Metabolic Acidosis

Normal pH of arterial blood = 7.35-7.45

Alkalemia = pH >7.45

Acidemia = pH <7.35

• High-Anion Gap Metabolic Acidosis (HAGMA): Anion gap > 12
• Normal-Anion Gap Metabolic Acidosis (NAGMA): Anion gap ≤ 12

Origin of the “Anion Gap”

• Na⁺ + unknown⁺ = HCO₃^– + Cl^– + unknown^–

• Na⁺ – (HCO₃^– + Cl^–) = unknown^– – unknown⁺

• Na⁺ – HCO₃^– – Cl^– = unknown^– – unknown⁺ = ANION GAP = ~10-12

High-Anion Gap Metabolic Acidosis (HAGMA) Differential Diagnosis

Mnemonic: KU LOST

• Ketones (Starvation, DKA, alcohol use)
  • Starvation and DKA: Decreased ability to use glucose as an energy source creates an increase in fatty acid metabolism, leading to ketone production as a byproduct.
  • Alcohol: Alcohol metabolism leads to an increased reduction reaction of NAD⁺ to NADH, which then reduces acetoacetate to β-hydroxybutyrate
• Uremia (renal failure)
• Lactic Acidosis (Type A, B, or D – see Lactic Acidosis)
• Osmolar Gap elevation
  • Lab serum osmolality – calculated serum osmolality [(2 x Na⁺) + (glucose/18) + (BUN/2.8)] >10
    • Ethylene Glycol ingestion (metabolized into oxalate, which precipitates with calcium to form calcium oxalate kidney stones)
    • Methanol ingestion (metabolized into formate, which is toxic to the retina and optic nerve -> can cause vision loss and even blindness)
    • Propylene Glycol (think lorazepam, phenobarbital, dilantin…medicines that may come mixed with propylene glycol)
    • Treat with fomepizole (competitive inhibitor of alcohol dehydrogenase, thereby slowing metabolism into the alcohol’s toxic metabolites)
  • If osmolar gap is elevated but there is no acidosis
    • Think isopropyl alcohol, mannitol, hyperproteinemia, severe hyperlipidemia
• Salicylate (Aspirin) ingestion: HAGMA occurs as a late presentation. The initial presentation will be a respiratory alkalosis, as salicylates stimulate the respiratory drive center of the brain to cause hyperventilation
• Tylenol/Toluene

Normal Anion Gap Metabolic Acidosis (NAGMA) Differential Diagnosis

• Think renal tubular acidosis (RTA) or diarrhea (although other diagnoses do exist, like toluene inhalation).
  • Check urine pH: will generally be elevated in patients with distal RTA
  • Check urine ammonium
    • Urine Anion Gap can be used as a surrogate measure ₍₁₎
      • Na⁺_U + K⁺_U – Cl^–_U: Elevated if >10. This elevated finding indicates a decreased chloride excretion, which by proxy indicates a low ammonium secretion, as the two are secreted together
    • Type I (Distal) RTA: pH > 5.5, urine anion gap elevated
      • Impaired ability of alpha-intercalated cells in distal convoluted tubule (DCT) to convert H₂O and CO₂ into H⁺ and HCO₃^–, which in turn keeps the H⁺/K⁺ ATPase from secreting H⁺ into the tubular lumen or reabsorbing K⁺ ₍₂₎
      • Hypercalciuria (due to calcium phosphate release from bone to buffer excess H⁺ ions), hypocitraturia (due to citrate being reabsorbed as a buffer for the excess H⁺ ions), and elevated urine pH are all risk factors for nephrolithiasis ₍₃₎
      • Caused by inheritance, autoimmune disease, multiple myeloma, or certain medications ₍₄₎
      • Management: Treat underlying condition. Bicarbonate therapy. However, excess sodium salts lead to a decrease in reabsorption of sodium in the PCT, which reduces passive calcium reabsorption and may worsen hypercalciuria, further increasing the risk of nephrolithiasis. Potassium bicarbonate or potassium citrate (which also treats the hypokalemia) may be preferred ₍₅₎
    • Type II (Proximal) RTA : pH < 5.5, urine anion gap frequently normal
      • Impaired ability to reabsorb HCO₃^– in the PCT. This leads to a higher urine flow rate, causing an osmotic diuresis and subsequent hypokalemia. Impaired sodium reabsorption also decreases effective intravascular volume, which increases aldosterone and stimulates further potassium losses ₍₆₎
      • Caused by genetic proximal tubular cell transporter mutations, medications (topiramate, acetazolamide, heavy metals), Fanconi Syndrome, interstitial nephritis, vitamin D deficiency, secondary hyperparathyroidism, chronic hepatitis ₍₂₎
      • Management: Treat underlying condition. Alkali therapy is recommended, but if using a sodium salt (sodium bicarbonate), the excess sodium load to the DCT may worsen hypokalemia through sodium/potassium exchange in principal cells. Also, bicarbonate itself may stimulate potassium secretion in the collecting duct as a mechanism to maintain electroneutrality. Potassium salts may be preferred. Thiazide diuretics can be used to induce a mild hypovolemia, causing sodium (and subsequently bicarbonate) reabsorption in the PCT. However, thiazide diuretics may also worsen hypokalemia ₍₂₎

Respiratory Compensation

• Winter’s Formula: Expected P_aCO₂ = (1.5 x HCO₃^–) + 8 +/- 2
  • If patient’s measured P_aCO₂ > expected P_aCO₂, there is a secondary respiratory acidosis
  • If patient’s measured P_aCO₂ < expected P_aCO₂, there is a secondary respiratory alkalosis

Secondary Metabolic Disturbance

• Delta Gap = Calculated Anion Gap – “Normal” Anion Gap (~10)

• Corrected HCO₃^– = “Normal” HCO₃^– (~24) – Delta Gap

• If measured HCO₃^– is significantly higher than the calculated corrected HCO₃^–: secondary metabolic alkalosis
• If measured HCO₃^– is significantly lower than the calculated corrected HCO₃^–: secondary metabolic acidosis

References

1. Alexander, Robert Todd, and Martin Bitzan. “Renal Tubular Acidosis.” Pediatric Clinics of North America, Elsevier, 17 Nov. 2018, http://www.sciencedirect.com/science/article/abs/pii/S0031395518301354?via=ihub.
2. Mustaqeem, R., & Arif, A. (n.d.). Renal tubular acidosis – statpearls – NCBI bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK519044/
3. Vallés PG, Batlle D. Hypokalemic distal renal tubular acidosis. Adv Chronic Kidney Dis. 2018;25(4):303–20.
4. U.S. Department of Health and Human Services. (n.d.). Renal tubular acidosis – niddk. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/kidney-disease/renal-tubular-acidosis
5. Palmer, B. F., Kelepouris, E., & Clegg, D. J. (2020). Renal tubular acidosis and management strategies: A narrative review. Advances in Therapy, 38(2), 949–968. https://doi.org/10.1007/s12325-020-01587-5
6. Ali, Y., Parekh, A., Baig, M., Ali, T., & Rafiq, T. (2014). Renal tubular acidosis type II associated with vitamin D deficiency presenting as chronic weakness. Therapeutic Advances in Endocrinology and Metabolism, 5(4), 86–89. https://doi.org/10.1177/2042018814547359