, respectively, in the childhood NS group. This was not significantly different from normal controls. In the childhood NS group, the allele frequencies of IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5 were 90.8, 7.6, 1.6, 0, and 0% [IL1RN*1 odds ratio (OR)=0.296, P=0.0001, IL1RN*2 OR=3.902, P=0.0002]. A high allele frequency of IL1RN*2 and a lower allele frequency of IL1RN*1 were found in childhood NS, although there was no association with IL-1β and TNF-α. A high allele frequency of the IL1RN*2 allele may affect disease susceptibility in childhood NS.

Acute oral toxicity study of Asiasari radix extract in mice.

Acute oral toxicity of methanol extract of Asiasari radix was evaluated in ICR mice of both sexes. In this study, mice were administrated orally with dosages of 1000, 3000, and 5000 mg/kg body weight of Asiasari radix extract. Mortality, signs of toxicity, body weight, food consumption, and gross findings were observed for 14 days post treatment of Asiasari radix extract. No mortality, signs of toxicity, and abnormalities in gross findings were observed. In addition, no significant differences were noticed in the body and organ weights between the control and treated groups of both sexes. These results show that the methanol extract of Asiasari radix is toxicologically safe by oral administration.

Association of CTLA4, CD28 and ICOS gene polymorphisms with clinicopathologic characteristics of childhood IgA nephropathy in Korean population

Primary IgA nephropathy (IgAN) is the most common glomerular disease in children and adolescents who undergo renal biopsy because of isolated microscopic haematuria or haematuria associated with proteinuria (Coppo 2008). Some evidence suggests the importance of the abnormal T-cell response in the pathogenesis of IgAN, and co-stimulatory molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA4), CD28 molecule and inducible costimulator (ICOS) have been found to be vital for naive T-cells to initiate and terminate immune responses (Carreno and Collins 2002; Carreno et al. 2005). In this study, we tested single nucleotide polymorphisms (SNPs) of CTLA4/CD28/ICOS genes, and they were found to be associated with pathophisipology of paediatric IgAN in Korean population. The best-characterized T-cell co-stimulatory pathway involves receptors such as the CD28 and CTLA4 (also known as CD152). In addition, the ICOS has been also defined recently as a new pathway (Keir and Sharpe 2005). The CD28/CTLA4/ICOS genes lie within the 300-kb region on human chromosome 2q33 and their expressions are differentially regulated; although CD28 is constitutively present on naive T-cells, whereas CTLA4 and ICOS are present only after activation (Collins et al. 2005). Moreover, all of these molecules were found to be expressed by regulatory T-cells for the development and maintenance (Keir and Sharpe 2005).

Apolipoprotein E polymorphism and clinical course in childhood nephrotic syndrome

Abstract.Numerous studies have reported on the role of apolipoprotein E (apoE) polymorphism in the progression of diseases associated with lipid abnormalities. However, few studies have been performed to date on the relationship between apoE polymorphism and childhood nephrotic syndrome (NS). In the present study, we evaluated the allelic and genotypic frequencies of the apoE gene and the possible association between the polymorphic forms of the apoE gene on the clinical course in 190 patients with childhood NS, who were further classified into frequent relapsers (FR, 92) and nonrelapsers or infrequent relapsers (IR, 98). Controls included 132 healthy Koreans. Allele-specific primers were used to detect polymorphism of the apoE gene. The allelic frequencies at the apoE locus were 5.9%, 82.6%, and 11.8% for alleles ε2, ε3, and ε4, respectively in the childhood NS group, while those in the control group were 6.8% for ε2, 88.3% for ε3, and 4.9% for ε4. The allelic frequency for ε4 in childhood NS was twice that of controls. Moreover, the allelic frequency of the ε4 allele in the FR group was 3.4 times that of the control group and 2.5 times that of the IR group. The high frequency of ε4 in patients with childhood NS suggests that ε4 may serve as a genetic marker for predisposition to childhood NS. We believe that the apoE allele type is of considerable significance in predicting the course of the disease.