Retrospective analyses and single-center prospective studies identify chronic
metabolic acidosis as an independent and modifiable risk factor for progression of CKD. In patients with CKD, untreated chronic
metabolic acidosis often leads to an accelerated reduction in GFR. Mechanisms responsible for this reduction include adaptive responses that increase
acid excretion but lead to a decline in kidney function.
Metabolic acidosis in CKD stimulates production of intrakidney paracrine
hormones including
angiotensin II,
aldosterone, and
endothelin-1 (ET-1) that mediate the immediate benefit of increased kidney
acid excretion, but their chronic upregulation promotes
inflammation and
fibrosis. Chronic
metabolic acidosis also stimulates ammoniagenesis that increases
acid excretion but also leads to
ammonia-induced complement activation and deposition of C3 and
C5b-9 that can cause tubule-interstitial damage, further worsening
disease progression. These effects, along with
acid accumulation in kidney tissue, combine to accelerate progression of
kidney disease. Treatment of chronic
metabolic acidosis attenuates these adaptive responses; reduces levels of
angiotensin II,
aldosterone, and ET-1; reduces ammoniagenesis; and diminishes
inflammation and
fibrosis that may lead to slowing of CKD progression.