RESUMO
Pseudohypoaldosteronism type II (PHAII) is a genetic disease characterized by association of hyperkalemia, hyperchloremic metabolic acidosis, hypertension, low renin, and high sensitivity to thiazide diuretics. It is caused by mutations in the WNK1, WNK4, KLHL3 or CUL3 gene. There is strong evidence that excessive sodium chloride reabsorption by the sodium chloride cotransporter NCC in the distal convoluted tubule is involved. WNK4 is expressed not only in distal convoluted tubule cells but also in ß-intercalated cells of the cortical collecting duct. These latter cells exchange intracellular bicarbonate for external chloride through pendrin, and therefore, account for renal base excretion. However, these cells can also mediate thiazide-sensitive sodium chloride absorption when the pendrin-dependent apical chloride influx is coupled to apical sodium influx by the sodium-driven chloride/bicarbonate exchanger. Here we determine whether this system is involved in the pathogenesis of PHAII. Renal pendrin activity was markedly increased in a mouse model carrying a WNK4 missense mutation (Q562E) previously identified in patients with PHAII. The upregulation of pendrin led to an increase in thiazide-sensitive sodium chloride absorption by the cortical collecting duct, and it caused metabolic acidosis. The function of apical potassium channels was altered in this model, and hyperkalemia was fully corrected by pendrin genetic ablation. Thus, we demonstrate an important contribution of pendrin in renal regulation of sodium chloride, potassium and acid-base homeostasis and in the pathophysiology of PHAII. Furthermore, we identify renal distal bicarbonate secretion as a novel mechanism of renal tubular acidosis.
Assuntos
Acidose Tubular Renal/fisiopatologia , Túbulos Renais Coletores/fisiopatologia , Proteínas Serina-Treonina Quinases/genética , Pseudo-Hipoaldosteronismo/complicações , Transportadores de Sulfato/metabolismo , Acidose Tubular Renal/sangue , Acidose Tubular Renal/etiologia , Animais , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Humanos , Túbulos Renais Coletores/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação de Sentido Incorreto , Potássio/sangue , Potássio/metabolismo , Pseudo-Hipoaldosteronismo/genética , Pseudo-Hipoaldosteronismo/fisiopatologia , Eliminação Renal , Cloreto de Sódio/metabolismo , Simportadores de Sódio-Bicarbonato/metabolismo , Transportadores de Sulfato/genética , Regulação para CimaRESUMO
Pseudohypoaldosteronism type 1 is a rare syndrome of resistance to aldosterone manifested by salt wasting, hyponatremia, hyperkalemia, hyperchloremic metabolic acidosis, and hiperreninemic hyperaldosteronism. The syndrome may be genetic, secondary to uropathies and urinary tract infection among other causes or it may occur sporadically. The salt wasting may be systemic and severe or localized to the kidney usually with better prognosis. The clinical picture is prevalent in the first seven months of life, failure to thrive and recurrent vomiting are usually the common clinical signs, an electrolyte emergency in the form of hypovolemic shock, hyperkalemic cardiac arrhythmias and hyponatremic seizures is rare. Four patients presenting with an electrolyte emergency are reported.
Assuntos
Pseudo-Hipoaldosteronismo/diagnóstico , Emergências , Feminino , Humanos , Lactente , Masculino , Pseudo-Hipoaldosteronismo/complicações , Desequilíbrio Hidroeletrolítico/etiologiaRESUMO
El seudohipoaldosteronismo de tipo 1 es un síndrome infrecuente de resistencia a la aldosterona que se manifiesta con pérdida salina, hiponatremia, hiperpotasemia, acidosis metabólica hiperclorémica e hiperaldosteronismo hiperreninémico. El síndrome puede ser genético; secundario a uropatías e infección urinaria entre otras causas o presentarse esporádicamente. La pérdida salina puede ser sistémica y grave o localizada a nivel renal, por lo general, con mejor pronóstico. El cuadro clínico se manifiesta predominantemente en los primeros siete meses de vida; un marcado retraso pondoestatural y vómitos recurrentes suelen ser los signos clínicos habituales, rara vez se presenta como una emergencia hidroelectrolítica en forma de shock hipovolémico, arritmias cardíacas hiperpotasémicas y crisis convulsiva por hiponatremia. Se presentan cuatro pacientes que debutaron como una emergencia hidroelectrolítica.
Pseudohypoaldosteronism type 1 is a rare syndrome of resistance to aldosterone manifested by salt wasting, hyponatremia, hyperkalemia, hyperchloremic metabolic acidosis, and hiperreninemic hyperaldosteronism. The syndrome may be genetic, secondary to uropathies and urinary tract infection among other causes or it may occur sporadically. The salt wasting may be systemic and severe or localized to the kidney usually with better prognosis. The clinical picture is prevalent in the first seven months of life, failure to thrive and recurrent vomiting are usually the common clinical signs, an electrolyte emergency in the form of hypovolemic shock, hyperkalemic cardiac arrhythmias and hyponatremic seizures is rare. Four patients presenting with an electrolyte emergency are reported.
Assuntos
Feminino , Humanos , Lactente , Masculino , Pseudo-Hipoaldosteronismo/diagnóstico , Emergências , Pseudo-Hipoaldosteronismo/complicações , Desequilíbrio Hidroeletrolítico/etiologiaRESUMO
Aerococcus viridans is a catalase-negative gram-positive bacterium rarely found as human pathogen. Some cases of urinary tract infection (UTI) have been described in immunocompromised adults. In this article we describe a UTI case caused by this agent in a child with severe obstructive uropathy, clinically presented with secondary pseudohypoaldosteronism (SPHA). Although A. viridans is rarely associated with child infection, it can be responsible for life threatening conditions/ situations. To our knowledge, A. viridans UTI has never been reported in pediatric patients.
Assuntos
Aerococcus/isolamento & purificação , Infecções por Bactérias Gram-Positivas/etiologia , Complicações Pós-Operatórias/etiologia , Pseudo-Hipoaldosteronismo/complicações , Infecções Urinárias/etiologia , Aerococcus/patogenicidade , Aldosterona/sangue , Cistostomia , Enterococcus faecalis/isolamento & purificação , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Recém-Nascido , Masculino , Complicações Pós-Operatórias/microbiologia , Pseudo-Hipoaldosteronismo/sangue , Renina/sangue , Sistema Urinário/anormalidades , Infecções Urinárias/microbiologia , Refluxo Vesicoureteral/complicações , Refluxo Vesicoureteral/congênitoRESUMO
OBJECTIVE: To study patients with autosomal recessive pseudohypoaldosteronism type 1 and to relate pulmonary disease to gene mutations of the epithelial sodium channel (ENaC). STUDY DESIGN: Clinical and laboratory data were collected from 4 Swedish patients with pseudohypoaldosteronism type 1. The genes for ENaC and cystic fibrosis transmembrane conductance regulator were analyzed for mutations with methods including DNA sequencing. RESULTS: Three novel mutations were found in the alpha-gene of ENaC, 2 frameshifts (1449delC and 729delA) and 1 missense mutation resulting in the substitution of leucine for serine 562 in the alpha-chain (S562L). The 1449delC mutation was found in all patients in either homozygous or heterozygous form and seems to be the predominant cause of pseudohypoaldosteronism in Sweden. The allele coding for S562L also contained a transition converting tryptophan 493 to arginine (W493R), which seems to be a rare polymorphism. All patients had pulmonary symptoms to various degrees. The bacterial findings resembled, to some extent, those in cystic fibrosis, but development of chronic lung disease and progressive decline in lung function were not observed. CONCLUSIONS: Genetic deficiencies of the alpha subunit of the ENaC are associated with prominent lung symptoms, which are, however, clearly different from those in cystic fibrosis.
Assuntos
Pneumopatias/genética , Pseudo-Hipoaldosteronismo/genética , Canais de Sódio/deficiência , Pré-Escolar , Epitélio , Feminino , Humanos , Pneumopatias/etiologia , Mutação , Polimorfismo Conformacional de Fita Simples , Pseudo-Hipoaldosteronismo/complicações , Análise de Sequência de DNA , Canais de Sódio/genéticaRESUMO
Four patients with severe pseudohypoaldosteronism caused by multiple end-organ resistance to aldosterone had frequently recurring lower respiratory tract infections and persistently elevated sweat and saliva electrolyte values. The increased saliva electrolyte values in these patients probably affect normal mucociliary function in the respiratory tract and facilitate the occurrence of frequent lower respiratory tract involvement. Patients with pseudohypoaldosteronism may require treatment similar to that for cystic fibrosis to prevent long-term respiratory complications.
Assuntos
Fibrose Cística/diagnóstico , Doenças em Gêmeos/diagnóstico , Pseudo-Hipoaldosteronismo/diagnóstico , Infecções Respiratórias/diagnóstico , Aldosterona/metabolismo , Criança , Diagnóstico Diferencial , Feminino , Humanos , Recém-Nascido , Masculino , Potássio/sangue , Pseudo-Hipoaldosteronismo/complicações , Pseudo-Hipoaldosteronismo/metabolismo , Recidiva , Renina/sangue , Testes de Função Respiratória , Infecções Respiratórias/complicações , Infecções Respiratórias/metabolismo , Saliva/metabolismo , Cloreto de Sódio/metabolismo , Suor/metabolismoRESUMO
We report four patients with pseudohypoaldosteronism, aged 5 months to 5 years. All patients had hypercalciuria and three had nephrocalcinosis. Two patients with nephrocalcinosis were treated with indomethacin. Polydipsia decreased and appetite and weight gain improved within 14 days of therapy. Hypercalciuria, polyuria, and creatinine clearance decreased 30% to 50% and urinary prostaglandin E2 levels decreased fourfold to eightfold.