RESUMO
Distal convoluted tubules (DCT), which contain the Na-Cl cotransporter (NCC) inhibited by thiazide diuretics, undergo complex modulation to preserve Na+ and K+ homeostasis. The lysine kinases 1 and 4 (WNK1 and WNK4), identified as hyperactive in the hereditary disease pseudohypoaldosteronism type 2, are responsible for activation of NCC and consequent hypokalemia and hypertension. WNK4, highly expressed in DCT, activates the SPAK/OSR1 kinases, which phosphorylate NCC and other regulatory proteins and transporters in the distal nephron. WNK4 works as a chloride sensor through a Cl- binding site, which acts as an on/off switch at this kinase in response to changes of basolateral membrane electrical potential, the driving force of cellular Cl- efflux. High intracellular Cl- in hyperkalemia decreases NCC phosphorylation and low intracellular Cl- in hypokalemia increases NCC phosphorylation and activity, which makes plasma K+ concentration a central modulator of NCC and of K+ secretion. The WNK4 phosphorylation by cSrc or SGK1, activated by angiotensin II or aldosterone, respectively, is another relevant mechanism of NCC, ENaC, and ROMK modulation in states such as volume reduction, hyperkalemia, and hypokalemia. Loss of NCC function induces upregulation of electroneutral NaCl reabsorption by type B intercalated cells through the combined activity of pendrin and NDCBE, as demonstrated in double knockout mice (KO) animal models, Ncc/pendrin or Ncc/NDCBE. The analysis of ks-Nedd-4-2 KO animal models introduced the modulation of NEDD4-2 by intracellular Mg2+ activity as an important regulator of NCC, explaining the thiazide-induced persistent hypokalemia.
Assuntos
Hiperpotassemia , Hipopotassemia , Camundongos , Animais , Proteínas Serina-Treonina Quinases/metabolismo , Sódio/metabolismo , Hipopotassemia/metabolismo , Hiperpotassemia/metabolismo , Túbulos Renais Distais/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Camundongos Knockout , Homeostase , Potássio/metabolismoRESUMO
The kidney controls body fluids, electrolyte and acid-base balance. Previously, we demonstrated that hyperpolarization-activated and cyclic nucleotide-gated (HCN) cation channels participate in ammonium excretion in the rat kidney. Since acid-base balance is closely linked to potassium metabolism, in the present work we aim to determine the effect of chronic metabolic acidosis (CMA) and hyperkalemia (HK) on protein abundance and localization of HCN3 in the rat kidney. CMA increased HCN3 protein level only in the outer medulla (2.74 ± 0.31) according to immunoblot analysis. However, immunofluorescence assays showed that HCN3 augmented in cortical proximal tubules (1.45 ± 0.11) and medullary thick ascending limb of Henle's loop (4.48 ± 0.45) from the inner stripe of outer medulla. HCN3 was detected in brush border membranes (BBM) and mitochondria of the proximal tubule by immunogold electron and confocal microscopy in control conditions. Acidosis did not alter HCN3 levels in BBM and mitochondria but augmented them in lysosomes. HCN3 was also immuno-detected in mitoautophagosomes. In the distal nephron, HCN3 was expressed in principal and intercalated cells from cortical to medullary collecting ducts. CMA did not change HCN3 abundance in these nephron segments. In contrast, HK doubled HCN3 level in cortical collecting ducts and favored its basolateral localization in principal cells from the inner medullary collecting ducts. These findings further support HCN channels contribution to renal acid-base and potassium balance.
Assuntos
Acidose/etiologia , Acidose/metabolismo , Hiperpotassemia/etiologia , Hiperpotassemia/metabolismo , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Néfrons/metabolismo , Canais de Potássio/metabolismo , Animais , Biomarcadores , Doença Crônica , Células Epiteliais/metabolismo , Imunofluorescência/métodos , Expressão Gênica , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Túbulos Renais Proximais/metabolismo , Alça do Néfron/metabolismo , Néfrons/ultraestrutura , Canais de Potássio/genética , RatosRESUMO
AIMS: Electroneutral (NBCn1) and electrogenic (NBCe1) isoforms of the Na(+)-HCO3(-) cotransporter (NBC) coexist in the heart. We studied the expression and function of these isoforms in hearts of Wistar and spontaneously hypertensive rats (SHR), elucidating the direct implication of the renin-angiotensin system in the NBC regulation. METHODS AND RESULTS: We used myocytes from Wistar, SHR, losartan-treated SHR (Los-SHR), and Angiotensin II (Ang II)-induced cardiac hypertrophy. We found an overexpression of NBCe1 and NBCn1 proteins in SHR that was prevented in Los-SHR. Hyperkalaemic-induced pHi alkalization was used to study selective activation of NBCe1. Despite the increase in NBCe1 expression, its activity was lower in SHR than in Wistar or Los-SHR. Similar results were found in Ang II-induced hypertrophy. A specific inhibitory antibody against NBCe1 allowed the discrimination between NBCe1 and NBCn1 activity. Whereas in SHR most of the pHi recovery was due to NBCn1 stimulation, in Wistar and Los-SHR the activity of both isoforms was equitable, suggesting that the deteriorated cardiac NBCe1 function observed in SHR is compensated by an enhanced activity of NBCn1. Using the biotin method, we observed greater level of internalized NBCe1 protein in SHR than in the non-hypertophic groups, while with immunofluorescence we localized the protein in endosomes near the nucleus only in SHR. CONCLUSIONS: We conclude that Ang II is responsible for the impairment of the NBCe1 in hypertrophied hearts. This is due to retained transporter protein units in early endosomes. Moreover, NBCn1 activity seems to be increased in the hypertrophic myocardium of SHR, compensating impaired function of NBCe1.
Assuntos
Bicarbonatos/metabolismo , Cardiomegalia/metabolismo , Hipertensão/metabolismo , Miócitos Cardíacos/metabolismo , Sistema Renina-Angiotensina , Sarcolema/metabolismo , Simportadores de Sódio-Bicarbonato/metabolismo , Compostos de Amônio/metabolismo , Angiotensina II , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Modelos Animais de Doenças , Regulação para Baixo , Endossomos/metabolismo , Concentração de Íons de Hidrogênio , Hiperpotassemia/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Losartan/farmacologia , Masculino , Miócitos Cardíacos/patologia , Potássio/metabolismo , Transporte Proteico , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos , Sarcolema/patologia , Fatores de TempoRESUMO
Tumor lysis syndrome (TLS) is an oncologic emergency triggered by the rapid release of intracellular material from lysing malignant cells. Most common in rapidly growing hematologic malignancies, TLS has been reported in virtually every cancer type. Central to its pathogenesis is the rapid accumulation of uric acid derived from the breakdown of nucleic acids, which leads to kidney failure by various mechanisms. Kidney failure then limits the clearance of potassium, phosphorus, and uric acid leading to hyperkalemia, hyperphosphatemia, and secondary hypocalcemia, which can be fatal. Prevention of TLS may be more effective than treatment, and identification of at-risk individuals in whom to target preventative efforts remains a key research area. Herein, we discuss the pathophysiology, epidemiology, and treatment of TLS with an emphasis on the kidney manifestations of the disease.
Assuntos
Injúria Renal Aguda/metabolismo , Síndrome de Lise Tumoral/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Alopurinol/uso terapêutico , Bicarbonatos/uso terapêutico , Soluções Tampão , Cálcio/uso terapêutico , Diuréticos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Febuxostat , Hidratação , Humanos , Hiperpotassemia/etiologia , Hiperpotassemia/metabolismo , Hiperpotassemia/terapia , Hiperfosfatemia/etiologia , Hiperfosfatemia/metabolismo , Hiperfosfatemia/terapia , Hiperuricemia/etiologia , Hiperuricemia/metabolismo , Hiperuricemia/terapia , Hipocalcemia/etiologia , Hipocalcemia/metabolismo , Hipocalcemia/terapia , Diálise Renal , Tiazóis/uso terapêutico , Síndrome de Lise Tumoral/complicações , Síndrome de Lise Tumoral/terapia , Urato Oxidase/uso terapêuticoRESUMO
OBJECTIVE: To determine whether early and higher intravenous amino acid (EHAA) supplementation decreases hyperkalemia in extremely low birth weight (ELBW) infants (<1000 g). STUDY DESIGN: Infants were enrolled at birth in a randomized, double-masked, prospective fashion and treated for 7 days. The standard group (SAA) infants received intravenous amino acid (AA) starting at 0.5 g x kg(-1) x d(-1) and increased by 0.5 g x kg(-1) every day to a maximum of 3 g x kg(-1) x d(-1). EHAA group infants received 2 g x kg(-1) x d(-1) of AA soon after birth and advanced by 1 g x kg(-1) every day to 4 g x kg(-1) x d(-1). Data analysis was by SPSS 11.5, with statistical significance at alpha = 0.05 and 90% power to determine a difference in mean K(+) level of 2. RESULTS: Sixty-two patients, mean gestational age of 26.0 +/- 2.0 weeks and birth weight of 775 +/- 136 g, were enrolled. Hyperkalemia (K(+) > or =6.5 mEq/L) occurred in 13% of the studied population; no difference in incidence of hyperkalemia was found between the SAA and EHAA groups (16% vs 10%, respectively, P = .70). Serum blood urea nitrogen was higher in the EHAA group. AA infusion was stopped early in 6 patients for high blood urea nitrogen or elevated ammonia level. CONCLUSIONS: During the study period, hyperkalemia decreased significantly and was not affected by EHAA supplementation in the first week of life.
Assuntos
Aminoácidos/administração & dosagem , Suplementos Nutricionais , Hiperpotassemia/prevenção & controle , Recém-Nascido de Peso Extremamente Baixo ao Nascer/metabolismo , Doenças do Prematuro/prevenção & controle , Nutrição Parenteral Total , Nitrogênio da Ureia Sanguínea , Humanos , Hiperpotassemia/metabolismo , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/metabolismo , Estudos ProspectivosAssuntos
Hemofiltração , Potássio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Transporte Biológico/fisiologia , Biomarcadores/sangue , Chile , Feminino , Humanos , Hiperpotassemia/metabolismo , Hiperpotassemia/terapia , Masculino , Pessoa de Meia-Idade , Potássio/sangue , Estatística como Assunto , Resultado do TratamentoRESUMO
OBJECTIVE: Nonoliguric hyperkalemia has been reported to occur in the first week of life in as many as 50% of extremely low birth weight (ELBW) infants. We studied potassium balance and renal function in the first 5 days of life to characterize potassium metabolism during the three phases of fluid and electrolyte homeostasis that we have described in ELBW infants and to elucidate the factors that contribute to the development of nonoliguric hyperkalemia. STUDY DESIGN: Plasma potassium concentration (PK), potassium intake and output, and renal clearances were obtained for the first 6 days of life in 31 infants with a birth weight of 1000 gm or less. Collection periods in which urine flow rate was greater than or equal to 3 ml/kg per hour and weight loss was greater than or equal to 0.8 gm/kg per hour were denoted to be diuretic. Prediuresis includes all collection periods before the first diuretic period; diuresis includes all collection periods between the first and last diuretic periods; postdiuresis includes all collection periods after the last diuretic period. Infants with a PK greater than 6.7 mmol/L on at least one measurement were denoted to have hyperkalemia. RESULTS: PK increased initially after birth--despite the absence of potassium intake- and then decreased and stabilized by the fourth day of life. Diuresis occurred in 27 of 31 infants. The age at which PK peaked was closely related to the onset of diuresis. PK decreased significantly during diuresis as the result of a more negative potassium balance, despite a significant increase in potassium intake. In fact, PK fell to less than 4 mmol/L in 13 of 27 infants during diuresis. After the cessation of diuresis, potassium excretion decreased even though there was a significant increase in potassium intake, potassium balance was zero, and PK stabilized. Hyperkalemia developed in 11 of 31 infants. The pattern of change in PK with age was similar in infants with normokalemia and hyperkalemia: PK initially increased (essentially in the absence of potassium intake) and then decreased and stabilized by the fourth day of life. However, the rise in PK after birth was greater in infants with hyperkalemia than in those with normokalemia: 0.7 +/- 0.2 versus 1.8 +/- 0.2 mmol/L (p < 0.001). No differences in fluid and electrolyte homeostasis or renal function were identified as associated with hyperkalemia. CONCLUSIONS: PK increases in most ELBW infants in the first few days after birth as a result of a shift of potassium from the intracellular to the extracellular compartment. The increase in the glomerular filtration rate and in the fractional excretion of sodium, with the onset of diuresis, facilitates potassium excretion, and PK almost invariably decreases. Hyperkalemia seems to be principally the result of a greater intracellular to extracellular potassium shift immediately after birth in some ELBW infants.
Assuntos
Recém-Nascido de muito Baixo Peso/metabolismo , Potássio/metabolismo , Fatores Etários , Peso ao Nascer , Água Corporal/metabolismo , Creatinina/urina , Diurese , Transfusão de Eritrócitos , Espaço Extracelular/metabolismo , Hidratação , Taxa de Filtração Glomerular , Glucose/administração & dosagem , Humanos , Hiperpotassemia/sangue , Hiperpotassemia/etiologia , Hiperpotassemia/metabolismo , Hiperpotassemia/fisiopatologia , Recém-Nascido , Recém-Nascido de muito Baixo Peso/sangue , Recém-Nascido de muito Baixo Peso/urina , Rim/metabolismo , Rim/fisiologia , Natriurese , Potássio/administração & dosagem , Potássio/sangue , Potássio/farmacocinética , Potássio/urina , Sódio/administração & dosagem , Sódio/urina , Urodinâmica , Equilíbrio Hidroeletrolítico , Redução de PesoRESUMO
Recessively inherited disorders can most often be considered loss of function: the patient has only defective copies of the defective gene (homozygous or hemizygous), with little or no functional protein products produced. Dominantly inherited disorders can most often be considered change of function: the patient has both mutant and normal copies of the gene (heterozygous); however, the mutant gene produces an abnormal protein product that causes dysfunction of the cell. Categorization of inherited disorders simply by their inheritance pattern thus affords some predictions concerning the underlying biochemical defect. To illustrate these generalizations, the molecular data on two important human inherited neurologic disorders will be described. X-linked recessive Duchenne/Becker muscular dystrophy has been shown to caused by loss of function of the dystrophin product. Dominantly inherited hyperkalemic periodic paralysis and paramyotonia congenita have been shown to be the result of single amino acid changes of the skeletal muscle voltage-sensitive sodium channel that alter the channel's function in response to environmental or physiologic stimuli (change of function).
Assuntos
Distrofina/genética , Distrofias Musculares/genética , Miotonia/genética , Distrofina/metabolismo , Feminino , Terapia Genética , Humanos , Hiperpotassemia/genética , Hiperpotassemia/metabolismo , Hiperpotassemia/fisiopatologia , Músculos/metabolismo , Músculos/transplante , Distrofias Musculares/diagnóstico , Distrofias Musculares/metabolismo , Distrofias Musculares/terapia , Mutação , Miotonia Congênita/genética , Miotonia Congênita/metabolismo , Miotonia Congênita/fisiopatologia , Paralisias Periódicas Familiares/genética , Paralisias Periódicas Familiares/metabolismo , Paralisias Periódicas Familiares/fisiopatologia , Canais de Sódio/metabolismo , Espectrina/genética , Espectrina/metabolismoRESUMO
We measured nitrogen balance and urinary 3-methylhistidine molar ratios in 33 extremely low birth weight infants (12 with hyperkalemia and 21 without) for the first 3 days of life. Although all infants were in negative nitrogen balance during the study, there was no difference in the degree of negative nitrogen balance between the two groups. There was also no difference in the 3-methylhistidine/creatinine molar ratios, indicating that muscle protein catabolism did not differ. We conclude that it is unlikely that catabolism contributes to the development of nonoliguric hyperkalemia in extremely low birth weight infants.
Assuntos
Hiperpotassemia/metabolismo , Doenças do Prematuro/metabolismo , Nitrogênio/metabolismo , Creatinina/urina , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Metilistidinas/urinaRESUMO
PURPOSE: To assess the frequency and pathogenesis of hyperkalemia in the very low birth weight infant. METHODS: Infants who weighed less than 1000 gm at birth were prospectively entered into the study within 12 hours of birth. Potential risk factors for hyperkalemia were assessed. Body weight, fluid and electrolyte balance, serum levels of sodium and potassium, creatinine clearance, fractional sodium excretion, and urine sodium/potassium ratio were measured every 8 hours for 72 hours. Measurements of plasma renin, serum aldosterone, and plasma atrial natriuretic factor were made at study entry and repeated when hyperkalemia (serum potassium greater than 6.5 mmol/L) occurred or at 72 hours. Infants in whom hyperkalemia developed were compared with those in whom it did not. RESULTS: Thirty-one infants completed the study; hyperkalemia developed in 16 (51.6%). The only difference in the occurrence of perinatal complications was the more frequent occurrence of pH less than 7.20 in infants with subsequent development of hyperkalemia. Creatinine clearance, urine output, and potassium excretion were significantly lower in the hyperkalemia group during the first 24 hours. Serum potassium concentration at 24 hours was inversely related to urine output in the prior 24 hours. Fractional sodium excretion, urine sodium/potassium ratio, and levels of renin, aldosterone, and atrial natriuretic factor did not differ between groups. CONCLUSIONS: Hyperkalemia is a frequent complication in very low birth weight infants. Infants with low urinary flow rates during the first few hours after birth are at greatest risk for the development of hyperkalemia.
Assuntos
Hiperpotassemia/etiologia , Recém-Nascido de Baixo Peso/metabolismo , Potássio/sangue , Aldosterona/sangue , Humanos , Hiperpotassemia/epidemiologia , Hiperpotassemia/metabolismo , Incidência , Recém-Nascido , Estudos Prospectivos , Fatores de TempoRESUMO
For several years now, it has been known that the administering of adrenergic beta antagonists, especially of the beta-2 type, induce hypokalemia as a result of the entering of potassium into the skeletal muscle cells. This fall in kalemia occurs independently from the effect of insulin, aldosterone or kidney excretion, is mediated by the beta-2 receptors and require the intervention of cAMP joined at the cell membrane and the subsequent stimulation of the Na-K-ATPase which bring the potassium into the striated muscle cell. Among the most outstanding drugs with beta-2 effect is salbutamol, which maintains the hypokalemic effect whether administered intravenously or inhaled. It has been used in cases of hyperkalemia, in both children and adults. The initially used intravenous dosage (0.5 mg) caused several side-effects, especially rapid heart beat, seen more in children. It has been recently found that the use of doses as low as 4 micrograms/kg lower the kalemia to values averaging 1.4 to 1.6 mEq/L (mmol/L); in addition, using these dosages intravenously in an average of 20 minutes, no side-effects were seen, even when administered to newborns. For the above, we considered that salbutamol, in the suggested dosages, constitutes an efficient and secure therapeutic method for the initial treatment of severe hyperkalemic patients.
Assuntos
Albuterol/uso terapêutico , Hiperpotassemia/tratamento farmacológico , Albuterol/administração & dosagem , Albuterol/efeitos adversos , Humanos , Hiperpotassemia/metabolismo , Rim/metabolismo , Potássio/metabolismo , Receptores Adrenérgicos/metabolismoRESUMO
The syndrome of hyporeninemic hypoaldosteronism (SHH) is not infrequent in adults with chronic renal failure caused by chronic tubulointerstitial nephritis, but it has been reported rarely in children. We present a systematic study of the interrelation between renal excretion of potassium and the renin-aldosterone axis in 23 children with CRF of different and unselected causes. Twenty children with chronic renal failure never had hyperkalemia, and both renin and aldosterone were normally stimulated by intravenous administration of furosemide, whereas three patients had moderate hyperkalemia (serum potassium concentration between 5.3 and 5.6 mEq/L) and failed to raise plasma renin activity and aldosterone values in response to furosemide. There three patients with SHH had lower basal and stimulated values of fractional potassium excretion than did patients with normokalemic chronic renal failure. Fractional potassium excretion was curvilinearly related to glomerular filtration rate (GFR), but in all three patients with SHH it was lower than expected for the level of GFR present. Fractional sodium excretion was also related to GFR, but no abnormalities were found. Two patients had hyperchloremic metabolic acidosis. After furosemide administration, they excreted an acid urine with low ammonium content, features characteristic of type 4 or hyperkalemic renal tubular acidosis. Prostaglandin E2 excretion was also significantly related to GFR, and appeared appropriate in two patients with SHH. The identification of three patients with SHH among 23 with chronic renal failure of unselected causes suggests that this entity is not rare in childhood.