Pathophysiology, Evaluation and Management of Metabolic Acidosis

Metabolic acidosis is a reduction in blood pH due to a primary reduction in serum bicarbonate (HCO3 − ). It is associated with a secondary reduction in carbon dioxide arterial pressure (PaCO2). Metabolic acidosis can be acute or chronic. Acute metabolic acidosis results from excess organic acids as in lactic acidosis, while chronic metabolic acidosis reflects reduced renal acidification. Metabolic acidosis is further classified into anion-gap (AG-MA) and hyperchloremic (normal anion-gap [NAG-MA]) based on serum anion gap (AG). Metabolic acidosis has adverse effects on a variety of body functions. Although base administration is helpful in the management of chronic metabolic acidosis, it is controversial in acute metabolic acidosis. Treatment of the underlying cause is the cornerstone of the management of acute metabolic acidosis.


Introduction
Normal arterial blood pH is 7.35-7.45 while intracellular pH is 7.0-7.30 [1,2]. A variety of intracellular and extracellular buffering systems along with renal and respiratory regulations keep arterial blood pH in this narrow range. A low blood pH defines acidemia, if serum HCO 3 − is low, the acidemia is due to metabolic acidosis; while if P a CO 2 2. Pathophysiology

Renal net acid excretion
The the inner medullary collecting duct (IMCD) [1]. The most important titratable acid is phosphate which has a pK a of 6.80. Creatinine and uric acid play a lesser role as titratable acids. In chronic metabolic acidosis titratable acids do not increase significantly, while ammonium excretion in the urine does, the response takes 4-7 days [1,5]. Therefore, the ammonia/ammonium system (NH 3 /NH 4 + ) is the critical component of net acid excretion [2].
Ammonium synthesis occurs in the PT. Figure 1.
Each glutamine ion produces two NH 4 + and two HCO 3 − ions [12]. The Na + -H + exchanger (antiporter) NHE3 at the apical membrane of the PT transport NH 4 + into the lumen [11]. The TAL reabsorbs NH 4 + paracellularly (passively), via the Na + -K + -2Cltransporter, and via the apical K + channel. The final step of NH 4 + cycle is its nonionic diffusion (secretion) into the lumen of the collecting duct [13].
Chronic acidosis and hypokalemia increase ammonium synthesis, while hyperkalemia decreases ammonium synthesis. This explains why patients with hypokalemia (especially due to hyperaldosteronism) have a concomitant metabolic alkalosis, while patients with type 4 renal tubular acidosis have hyperkalemia and metabolic acidosis [13]. Courtesy of Bruno and Valenti [8]. This is an open access article distributed under the Creative Commons Attribution License.

HCO 3 − Reabsorption in the proximal tubule
Most of HCO 3 − in the PT is reabsorbed via hydrogen (H + ) secretion by the Na + -H + exchanger (antiporter) NHE3 at the apical membrane [11]. NHE-3 exchanges a single Na + ion for one H + ion. Luminal Na + enters the cell from the lumen while H + exits the cell. The apical H + -ATPase plays a lesser role in H + secretion from the PT. Two types of the enzyme carbonic anhydrase (CA) exist in the PT, lumen or membrane bound CAIV and cytosolic CAII [14]. The following reaction occurs in the lumen and is catalyzed by CAIV, Figure 2:  [2]. It is essential for cell voltage to be negative to drive the above processes; the basolateral Na + -K + -ATPase pump generates the required negative charge by maintaining a low intracellular Na + .

Diagnosis
The following steps should be followed in establishing the diagnosis of metabolic acidosis [  negative U AG due to diarrhea where NH4 + excretion is increased. The third diagram represents an individual with toluene toxicity. NH 4 + excretion is increased but U AG is 0 due to the presence of hippurate in the urine.

Case Study
A 24-year-old man brought to ER due to altered mental status. He was not taking any medications. Expected PaCO 2 = (HCO 3 − x 1.5) + 8  2 = (10 x 1.5) Since P a CO 2 is 32 mmHg, the patient has both NAG-MA and respiratory acidosis (likely due to severe hypokalemia).

Causes
The causes of NAG-MA can be broadly divided into renal or extrarenal [4,25]

Metabolic acidosis in CKD
A study in 1038 adults with non-dialysis CKD stages 2-5 showed that the prevalence of metabolic acidosis is 7% in CKD-2, 13% in CKD-3 and 40% in CKD-