RESUMO
Biomarkers that accurately reflect renal function are essential in management of chronic kidney diseases (CKD). However, in children, age/physique and medication often alter established renal biomarkers. We studied whether amino acid enantiomers in body fluids correlate with renal function and whether they are influenced by physique or steroid medication during development. We conducted a prospective study of children 2 to 18 years old with and without CKD. We analyzed associations of serine/asparagine enantiomers in body fluids with major biochemical parameters as well as physique. To study consequences of kidney dysfunction and steroids on serine/asparagine enantiomers, we generated juvenile mice with uninephrectomy, ischemic reperfusion injury, or dexamethasone treatment. We obtained samples from 27 children, of which 12 had CKD due to congenital (n = 7) and perinatal (n = 5) causes. Plasma D-asparagine and the D/L-serine ratio had robust, positive linear associations with serum creatinine and cystatin C, and detected CKD with high sensitivity and specificity, uninfluenced by body size or biochemical parameters. In the animal study, kidney dysfunction increased plasma D-asparagine and the D/L-serine ratio, but dexamethasone treatment did not. Thus, plasma D-asparagine and the D/L-serine ratio can be useful markers for renal function in children.
Assuntos
Asparagina , Biomarcadores , Insuficiência Renal Crônica , Serina , Criança , Animais , Humanos , Asparagina/sangue , Asparagina/metabolismo , Insuficiência Renal Crônica/sangue , Pré-Escolar , Serina/sangue , Camundongos , Masculino , Feminino , Adolescente , Biomarcadores/sangue , Estudos Prospectivos , Dexametasona , Estereoisomerismo , Creatinina/sangue , Rim/metabolismoRESUMO
Although the clinical efficacy of tofacitinib has been reported in adult patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (Ab+) dermatomyositis, data on its use in refractory juvenile dermatomyositis (JDM) are scarce. We describe two female Japanese patients with anti-MDA5 Ab + JDM and rapidly progressive interstitial lung disease who achieved remission by adding tofacitinib to existing immunosuppressive drugs and present a literature review. While both patients received various immunosuppressive or anti-inflammatory treatments for induction therapy, remission could not be achieved. Subsequently, tofacitinib was administered to reduce the Krebs von den Lungen-6 level 5 months after diagnosis in one patient; the other patient received tofacitinib 4 months after diagnosis to reduce ferritin levels and skin manifestations. Subsequently, both patients achieved remission, and prednisolone was withdrawn. Tofacitinib reduced the interferon signature associated with dermatomyositis/JDM disease progression and exerted a therapeutic effect on dermatomyositis/JDM. We found six published cases from five articles of tofacitinib for refractory anti-MDA5 Ab + JDM. Except for one case of herpes simplex meningitis, the other cases, including ours, had improved disease activity without severe adverse events, and steroids and immunosuppressive medicines could be tapered. Tofacitinib could be considered an available therapy for refractory anti-MDA5 Ab + JDM.
Assuntos
Dermatomiosite , Helicase IFIH1 Induzida por Interferon , Piperidinas , Pirimidinas , Humanos , Dermatomiosite/tratamento farmacológico , Dermatomiosite/imunologia , Feminino , Helicase IFIH1 Induzida por Interferon/imunologia , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Autoanticorpos , Resultado do Tratamento , Criança , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Mammals exhibit systemic homochirality of amino acids in L-configurations. While ribosomal protein synthesis requires rigorous chiral selection for L-amino acids, both endogenous and microbial enzymes convert diverse L-amino acids to D-configurations in mammals. However, it is not clear how mammals manage such diverse D-enantiomers. Here, we show that mammals sustain systemic stereo dominance of L-amino acids through both enzymatic degradation and excretion of D-amino acids. Multidimensional high performance liquidchromatography analyses revealed that in blood, humans and mice maintain D-amino acids at less than several percent of the corresponding L-enantiomers, while D-amino acids comprise ten to fifty percent of the L-enantiomers in urine and feces. Germ-free experiments showed that vast majority of D-amino acids, except for D-serine, detected in mice are of microbial origin. Experiments involving mice that lack enzymatic activity to catabolize D-amino acids showed that catabolism is central to the elimination of diverse microbial D-amino acids, whereas excretion into urine is of minor importance under physiological conditions. Such active regulation of amino acid homochirality depends on maternal catabolism during the prenatal period, which switches developmentally to juvenile catabolism along with the growth of symbiotic microbes after birth. Thus, microbial symbiosis largely disturbs homochirality of amino acids in mice, whereas active host catabolism of microbial D-amino acids maintains systemic predominance of L-amino acids. Our findings provide fundamental insight into how the chiral balance of amino acids is governed in mammals and further expand the understanding of interdomain molecular homeostasis in host-microbial symbiosis.
Assuntos
Aminoácidos , Simbiose , Humanos , Animais , Camundongos , Aminoácidos/química , Serina , Biossíntese de Proteínas , Estereoisomerismo , MamíferosRESUMO
d-Serine modulates excitatory neurotransmission by binding to N-methyl-d-aspartate glutamate receptors. d-Amino acid oxidase (DAO) degrades d-amino acids, such as d-serine, in the central nervous system, and is associated with neurological and psychiatric disorders. However, cell types that express brain DAO remain controversial, and whether brain DAO influences systemic d-amino acids in addition to brain d-serine remains unclear. Here, we created astrocyte-specific DAO-conditional knockout mice. Knockout in glial fibrillary acidic protein-positive cells eliminated DAO expression in the hindbrain and increased d-serine levels significantly in the cerebellum. Brain DAO did not influence levels of d-amino acids in the forebrain or periphery. These results show that astrocytic DAO regulates d-serine specifically in the hindbrain.
Assuntos
D-Aminoácido Oxidase , Serina , Animais , Camundongos , Serina/metabolismo , D-Aminoácido Oxidase/genética , D-Aminoácido Oxidase/metabolismo , Astrócitos/metabolismo , Camundongos Knockout , Aminoácidos , Cerebelo/metabolismoRESUMO
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.
RESUMO
BACKGROUND: Congenital obstructive nephropathy (CKD) is commonly implicated in the pathophysiology of chronic kidney disease occurring in the pediatric and adolescent age groups and the release of reactive oxygen species contribute to the worsening of renal fibrosis. Molecular hydrogen (H2) protects against tissue injury by reducing oxidative stress. We evaluated the efficacy of oral H2-rich water (HW) intake in preventing unilateral ureteral obstruction (UUO)-induced renal injury in rats. METHODS: Male Sprague-Dawley UUO or control rats were administered with distilled water (DW) or HW for 2 weeks post-surgery. Histopathological and immunohistochemical analyses of kidney samples were performed. RESULTS: Histological changes were not apparent in the sham-operated kidneys. However, UUO kidneys were found to have widened interstitial spaces and tubular dilatation. Compared with the UUO + DW group, HW administration attenuated tubulointerstitial injury and reduced interstitial fibrotic area, causing a substantial decline in the frequency of α-SMA-, ED-1-, and TGF-ß1-positive cells in the UUO + HW group. The decrease in the klotho mRNA expression in the UUO + HW group was less pronounced than that in the UUO + DW group. CONCLUSION: Oral HW intake reduced oxidative stress and prevented interstitial fibrosis in UUO kidneys, potentially involving klotho in the underlying mechanism. IMPACT: Oral intake of hydrogen-rich water (HW) can reduce oxidative stress and suppress interstitial fibrosis in unilateral ureteral obstruction-induced renal injury in rats. This mechanism possibly involves klotho, which is known for its antiaging roles. The association between molecular hydrogen and klotho in renal fibrosis is well known; this is the first report on the association in a unilateral ureteral obstruction model. Drinking HW is a safe and convenient treatment for oxidative stress-induced pathologies, without side effects. As a prospect for future research, oral HW intake to treat oxidative stress may improve renal fibrosis in congenital obstructive nephropathy.
Assuntos
Nefropatias , Insuficiência Renal Crônica , Obstrução Ureteral , Adolescente , Animais , Fibrose , Humanos , Hidrogênio/metabolismo , Hidrogênio/farmacologia , Hidrogênio/uso terapêutico , Rim/metabolismo , Nefropatias/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , ÁguaRESUMO
Objectives: This study aimed to investigate the protective effects of hydrogen-rich water (HW) intake on renal injury in neonatal rats with high oxygen loading. Materials: We used pregnant and newborn Sprague-Dawley rats. Methods: Four groups were set up, with mother and newborn rats immediately after delivery as one group: RA-PW (room air and purified water), RA-HW (room air and HW), O2-PW (80% oxygen and purified water), and O2-HW (80% oxygen and HW). The newborn rats were maintained in either a normoxic (room air, 21% oxygen) or controlled hyperoxic (80% oxygen) environment from birth. Then, HW (O2-HW and RA-HW groups) or PW (O2-PW and RA-PW groups) was administered to parents of each group. Results: The number of immature glomeruli significantly increased in the O2-PW group (exposed to hyperoxia). Conversely, the O2-HW group had significantly fewer immature glomeruli than O2-PW group. In the RT-PCR analysis of kidney tissue, α-SMA, TGF-ß, and TNF-α levels were significantly higher in the O2-PW group than in the RA-PW group and significantly lower in the O2-HW group than in the O2-PW group. Conclusions: HW intake can potentially reduce oxidative stress and prevent renal injury in neonates with high oxygen loading.
RESUMO
Biallelic pathogenic variants in the laminin ß2 (LAMB2) gene, which encodes laminin ß2, are associated with Pierson syndrome characterized by a congenital nephrotic syndrome that rapidly progresses to end-stage renal disease, distinct ocular maldevelopment with bilateral microcoria, and neurodevelopmental deficits. However, the phenotypic spectrum of LAMB2-associated disorder is broader than expected, and cases with milder phenotypes such as isolated congenital or infantile nephrotic syndrome have also been reported. We report a patient with LAMB2-associated renal disorder showing an extremely mild phenotype. A 5-year-old girl presented with asymptomatic proteinuria and hematuria detected by urinalysis screening. She had been previously healthy without any additional renal symptoms. The serum albumin and creatinine levels were normal. Renal biopsy revealed minor glomerular abnormalities with occasional focal mesangial proliferation. Electron microscopy showed no structural changes in the glomerular basement membrane. Targeted sequencing of podocyte-related genes using next-generation sequencing was performed. As a result, previously reported biallelic pathogenic variants of the truncating variant (c.5073_5076dupCCAG) and a splice site variant (c.3797 + 5G > A) in the LAMB2 gene were detected, and the patient was diagnosed with LAMB2-associated renal disorder. Interestingly, a previously reported case with this splicing variant also showed an atypically mild phenotype. We suggest that clinicians should consider LAMB2-associated nephritis as an important differential diagnosis in children with asymptomatic proteinuria and microscopic hematuria if there is no structural change in the glomerular basement membrane. A comprehensive gene-screening system using next-generation sequencing is useful for diagnosing these atypical cases with isolated urine abnormalities.
Assuntos
Laminina/genética , Nefrite/diagnóstico , Criança , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger known as anion exchanger 1, have been reported as the sole genetic cause of autosomal dominant distal renal tubular acidosis (dRTA). This disorder is extremely rare and most patients show no clinical symptoms during childhood. Here, we report a case of an infant with early-onset autosomal dominant dRTA caused by SLC4A1 mutation p.Gly609Arg that is detected as a hot spot world widely. Despite the fact that the patient's mother and sister had the same SLC4A1 mutation, all family members presented different clinical courses. A 9-month-old boy was referred to our hospital because of insufficient body weight gain. At the initial visit, his height and weight were 68.2 cm (-1.0 SD) and 6.4 kg (-2.2SD) respectively. Metabolic acidosis with a normal serum anion gap and inappropriate alkaline urine were detected. Abdominal ultrasound indicated bilateral renal medullary high-echoic lesions which suspected nephrocalcinosis. The genetic test revealed a heterozygous mutation c.1825G > A (p.Gly609Arg) in SLC4A1 that directed his diagnosis of autosomal dominant dRTA. The genetic test was performed on the patient's family members, indicating that the same SLC4A1 mutation was detected in his mother and sister. His mother had nephrocalcinosis and metabolic acidosis at the age of 35 years. However, his sister had no clinical symptoms at the age of 6 years without any laboratory abnormalities. This familial case demonstrated that the significant heterogeneity in clinical manifestations may develop even among familial members sharing the same variant.
Assuntos
Acidose Tubular Renal/genética , Acidose/genética , Proteína 1 de Troca de Ânion do Eritrócito/genética , Nefrocalcinose/genética , Acidose/diagnóstico , Acidose/etiologia , Acidose Tubular Renal/diagnóstico , Acidose Tubular Renal/metabolismo , Adulto , Proteína 1 de Troca de Ânion do Eritrócito/sangue , Povo Asiático/etnologia , Criança , Antiportadores de Cloreto-Bicarbonato/genética , Família , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Mutação , Nefrocalcinose/diagnóstico , Nefrocalcinose/etiologia , Ultrassonografia/métodosAssuntos
Enurese Noturna/terapia , Fototerapia/métodos , Criança , Feminino , Humanos , Fototerapia/instrumentaçãoRESUMO
AIM: We examined the associations between late preterm (LPT) birth children aged ≥5 years and the frequency of bedwetting. Moreover, those who were born full-term/low birthweight (BW), LPT/low BW, LPT/normal BW and LPT/low BW were compared. METHODS: In total, we evaluated 614 patients who underwent assessments for frequent bedwetting at the three hospitals from January 2014 to December 2016. Data at the initial visit were collected from the electronic medical records. We assessed the patients' bladder diaries and questionnaires containing detailed information on demographics and frequency of bedwetting per month. Neonatal data were collected from the Maternal and Child Health Handbook. RESULTS: Frequency of bedwetting in the LPT/low BW group was higher than in the term/low BW group (28 vs. 22.5, p < 0.05). However, the frequency between the LPT/normal BW group and the LPT/low BW group was not significantly different (28 vs. 28, p = 1.00). Multiple regression analyses were conducted to eliminate potential confounding factors, attention-deficit/hyperactivity disorder and intellectual disability, but results were not changed. CONCLUSION: This study revealed that LPT/low BW was associated with increased frequency of bedwetting in children. The results suggest that gestational age should be considered when examining patients with severe bedwetting.
Assuntos
Peso ao Nascer , Enurese Noturna/epidemiologia , Nascimento Prematuro , Criança , Feminino , Humanos , Japão/epidemiologia , Masculino , Estudos RetrospectivosAssuntos
Enurese Noturna/fisiopatologia , Sono/fisiologia , Criança , Humanos , Enurese Noturna/terapiaRESUMO
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.
Assuntos
Fatores Imunológicos/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Rituximab/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Fatores Imunológicos/efeitos adversos , Imunossupressores/administração & dosagem , Masculino , Síndrome Nefrótica/complicações , Estudos Prospectivos , Recidiva , Estudos Retrospectivos , Rituximab/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Desmopressin is a synthetic V2 specific analogue of antidiuretic hormone (arginine vasopressin) that is widely used as first line treatment for monosymptomatic nocturnal enuresis. However, no biomarkers to predict desmopressin effectiveness have yet been established. Because arginine vasopressin is unstable, we prospectively measured the major urine concentration factor aquaporin 2 and serum copeptin (as a surrogate marker for vasopressin) in patients with monosymptomatic nocturnal enuresis, and evaluated whether they are useful for predicting desmopressin treatment outcome. MATERIALS AND METHODS: The study included 32 children 6 to 11 years old with monosymptomatic nocturnal enuresis and nocturnal polyuria. Exclusion criteria were daytime urinary symptoms and underlying diseases causing nocturnal enuresis. Subjects were treated with 120 µg or 240 µg desmopressin oral disintegrating tablet and were divided into responders (at 120 or 240 µg) and nonresponders (at 240 µg). Day/night ratios of plasma copeptin and urinary aquaporin 2 were measured during desmopressin treatment. RESULTS: There was no significant difference in baseline day/night ratio of urinary aquaporin 2 between desmopressin responders and nonresponders. After 8 weeks of treatment there was a significant correlation between day/night ratio of aquaporin 2 and percentage of wet nights. In responders (but not nonresponders) there was a significant difference in the change in aquaporin 2 day/night ratio from before treatment to complete remission (p = 0.0004). For plasma copeptin the baseline day/night ratio for responders at 120 µg was significantly lower than in the 240 µg nonresponder group (p = 0.02). CONCLUSIONS: Urinary aquaporin 2 appears to be a biomarker of desmopressin treatment effectiveness during therapy, while plasma copeptin levels before treatment are predictive of desmopressin response.
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Antidiuréticos/uso terapêutico , Aquaporina 2/urina , Desamino Arginina Vasopressina/uso terapêutico , Glicopeptídeos/sangue , Enurese Noturna/tratamento farmacológico , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Criança , Feminino , Humanos , Masculino , Enurese Noturna/sangue , Enurese Noturna/urina , Valor Preditivo dos Testes , Estudos Prospectivos , Recidiva , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Antidiuréticos/uso terapêutico , Alarmes Clínicos , Desamino Arginina Vasopressina/uso terapêutico , Enurese Noturna/terapia , Succinato de Solifenacina/uso terapêutico , Criança , Terapia Combinada , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Resultado do TratamentoRESUMO
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.
Assuntos
Hiperóxia/complicações , Rim/crescimento & desenvolvimento , Insuficiência Renal/etiologia , Retinopatia da Prematuridade/fisiopatologia , Animais , Animais Recém-Nascidos , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Retinopatia da Prematuridade/etiologia , Fatores de RiscoRESUMO
BACKGROUND: Although the evidence-based treatment for nocturnal enuresis is established, nearly one-third of patients are still enuretic with desmopressin, anti-cholinergic treatment and alarm. The fourth option, imipramine, is limited because of the risk of cardiotoxicity on overdose. Clonidine, an α2 -adrenoceptor agonist that also has noradrenergic effects like imipramine, is a new option for refractory enuresis. METHODS: A total of 148 patients (6-14 years of age; mean, 9.1 years) with refractory enuresis under desmopressin, anti-cholinergic treatment and alarm were enrolled. The patients consisted of 100 boys and 48 girls, of whom 23 had monosymptomatic nocturnal enuresis and 125 had non-monosymptomatic nocturnal enuresis. Clonidine 4 µg/kg/day (maximum, 75 µg/day) orally 30 min before bedtime was added and its effects were evaluated after 4 weeks of treatment. RESULTS: A total of 83 patients (56.1%) achieved partial or complete response with the additional clonidine. No significant adverse reactions were noted. CONCLUSIONS: Clonidine could be an aid for refractory enuresis, although further randomized controlled trials are needed.
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Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Clonidina/uso terapêutico , Enurese Noturna/tratamento farmacológico , Administração Oral , Adolescente , Criança , Esquema de Medicação , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Recent studies have shown that incontinence and attention-deficit/hyperactivity disorder (ADHD) coexist and there is an interaction between them. The treatment for nocturnal enuresis (NE) and ADHD, however, has not been established. METHODS: At the first visit to the outpatient clinic, physical examination and history taking were carried out in 265 new patients with NE. After excluding the possibility of comorbid ADHD and related disorders, patients with monosymptomatic NE (MNE) were treated with desmopressin and/or alarm, and those with non-monosymptomatic NE (NMNE) were treated with anti-cholinergics and/or alarm. This 12 week treatment did not work in 65 patients, and they were re-assessed for comorbid ADHD. A total of 24 were diagnosed with ADHD, and they were treated with atomoxetine (1.8 mg/kg/day) in addition to ongoing therapy for NE. RESULTS: After 8 weeks of atomoxetine, the average wet nights per months was significantly decreased: 18.5-4.6 in the MNE group (P = 0.001), and 22.1-12.4 in the NMNE group (P = 0.0251). Overall, atomoxetine was beneficial in 19 of 24 patients. CONCLUSIONS: Atomoxetine may be a suitable option for refractory NE with comorbid ADHD.