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Renal Tubular Acidosis

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Outline

Introduction to acid-base physiology
RTA Type I
RTA Type II
RTA Type III
RTA Type IV
Diagnosis
Management
Summary

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Content prepared by

�Dr. Benjamin Courchia MD

&

Dr. Daphna Yasova Barbeau MD

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Background and Introduction

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The term renal tubular acidosis (RTA) describes a group of disorders caused by defects in the molecular machinery of the renal tubules that facilitates the reabsorption of bicarbonate (HCO3-), the secretion of protons (H+), or both.

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Renal tubular acidosis should be suspected in poorly thriving young children with hyperchloremic and hypokalemic (in case of renal tubular acidosis types 1–3) normal anion gap metabolic acidosis, with or without syndromic features.

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Netter’s essential physiology 2^nd ed.

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Netter’s essential physiology 2^nd ed.

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Serum Anion Gap = Na⁺ - (HCO₃^- + Cl^-)

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Urine Anion Gap = Na⁺ + K⁺ - Cl^-

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Regulation of acid base homeostasis

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Netter’s essential physiology 2^nd ed.

A consequence of performing metabolic work is the generation of protons (H+).

Biological systems function optimally at a narrow pH range.

It is, therefore, necessary for an organism to eliminate H+ to maintain this homeostasis.

Mammals, including humans, have adopted 3 general mechanisms to maintain the pH within this narrow physiologic range.

#1 The first is to produce and maintain an adequate supply of buffer, both within and outside of cells. The most important intracellular buffers are phosphate and proteins. The major extracellular buffer is bicarbonate.

#2 The second mechanism regulating pH is respiration. Bicarbonate is in equilibrium with carbon dioxide and water (HCO3- + H+ ) <-- --> H2O + CO2);

#3 The third, the kidney eliminates protons directly in the urine, but also serves to generate new bicarbonate and to prevent it from being lost in the urine

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Proximal Renal Tubule and Bicarbonate Reabsorption

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Fetal and Neonatal Physiology 5^th ed.

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Alexander, R. T. & Bitzan, M. Renal Tubular Acidosis. Pediatr Clin N Am 66, 135–157 (2019)

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Distal Nephron and Acid Secretion

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Alexander, R. T. & Bitzan, M. Renal Tubular Acidosis. Pediatr Clin N Am 66, 135–157 (2019)

Acid (proton) secretion occurs from type A (alpha) intercalated cells in the connecting tubule and collecting duct

Its secretion is mediated by the apically expressed plasma membrane H+ ATPase.

H+ is generated in the cytosol via conversion of H2O and CO2 into a proton and bicarbonate, a process catalyzed by carbonic anhydrase isoform 2, CA2.

This de novo–generated bicarbonate leaves the cell via the anion exchanger in the basolateral membrane

Consequently, not only is acid extruded, but base is also generated via this process.

🗝 H+ is “trapped” in the lumen of the collecting duct through binding with ammonia (NH3) to generate ammonium (NH4+)

This buffering process is essential to maximize urinary acid excretion.

Ammonia is concentrated in the lumen of the collecting duct via a recycling mechanism.

It is first generated from glutamine in the mitochondria of the proximal tubule and extruded into the tubular lumen via a sodium proton exchange mechanism.

Luminal ammonium is absorbed across the epithelial cells in the loop of Henle and concentrated in the medullary interstitium. Ammonia can then diffuse into the lumen of the collecting duct, down its concentration gradient, a process mediated by the Rhesus family C glycoprotein (RhCG), and combine with secreted protons to form ammonium

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Renal Tubular Acidosis

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The metabolic acidosis is non-anion gap in both, because it is a problem with bicarbonate loss as opposed to the build up of additional acid. In general, the GFR is normal and this disorders do not progress to renal failure. However, they can cause a whole host of other problems.

�Clinical findings in addition to the non-anion gap metabolic acidosis.

-there can be polyuria

-they can both have hypokalemia (because aldosterone is not affected, volume contraction leads to increased aldosterone and increased K excretion.

-hypokalemia also worsens the kidneys ability to concentrate urine

-can cause muscle weakness

-can cause constipation 2/2 muscle weakness

-there is failure to thrive because metabolic acidosis itself blunts the release of growth hormone and dysregulates the axis

-in addition, metabolic acidosis itself causes decreased hunger/interest in feeding

��

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Renal Tubular Acidosis Type I

In Distal/ Type 1 RTA, the distal tubule is unable to secrete acid into the urine moving into the collecting duct. Presentation includes:
Non-anion gap metabolic acidosis
Inappropriately high urine pH (or alkalotic urine) especially in the face of acidosis.
Low serum potassium concentration because potassium is lost in the urine as a cation replacement for hydrogen.
Hypercalciuria and notoriously: urinary stones.

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Renal Tubular Acidosis Type I

autoimmune diseases like Sjogrens, Lupus, RA and primary hyperparathyroidism as well as hypothyroidism.
medications like amphotericin B, lithium, trimethoprim, NSAIDs and foscarnet.
In infants and children, single gene defects should be considered. Some genetic mutations also code for proteins in the ear and thus some children afflicted have sensorineural hearing loss.

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Renal Tubular Acidosis Type II

RTA 2 results from a reduction in the threshold for bicarbonate reabsorption in the proximal tubule. This leads to:
Normal anion gap metabolic acidosis
Hypokalemia
Normal urine pH

This means that the proximal tubule reabsorbs less bicarbonate ions, leading to profound urinary bicarbonate losses.

Initially this leads to a high urine pH. With time, the kidney compensates and distal acidification occurs leading to a lower urine pH. This is a very important point to help both understand and distinguish the laboratory findings between the two. Even though the proximal tubule fails to reabsorb bicarbonate, the kidney helps maintain balance because the urine still goes to the distal tubule which in type 2, functions correctly and acidifies the urine by secreting the hydrogen ions, eventually over time, maintaining a urine ph <5.5.

Hypercalciuria does not occur, thusly, stones are not seen in type 2. Citrate binds calcium and prevents it from precipitating as a calcium oxalate or calcium phosphate salt, because the urine is alkaline until it reaches the distal tubule, where it can be acidified-, there is decreased citrate reabsorption and increased urinary citrate which likely helps prevents stone formation.

��Regardings the genetics, the mutation implicated in Type 2 is the sodium bicarbonate cotransporter 1. Children with this condition have ocular manifestations like cataracts and glaucoma. In general, isolated Type 2 is rare. It is more commonly seen as a part of Fanconi syndrome characterized by more global dysfunction leading to hypophsphatemia, glycosuria, proteinuria and amino aciduria. It can be associated with other syndromes and caused by medications as well.

�This is also what is seen in a sort of functional renal immaturity in neonates. Commonly, term infants have a normal mild RTA, with serum bicarbonate concentrations of 20 to 24 mEq/L (20 to 24 mmol/L), and preterm infants may have values as low as 15 mEq/L (15 mmol/L). This improves with post natal age but can be particularly protracted in the very preterm neonate. One of the tips another study buddy came up with was that since this is what we see in the preterm infant, it feels “proximal” (or near and dear) to us. I also like to remember that there is an X in proximal, which is like two lines, therefore proximal, is type 2.

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Renal Tubular Acidosis Type II

Mutation implicated in Type 2 is the sodium bicarbonate cotransporter 1.
Children with this condition have ocular manifestations like cataracts and glaucoma.
Isolated RTA Type 2 is rare and is commonly seen as part of Fanconi Syndrome.
RTA Type 2 is also seen as functional immaturity in neonates.

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Renal Tubular Acidosis Type III

It is a rare autosomal-recessive disorder that manifests with osteopetrosis, cerebral calcifications, nephrocalcinosis and nephrolithiasis, facial dysmorphism, conductive hearing loss and cognitive impairment.
The only known cause of this disease is a mutation in Carbonic Anhydrase A2 (CA2).
The role of CA2 in proximal tubule bicarbonate absorption and in distal proton secretion accounts for the combined types of metabolic acidosis.

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Renal Tubular Acidosis Type IV

The primary abnormality is actual or effective hypoaldosteronism.
It results in sodium wasting from the collecting duct.
In contrast with RTA types 1 to 3, the defining feature of type 4 RTA is a high normal or increased plasma potassium level.
Type 4 RTA is also observed in patients with obstructive uropathy, pyelonephritis and, occasionally, lupus nephritis

Brodsky & Martin. Neonatology Review 3^rd ed.

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Renal Tubular Acidosis Type IV

There are several subtypes
Subtype I – Aldosterone deficiency – salt wasting, increased renin, decreased pH, hyperkalemia, decreased urine aldosterone.
Subtype IV – Pseudohypoaldosteronism (rare) - increased urine aldosterone but tubule insensitive to aldosterone leading to salt-wasting, decreased pH and hyperkalemia.
Subtype V – “Early childhood RTA” (most common) – tubule insensitive to aldosterone effect, salt reabsorption normal. Typically mature with age.

Brodsky & Martin. Neonatology Review 3^rd ed.

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Diagnosis

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Pelletier, J., Gbadegesin, R. & Staples, B. Renal Tubular Acidosis. Pediatr Rev 38, 537–539 (2017).

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Chan, J. C. M., Scheinman, J. I. & Roth, K. S. Consultation With the Specialist: Renal Tubular Acidosis. Pediatr Rev 22, 277–287 (2001).

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Chan, J. C. M., Scheinman, J. I. & Roth, K. S. Consultation With the Specialist: Renal Tubular Acidosis. Pediatr Rev 22, 277–287 (2001).

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RTA Management

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RTA Management

Brodsky & Martin. Neonatology Review 3^rd ed.

Ringer, S. A. Renal Tubular Acidosis. Neoreviews 11, e252–e256 (2010).

RTA Type I	RTA Type II	RTA type IV
Usually is treated successfully with added alkali (bicarbonate) in low doses, ranging from 1 to 3 mEq/kg per day. In the acquired types, correction of the underlying cause or stopping the associated drug therapy results in improvement.	Much greater need for bicarbonate compared to type I. Dose can be as high as 10 mEq/kg per day or more, titrated as needed to correct the acidosis. Additional therapy or dietary manipulation is determined by the presence of any associated metabolic disease.	Subtype I: Aldosterone Subtype 4: Bicarbonate Subtype 5: Bicarbonate

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Summary

RTAs are caused by defects in the reabsorption of bicarbonate (HCO3-), the secretion of protons (H+), or both
Renal tubular acidosis should be suspected in poorly thriving young children with hyperchloremic and hypokalemic (in case of renal tubular acidosis types 1–3) normal anion gap metabolic acidosis, with or without syndromic features.
RTA Type IV, also known as hyperkalemic RTA, involve abnormal aldosterone production or change in sensitivity to aldosterone
Management of RTA mostly involves the administration of bicarbonate for RTA type 1, 2, 3, and 4 (subtype 4 and 5).

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