The Continuum of Acid Stress

Abstract

Acid-related injury from chronic metabolic acidosis is recognized through growing evidence of its deleterious effects, including kidney and other organ injury. Progressive acid accumulation precedes the signature manifestation of chronic metabolic acidosis, decreased plasma bicarbonate concentration. Acid accumulation that is not enough to manifest as metabolic acidosis, known as eubicarbonatemic acidosis, also appears to cause kidney injury, with exacerbated progression of CKD. Chronic engagement of mechanisms to mitigate the acid challenge from Western-type diets also appears to cause kidney injury. Rather than considering chronic metabolic acidosis as the only acid-related condition requiring intervention to reduce kidney injury, this review supports consideration of acid-related injury as a continuum. This “acid stress” continuum has chronic metabolic acidosis at its most extreme end, and high-acid-producing diets at its less extreme, yet detrimental, end.

Acidosis, cognitive dysfunction and motor impairments in patients with kidney disease

“…More recently, a novel concept of eubicarbonataemic acidosis has been introduced postulating accumulation of acid equivalents in a tissue under conditions of normal systemic acid-base balance [9,10]. In kidney disease, acid retention in FIGURE 1: Prevalence of MCI and metabolic acidosis (MA) in patients with reduced kidney function.…”

“…Additionally, lower urine pH may lead to activation of the alternative complement pathway [35]. b. Renal tissue H þ retention has been proposed to stimulate the (local) production of hormones like endothelin, angiotensin II and aldosterone, which in turn cause renal inflammation and fibrosis [9,36,37]. c. a-Klotho is a protein required for FGF23 signalling that also has anti-inflammatory and renoprotective effects.…”

“…Metabolic acidosis is a common complication of patients with CKD and increases in prevalence with the progression of kidney disease [ 7 ]. Between 10% and 20% of patients with Stage G4 CKD have overt metabolic acidosis, which increases to 30–40% of patients with Stage G5 CKD ( Figure 1 ) [ 1 , 9–11 ]. Acidosis is defined here as a process causing a positive hydrogen (H + ) balance in (extracellular) fluid compartments and encompasses overt acidosis when serum or plasma bicarbonate (HCO 3 − ) [or total carbon dioxide (CO 2 )] falls to <22 mmol/L and/or a blood pH <7.36 as well as eubicarbonataemic acidosis when systemic HCO 3 − and pH are within normal limits but acid accumulation occurs in some organs (see also below).…”

“…More recently, a novel concept of eubicarbonataemic acidosis has been introduced postulating accumulation of acid equivalents in a tissue under conditions of normal systemic acid–base balance [ 9 , 10 ]. In kidney disease, acid retention in the kidney may drive kidney disease progression and possibly also some of the systemic alterations, such as changes in circulating hormones (i.e.…”

“…In CKD, this is typically caused by the diminished capacity of kidneys to excrete acids and generate new HCO 3 − rather than an augmented daily acid load, although the latter can aggravate pre-existing acidosis, for example, in diabetic nephropathy with ketoacidosis. The main process that causes acidosis in CKD is the loss of ammoniagenesis, which acts as the main adaptive mechanism to excrete acid in the form of ammonium and to regenerate HCO 3 − [ 9 , 19 ].…”