Molecular insights from dysregulation of the thiazide-sensitive WNK/SPAK/NCC pathway in the kidney: Gordon syndrome and thiazide-induced hyponatraemia.

Human blood pressure is dependent on balancing dietary salt intake with its excretion by the kidney. Mendelian syndromes of altered blood pressure demonstrate the importance of the distal nephron in this process and of the thiazide-sensitive pathway in particular. Gordon syndrome (GS), the phenotypic inverse of the salt-wasting Gitelman syndrome, is a condition of hyperkalaemic hypertension that is reversed by low-dose thiazide diuretics or a low-salt diet. Variants within at least four genes [i.e. with-no-lysine(K) kinase 1 (WNK1), WNK4, kelch-like family member 3 (KLHL3) and cullin 3 (CUL3)] can cause the phenotype of GS. Details are still emerging for some of these genes, but it is likely that they all cause a gain-of-function in the thiazide-sensitive Na(+) -Cl(-) cotransporter (NCC) and hence salt retention. Herein, we discuss the key role of STE20/sporulation-specific protein 1 (SPS1)-related proline/alanine-rich kinase (SPAK), which functions as an intermediary between the WNKs and NCC and for which a loss-of-function mutation produces a Gitelman-type phenotype in a mouse model. In addition to Mendelian blood pressure syndromes, the study of patients who develop thiazide-induced-hyponatraemia (TIH) may give further molecular insights into the role of the thiazide-sensitive pathway for salt reabsorption. In the present paper we discuss the key features of TIH, including its high degree of reproducibility on rechallenge, possible genetic predisposition and mechanisms involving excessive saliuresis and water retention. Together, studies of Gordon syndrome and TIH may increase our understanding of the molecular regulation of sodium trafficking via the thiazide-sensitive pathway and have important implications for hypertensive patients, both in the identification of new antihypertensive drug targets and avoidance of hyponatraemic side-effects.

Syndrome of inappropriate anti-diuretic hormone secretion secondary to carboplatin after docetaxel-carboplatin-trastuzumab combination for early stage HER-2 positive breast cancer.

Carboplatin is a platinum analogue, widely used in the treatment of numerous cancer types including lung, genitourinary and ovarian cancers. It is also used in the adjuvant treatment of human epidermal growth factor receptor 2 positive breast cancer, where a non-anthracycline regimen is preferred. It is considered generally to be less toxic though potentially less efficacious than cisplatin, another platinum compound. Cisplatin is well recognized as causing hyponatremia, through the mechanism of renal salt wasting. Conversely, carboplatin has only rarely been associated with hyponatremia. We report here a case of severe hyponatremia occurring 6 days after adjuvant treatment with a carboplatin-containing chemotherapy regimen for early stage breast cancer. The mechanism of hyponatremia was consistent with the syndrome of inappropriate anti-diuretic hormone secretion based on biochemical and clinical findings, and response to fluid restriction. With no previously reported cases of docetaxel-associated or trastuzumab-associated hyponatremia, the causative agent was considered to be carboplatin. Additionally there was no recurrence of hyponatremia on recommencement of docetaxel and trastuzumab therapy. Hyponatremia secondary to carboplatin has been rarely reported in the literature, with only three previously reported cases. Although it is rare, oncologists should be aware of the potential for carboplatin to cause hyponatremia and the need to monitor electrolytes throughout therapy.

Increasing creatine kinase concentrations at the 161-km Western States Endurance Run.

OBJECTIVE: Very high blood creatine kinase (CK) concentrations have been observed among recent finishers of the 161-km Western States Endurance Run (WSER), and it has been suggested that there is a link between rhabdomyolysis and hyponatremia. Therefore, the purpose of this study was to compare CK concentrations of finishers in the 2010 WSER with past values, and to determine whether there was an association between blood CK and sodium concentrations. METHODS: Consenting 2010 WSER finishers provided blood samples at the finish for determination of blood CK and sodium concentrations. Finish time, age, and gender were obtained from official race results, and running experience was determined from our database as number of prior 161-km ultramarathon finishes. RESULTS: From 216 (66%) of the 328 finishers, median and mean CK concentrations were found to be 20 850 IU/L and 32 956 IU/L, respectively (range 1500-264 300 IU/L), and 13 (6%) had values greater than 100 000 IU/L. These values were statistically higher (P < .0001) than those reported from the 1995 WSER. The CK concentration was not significantly associated with finish time, age, gender, or running experience. Blood sodium concentrations were obtained from a subgroup of 159 runners, and the relationship between blood CK and sodium concentrations did not reach statistical significance (P = .06, r = -0.12). CONCLUSIONS: Creatine kinase concentrations of 2010 WSER finishers are higher than values previously reported. More research should focus on explaining this observation and on whether there is a possible link between higher CK concentrations and hyponatremia.

Elevated levels of serum creatine kinase induced by hyponatraemia.

Elevated serum creatine kinase levels are one of the major criteria for the diagnosis of myocardial injury. Noncardiac causes such as muscular and brain damage may also be associated with elevated serum creatine kinase levels. Hyponatremia may induce increased serum creatine kinase in association with rhabdomyolysis or with hypothyroidism. A patient is described where three episodes of hyponatraemia not associated with rhabdomyolysis or hypothyroidism induced transient elevations of serum creatine kinase levels. The association between hyponatraemia and elevated creatine kinase levels should be emphasized to prevent erroneous diagnosis of myocardial injury.

Ectopic production and processing of atrial natriuretic peptide in a small cell lung carcinoma cell line and tumor from a patient with hyponatremia.

BACKGROUND: Tumors and tumor cell lines from two patients with small cell lung carcinoma (SCLC) (one with and one without hyponatremia) were studied. Ectopic production and prohormone processing of atrial natriuretic peptide (ANP) were investigated to determine if a biologically active peptide was produced in a tumor cell line from a patient with hyponatremia and no evidence of arginine vasopressin (AVP) production. METHODS: Ribonuclease (RNase) protection assays were performed on mRNA isolated from tumors and tumor cell lines established from two SCLC patients, one with and one without hyponatremia. Cellular extracts and conditioned media were studied using reversed-phase high performance liquid chromatography (HPLC) to determine the immunoreactive form of ANP. Tumor cell line sonicates were studied for subcellular localization of enzymatic activity that cleaved pro-ANP peptide substrates. RESULTS: RNase protection assays showed a 200-base pair protected fragment in the mRNA isolated from the tumor and tumor cell line from the patient with hyponatremia (Patient 4). HPLC characterization of the cellular extract and conditioned medium from the tumor and tumor cell line from Patient 4 demonstrated ANP immunoreactivity in the same fraction as ANP- (S99-Y126). The tumor cell line extract that localizes to a subcellular fraction enriched for lysosomes and secretory organelles contains a 60-kilodalton molecular weight protein with enzyme activity that hydrolyzes synthetic pro-ANP substrates and catalyzes the formation of ANP-(S99-Y126). CONCLUSIONS: A tumor cell line from a patient with hyponatremia was able ectopically to produce, process, and secrete ANP in the same immunoreactive form as the biologically active molecule. Preliminary studies show that tumor cell line NCI-H1284 contains an enzyme that can cleave precursors at the same amino acid sequences needed to produce ANP-(S99-Y126) from pro-ANP.

[Variability of corticosterone methyl oxidase (type II) deficiency. Presentation of three case reports]. / Zur Variabilität des Corticosteron-Methyl-Oxydase (Typ II)-Mangels. Darstellung von drei Fallberichten.

We report on three cases of Corticosterone Methyl Oxidase Typ II deficiency in two siblings and one boy. All three children were presented with typical symptoms of a saltlosing syndrome (vomiting, poor drinking, weight loss, hypotonia). Hyponatremia and hyperkalemia, low plasma aldosterone concentrations when related to high plasma-renin-activities suggested deficiency in the final steps of aldosterone biosynthesis. Variable degrees of enzyme deficiency and no relation of biochemical findings to the clinical symptoms were observed. Clinical symptoms became less severe with age. Diagnosis of CMO II-deficiency was established by an abnormal high ratio of 18-hydroxycorticosterone to aldosterone, by measurement of their precursors and metabolites in plasma and urine. In one sibling negative values may have been caused by suppression of the renin-angiotensin-system due to high sodium replacement therapy.

Fructose-1,6-diphosphatase deficiency.

A girl aged 3 years and 11 months, with recurrent episodes of unexplained metabolic acidosis, hepatomegaly, and fasting hypoglycemia unresponsive to glucagon, showed profound falls in blood glucose levels in response to oral fructose and glycerol challenge. In vitro analysis of her hepatic glycolytic and gluconeogenic enzymes demonstrated absent fructose-1,6-diphosphatase activity. A therapeutic trial of orally given folic acid, 30 mg daily, did not improve her tolerance for fructose and glycerol. Over the next two years she showed improvement in tolerance to fasting, and to fructose and glycerol loading on dietary management.

The effects of altered sodium balance and adrenergic blockade on renin release induced in rats by angiotensin antagonism.

Circulating angiotensin II is said to inhibit renin release by a direct, intrarenal action. This effect of angiotensin was studied indirectly using the selective angiotensin II antagonist saralasin (1Sar-8-Ala-angiotensin II) in conscious normal, sodium-depleted, and sodium-loaded rats. Saralasin caused a dose-related increase in plasma renin concentration (PRC) in normal and sodium-depleted rats, but had no effect on PRC in sodium-loaded animals. However, saralasin was 300 times more active in sodium-depleted rats than in normal rats. Saralasin caused hypotension and tachycardia in sodium-depleted rats, but not in normals. Propranolol inhibited saralasin-induced renin release by 99% in normal rats and by 75% in sodium-depleted rats but not alter the hypotensive effect of saralasin in the latter. Saralasin potentiated phentolamine-induced renin release, hypotension, and tachycardia in normal rats, and this potentiated renin release was blocked by propranolol. We conclude that a portion of saralasin-elicited renin release in sodium-depleted rats is mediated by hypotensive activation of the carotid baroreceptor reflex which increases sympathetic nervous activity in the kidney. However, in sodium-depleted rats saralasin induced a 42-fold increase in PRC, whereas an equipotent hypotensive dose of the vasodilator hydralazine caused only a 3.5-fold increase in PRC. Thus, we find that saralasin appears to have a selective effect on renin release over and above its hypotensive effect, which suggests an angiotensin-mediated, feedback mechanism inhibitory to renin release. Thus, we have come to the conclusion that for part of saralasin-induced renin release appears to be caused by disinhibition of angiotensin suppression of renin secretion. This "short-loop" feed-back mechanism is closely associated with intrarenal beta-adrenergic receptors, since propranolol impaired saralasin-induced renin release under all circumstances in our experiments.