What explains a low anion gap of 4 mEq/L in a 72‑year‑old man with stage 2 chronic kidney disease, bicarbonate 29 mEq/L and chloride 106 mmol/L, and how should it be evaluated?

Low Anion Gap Evaluation in Stage 2 CKD

In this 72-year-old man with stage 2 CKD, bicarbonate 29 mEq/L, chloride 106 mmol/L, and anion gap of 4 mEq/L, the most likely explanation is an increase in unmeasured cations (such as paraproteins from multiple myeloma, hypercalcemia, or lithium) or laboratory error, and evaluation should include serum protein electrophoresis, immunofixation, serum albumin, and verification of laboratory measurements. 1

Understanding the Clinical Context

A low anion gap (defined as <3-5 mEq/L using modern ion-selective electrode methods) is uncommon, occurring in only 2.9% of hospitalized patients. 2 The normal reference range for anion gap has shifted from the historical 8-16 mEq/L to 3-11 mEq/L (or 5-12 mEq/L) with contemporary laboratory methods. 2

In this patient, the anion gap of 4 mEq/L falls at the lower end of normal but warrants investigation given the clinical context of CKD and elevated bicarbonate.

Primary Causes to Evaluate

Paraproteinemia (Most Important)

• Screen immediately for multiple myeloma with serum protein electrophoresis and immunofixation, as IgG paraproteins are the most common pathologic cause of low anion gap, with documented cases showing anion gaps as low as 2 mEq/L. 2
• Multiple myeloma and similar paraprotein disorders represent the most clinically significant cause of persistently low anion gap. 1

Hypoalbuminemia

• Measure serum albumin to calculate a corrected anion gap, as hypoalbuminemia is a frequent contributor to low anion gap values in hospitalized patients. 1
• Each 1 g/dL decrease in albumin below 4 g/dL lowers the anion gap by approximately 2.5 mEq/L. 1
• If albumin is low, calculate corrected anion gap = observed anion gap + 2.5 × (4 - observed albumin). 1

Laboratory Error and Interference

• Verify the laboratory measurements by repeating electrolytes, as laboratory error and specimen contamination are common causes of spuriously low anion gap. 1
• Check for potential interfering substances including bromide (bromism), lithium, or barium, which can artificially lower the calculated anion gap. 3, 1

Unmeasured Cations in CKD

• In patients with CKD, accumulation of unmeasured cations (particularly guanidines such as guanidosuccinic acid and methylguanidine) can normalize or lower the anion gap despite retention of organic acids. 4
• This phenomenon explains why many CRF patients have normal or only minimally elevated anion gaps rather than the expected high anion gap. 4
• The osmolar gap may be elevated in CKD patients due to these low molecular weight cationic substances. 4

Evaluation Algorithm

Initial Laboratory Assessment

• Repeat basic metabolic panel to confirm the low anion gap and rule out laboratory error. 1
• Measure serum albumin to calculate corrected anion gap. 1
• Obtain serum protein electrophoresis with immunofixation to screen for paraproteins. 2, 1
• Check serum calcium (hypercalcemia increases unmeasured cations). 1
• Review medication list for lithium, bromide-containing compounds, or other interfering substances. 3, 1

Additional Considerations

• Calculate osmolar gap if available (measured osmolality - calculated osmolality), as an elevated osmolar gap in CKD suggests accumulation of unmeasured cations. 4
• Assess for liver disease (cirrhosis is associated with low anion gap). 2
• Evaluate for nephrotic syndrome (another cause of low anion gap). 2

Clinical Significance in This Patient

The elevated bicarbonate (29 mEq/L) combined with low-normal anion gap and stage 2 CKD creates an unusual pattern:

• The elevated bicarbonate suggests either metabolic alkalosis or compensated respiratory acidosis. 5
• The chloride of 106 mmol/L is relatively normal, making a pure hyperchloremic (non-anion gap) acidosis unlikely. 5
• In CKD, one would typically expect either normal or elevated anion gap, not low. 6

Critical Pitfalls to Avoid

• Do not dismiss a low anion gap as clinically insignificant without ruling out multiple myeloma, as this represents a potentially life-threatening diagnosis that requires urgent treatment. 2, 1
• Do not use outdated reference ranges (8-16 mEq/L); modern ion-selective electrode methods yield lower normal values (3-11 or 5-12 mEq/L). 2
• Do not forget to correct for hypoalbuminemia, as this is the most common benign cause of low anion gap and may mask a coexistent high anion gap acidosis. 1
• Recognize that negative anion gaps (≤0 mEq/L) are extremely rare and almost always indicate laboratory error, specimen contamination, or severe paraproteinemia. 1

Quality Control Perspective

From a laboratory quality control standpoint, anion gaps <2 mmol/L or >24 mmol/L should prompt verification of electrolyte measurements and assessment for hypoalbuminemia or hyperglobulinemia. 2