What are the common differentials for Non-Anion Gap Metabolic Acidosis (NAGMA)?

Differentials for Non-Anion Gap Metabolic Acidosis (NAGMA)

The primary differentials for NAGMA can be systematically categorized by serum potassium level: hyperkalemic causes (renal tubular acidosis type 4, early renal failure, hypoaldosteronism) versus hypokalemic causes (renal tubular acidosis types 1 and 2, diarrhea, urinary diversions), with gastrointestinal bicarbonate losses and iatrogenic causes from excessive saline administration being the most common in clinical practice. 1, 2

Systematic Approach to NAGMA Differentials

Initial Categorization by Potassium Level

The serum potassium concentration immediately narrows your differential into two major categories 2:

Hyperkalemic NAGMA (K+ >5.5 mEq/L):

• Renal tubular acidosis type 4 (hyporeninemic hypoaldosteronism) - most common in diabetic nephropathy and chronic kidney disease 2
• Early chronic kidney disease with decreased ammonia excretion 1, 2
• Medications: potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs, heparin 2
• Primary adrenal insufficiency 2

Hypokalemic or Normal Potassium NAGMA (K+ <3.5 or normal):

• Diarrhea - the most common non-renal cause of NAGMA from direct bicarbonate loss in stool 1, 2
• Renal tubular acidosis type 1 (distal RTA) - impaired distal H+ secretion 2
• Renal tubular acidosis type 2 (proximal RTA) - impaired proximal bicarbonate reabsorption 2
• High-volume ileostomy output causing large bicarbonate losses 1
• Urinary diversions (ileal neobladder, ureteroenterostomy) - allows urinary chloride reabsorption and bicarbonate loss 3

Iatrogenic and Treatment-Related Causes

Excessive normal saline administration is an increasingly recognized cause in hospitalized patients, particularly those receiving aggressive fluid resuscitation for shock states 4, 5. This dilutional hyperchloremic acidosis occurs from:

• Large-volume chloride-containing IV fluid administration 4, 5
• Treatment of hypovolemia and shock with normal saline 5

Recovery from diabetic ketoacidosis commonly causes transient NAGMA from excessive saline use for fluid and electrolyte replacement 6.

Gastrointestinal Losses

Direct bicarbonate losses occur through 1, 2:

• Severe diarrhea - colonic bicarbonate secretion is lost
• High-output ileostomy - particularly when output exceeds 1-2 liters daily 1
• Pancreatic or biliary fistulas - loss of bicarbonate-rich secretions 2
• Ureterosigmoidostomy or ileal conduit - urinary chloride reabsorption in exchange for bicarbonate 3

Renal Causes Requiring Urine Studies

When the diagnosis remains unclear after assessing potassium and excluding obvious GI losses, measure urine pH and estimate urine ammonium 1, 2:

Urine pH >5.5 with NAGMA suggests:

• Distal (type 1) RTA - inability to acidify urine below pH 5.5 2
• Proximal (type 2) RTA during bicarbonate loading 2

Urine pH <5.5 with NAGMA suggests:

• GI bicarbonate losses (appropriate renal compensation) 2
• Type 4 RTA (may have urine pH <5.5) 2

Critical Clinical Pitfalls

Do not confuse NAGMA with combined acid-base disorders. Calculate the anion gap and delta-delta ratio to identify patients with both a high anion gap acidosis AND a concurrent NAGMA, which changes management entirely 2. For example, a patient with DKA who received excessive saline may have both ketoacidosis and hyperchloremic acidosis 6.

Ileal neobladder patients are particularly vulnerable to severe NAGMA when they develop urinary tract infections or ureteral obstruction, as this increases contact time between urine and bowel mucosa 3. These patients have chronic bicarbonate deficits and hypokalemia at baseline 3.

In critically ill patients, hyperchloremic acidosis from saline resuscitation may reduce GFR through changes in chloride concentration in the distal tubule, potentially worsening renal function 5.