Does an Acid-Milieu in Chronic Kidney Disease Contribute to Its Increased Cardiovascular Mortality?

mote the increased atherosclerosis described in CKD [12] . Observational studies show that low serum [HCO 3 ] is associated with increased incidence of hypertension [13] , a major contributor to cardiovascular disease. In addition, high dietary acid increases the risk for CKD patients with reduced GFR to develop metabolic acidosis [14] and increases the risk for subsequent development of hypertension in children [15] . Furthermore, metabolic acidosis also enhances deposition of β 2 -microglobulin in many tissues, including the heart [16] . Together, these data support exploration of the potential contribution of metabolic acidosis and/or acid retention to the excess cardiovascular mortality of CKD. As noted, high dietary acid intake increases the risk for metabolic acidosis in CKD patients with reduced GFR [14] . Diets in developed societies are largely acid-producing due to high intake of acid-producing animal protein combined with comparatively low intake of base-producing proteins from fruits and vegetables [17] . These acidproducing diets increase net endogenous acid production [18] and typically do so without inducing frank metabolic acidosis in individuals with relatively preserved GFR [19] but might do so in those with very low GFR [14] . Nevertheless, these high acid diets might induce acid retention in CKD patients with reduced eGFR even in the setting of normal serum [HCO 3 ] [6, 7] . Reducing dietary acid with Na + -based dietary alkali or base-producing Patients with chronic kidney disease (CKD) suffer premature death compared to CKD patients with comparable underlying disease but no CKD [1], and this CKDrelated mortality is further increased in the presence of metabolic acidosis [2, 3] . Observational studies support that the more severe the metabolic acidosis as indicated by lower serum bicarbonate concentration ([HCO 3 ]) the greater the mortality in patients with stages 3 and 4 CKD [4] . Interestingly, the inverse relationship between serum [HCO 3 ] and mortality in CKD includes levels of serum [HCO 3 ] which extend into the normal range [5] . The importance of the latter observation is enhanced by studies supporting positive acid balance with acid retention in CKD patients with reduced estimated glomerular filtration rate (eGFR) but with serum [HCO 3 ] within the normal range [6, 7] . These data raise the intriguing hypothesis that treatment of metabolic acidosis in CKD or its associated acid retention in those with reduced glomerular filtration rate (GFR) but without metabolic acidosis reduces CKD-related mortality. Cardiovascular disease is a major contributor to the increased mortality of CKD [1] and its contribution increases as eGFR decreases [8] . The risk for metabolic acidosis in CKD also increases as GFR decreases [9, 10] , positing that metabolic acidosis or acid retention contributes to increased CKD-related cardiovascular mortality. Inflammation caused by metabolic acidosis [11] might proPublished online: May 28, 2016 Nephrology American Journal of