Renal/Urology · PANCE / PANRE

Metabolic Acidosis (Anion Gap and Non-Gap)

Primary decrease in bicarbonate; differentiated by anion gap into gap (MUDPILES) and non-gap (HARDUP).

Also known as: metabolic acidosis, anion gap acidosis, non-anion gap acidosis, MUDPILES

Overview

Primary decrease in serum bicarbonate (HCO3 <22 mEq/L) with compensatory hyperventilation (decreased PCO2). Classified by anion gap (AG = Na − (Cl + HCO3); normal 8-12) into high-anion-gap (HAGMA) and normal-anion-gap (non-gap / hyperchloremic) metabolic acidosis.

Epidemiology

Common in hospitalized and critically ill patients. Etiology varies: HAGMA dominates in DKA, lactic acidosis, ingestions, and AKI; non-gap acidosis in diarrhea, RTA, and dilutional acidosis.

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Risk factors

Diabetes (DKA, ketoacidosis)
Shock states, sepsis, tissue hypoperfusion (lactic acidosis)
Alcoholism (alcoholic ketoacidosis, methanol or ethylene glycol ingestion)
CKD/AKI (uremic acidosis)
Toxic ingestions: methanol, ethylene glycol, salicylates, isoniazid, iron
GI bicarbonate loss: diarrhea, pancreatic/biliary fistula, ureteral diversion
Renal tubular acidosis (types 1, 2, 4)
Metformin, propylene glycol, linezolid (lactic acidosis)

Pathophysiology

Acidosis results from accumulation of acid (organic acids in HAGMA, raising the anion gap; HCl in non-gap, maintaining chloride balance) or loss of bicarbonate (GI or renal). Buffering by extracellular HCO3 lowers serum HCO3; respiratory compensation (Winter's formula: PCO2 = 1.5×HCO3 + 8 ± 2) reduces PCO2. Failure of expected compensation indicates a coexisting respiratory disorder.

Clinical presentation

Symptoms

Hyperventilation (Kussmaul respirations) — deep, rapid, labored breathing
Fatigue, weakness, malaise
Nausea, vomiting, abdominal pain (especially DKA, uremia)
Confusion, altered mental status
Specific to cause: polyuria/polydipsia (DKA), neurologic symptoms (toxic ingestions), diarrhea, oliguria

Signs / physical exam

Tachypnea, Kussmaul breathing
Tachycardia, hypotension if shock or volume depletion
Fruity (acetone) breath in DKA
Altered mental status
Findings of underlying cause: dehydration, abdominal tenderness, retinal findings (methanol), kidney bruits, etc.

Classic findings

Young patient with hyperventilation, abdominal pain, dehydration, and fruity breath = DKA until proven otherwise.

Differential diagnosis

DKA — Hyperglycemia + ketones + AG acidosis; diabetic, recent insulin omission or illness
Lactic acidosis — Elevated lactate >2 mmol/L; sepsis, shock, ischemia, metformin, propylene glycol
Uremia — AKI/CKD with elevated BUN/Cr; AG from retained organic anions
Methanol / ethylene glycol — Ingestion history; osmolar gap >10; calcium oxalate crystals (EG); blurred vision/blindness (methanol)
Salicylate poisoning — Mixed AG metabolic acidosis + respiratory alkalosis; tinnitus, hyperventilation, hyperthermia
Alcoholic ketoacidosis — Recent binge with poor intake; high anion gap with predominant beta-hydroxybutyrate (may not register on ketone dipstick)
Diarrhea — Non-gap acidosis with low urine anion gap (negative); recent GI illness
RTA — Non-gap acidosis with positive urine anion gap; specific tubular defect

Diagnostic workup

Diagnostic criteria

Metabolic acidosis = pH <7.35 and HCO3 <22. Apply anion gap to subdivide: AG >12 = HAGMA (think MUDPILES); AG normal = non-gap (think HARDUP/GOLDMARK). Check expected compensation by Winter's formula.

Labs

BMP — Na, K, Cl, HCO3 (low), glucose, BUN, Cr; calculate anion gap = Na − (Cl + HCO3)
ABG — pH (low), PCO2 (low — compensation), HCO3
Lactate — for any unexplained AG acidosis
Serum ketones (beta-hydroxybutyrate preferred)
Serum osmolality + osmolar gap if toxic ingestion suspected (osmolar gap = measured − calculated >10 indicates osmotically active substance — methanol, ethanol, ethylene glycol, propylene glycol)
Salicylate, methanol, ethylene glycol, ethanol levels
Urine anion gap (UAG = Una + Uk − Ucl) for non-gap acidosis: negative (<-20) suggests GI loss; positive (>0) suggests RTA
Urinalysis — calcium oxalate crystals in ethylene glycol; ketones in DKA

Imaging

Generally not required for diagnosis of acidosis itself, but may be needed for underlying cause (CT for ischemic bowel in unexplained lactic acidosis)

Diagnostic algorithm

Type	Anion Gap	Mnemonic / Examples	Key Lab Clue
High AG (HAGMA)	>12	MUDPILES — methanol, uremia, DKA, propylene glycol, INH/iron, lactic, ethylene glycol, salicylate	AG >12, often with osmolar gap
Non-gap (HCMA)	Normal	HARDUP — hyperalimentation, acetazolamide/Addison, RTA, diarrhea, ureteral diversion, pancreatic fistula	Hyperchloremia, normal AG
Lactic acidosis	High	Sepsis, shock, ischemia, metformin	Lactate >2 mmol/L
DKA	High	Diabetic, missed insulin	Glucose >250 + ketones + AG
Toxic alcohols	High	Methanol, ethylene glycol	Osmolar gap >10
RTA (1, 2, 4)	Normal	Sjögren (RTA-1), Fanconi (RTA-2), diabetes (RTA-4)	Positive urine AG

Metabolic acidosis differential by anion gap — MUDPILES (high AG) vs HARDUP (non-gap).

Treatment

First-line

Treat the underlying cause — the most important and effective therapy
DKA: IV fluids (normal saline initially), IV insulin infusion (0.1 U/kg/h after K replete), K replacement, address precipitant
Lactic acidosis: restore perfusion (fluids, vasopressors), treat sepsis, source control
Methanol/ethylene glycol: fomepizole (alcohol dehydrogenase inhibitor) ± hemodialysis; folate (methanol), thiamine + pyridoxine (ethylene glycol)
Salicylate poisoning: aggressive IV fluids, urine alkalinization with sodium bicarbonate, hemodialysis if severe
Uremic acidosis: dialysis if severe; oral sodium bicarbonate for chronic CKD HCO3 <22
Diarrhea: rehydration, treat infection
RTA: oral bicarbonate (sodium bicarbonate or potassium citrate)

Second-line / adjunct

Sodium bicarbonate IV: controversial; consider for severe acidemia (pH <7.1) with hemodynamic compromise; for hyperkalemia with acidosis; for cyclic antidepressant or salicylate overdose
Hemodialysis indications: severe metabolic acidosis refractory to medical therapy, toxic ingestion (methanol, ethylene glycol, salicylate, metformin lactic acidosis), severe AKI with acidosis
Tris-hydroxymethyl aminomethane (THAM) — alternative buffer when CO2 retention is a concern (rarely used)
Address contributing medications (metformin, propylene glycol vehicles)
Monitor closely with repeat ABG, BMP, anion gap, lactate every 1-4 hours during acute treatment

Complications

Cardiovascular: decreased contractility, vasodilation, arrhythmias
Respiratory muscle fatigue from sustained hyperventilation
Altered mental status, coma
Hyperkalemia from cellular shift
Bone demineralization (chronic acidosis in CKD)
Insulin resistance, catabolism
Death — particularly in shock, severe DKA, toxic ingestions without prompt treatment

PANCE pearls

MUDPILES for AG acidosis: Methanol, Uremia, DKA (and AKA, starvation), Propylene glycol/Paraldehyde, Iron/INH, Lactic acidosis, Ethylene glycol, Salicylates.
HARDUP for non-gap acidosis: Hyperalimentation, Acetazolamide/Addison disease, RTA, Diarrhea, Ureteral diversion, Pancreatic fistula.
Osmolar gap >10 + AG acidosis = consider methanol or ethylene glycol ingestion. Treat empirically with fomepizole while confirming.
Winter's formula for expected respiratory compensation: PCO2 = 1.5 × HCO3 + 8 ± 2. Higher or lower than expected indicates additional respiratory disorder.
Urine anion gap (UAG) interprets non-gap acidosis: negative (chloride > Na + K) = appropriate ammonium excretion = GI loss; positive = inadequate ammonium = RTA.
Delta-delta (ΔAG/ΔHCO3): ratio of rise in AG to fall in HCO3. <1 suggests concurrent non-gap acidosis; >2 suggests concurrent metabolic alkalosis.
Sodium bicarbonate in DKA is generally NOT recommended unless pH <6.9 — may worsen intracellular acidosis and cerebral edema.

References

ADA 2024 — ADA Standards of Care in Diabetes 2024 — DKA management
Berend 2014 — Physiological Approach to Assessment of Acid-Base Disturbances (Berend et al., NEJM 2014)
Kraut Madias — Treatment of Acute Non-Anion Gap Metabolic Acidosis (Kraut and Madias, CJASN 2012)

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