Selective Assembly of Na,K-ATPase α2ß2 Heterodimers in the Heart: DISTINCT FUNCTIONAL PROPERTIES AND ISOFORM-SELECTIVE INHIBITORS.

The Na,K-ATPase α2 subunit plays a key role in cardiac muscle contraction by regulating intracellular Ca2+, whereas α1 has a more conventional role of maintaining ion homeostasis. The ß subunit differentially regulates maturation, trafficking, and activity of α-ß heterodimers. It is not known whether the distinct role of α2 in the heart is related to selective assembly with a particular one of the three ß isoforms. We show here by immunofluorescence and co-immunoprecipitation that α2 is preferentially expressed with ß2 in T-tubules of cardiac myocytes, forming α2ß2 heterodimers. We have expressed human α1ß1, α2ß1, α2ß2, and α2ß3 in Pichia pastoris, purified the complexes, and compared their functional properties. α2ß2 and α2ß3 differ significantly from both α2ß1 and α1ß1 in having a higher K0.5K+ and lower K0.5Na+ for activating Na,K-ATPase. These features are the result of a large reduction in binding affinity for extracellular K+ and shift of the E1P-E2P conformational equilibrium toward E1P. A screen of perhydro-1,4-oxazepine derivatives of digoxin identified several derivatives (e.g. cyclobutyl) with strongly increased selectivity for inhibition of α2ß2 and α2ß3 over α1ß1 (range 22-33-fold). Molecular modeling suggests a possible basis for isoform selectivity. The preferential assembly, specific T-tubular localization, and low K+ affinity of α2ß2 could allow an acute response to raised ambient K+ concentrations in physiological conditions and explain the importance of α2ß2 for cardiac muscle contractility. The high sensitivity of α2ß2 to digoxin derivatives explains beneficial effects of cardiac glycosides for treatment of heart failure and potential of α2ß2-selective digoxin derivatives for reducing cardiotoxicity.

Association of Familial Hyperkalemia and Hypertension with Proximal Renal Tubular Acidosis and Epileptic Seizures.

INTRODUCTION: Familial hyperkalemic hypertension (FHHt) is an inherited disease characterized by hyperkalemia, hypertension, and hyperchloremic acidosis (HCA). The primary defect is a hyperactive sodium chloride co-transporter, expressed in the renal distal tubule. FHHt is caused by mutation in either WNK1, WNK4, KLHL3, or Cul3. The mechanism of HCA is not completely understood. METHODS: Clinical and genetic data were collected from the largest family with FHHt described in the literature. Urine ammonia was measured in 26 family members. Epilepsy was diagnosed clinically. RESULTS: Of the 85 family members, 44 are affected by the Q565E WNK4 mutation, and 28 are newly described. In genetically engineered mice, urinary ammonium was decreased. In our study, urine ammonium did not change. In 11 unaffected subjects, urine ammonia per creatinine was 8.013 ± 3.620 mm/mm, and in 15 subjects affected by FHHt, it was 8.990 ± 4.300 mm/mm (p = 0.546, not significant). Due to the large family size and prolonged follow-up, rare conditions can be identified. Indeed, two children have genetic generalized epilepsy and one child has migraine. The prevalence of epilepsy is 4.545% (2/44) much higher than in the general population (0.681%). This difference is statistically significant (χ2 with Yates correction = 5.127, p = 0.023). CONCLUSIONS: We provide further evidence that the origin of HCA in FHHt lies in the proximal renal tubule. The association of FHHt with epilepsy leads us to speculate that the raised serum K in susceptible subjects may cause a rise in CSF K, and extracellular cerebral K, leading to epilepsy.

Cyclosporine metabolic side effects: association with the WNK4 system.

BACKGROUND: Cyclosporine is used for treatment of transplanted patients and for immune-mediated diseases. Cyclosporine is known to cause a combination of metabolic side effects including hypertension, hyperkalemia, hypercalciuria and hypomagnesemia. These side effects except for hypomagnesemia are the cardinal features of familial hyperkalemia and hypertension (FHHt), also called pseudohypoaldosteronism type II (PHA II). FHHt is caused by mutations in the kinases WNK1 and WNK4 resulting in an increase in renal Na-Cl cotransporter (NCC) apical distribution and function. Therefore, we studied whether cyclosporine's metabolic side effects are mediated by WNK4 and NCC. DESIGN: Sprague-Dawley (SD) rats were treated by cyclosporine 25 mg kg(-1) subcutaneously for 14 days. Blood pressure, blood chemistry values and kidney WNK4 protein were determined. In addition, mDCT cells were exposed to cyclosporine, and their WNK4 mRNA and protein content, and their NCC protein content and phosphorylation were determined. RESULTS: The rats developed an FHHt-like syndrome including hypertension, hyperkalemia and salt-sensitive hypercalciuria. A significant increase in their kidney WNK4 protein content (0·13 ± 0·01 vs. 0·67 ± 0·16 WNK4/GAPDH in controls, P = 0·0183) was found. In mDCT cells, cyclosporine caused a rise in WNK4 mRNA levels and also a threefold rise in WNK4 protein content. This rise was followed by a rise in NCC protein content and pSer71 phosphorylation. CONCLUSIONS: These observations may explain in part the mechanism of cyclosporine-induced hypertension, hyperkalemia and hypercalciuria.

Effect of age and affection status on blood pressure, serum potassium and stature in familial hyperkalaemia and hypertension.

BACKGROUND: The rare autosomal dominant genetic disorder familial hyperkalemia and hypertension which is caused by mutations in WNK4 kinase, is characterized by childhood hyperkalemia and hypercalciuria, and appearance of hypertension in the third to fourth decade. Accompanying short stature is often described. METHODS: We determined height, blood pressure and blood and urinary biochemical parameters in members of a very large family of FHHt with the WNK4 Q565E mutation. RESULTS: The family has 57 members, 30 of whom (including 14 children) are affected. Prehypertension occurred in 7/11 affected and 1/10 unaffected children (P = 0.024). Serum potassium (SK) was ~0.5 mmol/L higher in affected children vs adults [5.98 ± 0.42 vs 5.46 ± 0.40 mmol/L, respectively (P < 0.0001)] (33 samples from 11 children and 36 samples from eight adults). SK of ≥ 6.0 mmol/L occurred in 16/33 children's samples and in 3/36 adults' samples (P = 0.0003). Hyperkalaemia in children is currently untreated. Children also had more severe hyperchloraemia and hypercalciuria. The family contains four large subfamilies, and each includes 8-10 siblings. In one subfamily, height Z-score was lower in affected vs unaffected subjects [- 2.69 ± 0.36 vs -1.05 ± 0.16, respectively (P < 0.0001)]. In the other three subfamilies, no such difference was found. CONCLUSIONS: Short stature is not part of FHHt with the WNK4 Q565E mutation. Children affected with FHHt have a high prevalence of prehypertension, and their hyperkalaemia is more severe than that of affected adults. Children may have a more severe defect in the basic mechanism that produces hyperkalaemia. We suggest that, in affected adults, the attenuation of hyperkalaemia and appearance of hypertension may be the result of a late rise in the activity of renal transporters or channels such as the epithelial sodium channel.

Distinct pathways for the involvement of WNK4 in the signaling of hypertonicity and EGF.

WNK4 kinase mutations produce the autosomal dominant disorder familial hyperkalemia and hypertension (FHH), also known as pseudohypoaldosteronism type II, by a molecular mechanism that is not completely understood. In vitro experiments in frog oocytes showed that WNK4 affects ion transport systems such as the Na-Cl cotransporter and the renal outer medullary potassium channel. Some features of FHH suggest that long-term effects are involved in WNK4 signaling. In addition, WNK1 and WNK2, paralogs of WNK4, were shown to be involved in MAP kinase signaling. We therefore investigated possible WNK4 involvement in MAP kinase signaling. We stimulated HEK 293 cells overexpressing WNK4 by hypertonicity or using EGF, and measured phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and p38. WNK4 augmented the phosphorylation of ERK1/2 and p38 in response to both hypertonicity and EGF. The FHH-producing and kinase-deficient mutants behaved similarly to wild-type WNK4. Hypertonicity stimulation was accompanied by cellular relocalization of WNK4 as manifested by its reversible disappearance from the supernatant fraction following extraction with a detergent-containing buffer. Live-cell microscopy showed that the cytoplasmic-soluble WNK4 redistributes rapidly to membrane-bound organelles, which, in the case of WNK1 kinase, were recently shown to represent trans-Golgi network/recycling endosomes. In contrast, EGF stimulation was not accompanied by redistribution of WNK4 as determined by cell fractionation or cell microscopy. The observation that WNK4-induced MAP kinase stimulation caused by hypertonicity, but not that caused by EGF, is associated with WNK4 subcellular redistribution suggests that this redistribution has a role in WNK4 signaling.

Increased urinary Na-Cl cotransporter protein in familial hyperkalaemia and hypertension.

BACKGROUND: Familial hyperkalaemia and hypertension (FHH), also termed pseudohypoaldosteronism type II, is a rare monogenic form of hypertension caused by mutations in the WNK1 or WNK4 kinases. In vitro expression of WNK4 reduces surface abundance and activity of coexpressed NaCl cotransporter (NCCT). This effect is lost in disease-producing WNK4 mutants. In two mice models of FHH, one expressing two extra copies of mutant WNK4 (Q562E) and another in which a mutant (D561A) WNK4 replaced wild-type WNK4, renal distal tubule hyperplasia with overexpression of NCCT was found. Currently no FHH human renal tissue is available to test for increased distal tubule surface abundance of NCCT. The availability of a unique large family with FHH and the Q565E WNK4 mutation enabled us to investigate this issue in an indirect manner. METHODS: Assuming that shedding of NCCT to the urine reflects its abundance in the distal tubule epithelium, we measured urinary NCCT protein in eight subjects of the FHH family and in eight unrelated controls by western blotting. RESULTS: Urinary NCCT protein was about four times higher in FHH than in controls [111.1 +/- 40.5 versus 26.1 +/- 16.4 densitometry units (P < 0.0001)]. No significant difference in urinary sodium and potassium concentrations was seen between FHH and controls. CONCLUSIONS: The increased urinary NCCT in FHH most probably reflects increased NCCT abundance in the apical membrane of distal tubule cells in patients with FHH and the WNK4 mutation and points to the pathogenetic mechanism for the clinical phenotype of FHH and the WNK4 mutation, supporting results in transgenic mice with the same mutation and in knockin mice with another mutation.

Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase.

This article examines the central role of Na,K-ATPase (α1ß1FXYD2) in renal Mg handling, especially in distal convoluted tubule (DCT), the segment responsible for final regulation of Mg balance. By considering effects of Na,K-ATPase on intracellular Na and K concentrations, and driving forces for Mg transport, we propose a consistent rationale explaining basal Mg reabsorption in DCT and altered Mg reabsorption in some human diseases. FXYD2 (γ subunit) is a regulatory subunit that adapts functional properties of Na,K-ATPase to cellular requirements. Mutations in FXYD2 (G41R), and transcription factors (HNF-1B and PCBD1) that affect FXYD2 expression are associated with hypomagnesemia with hypermagnesuria. These mutations result in impaired interactions of FXYD2 with Na,K-ATPase. Renal Mg wasting implies that Na,K-ATPase is inhibited, but in vitro studies show that FXYD2 itself inhibits Na,K-ATPase activity, raising K0.5 Na. However, FXYD2 also stabilizes the protein by amplifying specific interactions with phosphatidylserine and cholesterol within the membrane. Renal Mg wasting associated with impaired Na,K-ATPase/FXYD2 interactions is explained simply by destabilization and inactivation of Na,K-ATPase. We consider also the role of the Na,K-ATPase in Mg (and Ca) handling in Gitelman syndrome and Familial hyperkalemia and hypertension (FHHt). Renal Mg handling serves as a convenient marker for Na,K-ATPase activity in DCT.

Hypermagnesuria in Humans Following Acute Intravenous Administration of Digoxin.

BACKGROUND: Hypomagnesemia is a known predisposing condition for the appearance of digitalis toxicity. The detection of a genetic form of Mg urinary wasting with hypomagnesemia being caused by a mutation in the γ subunit (FXYD2) of the Na,K-ATPase, the pharmacological target of Digoxin, prompted us to investigate whether Digoxin administration increases urinary Mg excretion. METHODS: Two groups of subjects, with rapid atrial fibrillation, received intravenous Digoxin (n = 9) or verapamil (n = 8), for heart rate control. During the following 4 h, blood and urinary creatinine, sodium, potassium, calcium, and magnesium levels were determined, and fractional excretion (Fex) values for Na, K, Ca, and Mg were calculated. RESULTS: In the Digoxin group, at 60 min Fex Mg rose from 3.07 ± 1.21 to 7.58 ± 2.51% (an increase of 269 ± 107% of baseline, p < 0.001), and at 240 min to 6.05 ± 2.30% (204 ± 56% of baseline, p < 0.01). No significant change was observed for Fex Na, Fex K, and Fex Ca. A striking correlation was found between individual values of Fex Mg and serum Digoxin concentration (r = 0.678, p < 0.0001). No significant correlation was found between Fex Na or Fex K and serum Digoxin. A correlation of borderline significance was found between Fex Ca and serum Digoxin (r = 0.349, p = 0.073). CONCLUSIONS: The hypermagnesuric effect of acute Digoxin treatment is reminiscent of the effect of the missense mutation in FXYD2, which assumes that FXYD2 is a positive regulator of Na,K-ATPase in the distal convoluted tubule (DCT). The borderline calciuric effect of Digoxin may point to an additional site of action, more proximal to the DCT, that is, the thick ascending limb.

Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter.

BACKGROUND: Familial hyperkalemia and hypertension (FHHt) is an inherited disorder manifested by hyperkalemia and hypertension. The following four causative genes were identified: WNK1, WNK4, CUL3, and KLHL3. For the first 3 genes, inheritance is autosomal dominant. For KLHL3, inheritance is mostly dominant. A few cases with autosomal recessive disease were described. The mechanism of these 2 modes of inheritance is not clear. In the recessive form, the phenotype of heterozygotes is not well described. METHODS: Clinical and genetic investigation of members of 2 families was performed, one with recessive FHHt, and the other, an expansion of a family with Q309R KLHL3 dominant mutation, previously reported by us. Urinary exosomal sodium chloride cotransporter (NCC) was measured. RESULTS: A family with recessive FHHt caused by a new KLHL3 mutation, S553L, is described. This consanguineous Jewish family of Yemenite extraction, included 2 homozygous and 7 heterozygous affected subjects. Increased urinary NCC was found in the affected members of the family with dominant Q309R KLHL3 mutation. In the recessive S553L family, homozygotes appeared to have increased urinary NCC abundance. Surprisingly, heterozygotes seemed to have also increased urinary NCC, though at an apparently lower degree. This was not accompanied by a clinical phenotype. CONCLUSIONS: A new recessive mutation in KLHL3 (S553L) was identified in FHHt. Increased urinary NCC was found in affected members (heterozygous) with dominant KLHL3 Q309R, and in affected members (homozygous) of the recessive form. Unexpectedly, in the recessive disease, heterozygotes seemed to have increased urinary NCC as well, apparently not sufficient quantitatively to produce a clinical phenotype.

Gastroenteritis-associated hyperamylasemia: prevalence and clinical significance.

BACKGROUND: Serum amylase levels can be elevated in various pathological conditions. However, acute gastroenteritis has not been widely recognized as a cause for hyperamylasemia. PATIENTS AND METHODS: We conducted a retrospective study of amylase results for all patients hospitalized or discharged from the emergency department with a diagnosis of gastroenteritis from April through November 1999. Patients with other possible medical causes for elevated amylase levels were excluded. We also compared the clinical and laboratory parameters of hyperamylasemic vs. normoamylasemic hospitalized patients with gastroenteritis. RESULTS: A total of 1041 patients with acute gastroenteritis were identified. Serum amylase levels were determined in 701 patients and were abnormally elevated in 66 of them. In 15 patients, other possible causes of hyperamylasemia were present, and these patients were excluded. The mean serum amylase level among the remaining 51 patients (7.4% of the remaining 686 patients with gastroenteritis) was 1.32 of the upper normal level, with a range of up to 2.2 times the upper normal range. Clinicians tended to admit more hyperamylasemic patients than normoamylasemic patients (10 of 51 vs. 65 of 635; P =.03, 1 sided). However, the course of gastroenteritis in the hospitalized hyperamylasemic patients did not differ significantly from that in the hospitalized normoamylasemic patients, as judged by the clinical signs and symptoms, laboratory results, length of hospital stay, and need for antibiotics. CONCLUSIONS: Gastroenteritis is associated with a mild to moderate elevation of serum amylase levels in a significant portion of patients and should be included in the differential diagnosis of hyperamylasemia. Such elevation, however, does not seem to bear clinical significance in terms of the severity of disease.

Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations.

BACKGROUND: Familial hyperkalemia and hypertension (FHHt) is a rare genetic disorder manifested by hyperkalemia and early hypertension. Hypercalciuria is another accompanying feature. Mutations in WNK4 and WNK1 were found initially, and recently additional mutations were found in two genes, KLHL3 and CUL3, which are components of the Ubiquitin system. It was not reported whether these latter mutations are accompanied by hypercalciuria. METHODS: We compared urinary calcium excretion (UCa) in affected subjects with FHHt and KLHL3 mutations, and in their unaffected family members, and in affected subjects with FHHt and WNK4 Q565E mutation. RESULTS: Two new families with FHHt including a total number of 23 subjects, 10 of them affected, in whom previously described mutations in KLHL3 (Q309R and R528H) were identified. Presenting features were short stature in the first family, and transient tachypnea of the newborn (TTN) in the second. Affected subjects had hypercalciuria. UCa levels in affected subjects in the two families were significantly higher than in unaffected subjects (0.608 ± 0.196 vs. 0.236 ± 0.053 mmol Ca per mmol creatinine, respectively (p < 0.0001)). Hypercalciuria in FHHt with KLHL3 mutations is less severe than that observed in FHHt with the Q565E WNK4 mutation (0.608 ± 0.196 (n = 10) mmol Ca per mmol creatinine versus 0.860 ± 0.295 (n = 29), respectively (p = 0.0168)). CONCLUSIONS: FHHt caused by KLHL3 mutations is accompanied by hypercalciuria as well as hyperkalemia and hypertension. The similar phenomena observed for FHHt caused by WNK4 mutations fits the other evidence that WNK4 mutations are activating, and the aberrant mechanism of calcium handling by the kidney in FHHt.

Hypercalciuria in familial hyperkalemia and hypertension accompanies hyperkalemia and precedes hypertension: description of a large family with the Q565E WNK4 mutation.

Familial hyperkalemia and hypertension (FHH; pseudohypoaldosteronism type II) is an autosomal dominant disorder characterized by hyperkalemia, hypertension, and low renin. WNK1 kinase overexpression and WNK4 kinase inactivating missense mutations cause FHH. When expressed in frog oocyte, WNK4 inhibits Na-Cl cotransporter surface expression, and WNK1 relieves this inhibition. We have reported hypercalciuria in subjects with the WNK4 Q565E mutation. In contrast, in subjects with WNK1 overexpression, normocalciuria was found. Here we report a major extension of our previously described kindred that contains 34 subjects, 18 of them affected by the mutation. Hypertension was diagnosed in 13 affected subjects at the age of 31 +/- 12 yr. Five of the affected or obligatory affected subjects had stroke, in four at the age of 50-62 yr. Seven subjects with FHH were diagnosed 27 yr previously. All four subjects who were normotensive at diagnosis became hypertensive during follow-up. The mean time between detection of hyperkalemia and appearance of hypertension was 13 yr. In the extended kindred, compared with the unaffected subjects, affected subjects had hyperkalemia, low transtubular potassium gradient, hyperchloremia, low bicarbonate, higher aldosterone, and marked suppression of renin. Urinary calcium levels in affected and unaffected subjects were 0.85 +/- 0.27 and 0.28 +/- 0.12 mmol/mmol creatinine, respectively (P < 0.0001). Hypercalciuria was accompanied by lower serum calcium levels [9.44 +/- 0.15 vs. 9.81 +/- 0.31 mg/dl (2.36 +/- 0.04 vs. 2.45 +/- 0.08 mmol/liter); P = 0.01], supporting a mechanism of renal calcium leak. The six affected, currently normotensive subjects had the same degree of hyperkalemia, hypercalciuria, and low renin as the affected hypertensive subjects. We conclude that in FHH with WNK4 mutations, with time all affected subjects will apparently develop hypertension. Hypercalciuria accompanies hyperkalemia, and both precede hypertension. Based on the recent findings that WNK4 regulates the renal outer medullary potassium channel as well as epithelial Cl(-)/base exchanger and the Na(+)-K(+)-2Cl(-) cotransporter, we suggest that WNK4 interacts with a calcium channel or transporter.

Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density.

Mutations in WNK kinases cause pseudohypoaldosteronism type II (PHA II) and may represent a novel signaling pathway regulating blood pressure and K(+) and H(+) homeostasis. PHA II is an autosomal dominant disorder characterized by hypertension, hyperkalemia, and metabolic acidosis, with normal glomerular filtration rate. Thiazide diuretics correct all abnormalities. Inactivating mutations in the thiazide-sensitive NaCl cotransporter cause Gitelman syndrome, featuring hypotension, hypokalemia, and metabolic alkalosis plus hypocalciuria and hypomagnesemia. We investigated whether hypercalciuria and hypermagnesemia occurred in a large family with PHA II. Eight affected and eight unaffected members of a PHA II family with the Q565E WNK 4 mutation were studied. In affected members blood and urinary chemistry were measured on and off hydrochlorothiazide (HCTZ), and bone mineral density was determined. Marked sensitivity to HCTZ was found. A mean dose of 20 mg/d reduced mean blood pressure in the six hypertensive subjects by 54.3 (systolic) and 24.5 (diastolic) mm Hg. In affected subjects, HCTZ reduced mean serum K(+) by 1.12 mmol/liter, mean serum Cl(-) by 6.2 mmol/liter, and mean urinary calcium by 65% and elevated mean serum calcium by 0.11 mmol/liter and mean serum urate by 118 micromol/liter. Compared with the literature, this represents an increase of 6-7 in HCTZ potency. Affected members had normomagnesemia, hypercalciuria (336 +/- 113 vs. 155 +/- 39 mg/d in unaffected relatives, P = 0.0002), and decreased bone mineral density. In PHA II the observed marked sensitivity to thiazides and the hypercalciuria are consistent with increased NaCl cotransporter activity. PHA II may serve as a model to investigate thiazides' beneficial effects and side effects.

Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland.

Many patients with cardiac arrhythmias require concomitant therapy with warfarin and amiodarone. Beyond the predictable pharmacokinetic drug-drug interaction requiring a significant warfarin dose reduction, the iodine-rich amiodarone affects the thyroid gland, causing overt hypothyroidism or thyrotoxicosis in 14%-18% of cases. In turn, thyroid disorders may affect warfarin sensitivity, with hypothyroidism and thyrotoxicosis resulting in increased or decreased warfarin requirements, respectively. We describe 3 patients on concomitant amiodarone and warfarin who developed amiodarone-induced thyrotoxicosis heralded by a significant decrease in warfarin requirements. We review the literature on the mechanisms of the complex drug-drug and drug-disease interactions within the thyroid gland, warfarin, and amiodarone triad. Given that significant thyroid disorders may be only mildly symptomatic and thus may escape clinical detection, we suggest that thyroid function should be tested in any patient with otherwise unexplained changes in warfarin dose requirements, particularly if concomitantly treated with amiodarone.

Clopidogrel-induced systemic inflammatory response syndrome.

Clopidogrel bisulfate, a widely used inhibitor of platelet aggregation, is considered at least as safe as aspirin. We describe a patient who developed a systemic inflammatory response syndrome consisting of high fever, tachycardia, cellulitis-like rash, impaired liver function, and mild leukopenia after receiving clopidogrel before coronary angiography and stent implantation. The reaction resolved promptly after withdrawal of the drug and recurred shortly after a rechallenge dose was administered, thus making the diagnosis of a clopidogrel-induced reaction highly probable. Recognition of this clopidogrel-induced syndrome is extremely important, both for rapid discontinuation of the offending drug and for avoidance of unnecessary drug therapy or invasive procedures.

Pericardial tamponade-associated hyponatremia.

We describe a 58-year-old patient with adenocarcinoma of the lung who suffered from severe weariness that was attributed to hyponatremia. The cause of hyponatremia was found to be a malignant pericardial effusion that caused pericardial tamponade. The hyponatremia was corrected rapidly after the evacuation of the malignant effusion. The pathogenetic mechanisms of hyponatremia secondary to pericardial effusion are discussed.