Clinical features and treatment strategies of febrile urinary tract infection caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae in children: a multicenter retrospective observational study in Japan.

OBJECTIVES: The incidence of infections caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria has increased. This study aimed to clarify the risk factors and treatment strategies for febrile urinary tract infection (fUTI) caused by ESBL-producing bacteria in Japanese children. METHODS: A retrospective observational study was conducted in 21 hospitals among children aged <16 years diagnosed with an fUTI between 2008 and 2017. Clinical data of children with fUTI caused by ESBL-producing and non-ESBL-producing bacteria were compared. RESULTS: Of the 2049 cases of fUTI, 147 (7.2%) were caused by ESBL-producing bacteria. Children in the ESBL group were more likely to have a history of recent antibiotic use or prophylactic antibiotic use, and experience recurrent UTIs (P <0.001) compared with those in the non-ESBL group. Of the 124 cases of fUTI due to ESBL-producing bacteria that were reviewed, 20 and 100 had concordant and discordant antibiotic use, respectively, and four had unknown antibiotic susceptibility. The median time from the start of treatment to fever resolution was 24 hours and did not differ significantly by therapy group (P = 0.39). CONCLUSION: ESBL-producing bacteria should be considered in children with recurrent UTIs and recent antibiotic use. Most children with fUTI experience clinical improvement regardless of the choice of antibiotic.

Frequent fractures and sclerotic thick bands on physes related to oral alendronate treatments.

Bisphosphonate treatment has known effects of improving bone mineral density and preventing fractures in children with steroid-induced osteoporosis. However, there have been reports that high-dosage pamidronate therapy induces osteopetrosis in the borders of bones. A 10-year-old boy undergoing long-term treatment with oral alendronate developed frequent fractures throughout adolescence while playing basketball. Radiographs showed osteosclerotic bands on the metaphyses of his long bones and vertebrae, and fractures were evident in the regions surrounding the osteosclerotic lesions: a stress fracture in the fourth metatarsal, anterior limbus vertebra (T12), spondylolysis (L3 and L5), and osteochondritis dissecans of the left lateral femoral condyle. Alendronate had been taken for a period of 6 years when the treatment was discontinued. Approximately 18 months after discontinuation, sclerotic bands remained evident; however, 4 years after discontinuation, sclerotic banding still surrounded the wing of the ilium but appeared diminished in the knees. In children and adolescents who engage in sports activities and are being treated with steroids and bisphosphonates, the possibility of pathological stress fractures should be considered.

Clinical characteristics of pediatric febrile urinary tract infection in Japan.

BACKGROUND: Febrile urinary tract infection (fUTI) is the most common serious bacterial infection in children. Despite this, there have been no studies examining the clinical features of pediatric fUTI in Japan. The purpose of this study was to describe the clinical characteristics of fUTI in Japanese children. METHODS: A multicenter, retrospective, observational study was conducted at 21 hospitals in Japan. Children under the age of 15 years who were diagnosed with fUTI between 2008 and 2017 were included. The diagnostic criteria were a temperature over 38 °C and the presence of a single bacterial pathogen in urine culture. Patient characteristics were obtained from medical records. RESULTS: In total, 2,049 children were included in the study. The median age was 5 months, and 59.3% were male. It was found that 87.0% of the males and 53.2% of the females were under 1 year of age. The main causative pathogens identified were Escherichia coli and Enterococcus spp., accounting for 76.6% and 9.8% of infections, respectively. CONCLUSIONS: There was a male predominance of fUTI in Japanese children, particularly in infants. Enterococcus spp. were the second most frequent causative pathogen; therefore, Gram staining of urine samples is strongly recommended before initiating antibiotic therapy.

Impaired nephrogenesis in neonatal rats with oxygen-induced retinopathy.

BACKGROUND: Preterm neonates are born while nephrogenesis is ongoing, and are commonly exposed to factors in a hyperoxic environment that can impair renal development. Oxidative stress has also been implicated in the development of retinopathy of prematurity (ROP). The rat model of oxygen-induced retinopathy (OIR) is the most clinically relevant model of ROP because its biologic features closely resemble those of ROP in preterm infants. We investigated impaired renal development in a rat model of OIR. METHODS: Newborn Sprague-Dawley rats were maintained in either a normoxic (room air, 21% O2 ; control group) or a controlled hyperoxic (80% O2 ; OIR group) environment from birth to postnatal day (P) 12. All pups were then raised in room air from P12 to P19. RESULTS: The hyperoxic environment led to significantly higher urinary excretion of 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage, and a reduction in nephrogenic zone width at P5 in OIR pups. Additionally, glomerular count was significantly reduced by 20% in the OIR group, and avascular and neovascular changes in the retina were observed only in the OIR group at P19. Messenger RNA levels of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-ß, essential angiogenic cytokines for glomerulogenesis, in the renal cortex were significantly lower at P5 and significantly higher at P19 in the OIR group compared with controls. CONCLUSION: Renal impairment was caused by exposure to a hyperoxic environment during nephrogenesis, and the pathology of the impaired nephrogenesis in this OIR model reflects the characteristics of ROP observed in preterm infants.

Gradual tapering of desmopressin leads to better outcome in nocturnal enuresis.

BACKGROUND: Although desmopressin therapy is effective in treating polyuric monosymptomatic nocturnal enuresis (MNE), the relatively high rates of recurrence are problematic. To date, the treatment protocol on the discontinuation of oral desmopressin melt (ODM) tablet, MinirinMelt, has not been established. We tested two protocols of tapering ODM when the patients achieved full response on ODM, and compared the treatment outcomes. METHODS: One hundred and fifty-seven polyuric MNE children were newly treated with ODM at the authors' outpatient clinics (Juntendo Nerima Hospital and Musashi-Murayama Hospital). When the patients did not respond to the 8 week ODM therapy, we added another options such as alarm, anti-cholinergics, and imipramine (92 patients; 58.6%). Sixty-five patients (41.4%) achieved full response on ODM alone, and 49 of them accepted gradual tapering of ODM: group B (n = 25), 240 µg ODM per day → 120 µg ODM per day → 120 µg ODM per alternate day → cessation; and group C (n = 24), 240 µg ODM per day → 120 µg ODM per day → 60 µg ODM per day → 60 µg ODM per alternate day → cessation. RESULTS: Fourteen patients in group B (56%) and four in group C (17%) had relapses of enuresis after the discontinuation of ODM (P = 0.026). CONCLUSIONS: Gradual tapering of ODM therapy in MNE patients leads to better outcome.

Traditional Japanese medicine, Yokukansan, for the treatment of nocturnal enuresis in children.

BACKGROUND: The major pathogenic factors involved in nocturnal enuresis are nocturnal polyuria, small bladder capacity and/or detrusor overactivity, and a high arousal threshold. Desmopressin is the first-line therapy for the patients with diuresis-dependent nocturnal enuresis. Yokukansan, a traditional Japanese medicine, has been used in Japan to treat patients with nervousness, insomnia, and children with night terrors and temper tantrums. We experienced the positive effect of Yokukansan in some of the patients who did not respond well to desmopressin therapy. METHODS: In total, 32 children with monosymptomatic nocturnal enuresis with nocturnal polyuria were treated with oral desmopressin melt tablets, which were approved for clinical use in Japan on 29 May 2012. This treatment was effective for 14 of them. For the rest (n = 18), Yokukansan was introduced in combination with desmopressin. RESULTS: Yokukansan was effective for 12 out of the 18 cases. CONCLUSIONS: Yokukansan should be a candidate for the medication of nocturnal enuresis.

[Long-term outcome of children treated with the ISKDC regimen for the first episode of INS].

We retrospectively analyzed the long-term outcome of 82 children (SRNS group, 10; SDNS group, 35; IRNS group, 37) who were initially treated with the ISKDC regimen at the Saitama Children's Medical Center. The ISKDC regimen consisted of PSL 60 mg/m2/day for 4 weeks, followed by 40 mg/m2 on alternate days for another 4 weeks. The aims of our study were to identify factors at onset that could predict the relapse pattern after using the initial ISKDC regimen, and to assess the prognosis and renal histology after long-term CsA therapy in 31 children. All of six asymptomatic children without edema and identified by chance proteinuria on a urinary screening program had an extremely favorable clinical course. Initial remission time of 9 or more days and the time interval from the initial therapy to the first relapse were significant predictors of steroid dependency. The sensitivity and specificity of these findings were 100% and 90%, respectively, with a positive predictive value of 95% and a negative predictive value of 100%. In addition, after the introduction of CsA therapy, termination of steroid therapy was achieved in 56% of patients with SRNS, and 64% of SDNS, respectively. However, after CsA therapy was tapered or stopped, most patients (21/20: 95%) developed relapses of NS. Of these, 76% (16/21) returned to SDNS, resulting in the reintroduction of CsA. Ten of 22 patients taking CsA (mean duration 31.3 months) had chronic nephrotoxicity. In conclusion, the initial ISKDC regimen is useful for the early prediction of whether or not the patient will develop SDNS. When pediatric nephrologists introduce CsA therapy in children with SDNS, an alternative strategy after long-term use of the agent should be considered.

Serum indoxyl sulfate as an early marker for detecting chronic cyclosporine nephrotoxicity.

BACKGROUND: Cyclosporine A (CsA) is an effective agent for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS), but its use can also be complicated by renal toxicity. Because no biochemical markers from urine or blood samples have yet been established for detecting CsA-induced renal injury to date, repeated renal biopsies are therefore required for all patients with long-term CsA treatment. The purpose of the present study was therefore to detect early change of CsA nephropathy (CsAN) using blood samples. METHODS: Several biochemical markers were analyzed in an attempt to examine the renal function in 24 patients with FR-SDNS who had been treated with CsA. Those included serum cystatin C and indoxyl sulfate, as well as creatinine and beta2-microglobulin. RESULTS: Renal biopsy findings indicated chronic CsAN in 13 of the 24 patients. Among those markers, only serum indoxyl sulfate was significantly elevated in patients with CsAN. CONCLUSIONS: It may be possible for measurement of serum indoxyl sulfate level to replace repeated renal biopsies in evaluation of chronic CsAN in pediatric patients with FR-SDNS.

Protective effects of Mizoribine on Cyclosporine A nephropathy in rats.

The therapeutic benefits of Cyclosporine A (CsA) are often limited by the chronic nephrotoxicity of its long-term use. Chronic nephrotoxicity is manifested by renal function impairment and progressive histopathological kidney lesions characterized by tubular vacuolization, tubular necrosis, interstitial fibrosis, and afferent arteriolopathy. This study tested the hypothesis that the concurrent administration of Mizoribine (MZR) may improve chronic CsA nephrotoxicity. Sprague-Dawley male rats were divided into the following four groups: group 1, control (n = 6); group 2, treated with CsA alone (n = 5); group 3, treated with CsA and MZR (n = 4); and group 4, treated with MZR alone (n = 6). The anti-inflammatory and antifibrotic effects of MZR were studied by evaluating the concentrations of the inflammatory mediator, osteopontin, renal function, and histopathology. The interstitial fibrosis was stained blue with Elastica-Massontrichrome and the sections were quantified. The CsA-treated rats showed decreased renal function and increased histologic parameters in comparison with the control rats and also showed significantly increased interstitial fibrosis area and macrophage in comparison with the control rats. The CsA MZR treatment significantly improved the interstitial fibrosis area and macrophage in comparison with the CsA-treated rats. On the basis of these findings, we suggest MZR effectively attenuates renal macrophage accumulation and the progression of interstitial fibrosis.

Maintenance therapy with mycophenolate mofetil for children with severe lupus nephritis after low-dose intravenous cyclophosphamide regimen.

Although recent studies on adults with lupus nephritis indicate that mycophenolate mofetil (MMF) may be effective in maintaining remission for patients who previously received short-term intravenous cyclophosphamide (IVCY) induction therapy, the experience with the new immunosuppressive agent in children with severe lupus nephritis has not been as satisfactory thus far. To assess the efficacy and safety of maintenance therapy with MMF, we prospectively analyzed four patients with biopsy-proven severe lupus nephritis (three girls, one boy; mean age 12 years; two with class IIIA, two with class IVG(A); mean duration of lupus nephritis 7 months) receiving MMF for at least 6 months after induction treatment. These patients had been treated previously with 6 months of low-dose IVCY combined with oral mizoribine and steroids for induction, followed by therapy with MMF adjusted to maintain predose mycophenolic acid (C0-MPA) levels at 2-5 mcg/ml. Mean follow-up after staring MMF was 27.5 months (range 6-41). The mean MMF dose required was 405 +/- 49 mg/m(2) per 12 h, which maintained mean C0-MPA levels of 3.3 +/- 0.41 mcg/ml. No patient experienced renal flares during maintenance therapy with MMF, which permitted a significant reduction in mean prednisolone dose from 11.9 +/- 1.3 to 3.9 +/- 2.6 mg/day (P = 0.003). No significant gastrointestinal or hematologic side effects of MMF were noted. This preliminary study demonstrates that maintenance therapy with MMF after a low-dose IVCY regimen appears to be a promising intervention without adverse effects in children with severe lupus nephritis. These data should be confirmed by a prospective randomized multicenter clinical trial.

Plasma exchange combined with immunosuppressive treatment in a child with rapidly progressive IgA nephropathy.

Although diffuse crescentic formation in immunoglobulin A (IgA) nephropathy, histologically characterized by extensive extracapillary proliferation, is assumed to have a poor prognosis, there has still been no established treatment because of the low prevalence of the condition, especially in pediatric patients. This paper reports on a 5-year-old boy with rapidly progressive IgA nephropathy requiring dialysis for 1 month. He had been treated with plasma exchange (PE) combined with immunosuppressive treatment, including steroids and mizoribine, because renal function deteriorated rapidly despite initial treatment with intravenous methylprednisolone pulse. The histological findings at that time revealed IgA nephropathy, with large circumferential cellular crescent formation in approximately 80% of the glomeruli. Three weeks after PE initiation, serum levels of creatinine and IgA-containing immune complexes returned to normal, and urinary protein excretion gradually decreased. The second renal biopsy taken 7 months later demonstrated mild IgA nephropathy with small fibrocellular crescents. This case report indicates that PE combined with immunosuppressive treatment may benefit children with rapidly progressive IgA nephropathy, even when extensive crescent formations are present.

A prospective study on the use of mycophenolate mofetil in children with cyclosporine-dependent nephrotic syndrome.

Cyclosporine A (CsA) has relieved children with steroid-dependent nephrotic syndrome (NS) from steroid toxicity. However, most patients frequently relapse again when CsA is withdrawn, resulting in the development of CsA nephropathy for its long-term use. In order to assess the efficacy of mycophenolate mofetil (MMF) therapy, we prospectively analyzed 12 children with idiopathic steroid-dependent NS requiring long-term CsA therapy with MMF for at least 6 months. Mean follow-up after starting MMF was 11 months (range 6-42). The mean MMF dose required was 610+/-95 mg/m(2)/12 h, which maintained mean predose mycophenolic acid (C0-MPA) levels of 2.4+/-1.1 mcg/ml. Treatment with MMF resulted in CsA and/or prednisolone (PSL) sparing, with a reduction in mean CsA dose from 3.5+/-1.3 to 1.5+/-2.4 mg/kg/day (p<0.01), and mean PSL dose from 0.29+/-0.16 to 0.21+/-0.11 mg/kg/day (p<0.05). Nine of 12 patients (75%) were finally able to be weaned off CsA. Mean relapse rates decreased from 2.7+/-1.6 to 0.6+/-0.9 episodes/year (p<0.01). Relapse-free ratio on MMF therapy was lower in patients whose average C0-MPA levels were less than 2 mcg/ml (p<0.05). Our experience demonstrates that MMF therapy results in significant CsA and/or steroid sparing and reduction in relapse rates in children with CsA-dependent NS.