RESUMO
BACKGROUND: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. METHODS: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. RESULTS: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. CONCLUSION: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.
Assuntos
DNA Mitocondrial/genética , Síndrome de Gitelman/genética , Mutação , Adolescente , Adulto , Idoso , Sequência de Bases , Criança , Pré-Escolar , Feminino , Genótipo , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/patologia , Células HEK293 , Humanos , Lactente , Rim/metabolismo , Rim/ultraestrutura , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Modelos Biológicos , Conformação de Ácido Nucleico , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA de Transferência de Isoleucina/química , RNA de Transferência de Isoleucina/genética , RNA de Transferência de Fenilalanina/química , RNA de Transferência de Fenilalanina/genética , Membro 3 da Família 12 de Carreador de Soluto/genética , Adulto JovemRESUMO
BACKGROUND: Children presenting with proliferative lupus nephritis (LN) are treated with intensified immunosuppressive protocols. Data on renal outcome and treatment toxicity is scare. METHODS: Twelve-month renal outcome and comorbidity were assessed in 79 predominantly Caucasian children with proliferative LN reported to the Lupus Nephritis Registry of the German Society of Paediatric Nephrology diagnosed between 1997 and 2015. RESULTS: At the time of diagnosis, median age was 13.7 (interquartile range 11.8-15.8) years; 86% showed WHO histology class IV, nephrotic range proteinuria was noted in 55%, and median estimated glomerular filtration rate amounted to 75 ml/min/1.73 m2. At 12 months, the percentage of patients with complete and partial remission was 38% and 41%, respectively. Six percent of patients were non-responders and 15% presented with renal flare. Nephrotic range proteinuria at the time of diagnosis was associated with inferior renal outcome (odds ratio 5.34, 95% confidence interval 1.26-22.62, p = 0.02), whereas all other variables including mode of immune-suppressive treatment (e.g., induction treatment with cyclophosphamide (IVCYC) versus mycophenolate mofetil (MMF)) were not significant correlates. Complications were reported in 80% of patients including glucocorticoid toxicity in 42% (Cushingoid appearance, striae distensae, cataract, or osteonecrosis), leukopenia in 37%, infection in 23%, and menstrual disorder in 20%. Growth impairment, more pronounced in boys than girls, was noted in 78% of patients. CONCLUSIONS: In this cohort of juvenile proliferative LN, renal outcome at 12 months was good irrespectively if patients received induction treatment with MMF or IVCYC, but glucocorticoid toxicity was very high underscoring the need for corticoid sparing protocols. Graphical abstract.
Assuntos
Ciclofosfamida/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Imunossupressores/administração & dosagem , Nefrite Lúpica/tratamento farmacológico , Ácido Micofenólico/administração & dosagem , Adolescente , Criança , Ciclofosfamida/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Feminino , Alemanha , Glucocorticoides/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Masculino , Ácido Micofenólico/efeitos adversos , Estudos Prospectivos , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
There are two forms of diabetes insipidus, central (neurohypophyseal), and nephrogenic, caused by pathogenic variants in the AVP gene and the AVPR2 or AQP2 genes, respectively. We report on a four-generation family, seven individuals had central diabetes insipidus (CDI) and the female index patient seen from age 16 to 26 years had (mild) nephrogenic diabetes insipidus. In her father with CDI, a known pathogenic heterozygous AVP variant c.232_234del p.(Glu78del) was identified, confirming the diagnosis of CDI in him and the other affected family members. In the proband, molecular analysis disclosed a novel heterozygous AVPR2 gene variant, c.962A > T p.(Asn321Ile) and an extremely skewed X-inactivation, confirming X-linked nephrogenic diabetes insipidus (XL-NDI). Whole exome sequencing showed no further causative mutation. This is the first report on the co-existence of CDI and NDI in one family. Our review of symptomatic female AVPR2 heterozygotes includes 23 families with at least one affected female (including this study). There were 21 different causative mutations. Mutation types in females did not differ from those in males. Both severe XL-NDI and mild forms were reported in females. All six females with severe XL-NDI had complete loss-of-function (null) mutations. The remaining 17 female probands had milder XL-NDI caused by 14 missense variants and three null variants of the AVPR2 gene. X-inactivation was studied in nine of these females; all showed extreme or slight skewing. The review underlines that XL-NDI in female AVPR2 heterozygotes is always accompanied by skewed X-inactivation, emphasizing a need for X-inactivation studies in these females.
Assuntos
Aquaporina 2/genética , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Neurogênico/genética , Neurofisinas/genética , Precursores de Proteínas/genética , Receptores de Vasopressinas/genética , Vasopressinas/genética , Adolescente , Adulto , Diabetes Insípido Nefrogênico/epidemiologia , Diabetes Insípido Nefrogênico/fisiopatologia , Diabetes Insípido Neurogênico/epidemiologia , Diabetes Insípido Neurogênico/fisiopatologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatologia , Feminino , Genes Ligados ao Cromossomo X/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Sequenciamento do Exoma , Inativação do Cromossomo X/genética , Adulto JovemRESUMO
Radiological voiding cystourethrography has long been considered the gold standard for reflux testing in paediatric urology. Additional contrast-based procedures such as voiding urosonography or radionuclide cystography have been established in recent decades. Their main indication is reflux diagnosis after pyelonephritis in early infancy and childhood. The selection of the appropriate method is based on factors such as clinical question, availability, economic aspects, expenditure of human resources and time, and the goal of finding of method that provides as much information as possible while keeping radiation exposure to a minimum. Modern strategies aim for a risk-oriented, individual indication independent of the method of reflux testing.
Assuntos
Uretra , Micção/fisiologia , Refluxo Vesicoureteral , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Pielonefrite/diagnóstico por imagem , Pielonefrite/fisiopatologia , Uretra/diagnóstico por imagem , Uretra/fisiopatologia , Refluxo Vesicoureteral/diagnóstico por imagem , Refluxo Vesicoureteral/fisiopatologiaRESUMO
BACKGROUND: This study correlates the clinical presentation of Henoch-Schönlein purpura nephritis (HSPN) with findings on initial renal biopsy. METHODS: Data from 202 pediatric patients enrolled in the HSPN registry of the German Society of Pediatric Nephrology reported by 26 centers between 2008 and 2014 were analyzed. All biopsy reports were re-evaluated for the presence of cellular crescents or chronic pathological lesions (fibrous crescents, glomerular sclerosis, tubular atrophy >5%, and interstitial fibrosis >5%). RESULTS: Patients with HSPN with cellular glomerular crescents were biopsied earlier after onset of nephritis (median 24 vs 36 days, p = 0.04) than those without, whereas patients with chronic lesions were biopsied later (57 vs 19 days, p < 0.001) and were older (10.3 vs 8.6 years, p = 0.01) than those without. Patients biopsied more than 30 days after the onset of HSPN had significantly more chronic lesions (52 vs 22%, p < 0.001), lower eGFR (88 vs 102 ml/min/1.73m2, p = 0.01), but lower proteinuria (2.3 vs 4.5 g/g, p < 0.0001) than patients biopsied earlier. Children above 10 years of age had lower proteinuria (1.98 vs 4.58 g/g, p < 0.001), lower eGFR (86 vs 101 ml/min/1.73m2, p = 0.002) and were biopsied significantly later after onset of nephritis (44 vs 22 days, p < 0.001) showing more chronic lesions (45 vs 30%, p = 0.03). Proteinuria and renal function at presentation decreased with age. CONCLUSIONS: In summary, we find an age-dependent presentation of HSPN with a more insidious onset of non-nephrotic proteinuria, impaired renal function, longer delay to biopsy, and more chronic histopathological lesions in children above the age of 10 years. Thus, HSPN presents more like Immunoglobulin A (IgA) nephritis in older than in younger children.
Assuntos
Vasculite por IgA/patologia , Rim/patologia , Nefrite/patologia , Fatores Etários , Biópsia , Criança , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: We recently showed that a 3-year growth hormone (GH) treatment improves linear growth in severely short children with X-linked hypophosphatemic rickets (XLH). It is unknown if GH therapy increases adult height in XLH patients. METHODS: We carried out a follow-up analysis of a randomized controlled open-label GH study in short prepubertal children with XLH on phosphate and active vitamin D treatment. The changes in SD scores (SDS) of height, sitting height, leg and arm length, and sitting height index (i.e., the ratio between sitting height and height) were analyzed in 11 out of 16 patients followed-up until adult height. RESULTS: At baseline, XLH patients showed disproportionately short stature with reduced standardized height (-3.2 ± 0.6), sitting height (-1.7 ± 0.6), leg (-3.7 ± 0.7) and arm (-2.5 ± 0.8) length, and markedly elevated sitting height index (3.3 ± 0.6; each p < 0.01 versus healthy children). In GH-treated patients, adult height, sitting height, leg length, and arm length exceeded baseline values by 0.7 SDS, 1.7 SDS, 0.7 SDS, and 1.2 SDS respectively, although this was only significant for sitting height. In controls, no significant changes in linear body dimensions were noted. Adult height did not statistically differ between groups (-2.4 ± 0.7 vs -3.3 ± 1.2, p = 0.082). GH did not exaggerate body disproportion. CONCLUSIONS: Growth hormone treatment did not significantly increase adult height in this group of short children with XLH, which may be at least partly due to the small number of patients included in our study.
Assuntos
Estatura/efeitos dos fármacos , Nanismo/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Adulto , Antropometria/métodos , Criança , Pré-Escolar , Nanismo/etiologia , Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Feminino , Seguimentos , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Masculino , Estudos Prospectivos , Resultado do TratamentoRESUMO
To promote the standardization of nephro-uroradiological terms used in children, the European Society of Paediatric Radiology uroradiology taskforce wrote a detailed glossary. This work has been subsequently submitted to European experts in pediatric urology and nephrology for discussion and acceptance to improve the quality of radiological reports and communication between different clinicians involved in pediatric urology and nephrology.
Assuntos
Pediatria/normas , Radiologia/normas , Terminologia como Assunto , Doenças Urológicas/diagnóstico por imagem , Urologia/normas , Criança , Europa (Continente) , HumanosRESUMO
To promote the standardization of nephro-uroradiological terms used in children, the European Society of Pediatric Radiology uroradiology taskforce wrote a detailed glossary. This work has been subsequently submitted to European experts in pediatric urology and nephrology for discussion and acceptance to improve the quality of radiological reports and communication among different clinicians involved in pediatric urology and nephrology.
Assuntos
Pediatria , Radiologia , Doenças Urológicas , Urologia , Criança , Europa (Continente) , HumanosRESUMO
Epididymitis is one of the most frequent causes of acute scrotum during childhood. Unlike in adults, ascending bacterial infections are rarely the underlying cause of the condition in children. Antibacterial treatment in accordance with a prior antibiogram is possible in the presence of leukocyturia and significant bacteriuria. For the remaining cases, there are no definite criteria allowing for a decision on acute antibacterial treatment. The fact that antibacterial treatment is still initiated in cases of epididymitis in the clinical routine setting is based on the assumption of a possible infection rather than being based on facts. This dilemma will probably not be entirely resolved until adequate diagnostic markers for the different trigger mechanisms of epididymitis have been found.
Assuntos
Epididimite , Doença Aguda , Criança , Diagnóstico Diferencial , Epididimite/diagnóstico , Epididimite/fisiopatologia , Epididimite/terapia , Humanos , Masculino , EscrotoRESUMO
BACKGROUND: Considering the improved outcome, a better understanding of the late effects in Wilms tumor survivors (WT-S) is needed. This study was aimed at evaluating renal function and determining the prevalence of clinical and subclinical renal dysfunction in a cohort of WT-S using a multimodal diagnostic approach. METHODS: Thirty-seven WT-S were included in this prospective cross-sectional single center study. To evaluate renal function, glomerular filtration rate (GFR) and urinary protein excretion were assessed. Additionally, kidney sonomorphology and blood pressure were analyzed. RESULTS: All examined WT-S (mean age 28.7 years, mean follow-up 24.8 years) had been treated with a combination of surgery and chemotherapy; 59.5% had received adjuvant radiotherapy. Impaired glomerular renal function was detected in a considerable proportion of WT-S, with age-adjusted cystatin-based GFR estimation below age norm in 55.9%. A lower cystatin-based estimated GFR (eGFR) correlated with longer follow-up time and higher irradiation dose. In 5 patients (13.5%) albuminuria was identified. Analysis of sonomorphology detected compensatory contralateral renal hypertrophy in 83.3% of WT-S. Chronic kidney disease (CKD) ≥ stage II was present in 55.9% of WT-S. Blood pressure measurements revealed arterial hypertension in 15 (40.5%) WT-S (newly diagnosed n=10). In 24.3% both CKD ≥ stage II and arterial hypertension were determined. CONCLUSION: Even though WT-S are believed to carry a low risk for end-stage renal disease, in this study, a remarkable number of WT-S presented with previously unidentified subclinical signs of renal function impairment and secondary morbidity. Therefore, it is important to continue regular follow-up, especially after transition into adulthood.
Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias Renais/fisiopatologia , Rim/fisiopatologia , Insuficiência Renal Crônica/epidemiologia , Tumor de Wilms/fisiopatologia , Adolescente , Adulto , Antineoplásicos/efeitos adversos , Quimioterapia Adjuvante , Estudos Transversais , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Rim/cirurgia , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Nefrectomia/efeitos adversos , Nefrectomia/métodos , Prevalência , Estudos Prospectivos , Proteinúria/epidemiologia , Proteinúria/fisiopatologia , Proteinúria/urina , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/urina , Ultrassonografia , Tumor de Wilms/mortalidade , Tumor de Wilms/terapia , Adulto JovemRESUMO
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Genes Dominantes/genética , Músculo Liso/embriologia , Mutação/genética , Proteínas com Domínio T/genética , Ureter/embriologia , Sistema Urinário/anormalidades , Sequência de Bases , Ensaio de Desvio de Mobilidade Eletroforética , Exoma/genética , Células HEK293 , Humanos , Imuno-Histoquímica , Imunoprecipitação , Microscopia de Fluorescência , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNARESUMO
Urinary bladder malignancies are uncommon in children. Approximately 80 children with papillary carcinoma have been described to date, presenting as papillary neoplasms of both low grade and low stage. On the basis of the 1973 World Health Organization classification, tumors were classified as transitional cell carcinoma of the urinary bladder (TCCB). Owing to more detailed histologic criteria, this term has been replaced by papillary urothelial neoplasm of low malignant potential and low-grade carcinoma of the urinary bladder in the World Health Organization-International Society of Urologic Pathology consensus classification system of urothelial neoplasms 2004. Nevertheless, TCCB still remains a common term in contemporary literature. Thus, the differences between papillary urothelial neoplasm of low malignant potential, low-grade carcinoma of the urinary bladder, and TCCB will be illustrated by means of 4 examples of pediatric patients with papillary tumors.
Assuntos
Carcinoma de Células Renais/classificação , Carcinoma de Células de Transição/classificação , Neoplasias da Bexiga Urinária/classificação , Adolescente , Criança , Feminino , Humanos , Masculino , Gradação de Tumores , Organização Mundial da SaúdeRESUMO
PURPOSE: Ureteropelvic junction obstruction in association with a duplex collecting system is a rare but challenging upper urinary tract pathology. We report our 21-year experience with this anomaly in terms of presentation, diagnostic evaluation and management. MATERIALS AND METHODS: We retrospectively identified all patients with ureteropelvic junction obstruction in a duplex collecting system between 1991 and 2012. We reviewed each case for presenting symptoms, anatomy and management. Median followup was 10.8 years (range 2 to 22). RESULTS: Ureteropelvic junction obstruction in duplex kidneys was diagnosed in 21 patients. Ten patients presented with clinical symptoms such as flank pain and urinary tract infection but 11 were asymptomatic. Six patients were diagnosed by prenatal ultrasound. The lower pole and the upper pole were affected in 22 and 3 renal units, respectively. Bilateral ureteropelvic junction obstruction was found in 4 cases. Duplication was complete in 5 patients, incomplete in 11 and undetermined in 5. Surgery was performed in 14 patients, including pyelopyelostomy or ureteropyelostomy in 7, dismembered pyeloplasty in 6 and heminephrectomy in 1. Reintervention was required in 1 case. Conservative treatment was adopted in 7 patients with clinically insignificant obstruction and unimpaired renal function. In all of these patients upper urinary tract dilatation gradually improved during 3 years. CONCLUSIONS: Ureteropelvic junction obstruction in a duplex kidney is a rare but challenging anomaly that requires careful evaluation. Treatment should be individualized according to clinical presentation (symptomatic/asymptomatic), anatomy (lower/upper pole), duplication type (complete/incomplete) and obstruction with time (severity/development) on dynamic renogram.
Assuntos
Gerenciamento Clínico , Previsões , Nefropatias/congênito , Rim/anormalidades , Ureter/cirurgia , Obstrução Ureteral/cirurgia , Procedimentos Cirúrgicos Urológicos/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Nefropatias/complicações , Nefropatias/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Obstrução Ureteral/etiologia , Adulto JovemAssuntos
Antibacterianos/uso terapêutico , Febre de Causa Desconhecida/etiologia , Infecções Urinárias/diagnóstico , Infecções Urinárias/tratamento farmacológico , Pré-Escolar , Medicina Baseada em Evidências , Humanos , Lactente , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção Secundária , Infecções Urinárias/etiologiaRESUMO
PURPOSE OF REVIEW: The prevalence of urinary tract infections (UTIs) among full-term neonates has been reported to be up to 1.1%, increasing up to 7% among those with fever. UTI in neonates may be the first indicator of underlying abnormalities of kidneys and the urinary tract. RECENT FINDINGS: Early recognition and therapy of UTI and detection of risk factors offer chances for applying strategies to avoid renal damage and recurrences. However, established diagnostic strategies and prophylactic concepts today are under debate. Currently, the main focus has been on renal changes as indicators for underlying risk factors like vesicoureteral reflux, attaching much importance to dimercaptosuccinyl acid scans. Serum and urine markers will probably allow more restrictive diagnostic imaging. Prenatal and postnatal ultrasound screenings provide additional opportunities for prophylactic measures. SUMMARY: Main objectives in the management of neonatal UTIs are the prevention of acute infection-related complications and renal damage. Neonates and very young infants with suspicious pyelonephritis should obligatorily be treated with a combination of parenterally administered antibiotics. As far as possible, diagnostic imaging should be risk-oriented and restricted to noninvasive, nonstressful procedures. The strategies of antibacterial prophylaxis for the prevention of recurrent UTIs are changing. In infants at risk, its benefits have not yet been proven by evident data.
Assuntos
Infecções Urinárias/diagnóstico , Antibacterianos/uso terapêutico , Antibioticoprofilaxia/métodos , Biomarcadores/metabolismo , Técnicas de Diagnóstico Urológico , Humanos , Recém-Nascido , Infecções Urinárias/epidemiologia , Infecções Urinárias/etiologia , Infecções Urinárias/prevenção & controle , Refluxo Vesicoureteral/complicaçõesRESUMO
Urinary bladder malformations associated with bladder outlet obstruction are a frequent cause of progressive renal failure in children. We here describe a muscarinic acetylcholine receptor M3 (CHRM3) (1q41-q44) homozygous frameshift mutation in familial congenital bladder malformation associated with a prune-belly-like syndrome, defining an isolated gene defect underlying this sometimes devastating disease. CHRM3 encodes the M3 muscarinic acetylcholine receptor, which we show is present in developing renal epithelia and bladder muscle. These observations may imply that M3 has a role beyond its known contribution to detrusor contractions. This Mendelian disease caused by a muscarinic acetylcholine receptor mutation strikingly phenocopies Chrm3 null mutant mice.
Assuntos
Erros Inatos do Metabolismo/genética , Síndrome do Abdome em Ameixa Seca/genética , Receptor Muscarínico M3 , Bexiga Urinária , Animais , Sequência de Bases , Consanguinidade , Feminino , Mutação da Fase de Leitura/genética , Humanos , Mutação INDEL/genética , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Modelos Moleculares , Síndrome do Abdome em Ameixa Seca/patologia , Receptor Muscarínico M3/deficiência , Receptor Muscarínico M3/genética , Homologia de Sequência do Ácido Nucleico , Fatores Sexuais , Bexiga Urinária/embriologia , Bexiga Urinária/patologia , Obstrução do Colo da Bexiga Urinária/genética , Obstrução do Colo da Bexiga Urinária/patologiaRESUMO
The main objectives in childhood urinary tract infections are rapid recovery from complaints, prevention of urosepsis and infection-related complications as well as the prevention of renal parenchymal damage. Calculated antibiotic therapy should take the local resistance rates of uropathogens into consideration. The current situation of bacterial resistances differs from region to region. In Escherichia coli, resistance rates against cephalosporins, aminoglycosides, nitrofurantoin und chinolones have been relatively low. In contrast, resistance rates against ampicillin have increased over the last 20 years. A similar trend has been observed for TMP/SMX. The choice of appropriate antibiotics, the duration of therapy and the form of application depend on age, severity of clinical symptoms and the presence of complicating factors. In early infancy, a combination of aminoglycoside/ampicillin or ceftazidime/ampicillin is commonly recommended as first-line treatment in pyelonephritis. Pyelonephritis in young infants should always be treated in a paediatric clinic. In later infancy and childhood, an oral third-generation cephalosporin can be used.
Assuntos
Antibacterianos/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Criança , Pré-Escolar , Farmacorresistência Bacteriana , Quimioterapia Combinada/métodos , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
Haploinsufficiency of the zinc finger transcription factor GATA3 causes the triad of hypoparathyroidism, deafness and renal dysplasia, known by its acronym HDR syndrome. The purpose of the current study was to describe in detail the auditory phenotype in human HDR patients and compare these to audiometrical and histological data previously described in a mouse model of this disease. Pure tone audiometry, speech audiometry, speech in noise, auditory brainstem responses and transiently evoked otoacoustic emissions were measured in 2 patients affected by HDR syndrome. Both patients were affected by a moderate-to-severe sensorineural hearing loss. Speech reception thresholds were shifted and speech recognition in noise was disturbed. No otoacoustic emissions could be generated in either patient. Auditory brainstem response interpeak intervals were normal. The human and murine audiological phenotypes seem to correspond well. Hearing loss in HDR syndrome is moderate to severe, seems to be slightly worse at the higher end of the frequency spectrum and may be progressive with age. The absence of otoacoustic emissions and the loss of frequency selectivity suggest an important role for outer hair cells in causing the hearing loss.
Assuntos
Limiar Auditivo/fisiologia , Perda Auditiva Neurossensorial/fisiopatologia , Hipoparatireoidismo/fisiopatologia , Rim Displásico Multicístico/fisiopatologia , Adulto , Audiometria de Tons Puros , Audiometria da Fala , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Fator de Transcrição GATA3/deficiência , Fator de Transcrição GATA3/genética , Perda Auditiva Neurossensorial/genética , Humanos , Hipoparatireoidismo/genética , Masculino , Rim Displásico Multicístico/genética , Ruído , Emissões Otoacústicas Espontâneas/fisiologia , Fenótipo , SíndromeRESUMO
Genetic defects of the Na+-K+-2Cl- (NKCC2) sodium potassium chloride co-transporter result in severe, prenatal-onset renal salt wasting accompanied by polyhydramnios, prematurity, and life-threatening hypovolemia of the neonate (antenatal Bartter syndrome or hyperprostaglandin E syndrome). Herein are described two brothers who presented with hyperuricemia, mild metabolic alkalosis, low serum potassium levels, and bilateral medullary nephrocalcinosis at the ages of 13 and 15 yr. Impaired function of sodium chloride reabsorption along the thick ascending limb of Henle's loop was deduced from a reduced increase in diuresis and urinary chloride excretion upon application of furosemide. Molecular genetic analysis revealed that the brothers were compound heterozygotes for mutations in the SLC12A1 gene coding for the NKCC2 co-transporter. Functional analysis of the mutated rat NKCC2 protein by tracer-flux assays after heterologous expression in Xenopus oocytes revealed significant residual transport activity of the NKCC2 p.F177Y mutant construct in contrast to no activity of the NKCC2-D918fs frameshift mutant construct. However, coexpression of the two mutants was not significantly different from that of NKCC2-F177Y alone or wild type. Membrane expression of NKCC2-F177Y as determined by luminometric surface quantification was not significantly different from wild-type protein, pointing to an intrinsic partial transport defect caused by the p.F177Y mutation. The partial function of NKCC2-F177Y, which is not negatively affected by NKCC2-D918fs, therefore explains a mild and late-onset phenotype and for the first time establishes a mild phenotype-associated SLC12A1 gene mutation.