Regulation of kidney on potassium balance and its clinical significance / 生理学报

Virtually all of the dietary potassium intake is absorbed in the intestine, over 90% of which is excreted by the kidneys regarded as the most important organ of potassium excretion in the body. The renal excretion of potassium results primarily from the secretion of potassium by the principal cells in the aldosterone-sensitive distal nephron (ASDN), which is coupled to the reabsorption of Na+ by the epithelial Na+ channel (ENaC) located at the apical membrane of principal cells. When Na+ is transferred from the lumen into the cell by ENaC, the negativity in the lumen is relatively increased. K+ efflux, H+ efflux, and Cl- influx are the 3 pathways that respond to Na+ influx, that is, all these 3 pathways are coupled to Na+ influx. In general, Na+ influx is equal to the sum of K+ efflux, H+ efflux, and Cl- influx. Therefore, any alteration in Na+ influx, H+ efflux, or Cl- influx can affect K+ efflux, thereby affecting the renal K+ excretion. Firstly, Na+ influx is affected by the expression level of ENaC, which is mainly regulated by the aldosterone-mineralocorticoid receptor (MR) pathway. ENaC gain-of-function mutations (Liddle syndrome, also known as pseudohyperaldosteronism), MR gain-of-function mutations (Geller syndrome), increased aldosterone levels (primary/secondary hyperaldosteronism), and increased cortisol (Cushing syndrome) or deoxycorticosterone (hypercortisolism) which also activate MR, can lead to up-regulation of ENaC expression, and increased Na+ reabsorption, K+ excretion, as well as H+ excretion, clinically manifested as hypertension, hypokalemia and alkalosis. Conversely, ENaC inactivating mutations (pseudohypoaldosteronism type 1b), MR inactivating mutations (pseudohypoaldosteronism type 1a), or decreased aldosterone levels (hypoaldosteronism) can cause decreased reabsorption of Na+ and decreased excretion of both K+ and H+, clinically manifested as hypotension, hyperkalemia, and acidosis. The ENaC inhibitors amiloride and Triamterene can cause manifestations resembling pseudohypoaldosteronism type 1b; MR antagonist spironolactone causes manifestations similar to pseudohypoaldosteronism type 1a. Secondly, Na+ influx is regulated by the distal delivery of water and sodium. Therefore, when loss-of-function mutations in Na+-K+-2Cl- cotransporter (NKCC) expressed in the thick ascending limb of the loop and in Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule (Bartter syndrome and Gitelman syndrome, respectively) occur, the distal delivery of water and sodium increases, followed by an increase in the reabsorption of Na+ by ENaC at the collecting duct, as well as increased excretion of K+ and H+, clinically manifested as hypokalemia and alkalosis. Loop diuretics acting as NKCC inhibitors and thiazide diuretics acting as NCC inhibitors can cause manifestations resembling Bartter syndrome and Gitelman syndrome, respectively. Conversely, when the distal delivery of water and sodium is reduced (e.g., Gordon syndrome, also known as pseudohypoaldosteronism type 2), it is manifested as hypertension, hyperkalemia, and acidosis. Finally, when the distal delivery of non-chloride anions increases (e.g., proximal renal tubular acidosis and congenital chloride-losing diarrhea), the influx of Cl- in the collecting duct decreases; or when the excretion of hydrogen ions by collecting duct intercalated cells is impaired (e.g., distal renal tubular acidosis), the efflux of H+ decreases. Both above conditions can lead to increased K+ secretion and hypokalemia. In this review, we focus on the regulatory mechanisms of renal potassium excretion and the corresponding diseases arising from dysregulation.

Actualización en el manejo clínico de la hipertensión hiporreninémica / Update in the clinical management of low renin hypertension

The renin-angiotensin-aldosterone system modulates volume, sodium and potassium homeostasis. In the setting of a high sodium diet, up to 30% of patients with hypertension have a low or suppressed renin and increased volume. This phenotype of low renin hypertension (LRH) is multifactorial and includes infrequent inherited genetic syndromes, milder phenotypes of classic diseases and environmental exposures. All these conditions have in common a higher cardiovascular risk mediated by the over activation of the mineralocorticoid receptor (MR), present not only in the kidney, but also in vasculature, myocardium and adipocytes. Consequently, the aim of LRH treatment goes beyond the control of blood pressure and requires antagonizing MR with specific pharmacologic agents, pursuing normalization of renin as a clinical objective. Due to the unusual evaluation of renin status by non-endocrinologists and lack of disease awareness, only a minority of hypertensive patients receive this pathophysiologically-driven treatment that should reduce cardiovascular outcomes.

Aldosterone-Producing Adrenocortical Carcinoma without Hypertension

Although adrenocortical tumors are common, adrenocortical carcinomas are rare. Moreover, aldosterone-producing adrenocortical carcinomas without hypertension are exceedingly rare, with only two previously reported cases.

Las formas clínicas del aldosteronismo primario curables con cirugía: [revisión] / Identification of the surgically curable subtypes of primary aldosteronism: [review]

La identificación de las formas quirúrgicamente corregibles de aldosteronismo primario (AP) requiere implementar la medición en sangre venosa suprarrenal (M-SVS) para demostrar la lateralización del exceso de aldosterona. En los pacientes con AP y secreción lateralizada de aldosterona, la suprarrenalectomía puede permitir la normalización de la presión arterial a largo plazo, así como la corrección del AP. En esta presentación resumimos los criterios para la selección de los pacientes candidatos a la M-SVS, la técnica para su realización y los parámetros para el análisis e interpretación de sus resultados.

Preeclampsia, migración celular y canales iónicos / Preeclampsia, cellular migration and ion channels

En la placenta humana, el sinciciotrofoblasto es la barrera que regula el transporte de nutrientes, solutos y agua entre la sangre materna y fetal. Dentro de este movimiento transepitelial se encuentra el del Na+, su contribución a la presión osmótica es fundamental en la regulación del volumen de líquido extracelular. El canal epitelial de sodio sensible al amiloride (ENaC) media el transporte de Na+ desde el lumen hacia el interior celular en numerosos epitelios absortivos. Está regulado por la aldosterona, vasopresina, catecolaminas, estrógenos y progesterona. Es bloqueado por el amiloride y sus análogos. Para su activación, diversas proteasas lo escinden en la membrana plasmática y esto a su vez es regulado por la aldosterona. El ENaC está expresado también en la placenta humana y aunque su función no es conocida, podría participar en la homeostasis de agua y electrolitos. El ENaC también es influenciado por el estado de las proteínas del citoesqueleto y los cambios en el volumen celular alteran a su vez a éste. De esta manera existe una relación entre el ENaC y el citoesqueleto. Además, las corrientes de Na+ por el ENaC y otros canales de sodio participan en la migración celular en células normales y cancerosas. Aquí presentamos evidencias que avalan la hipótesis que el ENaC es necesario para la migración celular en células BeWo, derivadas del trofoblasto humano, que sintetizan hormonas y expresan el ENaC. Las células BeWO han sido utilizadas como modelo experimental para estudiar el transporte en células de placenta.

The syncytiotrophoblast acts in human placenta as a transporting barrier regulating the transference of nutrients, solutes and water between maternal and fetal blood. This transepithelial transport involves movement of Na+ and its contribution to the osmotic pressure is an important determinant of the extracellular fluid volume. ENaC is a channel that mediates entry of Na+ from the luminal fluid into the cells in many reabsorbing epithelia; it is aldosterone, vasopressin, insulin and catecholamine-inducible, modulated by estrogens and progesterone and blocked by amiloride and its analogs. Multiple proteases are involved in the proteolytic processing and activation of ENaC subunits and aldosterone alters the protease-protease inhibitors balance. ENaC is also expressed in human placenta; although its function is not well known, the Na+ conductive properties may participate in electrolyte and extracellular volume homeostasis. The activity of ENaC channels and other ion channels and transporters is regulated by the state of actin filaments; on the other hand, changes in volume influence the actin cytoskeleton. Thus, there is an interaction between ENaC and components of the apical membrane cytoskeleton. In addition to their role in cellular homeostasis and electrical properties, Na+ currents through ENaC and other sodium channels are involved in cell migration, well documented in normal and cancer cells. In this work we presented evidences supporting the hypothesis that ENaC channels are required for the migration of BeWo cells, a human hormone-synthesizing trophoblastic cell line that express the three subunits of the ENaC channels. BeWo cell line has also been used as a model to investigate the placental transport mechanisms.

Hiperaldosteronismo primario / Primary aldosteronism

Primary aldosteronism (PA) is a known cause of hypertension. In the kidney, aldosterone promotes sodium and water reabsorption, increasing the intravascular volume and blood pressure (BP). In the cardiovascular system, aldosterone modifies endothelial and smooth muscle cell response, increasing cardiovascular risk in a blood pressure-independent way. Recently a high prevalence of PA (near to 10 percent) in hypertensive population, has been detected measuring plasma aldosterone/renin activity ratio (ARR) as screening test. This ratio increases along with the severity of the hypertensive disease. The diagnostic work up of PA should confirm the autonomy of aldosterone secretion from the renin-angiotensin system and should differentiate the clinical subtypes of the disease. These are idiopathic aldosteronism (IA) and aldosterone-producing adenoma (APA). Other causes are familial hyperaldosteronism (FH) type I (glucocorticoid-remediable aldosteronism), FH-II (non glucocorticoid-remediable aldosteronism), primary adrenal hyperplasia and adrenal carcinoma. This article reviews the prevalence, diagnosis and treatment of PA and also the clinical, biochemical and genetic characteristics ofits different subtypes.

Hiperaldosteronismo primário / Primary aldosteronism

O hiperaldosteronismo primário (HAP) é uma síndrome decorrente do aumento da secreção autônoma de aldosterona pela glândula adrenal, independente do controle da renina. O rastreamento do HAP está indicado em indivíduos com hipertensão arterial sistêmica (HAS) e hipocalemia espontânea ou grave com doses moderadas de diuréticos ou HAS refratária ao tratamento (%3 agentes anti-hipertensivos). No presente relato, paciente masculino apresentava diabete melito (DM) de início recente e HAS, emagrecimento, poliúria, polidipsia, e cansaço aos médios esforços. Apresentava hipocalemia grave e investigação laboratorial confirmou a suspeita de HAP, com medida de aldosterona sérica e urinária elevadas com diminuição da atividade da renina plasmática e aumento da razão aldosterona sérica/renina. Tomografia computadorizada de adrenais mostrou adenoma na adrenal esquerda. Após cirurgia, o paciente evoluiu com melhora dos níveis tensionais e normalização do metabolismo da glicose. Embora a prevalência de HAP em pacientes com DM não seja diferente da população de hipertensos não-diabéticos, a sua presença deve ser investigada nos casos de HAS refratária ou quando há hipocalemia. Em pacientes com DM, o metabolismo do cortisol também deve ser investigado para afastar a concomitância de hipercortisolismo decorrente de adenoma misto.

Primary aldosteronism (PA) is a syndrome that results from adrenal autonomous secretion of aldosterone. The screening for this syndrome is indicated for individuals with arterial hypertension (AH) and spontaneous or severe hypocalemia after diuretics, and refractory AH (%3 antihypertensive agents). In this report, a male patient presented recent-onset diabetes mellitus (DM) and AH, weight lost, poliuria, polidipsia, and tiredness. Severe hypocalemia was present, and the laboratory workup confirmed the hypothesis of PA, with increased plasmatic and urinary aldosterone levels, low plasma renin activity and increased aldosterone/renin ratio. Adrenal computerized tomography showed a left adrenal adenoma. After the surgical procedure, blood pressure levels and glycemia were brought to normal. Though the prevalence of PA is not increased in patients with DM, it should be screened in patients with refractory AH or persistent hypocalemia. In patients with DM, cortisol metabolism should also be evaluated to rule the presence of hypercortisolism in a mixed adenoma.

Conn's Syndrome Associated with Behcet's Disease

A 39-yr-old woman, who had been treated for Behcet's disease for 4 yr, was admitted for further investigation of recently identified hypokalemia and hypertension. Suppressed plasma renin activity with elevated plasma aldosterone concentration and an anomalous postural decrease in plasma aldosterone were observed. An abdominal CT scan revealed a right adrenal mass. The patient was diagnosed with Conn's syndrome. The association of Conn's syndrome with Behcet's disease was thought to be coincidental. To our knowledge, this is the first case of Conn's syndrome associated with Behcet's disease.

Avaliaçäo hormonal e de reflexos cardiovasculares em portadora de falência autonômica pura / Hormonal and cardiovascular reflex assessment in a female patient with pure autonomic failure

We report the case of a 72-year-old female with pure autonomic failure, a rare entity, whose diagnosis of autonomic dysfunction was determined with a series of complementary tests. For approximately 2 years, the patient has been experiencing dizziness and a tendency to fall, a significant weight loss, generalized weakness, dysphagia, intestinal constipation, blurred vision, dry mouth, and changes in her voice. She underwent clinical assessment and laboratory tests (biochemical tests, chest X-ray, digestive endoscopy, colonoscopy, chest computed tomography, abdomen and pelvis computed tomography, abdominal ultrasound, and ambulatory blood pressure monitoring). Measurements of catecholamine and plasmatic renin activity were performed at rest and after physical exercise. Finally the patient underwent physiological and pharmacological autonomic tests that better diagnosed dysautonomia.

Hipertensión arterial y mineralocorticoides: utilidad de las mediciones de renina y aldosterona / Hypertension and mineralcorticoids: usefulness of renin and aldosterone measurements

Recently, some genetic forms of hypertension have been well characterized. These forms can be globally called mineralocorticoid hypertension and are due to different alterations of the renin-angiotensin-aldosterone system (SRAA). Among these, classic primary hyperaldosteronism and its glucocorticoid remediable variety, in which hypertension is secondary to aldosterone production, must be considered. There are also conditions in which mineralocorticoid activity does not depend on aldosterone production. These conditions generate a hyporeninemic hyperaldosteronism, observed in Liddle syndrome, apparent mineralocorticoid hypertension, 11- and 17-hydroxilase deficiency, among others. The detection of these forms of hypertension is only feasible if the renin-angiotensin-aldosterone system is assessed, measuring renin and aldosterone levels. This article reviews these forms of hypertension, their clinical workup and their relevance in the usual hypertensive patients

Regulation of nephron acidification by costicosteroids

The present paper reviews work from our laboratories evaluating the importance of adrenal cortical hormones in acidification by proximal and cortical distal tubules. Proximal acidification was determined by stationary microperfusion, and measurement of bicarbonate reabsorption using luminal pH determination was performed with H+ -ion-sensitive microelectrodes. Rats were adrenalectomized (ADX) 48 h before the experiments, and corticosteroids (aldosterone(A), corticosterone(B), and 18-OH corticosterone (18-OH-B)) were injected intramuscularly 100 and 40 min before the experiments. In ADX rats stationary pH increased significantly to 7.03 as compared to sham-operated rats (6.78). Bicarbonate reabsorption decreased from 2.65 + 0.18 in sham-operated rats to 0.50 + 0.07 mmol cm-2 S(-1) after ADX. The administration of the three hormones stimulated proximal tubule acidification, reaching, however, only 47.2 per cent of the sham values in aldosterone-treated rats. Distal nephron acidification was studied by measuring urine minus blood pCO2 differences (U-B pCO2) in bicarbonate-loaded rats treated as above. This pCO2 difference is used as a measure of the distal nephron ability to secrete H+ ions into an alkaline urine. U-B pCO2 decreased significantly from 39.9 + 1.26 to 11.9 + 1.99 mmHg in ADX rats. When corticosteroids were given to ADX rats before the experiment, U-B pCO2 increased significantly, but reached control levels only when aldosterone (two 3-mug doses per rat) plus corticosterone (220 mug) were given together. In order to control for the effect of aldosterone on distal transepithelial potential difference one group of rats was treated with amiloride, which blocks distal sodium channels. Amiloride-treated rats still showed a significant reduction in U-B pCO2 after ADX. Only corticosterone and 18-OH-B but not aldosterone increased U-B pCO2 back to the levels of sham-operated rats. These results show that corticosteroids stimulate renal tubule acidification both in proximal and distal nephrons and provide some clues about the mechanism of action of these steroids.

El peptido natriuretico auricular y el sistema renina-aldosterona en el anciano normal y en el hipertenso: respuesta a los suplementos del calcio / The natruretia atrial peptide and the renin-aldosterone system in hormal and hypertensive elder, response to calcium

La concentracion plasmatica del peptido natriuretico auricular se encuentra elevada en los ancianos y si son hipertensos, sus valores son mucho mas altos. Con el obejto de estudiar el peptido natriuretico auricular y la respuesta del sistema angiotensina aldosterona, se le administro un suplemento de calcio oral a un grupo de ancianos hipertensos y a otro grupo de normotensos, que nos sirvio de control. Se seleccionaron 22 ancianos hipertensos (2 hombres y 20 mujeres), con una edad de 75 +/- años y 10 ancianos normotensos (2 hombres y 8 mujeres) con igual promedio de edad. Se le practicaron tomas tensionales con esfignomanometro de Hg en 3 posiciones (de cubito, sentado y de pie). Por el metodo de radioinmunoensayo se les dosificaron el peptido natriuretico auricular, de actividad de la renian plasmatica, la aldosterona plasmatica por absorcion atomica se le determino el calcio serico total, antes y despues de recibir 1.5 g/dia de CaCO3, por un periodo de 4 semanas. En los hipertensos se obtuvieron los siguientes resultados: el peptido natriuretico auricular descendio de manera imporatante (P<0.001), en igual forma lo hizo la aldosterona (P<0.001), por el contrario la reina (P<0.001) y el Calcio (P<0.001) aumentaron sus valores. Igualmente se consiguieron las correlaciones inversas entre renina/peptido y entre peptido/calcio, pero no se observo esta relacion entre aldosterona/peptido. En los acnianos normotensos, se obtuvo un descenso del peptido (P<,05) y un incremento del calcio serico total (P<0,05). En los hipertensos descendieron sus cifras tensionales sistolica (P<0.001) y las distolicas (P<0,05). Estos resultados ponene en evidencia las relaciones tan estrecha que existen entre la tension arterial (especialmente la sistolica, peptido, renina, aldosterona, calcio serico en ancianos hipertensos y menos significativos en los normotensos. En conclusion la administracion de calcio oral a ancianos, especialmente hipertensos, determino en ellos una serie de cambios en los grupos hormonales que manejan la homeostasis agua-sodio. Esta accion se ejerce probablemente de manera indirecta, yaque al actuar como hipotensor, se van a corregir lasalteraciones antes mencionadas en los dos grupos hormonales que intervienen en este equilibrio.

Endocrinología en las grandes alturas / Endocrinology at high altitude

El vivir en las grandes alturas, significa someterse a un medio donde predomina una baja presión de oxígeno. Ante tal situación el organismo responde en diversas formas para obtener una adaptación a este medio hipóxico. Estas respuestas pueden ser diferentes de acuerdo a la magnitud de la hipoxia. El estudio de la fisiología de altura, realizado por destacados científicos peruanos se ha constituido en uno de los más importantes campos de investigación en nuestro país en los últimos cincuenta años. En la presente revisión se ha tratado de resumir los trabajos sobre endocrinología en el nativo de la altura, que han realizado diversos investigadores del país y del extranjero, y se ha tratado de explicar en lo posible, las diferencias observadas con respecto a la endocrinología del nativo del nivel del mar. Los resultados demuestran diferencias endocrinas en el nativo de la altura, que están relacionados principalmente en el metabolismo intermedio, y en la reproducción

Aldosterona plasmática y urinaria: la actividad de la renina plasmática en sujetos normales / Aldosterone plasmatic and urinary: plasma renin activity in elderly normal subject

Con el objeto de estudiar las variaciones de los índices AP/ARP y AU/ARP en sujetos normales de edad avanzada, así como la influencia que ejercen sobre ellos la edad y la función renal, se seleccionaron 21 sujetos ancianos (79 ñ 9 años), nueve hombres y doce mujeres, y se compararon con 24 sujetos normales de menor edad (39 ñ 10 años), trece hombres y once mujeres, estudiados bajo las mismas condiciones. El hallazgo más importante que se encontró en este trabajo, fue una correlación inversa y estadísticamente muy significativa entre dichos índices y la función renal (p < 0,001), por lo que deducimos que en los ancianos la caída de la función renal debe ejercer alguna influencia sobre el incremento de los valores de estos índices. Los valores de la AP, relativamente más elevados, que presentan estos sujetos, podrían ser un mecanismo compensatorio para mantener la homeostasis del potasio en ancianos