Urinary Anion Gap

OVERVIEW

Urinary Anion Gap (UAG) = (UNa+ UK) – UCl

• the cations normally present in urine are Na⁺, K⁺, NH4⁺, Ca²⁺,and Mg²⁺.
• the anions normally present are Cl^–, HCO3^–, sulphate, phosphate and some organic anions.
• only Na⁺, K⁺ and Cl^– are commonly measured in urine by clinical laboratories so the other charged species are the unmeasured anions (UA) and cations (UC).
• as electrical neutrality must be maintained, it follows that (UNa + UK + UUC) = (UCl + UUA), so UAG also = UUA – UUC (unmeasured anions minus unmeasured cations)

TRADITIONAL USE AND INTERPRETATION OF UAG

The urinary anion gap was proposed as a tool to differentiate between gastrointestinal and renal causes of a hyperchloraemic metabolic acidosis (Goldstein et al, 1986; Batlle et al, 1998)

• hyperchloraemic acidosis can be caused by:
  • Loss of base via the kidney (eg renal tubular acidosis)
  • Loss of base via the bowel (eg diarrhoea)
  • Gain of mineral acid (eg HCl infusion)
• if the acidosis is due to loss of base via the bowel then the kidneys can respond appropriately by increasing ammonium excretion to cause a net loss of H+ from the body
  => increased urinary ammonium (UNH4) (and increased UCl)
  => increased unmeasured urinary cations
  => decreased UAG
• if the acidosis is due to loss of base via the kidney due to renal disease, the kidney is not able to increase NH4 excretion and the UAG will not change.

UAG was believed to provide a rough index of urinary ammonium excretion , due to a negative correlation (Goldstein et al, 1986; Batlle et al, 1998)

• NH4 is positively charged so a rise in its urinary concentration (ie increased unmeasured cations) will cause a low or negative UAG
• experimentally, it was found that:
  • patients with diarrhoea severe enough to cause hyperchloraemic acidosis have a negative UAG (average value -27 +/- 10 mmol/L)
  • patients with acidosis due to altered urinary acidification (renal tubular acidosis) had a positive UAG

In summary, based on this rationale, the urinary anion gap can be interpreted as follows when a hyperchloraemic acidosis is present:

• negative UAG = severe diarrhoea; NH4Cl administration
• low UAG = GI loss of base
• no change in UAG = renal loss of base
• positive (high) UAG = altered urinary acidification (renal tubular acidosis)

Note that this interpretation assumes normal kidney function.

• Renal disease limits the kidney’s ability to form NH4 and produces additional acids, so UAG cannot be used to assess hyperchloraemic acidosis in acute or chronic kidney disease (Battle et al, 2018).

CRITIQUE AND REVISED INTERPRETATION OF UAG

Uribarri et al (2021) argue that the traditional interpretation of the UAG described above is incorrect even in the absence of renal disease, for these reasons:

• in the steady state UAG mainly reflects daily intake of Na, K, and Cl as this matches urinary excretion (corrected for the minor amount of K lost in the faeces), so UAG indicates either:
  • non-steady state or
  • selective extra-renal loss (e.g. diarrhoea) of one these electrolytes.
• UNH4 excretion in people with healthy kidneys does not correlate with UAG.
  • UNH4 actually depends mainly on the daily acid load
  • Urinary pH normally varies from 4 to 7, greatly changing the concentration of unmeasured anions (e.g. HCO3, PO4) replacing Cl, and greatly affecting the UAG.
• the numerical normal value of UAG has increased in recent decades from 41 mEq/d to >70mEq/d, with a very wide range in healthy individuals, due to:
  • increased dietary intake of K+
  • widespread use of food additives that include sodium salts with anions other than chloride

Non-steady state occurs during:

• treatment of K depletion
  • Cl is renally excreted as K is exchanged for intracellular H+
    -> negative UAG
  • reverse effect on UAG occurs during K depletion
• acute respiratory alkalosis
  • Na is excreted with HCO3- while Cl- is retained
    -> high UAG
  • reverse effect on UAG occurs during recovery phase of respiratory alkalosis as HCO3 is generated and NH4Cl excreted
• acute respiratory acidosis
  • Cl is renally excreted alongside H
    -> low UAG
  • reverse effect on UAG occurs during recovery phase of respiratory acidosis
• lithium chloride treatment
  • initially lithium enters cells in exchange with Na, which is renally excreted with part of the administered Cl
    -> UAG unchanged
  • once steady state is achieved with continued treatment, Li (an unmeasured cation) is excreted along with Cl
    -> negative UAG (exactly matching amount of excess Cl administered)
• renal tubular acidosis
  • increase K excretion as H+ enters cells
    -> positive UAG
  • reverse occurs when recovering from K depletion (see above)
    -> negative UAG

ERRORS MADE IN FORMULATING THE TRADITIONAL INTERPRETATION OF UAG

Uribarri et al (2021) highlight the following misinterpretations in the studies by Goldstein et al (1986) and Batlle et al (1988)

• UAG was used as surrogate for UNH4, which is not usually measured in clinical laboratories so a decrease in UAG in patients was interpreted as being due to increased UNH4, but was actually due to increased Cl intake and consequent increased UCl (in the absence of an increase in Na or K intake, and UNa or UK).
• increased UNH4 stimulated by acids that do not contain Cl does not decrease UAG (e.g. methionine administration, ketoacidosis)

CONCLUSION

Although traditionally used as a tool to distinguish among causes of hyperchloraemic acidosis, UAG has little clinical utility due to:

• lack of correlation with urinary NH4, so lacks ability to distinguish GI and renal causes of hyperchloraemic acidosis
• uncertainty, and wide variability, in normal values in healthy individuals
• lack of utility in patients with acute or chronic renal disease

REFERENCES

Journal articles

• Batlle DC, Hizon M, Cohen E, Gutterman C, Gupta R. The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl J Med. 1988 Mar 10;318(10):594-9. doi: 10.1056/NEJM198803103181002. PMID: 3344005.
• Batlle D, Ba Aqeel SH, Marquez A. The Urine Anion Gap in Context. Clin J Am Soc Nephrol. 2018 Feb 7;13(2):195-197. doi: 10.2215/CJN.13791217. Epub 2018 Jan 8. PMID: 29311217; PMCID: PMC5967442.
• Goldstein MB, Bear R, Richardson RM, Marsden PA, Halperin ML. The urine anion gap: a clinically useful index of ammonium excretion. Am J Med Sci. 1986 Oct;292(4):198-202. doi: 10.1097/00000441-198610000-00003. PMID: 3752165.
• Kamel KS, Halperin ML. Use of Urine Electrolytes and Urine Osmolality in the Clinical Diagnosis of Fluid, Electrolytes, and Acid-Base Disorders. Kidney Int Rep. 2021 Feb 13;6(5):1211-1224. doi: 10.1016/j.ekir.2021.02.003. PMID: 34013099; PMCID: PMC8116912.
• Uribarri J, Oh MS. The Urine Anion Gap: Common Misconceptions. J Am Soc Nephrol. 2021 May 3;32(5):1025-1028. doi: 10.1681/ASN.2020101509. Epub 2021 Mar 5. PMID: 33769949; PMCID: PMC8259693.