Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance.

[5] Metabolic acidosis can lead to acidemia, which is defined as arterial blood pH that is lower than 7.35.

Acute metabolic acidosis, lasting from minutes to several days, often occurs during serious illnesses or hospitalizations, and is generally caused when the body produces an excess amount of organic acids (ketoacids in ketoacidosis, or lactic acid in lactic acidosis).

[7] Symptoms are not specific, and diagnosis can be difficult unless patients present with clear indications for blood gas sampling.

People with acute metabolic acidosis may exhibit deep, rapid breathing called Kussmaul respirations which is classically associated with diabetic ketoacidosis.

Cranial nerve abnormalities are reported in ethylene glycol poisoning, and retinal edema can be a sign of methanol intoxication.

[citation needed] Chronic metabolic acidosis has non-specific clinical symptoms but can be readily diagnosed by testing serum bicarbonate levels in patients with chronic kidney disease (CKD) as part of a comprehensive metabolic panel.

[5] In the absence of chronic respiratory alkalosis, metabolic acidosis can be clinically diagnosed by analysis of the calculated serum bicarbonate level.

[citation needed] Chronic metabolic acidosis is most often caused by a decreased capacity of the kidneys to excrete excess acids through renal ammoniagenesis.

[12] There are many causes of acute metabolic acidosis, and thus it is helpful to group them by the presence or absence of a normal anion gap.

An elevated anion gap (i.e. > 16 mmol/L) indicates the presence of excess 'unmeasured' anions, such as lactic acid in anaerobic metabolism resulting from tissue hypoxia, glycolic and formic acid produced by the metabolism of toxic alcohols, ketoacids produced when acetyl-CoA undergoes ketogenesis rather than entering the tricarboxylic (Krebs) cycle, and failure of renal excretion of products of metabolism such as sulphates and phosphates.

[citation needed] Adjunctive tests are useful in determining the aetiology of a raised anion gap metabolic acidosis including detection of an osmolar gap indicative of the presence of a toxic alcohol, measurement of serum ketones indicative of ketoacidosis and renal function tests and urinanalysis to detect renal dysfunction.

[citation needed] Elevated protein (albumin, globulins) may theoretically increase the anion gap but high levels are not usually encountered clinically.

As a rule of thumb, a decrease in serum albumin by 1 G/L will decrease the anion gap by 0.25 mmol/L[citation needed] Metabolic acidosis is characterized by a low concentration of bicarbonate (HCO−3), which can happen with increased generation of acids (such as ketoacids or lactic acid), excess loss of HCO−3 by the kidneys or gastrointestinal tract, or an inability to generate sufficient HCO−3.

[citation needed] The decreased bicarbonate that distinguishes metabolic acidosis is therefore due to two separate processes: the buffer (from water and carbon dioxide) and additional renal generation.

The Henderson–Hasselbalch equation mathematically describes the relationship between blood pH and the components of the bicarbonate buffering system:

In clinical practice, the CO2 concentration is usually determined via Henry's law from PaCO2, the CO2 partial pressure in arterial blood:

[2] At lower pH levels, acute metabolic acidosis can lead to impaired circulation and end organ function.

[citation needed] Chronic metabolic acidosis commonly occurs in people with chronic kidney disease (CKD) with an eGFR of less than 45 ml/min/1.73m2, most often with mild to moderate severity; however, metabolic acidosis can manifest earlier on in the course of CKD.

Multiple animal and human studies have shown that metabolic acidosis in CKD, given its chronic nature, has a profound adverse impact on cellular function, overall contributing to high morbidities in patients.

The most adverse consequences of chronic metabolic acidosis in people with CKD, and in particular, for those who have end-stage renal disease (ESRD), are detrimental changes to the bones and muscles.

[31][32][33][34] Treatment of metabolic acidosis depends on the underlying cause, and should target reversing the main process.

In the BICAR-ICU trial,[35] bicarbonate therapy for maintaining a pH >7.3 had no overall effect on the composite outcome of all-cause mortality and the presence of at least one organ failure at day 7.

However, amongst the sub-group of patients with severe acute kidney injury, bicarbonate therapy significantly decreased the primary composite outcome, and 28-day mortality, along with the need for dialysis.

[36] Dietary interventions for treatment of chronic metabolic acidosis include base-inducing fruits and vegetables that assist with reducing the urine net acid excretion, and increase TCO2.

[9][10] Studies investigating the effects of oral alkali therapy demonstrated improvements in serum bicarbonate levels, resulting in a slower decline in kidney function, and reduction in proteinuria – leading to a reduction in the risk of progressing to kidney failure.

Furthermore, large doses of oral alkali are required to treat chronic metabolic acidosis, and the pill burden can limit adherence.

[38] Veverimer (TRC 101) is a promising investigational drug designed to treat metabolic acidosis by binding with the acid in the gastrointestinal tract and removing it from the body through excretion in the feces, in turn decreasing the amount of acid in the body, and increasing the level of bicarbonate in the blood.

Results from a Phase 3, double-blind placebo-controlled 12-week clinical trial in people with CKD and metabolic acidosis demonstrated that Veverimer effectively and safely corrected metabolic acidosis in the short-term,[39] and a blinded, placebo-controlled, 40-week extension of the trial assessing long-term safety, demonstrated sustained improvements in physical function and a combined endpoint of death, dialysis, or 50% decline in eGFR.