Wesson DE, et al. - Since untreated chronic metabolic acidosis in CKD patients commonly results in an accelerated reduction in GFR, researchers focused on the mechanisms accountable for this reduction. They found that adaptive responses that improve acid excretion but result in a decline in kidney function are held responsible for such a reduction. The generation of intrakidney paracrine hormones including angiotensin II, aldosterone, and endothelin-1 (ET-1) is stimulated by metabolic acidosis in CKD, this mediates the immediate benefit of improved kidney acid excretion, but chronic upregulation of these increases inflammation and fibrosis. As a result of chronic metabolic acidosis, ammoniagenesis gets stimulated resulting in a rise in acid excretion but also causing ammonia-induced complement activation and deposition of C3 and C5b-9 that can result in tubule-interstitial damage, which further worsens the disease progression. These effects together with acid accumulation in kidney tissue lead to accelerated progression of kidney disease. Consequences of chronic metabolic acidosis management included attenuation of these adaptive responses, decrease in levels of angiotensin II, aldosterone, and ET-1, reduced ammoniagenesis and reduction in inflammation and fibrosis that may result in slowing of CKD progression.