Yoshifusa Abe

Pharmacokinetic study of mizoribine in an adolescent with lupus nephritis

Mizoribine was previously isolated from the soil fungus Eupenicillum brefeldianum and has been shown to be an effective immunosuppressant. 1–6 In many studies, mizoribine has been used at a daily dosage of 2–5 mg/kg or 150–200 mg. 1,4,5 Our patient was given two different total daily dosages of mizoribine. The first total daily dosage was 250 mg and the second was 300 mg. We monitored the serum concentration of mizoribine. Although plasma concentration of mizoribine has been investigated in adult patients with lupus nephritis, 7 to our knowledge there are no reports about monitoring the serum concentration of mizoribine in a pediatric case of lupus nephritis.

Urinary leukotriene E4 in Henoch-Schonlein purpura.

Background Children with Henoch–Schonlein purpura (HSP) occasionally have allergic disease. We have previously shown that pranlukast hydrate was effective for purpura in HSP. Pranlukast hydrate is a leukotriene (LT) receptor antagonist; therefore, it is likely that LTs take part in the cause of HSP. Urinary leukotriene E4 (LTE4u) levels are a useful index of whole‐body cysteinyl LT production in vivo. In this study, LTE4u was examined in children with HSP.

Juvenile amyopathic dermatomyositis complicated by progressive interstitial pneumonia.

ACT may be the expression of an inborn error of metabolism with the features of an endoplasmic reticulum storage disease, such as seen in PiZZ AAT patients. In fact the pathological features of both deficiencies are very much alike. In the present case the presence of micronodular cirrhosis with PAS-positive diastase-resistant coarse globules in the hepatocytes, led initially to a misdiagnosis of cirrhosis associated with AAT deficiency. Nevertheless, immunohistochemistry showed no AAT immunoreactivity in the hepatocytes, but plasma level of AAT within normal limits. In contrast, although the plasma level was not measured, because the biochemical method was not available, immunohistochemistry with ACT antisera showed the intense reactivity, in the cytoplasmic granules of hepatocytes to be ACT. Ultrastructure could not be investigated but the presence of fluffy material in the dilated endoplasmic reticulum has been reported. The occurrence of cirrhosis in AAT and ACT deficiency could be explained by the fact that the hepatocytes are not capable of degrading the polymerized protein or by an increased synthesis of serpins, as might occur in some infections. In addition, the conformational instability can be accelerated by an increase in temperature as seen in AAT deficiency. We think that ACT deficiency was the cause of the cirrhosis in the present patient because the pathological features are consistent with this etiology, and because other causes have been ruled out on serologic and morphologic grounds. The patient, and his family, returned to Venezuela and has been lost to follow up so, no further studies could be done. It can be advocated that in children with chronic liver disease of unknown etiology, ACT plasma measurement or immunohistochemistry, with ACT antisera, on biopsy material must be performed for the diagnosis of ACT deficiency, especially in areas of high prevalence of this disorder. References

Validation of Cefazolin as Initial Antibiotic for First Upper Urinary Tract Infection in Children

To validate the policy of administering cefazolin (CEZ) as a first-line antibiotic to children who are hospitalized with their first febrile urinary tract infection (UTI), we evaluated microbial susceptibility to CEZ and the efficacy of CEZ. The 75 enrolled children with febrile UTI were initially treated with CEZ. Switching CEZ was not required in 84% of the patients. The median fever duration, prevalence of bacteremia, prevalence of UTI caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli, and median duration of hospitalization were significantly higher in the CEZ-ineffective group. The risks of vesicoureteral reflux, indication of operation, and renal scarring are not increased, even when CEZ is ineffective as a first-line antibiotic. CEZ is effective in more than 80% of pediatric patients with their first febrile UTI, but it should be switched to appropriate antibiotics considering sepsis or the ESBL-producing Enterobacteriaceae pathogen, when fever does not improve within 72 hours.

Mizoribine requires individual dosing due to variation of bioavailability.

Mizoribine (MZR) is an immunosuppressant used for the treatment of glomerular diseases, but there are few reports on the pharmacokinetics of MZR in children.

Pharmacokinetic study of mizoribine in child‐onset glomerulonephritis

Background: Mizoribine (MZR) has been successfully used without serious adverse effects in patients with various types of glomerulonephritis, but there are only a few pharmacokinetic studies of MZR. The purpose of the present paper was to report the results of a pharmacokinetic study of MZR in child‐onset glomerulonephritis.

Post-streptococcal acute glomerulonephritis associated with pneumococcal infection.

Streptococcus pyogenes is the most common cause of post‐infectious glomerulonephritis. Described herein is the case of a 5‐year‐old girl with febrile post‐streptococcal acute glomerulonephritis (PSAGN) associated with pneumococcal bacteremia. The chief complaints were fever and macrohematuria without respiratory symptoms. Urinalysis indicated a protein level of 3+. Serological data showed elevated anti‐streptolysin O (ASO) and hypocomplementemia. Blood culture was positive for S. pneumoniae. Her acute renal failure was mild and improved over several days. Although PSAGN was confirmed by elevated ASO and transient hypocomplementemia, the clinical course was consistent with those of several reported cases of AGN associated with pneumococcal infection. To our knowledge, there have been few reports on the relationship between pneumococcal infection and the incidence of PSAGN. We suggest the hypothesis that pneumococcal infection itself could exaggerate the complement reaction leading to PSAGN. It is important to consider PSAGN associated with a microbial infection such as S. pneumoniae when faced with a febrile patient with AGN.

Case of insertion, inversion and deletion of chromosome 6

The infant boy involved in the present study was the only child born to Japanese healthy unrelated parents. The pregnancy was complicated by breech presentation, oligohydramnios and intrauterine growth retardation (IUGR). He had a left-sided hydronephrosis in his mother’s uterine. His mother took traditional Chinese medicine (Toki-inshi and Daio-kanzo-to) and oxatomide because of atopic dermatitis. At the 39th week of pregnancy, he was delivered by cesarean section because of fetal distress. His birthweight was 2592 g and his body length was 48.5 cm. Apgar scores were nine and 10 at 1 and 5 min, respectively. The infant required oxygen therapy for 13 days because of dyspnea. During the clinical course, the following manifestations were observed: developmental delay; hypotonia; auricular fistula; failure to thrive; hypertelorism; patent foramen ovale (PFO); patent ductus arteriosus (PDA); cleft lip; cleft palate; left hydronephrosis; sensorineural deafness; hyperuricemia; overlapping in the lower legs; bell-shaped thorax and dyspnea. He had recurrent episodes of respiratory tract infections with dyspnea. Patent foramen ovale and PDA were shown by echocardiogram. Left-sided hydronephrosis was shown by magnetic resonance imaging at the age of 5 months. According to the auditory brainstem response he had a sensorineural deafness. At the age of 5 months, he was admitted to our hospital for a cleft lip operation. However, the operation was postponed because he had an upper respiratory infection, which was treated with antibiotics and discharged once recovered. At the age of 7 months, he underwent a cleft lip operation. His bodyweight was 6590 g (–2.1 SD) and his body length was 66.0 cm (–1.5 SD). At the age of 8 months, he was admitted to our hospital for pneumonia and bronchial asthma. He was treated with theophylline for bronchial asthma. After 14 days of treatment, his uric acid became higher than 10 mg/dL. He was given allopurinol initially, with a dose of 20 mg daily and thereafter in doses of 40 mg daily. We also used sodium bicarbonate for his hyperuricemia. After 61 days of this treatment, his hyperuricemia improved. At the age of 11 months, his bodyweight was 6040 g (–3.3 SD) and body length was 66.4 cm (–3.1 SD). Anterior fontanel was 3.5 × 3.0 cm. Patellar tendon reflex was brisker than average. Scarf sign, head lag and loose shoulder were all positive. He could not achieve head control and he could not sit. He was discharged after recovery from pneumonia and bronchial asthma.

AICAR Attenuates TNFα-Induced Inappropriate Secretion of Monocyte Chemoattractant Protein-1 and Adiponectin in 3T3-L1 Adipocytes.

Aim: The increase in monocyte chemoattractant protein-1 (MCP-1) and the decrease in adiponectin production from hypertrophic adipocytes are associated with adipose tissue inflammation and its metabolic complications. The aim of this study was to determine whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an adenosine monophosphate-activated protein kinase (AMPK) activator, modulates these adipocytokine productions in tumor necrosis factor-α (TNFα)-treated adipocytes. Methods: AICAR and/or other reagents were added to the culture medium, and then, TNFα was added to fully differentiated 3T3-L1 adipocytes. The MCP-1 and adiponectin production in the culture supernatant was measured by ELISA. AMPK, phosphatidylinositol 3-kinase (PI3K), and nuclear factor-κB (NF-κB) activities were also assayed. Results: Treatment with TNFα increased MCP-1 and decreased adiponectin secretion dose-dependently in the 3T3-L1 adipocytes, and AICAR significantly inhibited these TNFα-mediated changes. Interestingly, metformin, another AMPK activator, did not have such effects on these adipocytokines. Both the AMPK and PI3K systems in the cells were significantly activated by the AICAR treatment, but the effects of AICAR on adipocytokines were not weakened by the addition of dorsomorphin, an AMPK inhibitor, or LY294002, a PI3K inhibitor. Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, showed protective effects similar to those as AICAR. AICAR, but not metformin, significantly inhibited the TNFα-stimulated activation of NF-κB, and dorsomorphin did not change AICARs effect. Conclusion: AICAR attenuates the TNFα-induced secretion of MCP-1 and adiponectin in 3T3-L1 adipocytes. The observed effects of AICAR seem to be mainly due to the inhibition of NF-κB activation rather than the activation of the AMPK pathway, at least in TNFα-treated adipocytes.

Renal function in angiotensinogen gene-mutated renal tubular dysgenesis with glomerular cysts

BackgroundInherited renal tubular dysgenesis (RTD) is caused by mutations in the genes encoding the components of the renin–angiotensin system (RAS). RTD is characterized by oligohydramnios, renal failure, neonatal hypocalvaria, and severe hypotension. The histological characteristics, underlying mechanism, and long-term prognosis remain poorly known.Case-diagnosis/treatmentWe describe here a 4-year-old female with RTD. Endocrinologic analysis showed a discrepancy between low plasma renin activity and high active renin concentration, suggesting a loss of the renin substrate, angiotensinogen (AGT). Direct sequencing revealed a frameshift deletion at nucleotide 1,355 in exon 5 in the AGT gene. Although a histological hallmark is regarded to be the absence or poor development of the proximal tubule, the patient does have minimally impaired function of the proximal tubule. Glomerular cysts without glomerular tufts were noted in approximately half of the glomeruli. The urinary concentrating ability and sodium reabsorption and potassium excretion in the distal nephron were severely affected.ConclusionsThe patient has an impaired function of the distal nephron despite minimally affected function of the proximal tubule, probably attributed to renal tubular dysgenesis and fetal hypoperfusion. The renal tubular maturity and the severity of ischemic injury may be key determinants of the clinical symptoms and pathological findings in RTD, in which the RAS plays an important role.