Fractional excretion of total protein in patients with nephrotic syndrome.

BACKGROUND: The urine protein to creatinine ratio (UPCR) correlates well with the 24-h urine protein test (24-h UPT) and is a reliable indicator of proteinuria. However, in nephrotic syndrome, the correlation between the UPCR and the 24-h UPT tends to decrease. To address this, we introduced the fractional excretion of total protein (FETP), which reflects serum total protein and creatinine levels because severe hypoproteinemia and/or elevated serum creatinine levels tend to occur under these conditions. The 24-h UPT corrected for body surface area (BSA) (24-h UPT/BSA) was used to take body size into consideration. The correlation coefficients for 24-h UPT/BSA and FETP and 24-h UPT/BSA and UPCR were calculated. The statistical significance of the differences between these coefficients was also calculated. METHODS: Thirty-six pediatric patients with nephrotic syndrome were included in this study. The FETP was calculated as total protein clearance/creatinine clearance (%). Correlation coefficients were calculated for 24-h UPT/BSA and FETP and 24-h UPT/BSA and UPCR. The statistical significance of the differences between these coefficients was also calculated. RESULTS: The mean ± standard error of FETP was 0.11% ± 0.013%. The correlation coefficients of FETP and UPCR with 24-h UPT/BSA were 0.91 and 0.81, respectively. The FETP demonstrated a significantly stronger correlation with 24-h UPT/BSA than with UPCR (p = 0.01). CONCLUSIONS: The FETP correlated more strongly with 24-h UPT/BSA than with UPCR in patients with nephrotic syndrome. The FETP is a reliable indicator of proteinuria in nephrotic syndrome, especially in patients with severe hypoproteinemia or elevated serum creatinine levels.

Survival analysis among pediatric patients receiving kidney replacement therapy: a Japanese nationwide cohort study.

BACKGROUND: Limited data are available on the survival and causes of death in pediatric patients with chronic kidney disease (CKD) stage 5 receiving kidney replacement therapy (KRT) in Asia. METHODS: Data were obtained from the Japanese nationwide cross-sectional CKD stage 5 survey on pediatric patients (<20 years of age) who started KRT from 2006 to 2013. The cohort was divided into three groups according to age at the start of KRT: <1, 1-5, and 6-19 years. RESULTS: Among the 701 children who were included, 59.3% were boys. Peritoneal dialysis was the most common initial modality of KRT (60.3%). Median age at KRT initiation was 10.2 years. Infants (<1 year old) accounted for 16.0% of the total cohort. Overall survival at 1 and 5 years was 97.2% and 92.5%, respectively. Infants had significantly lower survival rates than the other groups (hazard ratio, 5.35; 95% CI, 2.60-11.03; P < 0.001). In contrast, after the age of 1 year, the survival rate improved and did not differ from that of other age groups. The most common causes of death were infection (35.9%) and sudden death (15.4%). CONCLUSIONS: The overall survival rate of pediatric patients with CKD stage 5 in Japan is like that in other high-income countries. Age at initiation of KRT is an important factor affecting survival since the poorest survival rate was observed in infants. Further improvement in infant dialysis therapy is still needed to improve survival of the youngest children. A higher resolution version of the Graphical abstract is available as Supplementary information.

ß2-microglobulin measurement with dried urine spots for congenital anomalies of the kidney and urinary tract screening in 3-year-old children.

BACKGROUND: Screening using dipstick urinalysis has long been performed in 3-year-old children; however, it is ineffective in detecting congenital anomalies of the kidney and urinary tract (CAKUT). Measurement of the urinary ß2-microglobulin (ß2MG)/creatinine (Cr) ratio may be more effective for this purpose. Analysis of dried urine spots (DUS) on filter paper is suitable for mass screening since operational costs are low and samples are easy to collect and transport. We examined the accuracy of measuring the urinary ß2MG/Cr ratio in DUS on filter paper. METHODS: We collected 2,623 urine samples from 3-year-old children. ß2MG and Cr levels were measured in DUS on filter paper. We examined the correlation between the ß2MG/Cr ratios measured in DUS and using the conventional method in 640 samples using the coefficient of determination test. Children with high ß2MG/Cr ratios (>0.6 µg/mg Cr) in DUS samples were further examined to establish a definitive diagnosis. RESULTS: There was strong correlation between the two methods for determination of ß2MG levels (r2 = 0.68; P < 0.001) and ß2MG/Cr ratios (r2 = 0.69; P < 0.001). Of the 2,623 children, 38 (1.45%) had ß2MG/Cr ratios >0.6. Thirty-five children were subsequently examined, resulting in findings of renal hypodysplasia (n = 2, 0.08%), horseshoe kidney (n = 1, 0.04%), renal tubular dysfunction with hepatoblastoma (n = 1, 0.04%), data abnormality (high urine ß2MG level, n = 6, 0.23%; high serum Cr level, n = 1, 0.04%), and normal values (n = 24, 0.91%). CONCLUSIONS: We evaluated a practical method for measuring ß2MG/Cr ratios in DUS as a screening method to detect CAKUT in 3-year-old children.

Clinical characteristics at the renal replacement therapy initiation of Japanese pediatric patients: a nationwide cross-sectional study.

BACKGROUND: Although there is debate regarding the timing of initiation of renal replacement therapy (RRT) in adults with end-stage renal disease, there is a paucity of reliable epidemiological data on pediatric patients. The present study was performed to investigate current practice in Japan with regard to the timing of initiation of RRT in children based on estimated glomerular filtration rate (eGFR). METHODS: A total of 649 pediatric patients < 20 years old with eGFR at the initiation of RRT between 1 January 2006 and 31 December 2013 were included in the study. Baseline eGFR was calculated for each patient using the Schwartz formula. RESULTS: eGFR at the start of RRT was 12.1 mL/min/1.73 m2 [interquartile range (IQR) 8.4-16.3]. A total of 209 children (32.2%) had high eGFR (eGFR > 15 mL/min/1.73 m2) at the initiation of RRT. Initiation of RRT was more likely in those undergoing preemptive transplantation (PEKT) with high eGFR [odds ratio (OR) 4.16; 95% confidence interval (CI) 1.95-8.90, P < 0.001]. There were 31 deaths of various causes during follow-up, with infections representing the leading causes of death. CONCLUSIONS: The median eGFR at the initiation of RRT in children showed a wide range of variation. Further studies are needed to investigate the impact of the decision regarding when to initiate RRT in individual pediatric patients.

Characterization of chylomicron in preterm infants.

BACKGROUND: The aim of this study was to investigate cholesterol and triglyceride levels in the chylomicron fraction of preterm infants at birth and during the early postnatal period. METHODS: The subjects consisted of 133 infants (81 boys and 52 girls): 74 were term infants born at 37-41 weeks of gestation and 59 were preterm infants born at 29-36 weeks of gestation. Cholesterol and triglyceride in the chylomicron fraction were measured using high-performance liquid chromatography. RESULTS: Compared with term infants, preterm infants had higher cholesterol and lower triglyceride in the chylomicron fraction, both in cord blood and at 1 month after birth. Thus, the chylomicron triglyceride/cholesterol ratio was significantly lower in preterm infants than in term infants in cord blood and at 1 month of age. On single regression analysis the chylomicron triglyceride/cholesterol ratio correlated positively with gestational age at birth (r = 0.331, P = 0.0003) and at 1 month (r = 0.221, P = 0.0119). CONCLUSIONS: Preterm infants have a less-lipidated chylomicron composition at birth and at 1 month of age. Some prenatal factors may persist to influence chylomicron lipidation during the early postnatal period.

Unusual presentation of a skull base mass lesion in sarcoidosis mimicking malignant neoplasm: a case report.

BACKGROUND: Sarcoidosis is a multi-organ disease of unknown etiology characterised by the presence of epithelioid granulomas, without caseous necrosis. Systemic sarcoidosis is rare among children, while neurosarcoidosis in children is even rarer whether it is systemic or not. CASE PRESENTATION: We described the case of a 12-year-old boy who presented with monocular vision loss accompanied by unusual MRI features of an extensive meningeal infiltrating mass lesion. The patient underwent surgical resection (biopsy) via a frontotemporal craniotomy to establish a definitive diagnosis based on the histopathology, since neurosarcoidosis remains a very difficult diagnosis to establish from neuroradiogenic imagings. Based on the histopathology of the resected mass lesion, neurosarcoidosis was diagnosed. On follow-up after 3 months of steroid therapy, the patient displayed a good response on the imaging studies. MRI revealed that the preexisting mass lesion had regressed extremely. We also conducted a small literature review on imaging studies, manifestations, appropriate treatments, etc., in particular neurosarcoidosis including children. CONCLUSION: Although extremely rare, neurosarcoidosis, even in children, should be considered in the differential diagnosis of skull base mass lesions to avoid unnecessary aggressive surgery and delay in treatment, since surgery may have little role in the treatment of sarcoidosis.

Frequent isolation of extended-spectrum beta-lactamase-producing bacteria from fecal samples of individuals with severe motor and intellectual disabilities.

Extended-spectrum beta-lactamase (ESBL) producing bacteria spread worldwide and became major concern for antibiotic treatment. Although surveillance reports in general hospitals and long-term care facilities are increasing, their frequencies in individuals with severe motor and intellectual disabilities (SMID) are so far unknown. In this study, we examined the frequency of ESBL in stool samples collected from 146 asymptomatic SMID subjects hospitalized in a single institution. With their clinical information, we evaluated possible risk factors for ESBL colonization. From 146 fecal samples, ESBL-producing bacteria were isolated in 45 cases (31%). Drug sensitivity testing showed that 82% of the isolates were resistant to levofloxacin but were sensitive to tazobactam/piperacillin and cefmetazole. The most frequent genotype was CTX-M-9 detected in 36/45 (80%). A high degree of disability, antibiotic use within three months before sampling and post-tracheostomy were statistically significant risk factors. Tube feeding was also strongly correlated with ESBL colonization (p < 0.001) and associated with lower micro-organismic diversities. Our findings are the first to reveal a high prevalence of ESBL in the fecal samples of SMID individuals and suggest possible relationships between high degree disability, tube feeding and latest histories of antibiotic use.

Cardiac function on 3-D speckle tracking imaging and cytokines in Kawasaki disease.

BACKGROUND: Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) tends to rise in acute phase Kawasaki disease (KD), but the cause of NT-proBNP elevation has not been clarified. In a previous study, cardiac function evaluated on 2-D echocardiography (2D-E) such as ejection fraction was normal, but this does not reflect subtle changes in cardiac dysfunction, and hence the association between cardiac function and NT-proBNP elevation is still controversial. The aim of this study was therefore to elucidate the influence of cardiac function on NT-proBNP elevation, by evaluating cardiac function via strain on 3-D speckle tracking imaging (3D-STI), in acute and subacute KD patients. Given that cytokines are also thought to induce NT-proBNP in acute phase KD, serum cytokines and cytokine receptors were measured at the same time. METHODS: Laboratory data and echocardiography in 52 KD patients in the acute and subacute phases were reviewed. RESULTS: Median NT-proBNP was significantly elevated in the acute phase compared with the subacute phase (356.5 pg/mL; IQR, 145-904 pg/mL vs 103.5 pg/mL; IQR, 59-150 pg/mL, P < 0.01). All cytokines were also significantly elevated in the acute phase compared with the subacute phase. Tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, and sTNFR2 concentration were all significantly higher in the acute phase. Indices of cardiac function were not significant different between phases. NT-proBNP in the acute and subacute phases correlated with sTNFR1 (r = 0.63/0.43, P < 0.01), sTNFR2 (r = 0.50/0.31, P < 0.05), and interleukin-6 (r = 0.58/0.43, P < 0.01). NT-proBNP did not correlate with global longitudinal strain (GLS) on 3D-STI. CONCLUSION: Although no correlation was seen between NT-proBNP and GLS on 3D-STI, correlations between NT-proBNP and cytokines were clear. NT-proBNP might be a marker of inflammation in KD, but is not a marker of cardiac function.

Hypocarnitinemia Observed in an Infant Treated with Short-Term Administration of Antibiotic Containing Pivalic Acid.

Carnitine is a water-soluble amino acid derivative required for ß-oxidation of long-chain fatty acids. In carnitine cycle abnormalities and low carnitine states, fatty acid ß-oxidation is inhibited during fasting, resulting in hypoglycemia. Pivalic acid is a substance used in prodrugs to increase absorption of parent drugs, and antibiotics containing pivalic acid are frequently used as wide spectrum antibiotics for pediatric patients in Japan. Pivalic acid released after absorption is conjugated with free carnitine to form pivaloylcarnitine, which is then excreted in urine. As a consequence, long-term administration of pivalic acid containing antibiotics has been associated with depletion of free carnitine, inhibition of energy production and subsequent hypoglycemia. Here we report a case of a 23-month-old boy treated with an antibiotic containing pivalic acid for 3 days for upper respiratory tract infection. Laboratory data at referral indicated hypoglycemia, decreased free carnitine and elevated five-carbon acylcarnitine. Isomer separation confirmed the major component of increased five-carbon acylcarnitine to be pivaloylcarnitine, thereby excluding the possibility of a genetic metabolic disorder detected with similar acylcarnitine profile. The level of carnitine was normal when the antibiotic was not administered. Our case shows that the use of antibiotics containing pivalic acid in young children requires consideration of hypocarnitinemia, even with short-term administration.

Prediction of Poor Prognosis After Severe Head Injury in Children Using Logistic Regression.

OBJECTIVES: Head trauma is one of the main causes of death in childhood and often leaves severe disability with serious neurological damage. Appropriate treatment must be provided immediately to improve outcomes. This study was performed to identify factors associated with a poor prognosis at an early stage of severe head injury in children. METHODS: The subjects were registered in the Japan Neurotrauma Data Bank. They were 119 children (mean age, 8 years; male, 67.2%) with severe head injury registered during a period of 4 years (from July 1, 2004 to June 30, 2006 and from July 1, 2009 to June 30, 2011). Univariate and multivariate analyses were performed to examine relationships among factors and outcome 6 months after discharge. Logistic regression analysis was performed to develop models for poor prognosis and death. RESULTS: Outcome was evaluated based on the Glasgow Outcome Scale: 73 children (61.3%) had good recovery, 11 (9.2%) had moderate disability, 8 (6.7%) had severe disability, 4 (3.3%) were in a vegetative state, and 23 (19.3%) had died. Four factors were identified as predictors of a poor prognosis: serum glucose level greater than or equal to 200 mg/dL, Glasgow Coma Scale score on admission less than or equal to 5, presence of mydriasis, and presence of traumatic subarachnoid hemorrhage. Three factors were identified as predictors of death: serum glucose level greater than or equal to 200 mg/dL, Glasgow Coma Scale score on admission less than or equal to 5, and presence of mydriasis. CONCLUSIONS: Using these predictors, subsequent exacerbation may be predicted just after arrival at the hospital and appropriate treatment can be provided immediately.

Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients.

Leigh syndrome (LS) is a progressive neurodegenerative disorder of infancy and early childhood. It is clinically diagnosed by typical manifestations and characteristic computed tomography (CT) or magnetic resonance imaging (MRI) studies. Unravelling mitochondrial respiratory chain (MRC) dysfunction behind LS is essential for deeper understanding of the disease, which may lead to the development of new therapies and cure. The aim of this study was to evaluate the clinical validity of various diagnostic tools in confirming MRC disorder in LS and Leigh-like syndrome (LL). The results of enzyme assays, molecular analysis, and cellular oxygen consumption rate (OCR) measurements were examined. Of 106 patients, 41 were biochemically and genetically verified, and 34 had reduced MRC activity but no causative mutations. Seven patients with normal MRC complex activities had mutations in the MT-ATP6 gene. Five further patients with normal activity in MRC were identified with causative mutations. Conversely, 12 out of 60 enzyme assays performed for genetically verified patients returned normal results. No biochemical or genetic background was confirmed for 19 patients. OCR was reduced in ten out of 19 patients with negative enzyme assay results. Inconsistent enzyme assay results between fibroblast and skeletal muscle biopsy samples were observed in 33% of 37 simultaneously analyzed cases. These data suggest that highest diagnostic rate is reached using a combined enzymatic and genetic approach, analyzing more than one type of biological materials where suitable. Microscale oxygraphy detected MRC impairment in 50% cases with no defect in MRC complex activities.

A case of classical maple syrup urine disease that was successfully managed by living donor liver transplantation.

Classical MSUD is often fatal without appropriate medical interventions because of metabolic crisis. There are numerous reports suggesting the therapeutic potential of deceased donor liver transplantation for MSUD. However, the usefulness of LDLT for MSUD is unknown. We report a case of classical MSUD, which was successfully managed by LDLT from the patient's father at 1 year of age. Abnormal brain findings, which were cured with effective treatment, gradually disappeared after LDLT. The patient then developed normally. Findings from this case suggest the importance of LDLT for maintaining low leucine levels and subsequent normal neurological development. Although LDLT involves a modest surgical insult, LDLT with a related donor achieves acceptable leucine levels for life.

Long-term outcome of childhood-onset complicated nephrotic syndrome after a multicenter, double-blind, randomized, placebo-controlled trial of rituximab.

BACKGROUND: Although rituximab effectively prevents relapses of complicated frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS), data of long-term outcomes and safety are limited. METHODS: Fifty-one patients (age, 3-38 years) with childhood-onset complicated FRNS or SDNS, who received rituximab in investigator-initiated multicenter prospective trials were enrolled. Rituximab was administered at 375 mg/m2 once weekly for 4 weeks, and immunosuppressive agents were discontinued according to the study protocol. We investigated relapses, re-administration of immunosuppressive agents, additional rituximab treatment, body height, renal function, and late adverse events during the observation period. RESULTS: Forty-eight patients (94%) developed relapses during the observation period (median, 59 months) and the 50% relapse-free survival was 261 days. Thirty patients (59%) developed SDNS, 44 (86%) required re-administration of immunosuppressive agents, and 22 (43%) received additional rituximab treatment. All patients who were receiving immunosuppressive agents at rituximab treatment required either immunosuppressive agents or additional rituximab treatment. On the contrary, 5 of the 13 patients without immunosuppressive agents at rituximab treatment required neither immunosuppressive agents nor additional rituximab treatment and 3 of them did not develop relapse during observation period. Growth failure due to steroid toxicity did not progress and none of the patients developed chronic renal insufficiency. None of the patients suffered from rituximab-related late adverse events. CONCLUSIONS: As most patients suffer from relapses after B-cell recovery, long-term immunosuppressive agents or additional rituximab treatment is necessary. However, some patients who can discontinue immunosuppressive agents before rituximab treatment may achieve long-term remission after rituximab treatment without immunosuppressive agents.

Nasopharynx is well-suited for core temperature measurement during hypothermia therapy.

BACKGROUND: Rectal temperature is commonly used as the core temperature during therapeutic hypothermia therapy in neonates with hypoxic-ischemic encephalopathy (HIE). The purpose of this study was to examine whether nasopharyngeal temperature could serve as a substitute for rectal temperature. METHODS: We prospectively investigated 40 neonates with HIE who underwent therapeutic hypothermia by selective head cooling, which involved cooling the body to 34°C for 72 h. During this period, nasopharyngeal temperature was measured and compared with rectal temperature every hour. RESULTS: For 40 neonates included in this study, the mean rectal and nasopharyngeal temperatures were 34.3 ± 0.4°C (n = 2920) and 34.3 ± 0.4°C (n = 2920), respectively. Nasopharyngeal temperature strongly correlated with rectal temperature (R2 = 0.623, P < 0.0001) and magnitude of the mean difference between nasopharyngeal and rectal temperature varied little during the 72 h of therapeutic hypothermia. CONCLUSIONS: Nasopharyngeal temperature in neonates with perinatal HIE undergoing therapeutic hypothermia may be a suitable substitute for rectal temperature.

Target value of oxygen saturation during the first 10 min after birth.

BACKGROUND: During neonatal resuscitation, careful oxygenation is needed. Pulse oximetry is recommended to evaluate the need for oxygenation, but it is not clear whether peripheral perfusion is adequate for the evaluation of arterial oxygen saturation (SpO2 ). Additionally, there has been no study on the changes in SpO2 immediately after birth in Japan, despite the indispensable need for definitive oxygenation criteria. METHODS: A prospective observational study was performed in neonates at gestational age 35-41 weeks. An SpO2 measurement probe was attached to the neonates immediately after birth at the right palm or wrist, and the perfusion index (PI), pulse rate, and SpO2 were measured until 10 min after birth. RESULTS: Sixty neonates were examined. Stable PI was obtained soon after birth, preceding SpO2 measurement. The median PI (%) was constant at approximately 1.3, and the median SpO2 at 2-10 min was 70%, 81%, 82%, 87%, 89%, 92%, 92%, 94%, and 95%, respectively. The current target value for SpO2 in the Neonatal Cardiopulmonary Resuscitation (NCPR) guideline in Japan is approximately the 25th percentile. CONCLUSION: PI is stable and sufficient in the early postnatal period, meaning that peripheral perfusion is adequate for the measurement of SpO2 . The current target SpO2 used in the NCPR guidelines is at approximately the 25th percentile and is thought to be sufficient for meeting oxygenation criteria.

Severe Acute Subdural Hemorrhages in a Patient with Glutaric Acidemia Type 1 under Recommended Treatment.

Glutaric acidemia type 1 is a rare autosomal recessive disease caused by a deficiency of glutaryl-CoA dehydrogenase. Previous studies have reported subdural hemorrhage in untreated patients with glutaric acidemia type 1. However, there is only one report of severe acute subdural hemorrhage after minor head trauma in a patient with glutaric acidemia type 1 under guideline-recommended treatment. We report a second case of life-threatening severe acute subdural hemorrhage after a minor head trauma in a patient with glutaric acidemia type 1. This patient was previously diagnosed by newborn screening, and treatment began at 25 days of age. Early diagnosis and guideline-recommended treatment produce better outcomes for patients with glutaric acidemia type 1, although the risk of subdural hemorrhage remains.

Acute Focal Bacterial Nephritis Associated With Central Nervous System Manifestations: A Report of 2 Cases and Review of the Literature.

Acute focal bacterial nephritis (AFBN) is a localized bacterial infection of the kidney presenting as an inflammatory mass without frank abscess formation. In children, most patients with AFBN present with nonspecific conditions, such as fever, vomiting, and abdominal pain. A small number of reported cases are accompanied by neurological symptoms, including meningeal irritation, unconsciousness, and seizures. We experienced 2 rare cases of AFBN associated with central nervous system lesions. The first case was a 3-year-old girl who had neurological symptoms, including unconsciousness and seizures, with AFBN associated with acute reversible encephalopathy. The second case was a 5-year-old girl who had neurological symptoms, including unconsciousness, with AFBN accompanied by clinically mild encephalitis/encephalopathy with a reversible splenial lesion.

Extrapontine myelinolysis associated with severe hypernatremia in infancy.

Extrapontine myelinolysis (EPM) is an uncommon disorder in children, with few pediatric cases reported to date. We report the first case of an infant with EPM without central pontine myelinolysis (CPM) presenting with severe hypernatremia. On admission, the infant had impaired consciousness, mild dehydration, and severe hypernatremia (190 mmol/L). The following day, the patient developed abnormal involuntary movements. Brain magnetic resonance imaging (MRI) confirmed EPM without CPM. He recovered without sequelae, and clinical examinations were within normal limits approximately 6 months after discharge. Brain MRI at 1 year after onset showed complete disappearance of the previous EPM regions. To the best of our knowledge, this represents the youngest patient with EPM without CPM presenting with severe hypernatremia. Given that treatment for osmotic demyelination syndrome (ODS) is yet to be established, preventing the development of ODS is crucial.

Severe hypoglycemic encephalopathy due to hypoallergenic formula in an infant.

A 7-month-old girl was brought to hospital due to vomiting. Upon admission, she was in a convulsive state and stupor with extremely low blood glucose. Head computed tomography showed brain edema, and comprehensive treatment for acute encephalopathy was initiated immediately. Severe hypoglycemia, metabolic acidosis, elevation of ammonia and serum transaminases and creatine kinase suggested metabolic decompensation. Infusion of a high-glucose solution containing vitamins, biotin, and l-carnitine resolved the metabolic crisis quickly, but brain damage was irreversible. She was found to have been fed exclusively on a hypoallergenic formula (HF) for 7 months, although she was found later to be non-allergic. Evidence of inborn metabolic diseases was absent, therefore biotin deficiency and carnitine deficiency were concluded to be a consequence of reliance on a HF for a prolonged period. Health-care professionals should warn parents of the consequences of using HF.