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Renal System

Renal tubular acidosis (RTA)

Group of disorders affecting the renal tubules characterized by an impaired ability to acidify the urine and excrete acid.

Renal tubular acidosis (RTA) refers to a group of disorders affecting the renal tubules characterized by an impaired ability to acidify the urine and excrete acid. The condition results in a hyperchloremic metabolic acidosis with a normal serum anion gap. | Medcomic/Jorge Muniz

Group of disorders affecting the renal tubules characterized by an impaired ability to acidify the urine and excrete acid.

Mnemonic device:

Physiology

Normal Acid–Base Homeostasis:

The kidneys contribute to the maintenance of acid–base homeostasis by reabsorbing HCO3− in the proximal tubule, as well as regenerating HCO3– in the cortical collecting duct
Schematic diagrams illustrating bicarbonate (HCO3–) reabsorption and regeneration in the kidney
Schematic diagrams illustrating bicarbonate (HCO3–) reabsorption and regeneration in the kidney. a HCO3– reabsorption in the proximal tubule. Hydrogen ions (H+) are secreted into the lumen via apical sodium (Na+)/H+ exchanger 3 (NHE3) and H+-ATPase transporters. Apical carbonic anhydrase (CA) IV catalyzes the reaction between H+ and HCO3–, which forms H2CO3 that rapidly dissociates to water and carbon dioxide (CO2). CO2 diffuses back across the apical membrane, where CA-II catalyzes its reaction with intracellular hydroxide ions (OH–) to form H+ and HCO3–. HCO3– is transported across the basolateral membrane by the Na+/HCO3–/CO32– cotransporter (NBCe1). b HCO3– reabsorption in the thick ascending limb. As in the proximal tubule, H+ is secreted into the lumen via NHE3, where it reacts with HCO3– to release CO2 that diffuses back across the apical membrane. HCO3– is transported across the basolateral membrane by NBCe1 and the kidney anion exchanger (AE1). c H+ secretion by α-intercalated cells in cortical collecting duct (CCD). H+ is secreted into the lumen by H+/K+-ATPase and vacuolar (v) H+-ATPase transporters on the apical membrane. Intracellular OH– generated by H+ secretion reacts with CO2 via CA-II to form HCO3–, which is removed by basolateral AE1. The resulting intracellular chloride (Cl–) exits via conductance channels in the basolateral membrane. Luminal K+ transported into the cell via H+/K+-ATPase can exit via channels in the apical or basolateral membrane, depending on K+ balance. d HCO3– secretion by β-intercalated cells in CCD. H+-ATPase transports H+ across the basolateral membrane. Intracellular OH– generated by H+ secretion reacts with CO2 via CA-II to form HCO3–, which is transported into the lumen by the apical Cl–/HCO3– exchanger pendrin. Intracellular Cl– exits via conductance channels in the basolateral membrane
| Palmer BF. Normal acid-base balance. In: Johnson RJ, Feehally J, Floege J, editors. Comprehensive clinical nephrology. 5th ed. Philadelphia: Elsevier; 2014. p. 142–8.
Schematic diagrams illustrating ammonia (NH3) production and transport in the kidney
Schematic diagrams illustrating ammonia (NH3) production and transport in the kidney. a NH3 production in the proximal tubular cells. After glutamine uptake via sodium (Na+)-coupled neutral amino acid transporter 3 (SNAT3), mitochondrial glutamine metabolism results in production of ammonium (NH4+). NH3 passively diffuses across apical membrane and hydrogen (H+) is transported via apical Na+/H+ exchanger 3 (NHE3) and H+-ATPase; NH3 and H+ combine in the lumen to form NH4+. b NH3 transport in the thick ascending limb. Lumen-positive voltage drives passive paracellular transport of NH4+ from the lumen into the blood. By substituting for potassium (K+), NH4+ is also transported into the cell via the Na+/K+/2Cl– transporter and the apical membrane K+ channel (ROMK). The basolateral Na+/bicarbonate (HCO3–) cotransporter (NBCn2) may play a role in maintaining cellular pH. NH4+ crosses the basolateral membrane into the blood via NHE4 | Palmer BF. Normal acid-base balance. In: Johnson RJ, Feehally J, Floege J, editors. Comprehensive clinical nephrology. 5th ed. Philadelphia: Elsevier; 2014. p. 142–8.

Etiopathogeneis

Classification:

  1. Type 1: Distal RTA
  2. Type 2: Proximal RTA
  3. Type 3: Mixed RTA
  4. Type 4: Hyporeninemic hypoaldosteronism RTA
Schematic diagram illustrating the underlying kidney tubule defects causing the different types of renal tubular acidosis (RTA)
A schematic diagram illustrating the underlying kidney tubule defects causing the different types of renal tubular acidosis (RTA). Distal (type 1) RTA is caused by either impaired hydrogen (H+) secretion by vacuolar (v) H+-ATPase or H+/K+-ATPase or increased H+ permeability of luminal membrane by α-intercalated cells of the collecting duct, which leads to a reduction in net H+ secretion. Proximal (type 2) RTA is caused by defects in bicarbonate (HCO3–) reabsorption in the proximal tubule, due to either impaired HCO3– transport across the basolateral membrane or inhibition of carbonic anhydrase (CA) activity. Hyperkalemic (type 4) RTA is caused by aldosterone deficiency or resistance, which leads to reduced Na+ (sodium) reabsorption by principal cells of the collecting duct and decreased transepithelial voltage, leading to diminished H+ secretion by α-intercalated cells and K+ secretion by principal cells. AE1 kidney anion exchanger, ENaC epithelial Na+ channel, MR mineralocorticoid receptor, NHE3 Na+/H+ exchanger 3, ROMK apical membrane K+ channel
| Palmer, B.F., Kelepouris, E. & Clegg, D.J. Renal Tubular Acidosis and Management Strategies: A Narrative Review. Adv Ther 38, 949–968 (2021). https://doi.org/10.1007/s12325-020-01587-5

Type 1 (distal RTA) “Classical RTA”:

Distal tubule is responsible for generating new bicarbonate under influence of aldosterone. Damage to α-intercalated cells of distal tubule causes no new generation of HCO3– and thus no H+. This raises the pH of urine due to an inability to excrete acid and generate acidic urine in the distal tubule, even in states of metabolic acidosis.

Defective H+ ion secretion by α-intercalated cells in late DCT & CT → ↑ H+ ions (blood acidemia)

  • Autoimmune diseases: Sjogren’s syndrome, SLE
  • Liver cirrhosis
  • Medullary sponge kidney
  • Drugs: Amphotericin B, lithium)

Type 2 (proximal) RTA:

Normally 85% to 90% of bicarbonate is reabsorbed at proximal tubule, and only 10% reabsorbed at distal tubule. Due to a HCO3– leak, impaired proximal HCO3– reabsorption in proximal tubule results in excess HCO3–in urine leading to metabolic acidosis.

Impaired HCO3– reabsorption in PCT → ↑ HCO3– loss in urine → ↑ Blood acidity

  • Multiple myeloma
  • Fanconi syndrome
  • Lowe syndrome
  • Dent’s disease
  • Amyloidosis
  • Metabolic disease: Wilson disease, hereditary fructose intolerance, cystinosis, galactosemia
  • Drugs: Acetazolamide, outdated tetracycline

Type 3 (mixed) RTA:

Rare inherited type 3 RTA is caused by mutations of CA II (chromosome 8q22) resulting in carbonic anhydrase II deficiency.
  • Kartagener’s syndrome (KS)

Type 4 (hyperkalemic) RTA: Hyporeninemic hypoaldosteronism RTA

Hypoaldosteronism causes hyperkalemia and metabolic acidosis. Hyperkalemia impairs ammonia genesis in the proximal tubule and reduces the availability of NH3 to buffer urinary H+ and decreases H+ excretion in urine. The ability to acidify urine in this type of RTA is due to the inadequate amount rather than the complete absence of NH3 available for buffering of protons. Even if only a few protons are secreted distally, urine pH will fall, and this is why these patients have a urine pH < 5.5.

Aldosterone deficiency/resistance in CT → ↑ K+ & ↓ Na+

M/C type and always acquired

  • Diabetic nephropathy (M/C cause)
  • Addison’s disease
  • SLE
  • Sickle cell disease
  • Obstructive uropathy
  • Drugs: Trimethoprim, NSAIDs, ACE inhibitors, spironolactone)
Pathogenesis of hyperkalemia. Medications, diseases, and the renin-angiotensin II-aldosterone axis and their role in potassium ion (K+) homeostasis. Abbreviations: Na+, sodium ion; NSAID, nonsteroidal anti-inflammatory drug.
Pathogenesis of hyperkalemia. Medications, diseases, and the renin-angiotensin II-aldosterone axis and their role in potassium ion (K+) homeostasis. | Abbreviations: Na+, sodium ion; NSAID, nonsteroidal anti-inflammatory drug. | Palmer (“A Physiologic-Based Approach to the Evaluation of a Patient With Hyperkalemia” AJKD 2010;56:387-393

Presentation

General symptoms:

D/t metaoblic acidosis
  • Gastrointestinal features: ↓ apetite, vomiting, abdominal pain
  • Kussmaul breathing (hyperventilation in response to acidosis): Rapid, shallow breaths that get deeper over time (to blow off CO2)
Abnormal breathing patterns
Breathing abnormal patterns that can help diagnose or discover the underlying cause of pathological breathing. 4 graphs resembling: Normal breathing, Cheyne-Stokes respiration, Biot’s respiration and Kussmaul breathing | By Sav vas – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=21156397

Distal RTA (type 1 RTA):

Commonly observed in children as a primary genetic defect. Acquired deficits usually manifest in adults and are most typically associated with autoimmune conditions or nephrotoxins.
  • Vomiting and profound dehydration
  • Obtundation (reduced level of alertness/consciousnes)
  • Restricted skeletal growth
  • Rickets

Proximal RTA (type 2 RTA):

Most cases are discovered in children with heritable mutations
  • Mild disease: Short stature and lethargy
  • Severe cases: Respiratory distress, vomiting, and feeding difficulties

Fanconi syndrome:

Fanconi syndrome is a malabsorptive state of the proximal convoluted tubules, while proximal RTA refers only to the deficiency in HCO3− retention

Most cases of proximal RTA occur as a component of Fanconi syndrome

  • Failure to thrive
  • Volume depletion
  • Rickets
  • Constipation
  • Rare genetic disorders associated with Fanconi syndrome can manifest:
    • Ocular abnormalities
    • Tooth deformities
    • Intellectual impairment

Hyperkalemic RTA (type 4 RTA):

Manifestations are a consequence of the effects of aldosterone deficiency or insensitivity. Biochemical findings are routinely the only detectable change in these patients.
  • Postural hypotension and lethargy

Mixed syndrome (type 3 RTA):

Rarely seen in clinical practice and has diagnostic findings characteristic of both distal and proximal RTA
  • Debilitating congenital syndromes in children and is principally associated with carbonic anhydrase II deficiency

Long term complications:

  • Shock (d/t vasodilation of peripheral arterioles)
  • Nephrolithiasis (calcium phosphate stones) is frequently associated with untreated type 1 RTA.
Clinical and laboratory features, pathogenesis, and major complications of incomplete distal renal tubular scidosis (idRTA). Abbreviation: NH3, ammonia.
Clinical and laboratory features, pathogenesis, and major complications of incomplete distal renal tubular scidosis (idRTA). | Abbreviation: NH3, ammonia. | Soleimani, M., & Rastegar, A. (2016). Pathophysiology of Renal Tubular Acidosis: Core Curriculum 2016. American Journal of Kidney Diseases, 68(3), 488–498. https://doi.org/10.1053/j.ajkd.2016.03.422

Diagnosis

In general, RTA should be suspected when metabolic acidosis is accompanied by hyperchloremia and a normal plasma anion gap (Na+ − [Cl− + HCO3−] = 8 to 16 mmol/L) in a patient without evidence of gastrointestinal HCO3− losses and who is not taking acetazolamide or ingesting exogenous acid.

Biochemical findings:

In all cases of metabolic acidosis, plasma or serum anion gap should be the first laboratory assessment; hyperchloremic metabolic acidosis with a normal anion gap is present in all types of RTA
Summary of renal tubular acidosis classification, diagnostic characteristics, and treatment options
Summary of renal tubular acidosis classification, diagnostic characteristics, and treatment options | Palmer, B.F., Kelepouris, E. & Clegg, D.J. Renal Tubular Acidosis and Management Strategies: A Narrative Review. Adv Ther 38, 949–968 (2021). https://doi.org/10.1007/s12325-020-01587-5

Urinalysis:

Analysis of urine biochemistry may also be useful in the evaluation of RTA; in patients with hyperchloremic metabolic acidosis and alkaline urine (i.e., pH > 5.5), RTA of some type should be strongly suspected
  • Urine pH: Inappropriately, or persistently, alkaline (DIAGNOSTIC)
Urine pH versus plasma bicarbonate in renal tubular acidosis (RTA)
Urine pH versus plasma bicarbonate in renal tubular acidosis (RTA) | Unwin, R. J., & Capasso, G. (2001). The renal tubular acidoses. Journal of the Royal Society of Medicine, 94(5), 221–225. https://doi.org/10.1177/014107680109400506

Acid load test:

Infusion of acid into blood with 100 mg/kg of ammonium chloride and check urine pH hourly and plasma HCO3 at 3-hour interval.
  • A healthy person will be able to excrete acid and will decrease urine pH. Those with distal RTA cannot excrete acid and urine pH will remain basic despite increasingly acidic serum.
  • Distal RTA: Measurement of the urine-to-blood (U-B) pCO2 gradient during an NaHCO3 infusion can be used to diagnose H+-ATPase secretory defect
  • Proximal RTA: NaHCO3 loading test (during an IV NaHCO3, the increase in serum HCO3– above the reabsorption threshold will lead to fractional excretion of HCO3– > 15% or urine pH > 7.5 in patients with proximal RTA)
    • Patients with proximal RTA should also be evaluated for Fanconi syndrome by assessment of serum and urine samples for glycosuria, hypophosphatemia, and hypouricemia.
Diagnostic work-up of a patient with hyperchloremic metabolic acidosis and a negative urine anion gap.
Diagnostic work-up of a patient with hyperchloremic metabolic acidosis and a positive urine anion gap.

Bicarbonate infusion test:

Fractional bicarbonate excretion is measured after an infusion of bicarbonate.
  • Serum bicarbonate concentration approaches the normal level in the body after the infusion, which is more than the reabsorption threshold of the patient with type 2 Proximal RTA.

Urine Na test:

Type 4 RTA presents with persistently high urine Na despite restricted Na diet because of aldosterone deficiency or resistance.

Management

Type I & II RTA:

The basis of therapy is the continuous administration of appropriate amounts of alkali in the form of either bicarbonate or citrate. The amount of alkali administered should compensate for the urinary loss of HCO3− plus the amount of acid generated by the catabolism of proteins and the skeletal growth.
  • Alkali therapy: Oral HCO3– (10-15 mEq/kg/day) + potassium supplementation
  • Hydrochlorothiazide: Increases HCO3– tubular maximum (hypokalemia prevented with supplemental potassium)
  • Fanconi syndrome: Phosphate supplementation
  • Vitamin D supplementation
  • Long-term follow-up (for renal stone complications)

Type IV RTA:

For hyperkalemic RTA, treatment and prognosis depends on the underlying cause. Potassium-retaining drugs should always be withdrawn. Hypoaldosteronism due to adrenal failure may respond adequately to replacement doses of fludrocortisone.
  • Fludrocortisone therapy
  • Loop diuretic (eg furosemide): Reduce risk of extracellular fluid volume expansion
  • Alkali supplements (1.5 to 2 mmol/kg per 24 h)

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