Mind the gap…

the case.

a 29-year old female with a past history of anorexia nervosa, polycystic ovarian syndrome, chronic back pain and analgesic abuse presents to the Emergency Department.  She describes 3 days of bilateral ankle and facial swelling.  She tells you that she has been taking ‘lots of painkillers’ for her back pain.

On examination she appears well.  Her physical examination is only remarkable for perioribtal and bilateral ankle oedema.

[DDET What are the differential diagnoses for bilateral pedal oedema ?]

Common causes:

  • Cardiac.
    • Systolic dysfunction
    • Diastolic dysfunction
    • Cor pulmonale
  • Vascular.
    • Deep vein thrombosis
    • Chronic venous insufficiency
  • Renal.
    • Nephrotic syndrome
    • Renal failure
  • Hepatic.
    • Cirrhosis
  • Pregnancy.

Not-so-common causes:

  • Cardiac:
    • Pericardial effusion
    • Constrictive pericarditis
    • Tricuspid regurgitation
  • Obstructive sleep apnoea
  • Protein-losing enteropathy
  • Lymphoedema
  • Hypothyroidism / Myxoedema
  • Medication-induced:
    • Calcium-channel blockers
    • Steroids
    • NSAIDS
    • Monoxidine
    • Gabapentin / pregabalin
    • Thiazolidinediones


[DDET Describe and interpret her initial venous blood gas…]

Initial VBG

  • Primary metabolic acidosis.
    • pH 7.01, HCO3 9, BE -22. pCO2 33.
  • Expected CO2.
    • [HCO3 x 1.5] +8  (±2) – Winter’s formula
    • [9x 1.5] +8
    • 21.5 (±2)
    • Incomplete respiratory compensation or concomitant/additional respiratory acidosis.
  • Anion gap.
    • Na – [Cl – HCO3]
    • 138 – [120 + 9]
    • 9 – ie. normal.
  • Delta ratio.
    • [AG – 12 / 24 – HCO3]
    • [ 9-12 / 24 – 9 ]
    • 3 / 15
    • 0.2 ~ pure NAGMA.
  • Hyperchloraemia.
    • Likely contributing to the non-gap acidosis.
  • Normokalaemia.
    • In the setting of severe metabolic acidosis, this however likely represents marked whole-body depletion.
    • With expectation that this will fall with correction of acidosis, this requires early replacement & serial rechecks.
  • Moderate renal impairment.
    • Urea 16.4, Creatinine 164.
    • ?acute vs chronic
    • May be contributing to (1) acidosis via uraemia & (2) the patients oedematous state !!


Life-threatening, non-anion gap metabolic acidosis with incomplete respiratory compensation (or concomitant respiratory acidosis).


[DDET What are the causes of the non-anion gap metabolic acidosis ?]

Causes of non-anion gap metabolic acidosis
Causes of non-anion gap metabolic acidosis

This can essentially be subdivided into three groups;

  1. Loss of base via kidney [eg. RTA]
  2. Loss of base via bowel [eg. diarrhoea]
  3. Gain of mineral acid [eg. HCl infusion]


[DDET How can we further evaluate this issue?]


  • = urinary anions – urinary cations.
  • = [Na+] + [K+] – [Cl-]

The urinary anion gap can help to differentiate between GIT and renal causes of a hyperchloraemic metabolic acidosis.

  • It provides a indirect index of urinary ammonium excretion.
  • Ammonium is positively charged so a rise in its urinary concentration (ie increased unmeasured cations) will cause a fall in UAG (as this is paralleled by an increase in Cl- excretion)
  • Principle idea: UAG ≈ concentration of ammonium [- unmeasured anions, which remains essentially constant]


  • Loss of base via bowel – negGUTive !
  • ie. kidneys can respond by increasing ammonium excretion [to balance H+], ∴ reducing UAG.


  • Loss of base via kidney.
  • ie. the kidney is unable to increased ammonium excretion to balance H+.


Urine chemistry demonstrating a raised urinary anion-gap
Urine chemistry demonstrating an elevated urinary anion-gap
  • UAG = [Na+] + [K+] – [Cl-]
  • = [87+16] – [54]
  • = 49 ∴ elevated !!

The on-call Renal Physician feels this is likely a case of distal renal tubular acidosis (dRTA) caused by her ibuprofen ingestion.  She is admitted to HDU and treated with IV bicarbonate and potassium replacement….


[DDET The diagnosis…]

Renal tubular acidosis.

A group of disorders in which, due to either abnormal bicarbonate reabsorption (proximal) or hydrogen ion excretion (distal), results in development of a metabolic acidosis.

The basics.

  • Hyperchloraemic (non-anion gap) metabolic acidosis
  • Does not impair glomerular filtration
  • There are three major subgroups of RTA’s with different clinical characteristics;
    1. Distal (Type 1) RTA
    2. Proximal (Type 2) RTA
    3. Hypoaldosteronism (Type 4) RTA
Types of renal tubular acidosis
Features of subtypes of Renal Tubular Acidosis


Type 1.

  • Idiopathic
  • Autoimmune diseases – Sjogren’s, SLE, rheumatoid arthritis, primary biliary cirrhosis, chronic active hepatitis, congenital adrenal hyperplasia
  • Calcium disorders – primary hyperparathyroidism, vitamin D toxicity, hypercalcaemic hyperthyroidism
  • Drugs/toxins – amphotericin B, lithium, toluene, amiloride, analgesic abuse
  • Renal – renal transplant rejection, medullary sponge kidney, obstructive + reflux uropathy

Type 2.

  • Associated with other proximal tubule defects
  • Fanconi syndrome
  • Heavy metals
  • Renal transplant, medullary cystic disease, recurrent nephrolithiasis
  • Chemotherapy
  • Amyloidosis

Type 4.

  • Adrenal insufficiency – Addison’s disease, hypoaldosteronism, congenital adrenal hyperplasia
  • Hyporeninaemia
  • Drugs – NSAIDs, ACE inhibitors, cyclosporin, amiloride, spironolactone, trimethoprim
  • Diabetes
  • Interstitial nephropathies – obstructive, medullary-cystic, drug-induced, transplant-rejection + AIDS nephropathy
  • Analgesic nephropathy.

Specific to this case…

There are multiple case reports of Ibuprofen causing a distal RTA, usually when taken in excessive doses.  Such doses are most commonly taken in combination analgesics that also contain codeine.  Although the mechanism is unknown it is postulated that it may involve inhibition of carbonic anhydrase.  It may be associated with marked hypokalaemia and hypokalaemic paralysis.


  • Treat the underlying cause / Remove the precipitant.
  • Correct the acidosis;
    • Alkali therapy [sodium bicarbonate]
      • DISTAL RTA ~ typically 1-4 mmol/kg/day !
      • PROXIMAL RTA requires very large quantities of alkali [up to 10-20 mmol/kg/day]
      • Ideally mixture of both Na+ & K+ salts.
    • Aims to provide adequate base to balance H+ production.
  • Correction of hypercalciuria.
  • Correct electrolytes.
    • Cautious potassium replacement.


[DDET Case follow-up…]

  • Over the next 24 hours, the acid-base disturbance returns to essentially normal.
  • Unfortunately she signs herself out of hospital on Day 3 & is lost to follow-up….


[DDET References & Credits]

  1. Bersten AD, Soni N. Oh’s Intensive Care Manual (6th edition), Butterworth-Heinemann 2009.
  2. Overview of renal tubular acidosis – UpToDate.com
  3. Rodríguez Soriano, J. (2002). Renal tubular acidosis: the clinical entity. Journal of the American Society of Nephrology : JASN, 13(8), 2160–2170. doi:10.1097/01.ASN.0000023430.92674.E5
  4. Ring, T., Frische, S., & Nielsen, S. (2005). Clinical review: Renal tubular acidosis–a physicochemical approach. Critical care (London, England), 9(6), 573–580. doi:10.1186/cc3802
  5. Ng, J. L., Morgan, D. J. R., Loh, N. K. M., Gan, S. K., Coleman, P. L., Ong, G. S. Y., & Prentice, D. (2011). Life-threatening hypokalaemia associated with ibuprofen-induced renal tubular acidosis. The Medical Journal of Australia, 194(6), 313–316.
  6. BMJ Best Practice: Assessment of Peripheral Oedema
  7. The Urinary Anion Gap – AnaesthesiaMCQ.com
  8. Acidosis in Kidney Disease – Paul Young’s Intensive Care Mind Maps 
  9. Renal Tubular Acidosis and Uraemic Acidosis – Life in the Fast Lane

Author: Jimmy Bliss
Web editing + additional writing: Chris Partyka


Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.