What is the initial work‑up for a patient with non‑anion‑gap metabolic acidosis?

Initial Workup for Non-Anion Gap Metabolic Acidosis (NAGMA)

Immediate Laboratory Assessment

Begin with arterial or venous blood gas analysis to confirm metabolic acidosis (pH <7.35, bicarbonate <22 mmol/L), followed by serum electrolytes to calculate the anion gap and determine the potassium level. 1, 2

Essential First-Line Tests

• Arterial blood gas (ABG) or venous blood gas to measure pH, PaCO₂, and confirm metabolic acidosis 1, 2
• Complete metabolic panel including sodium, potassium, chloride, and bicarbonate to calculate anion gap using the formula: Na⁺ − (HCO₃⁻ + Cl⁻), with normal values 10–12 mEq/L 1, 2
• Blood urea nitrogen and creatinine to assess renal function 1, 3
• Serum glucose to exclude diabetic ketoacidosis 1

Systematic Diagnostic Algorithm

Step 1: Confirm True NAGMA

Calculate the anion gap to verify it is ≤12 mEq/L, then perform gap-gap analysis to exclude a mixed disorder where both high anion gap and normal anion gap acidosis coexist. 2, 3

• If anion gap is elevated (>12 mEq/L), this is NOT pure NAGMA and requires evaluation for high anion gap causes 2
• Calculate delta-delta (Δ anion gap / Δ bicarbonate) to detect concurrent NAGMA in patients recovering from diabetic ketoacidosis who received excessive saline 4, 2

Step 2: Categorize by Serum Potassium

The serum potassium level immediately narrows the differential diagnosis and directs subsequent testing. 5, 3

Hypokalemic NAGMA (K⁺ <3.5 mEq/L)

• Suggests gastrointestinal bicarbonate losses (diarrhea, ileostomy, fistulas) or renal tubular acidosis types 1 or 2 5, 3
• Obtain urine pH as the next critical test 3

Hyperkalemic NAGMA (K⁺ >5.5 mEq/L)

• Suggests renal tubular acidosis type 4, early chronic kidney disease, or hypoaldosteronism 3
• Check urine pH and consider aldosterone/renin levels 3

Normokalemic NAGMA

• Consider early CKD, recovery phase of ketoacidosis, or iatrogenic causes 4, 3

Step 3: Measure Urine pH

Urine pH distinguishes between gastrointestinal and renal causes of NAGMA. 5, 3

• Urine pH <5.5 indicates intact renal acidification, pointing to extrarenal bicarbonate loss (diarrhea, ileostomy, pancreatic fistula) 5, 3
• Urine pH >5.5 despite systemic acidosis suggests impaired renal acidification (renal tubular acidosis) 3

Step 4: Calculate Urine Anion Gap (When Urine pH >5.5)

The urine anion gap indirectly estimates urinary ammonium excretion to differentiate renal from gastrointestinal causes when urine pH is inappropriately high. 2, 3

• Formula: Urine Na⁺ + Urine K⁺ − Urine Cl⁻ 2, 3
• Negative urine anion gap (typically −20 to −50 mEq/L) indicates high urinary NH₄⁺ excretion, suggesting appropriate renal response to extrarenal acid load (gastrointestinal losses) 3
• Positive urine anion gap indicates impaired urinary NH₄⁺ excretion, confirming renal tubular acidosis 3

Clinical History and Physical Examination Priorities

Key Historical Elements

• Diarrhea history: Volume, duration, and character to assess gastrointestinal bicarbonate losses 5, 3
• Medication review: Recent saline administration, acetazolamide, topiramate, NSAIDs, or potassium-sparing diuretics 4, 3
• Chronic kidney disease history: Stage 3–5 CKD commonly causes NAGMA from impaired hydrogen ion excretion 1, 3
• Recent diabetic ketoacidosis treatment: Excessive normal saline causes transient hyperchloremic acidosis 4

Physical Examination Focus

• Volume status: Orthostatic hypotension, decreased skin turgor, dry mucous membranes suggest gastrointestinal losses 5
• Signs of CKD: Uremic features, hypertension, edema 1

Common Etiologies by Category

Gastrointestinal Bicarbonate Loss (Most Common)

• High-volume diarrhea from any cause (infectious, inflammatory bowel disease, celiac disease) 5, 3
• Ileostomy or colostomy with high output 5
• Pancreatic or biliary fistulas 3

Renal Causes

• Chronic kidney disease stages 3–5: Impaired ammonia synthesis and hydrogen ion excretion 1, 3
• Renal tubular acidosis: Types 1,2, or 4 depending on potassium level and urine pH 3

Iatrogenic Causes

• Large-volume normal saline administration: Dilutional hyperchloremic acidosis from chloride loading 4, 6
• Recovery phase of diabetic ketoacidosis: Excessive saline for fluid replacement 4
• Medications: Acetazolamide, topiramate, potassium-sparing diuretics 3

Critical Pitfalls to Avoid

• Do not assume pure NAGMA without calculating the anion gap and performing gap-gap analysis—patients recovering from ketoacidosis often have mixed disorders 4, 2
• Do not overlook iatrogenic causes—recent hospitalization with aggressive saline resuscitation commonly produces transient NAGMA that resolves spontaneously 4, 6
• Do not order expensive renal tubular acidosis workups before excluding gastrointestinal losses and medication causes through history and basic urine studies 5, 3
• Recognize that urine anion gap becomes unreliable in advanced CKD (GFR <20 mL/min) due to reduced ammonium excretion capacity 3

When to Measure Urinary Ammonium Directly

Direct measurement of urine NH₄⁺ concentration is reserved for cases where urine anion gap results are equivocal or when advanced CKD makes indirect estimates unreliable. 3

• Normal urinary NH₄⁺ excretion is >40 mEq/day in the setting of metabolic acidosis 3
• Low urinary NH₄⁺ (<20 mEq/day) confirms renal tubular acidosis 3