Clinical, biochemical and molecular genetic data in five children with Gitelman's syndrome.

Gitelman's variant of Bartter's syndrome, inherited hypokalemic alkalosis, is caused by mutation in the thiazide-sensitive NaCl co-transporter (NCCT). The main clinical symptoms are: muscular weakness, carpopedal spasm, constipation and short stature. The diagnosis was suspected in five children according to clinical criteria. All patients exhibited carpopedal spasm during febrile illness, three patients had short stature. Biochemical features were: metabolic alkalosis, hypokalemia, hypomagnesemia, low IGF-I levels, hyperkaliuria, hypernatriuria, hypocalciuria and normoprostaglandinuria. Three patients had elevated plasma renin activity and hyperaldosteronism. Mutational analysis of the NCCT gene confirmed the diagnosis in all five patients. Different forms of therapy, potassium and magnesium substitution, spironolactone and indomethacin failed to fully correct hypokalemia and hypomagnesemia, but markedly improved growth velocity and normalized IGF-I levels in the three patients with short stature. During therapy, clinical symptoms disappeared. We conclude that Gitelman's syndrome is a disorder with a variable symptom profile, but can be suspected on clinical signs already in early childhood. The early diagnosis is essential in preventing complications.     

Fecal and salivary electrolytes in the diagnosis of primary aldosteronism

Fecal and salivary sodium and potassium concentrations were measured in 22 hypertensive patients with hypokalemia who were undergoing investigation for primary aldosteronism due to an adrenocortical adenoma (Conn''s syndrome). Of eight patients with a high aldosterone secretion rate, five had clearly low fecal Na/K ratios, (including all four patients with Conn''s syndrome), in three the ratios were equivocal. Of 14 patients with hypertension and a normal aldosterone secretion rate, none had a sufficiently low fecal Na/K ratio strongly to suggest hyperaldosteronism, although two were borderline. Salivary electrolyte concentrations were not as consistent an indicator of mineralocorticoid hormone excess. Estimation of fecal sodium and potassium concentrations may be useful in the diagnosis of mineralocorticoid hormone excess and in assessing the results of therapy.     

Hypokalemia and alkalosis in adipsic hypernatremia are not associated with hyperaldosteronism

Idiopathic adipsic hypernatremia (AH) is a rare disorder associated with hypokalemia and alkalosis. Hypokalemic alkalosis has been presumed to be secondary to hyperaldosteronism. We evaluated plasma renin activity, serum aldosterone, serum and urine electrolytes in a 17-year-old patient with AH on several occasions. Despite evidence of mild dehydration, serum Na >160 and K <3.2, aldosterone levels were suppressed and plasma renin activity was not elevated. Urine Na and K were not conserved. We also examined electrolyte and hormone levels in previously reported cases of AH. Aldosterone levels were not increased in any of the cases when measured. Renin secretion was increased in 2 patients. Among the compiled cases serum K was inversely correlated with serum Na (r = -0.73, p < 0.002, n = 15). Hypokalemia and alkalosis occurring in AH are not associated with secondary hyperaldosteronism. Patients with AH may have chronic renal losses of potassium leading to hypokalemia and alkalosis.     

Relationship of hypokalemia to metabolic alkalosis in the intact Yucatan miniature boar following implantation of deoxycorticosterone-acetate (DOCA) or d-aldosterone

1. Normo-kalemic Yucatan miniature boars were implanted with deoxycorticosterone-acetate (DOCA) or d-aldosterone (Aldo) to evaluate the relationship of hypokalemia to the pathogenesis of metabolic alkalosis following mineralocorticoid administration. 2. Serum potassium was significantly less than control within 24 hr, serum bicarbonate significantly elevated within 4 days and pH 1-2 days later with no significant differences between DOCA and Aldo. 3. These data demonstrate that pre-existing potassium deficits are not required for the development of alkalosis with mineralocorticoid administration, DOCA and Aldo are equally effective, co-existing hypokalemia is necessary in the genesis, and perhaps maintenance, of metabolic alkalosis with excess mineralocorticoids, and hypokalemia is not a consequence of the alkalosis.     

Effect of hypokalemia on renal expression of the ammonia transporter family members, Rh B Glycoprotein and Rh C Glycoprotein, in the rat kidney

Hypokalemia is a common electrolyte disorder that increases renal ammonia metabolism and can cause the development of an acid-base disorder, metabolic alkalosis. The ammonia transporter family members, Rh B glycoprotein (Rhbg) and Rh C glycoprotein (Rhcg), are expressed in the distal nephron and collecting duct and mediate critical roles in acid-base homeostasis by facilitating ammonia secretion. In the current studies, the effect of hypokalemia on renal Rhbg and Rhcg expression was examined. Normal Sprague-Dawley rats received either K(+)-free or control diets for 2 wk. Rats receiving the K(+)-deficient diet developed hypokalemia and metabolic alkalosis associated with significant increases in both urinary ammonia excretion and urine pH. Rhcg expression increased in the outer medullary collecting duct (OMCD). In OMCD intercalated cells, hypokalemia resulted in more discrete apical Rhcg expression and a marked increase in apical plasma membrane immunolabel. In principal cells, in the OMCD, hypokalemia increased both apical and basolateral Rhcg immunolabel intensity. Cortical Rhcg expression was not detectably altered by immunohistochemistry, although there was a slight decrease in total expression by immunoblot analysis. Rhbg protein expression was decreased slightly in the cortex and not detectably altered in the outer medulla. We conclude that in rat OMCD, hypokalemia increases Rhcg expression, causes more polarized apical expression in intercalated cells, and increases both apical and basolateral expression in the principal cell. Increased plasma membrane Rhcg expression in response to hypokalemia in the rat, particularly in the OMCD, likely contributes to the increased ammonia excretion and thereby to the development of metabolic alkalosis.     

Laxative-induced Diarrhoea: A Continuing Clinical Problem

Seven women spent an average of 127 days in hospital and were extensively investigated, including a laparotomy, before their complaints of abdominal pain, diarrhoea, and weight loss were shown to be due to excessive taking of laxatives. All denied taking laxatives and in none were the characteristic features of the effects of cathartics on the colon seen on sigmoidoscopy or radiological examination.Hypokalaemia and other electrolyte abnormalities were common and were thought to be due to a combination of severe diarrhoea and vomiting. The rectal mucosa was seen to be abnormal on biopsy only in the three patients who had taken senna preparations. The diagnosis was not easy and was finally established either by analysis of the urine and stools or by searching the patient''s ward locker.     

Effects of saline infusion and acute metabolic acidosis and alkalosis on water and electrolyte transport in the human colon.

Both the kidney and colon secrete bicarbonate and transport water and electrolytes. The respective contributions of these two organs to acid-base and electrolyte balance in normal man has thus been studied in eight healthy male volunteers who underwent simultaneous renal clearance studies, and colonic perfusion with a 0.9% saline or 7.2% mannitol solution, during metabolic alkalosis and acidosis, extracellular volume expansion, and control conditions. There was no influence of these acid-base conditions on electrolyte transport in the colon. In the urine, preferential loss of chloride over sodium averaged 81, 143 (P less than 0.001), and 141 (P less than 0.05) muequiv./min, during control, metabolic acidosis, and extracellular volume expansion conditions, respectively. During alkalosis more sodium than chloride was lost (146 muequiv./min) (P less than 0.001). Colonic pH averaged 7.41 during saline and 6.75 (P less than 0.005) during mannitol perfusion. Titratable acid was not produced in the colon during saline perfusion, and averaged 18 muequiv./min during mannitol perfusion. Urinary titratable acid increased from 19 to 25 muequiv./min (P less than 0.01) during volume expansion. With saline perfusion, bicarbonate secretion rate in the colon rose from 249 muequiv./min during control conditions to 289 muequiv./min during metabolic alkalosis (P less than 0.05). More bicarbonate was excreted in the urine during alkalosis when mannitol was introduced in the colon (243 muequiv./min) than when saline was perfused (152 muequiv./min) (P less than 0.05). This study indicates that the response of the human colon is trivial compared with that of the kidney during acute changes in acid-base balance.     

Hypokalaemia,Metabolic Alkalosis,and Hypernatraemia due to “Massive” Sodium Penicillin Therapy

Hypokalaemia and metabolic alkalosis were seen in three patients and additionally hypernatraemia in two patients treated with 100 mega units of sodium penicillin G for subacute bacterial endocarditis. The hypernatraemia was probably due to the administration of insufficient fluid, while urinary potassium loss was an important factor in producing hypokalaemia and metabolic alkalosis after. Penicillin may promote urinary potassium excretion by acting as a non-reabsorbable anion.Potassium depletion during treatment with massive doses of sodium penicillin G may be prevented by concurrently administering potassium-sparing diuretics or by using the potassium salt of penicillin.     

Metabolic alkalosis in the Yucatan miniature boar following desoxycorticosterone-acetate (DOCA) implantation

Metabolic alkalosis was induced in adult Yucatan miniature boars by subcutaneous implantation of desoxycorticosterone-acetate impregnated silicone rubber strips. Serum pH, bicarbonate, and PaCO2 increased rapidly and consistently following implantation. As in the dog and the rat, hypokalemia was accompanied by hypochloremia. As in the rabbit, hypokalemia developed in the presence of a decreased urinary output of potassium and apparent absence of kaliuresis. The pig is resistant to the paralytic effects of hypokalemia. Implantation of DOCA is an effective means of producing chronic metabolic alkalosis in the pig which is characterized by hypokalemia and hypochloremia.     

Prolonged pseudoaldosteronism induced by glycyrrhizin.

We describe the natural recovery from the aggravated hypertension, hypokalemia and suppression of the renin-aldosterone axis after the glycyrrhizin discontinuation in two mild hypertensive women aged 71 and 68 years, who had been administered 273 to 546 mg glycyrrhizin daily for 1.5 and 6 months, respectively, for the treatment of liver disease. About one month after the glycyrrhizin discontinuation, acceleration of hypertension, hypokalemia and suppression of the renin-aldosterone system still continued in both patients. At this stage, sodium restriction resulted in the normalization of blood pressure with weight loss and the subsequent sodium repletion produced a rapid increase in blood pressure to hypertensive levels observed before sodium restriction, with weight gain. Plasma renin activity and plasma aldosterone were low and did not respond to sodium restriction. Inappropriately excessive amounts of potassium were also excreted in the presence of hypokalemia. About one and a half months later, the improvements of aggravated hypertension, hypokalemia and suppressed renin-aldosterone system gradually occurred in both patients. Sodium restriction performed about three months later in case 2 no longer produced the changes in blood pressure and body weight. Plasma renin activity and plasma aldosterone responded subnormally to sodium restriction. These results demonstrate that both patients had a prolongation of the syndrome resembling primary aldosteronism except the low plasma aldosterone level about one month after the glycyrrhizin discontinuation. The possible mechanisms by which this prolongation was caused are discussed.     

Renal regulation of potassium homeostasis in calves in the first week of life including the role of atrial natriuretic peptide

The experiment was carried out on 10 clinically healthy Polish-Friesian var. Black-and-White cow calves, during the first seven days of postnatal life. The results indicate that renal removal of potassium depends primarily on the quantity reabsorbed in the tubules, whereas clearance of the electrolyte, due to stable levels in the blood plasma, depends on the amount excreted in the urine. With stable tubular reabsorption of potassium, a relatively unchanging amount of excreted potassium was observed in the urine. However, reduced tubular reabsorption caused a significant increase in excretion and clearance of the electrolyte. Changes in the amount of filtered potassium play a minor role in the regulation of excretion. Small changes in the blood plasma potassium concentration observed primarily resulted from changes in glomerular filtration rate and tubular reabsorption, since the concentration of electrolyte in the blood after birth remained within the physiological range. The results ofthis study suggest that neonate calf kidneys are sufficiently prepared to regulate kalemia. Atrial natriuretic peptide is not directly involved in the regulation of tubular reabsorption of potassium in calves in the first week of life, although it is highly likely that the peptide is involved in the excretion of potassium in the urine in calves during the first seven days of life.     

低血钾对原发性醛固酮增多症诊断的影响

目的：探讨低血钾对原发性醛固酮增多症（原醛）患者醛固酮水平的影响.方法：回顾性分析29例原醛患者,这些患者均接受血、尿醛固酮测定及立卧位速尿激发试验,并进行手术治疗.观察原醛患者血钾与醛固酮分泌的关系.结果：原醛患者低血钾时出现醛固酮正常的比例（8/16,50%）较正常血钾组高（2/13,15.4%）,P〈0.05.结论：低血钾可以抑制原醛患者尤其是特发性醛固酮增多症患者的醛固酮水平.     

Treatment of congenital nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride in an adult patient

AIM: The effects of treatment with hydrochlorothiazide (HCTZ) combined with amiloride were elucidated and compared to HCTZ treatment alone and combined with acemetacin or triamterene in a Japanese adult patient with congenital nephrogenic diabetes insipidus. METHODS: The study was divided into seven periods: (1) HCTZ and acemetacin; (2) control period; (3) HCTZ; (4) a second control period; (5) HCTZ and amiloride; (6) a third control period, and (7) HCTZ and triamterene. Fluid intake, urine volume, urinary Na, K, creatinine, and osmolality and serum Na, K, Cl, CO2, and osmolality were measured, and free water clearance and proximal and distal tubular Na reabsorption rates were calculated. RESULTS: Without drug administration, the urine volume was about 8,000 ml/day. The urine volume was reduced to about 6,000 ml/day with HCTZ. A further urine volume reduction to about 5,000 ml/day was obtained with the second drug administration, and the effects were similar among the three regimens. Serum and urinary osmolality and free water clearance were also similar among the three combinations, whereas the urinary potassium excretion was the least, and the serum potassium concentration was the highest with HCTZ plus amiloride. Besides, no alkalosis was observed only with this combination. CONCLUSION: HCTZ plus amiloride may be superior to HCTZ plus acemetacin and HCTZ plus triamterene in preventing hyperkaliuria, hypokalemia, and metabolic alkalosis.     

Homeostatic Problems in General Surgery

For electrolyte problems that arise during surgical procedures, the surgeon must be versed in the physiologic function of the organs that play vital roles in homeostasis. Pulmonary and renal evaluation before operation can give forewarning of potential dangers. Hyperaldosteronism, a disease entity influencing electrolytic changes and causing other pathophysiological effects, should be understood by the surgeon. Not only should he understand the causes of dehydration, hyperhydration, metabolic and respiratory acidosis and metabolic and respiratory alkalosis, he should also be able to recognize their deleterious effects clinically, know how to make use of adequate laboratory procedures to substantiate a diagnosis and determine the effect of treatment.The effect of water deficit and water excess, and of deficits and excesses of such ions as sodium, potassium, calcium, carbon dioxide and bicarbonate on the renal, cardiac, pulmonary and neuromuscular systems must be considered.Tetany before or after operation challenges a surgeon''s diagnostic acuity. Relying on laboratory tests only, without correlating the results with history and clinical features, may lead to errors in the administration of electrolytic fluids.     

Electrolytes, protein, and lactate dehydrogenase isozymes of parotid saliva in mineralocorticoid-treated rats.

Small quantities of parotid saliva were obtained from 7 of 11 rats in which hypokalemia was induced by treatment with deoxycorticosterone acetate (DOCA). Thirst in the treated rats was indicated by an increase in water consumption. A decrease of 28% in plasma potassium levels indicated that the DOCA-treated rats had become hypokalemic; chloride decreased 6-7% while sodium was unchanged. Saliva showed significant increases in potassium and protein and a decrease in sodium; lactate dehydrogenase-2 and -4 bands appeared darker on the electrophoretic profile. These changes are relevant to the clinical manifestations and diagnosis of hypokalemia.     

Intracellular sodium concentration and transport in red cells in essential hypertension, hyperthyroidism, pregnancy and hypokalemia

Intracellular sodium content ([Nai]), ouabain-sensitive ('Na-K ATPase') and ouabain-insensitive ('passive permeability') sodium efflux, Na-K cotransport and Na-Li ('Na-Na') countertransport were estimated in erythrocytes in 39 control subjects, 20 patients with essential hypertension, 14 patients with hypokalemia of renal or unknown etiology, 13 hyperthyroid patients and 19 pregnant women. In normokalemic essential hypertension there was only a moderate, but significant elevation of the activity of the Na-Li countertransport system. In the group of patients with hypokalemia, there was a significant increase of [Nai], ouabain-insensitive sodium efflux and Na-Li countertransport. In hyperthyroidism, a marked decrease of Na-Li countertransport was associated with a marked elevation of [Nai], in pregnancy an elevation of the Na-Li countertransport with a [Nai] 43% lower than the control values. The ouabain-sensitive sodium efflux was elevated in hyperthyroidism and hypokalemia, in which [Nai] was increased. In the control subjects there was a positive linear correlation between ouabain-sensitive sodium efflux and [Nai]. The sodium component of the Na-K cotransport was decreased to about one third of the unchanged furosemide-sensitive potassium component during pregnancy. Conclusions: The changes of cellular sodium metabolism in essential hypertension are of minor degree as compared to those in the other conditions studied. Cellular sodium metabolism in blood cells is influenced by thyroid hormones and metabolic disorders. Na-Li countertransport, i.e. Na-Na countertransport, seems to be involved in the regulation of [Nai]: an increase of its activity diminishes [Nai] (pregnancy); a decrease elevates [Nai] (hyperthyroidism). Ouabain-sensitive sodium efflux, i.e. 'Na-K ATPase', is mainly regulated by its substrate, [Nai].     

Influence of Medetomidine on Acid-base Balance and Urine Excretion in Goats

Seven goats were given medetomidine 5 μg/kg as an iv bolus injection. Venous blood samples were taken repeatedly and urine was collected continuously via a catheter up to 7h after the injection. Medetomidine caused deep clinical sedation. Base excess, pH and PCO2 in venous blood rose after medetomidine administration. There were no significant changes in plasma concentrations of sodium, calcium, magnesium, creatinine or osmolality, whereas potassium and bicarbonate concentrations increased, and phosphate and chloride decreased. Medetomidine increased plasma glucose concentration, and in 4 of 7 goats glucose could also be detected in urine. Medetomidine did not influence urine flow rate, free water clearance, bicarbonate and phosphate excretion or pH, but renal chloride, sodium, potassium, calcium, magnesium and creatinine excretion were reduced. The results suggest that the metabolic alkalosis recorded after medetomidine administration is not caused by increased renal acid excretion.     

Hypokalemia and sodium retention in patients with diabetes and chronic hepatitis receiving insulin and glycyrrhizin

Of 9 patients with chronic hepatitis treated with intravenous administration of 40 to 200 mg/day of glycyrrhizin, 3 diabetic patients receiving concomitant insulin developed hypokalemia, sodium retention and suppression of both plasma aldosterone concentration and plasma renin activity after the administration for 3 to 6 days. In the remaining 6 patients (5 nondiabetic and 1 diabetic) receiving no insulin, the administration over the long term (18 to 266 days) never caused these abnormalities. The development of hypokalemia and sodium retention in the patients was not associated with increased urinary excretion of potassium, indicating a different condition from pseudoaldosteronism caused by the desoxycorticosterone-like action of glycyrrhizin. These findings suggest that insulin which is known to have hypokalemic, antinatriuretic and antikaliuretic activity, as well as glycyrrhizin plays an important pathogenetic role in the observed electrolyte disturbance, and suppression of both renin and aldosterone.     

Clinical Experience with a New Diuretic,Triamterene, in Congestive Heart Failure

Triamterene therapy was evaluated in 35 patients with congestive heart failure over a period of two and one-half years. The parameters used were: clinical assessment; daily 24-hour urine sodium, potassium, chloride, and total volume; bi-weekly serum sodium, potassium, chloride, uric acid, and SGOT; hemogram, and BUN.Triamterene is a moderately potent diuretic and natriuretic, with the added desirable property of potassium conservation. It acts synergistically with spironolactone and not only potentiates the effects of hydrochlorothiazide but greatly minimizes its kaluretic effect.It is particularly useful in patients in whom cardiac arrhythmias are associated with digitalis intoxication or with inadvertently induced hypokalemia. Its main therapeutic value, used either alone or in combination with other diuretics, is in the longterm management of chronic edema, especially in certain patients refractory to the currently used diuretics.No significant undesirable side effects were noted.     

Effects on tissue and electrolytes of a mineralocorticoid blocker during DOCA-induced potassium depletion.

Chronic experiments were carried out on three groups of rats to evaluate tissue and electrolyte effects of a mineralocorticoid blocker canrenoate potassium (SC-14266) during DOCA-induced hypokalemic metabolic alkalosis. Group I animals received DOCA alone, group II received DOCA plus canrenoate, while group III received canrenoate alone. The daily dose ratio (per kilogram of body weight) was 180 mg canrenoate-0.45 mg DOCA. All animals ate a synthetic diet and drank 0.15 N NaHCO3. Group II animals demonstrated a lesser degree of metabolic alkalosis and a higher muscle potassium content when compared with group I rats. The most conspicuous histological abnormality was myocardial necrosis, the degree and extent of which was impressively reduced by the blocking agent.