Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of plasma renin assays in clinical practice is reviewed and experience with an assay for plasma renin activity (PRA) is reported. In normal subjects, 10am ambulant PRA was significantly related to plasma angiotensin II levels but not related to daily urine sodium exretion in these subjects consuming normal diets. PRA was suppressed in patients with mineralocorticoid hypertension and in a small proportion of patients with essential hypertension. Very high values were observed in patients with untreated primary adrenal insufficiency, treatment of which resulted in a prompt fall of PRA to normal. PRA was usually normal in adrenalectomised patients and those with chronic adrenal insufficiency receiving satisfactory steroid replacement therapy. It is concluded that provided standardised conditions are used for the collection and assay, PRA is helpful in the assessment of hypokalaemic hypertension as well as in the early detection and management of patients with primary adrenal insufficiency or related conditions of salt wasting.
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PMID:Clinical use of plasma renin assays. 27 2

Cardiac cachexia has recently been identified as an independent risk factor for mortality in chronic congestive heart failure. The aims of our study were to further identify the clinical or biochemical predictors or correlates of the cachexia, and to quantitate the magnitude of wasting. We undertook an anthropometric comparison of 30 patients with congestive heart failure, aged 56 (13) years, with ten age- and sex-matched healthy volunteers and 16 patients with essential hypertension. In comparison to the healthy volunteers, the heart failure patients exhibited a trend towards a lower body mass index, 21 (2.7) versus 23 (3.8) kg/m2, the 95% confidence interval for the difference being -0.54 to 5.4. However, the mid-upper arm circumference, of 24 (3.8) cm in the heart failure patients, was significantly (P<0.02) lower than the 27 (2.0) cm in the healthy volunteer group, with a 95% confidence interval for the difference being 1.18 to 4.82 cm. The triceps, mid-thigh, scapula and abdominal skinfold thicknesses were separately and significantly (P<0.05) diminished in the heart failure patients compared to the healthy controls. The sum of the four skin fold thicknesses, with a value of 68 (13) mm in the healthy volunteers, was highly significantly greater (P<0.001) than the value of 35.6 (9) mm in the heart failure patients. The 95% confidence interval for this difference was 22.7 to 41.3 mm. The patients with essential hypertension differed significantly from the heart failure patients in all of these parameters (P<0.01), but were not statistically different from the healthy controls in the anthropometric parameters. Among the heart failure patients, those with tricuspid regurgitation (n = 12) had a worse clinical, biochemical and cachexia profile compared to patients without the tricuspid regurgitation (n = 18). The values (tricuspid regurgitation versus no regurgitation) were New York Heart Association Class, 3.5 (0.65) versus 2.7 (0.75), P<0.01; ejection fraction of 34 (9) versus 43 (13)%, not significant; greater hepatomegaly of 159 (31) versus 135 (29) mm, P<0.05; more severe hypoalbuminemia, 24.5 (2.7) versus 28.5 (6.8) g/l, P<0.05; and worse hyponatremia, 128 (4) versus 133 (5) mmol/l, P<0.05. The tricuspid regurgitation group had a significantly more severe reduction in abdominal and scapula skin fold thickness (P<0.01) than that found in patients without tricuspid regurgitation. The sum of the four skin fold thicknesses was significantly lower (P<0.05) in tricuspid regurgitation, 30.9 (8) mm, than in heart failure without associated regurgitation, 38.0 (9.6). The 95% confidence interval for the difference was 0.8 to 13.4 mm. It is concluded that significant diminution of muscle bulk and subcutaneous fat occurs in chronic heart failure. Tricuspid regurgitation may be an accentuating and accelerating risk factor for cardiac cachexia, on account of a greater hypoalbuminemia and hyponatremia, which, presumably, results from the associated protein-losing enteropathy.
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PMID:Anthropometric evaluation of cachexia in chronic congestive heart failure: the role of tricuspid regurgitation. 1057 94

Although the aldosterone-responsive segments of the nephron together reabsorb <10% of the filtered Na+, certain single-gene defects that affect the epithelial Na+ channel (ENaC) in the luminal membrane of the collecting duct (CD) or its regulation by aldosterone cause severe hypertension, whereas others cause salt wasting and hypotension. These rare defects illustrate the key role of the distal nephron in maintaining normal extracellular volume and blood pressure. Genetic defects that increase the Cl- conductance of the junctional complexes may also lead to salt retention and hypertension. Less dramatic alterations in regulatory actions of other hormones such as vasopressin (VP), either alone or with other genetic variations, diet, or environmental factors, may also produce Na+ retention or loss. Although VP acts primarily to regulate water balance, it is also an antinatriuretic hormone. Elevated basal plasma VP levels, and/or augmented VP release with increased Na+ intake, have been linked to essential hypertension in humans and in animal models of congestive heart failure and cirrhosis. Norepinephrine, dopamine, and prostaglandin E2 can inhibit the antinatriuretic effects of VP, and changes in the actions of these autocrine and paracrine regulators may also be involved in abnormal regulation of Na+ reabsorption.
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PMID:Abnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting duct. 1211 May 5

The epithelial sodium channel (ENaC) is a membrane protein made of three different but homologous subunits (a, b, and g) present in the apical membrane of epithelial cells of, for example, the distal nephron. This channel is responsible for salt reabsorption in the kidney and can cause human diseases by increasing channel function in Liddle's syndrome, a form of hereditary hypertension, or by decreasing channel function in pseudohypoaldosteronism type I, a salt-wasting disease in infancy. This review briefly discusses recent advances in understanding the implication of ENaC in Liddle's syndrome and in pseudohypoaldosteronism type I, both caused by mutations in the SCNN1 (ENaC) genes. Furthermore, it is still an open question to which extent SCNN1 genes coding for ENaC might be implicated in essential hypertension. The development of Scnn1 genetically engineered mouse models will provide the opportunity to test the effect of environmental factors, like salt intake, on the development of this kind of salt- sensitive hypertension.
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PMID:Epithelial sodium channel, salt intake, and hypertension. 1253 Sep 30

Gitelman's syndrome is an autosomal recessive disorder characterized by sodium wasting and hypotension. A middle-aged woman was diagnosed with Gitelman's syndrome because of typical clinical manifestations in the youth and homozygous mutations of 18-base-pair insertion in exon 6 of thiazide-sensitive NaCl-cotransporter gene. It was unusual that she showed hypertension with advancing age. Her serum potassium levels remained low at around 3.5 mEq/l despite potassium supplementation. This case demonstrates that hypertension could result in spite of the extremely decreased sodium reabsorption in Gitelman's syndrome and that essential hypertension is genetically heterogeneous, and abnormality of all genes may not be necessarily required to cause blood pressure rise.
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PMID:Hypertension in a patient with Gitelman's syndrome. 1500 4

The chloride channel ClC-Kb is expressed in the basolateral cell membrane of the distal nephron and participates in renal NaCl reabsorption. Loss-of-function mutations of ClC-Kb lead to classic Bartter syndrome, a rare salt-wasting disorder. Recently, we identified the ClC-Kb(T481S) polymorphism, which confers a strong gain-of-function effect on the ClC-Kb chloride channel. The present study has been performed to explore the prevalence of the mutation and its functional significance in renal salt handling and blood pressure regulation. As evident from electrophysiological analysis with the 2-electrode voltage-clamp technique, heterologous expression of ClC-Kb(T481S) in Xenopus oocytes gave rise to a current that was 7-fold larger than the current produced by wild-type ClC-Kb. The prevalence of the mutant allele was significantly higher in an African population from Ghana (22%) than in whites (12%). As tested in 1 white population, carriers of ClC-Kb(T481S) were associated with significantly higher systolic (by approximately 6.0 mm Hg) and diastolic (by approximately 4.2 mm Hg) blood pressures and significantly higher prevalence (45% versus 25%) of hypertensive (> or =140/90 mm Hg) blood pressure levels. Individuals carrying ClC-Kb(T481S) had significantly higher plasma Na+ concentrations and significantly decreased glomerular filtration rate. In conclusion, the mutation ClC-Kb(T481S) of the renal epithelial Cl- channel ClC-Kb strongly activates ClC-Kb chloride channel function in vitro and may predispose to the development of essential hypertension in vivo.
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PMID:Activating mutation of the renal epithelial chloride channel ClC-Kb predisposing to hypertension. 1644 91

Several monogenic hypertensive disorders are caused by genetic mutations leading to the deranged function and/or regulation of renal tubular NaCl transport, such as mutations of the renal epithelial Na+ channel (ENaC) in Liddle syndrome, of the kinase WNK1 (with no K) in Gordon syndrome, and of the mineralocorticoid receptor, or of 11beta-hydroxysteroid dehydrogenase. Moreover, excessive formation of aldosterone in glucocorticoid-remediable hypertension leads to severe hypertension. Conversely, impaired function of the Na+,K+,2Cl- cotransporter (NKCC2), the renal outer medullary K+ channel (ROMK1), and the renal epithelial Cl- channel ClCKb/Barttin causes Bartter syndrome and defective Na+,Cl+ cotransporter (NCCT) Gitelman syndrome, salt-wasting disorders with hypotension. These monogenic disorders are rare, but illustrate the significance of renal tubular transport in blood pressure regulation. There is little doubt, however, that deranged renal salt reabsorption significantly contributes to essential hypertension polymorphisms of several genes participating in the regulation of renal Na+ transport have been shown to be associated with blood pressure and prevalence of hypertension. Two common genes will be discussed in more detail. The first encodes the renal Cl- channel ClCKb. A gain-of-function mutation of ClCKb, increasing channel activity by 7- to 20-fold is found in approximately 20% of unselected Caucasians and 40% of an unselected African population. The second common gene variant (prevalence, 3%-5% in unselected Caucasians), to be discussed in more detail, affects the serum and glucocorticoid inducible kinase SGK1, a kinase upregulated by mineralocorticoids and enhancing the activity of ENaC, ROMK, and Na+/K+ATPase. Both gene variants are associated with slightly increased blood pressure. SGK1 further stimulates the glucose transporter SGLT1, and the SGK1 gene variant correlates, in addition, with increased body mass index.
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PMID:Renal tubular transport and the genetic basis of hypertensive disease. 1598 Sep 41

Thiazide-sensitive Na-Cl cotransporter (TSC, SLC12A3) is located on chromosome 16q13 and is expressed specifically in the renal distal convoluted tubule, where it mediates the reabsorption of Na+ and Cl-. Mutation of TSC is known to be responsible for Gitelman's syndrome, an autosomal recessive renal tubular disorder characterized by low blood pressure due to renal sodium wasting, hypokalemia, metabolic alkalosis, hypomagnesemia and normocalcemic hypocaliuria. We assessed mutational analysis of the TSC gene in 35 patients with Gitelman's syndrome. We found 16 missense mutaions, insertion of 18bp in the 6th exon, deletion of C in the 9th exon and deletion of C in the 16th exon. These results suggest that there is no mutational hot spot in the TSC gene. These 19 mutations include eight novel mutations: R261C, N406H, A523T, M672I, R1009Q, N1014K, deletion of C in the 9th exon and deletion of C in the 16th exon. The eight novel mutations might be responsible for impairment of NaCl reabsorption leading to the principal clinical features of Gitelman's syndrome in these patients. These mutations could bring new insights into genotype-phenotype correlations among the hypokalemic tubulopathies. Recently, genome-wide association studies, using SNPs to identify loci involved in susceptibility to common diseases, showed that the TSC gene may contribute to genetic susceptibility to diabetic nephropathy in Japanese. In addition, substitution of Arg904 to Gln in the TSC gene has been reported to predispose essential hypertension in Swedish and Japanese populations. Further studies are needed to clarify the possible associations of the TSC gene with common diseases.
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PMID:[Clinical significance of thiazide-sensitive Na-Cl cotransporter gene by mutational analysis]. 1751 Dec 64

STK39 encodes a serine threonine kinase, SPAK, which is part of a multi-kinase network that determines renal Na+ reabsorption and blood pressure (BP) through regulation of sodium-chloride co-transporters in the kidney. Variants within STK39 are associated with susceptibility to essential hypertension, and constitutively active SPAK mice are hypertensive and hyperkalemic, similar to familial hyperkalemic hyperkalemia in humans. SPAK null mice are hypotensive and mimic Gitelman syndrome, a rare monogenic salt wasting human disorder. Mice exhibit nephron segment-specific expression of full length SPAK and N-terminally truncated SPAK isoforms (SPAK2 and KS-SPAK) with impaired kinase function. SPAK2 and KS-SPAK function to inhibit phosphorylation of cation co-transporters by full length SPAK. However, the existence of orthologous SPAK2 or KS-SPAK within the human kidney, and the role of such SPAK isoforms in nephron segment-specific regulation of Na+ reabsorption, still have not been determined. In this study, we examined both human and mouse kidney transcriptomes to uncover novel transcriptional regulation of STK39. We established that humans also express STK39 transcript isoforms similar to those found in mice but differ in abundance and are transcribed from human-specific promoters. In summary, STK39 undergoes species-specific transcriptional regulation, resulting in differentially expressed alternative transcripts that have implications for the design and testing of novel SPAK-targeting antihypertensive medications.
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PMID:Identification and characterization of alternative STK39 transcripts within human and mouse kidneys reveals species-specific regulation of blood pressure. 3210 41