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 ß1 (TGF-ß1) 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.

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.

Linkage and association study of discoidin domain receptor 1 as a novel susceptibility gene for childhood IgA nephropathy.

In several experimental studies, it has been suggested that discoidin domain receptor 1 (DDR1) plays an important role in the regulation of mesangial proliferation, glomerular basement membrane thickening, renal fibrosis, and in the development of inflammation in several tissue types, including renal tissues. The present study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) of the DDR1 gene and childhood IgA nephropathy (IgAN). The genotyping data of 180 childhood IgAN patients and 336 controls showed significant differences in the frequency of rs1264319 (dominant model, P=0.040). Subgroup analysis revealed that development of proteinuria (>4 and

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.

Multidetector computed tomography findings and correlations with proteinuria in nutcracker syndrome.

We evaluated the effectiveness of multidetector computed tomography (MDCT) as a diagnostic tool for nutcracker syndrome (NS) and its association with proteinuria. The angle and distance between the aorta and the superior mesenteric artery (SMA), the degree of difference in corticomedullary enhancement (DCE) between kidneys in the nephrographic phase of computed tomography, peak velocity ratio (PVR), and anteroposterior diameter ratio (APDR) in the sonogram were measured. The MDCT results, sonogram results, and the ratio of protein:creatinine were significantly different between NS patients and the controls. The area under the curve for angle, distance, and DCE were 0.895 +/- 0.058, 0.876 +/- 0.063, and 0.942 +/- 0.036, respectively. The cutoff values for angle and distance had sensitivity and specificity values of 96.2 and 80% for <22.4 degrees and 84.6 and 80% for <4.9 mm, respectively. The DCE had a sensitivity of 88.5% and a specificity of 100% for the positive scores. There were significant correlations between the degree of DCE and the ratio of protein:creatinine (r = 0.337, p = 0.031), and between distance and the ratio of protein:creatinine (r = -0.419, p = 0.006). We conclude that MDCT has diagnostic value for NS in children and that MDCT findings are correlated with proteinuria.

Effects of Bupleurum falcatum and its combination with an angiotensin II receptor blocker on cytokine and chemokine expression in human mesangial cells.

This study aimed to investigate the inhibitory effect of Bupleurum falcatum and its combination with angiotensin II receptor blocker (ARB) on cytokine and chemokine production in cultured human mesangial cells. Human mesangial cells were isolated and cultured in Dulbecco's modified Eagle's medium culture medium. Bupleurum falcatum, ARB, and the combination of the two were added to human mesangial cells. Cytokine and chemokine levels were analysed using an enzyme-linked immunosorbent assay. There were no significant differences in the expression of IL-1ss, IL-2 or TNF-a between controls and the experimental groups. However, IL-11 and monocyte chemoattractant protein-1 (MCP-1) levels were significantly reduced in response to ARB, Bupleurum falcatum, or their combination when compared with controls. IL-8 expression was reduced significantly only in cells treated with ARB. Both Bupleurum falcatum and ARB treatments alone reduced the cytokine concentration, but there was not a stronger reduction when the two drugs were combined. It was shown that Bupleurum falcatum inhibited cytokine production in human mesangial cells. However, there were no additive effects on the suppression of cytokine production when Bupleurum falcatum was combined with ARB. Further studies are needed to elucidate the renoprotective effects of Bupleurum falcatum.

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 = or >4 mg/m(2)/h), rs12043633 was significantly different between the two groups. With regard to maximum proteinuria (< or = or >4 mg/m(2)/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.

Interleukin-1 cluster gene polymorphisms in childhood IgA nephropathy.

We have carried out a study with the aim of investigating the association between single nucleotide polymorphisms (SNPs) of the IL-1 gene cluster and childhood IgA nephropathy (IgAN). SNPs of the IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist (RN) genes (IL1A, IL1B, and IL1RN, respectively) were analyzed in 182 patients with childhood IgAN and in 500 healthy controls. The IgAN patients were also dichotomized and compared with respect to proteinuria (<4 mg and >or=4 mg/m(2) per hour, respectively), the presence or absence of podocyte foot process effacement, and the presence of pathologically early and advanced disease markers, such as interstitial fibrosis, tubular atrophy, or global sclerosis. Significant differences in SNP frequencies were observed for the IL1B and IL1RN genes (rs1143627, rs3917356, and rs1143633 in the IL1B gene, and rs928940, rs439154, and rs315951 in the IL1RN gene). Moreover, rs1143627, rs3917356, and rs1143633 of IL1B were found to be significantly associated with the presence of podocyte foot process effacement. Our results suggest that the IL1B and IL1RN genes are associated with increased susceptibility to IgAN in children. They also suggest that the development of proteinuria in IgAN is related to IL1A and that podocyte foot process effacement is associated with IL1B.

Necrotizing fasciitis in a neonate - the role of keratinocyte allografts.

The authors report the case of a 9-day-old female infant with necrotizing fasciitis of the lower back due to methicillin-resistant Staphylococcus aureus (MRSA) to emphasize the role of keratinocyte allografts. Keratinocyte allografts were found helpful in this case to manage an extensive skin defect.

Two Korean infants with genetically confirmed congenital nephrotic syndrome of Finnish type.

Congenital nephrotic syndrome is defined as nephrotic syndrome which manifests in utero or during the first 3 months of life. The prototype of congenital nephrotic syndrome is congenital nephrotic syndrome of Finnish type (CNF, OMIM #602716), which is caused by loss-of-function mutations of the nephrin gene (NPHS1). There have been few clinical case reports of CNF in Korea, but none of which was confirmed by genetic study. Here, we report two children with congenital nephrotic syndrome. Genetic analysis of the NPHS1 gene revealed compound heterozygous frame-shifting mutations (c.2156_2163 delTGCACTGC causing p.L719DfsX4 and c.3250_3251insG causing p.V1084GfsX12) in one patient and a missense mutation (c.1381G>A causing p.R460Q) and a nonsense mutation (c.2442C>G causing p.Y814X) in the other patient. The nonsense mutation was novel. The clinical courses of the patients were typical of CNF. This is the first report of genetically confirmed CNF in Korea to date. The early genetic diagnosis of CNF is important for proper clinical management of the patients and precise genetic counseling of the families.

Remission of refractory minimal change nephrotic syndrome after basiliximab therapy.

Minimal change nephrotic syndrome has been proposed to be a disorder of T cell dysfunction. It is hypothesized that a circulating factor(s) from activated T cells might alter glomerular permeability to protein. Some studies have provided evidence that up-regulation of interleukin-2 may be involved, not only in the pathophysiology of minimal change nephrotic syndrome, but also in steroid resistance. Basiliximab, an anti-interleukin-2 receptor antibody, is indicated for the prophylaxis of acute organ rejection in adults and children with kidney transplants. Clinical trials have shown that basiliximab is effective and well tolerated. We describe here a pediatric patient who continuously had massive proteinuria and hypoalbuminemia for 5 years, despite pulse therapy with methylprednisolone and cyclophosphamide and prolonged oral treatment with cyclosporine and mizoribine. He had experienced several disease- and treatment-associated complications, such as bacterial infections, indirect inguinal hernias, and cataracts. After he had been given a single dose of basiliximab, he achieved complete remission of proteinuria and then discontinued all immunosuppressant treatment.

School urinalysis screening in Korea.

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.

Long-term Follow up of Congenital Adrenal Hyperplasia Patients with Hyponatremia.

Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is an autosomal recessive disease, which leads to cortisol and aldosterone deficiency and hyperandrogenism. Typical medical treatment includes oral glucocorticoid and mineralocorticoid administration to suppress adrenal androgens and to compensate for adrenal steroid deficiencies. However, some patients stopped taking medicine without the doctor's consent. Among these patients, four cases of CAH patients showing the presence of hyponatremia as an initial electrolyte disorder were found with adrenal adenoma. Hypersecretion of adrenocorticotrophic hormone and chronic poor compliance to therapy appears to be associated with the development of the adrenal tumor. Two cases were managed with adrenalectomy because of increasing adrenal tumor size and virilization. Whereas the other two cases did not increase in size and were observed without adrenalectomy. Therefore, it is important that patients with CAH maintain steroid medication to avoid the appearance of adrenal tumor.

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 creatinine 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.

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

Association of IL-1beta, IL-1ra, and TNF-alpha gene polymorphisms in childhood nephrotic syndrome.

We investigated the association between IL-1beta, IL-1ra, and TNF-alpha gene polymorphisms and childhood nephrotic syndrome (NS). We analyzed the genetic polymorphism of IL-1beta, IL-1ra, and TNF-alpha genes in 152 patients with childhood NS and 292 healthy adult controls. The C to T exchange at position -511 of IL-1beta and the G to A at -308 of the TNF-alpha 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-1beta1 (-511C), IL-1beta2 (-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-1beta and TNF-alpha. A high allele frequency of the IL1RN*2 allele may affect disease susceptibility in childhood NS.

The inhibitory effects of aqueous extract of Magnolia officinalis on human mesangial cell proliferation by regulation of platelet-derived growth factor-BB and transforming growth factor-beta1 expression.

Mesangial cell (MC) proliferation, mediated by platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-beta1, and cyclin-dependent kinases (CDK), is the common feature of glomerulosclerosis. Magnolia officinalis, stem bark of Machilus thunbergii S., has multiple pharmacological effects. In this study, we investigated the influence of aqueous extract of Magnolia officinalis on MC proliferation, DNA synthesis, and expression of PDGF-BB, TGF-beta1, CDK1, CDK2, and CDK4 in fetal bovine serum (FBS)-activated human MC. Magnolia officinalis inhibited the MC proliferation, DNA synthesis, and the expression of PDGF-BB, CDK1, and CDK2 gene and CDK1, CDK2, and TGF-beta1 protein. These results suggest that the inhibitory effect of Magnolia officinalis on MC proliferation may be mediated by regulation of PDGF-BB and TGF-beta1expressions and by modulation of CDK1 and CDK2 expression.

Apolipoprotein E polymorphism and clinical course in childhood nephrotic syndrome.

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 epsilon2, epsilon3, and epsilon4, respectively in the childhood NS group, while those in the control group were 6.8% for epsilon2, 88.3% for epsilon3, and 4.9% for epsilon4. The allelic frequency for epsilon4 in childhood NS was twice that of controls. Moreover, the allelic frequency of the epsilon4 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 epsilon4 in patients with childhood NS suggests that epsilon4 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.