Dent disease is an X-linked tubulopathy caused by mutations affecting the voltage-gated chloride channel called ClC-5. Recently, it demonstrated that OCRL1 mutations can also cause not only Lowe syndrome but Dent disease. We have investigated 7 patients from 6 families diagnosed as Dent disease to elucidate the correlation between genotype and phenotype of Dent disease. In being diagnosed, all the patients show extremely high in low-molecular-weight proteinuria without apparent mental retardation or ocular abnormalities. All patients have been detected genetic mutations; three of them have CLCN5 and the others from three families OCRL1. Two CLCN5 mutations (nonsense and missense) and one OCRL1 (missense) were novel. After being diagnosed as Dent disease, two patients showed mental retardation mildly and they have OCRL1 mutations. Urinalysis and blood chemistry don't show Fanconi syndrome with renal tubular acidosis. Serum AST and LDH in patients with OCRL1 mutations were tend to be higher than those in patients with CLCN5 mutations. Two patients show renal dysfunction, one of which was the case of CLCN5 mutation.
  We could detect genetic mutations of CLCN5 or OCRL1 in all 7 cases but couldn't clearly elucidate the genotype-phenotype correlation. The slight resemblance between Lowe syndrome and Dent disease with OCRL1 mutations suggests that we must reconsider the diagnostic criteria for both Lowe syndrome and Dent disease. Further studies are necessary to clarify pathophysiology about Dent disease.

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  Streptococcicosis is a popular bacterial infectious disease in pediatric outpatient clinic. Acute poststreptococcal glomerulo-nephritis is known as an important and general complication of Streptococcicosis.
  However, there are various ways of diagnosis and therapy on this disease. This fact throws not only pediatricians but also the patients and their families into confusion. Therefore, we conducted a questionnaire survey of the diagnostic way of acute poststreptococcal glomerulo-nephritis and other issues on general pediatricians. In this study, we found various ways of thinking on the acute poststreptococcal glomerulo-nephritis. It will be necessary to establish the diagnostic standard on acute poststreptococcal glomerulo-nephritis and the therapeutic indication on the prevention of acute poststreptococcal glomerulo-nephritis.

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  To evaluate the pharmacokinetics of cyclosporine (CyA) in pediatric nephrotic syndrome, 96 CyA pharmacokinetic profiles were obtained from 25 male and 11 female patients. The mean age was 9.1 years (range 1.0-19.7). CyA was administered immediately prior to a meal (twice a day). The patients were divided according to their age into three groups;group 1:1-5 years, group 2:6-10 years, group 3:11 years and over, and pharmacokinetic parametervalues were estimated. The dose of CyA (milligrams per kilogram) ranged from 4.8±1.0 (group 1) and 3.8±0.9 (group 2) to 3.0±0.6 (group 3). There were significant differences in dose of CyA among the three groups. However, no significant differences between the three groups were found in the 4h area under the time-concentration curve (AUC_0-4) and the maximum concentration (Cmax). The dose-normalized Cmax and AUC_0-4 showed significant differences among the age groups;the younger age group showed lower than the older age group. These findings suggest that younger children require higher doses of CyA to achieve the target AUC level than older children.

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  Diagnosis of hydronephrosis, including the intermittent form is difficult. We investigated five patients with ureteropelvic junction obstruction in whom the chief complaint was recurrent intermittent flank pain accompanied by vomiting. All five patients were boys aged between 4 and 7 years in whom the left side was affected. In 4 of 5 patients, the presenting symptoms were intermittent flank pain and vomiting. Only one patient (case 5) complained of abdominal discomfort in addition to intermittent flank pain and vomiting. Ultrasonography performed during the pain attack demonstrated dilatation of the renal pelvis in all patients, and this dilatation was more pronounced during the attackthan during convalescence in 3 of the 5 patients. During convalescence, ultrasonography demonstrated mild dilatation of the renal pelvis in these 3 patients and thickening of the renal pelvis in one patient. Urinalysis showed microscopic hematuria despite normal results of blood examinations. Abdominal X-ray examination performed in 2 of the 5 patients demonstrated deviation of colon gas to the outside because of a mass effect of the dilated pelvis. The cause of ureteropelvic junction obstruction was intrinsic stenosis in one case, fibrous band in one case, ureteral kinking in two cases, and a ureteral polyp in one case. Postoperatively, all patients were relieved of pain. On the basis of our experience, we suggest that abdominal ultrasound examination should be done for children presenting with recurrent intermittent flank pain, microscopic hematuria, and deviation of colon gas to the outside on abdominal X-ray films.

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  To clarify the diagnosis of urinary tract infection (UTI) and the existing state of antibiotic prophylaxis in children, we analyzed mailed questionnaires obtained from the secretary institutions of Reflux Nephropathy Forum Japan. A mailed questionnaire regarding UTI was sent to 46 institutions, including 32 surgical department and 14 internal department. Thirty-two (22 surgical and 10 internal) of 46 (70%) institutions returned the questionnaire. Based on this data, we were surprised at a great difference with diagnosis of UTI in each institution. The drugs used for prophylaxis comprised cepharosporin for the most part. Despite the use of antibiotic prophylaxis as a treatment of patients with VUR, selected patients with antibiotic prophylaxis were various in each institution. In conclusion, we must make out a guideline for UTI in children immediately.

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  Congenital renal and urinary tract anomalies are a major cause of renal impairment in children and young adults. Reactive oxygen species and nitric oxide are important mediators of tissue injury and inflammation. The aim of this study was to examine the oxidative stress status in children with congenital renal and urinary tract anomalies to further understand the pathogenesis of the renal impairment. Early-morning void urine samples were obtained from 46 children aged 1-16 years (32 males and 14 females) with congenital renal and urinary tract anomalies (20 with VUR and 26 with non-VUR (10 with MCDK, 6 with renal aplasia, 5 with UPJ stenosis, 3 with renal hypoplasia, 1 with megaureter, 1 with PKD)). The concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG), acrolein-lysine and nitrite/nitrate relative to creatinine were determined according to the procedures described recently (Tsukahara H. Curr Med Chem 14:339-351, 2007). Using the reference values reported by us (Tamura S, et al. Free Radic Res 40:1198-1205, 2006), age-specific SD scores were calculated for each subject. The mean SD scores of 8-OHdG, acrolein-lysine and nitrite/nitrate were -0.21, +0.57 and -0.51 in the VUR group and -0.16, +2.26 and -0.37 in the non-VUR group, respectively. The number of patients having SD scores more than +2.0 was1for 8-OHdG, 2 for acrolein-lysine and 1 for nitrite/nitrate in the VUR group. The number of patients having SD scores more than 2.0 was 3 for 8-OHdG, 15 for acrolein-lysine (4 with MCDK, 4 with renal aplasia, 3 with UPJ stenosis, 2 with renal hypoplasia, 1 with megaureter, 1 with PKD) and 0 for nitrite/nitrate. Serum nitrite/nitrate concentrations were not increased in either group. Twenty-two children (6 with VUR and 16 with non-VUR; 15 males and 7 females) were studied sequentially, and the similar results were obtained. Among renal and urinary tract anomalies, renal aplasia/dysplasia/hypoplasia is likely to associated with the state of increased oxidative stress (especially lipid and protein peroxidation), which can contribute to the progression of renal impairment.

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  Polycystic kidney disease includes many different disease entities; however, inborn error of organic acid metabolism is not usually a prime suspect. We report our experience with polycystic kidneys and thickened myocardium in newborn siblings with the further diagnosis of glutaric aciduria type II in the younger sister. Both female fetuses were found to have enlarged hyperechoic kidneys and thickened myocardium on fetal ultrasound in two singleton pregnancies. Both were delivered at term by cesarean section due to reduced amniotic fluid and developed metabolic acidosis on the same day. In the older sister, autosomal recessive polycystic kidney disease was suspected based on negative family history, clinical course, and renal histological findings. However, the younger sister was confirmed to have glutaric aciduria type II through urine and fibroblasts analyses. Therefore, the older sister was also suspected to have the same disease. Although polycystic kidneys and cardiac steatosis are associated with glutaric aciduria type II, cardiac lesion has not been described as a requisite extrarenal lesion for the differential diagnosis of polycystic kidney disease. The combination of enlarged hyperechoic kidneys and thickened myocardium on fetal ultrasound suggests glutaric aciduria type II, and organic acid analysis should be conducted on amniotic fluid or postnatal urine to make the diagnosis.

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  We studied various factors for blood purification in only severe pediatric patients concerning with survival rate.
  Method: We defined survival rate as an endpoit. There are 34 severe critical cases who was performed blood purification from 2002 to 2005. We excluded patients who had severe neurological problems or were performed ECMO, because we cannot calculate D-PELOD (PELOD). We analyzed effect of age, body weight, with or without CPR, cathecolamine index (CAI), PELOD before blood purification on survival rate and blood purification. We used chi-square test.
  Results: Patients mean age was 2 years and 6 months old. Mean body weight is 8.9kg. About blood purification, There were 16 cases of CHF. There were 19 cases of CHDF. There were 8 cases of PEX. There were 6 cases of PMX-DHP.
  We found out that survival rate is statistically higher among the children who are one year or older, who are more than four kilograms in weight, who are supported by five μg/kg/min or less inotropes, whose PELOD score is less than twenty or who have never experienced cardiopulmonary resuscitation (p<0.01).
  On the other hand, sepsis cases have much better survival than previously reported by us (p<0.05).
  In PELOD, circulation factor and blood factor significantly made survival rate worse when those score was over ten points. On the contrary, when Kidney and Liver score of PELOD were higher, survival rate was lower. When Kidney and Liver score of PELOD were lower, survival rate was higher.
  Conclusion: Our study shows that we can achieve better survival before the deterioration of circulation status (below CAI 5) and we should perform blood purification earlier below PELOD 20. In severe sepsis patients, we can achieve sighnificantly much better survival rate by using PMX-DHP.

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  Extracellular signal regulated kinase 1/2 (ERK1/2) and ERK5 are members of the mitogen activated protein kinase (MAPK) family and have the Thr-Glu-Tyr (TEY) activation motif. Both ERK5 and ERK1/2 are activated by growth factors and have an important role in the regulation of cell proliferation and cell differentiation. Despite these similarities, recent studies have revealed distinctive features of the ERK pathway in renal pathophysiology. We propose thatcontrolled regulation of ERK signals could provide the basis for an effective therapeutic method for inhibition of kidney disease progression.

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  Type III Bartter Syndrome (BS: OMIM607364) is caused by mutations in the basolateral chloride channel ClC-Kb gene (CLCNKB). This report concerns a genetic analysis of 5 Japanese patients with type III BS. To identify the mutations, we used PCR and direct sequencing. To detect large heterozygous deletion mutations of the CLCNKB gene, we conducted semi-quantitative PCR amplification using capillary electrophoresis. Capillary electrophoresis is a new method and extremely useful for detecting large heterozygous deletions, and should be employed to examine type III BS cases in whom only a heterozygous mutation has been detected by direct sequencing. This is the first report to identify large heterozygous deletion mutations in the CLCNKB gene in patients with type III BS.

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  Recently, attempts to make guidelines and treatment strategies of nocturnal enuresis have been performed in Japan and other countries in order to establish standardized comprehensions and treatments based on evidences. In this paper, threereports, which are “The standardization of terminology of lower urinary tract function in children and adolescents”, “Management strategy for nocturnal enuresis in children” and “Nocturnal enuresis: an international evidence based management strategy”, are reviewed.

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[in Japanese]

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  IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide and in Japan. However, even within Japan, the therapeutic approach and its timing are different between childhood and adult IgAN.
  We have previously compared both histology and leukocyte accumulation in biopsies of recently diagnosed childhood and adult IgAN, and found that glomerular hypercellularity owing to increased cells in mesangial area was prominent in pediatric IgAN and significantly greater than in adult IgAN. In contrast, glomerular matrix expansion and interstitial damage were more severe in adult compared to pediatric IgAN. Glomerular and interstitial activated macrophages were identified in both pediatric and adult IgAN, being significantly greater in number in adult IgAN. These findings suggested that activated macrophages are implicated in the pathogenesis of the chronic lesions of IgAN.
  Our data suggest that adult onset IgAN required more early diagnosis and treatment targeting activated macrophage than that for pediatric IgAN. The importance of physical examination and its enlightenment for people should be more encouraged.

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  The mechanisms of glomerular filtration have been a matter of controversy, but recent data have revealed the molecular details about the size selective barrier formed by the podocyte slit diaphragm. Recent studies have also emphasized the critical role of the intracellular signaling of podocyte, and revealed novel aspects of the mechanism that lead to proteinuria. Extensive research will explain the mechanisms of glomerular filtration and development of diseases.

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  We report a case of ORN with prolonged proteinuria after pathologically improvement of membranoproliferative glomerulonephritis (MPGN) type III.
  First renal biopsy (12 y.o.) revealed diffuse mesangial hypercellularity in light microscopy, and glomerular subendothelial and subepithelial deposits in electron microscopy. Immunofluorescence techniques showed IgG, C3 and IgM in a finely granular pattern along the glomerular capillaries and in the mesangial regions. She was diagnosed as MPGN, so she was treated by predonisolone, warfarin, dilazep dihydrochloride and lisinopril, leading to complete remission in 7 months.
  But again she showed proteinuria at 17 y.o. so second biopsy was performed, which revealed only focal mesangial hypercellularity in light microscopy, and glomerular diameter was larger than the first one. Although there were no electron dense deposits, her BMI increased from 26.8 to 36.3. We diagnosed her as obesity-related glomerulopathy (ORN).
  ORN was defined morphologically as focal segmental glomerulosclerosis and/or glomerulomegaly. Recently it is said that metabolic syndrome and obesity in children are increasing, so in future, ORN will also increase in children. In conclusion, we pediatrician have to care and know this renal disease.

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 nbsp;We reported a case of J-Dent. The patient was 17-year-old boy who was detected at a mild proteinuria on urinary screening at the age of 3 years. He was diagnosed with J-Dent based on a marked increase in excretion of urinary β2-microglobulin and CLCN5 gene anomaly. First percutaneous renal biopsy specimens showed minor alterations in glomeruli and tubulointerstitium in 9-year old. During follow up duration, significant increases in urinary protein and albumin were observed. Second renal biopsy performed after 8 years revealed several global sclerosis with tubulointerstitial changes. These results suggest that the prognosis of the patient with J-Dent might be poor.

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  We report a 6-year-old boy with acute focal bacterial nephritis (AFBN). He was referred to us for high fever, abdominal pain, and diarrhea. His abdominal ultrasonogram showed nephromegaly and high echogenic mass in the upper and lower pole of the left kidney. Post-contrast computed tomography showed wedge-shaped mass like hypodense lesions. The diagnosis was AFBN for which he was treated with parenteral cefpirome sulfate. He recovered and discharged without sequela. Follow-up sonographies were performed and showed the change of echogenisity of the mass from high echogenic to hypoechogenic. Our serial observation suggests that the sonographic appearance can alter with the time course of the infective process or during the period of antibiotic treatment.

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  C1q nephropathy is an immune complex glomerulonephritis defined by the presence of mesangial immunoglobulins and complement deposits, most notably C1q, and the absence of clinical and laboratory evidence of systemic lupus erythematosus. Histology in C1q nephropathy is characterized by a slight to severe increase in mesangial cellularity and matrix, with or without segmental sclerosis. C1q nephropathy usually presents with nephrotic-range proteinuria in older children and young adults, and has a poor response to steroids.
  We reported on 1-year-old-girl with C1q nephropathy. She had heavy proteinuria and edema with nephrotic syndrome. She was treated with oral prednisolone for 6 weeks, but predonisolone could not lead her to remission. It was diagnosed as steroid resistance nephrotic syndrome. Histology of the patient renal biopsy revealed a minimal change and immunofluorescene study revealed dominant positive staining (3+) of C1q in the glomerular mesangium with lesser C3, IgA, IgM. Staining for IgG was negative. Electron-dense deposits were present in the paramesangial area. There was no serological or clinical findings of lupus nephritis. The histopathological studies were compatible with C1q nephropathy. So we diagnosed C1q nephropathy with steroid-resistant nephrotic syndrome. We selected cyclosporine as therapy and were effective. The patient was led to complete remission. It is assumed that C1q nephropathy tends to occur in older children. But our patient was 1-year-old. C1q nephropathy should be added to the cause of steroid-resistant or steroid-dependent nephrotic syndrome in young children. In addition, it is reported that 10% of C1q nephropathy develops renal insufficiency. We have to be careful to progress of this patient and need more research about C1q nephropathy.

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  Familial focal segmental glomerulosclerosis (FSGS) is a heterogeneous renal disease characterized by heavy proteinuria and progressive renal insufficiency. Previous reports have demonstrated several mutations in genes affecting the podocyte in Mendelian-inherited families, and yet the correspondence between severity, clinical course and genotype remains unclear. There is generally no response to immunosuppressive agents, but some patients or families with familial FSGS show a level of responsiveness equal to that of sporadic FSGS patients. Recently, cyclosporine (CsA) has been successfully used to treat adults with FSGS and is regarded as the main second-line drug. We herein report a nephrotic boy with familial FSGS, who successfully achieved remission following administration of CsA despite the lack of response to steroid.
  The patient was first brought to our hospital at one year of age. Moderate proteinuria had been noted since birth, but renal excretory function was normal. He underwent the first renal biopsy showing FSGS at two years of age, and prednisolone (PDN) was soon initiated according to the protocol of the International Study of Kidney Disease in Children. He obtained partial remission through PDN induction therapy, with relapse prevented for the subsequent six years. His sister also presented with proteinuria in infancy, and so we performed rebiopsy on the siblings when the proband was five and his sister was four. Histological studies demonstrated that both siblings had FSGS, partial global sclerosis with interstitial fibrosis and positive expressions of podocin, nephrin, and α-actinin in the glomeruli. Furthermore, we demonstrated a genome-wide linkage analysis of genes affecting the podocyte and causing familial FSGS (NPHS-1, NPHS-2, ACTN4, etc.), but there was no locus identified in this family. At the age of nine, the patient developed gastroenteritis and relapsed into nephrotic syndrome. Although we restarted steroid therapy with blockade of the renin-angiotensin system, he developed resistance to PDN and heavy proteinuria persisted. We subsequently administered CsA as a single daily dose while maintaining a two-hour post-dose (C2) level of 600 to 800 ng/ml. This CsA therapy markedly decreased the urinary protein-to-urinary creatinine ratio (UP/UC) from 7.49 to 0.70 in four months. Except for transient headache, there have not been any significant adverse effects of CsA. He has maintained remission to date.
  Several mechanisms that explain the ability of CsA to induce reduction of proteinuria in nephrotic syndrome have been proposed, for example reduction in glomerular plasma flow or filtration pressure. CsA therapy may reduce proteinuria without severe side effects in some patients with familial FSGS. Affirmative administration of CsA therapy should be considered, not least in genetically-unknown familial FSGS.

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  A 3-year-old boy presented nephrotic syndrome with macroscopic hematuria, without hypocomplementemia was reported. By light microscopy, the renal biopsy revealed diffuse mesangial expansion with mesangial hypercellularity. By immunofluorescence, intense granular deposits of IgG, IgA, C3 and fibrinogen along the glomerular capillary wall were found. By electron microscopy, prominent subepithelial, subendothelial and some mesangial deposits were observed. Mesangial interposition was also observed. There was a significant effacement of foot processes. There was no serological or clinical evidence of collagen disease. He was treated with steroid pulse therapy (30mg/kg intravenous mehtylprednisolone for 3 alternate-days a week, for three cycles, followed by oral prednisolone), immunosuppressant (mizoribine), angiotensin-converting enzyme inhibitor (enalapril) and angiotensin-II receptor antagonist (losartan). The proteinuria and hematuria were reduced but persisted. Although histopathological studies were compatible with secondary membranous nephropathy or membranoproliferative glomerulonephritis type III, IgA deposition along glomerular capillary wall is unusual in such diseases. We assume this is a rare form of primary MPGN type III with capillary IgA deposition.

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[in Japanese]

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