The pathophysiological and molecular basis of Bartter's and Gitelman's syndromes.
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Molecular defects affecting the transport of sodium, potassium and chloride in the nephron through the ROMK K+ channel, Na+/K+/2Cl- cotransporter, the Na+/Cl- cotransporter and chloride channel have been identified in patients with Bartter's and Gitelman's syndromes. Defects of the angiotensin II type I receptor and CFTR have also being described. These defects are simple (i.e., most are single amino acid substitutions) but affect key elements in tubular transport. The simplicity of the genetic defects may explain why the inheritance of these conditions remains unclear in most kindreds (i.e., not just recessive or dominant) and emphasises the crucial importance of the conformational structure of these channels. Application of this molecular information will allow the early genetic identification of patients with these syndromes and enable us to differentiate between the various disorders at a functional level. It may also identify a subgroup in which the heterozygous form may make patients potentially exquisitely sensitive to diuretics. (+info)
Intestinal permeability and diarrhoeal disease in Aboriginal Australians.
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BACKGROUND: Northern Territory Aboriginal children hospitalised with acute gastroenteritis have high rates of acidosis, hypokalaemia, and dehydration. AIMS: To determine whether Aboriginal children with and without diarrhoea have greater impairment in intestinal function than non-Aboriginal children, as assessed by increased permeability ratios. METHODS: A descriptive study of 124 children (96 Aboriginal and 28 non-Aboriginal) hospitalised with and without diarrhoea. Intestinal permeability was assessed by the lactulose to rhamnose (L-R) ratio from a five hour urine collection. RESULTS: In Aboriginal children, mean L-R ratios (95% confidence intervals) were 18.3 (17.1 to 19.6) with diarrhoea and 9.0 (7.3 to 11.0) without diarrhoea, and in non-Aboriginal children they were 5.9 (2.8 to 12. 3) and 4.2 (3.3 to 5.2), respectively. In patients with diarrhoea, L-R ratios were significantly raised when accompanied by acidosis (mean, 22.8; 95% CI, 17.0 to 30.5), hypokalaemia (mean, 20.7; 95% CI, 15.4 to 27.9), and >/= 5% dehydration (mean, 24.3; 95% CI, 19.0 to 29.6) compared with none of these complications (mean, 7.0; 95% CI, 3.5 to 13.8). CONCLUSION: The high incidence of acidosis, hypokalaemia, and dehydration in Aboriginal children admitted with diarrhoeal disease is related to underlying small intestinal mucosal damage. (+info)
Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman's syndrome.
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Gitelman's syndrome is an autosomal recessive disorder of salt wasting and hypokalemia caused by mutations in the thiazide-sensitive Na-Cl cotransporter. To investigate the pathogenesis of Gitelman's syndrome, eight disease mutations were introduced into the mouse thiazide-sensitive Na-Cl cotransporter and studied by functional expression in Xenopus oocytes. Sodium uptake into oocytes that expressed the wild-type clone was more than sevenfold greater than uptake into control oocytes. Uptake into oocytes that expressed the mutated transporters was not different from control. Hydrochlorothiazide reduced Na uptake by oocytes expressing the wild-type gene to control values but had no effect on oocytes expressing the mutant clones. Western blots of oocytes injected with the wild-type clone showed bands representing glycosylated (125 kDa) and unglycosylated (110 kDa) forms of the transport protein. Immunoblot of oocytes expressing the mutated clones showed only the unglycosylated protein, indicating that protein processing was disrupted. Immunocytochemistry with an antibody against the transport protein showed intense membrane staining of oocytes expressing the wild-type protein. Membrane staining was completely absent from oocytes expressing mNCC(R948X); instead, diffuse cytoplasmic staining was evident. In summary, the results show that several mutations that cause Gitelman's syndrome are nonfunctional because the mutant thiazide-sensitive Na-Cl cotransporter is not processed normally, probably activating the "quality control" mechanism of the endoplasmic reticulum. (+info)
NH4+ secretion in inner medullary collecting duct in potassium deprivation: role of colonic H+-K+-ATPase.
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NH4+ secretion in inner medullary collecting duct in potassium deprivation: Role of colonic H+-K+-ATPase. BACKGROUND: In K+ deprivation (KD), gastric (g) H+-K+-ATPase (HKA) is suppressed, whereas colonic (c) HKA is induced in the terminal inner medullary collecting duct (IMCD). We hypothesized that in KD, cHKA is induced and can mediate the secretion of NH4+. METHODS: Rats were sacrificed after 2, 3, 6, or 14 days on regular (NML) or K+-free (KD) diet. mRNA expression of HKA isoforms in terminal inner medulla was examined and correlated with NH4+ secretion in perfused IMCD in vitro. RESULTS: Urinary NH4+ excretion increased after K+-free diet for six days. In terminal inner medulla, cHKA expression was strongly induced, whereas gHKA expression was decreased. NH4+ secretion increased by 62% in KD (JtNH4+ 0.57 vs. 0.92 pmol/min/mm tubule length, P < 0.001). Ouabain (1 mM) in perfusate inhibited NH4+ secretion in KD by 45% (P < 0.002) but not in NML. At luminal pH 7.7, which inhibits NH3 diffusion, NH4+ secretion in IMCD was 140% higher in KD (0.36 vs. 0.15, P < 0.03) and was sensitive to ouabain. ROMK-1 mRNA expression was induced in parallel with cHKA in inner medulla. CONCLUSIONS: These data suggest that in KD, cHKA replaces gHKA and mediates enhanced secretion of NH4+ (and H+) into the lumen facilitated by K+ recycling through ROMK-1. (+info)
In rat tIMCD, NH4+ uptake by Na+-K+-ATPase is critical to net acid secretion during chronic hypokalemia.
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The purpose of this study was to determine the magnitude of Na+ pump-mediated NH4+ uptake in the terminal inner medullary collecting duct (tIMCD) at K+ and NH4+ concentrations observed in vivo in the inner medullary interstitium of normal and in K+-restricted rats. Interstitial K+ and NH4+ concentrations in the terminal half of the inner medulla were taken to be 10 and 6 mM in K+-restricted rats, but 30 and 6 mM in K+-replete rats. In tubules from K+-restricted rats, when perfused at a K+ concentration of 10 mM, addition of ouabain to the bath reduced total bicarbonate flux (JtCO2) by 40% and increased intracellular pH (pHi), indicating significant NH4+ uptake by the Na+-K+-ATPase. In tubules from K+-restricted rats, JtCO2 was reduced with increased extracellular K+. At a K+ concentration of 30 mM, ouabain addition neither reduced JtCO2 nor increased pHi in tubules from rats of either treatment group. In conclusion, in the tIMCD from hypokalemic rats, 1) acute changes in extracellular K+ concentration modulate net acid secretion, and 2) Na+ pump-mediated NH4+ uptake should be an important pathway mediating transepithelial net acid secretion in vivo. (+info)
Potassium-magnesium citrate versus potassium chloride in thiazide-induced hypokalemia.
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BACKGROUND: The purpose of this study was to compare the value of potassium-magnesium citrate (KMgCit) with potassium chloride in overcoming thiazide-induced hypokalemia. METHODS: Sixty normal subjects first took hydrochlorothiazide (HCTZ; 50 mg/day). After three weeks of treatment (or earlier if hypokalemia developed), they were randomized to take KMgCit (42 mEq K, 21 mEq Mg, and 63 mEq citrate/day) or potassium chloride (42 mEq/day) for three weeks while continuing on HCTZ. RESULTS: KMgCit significantly increased the serum potassium concentration from 3.42 +/- 0.30 mEq/L on HCTZ alone to about 3.8 mEq/L (P < 0.001). Potassium chloride produced a similar increase in serum potassium concentration from 3.45 +/- 0.44 mEq/L to about 3.8 mEq/L (P < 0. 001). KMgCit significantly increased the serum magnesium concentration by 0.11 to 0.12 mEq/L (P < 0.01), whereas potassium chloride produced a marginal decline or no significant change. KMgCit was less effective than potassium chloride in correcting HCTZ-induced hypochloridemia and hyperbicarbonatemia. KMgCit, but not potassium chloride, significantly increased urinary pH (by about 0.6 unit), citrate (by about 260 mg/day), and urinary magnesium. CONCLUSIONS: KMgCit is equally effective as potassium chloride in correcting thiazide-induced hypokalemia. In addition, KMgCit, but not potassium chloride, produces a small but significant increase in serum magnesium concentration by delivering a magnesium load, and it confers alkalinizing and citraturic actions. (+info)
Alcohol withdrawal and hypokalaemia: a case report.
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A case is presented where a 25-year-old man developed a serious hypokalaemia (K(+) 2.2 mmol/l) during alcohol withdrawal, despite intravenous saline treatment and normal feeding. As hypokalaemia can be symptom-free, we want to draw attention to the combination of vomiting, malnutrition and alcohol withdrawal, as these can cause lethal complications. We therefore recommend that potassium serum level should be routinely monitored during alcohol withdrawal, even when this is being managed in the community. (+info)
Liddle's syndrome: a report in a middle-aged woman.
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A 54-year-old woman with diabetes mellitus was hospitalized with generalized edema and weakness. She was also found to have hypertension, hypokalemia and metabolic alkalosis. Detailed examination showed subnormal plasma renin activity and plasma aldosterone concentration. Adrenal CT scanning revealed no adrenal tumor. A successful treatment with amiloride established the diagnosis of Liddle's syndrome for the patient. Liddle's syndrome, a rare hereditary disease usually found in young patients, should be considered in the differential diagnosis of hypertension even in elderly individuals. (+info)