BackgroundIn hemodialysis patients, fluid overload and malnutrition are accompanied by extracellular fluid (ECF) expansion and intracellular fluid (ICF) depletion, respectively. We investigated the relationship between ECF/ICF ratio (as an integrated marker reflecting both fluid overload and malnutrition) and survival and cardiovascular disease (CVD) in the context of malnutrition-inflammation-arteriosclerosis (MIA) complex.MethodsSeventy-seven patients from a single hemodialysis unit were prospectively enrolled. The ECF/ICF volume was measured by segmental multi-frequency bioimpedance analysis. MIA and volume status were measured by serum albumin, C-reactive protein (CRP), pulse wave velocity (PWV) and plasma B-type natriuretic peptide (BNP), respectively.ResultsThe mean ECF/ICF ratio was 0.56±0.06 and the cut-off value for maximum discrimination of survival was 0.57. Compared with the low ECF/ICF group, the high ECF/ICF group (ratio≥0.57, 42%) had higher all-cause mortality, CVD, CRP, PWV, and BNP, but lower serum albumin. During the 5-year follow-up, 24 all-cause mortality and 38 CVD occurred (18 and 24, respectively, in the high ECF/ICF group versus 6 and 14 respectively in the low ECF/ICF group, P<0.001). In the adjusted Cox analysis, the ECF/ICF ratio nullifies the effects of the MIA and volume status on survival and CVD and was an independent predictor of all-cause mortality and CVD: hazard ratio (95% confidence interval); 1.12 (1.01–1.25) and 1.09 (1.01–1.18) for a 0.01 increase in the ECF/ICF ratio. The degree of malnutrition (albumin), inflammation (CRP), arteriosclerosis (PWV), and fluid overload (BNP) were correlated well with the ECF/ICF ratio.ConclusionsHemodialysis patients with high ECF/ICF ratio are not only fluid overloaded, but malnourished and have stiff artery with more inflammation. The ECF/ICF ratio is highly related to the MIA complex, and is a major risk indicator for all-cause mortality and CVD.

Magnesium is the second most common intracellular divalent cation. Magnesium balance in the body is controlled by a dynamic interplay among intestinal absorption, exchange with bone, and renal excretion. Intestinal magnesium absorption proceeds in both a passive paracellular and an active transcellular manner. Regulation of serum magnesium concentrations is achieved mainly by control of renal magnesium reabsorption. Only 20% of filtered magnesium is reabsorbed in the proximal tubule, whereas 60% is reclaimed in the cortical thick ascending limb (TAL) and another 5-10% in the distal convoluted tubule (DCT). The passive paracellular transport of magnesium in the TAL is closely related with the mutations in claudin-16/paracellin-1 and is responsible for familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The active transcellular transport of magnesium in the DCT was similarly enhanced by the realization that defects in transient receptor potential melastatin 6 (TRPM6) cause hypomagnesemia with secondary hypocalcemia. This channel regulates the apical entry of magnesium into epithelia and alters whole-body magnesium homeostasis by controlling urinary excretion. TRPM6 is regulated at the transcriptional level by acid-base status, 17β-estradiol, and both FK506 and cyclosporine. The molecular identity of the protein responsible for the basolateral exit of magnesium from the epithelial cell remains unidentified.

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