Background: Though a diagnosis of urinary tract infection (UTI) should be made by the confirmation of significant bacteriuria, the presence of pyuria which can be examined by microscopic analysis using urine sediment leads us to have a high index of suspicion for UTI in children. Recently, we encountered several children with upper UTI having no pyuria.
Aims: To characterize the children with upper UTI having no pyuria.
Subjects and Methods: Retrospective analysis using medical record was performed in 129 children (male/female 88/41, median age 4.12 mo.) with upper UTI admitted to our hospital during 2004 and 2008. These children were classified into 2 groups according to the presence of pyuria: group A, children with upper UTI having pyuria, group B, children with upper UTI having no pyuria. Significant pyuria was defined as more than 4 leukocytes in the urine sediment per high power field under light microscopy.
 Age (mo.), sex ratio (male/female), time from the onset of pyrexia to urine sampling (hours), maximum body temperature (°C), maximum white blood cell count (WBC) in the peripheral blood (per mL), maximum serum level of c- reactive protein (CRP, mg/dL) during the course of illness were compared between groups. Furthermore, the prevalence of vesicoureteral reflux (VUR) in both groups was also analyzed.
Results: Among 129 children with upper UTI, 111 had significant pyuria (86%, group A) while 18 children did not (14%, group B). There were no significant differences between group A and group B in age, sex ratio, time from the onset of pyrexia to urine sampling, maximum body temperature, maximum WBC count, maximum serum level of CRP and the prevalence of VUR. Interestingly enough, there was a difference in the most frequently detected causative pathogen between group A and group B: E. coli was detected in 90 out of 111 (81%) in group A, whereas Enterococcus was detected in 7 out of 18 (39%) in group B.
Conclusion: In children with upper UTI, absence of pyuria is not rare finding, particularly in children with UTI caused by Enterococcus spp. The presence of significant bacteriuria, therefore, should be sought in suspected cases.

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 There are some reports on the cases with child refractory nephrotic syndrome effectively treated with rituximab. We report a 7-year-old boy with steroid-dependent nephrotic syndrome (minimal change), who developed severe neutropenia (neutrophil count 0%) with fever three months after the administration of rituximab (375mg/m²/dose) four times. As to neutropenia, the patient was treated with G-CSF, and rapidly recovered. Some cases of delayed-onset (1 to 5 months later) severe neutropenia have been reported in patients with other diseases such as lymphoma. Many of them were treated with G-CSF or naturally recovered. There, however, is a case of long-lasting neutropenia for one year. As far as reviewed in the literature, there are no reports on cases of nephrotic syndrome with rituximab-related delayed-onset neutropenia. Rituximab treatment will be widely used to child refractory nephrotic syndrome in the near future. When treated with rituximab, those patients must be carefully followed at least for one year regarding delayed-onset severe neutropenia.

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 Although recombinant human serum albumin (rHSA) has been recently developed from Pichia pastoris without using any animal-derived materials, its clinical use is yet limited especially in pediatric patients. We report our preliminary experience regarding the safety of rHSA in selected patients with nephrotic syndrome (NS). For the controlling refractory edema caused by NS, rHSA in combination with loop diuretics was administred to 6 NS patients, including one patient who received rHSA 3 times at every other month, from September 2008 to January 2009 in our hospital. One treatment course of rHSA was performed at least 3 consecutive days (3-22 days). Specific IgE antibody titers against Pichia yeast components measured before and after treatment remained negative all the study subjects. No allergic adverse events were observed. On the basis of changes in serum albumin level, urinary output, edema and body weight, the clinical usefulness seemed to be similar to that of conventional plasma-derived human serum albumin, as postulated in recent reports concerning the successful treatment of adult liver cirrhosis using rHSA. Our preliminary experience suggest that the safety and clinical usefulness of rHSA in the treatment of pediatric patients with NS. Further studies to confirm the long-term safety and clinical usefulness of rHSA in a large number of patients are, however, needed.

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 Membranous nephropathy rarely occurs as a familial disease. There are few past reports of familial membranous nephropathy. We describe two cases of membranous nephropathy in monozygotic brothers of dizygotic triplets.
 There was no past history of intake of toxic agents or drugs. Other possible etiologies were ruled out (Hepatitis B surface antigen and antibody were negative as were anti-nuclear and anti DNA antibodies). Renal biopsy specimens of both patients showed mild thickening of the glomerular capillary walls with characteristic membranous spikes. A fine granular deposition of IgG and C3 along the capillary wall was disclosed on immunofluorescence. Electron microscopy demonstrated numerous electron dense deposits in the subepithelial, subendothelial and para-mesangium areas. The distribution of electron dense deposits suggest secondary rather than primary membranous nephropathy.

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 We evaluated the efficacy of cyclophosphamide (CPM) treatment for nephrotic syndrome in 43 children. CPM was used as a first-choice immunosuppressive agent to treat steroid-dependent nephrotic syndrome and frequently relapsing nephrotic syndrome, and was administrated at a dose of 2.0 mg/kg/day for 8-12 weeks. Mean duration of follow-up was 108.4 months (range: 25-330 months). The cumulative percentage of sustained remissions after the initiation of CPM was 65%%, 53%%, 39%%, 32%, and 30% in 6, 12, 24, 36, and 48 months, respectively. CPM was considered efficacious if predonisolone doses of half or less were required on recurrence in patients with steroid-dependent nephrotic syndrome or if no recurrence was observed for 6 months or more in patients with frequently relapsing nephritic syndrome. Twenty-nine of 43 patients (67%) responded to CPM, and 14 patients (33%) were non-responsive. In those patients who required immunosuppressive agents besides CPM, the initiation of the other immunosuppressive agents occurred 32 months later on average in CPM-responsive patients than in CPM-nonresponsive patients. In addition, no serious side effects occurred during CPM treatment or after its discontinuation. We conclude that CPM is efficacious and is suitable as a first-choice immunosuppressive agent to treat steroid-dependent nephrotic syndrome and frequently relapsing nephrotic syndrome.

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 To identify a significance of mesangial IgA-IgG co-deposition in pediatric IgA nephropathy (IgAN) and Henoch-Schonlein purpura nephritis (HSPN), we performed multilateral investigation on clinical and pathological features, and short-term prognosis. From January 1998 to December 2008, 175 IgAN patients and 61 HSPN patients were diagnosed by renal biopsy in our hospital. Patients were divided into two groups according to the positive (71 cases in IgA nephropathy and 16 cases in HSPN) or negative deposition for mesangial IgG by immunofluorescence. Clinical, laboratory, and pathological data from each group at renal biopsy were analyzed using Student-t or χ² test. Urinary protein excretion, number of urinary podocytes, and days of renal biopsy from onset were significantly increased, and 24-hour creatinine clearance (24-hr Ccr) was significantly decreased in IgG-postive IgAN group compared with IgG-negative IgAN groups. Pathologically, IgG-positive IgAN group showed increased mesangial proliferation, endocapillary proliferation, and crescent formation. Furthermore, IgG-positive IgAN group showed a higher tendency of sustained proteinuria than IgG-negative IgAN group after two years from the first renal biopsy. Only 24-hr Ccr was different in IgG-positive HSPN group compared with IgG-negative HSPN group. In conclusion, mesangial IgA-IgG co-deposition may have a role in the pathogenesis and progression of IgAN.

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 Pseudohypoaldosteronism type 1 (adPHA1) is a rare inherited condition that is characterized by ranal resistance to aldsterone, with salt wasting, hyperkalemia, and metabolic acidosis. At least two forms of PHA1, autosomal dominant (adPHA1) and recessive forms (arPHA1) of the disease have been descried. In most cases, adPHA1 is caused by mutations of the gene coding human mineralcorticoid receptor (MR), and arPHA1 is caused by genes coding epithelial Na channel (ENaC). AdPHA1 form shares many of the same clinical features as arPHA1, including failure to thrive, salt loss, hyperkalemia, and metabolic acidosis despite elevated aldosterone and plasma renin activity (PRA) levels. However, patients with arPHA1 generally have much severe symptoms than them with adPHA1 patients. Recently, it is reported that the symptoms with PHA1 are similar to those with Bartter syndrome type II. Patients with PHA1 genenrally require oral salt supplementation, but typically show a gradual clinical improvement with regard renal salt loss during childhood.

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 Recently new technologies to analyze human genome in diseases emerged, which enabled us to isolate genes responsible for diseases efficiently and to screen rapidly a large number of candidate genes. As for mapping disease loci, genome microarray and high density SNP array are quite useful (even for small-sized families). As for rapid screening of many candidate genes, high resolution melting curve method, resequencing array, and next generation sequencing are expected to yield high throughputs. All the technologies presented here possess more advantage than any other conventional technologies, but each has some drawbacks. We should utilize these new technologies to attain reasonable goals, but proper understanding of their weak points is essential.

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 Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder caused by mutations in the FOXP3 gene that result in the defective development of CD4⁺CD25⁺ regulatory T cells. In the absence of CD4⁺CD25⁺ regulatory T cells, activated CD4⁺ T cells instigate multi-organ damage. IPEX syndrome is often initially treated with immunosuppressive drugs, but only allogeneic hematopoietic stem cell transplantation has offered the possibility of cure. Kidney complications in IPEX syndrome patients have been reported to be membranous nephropathy, tubulointerstitial damage and minimal change nephritic syndrome (MCNS). We suspected that this complication is caused by a disorder of a T cell function due to IPEX syndrome. Now we report the relationship between IPEX syndrome and its complication of the kidney disease from a point of view of regulatory T cells.

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 Bcl-2 is the founding member of a family of proteins that influence apoptosis. Loss of bcl-2 results in renal hypoplasia/cystic dysplasia at birth. In this review, we show that re-expression of bcl-2 in the ureteric bud/collecting duct resulted in increased nephron numbers partially rescuing renal hypoplasia/cystic dysplasia in bcl-2 -/- mice.

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 In 1992, the characteristic structure of O-linked oligosaccharides (O-glycans) in the IgA1 hinge and its possible aberrancy were simultaneously and independently proposed by Mesteckey et al., Allen et al., and our group at the International Congress of Nephrology (IgA Nephropathy 25^th Year) held in Nancy, France. Since then, the aberrancy has been confirmed by several research groups and is suspected to play a role in the occurrence and/or the progression of IgAN.
 In the serial investigations, it has been shown that the aberrant O-glycan structure in IgA1 may cause mesangial deposition of IgA in IgAN patients, but could not be proved that the aberrant IgA provokes tissue injury directly. Recently, the presence of antibody against aberrantly glycosylated IgA1 was elucidated.
 This review illustrates the difficulty in elucidating the mechanisms of the development and aggravation of this disease.

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 Idiopathic renal hypouricemia, mainly caused by a defect in a gene (SLC22A12) encoding the urate transporter (URAT1), is a disorder with an incidence of 0.15% in Japan. Patients exhibit an increase in uric acid excretion due to an isolated defect in renal tubular transport of uric acid and are known to be frequently complicated by an exercise-induced acute renal failure (ARF).
 The mechanisms for development in exercise-induced ARF in patients with idiopathic renal hypouricemia remain unclear while two possible explanations have been proposed: either urate nephropathy results from an increase in urate production during exercise, or renal reperfusion injury due to vasoconstriction results from an exercise- induced increase in oxygen free radicals and a lack of urate, one of the free radical scavengers.
 In this review, we summarized the putative mechanisms regarding the development for exercise-induced ARF in patients with idiopathic renal hypouricemia based on the previous reports. Furthermore, we found the oxidative imbalance after exercise in a patient with idiopathic renal hypouricemia and postulate as a cause for exercise-induced ARF in this condition.
 A 15 year-old-girl with idiopathic renal hypouricemia caused by a mutation in the URAT1 gene (compound heterozygous mutation for R90H/W258X) was referred us for further evaluation of exercise-induced ARF. We therefore studied the oxidative balance during and soon after exercise in this girl to investigate causal relationship between idiopathic renal hypouricemia and exercise-induced ARF, after written informed consent was obtained. As a result, her serum level of reactive oxygen species (ROS) increased with decreasing antioxidant potential capacity soon after the initiation of anaerobic stress due to treadmill exercise. Thereafter, serum levels of ROS and antioxidant potential showed a parallel course, returning to the baseline values at 240 min after exercise.
 Thus, some patients with idiopathic renal hypouricemia demonstrate oxidative imbalance soon after exercise with a predisposition to exercise-induced ARF and we therefore postulate that oxidative imbalance after exercise in a patient with idiopathic renal hypouricemia plays an important role. Antioxidant properties may alter this imbalance by augmenting the antioxidant activity.

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 Glomerular podocytes form slit diaphragm (SD) that performs as a filtration barrier of the kidney. Mutations of genes encoding the components of SD cause the onset of familial nephrotic syndromes. Recently, lines of evidence revealed that SD components are regulated dynamically by tyrosine phosphorylation. We analyzed the tyrosine phosphorylation of major SD components, Nephrin and Neph1. Nephrin binds PLC-γ, as well as various SH2-containing factors, and Neph1 binds CSK and Grb2. Nephrin, through the regulation of PLC-γ and TRPC6, maintains calcium homeostasis in podocytes. Nephrin suppresses the translocation of wild type TRPC6, whereas TRPC6 mutants found in the familial focal segmental glomerulosclerosis (FSGS) are not regulated by Nephrin. Tyrosine phosphorylation of SD components is an outcome of the balance between phosphorylation by Fyn and dephosphorylation by SIPRα/SHP-1/2.

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 Hemolytic uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, acute renal failure, and is usually induced by enterohemorrhagic Escherichia coli (EHEC). Central nervous system (CNS) involvement, including encephalopathy, is one of severe complications in HUS and EHEC infection. But little has been reported on acute necrotizing encephalopathy of childhood (ANE) as a complication in HUS. We had two cases of EHEC infection, HUS and encephalopathy with symmetrical thalamic lesions typical of ANE. We summarized previous case reports of HUS with CNS involvement, and those of rare association of HUS and ANE. It is suggested that the pathogenesis of severe CNS involvement in HUS, including ANE, is under the influence of cytokine release, which may be the therapeutic target against severe CNS involvement in HUS.

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 The most important thing on treating glomerular disease is to prevent deterioration of kidney function. It is previously shown that prognosis of kidney function depends on the dose of proteinuria. Moreover, the risk to be end stage renal failure will get serious, if high molecular weight proteins are included in proteinuria.
 A portion of proteins filtered through glomeruli are reabsorbed to proximal tubule cells (PTCs) by endocytosis. The most important receptor of PTCs related to endocytosis is megalin, which exists on apical membrane of PTCs. There are many kinds of protein which are established to be ligands of megalin. Some of the ligands are vitamin-binding proteins, carrier proteins, lipoproteins, hormones, hormone precursors, enzymes, enzyme inhibitors and immune- and stress- response-related proteins. A part of the proteins are transported to lysosome after reabsorption to PTC and degraded. Others are transported from apical membrane to basolateral membrane through PTC without degradation.
 When glomerular diseases occur, not only low to intermediate proteins but also high molecular weight proteins are filtered through glomeruli. Utilizing kidney-specific megalin knockout mice, we have shown that high molecular weight proteins, namely IgG and IgA, are reabsorbed to PTCs by mediation of megalin. When large amount of proteins is overloaded to PTCs, mediators which are related to inflammation and fibrosis, namely monocyte chemoattractant protein-1, RANTES, interleukin-8, fractalkine, tumor necrosis factor-α, endothelin, and transforming growth factor-β, are released by PTCs to tubulointerstitial area. The release of mediators is considered as beginning of tubule injury and interstitial fibrosis. Apoptosis of PTCs are also induced after protein overload to the cells.
 In spite of previous exertions done by many researchers, there are many ambiguous points left to elucidate the process of deterioration of kidney function. However, we consider that direct damage of PTCs induced by reabsorbed proteins might cause a vicious circle and take much part in progression to end stage renal disease.

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 Hydronephrosis and vesico-ureteral reflux (VUR) are fundamental anomalies of urinary tract in small children. Renal deterioration due to hydronephrosis is a condition called obstructive nephropathy. Also the term “reflux nephropathy” describes the renal scarring in the presence of VUR. The advent of prenatal ultrasound in 1980 led to the early detection of hydronephrosis and enthusiasm for prevention of reflux nephropathy increased early radiological investigation in infants with VUR. However, long term outcome of fetal and neonatal hydronephrosis is still uncertain and the role of early detection of VUR after initial urinary tract infection is also uncertain. Herein, a current appropriate management and a review of the literature are discussed.

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 We encountered a male patient with minimal change nephrotic syndrome (MCNS) associated with STAT3 gene abnormality. He experienced approximately ten times relapse of NS and showed corticosteroid-sensitive or -resistance nephrotic conditions repeatedly. Serum IgE level had markedly increased to 4000∼25000 IU/ml. He suffered from severe atopic dermatitis together with staphylococcus infection of the skin. He had no apparent abnormalities involving hair, bone, and connective tissues. Gene testing revealed a novel mutation of STAT3 gene in exon 23 (A744V) in trans-activation domain. Our present finding suggested that STAT3 gene abnormality may be one of the pathogen for onset of MCNS, especially in patient with allergic condition and high serum IgE.

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 Hemolytic-uremic syndrome (HUS) patients often need treatment with dialysis temporally at the acute phase of HUS and rarely develop chronic renal failure after years of apparent recovery. We report a 14-year-old girl who developed HUS at 3 years of age. She showed acute renal failure and treated with peritoneal dialysis for about a month. She also showed seizure and disturbed consciousness on acute phase. Although her kidney function normalized, and her protenuria was disappeared, high urine β2MG level was persisted. Therefore we performed kidney biopsy, and showed a portion of scarring tissue which findings may derived from the cortical necrosis on acute phase. Because of these findings, we started to treat with ACE inhibitor. After the induction of this treatment, her urine β2MG level was normalized. Eight years after the onset of HUS, she began to showed severe proteinuria and we performed repeated kidney biopsy. It showed focal segmental glomerular sclerosis and severe fibrosis of intestitiums and predicted to have bad renal prognosis. We should follow up HUS patients carefully and need long period observation after the onset of HUS in patients with prolonged renal failure on early phase.

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  We report a case of recurrent renal vein thrombosis associated with idiopathic membranous nephropathy in an 11-year-old boy. He did not have any significant family or medical history. He was diagnosed membranous nephropathy by open renal biopsy.
  We used a combination of oral corticosteroid and immunosuppressive drugs for treatment, because the disease recurred only when thrombolytic treatment was administered.
  During cyclosporine treatment, a remission of nephritis was observed and there was no persistence of blood clots. However, renal biopsy performed 2 years later revealed progression from stage II to III with an increase in tylosis of the basement membrane and the number of electron dense deposits.

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 We report two cases of posterior reversible encephalopathy syndrome (PRES) associated with abdominal complications of nephrotic syndrome.
 The first case was a 12 year old girl who developed secondary nephrotic syndrome accompanied by angitis. Prednisolone therapy was not effective, and severe proteinuria persisted for about two months. Light microscopy findings of a renal biopsy specimen demonstrated rapidly progressive glomerulonephritis. Sudden severe anemia as a result of a small intestine hemorrhage occurred, and on the 56th day of admission laparoscopic intestinal partial-resection was undertaken. The day after the operation, she showed hypertension, generalized tonic-clonic seizure and synchronous seizures with strong abdominal pain.
 The other case was a 9 year old boy with frequent relapses of nephrotic syndrome. His 6th relapse was complicated with bacterial peritonitis. He was treated with prednisolone, antibiotics and immunoglobulin. His peritonitis improved without surgical drainage. He suffered headache and hypertension on the 5th day of admission, and the next day had a generalized seizure.
 These two cases had a hyperintensive lesion dominantly in the occipital lobes identified with T2WI and FLAIR of head MRI. Both recovered with no sequelae, thus we diagnosed PRES. A calcineurin inhibitor, considered a strong risk factor of PRES, was not used for these patients. Factors related to the operation, general anesthesia, angitis and bacterial infection were thought to accelerate the increase of vascular permeability.

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 The case of a patient with hyponatremic-hypertensive syndrome (HHS) without hypertension at admission is reported.
 HHS occurs in patients with unilateral renal ischemia from occlusion or stenosis of the renal artery. The etiologies of the symptoms and the blood and urine examination abnormalities in HHS are not straightforward. “Malignant” hypertension, hypokalemia, and metabolic alkalosis are caused by an accelerated renin-angiotesin II -aldosterone system. A sudden increase in arterial pressure in the normal kidney causes pressure natriuresis leading to hyponatremia and polyuria. Volume depression induces further renin release from the ischemic kidney. Increased angiotensin II levels change the permeability of the glomerular basement membrane resulting in massive proteinuria. Increased pressures in the surviving glomeruli also cause proteinuria.
 A three-year-old girl was admitted to Dokkyo Koshigaya Hospital due to polydipsia and polyuria. She appeared mildly dehydrated and complained of fatigue. Her blood pressure was normal (86/42 mmHg) on admission, but her laboratory tests showed hyponatremia (133 mEq/l), hypokalemia (2.8 mEq/l), metabolic alkalosis (pH 7.56) and heavy proteinuria (P/Cr 8.7). The serum renin activity level was more than 20 ng/ml/h, and the serum aldosterone level was 2560 pg/ml; both were extremely elevated.
 On the seventh hospital day, after her dehydration had been corrected by two days of intravenous infusion, her blood pressure increased to 200/140 mmHg. Her hypertension then gradually normalized with ACE-I administration and Ca blocker infusion. As the blood pressure became normal, the electrolyte disorders, metabolic alkalosis, and heavy proteinuria resolved immediately. The angiography and other radiological examinations showed a renal artery variant (two renal arteries from each side of aorta) and ischemia of the lower part of the left kidney. She was diagnosed with renovascular hypertension with HHS. Significant occlusion of the proximal part of the renal artery could not be detected, but peripheral blood flow was largely disrupted, which meant that intervention was not indicated. Her blood pressure has been well controlled with ACE-I and Ca blocker administration.
 The reason why her blood pressure was normal on admission is not clear. We speculated that one cause was dehydration, but it did not seem severe enough to decrease her systolic blood pressure from 200 mmHg to 86 mmHg. Other factors might have been mediators including PGE₂, PGI₂ or Cyclooxygenase (COX) 1, 2. Those mediators play an important role in controlling vascular tone, salt and water balance, and rennin release in renovascular hypertension. In general, the vasodilating or diuretic effects of PGE₂, PGI₂, or COX2 act as a protective mechanism against hypertension. In the present case, however, the elevated angiotensin II level may have stimulated the secretion of those prostanoids excessively, the net effect of which resulted in normotension.
 This case shows that hypertension may be masked by dehydration and other factors in renovascular hypertension complicated by HHS.

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