Experimental studies with animal models and clinical studies of humans with CKD before maintenance dialysis have shown that chronic metabolic acidosis has diverse potential adverse effects, ie., muscle wasting by increasing transcription gene of the ATP-dependent ubiquitin proteosome system and the enzyme branchedchain keto acid dehydrogenase (BCKAD) and reducing albumin synthesis with protein malnutrition inflammation complex syndrome, bone disease, impaired insulin sensitivity, beta-2 microglobulin accumulation, exacerbation of renal failure, impaired thyroid metabolism, stunted growth in children, cardiac disease with depressed myocardial contractility (though not proven), and increased inflammation15). Many CKD patients have progressive muscle wasting and malnutrition despite adequate dialysis, and it is now recognized that one of the major causes of malnutrition in CKD, particularly before the initiation of dialysis, is systemic metabolic acidosis16). In fact, the analysis of the Third National Health and Nutrition Examination Survey (NHANES III) showed that low serum bicarbonate was associated with hypoalbuminemia, explaining the high prevalence of hypoalbuminemia in CKD before dialysis17). Even in MHP, the correction of metabolic acidosis improved serum albumin levels of MHP4). However, it remains disputable whether the adverse nutritional effects and poor clinical outcomes of metabolic acidosis in CKD patients before initiation of hemodialysis can be applicable equally to MHP.

As shown in Table 1, the deleterious effect of metabolic acidosis on nutritional status has been noted in some earlier studies for small population of MHP by the studies of Ge et al and Movilli et al.3, 4), whereas, the vast majority of recent epidemiologic studies in MHP have revealed a paradoxically inverse relationship between nutritional parameters and metabolic acidosis. In the analysis of the HEMO study, Uribarri et al reported a significant inverse relationship between serum HCO₃ and normalized protein equivalent of nitrogen appearance (nPNA) and showed that MHP with serum HCO₃ levels (≤21 mEq/L), compared to those with serum HCO₃ levels (≥25 mEq/L), had a higher serum creatinine and urea level6). Dumler et al reported a higher serum albumin, creatinine, and nPNA in MHP with metabolic acidosis7). Gao et al, Lin et al, and three epidemiologic studies with large sample sizes reported by Leavey et al, Chauveau et al, and the recent report by the Dialysis Outcomes and Practice Patterns Study (DOPPS, n=7,140) investigators also found an inverse association between serum HCO₃ levels and nutritional factors, ie., moderate predialysis acidosis in levels between 19 and 22 mEq/L seemed to be associated with better nutritional status and lower relative risk for mortality or hospitalization than was observed in patients with normal ranges of midweek predialysis serum bicarbonate concentration of more than 24 mEq/L or severe acidosis less than 16 mEq/L8-12). In contradiction to most of the previous epidemiologic studies, the most recent study of the largest sample size by Wu et al. (n=56,835) showed significant associations between hypobicarbonatemia less than 23 mEq/L and higher death risk after case-mix and MICS multivariate adjustment13). Therefore, this study supports that MICS may be the substantial contributor to the counteracting associations between serum bicarbonate levels and mortality in MHD, which could be described as cardiovascular risk-factor paradox or reverse epidemiology in MHD as seen in other cardiovascular risk factors. Given this on-going controversy on epidemiologic studies, it still remains unresolved whether metabolic acidosis is truly harmful.