Fibroblast growth factor 23: a potential cause of cardiovascular diseases in chronic kidney disease patients

Fibroblast growth factor 23 (FGF-23) has been identified as one of the risk factors for the development of cardiovascular diseases (CVDs) in chronic kidney disease (CKD) patients. Although FGF-23 is necessary for the maintenance of phosphate balance, it has been implicated in the pathogenesis of left ventricular hypertrophy, vascular dysfunction, and hypertension in CKD patients. FGF-23 induced alterations in intracellular calcium is hypothesized to be a key mechanism in the development of these CVDs. In addition, increased angiotensin II levels, upregulation of the renal Na+Cl- co-transporter and inhibition of endothelium-dependent vasorelaxation are among the potential mechanisms by which elevated FGF-23 levels cause hypertension in CKD. This review discusses these mechanisms and how these mechanistic pathways may be targeted in future experiments aimed at generating preventive and management therapies for CVDs in CKD patients.Keywords: Fibroblast growth factor 23, Chronic Kidney Disease and Cardiovascular Diseas

Circadian changes in urinary Na+/K+ ratio in humans: is there a role for aldosterone?

Background: There are indications that the renal excretion of Na+ and K+ is affected by the body's circadian rhythm. Aldosterone is known to be the major determinant of urinary Na+/K+ ratio. However, recent reports suggest that the circadian rhythm of K+ excretion does not depend on endogenous aldosterone. We therefore aimed to investigate the diurnal and nocturnal changes in urinary Na+/K+ ratio, and to test if aldosterone plays a key role.Methods: We investigated the Na+/K+ ratios and aldosterone excretion in 12h-day and night urine. Ethical approval was obtained for 24 healthy male subjects, aged 20-30 years, who were included in this study. 12h-day and 12h-night urine samples were collected. Urine concentrations of Na+ and K+ were analysed using flame photometry and the amount in mmol of these electrolytes was calculated. Urine aldosterone concentrations were analysed using the enzyme immunoassay method. Urinary Na+/K+ ratios were calculated by dividing the amount of Na+ by that of K+, both in mmol/12h. Results are presented as mean ± SEM, and analysed using unpaired Student’s t-test.Results: While a significantly higher Na+/K+ ratio was observed in the 12h-night urine compared with the 12h-day urine (4.22 ± 0.18 vs 2.91± 0.18, p<0.001, n=24), aldosterone excretion (μg/12h) was similar in both the day and night urine.The significantly increased Na+/K+ ratio in the nighttime urine observed in this study was shown to be as a result of a significant decrease (p<0.001) in K+ excretion at night. Correlation analysis revealed no significant relationships between aldosterone and the Na+/K+ ratio in both the day and night urine.Conclusion: Our results suggest that an aldosterone independent mechanism may be responsible for the night time dip in the renal excretion of K+. Understanding this mechanism will provide more insights into how this pathway may be targeted in hypertension caused by non-dipping night time renal K+ excretion.Keywords: Na+, K+, Na+/K+ ratio, aldosterone, 12h-day, 12h-night, urin

Gargling-induced reduction in urinary Na/K ratio in dehydrated humans: Is there a dual role for oropharnygeal receptors in vasopressin regulation?

Background: A linear relationship exists between plasma osmolality (Posm) and thirst perception (TP) and also between plasma arginine vasopressin (Pavp) and Posm. Thus, an increase in Posm leads to an increase in Pavp secretion, which are systemic indicators of thirst. Recent studies have also shown that Pavp secretion is associated with sodium retention. The role of Pavp in termination of thirst during drinking while Posm remains unchanged is however inconclusive. This informed the basis for the present study. Methods: Ten (10) apparently healthy male volunteers aged between 20 and 30 years, non-smokers and not on any medication prior to the experiments, were recruited for this study. They dehydrated for 18hrs and their 12-hour urine samples as well as thirst perception were measured with standard methods and compared with those of 10 euhydrate control subjects. Urine volume as well sodium and potassium concentrations were estimated. Results: We observed a gradual decrease in TP of the subject who gargled with D/H2o; this decrease became significant (P<0.05, respectively) after 30mins and remained so till the end of the experiment. Gargling with various concentrations of saline (0.9 - 2.7%) did not show any significant change; however, in comparison with controls, the Na+/K+ ratio significantly decreased in all samples collected after gargling at every 30mins for 1Hr and after ad libitum distilled water drinking (P<0.05, respectively). Also, the Na/K ratio obtained during gargling (30mins and 60mins) were relatively stable but decreased significantly (P<0.05) at 90mins; which was 30mins after ad libitum drinking. Conclusion: We conclude that oropharygeal receptors play a dual role in stimulating immediate inhibition of vasopressin as well as aldosterone release in the regulation of thirst during dehydration and gargling, to eliminate thirst

FAM111A is dispensable for electrolyte homeostasis in mice.

Autosomal dominant mutations in FAM111A are causative for Kenny-Caffey syndrome type 2. Patients with Kenny-Caffey syndrome suffer from severe growth retardation, skeletal dysplasia, hypoparathyroidism, hypocalcaemia, hyperphosphataemia and hypomagnesaemia. While recent studies have reported FAM111A to function in antiviral response and DNA replication, its role in regulating electrolyte homeostasis remains unknown. In this study, we assessed the role of FAM111A in the regulation of serum electrolyte balance using a Fam111a knockout (Fam111a(-/-)) C57BL/6 N mouse model. Fam111a(-/-) mice displayed normal weight and serum parathyroid hormone (PTH) concentration and exhibited unaltered magnesium, calcium and phosphate levels in serum and 24-hour urine. Expression of calciotropic (including Cabp28k, Trpv5, Klotho and Cyp24a1), magnesiotropic (including Trpm6, Trpm7, Cnnm2 and Cnnm4) and phosphotropic (Slc20a1, Slc20a2, Slc34a1 and Slc34a3) genes in the kidneys, duodenum and colon were not affected by Fam111a depletion. Only Slc34a2 expression was significantly upregulated in the duodenum, but not in the colon. Analysis of femurs showed unaffected bone morphology and density in Fam111a(-/-) mice. Kidney and parathyroid histology were also normal in Fam111a(-/-) mice. In conclusion, our study is the first to characterise the function of FAM111A in vivo and we report that mice lacking FAM111A exhibit normal electrolyte homeostasis on a standard diet