Chapter Nineteen, Part 1: Metabolic Acidosis, The Show

This is it, the chapter we have all been waiting for, metabolic acidosis. And I just realized that I did not post the exciting conclusion to chapter 18. I’ll get to it next. My bad.

References

Chapter 19, Part 1 

Metabolic acidosis  June 14, 2023

  1. American Society of Nephrology | Medical Students - Kidney TREKS this is the program that Josh mentioned at Mount Desert Island! 

  2. Effects of pH on Potassium: New Explanations for Old Observations - PMC here’s the review melanie from Peter Aronson that clarifies the fact that there are no H+-K+ antiporters outside the kidney but rather coupled transport-

  3. We discussed whether we like “Winter’s formula” Quantitative Displacement of Acid-Base Equilibrium in Metabolic Acidosis | Annals of Internal Medicine 

  4. Dr. R. W. Winters was charged with larceny https://www.nytimes.com/1982/05/16/nyregion/ex-columbia-u-doctor-charged-with-larceny.html

  5. JCI - The Maladaptive Renal Response to Secondary Hypocapnia during Chronic HCl Acidosis in the Dog this was a classic experiment exploring the respiratory response to an infusion of HCl but the animals were maintained in a high pCO2 milieu (not generalizable to humans!)

  6. Here’s the thoughtful Pulmcrit post (by Josh Farkas)  that Josh mentioned regarding correction of anion gap for hypoalbuminemia: Mythbusting: Correcting the anion gap for albumin is not helpful

  7. JC mentioned that the anion gap does change in cirrhosis when the albumin is very low but using the correction factor may not change the clinical findings Acid-base disturbance in patients with cirrhosis: relation to hemodynamic dysfunction

  8. Diagnostic Importance of an Increased Serum Anion Gap | NEJM Melanie mentioned the work of Patricia Gabow on the anion gap. In this review, she refers to work that she had done to try to identify all the organic anions in the anion gap but it falls short. 

  9. Also, check out this critical look at the delta/delta: The Δ Anion Gap/Δ Bicarbonate Ratio in Lactic Acidosis: Time for a New Baseline?

  10. Roger mentioned near drowning in the Dead Sea and the unusual electrolytes in that instance. Near-Drowning in the Dead Sea: A Retrospective Observational Analysis of 69 Patients

  11. We discussed this classic NEJM article by Daniel Batlle The Use of the Urinary Anion Gap in the Diagnosis of Hyperchloremic Metabolic Acidosis

  12. Amy mentioned this review from  Uribarri  and Oh in JASN on the urine anion gap: The Urine Anion Gap: Common Misconceptions

  13. Joel has a great blog post on the urine osmolar gap. urine osmolar gap – Precious Bodily Fluids 

  14. Anna’s VoG on the bicarb deficit:  Kurtz, I Acid-Base Case Studies, 2nd Edition. Trafford Publishing 2004.  And the Fernandez paper that derived a better equation

  15. Reference for Josh’s VoG: Key enzyme in charge of ketone reabsorption of renal tubular SMCT1 may be a new target in diabetic kidney disease

  16. Severe anion gap acidosis associated with intravenous sodium thiosulfate administration

  17. Unexpectedly severe metabolic acidosis associated with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathy

  18. Sodium Thiosulfate Induced Severe Anion Gap Metabolic Acidosis

  19. Sodium Thiosulfate and the Anion Gap in Patients Treated by Hemodialysis

Outline: Chapter 19 Metabolic Acidosis

  • Overview

    • Low arterial pH

    • Reduced HCO3

    • Compensatory hyperventilation (↓ pCO2)

    • Bicarb < 10 strongly suggests metabolic acidosis (renal compensation for respiratory alkalosis does not go that low)

  • Pathophysiology

    • H+ + HCO3- <=> H2CO3 <=> CO2 + H2O

    • Acidosis results from H+ addition or HCO3 loss

    • Response to Acid Load

      • Extracellular buffering

        • Example: Add 12 mmol H+/L → HCO3 falls from 24 → 12 → pH drops to 7.1 (40 to 80 nmol/L)

      • Intracellular and bone buffering

        • 55–60% buffered intracellularly and in bone

        • 12 mEq/L acid load only reduces serum HCO3 by ~5 mEq/L

        • H+ into cells → K+ out (hyperkalemia)

          • Notably in diarrhea or renal failure

          • Less effect with organic acidosis (e.g., DKA, lactic acidosis)

      • Respiratory compensation

        • Stimulates chemoreceptors → ↑ tidal volume (more than RR)

        • Decreases pCO2, increases pH

        • Begins within 1–2 hours; peaks at 12–24 hours

        • Winters formula alternative: for every 1 mEq ↓ HCO3, pCO2 ↓ by 1.2

        • Chronic: respiratory compensation is blunted by renal adaptation

      • Renal hydrogen excretion

        • 50–100 mEq/day acid generated from diet

        • 90% filtered HCO3 reabsorbed in PT

        • Acid secreted:

          • 10–40 mEq via titratable acid (TA)

          • 30–60 mEq via NH3/NH4 (can ↑ to 250 mEq in acidosis)

          • TA: phosphate (DKA → ketones act as TA)

        • Max excretion up to 500 mEq/day in severe acidosis

  • Generation of Metabolic Acidosis

    • Mechanisms

      • Inability to excrete H+ (slow)

      • Addition of H+ or loss of HCO3 (rapid)

    • Anion Gap (AG)

      • Normal: 5–11 (falling due to rising Cl-)

      • Mostly due to negatively charged proteins (albumin)

      • Adjust for albumin: AG ↓ 2.5 per 1 g/dL albumin ↓

      • Revised: AG = unmeasured anions - unmeasured cations

      • ↑ AG = addition of unmeasured anions (e.g., lactate, ketones)

      • Hyperchloremic acidosis: ↓ HCO3 replaced by ↑ Cl (normal AG)

      • Delta–Delta Analysis

        • Adjust AG for albumin

        • Normal ΔAG:ΔHCO3 = 1.6:1 (early 1:1)

        • <1 → high + normal AG acidosis

      • Other causes of AG variation

        • High AG without acidosis: hemoconcentration, alkalosis

        • Low AG: hypoalbuminemia, ↑ unmeasured cations (lithium, IgG, lab artifact)

      • Urine Anion Gap (UAG)

        • Normal = ~0; should be very negative (< -20) in acidosis

        • Type 1 & 4 RTA → UAG positive or near zero

        • Invalid in ketoacidosis or volume depletion (Na retention → ↓ distal acidification)

      • Urine Osmolal Gap

        • Estimate NH4+ via osmolar gap

        • Requires urine Na, K, glucose, urea

  • Etiologies and Diagnosis

    • Lactic Acidosis

      • Pyruvate → lactate (LDH; NADH → NAD+)

      • Normal production: 15–20 mmol/kg/day

      • Metabolized in liver/kidney → pyruvate → glucose or TCA

      • Normal lactate: 0.5–1.5 mmol/L; acidosis if > 4–5 mmol/L

      • Causes:

        • ↑ production: hypoxia, redox imbalance, seizures, exercise

        • ↓ utilization: shock, hepatic hypoperfusion

        • Malignancy, alcoholism, antiretrovirals

      • D-lactic acidosis

        • Short bowel/jejunal bypass

        • Glucose → D-lactate (not metabolized by LDH)

        • Symptoms: confusion, ataxia, slurred speech

        • Special assay needed

        • Tx: bicarb, oral antibiotics

      • Treatment

        • Underlying cause

        • Bicarb controversial: may worsen intracellular acidosis, overshoot alkalosis, ↑ lactate

        • Target pH > 7.1; prefer mixed venous pH/pCO2

    • Ketoacidosis (Chapter 25 elaborates)

      • FFA → TG, CO2, H2O, ketones (acetoacetate, BHB)

      • Requires:

        • ↑ lipolysis (↓ insulin)

        • Hepatic preference for ketogenesis

      • Causes:

        • DKA (glucose > 400)

        • Fasting ketosis (mild)

        • Alcoholic ketoacidosis

          • Poor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysis

          • Mixed acid-base (vomiting, hepatic failure, NAGMA)

        • Congenital organic acidemias, salicylates

      • Diagnosis:

        • AG, osmolar gap (acetone, glycerol)

        • Ketones: nitroprusside only detects acetone/acetoacetate

          • BHB can be 90% of total (false negative)

        • Captopril → false positive

      • Treatment:

        • Insulin +/- glucose

    • Renal Failure

      • ↓ excretion of daily acid load

      • GFR < 40–50 → ↓ ammonium/TA excretion

      • Bone buffering stabilizes HCO3 at 12–20 mEq/L

      • Secondary hyperparathyroidism helps with phosphate buffering

      • Alkali therapy controversial in adults

    • Ingestions

      • Salicylates

        • Symptoms at >40–50 mg/dL

        • Early: respiratory alkalosis → Later: metabolic acidosis

        • Treatment: bicarb, dialysis (>80 mg/dL or coma)

      • Methanol

        • Metabolized to formic acid → retinal toxicity

        • Osmolar gap elevated

        • Tx: bicarb, ethanol/fomepizole, dialysis

      • Ethylene glycol

        • → glycolic/oxalic acid → renal failure

        • Same treatment + thiamine/pyridoxine

      • Other

        • Toluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)

    • GI Bicarbonate Loss

      • Diarrhea, bile/pancreatic drainage → loss of alkaline fluids

      • Ureterosigmoidostomy → Cl-/HCO3- exchange in colon

      • Cholestyramine → Cl- for HCO3-

    • Renal Tubular Acidosis (RTA)

      • Type 1 (Distal)

        • ↓ H+ secretion in collecting duct → urine pH > 5.3

        • Etiologies: Sjögren, RA, amphotericin

        • Features: nephrocalcinosis, stones, hypokalemia

        • Diagnosis: NAGMA, persistent ↑ urine pH

        • Treatment: alkali (1–2 mEq/kg/d adults; 4–14 kids), K+ if needed

      • Type 2 (Proximal)

        • ↓ HCO3 reabsorption

        • Bicarb threshold reduced → self-limited

        • Causes: multiple myeloma, Fanconi, ifosfamide

        • Features: rickets/osteomalacia, no stones, pH variable

        • Diagnosis: NAGMA, pH < 5.3, high FE HCO3 when HCO3 loaded

        • Treatment: alkali (10–15 mEq/kg/d), thiazides

      • Type 4

        • Aldo deficiency/resistance → hyperkalemia + mild acidosis

        • K+ inhibits NH4 generation

        • Tx: correct K+, consider loop diuretics

  • Symptoms

    • Hyperventilation (dyspnea)

    • pH < 7.0–7.1 → arrhythmias, ↓ contractility

    • Neurologic: lethargy → coma (CSF pH driven)

    • Skeletal growth issues in children

  • Treatment Principles

    • No alkali needed for keto/lactic acidosis unless pH < 7.2

    • Bicarbonate Deficit

      • Deficit = HCO3 space * (desired - actual HCO3)

      • HCO3 space: 50–70% of body weight

    • Watch for:

      • K+ shifts: beware hypokalemia when correcting acidosis

      • Na+ load in CHF

    • Dialysis if necessary