Metabolic alkalosis after orthotopic liver transplantation.
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To ascertain the etiology of metabolic alkalosis (MA) following orthotopic liver transplantation (OLT) the records of patients with 123 consecutive OLTs from 1995 to 2000 were reviewed. Metabolic alkalosis occurred in 51.2% of patients. Patients with MA had a larger fluid deficit (-3991 +/- 4324 vs. -1018 +/- 4863, p < 0.05), cumulative furosemide dose (406 +/- 356 vs. 243 +/- 189, p < 0.02), and citrate load from blood transfusions (9164 +/- 4870 vs. 7809 +/- 3967, p < 0.05). There was no difference in serum lactate concentration (3.15 +/- 1.63 vs. 3.11 +/- 1.91) in patients with and without MA. The duration of ICU stay was longer in patients with MA (14.9 +/- 15.3 vs. 5.3 +/- 3.9 days, p < 0.004). Treatment of severe MA in 19 (15.4%) patients consisted of 0.1 N hydrochloric acid and/or acetazolamide. Hypokalemia and hypomagnesemia occurred in 37.4% and 59.3% of patients, respectively. In conclusion, MA is a common post-OLT complication that is associated with a longer ICU stay. Diuretic-induced volume depletion, the citrate load from blood transfusions, hypokalemia, and hypomagnesemia contribute to the pathogenesis of MA in OLT. (+info)
Ureagenesis: evidence for a lack of hepatic regulation of acid-base equilibrium in humans.
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Ureagenesis in the liver consumes up to 1,000 mmol of HCO3-/day in humans as a result of 2NH4+ + 2HCO3- --> urea + CO2 + 3H2O. Whether the liver contributes to the regulation of acid-base equilibrium by controlling the rate of ureagenesis and, therefore, HCO3- consumption in response to changes in plasma acidity has not been adequately evaluated in humans. Rates of ureagenesis were measured in eight healthy volunteers during control, chronic metabolic acidosis (induced by oral administration of CaCl2 3.2 mmol.kg body wt-1.day-1 for 11 days), and recovery as well as during bicarbonate infusion (200 mmol over 240 min; acute metabolic alkalosis). Rates of ureagenesis were correlated negatively with plasma HCO3- concentration both during adaption to metabolic acidosis and during the chronic, steady-state phase. Thus ureagenesis, an acidifying process, increased rather than decreased in metabolic acidosis. During bicarbonate infusion, rates of ureagenesis decreased significantly. Thus ureagenesis did not appear to be involved in the regulated elimination of excess HCO3-. The finding of a negative correlation between ureagenesis and plasma HCO3- concentration over a wide range of HCO3- concentrations, altered both chronically and acutely, suggests that the ureagenic process per se is maladaptive for acid-base regulation and that ureagenesis has no discernible homeostatic effect on acid-base equilibrium. (+info)
Metabolic effects of induced alkalosis during progressive forearm exercise to fatigue.
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Metabolic alkalosis induced by sodium bicarbonate (NaHCO(3)) ingestion has been shown to enhance performance during brief high-intensity exercise. The mechanisms associated with this increase in performance may include increased muscle phosphocreatine (PCr) breakdown, muscle glycogen utilization, and plasma lactate (Lac(-)(pl)) accumulation. Together, these changes would imply a shift toward a greater contribution of anaerobic energy production, but this statement has been subject to debate. In the present study, subjects (n = 6) performed a progressive wrist flexion exercise to volitional fatigue (0.5 Hz, 14-21 min) in a control condition (Con) and after an oral dose of NaHCO(3) (Alk: 0.3 g/kg; 1.5 h before testing) to evaluate muscle metabolism over a complete range of exercise intensities. Phosphorus-31 magnetic resonance spectroscopy was used to continuously monitor intracellular pH, [PCr], [P(i)], and [ATP] (brackets denote concentration). Blood samples drawn from a deep arm vein were analyzed with a blood gas-electrolyte analyzer to measure plasma pH, Pco(2), and [Lac(-)](pl), and plasma [HCO(3)(-)] was calculated from pH and Pco(2). NaHCO(3) ingestion resulted in an increased (P < 0.05) plasma pH and [HCO(3)(-)] throughout rest and exercise. Time to fatigue and peak power output were increased (P < 0.05) by approximately 12% in Alk. During exercise, a delayed (P < 0.05) onset of intracellular acidosis (1.17 +/- 0.26 vs. 1.28 +/- 0.22 W, Con vs. Alk) and a delayed (P < 0.05) onset of rapid increases in the [P(i)]-to-[PCr] ratio (1.21 +/- 0.30 vs. 1.30 +/- 0.30 W) were observed in Alk. No differences in total [H(+)], [P(i)], or [Lac(-)](pl) accumulation were detected. In conclusion, NaHCO(3) ingestion was shown to increase plasma pH at rest, which resulted in a delayed onset of intracellular acidification during incremental exercise. Conversely, NaHCO(3) was not associated with increased [Lac(-)](pl) accumulation or PCr breakdown. (+info)
Myoclonus and metabolic alkalosis from licorice in antacid.
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A 90-year-old woman with hypertension developed metabolic alkalosis and myoclonus. Her medications included diltiazem hydrochloride, benidipine hydrochloride, kallidinogenase, procaterol hydrochloride, sennoside, dihydrocodeine phosphate, and KM powder antacid that contained 354 mg of licorice and 900 mg of sodium bicarbonate per 3.9 g of powder. Endocrinological studies showed slightly reduced plasma renin activity and normal plasma aldosterone concentration. A provisional diagnosis of licorice-induced metabolic alkalosis was established and the patient was successfully treated after correction of serum pH and cessation of the medications. Licorice-induced metabolic alkalosis must be considered in the differential diagnosis of myoclonus. (+info)
Elevated lactate and alkalosis in chronic human brain infarction observed by 1H and 31P MR spectroscopic imaging.
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The goal of this study was to investigate lactate and pH distributions in subacutely and chronically infarcted human brains. Magnetic resonance spectroscopic imaging (MRSI) was used to map spatial distributions of 1H and 31P metabolites in 11 nonhemorrhagic subacute to chronic cerebral infarction patients and 11 controls. All six infarcts containing lactate were alkalotic (pHi = 7.20 +/- 0.04 vs. 7.05 +/- 0.01 contralateral, p less than 0.01). This finding of elevated lactate and alkalosis in chronic infarctions does not support the presence of chronic ischemia; however, it is consistent with the presence of phagocytic cells, gliosis, altered buffering mechanisms, and/or luxury perfusion. Total 1H and 31P metabolites were markedly reduced (about 50% on average) in subacute and chronic brain infarctions (p less than 0.01), and N-acetyl aspartate (NAA) was reduced more (approximately 75%) than other metabolites (p less than 0.01). Because NAA is localized in neurons, selective NAA reduction is consistent with pathological findings of a greater loss of neurons than glial cells in chronic infarctions. (+info)
Pathophysiology of functional mutations of the thiazide-sensitive Na-Cl cotransporter in Gitelman disease.
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Most of the missense mutations that have been described in the human SLC12A3 gene encoding the thiazide-sensitive Na(+)-Cl(-) cotransporter (TSC, NCC, or NCCT), as the cause of Gitelman disease, block TSC function by interfering with normal protein processing and glycosylation. However, some mutations exhibit considerable activity. To investigate the pathogenesis of Gitelman disease mediated by such mutations and to gain insights into structure-function relationships on the cotransporter, five functional disease mutations were introduced into mouse TSC cDNA, and their expression was determined in Xenopus laevis oocytes. Western blot analysis revealed immunoreactive bands in all mutant TSCs that were undistinguishable from wild-type TSC. The activity profile was: wild-type TSC (100%) > G627V (66%) > R935Q (36%) = V995M (32%) > G610S (12%) > A585V (6%). Ion transport kinetics in all mutant clones were similar to wild-type TSC, except in G627V, in which a small but significant increase in affinity for extracellular Cl(-) was observed. In addition, G627V and G610S exhibited a small increase in metolazone affinity. The surface expression of wild-type and mutant TSCs was performed by laser-scanning confocal microscopy. All mutants exhibited a significant reduction in surface expression compared with wild-type TSC, with a profile similar to that observed in functional expression analysis. Our data show that biochemical and functional properties of the mutant TSCs are similar to wild-type TSC but that the surface expression is reduced, suggesting that these mutations impair the insertion of a functional protein into the plasma membrane. The small increase in Cl(-) and thiazide affinity in G610S and G627V suggests that the beginning of the COOH-terminal domain could be implicated in defining kinetic properties. (+info)
Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.
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BACKGROUND: Gitelman's syndrome (GS) is an autosomal recessive disorder resulting from inactivating mutations in the thiazide-sensitive Na-Cl co-transporter (NCCT) gene. To date, almost 90 mutations have been identified. It is possible that there is a population-specific distribution of mutations. In this study, we analysed mutations in the NCCT gene of seven Japanese patients with GS. METHODS: Peripheral blood mononuclear cells were isolated from patients with GS, their family members and healthy control subjects. A mutation analysis of the NCCT gene was performed completely by direct automated sequencing of polymerase chain reaction-amplified DNA products. In patients with a deletion or splice site mutation, we undertook cDNA sequence analysis. RESULTS: We identified nine mutations. Five of them [c.185C>T (Thr60Met), c.1712C>T (Ala569Val), c.1930C>T (Arg642Cys), c.2552T>A (Leu849His) and c.1932delC] have been reported in Japanese patients, but not in GS patients from other ethnic groups. The remaining four mutations [c.7A>T (Met1Leu), c.1181_1186+20del26, c.1811_1812delAT and IVS16+1G>A] were novel. In cDNA derived from a patient with c.1181_1186+20del26, a deletion of exon 9 and a frameshift at the start of exon 10 were observed. In cDNA derived from patients with IVS16+1G>A, an additional 96 bp insertion between exons 16 and 17 was observed. Six out of seven patients were compound heterozygotes, and the remaining one carried a single heterozygous mutation. CONCLUSIONS: We found four novel mutations in the NCCT gene in seven Japanese patients with GS. Moreover, our study suggests that the distribution of mutations in the NCCT gene in Japanese GS patients potentially differs from that in other populations. (+info)
Salt handling and hypertension.
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The kidney plays a central role in our ability to maintain appropriate sodium balance, which is critical to determination of blood pressure. In this review we outline current knowledge of renal salt handling at the molecular level, and, given that Westernized societies consume more salt than is required for normal physiology, we examine evidence that the lowering of salt intake can combat hypertension. (+info)