Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone

Abstract

Dietary alkali slows GFR decline in humans with a moderately reduced glomerular filtration rate (GFR) despite the absence of metabolic acidosis. Similarly, dietary alkali slows GFR decline in animals with 2/3 nephrectomy (Nx), a chronic kidney disease (CKD) model without metabolic acidosis in which GFR decline is mediated by acid (H(+)) retention through endothelin (ET) and mineralocorticoid receptors. To gain insight as to whether this mechanism might mediate GFR decline in humans, we explored whether macroalbuminuric subjects with moderately reduced (CKD stage 2 = 60-90 ml/min; CKD 2) compared with normal estimated GFR (> 90 ml/min; CKD 1), each without metabolic acidosis, have H(+) retention that increases plasma levels of ET-1 and aldosterone. Baseline plasma ET and aldosterone concentrations were each higher in CKD 2 than CKD 1. Baseline dietary H(+) and urine net acid excretion (NAE) were not different between groups, but an acute oral NaHCO₃ bolus reduced urine NAE less (i.e., postbolus urine NAE was higher) in CKD 2 than CKD 1, consistent with greater H(+) retention in CKD 2 subjects. Thirty days of oral NaHCO₃ reduced H(+) retention in CKD 2 but not CKD 1 subjects and reduced plasma ET and aldosterone in both groups but to levels that remained higher in CKD 2 for each. Subjects with CKD stage 2 eGFR and no metabolic acidosis nevertheless have H(+) retention that increases plasma ET and aldosterone levels, factors that might mediate subsequent GFR decline and other untoward vascular effects.

Effects of Oral Sodium Bicarbonate in Patients with CKD

“…Participants with edema experienced similar reductions in STS time as those participants without edema, despite smaller increments in the serum bicarbonate. A study of patients with mildly reduced eGFR and normal serum bicarbonate found that changes in urine net acid excretion may be seen even without a change in blood acid-base parameters (36). Finally, we have speculated regarding a mechanistic explanation for our results based on the reduction in urinary nitrogen, although we are unable to definitively comment on nitrogen balance.…”

Dietary Acid, Age, and Serum Bicarbonate Levels among Adults in the United States

“…It should be noted, however, that acid retention may occur even without apparent perturbation of the serum bicarbonate or extracellular pH. A study of patients with mildly reduced eGFR and normal serum bicarbonate found that changes in urine net acid excretion may be seen even without a change in blood acid-base parameters (32). Therefore, high dietary acid could produce the sequelae of a subclinical acidosis in these younger adults even without observable differences in plasma acid-base parameters.…”

Inflammation: A Key Contributor to the Genesis and Progression of Chronic Kidney Disease

“…Patients in early stages of CKD, due to an unchanged net endogenous acid production, are at constant risk for acid accumulation. Data indicate that CKD patients are in positive acid balance [21] . Their serum HCO 3 -or total CO 2 is maintained within the normal range at the cost active compensation.…”

“…NH 4 + is generated in the proximal tubules and secreted into the lumen via [21,28,29] and potentially promoting ongoing kidney damage. Indeed, metabolic acidosis in CKD is associated with more rapid CKD progression [30,31] and increased mortality [32] .…”