Serum sodium level is inversely correlated with body temperature in children.

BACKGROUND: Several studies have demonstrated that non-osmotic antidiuretic hormone activity contributes to the development of hyponatremia in children with common febrile diseases. However, the relationship between hyponatremia and body temperature has remained unclear. We therefore examined this relationship in children with common diseases. METHODS: In this retrospective case study based on a chart review, 1,973 children presenting with acute illnesses at Hirakata City Hospital between November 2008 and October 2009, and for whom blood test data were available, were enrolled. The median age of this cohort was 2.7 years and the mean serum sodium concentration was 136.4 mEq/L; 454 patients showed hyponatremia (<135 mEq/L). The patients were classified into four groups on the basis of body temperature, <37 °C, 37 °C (37.0-37.9 °C), 38 °C (38.0-38.9 °C) and ≥39 °C, and their serum sodium concentration was compared. RESULTS: The mean sodium level was significantly lower in febrile (135.9 mEq/L) than in non-febrile (138.5 mEq/L) patients. The mean serum sodium levels in the four temperature groups were, in ascending order, 138.5 mEq/L (95% CI, 138.3-138.8 mEq/L), 137.3 mEq/L (137.1-137.5 mEq/L), 136.1 mEq/L (135.8-136.3 mEq/L) and 134.6 mEq/L (134.4-134.9 mEq/L), respectively. The serum sodium level in each individual temperature range became significantly lower as body temperature increased (P < 0.001). CONCLUSIONS: There is a clear inverse correlation between serum sodium level and body temperature in children with common febrile diseases, and fever may play an important role in this relationship.

Possible Roles of Periostin in the Formation of Hemodialysis Vascular Access Stenosis after Polytetrafluoroethylene Graft Implantation in Dogs.

Periostin, a recently found matricellular protein, has been implicated in neointima formation after balloon injury. However, the relationship between periostin and hyperplastic intima formation after PTFE graft implantation is unclear. Under mixed anesthesia, PTFE grafts were implanted between the canine carotid artery and jugular vein, and PTFE graft samples were harvested 1, 2, and 4 months after implantation. Intima formation started on the luminal surface of PTFE grafts at the venous anastomotic region 1 month after implantation. Thereafter, the increase in intimal volume was not only observed in the venous and arterial anastomotic regions, but also in the middle region of the PTFE grafts. In accordance with the increased intimal formation, time-dependent increases in mRNA expressions of periostin and transforming growth factor beta 1 (TGF-ß1), as well as a strong positive correlation between periostin and TGF-ß1, were observed. These findings suggest that periostin may play a very important role in the pathogenesis of hemodialysis vascular access stenosis through the acceleration of intimal formation. Thus, periostin may be a very important therapeutic target for the treatment of vascular access graft dysfunction in hemodialysis patients.

Clinical features in a series of 258 Japanese pediatric patients with thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathy (TMA) includes hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). This study examined the epidemiological characteristics of pediatric patients with TMA classified according to etiology. METHODS: The survey evaluated 258 Japanese pediatric patients diagnosed with TMA between 2012 and 2015. RESULTS: The primary diseases responsible for TMA were categorized as TTP (15 cases), Shiga toxin-producing Escherichia coli-associated HUS (STEC-HUS) (166 cases), atypical HUS (aHUS) (40 cases), and secondary TMA (27 cases). The remaining 10 cases were unable to be classified to one of the four categories of the primary disease. Renal replacement therapy was required in the acute phase in 103 patients with TMA, including 65 with STEC-HUS, 22 with aHUS, two with TTP, 10 with secondary TMA, and four unclassified cases. The last observational findings were normal renal function in 95 patients and chronic kidney disease (CKD) stage 1 in 62. For 31 patients, chronic renal insufficiency (CKD stage 2-5) persisted, including four patients with end-stage kidney disease (CKD stage 5). Seventeen patients suffered recurrence of TMA, and eight patients died. CONCLUSION: This study clarified differences in the relative proportions of primary diseases between patients from Japan and North America and Europe. The difference may be attributable to the lower estimated incidence of STEC-HUS in Japan.

Clinical characteristics of rotavirus gastroenteritis with urinary crystals.

BACKGROUND: Rotavirus gastroenteritis is severe and often results in dehydration and pre-renal azotemia. In addition, some patients with acute obstructive uropathy due to ammonium acid urate stones, developing approximately 6-7 days after the onset of rotavirus gastroenteritis, have been reported, mainly in Japan. The pathophysiological mechanism responsible for stone formation has not been clarified. In the present study, we investigated the clinical characteristics of these patients, and analyzed the pathophysiology underlying the formation of urinary stones. METHODS: A total of 164 patients were enrolled. All had acute gastroenteritis due to rotavirus infection and were treated at Osaka Medical College Hospital and affiliated hospitals between January 2009 and May 2011. All were younger than 15 years of age, and their laboratory data, including urinalysis, were available. RESULTS: Among the enrolled patients, 30 (20 boys and 10 girls aged 0.2-10 years; median, 1.5 years; interquartile range, 1-3 years) had crystals in their urine. Most of the patients were admitted approximately 2 days after onset of gastroenteritis and had hyperuricemia and aciduria. The crystals consisted mainly of uric acid, and rarely of ammonium acid urate. CONCLUSION: In order for ammonium acid urate stones to form in patients with acute obstructive uropathy associated with rotavirus gastroenteritis, prolonged continuous acidosis with hyperuricemia, might be necessary. Therefore, normalization of metabolic acidosis is important in order to prevent the onset of obstructive uropathy associated with rotavirus gastroenteritis.

Molecular effect of a novel missense mutation, L266V, on function of ClC-5 protein in a Japanese patient with Dent's disease.

UNLABELLED: We report the use of three dimensional computational analysis of chloride channel 5 (ClC-5) based on a novel mutation, L266V, identified in a 15-year-old Japanese boy with Dent's disease. Since both leucine and valine are branched-chain amino acids, it has not been proved conclusively whether L266V mutation is actually responsible for the development of Dent's disease. In the present study using molecular analysis, we investigated the mechanism for loss of function of the ClC-5 protein resulting from the L266V mutation. Structural analysis of the normal ClC-5 transmembrane region using molecular modeling showed that the two respective Leu266 residues were located at the interface of the dimer formed by the aligned ClC-5 monomers. The Leu266 side-chains were positioned close to each other through hydrophobic interaction, resembling two interconnecting hooks. When Leu266 was replaced by a valine residue, the hydrophobic interaction between the CLC-5 monomers was reduced, and dimer formation was impaired. This computer simulation analysis has thus provided strong evidence for the important role of Leu266 in the dimerization of human ClC-5 in membranes. CONCLUSION: The finding of the present study suggest that computational modeling and molecular analysis could be an alternative to labor-intensive in vitro functional studies.

Darbepoetin alfa for the treatment of anemia in children undergoing peritoneal dialysis: a multicenter prospective study in Japan.

BACKGROUND: Darbepoetin alfa (DA) is an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia. Since DA has not been approved by the appropriate Japanese drug regulatory agencies for the indication of renal anemia in children in Japan, we have conducted a multicenter prospective study to determine the efficacy and safety of DA in Japanese children undergoing peritoneal dialysis (PD). METHODS: Pediatric patients subcutaneously receiving rHuEPO were switched to DA treatment for a period of 28 weeks. The conversion to the initial dose of DA was calculated as 1 µg DA for 200 IU rHuEPO, and DA was administered intravenously once every 2 weeks. The target hemoglobin (Hb) concentration was defined as 11.0 to ≤13.0 g/dL. In some patients, the dose of DA was adjusted appropriately to achieve this target level, and/or the dosing frequency changed to once every 4 weeks. RESULTS: In the 25 patients switched from rHuEPO to DA the mean Hb concentration increased from 9.9 ± 1.0 to 11.1 ± 1.0 g/dL at 8 weeks following commencement of the DA treatment. The target Hb concentration was achieved in 88 % of these patients, and 60 % maintained this target value on completion of the study. The dosing frequency was extended to once every 4 weeks in 60 % of patients. Twenty-four adverse events were noted in 11 of 25 patients (44 %); however, there was no causality between DA and adverse events. CONCLUSIONS: The results of this study suggest that intravenous administration of DA once every 2 or 4 weeks is an effective and safe treatment for renal anemia in Japanese children undergoing PD.

Clinical characteristics of obstructive uropathy associated with rotavirus gastroenteritis in Japan.

AIMS: Rotavirus gastroenteritis is severe and often results in dehydration and pre-renal azotemia. However, we have encountered four children with acute obstructive uropathy associated with acute rotavirus gastroenteritis, and several similar cases have been reported. Therefore, the aim of the present study was to clarify the epidemiology and clinical features of acute obstructive uropathy associated with acute rotavirus gastroenteritis in Japanese children. PATIENTS AND METHODS: We sent questionnaires to all members of the Japanese Society for Nephrology and all authors who had published case reports of this disease in Japan, inquiring about patient age at diagnosis, sex, the type of stones, laboratory data and other factors. RESULTS: 21 reported patients were evaluable, ranging from 0.4 to 3 years. The sex distribution showed a strong male prevalence. Oliguria had appeared about 7 days after the onset of gastroenteritis. Most of the patients showed hyperuricemia and hyponatremia. The stones consisted mainly of ammonium acid urate. The patients were discharged with normal renal function. CONCLUSION: Although obstructive uropathy associated with rotavirus gastroenteritis is very rare, this disease condition should be explored when anuria is refractory to sufficient fluid replacement therapy or when oliguria persists despite recovery of the gastrointestinal symptoms.

Efficacy of a mitochondrion-targeting agent for reducing the level of urinary protein in rats with puromycin aminonucleoside-induced minimal-change nephrotic syndrome.

BACKGROUND: Oxidative stress is a major factor responsible for minimal-change nephrotic syndrome (MCNS), which occurs most commonly in children. However, the influence of oxidative stress localized to mitochondria remains unclear. We examined the effect of a mitochondrion-targeting antioxidant, MitoTEMPO, in rats with puromycin aminonucleoside (PAN)-induced MCNS to clarify the degree to which mitochondrial oxidative stress affects MCNS. MATERIALS AND METHODS: Thirty Wistar rats were divided into three groups: normal saline group (n = 7), PAN group (n = 12), and PAN + MitoTEMPO group (n = 11). Rats in the PAN and PAN + MitoTEMPO groups received PAN on day 1, and those in the PAN + MitoTEMPO group received MitoTEMPO on days 0 to 9. Whole-day urine samples were collected on days 3 and 9, and samples of glomeruli and blood were taken for measurement of lipid peroxidation products. We also estimated the mitochondrial damage score in podocytes in all 3 groups using electron microscopy. RESULTS: Urinary protein excretion on day 9 and the levels of lipid peroxidation products in urine, glomeruli, and blood were significantly lower in the PAN　+　MitoTEMPO group than in the PAN group (p = 0.0019, p = 0.011, p = 0.039, p = 0.030). The mitochondrial damage score in podocytes was significantly lower in the PAN　+　MitoTEMPO group than in the PAN group (p <0.0001). CONCLUSIONS: This mitochondrion-targeting agent was shown to reduce oxidative stress and mitochondrial damage in a MCNS model. A radical scavenger targeting mitochondria could be a promising drug for treatment of MCNS.

Clinical features and mutational survey of NPHS2 (podocin) in Japanese children with focal segmental glomerulosclerosis who underwent renal transplantation.

Recurrent FSGS is a major challenge in the field of nephrology. To clarify the role of NPHS2 defects in the pathogenesis of FSGS recurrence, we sequenced all eight exons of NPHS2 in 11 Japanese pediatric FSGS patients with or without post-transplant recurrence. All patients had biopsy-proven primary FSGS, had no family history of renal diseases or consanguinity, were steroid-resistant, and received living-related renal transplantation. The mean age at onset was 5.0 +/- 3.1 yr and mean age at renal transplantation was 10.4 +/- 4.1 yr. Mutational analysis of NPHS2 was performed using polymerase chain reaction and direct sequencing. We found a synonymous T/C polymorphism at alanine 318 (GCC to GCT) in seven of 11 patients but no other causative NPHS2 mutations. FSGS recurred immediately after transplant in seven patients, while the remaining four patients had no recurrence for 3.2-5.8 yr. There were no differences between recurrent and non-recurrent patients in the onset age and the interval from onset to ESRD. In conclusion, we detected no causative NPHS2 mutations in Japanese pediatric FSGS patients with or without post-transplant recurrence. Further studies on the involvement of other genes are required to better understand recurrent FSGS.

Expression of beta-carotene 15,15'- monooxygenase gene and retinol status in rats with puromycin aminonucleoside-induced nephrosis.

Retinol and its metabolite retinoic acid play a critical role in immunity, reproduction, and development. Retinoids are known to influence renal development, and show beneficial effects in experimental models of renal disease. beta-Carotene (provitamin A) is cleaved to retinal by beta-carotene 15,15'- monooxygenase (BCM), which is an essential enzyme for retinoid biosynthesis. However, the metabolism of retinol and beta-carotene in renal diseases such as nephrosis remains unclear. We studied BCM gene expression and retinol status in rats with nephrotic syndrome induced by puromycin aminonucleoside (PAN). BCM gene expression in the liver and intestines of PAN-treated rats was decreased compared with that in controls, while the expression in the kidney of PAN-treated animals was increased. Plasma retinol and retinol-binding protein levels were decreased in PAN-treated rats, but hepatic retinol level did not differ between PAN-treated and control rats. Up-regulation of BCM gene expression in the kidneys of rats with nephrotic syndrome may result in increased conversion of beta-carotene to retinal, so this change might supply more retinoic acid to the damaged glomeruli. Changes in the metabolism of retinol and beta-carotene might have an important role in protection against the development of nephrosis.

[Sequential combined liver-kidney transplantation for a one-year-old boy with infantile primary hyperoxaluria type 1].

We present the case of a one-year-old male patient with infantile primary hyperoxaluria type 1 (PH1). The patient visited hospital because of growth delay and poor feeding when he was six months old, and was diagnosed as PH1 with chronic renal failure. He underwent peritoneal dialysis until receiving a living-related liver transplantation when he was seventeen months old, and after the operation, underwent hemodialysis or hemodiafiltration four times per week. Six months after the liver transplantation, his serum oxalate level decreased to around 20 micromol/l and a living-related kidney transplantation was successfully performed. Nine months have passed since the kidney transplantation, and the patient's liver and kidney functions have been good and his growth and development much better than before the sequential liver and kidney transplantation. However, his serum and urine oxalate levels remained high and he has required high dose hydration to prevent deposition of calcium oxalate crystals in his grafted kidney. The key-points for treating infantile PHI patients are summarized as follows; 1) make a precise diagnosis as soon as possible, 2) perform a combined liver-kidney transplantation successfully, 3) conduct careful monitoring of the serum and urine oxalate levels and continue adequate hydration after kidney transplantation until the serum and urine oxalate levels normalize. Furthermore, cooperation between the medical staff and the patient's family seems to be essential.

A combined low-density lipoprotein apheresis and prednisone therapy for steroid-resistant primary focal segmental glomerulosclerosis in children.

BACKGROUND: Treatment of steroid-resistant (SR) primary focal segmental glomerulosclerosis (FSGS) remains a major challenge in nephrology. A prospective study was conducted to clarify the therapeutic role of low-density lipoprotein apheresis (LDL-A) in 11 nephrotic children with SR and cyclosporine A (CsA)-resistant primary FSGS. METHODS: Based on entry criteria, all 11 eligible patients had biopsy-proven primary FSGS presenting with nephrotic syndrome (NS) and were resistant to steroid and conventional-dose CsA therapy. LDL-A was performed twice a week for 3 weeks (first course), then weekly for 6 weeks (second course). Beginning from the second LDL-A course, a dosage of 1 mg/kg/d of prednisone was administered for 6 weeks, then tapered. RESULTS: Seven patients experienced remission of NS, 5 of whom achieved complete remission within 4 weeks after initiating prednisone therapy with LDL-A. These 5 patients maintained normal renal function during follow-up (median, 4.4 years). Of 2 patients with partial remission, 1 patient maintained stable renal function during follow-up (4.5 years), whereas the other patient showed a gradual decline in renal function and progressed to end-stage renal failure (ESRF) 7.8 years after LDL-A therapy. Four patients who were considered to experience treatment failure had persistent NS and progressed to ESRF in 1.3 years (median) after LDL-A therapy. Complete remission (n = 5) was associated with significantly more highly selective proteinuria compared with treatment failure (n = 4). CONCLUSION: This study suggests that combined LDL-A and prednisone therapy can be a valuable addition to therapeutic options for treating patients with SR-FSGS. The role of LDL-A in treating these patients deserves to be assessed further in larger randomized controlled trials.

A case report of successful treatment with plasma exchange for hemophagocytic syndrome associated with severe systemic juvenile idiopathic arthritis in an infant girl.

An infantile case of hemophagocytic syndrome (HPS) with systemic juvenile idiopathic arthritis (s-JIA), refractory to methylprednisolone pulse therapy and cyclosporine A administration, was successfully treated by plasma exchange. The patient was a one-year-old Japanese girl who had developed recurrent steroid-dependent signs, including fever, skin eruption, and hepatopathy, while in France, where she had been diagnosed as having s-JIA at eight months of age. As a high fever and rheumatoid rash were evident on arrival at our hospital, she was admitted and given intravenous methylprednisolone pulse therapy and cyclosporine A. She developed pancytopenia with a generalized clonic seizure, high fever, and liver dysfunction after her cytomegalovirus (CMV) titer became positive during the course of treatment; therefore, she was treated with ganciclovir. She was subsequently diagnosed as having HPS complicating s-JIA from the findings of a bone marrow aspirate. At this time, her blood examination data including a high level of C-reactive protein and hyperferritinemia, suggested that her s-JIA was very active, and the pancytopenia continued after her CMV titer became negative. Therefore, CMV infection against a background of active s-JIA could have triggered the HPS in this case. Because the HPS was resistant to an immunosuppressive regime of methylprednisolone pulse therapy and cyclosporine A, plasma exchange therapy was started. After three sessions of this therapy, the patient's symptoms and laboratory data were markedly improved. Our experience suggests that plasma exchange should be considered as a therapeutic tool for HPS refractory to conventional therapy.

A case of nephrogenic diabetes insipidus with a novel missense mutation in the AVPR2 gene.

We describe a pediatric case of nephrogenic diabetes insipidus (NDI) with a novel missense mutation in the arginine vasopressin receptor 2 (AVPR2) gene. The patient, a 3-year-old boy, had polyuria (4357 ml/day, 7230 ml/m(2)/day) and polydipsia. Water deprivation testing demonstrated no decrease of urine volume, and urinary volume did not respond to subcutaneous injection of 0.1 U/kg pitressin. Molecular genetic analysis demonstrated that the patient had an AVPR2 missense mutation involving substitution of phenylalanine for tyrosine at position 205 (Y205F). It was also found that the patient's mother was heterozygous for this Y205F mutation. Analysis of the intermolecular interaction of the Tyr-205 hydrogen group by molecular modeling showed that Tyr-205 was located in transmembrane domain (TM) 5, and that its hydroxy group formed a hydrogen bond with Leu-169 main-chain =O located in TM 4. The mutation of Tyr-205 to phenylalanine would cause loss of this hydrogen bond and decrease or change the interaction between these TM coils, thus affecting the ability of AVP to bind to the receptor. According to this molecular model of AVPR2, the Y205F mutation would cause nephrogenic diabetes insipidus.

Two cases of hyponatremic-hypertensive syndrome in childhood with renovascular hypertension.

UNLABELLED: We report two children with renovascular hypertension and fibromuscular dysplasia. They initially presented with severe hyponatremia, hypokalemia, polyuria, and transient proteinuria. This combination of symptoms is known to occur in patients with renovascular and malignant hypertension, and is known as hyponatremic-hypertensive syndrome (HHS), although it is considered rare in children. Since in both of our patients, the renal arterial stenosis was very severely or almost totally occlusive, we could not perform percutaneous transluminal renal artery angioplasty, and therefore nephrectomy was the only option. A histological study showed partial or complete occlusion with intimal hyperplasia and medial fibroplasia of intrarenal arteries such as the interlobular arteries. CONCLUSION: Both patients showed rapidly progressive renovascular hypertension and loss of function of the affected kidney. In order to preserve renal function in such cases, early invasive intervention appears to be necessary.

Oxidative stress in a rat model of nephrosis can be quantified by electron spin resonance.

The pathogenesis of nephrotic syndrome is not clear. In this study, we used electron spin resonance (ESR) to evaluate levels of reactive oxygen species in rats with puromycin aminonucleoside (PAN)-induced nephrosis. Twenty-six Wistar rats were divided into four groups: (1) PAN treated, (2) PAN treated and alpha-tocopherol supplemented, (3) supplemented with alpha-tocopherol only, (4) control. On day 9, urinary protein excretion was measured. On day 10, all animals were sacrificed with retrograde perfusion via the aorta to obtain renal venous perfusates. The signal intensities of ascorbate radicals in the perfusates were determined by ESR. After perfusion, the kidneys were isolated and sieved to obtain glomeruli for determination of glomerular thiobarbituric acid-reactive substance (TBArs) and alpha-tocopherol. Urinary protein excretion by PAN-treated rats increased significantly on day 9 and was reduced by alpha-tocopherol supplementation. The ascorbate radical intensity and glomerular TBArs level were higher in PAN-treated than in control rats and were both suppressed to control levels by alpha-tocopherol supplementation. There were positive correlations between ascorbate radical intensity and the daily urinary protein, as well as between ascorbate radical intensity and the glomerular TBArs level. Hence, it is possible to quantify oxidative stress due to PAN nephrosis by ESR. Our findings suggest that lipid peroxidation plays an important role in the pathogenesis of proteinuria in PAN-treated rats.