Acid retention during kidney failure induces endothelin and aldosterone production which lead to progressive GFR decline, a situation ameliorated by alkali diet

Abstract

Rats with 5/6 nephrectomy have metabolic acidosis with a progressive decline in the glomerular filtration rate (GFR) ameliorated by endothelin and aldosterone antagonists and by dietary alkali. Interestingly, rats with 2/3 nephrectomy have no metabolic acidosis yet have a progressive GFR decline induced by acid retention and ameliorated by dietary alkali. Because patients without metabolic acidosis but with a moderately reduced GFR have a progressive GFR decline, ameliorated by oral sodium bicarbonate, we used rats with 2/3 nephrectomy to model these patients. Kidney acid content, endothelin-1, and aldosterone (measured by microdialysis) were higher in the rats with 2/3 nephrectomy than those with a sham operation despite no differences in plasma acid-base parameters. The GFR of the former but not the latter was lower at 25 than at 1 week after nephrectomy. Endothelin and aldosterone antagonism improved the preservation of GFR; however, this remained lower at week 24 than at week 1. By contrast, the GFR at weeks 24 and 1 was not different if the rats were given dietary alkali to normalize the kidney acid content. Antagonist of endothelin and aldosterone yielded no added GFR benefit. Thus, our study shows that (1) the decline in GFR in 2/3 nephrectomy is mediated by acid retention-induced kidney endothelin and aldosterone production; (2) receptor antagonism and dietary alkali are not additive; and (3) dietary alkali better preserves GFR than both endothelin and aldosterone receptor antagonism.

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

“…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] .…”

Molecular Mechanisms of Acid-Base Sensing by the Kidney

“…70, 71 The mechanism may involve the activation of the complement system on one hand 72 and an endothelin and aldosterone-dependent mechanism on the other. [73][74][75][76] However, it remains to be established which processes in the progression of CKD are stimulated by acidosis, 77,78 and how alkali supplementation slows its progression. It is also not clear why chronic acidosis in the setting of inborn forms of renal tubular acidosis does not lead to renal insufficiency, suggesting that acidosis alone is not sufficient to drive disease progression.…”

Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23

“…Furthermore, high serum potassium levels induce aldosterone release from adrenal cortical gland. In addition, previous studies demonstrated that plasma aldosterone concentrations were elevated in CKD [15,[26][27][28][29][30] and were correlated inversely with renal function [15] (Fig. 1).…”