In addition to today’s resource, please see emedicine.medscape.com‘s Anion Gap
Updated: Sep 01, 2025. This resource is an excellent discussion of Anion Gap.

In addition to today’s resource, please see StatPearls‘ Renal Tubular Acidosis. Last Update: July 17, 2023.

Reference Range

• Remember the calculation for serum anion gap: AG = Na – (Cl + bicarb) [from Cribsiders podcast #150.

The reference range for the anion gap in blood is as follows ^[1] :

• 16 ± 4 mEq/L (if the calculation employs potassium)
• 12 ± 4 mEq/L (if the calculation does not employ potassium)

There are no normal urine anion gap (UAG) values due to the wider range of the UAG. ^[2] However, various studies have reported a significant increase in the reference range for UAG in healthy individuals from 41 mEq/day to > 70 mEq/day. ^[3]

Today, I review, link to, and excerpt from The Cribsiders‘ #150: NepHron Nuances: Approach to Diagnosing and Treating RTAs.*

*Producer Starr M, Berk J, Chiu C, Masur S. “#150: NepHron Nuances: Approach to Diagnosing and Treating RTAs”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ 27th August, 2025.

All that follows is from the above resource.

In this episode, returning guest Dr. Michelle Starr joins us to unpack the complexities of renal tubular acidosis. Together, we explore how to distinguish between RTA types and highlight the key diagnostic clues and treatment strategies most relevant to pediatric patients. Whether you’re managing a challenging case on the wards or brushing up for boards, this conversation will deepen your understanding and knowledge-base!

RTA Pearls

• RTA is a cause of non-anion gap metabolic acidosis (NAGMA). Always consider it in pediatric patients with low bicarb and absence of GI losses. If you are concerned about this, check a VBG, followed by urine electrolytes after confirming acidosis.
• If urine pH is high (> 5.5) in a patient with RTA, think Type I (distal) RTA.
• In Type II RTA, urine acidification is initially impaired but can recover as serum bicarb drops.
• Hypokalemia is common in Type I and Type II RTA, while Type IV RTA features hyperkalemia.
• Nephrocalcinosis on imaging is a major clue – if you see it, suspect Type I RTA.
• Treatment = Alkali therapy ± potassium depending on the type. Early diagnosis and adherence can normalize growth and development.

RTA Notes 

Overview

• Renal tubular acidoses are a group of disorders characterized by the kidneys’ inability to properly acidify the urine, leading to a normal anion gap metabolic acidosis. This is usually due to impaired renal hydrogen ion secretion, bicarbonate reabsorption, or both.
• RTA can develop due to various causes, including medications (such as topiramate or acetazolamide), inherited genetic conditions, urinary obstruction, infection, and autoimmune diseases such as SLE.
• The kidneys excrete acid in the form of hydrogen phosphate and ammonium (the latter being the primary mechanism).
• There are 3 main types of RTAs (Type I, Type II, and Type IV). Controversy exists as to whether there is also a Type III RTA (mixed proximal and distal RTA); this typically refers to tubular dysfunction leading to immature tubular acid handling, and is most often seen transiently in neonates due to high daily acid load, inadequate bicarbonate reabsorption, and poor acid tubular acid secretion.
• The most common unifying presentation is failure to thrive (height typically more affected with weight relatively preserved). Urine output is typically preserved. Depending on RTA type, you may also see nephrocalcinosis and/or hearing loss.
• Failure to appropriately recognize and treat RTAs can result in failure to thrive, poor neurodevelopmental outcomes, and other downstream manifestations such as rickets/osteomalacia and/or nephrocalcinosis depending on the underlying defect.

Workup

Initial Labs

• Blood gas (look for low pH, low bicarb, normal AG)
  • Remember the calculation for serum anion gap: AG = Na – (Cl + bicarb)
• Serum electrolytes (Na, K, Cl, bicarb)
• If you have a non-gap acidosis and have ruled-out other more common etiologies (see above), send urine electrolytes (urine Na, urine K, and urine Cl). This is used to calculate the urine anion gap (UAG). This helps us assess whether enough ammonium (i.e. acid) is being excreted
  • UAG = (urine Na + urine K) – urine Cl
  • Urine chloride acts as a surrogate marker for ammonium; this is the primary acid excreted by the kidneys
  • A positive UAG is suspicious for RTA, as it suggests the kidneys are not appropriately excreting acid
    • A negative UAG is indicative of a non-RTA cause of metabolic acidosis (i.e. GI losses)
• Urine pH (included in urinalysis)

Additional Workup to Consider

• Fractional excretion of bicarbonate (can help differentiate proximal vs distal defect)
• Workup for Fanconi syndrome if proximal tubule defect is suspected
• Renal ultrasound (check for nephrocalcinosis)