What type of Renal Tubular Acidosis (RTA) is characterized by a defect in the proximal tubules?

Type II Renal Tubular Acidosis (Proximal RTA)

Type II Renal Tubular Acidosis (RTA) is characterized by a defect in bicarbonate reabsorption in the proximal tubules of the kidney. 1, 2

Pathophysiology

• Type II RTA results from impaired bicarbonate reabsorption in the proximal tubule, leading to bicarbonate wastage in the urine and a normal anion gap metabolic acidosis 1
• The proximal tubular defect is severe enough to overwhelm the capacity for bicarbonate reabsorption in the thick ascending limb of Henle's loop and more distal nephron segments 3
• Type II RTA can occur as an isolated defect or as part of a broader proximal tubular dysfunction known as Fanconi syndrome 1, 4

Key Clinical and Laboratory Findings

• Normal anion gap hyperchloremic metabolic acidosis is the hallmark finding 5
• Bicarbonate wastage in the urine reflecting impaired proximal tubular reabsorption 4
• When part of Fanconi syndrome, additional findings include:
  • Glucosuria despite normal serum glucose levels 1
  • Generalized aminoaciduria 1
  • Hypophosphatemia due to impaired phosphate reabsorption 1
  • Hypokalemia from increased urinary potassium losses 1
  • Increased urinary excretion of uric acid and low-molecular-weight proteins 4

Diagnostic Features

• Positive urine anion gap (Cl- less than Na+ + K+) indicating a defect in acid excretion 5
• Elevated fractional excretion of bicarbonate at normal plasma bicarbonate concentration 5
• Urine pH that can be appropriately acidified when plasma bicarbonate falls below the proximal tubular threshold 2
• Distinction from other types of RTA:
  • Unlike Type I (distal) RTA, the proximal tubule can still acidify urine when plasma bicarbonate is low 2
  • Unlike Type IV RTA, potassium levels are typically low rather than high 2, 6

Associated Conditions

• Inherited forms:
  • Mutations in the basolateral sodium-bicarbonate cotransporter (NBCe1) 4
  • Can be part of systemic diseases like tyrosinemia type I 7
• Acquired causes:
  • Drug-induced (most common cause) - particularly carbonic anhydrase inhibitors, ifosfamide, valproic acid, and certain antiretrovirals 4
  • Heavy metal poisoning 3
  • Multiple myeloma and other paraproteinemias 3

Clinical Implications

• Hypophosphatemia can lead to osteomalacia, bone pain, and rickets in children 1
• Chronic metabolic acidosis may impair growth in children 2
• Hypokalemia can cause muscle weakness and cardiac arrhythmias 1

Management

• Treatment focuses on replacing lost electrolytes, particularly bicarbonate, phosphate, and potassium 1
• Alkali therapy (sodium bicarbonate or citrate) is the cornerstone of treatment 6
• Higher doses of alkali are typically required compared to distal RTA due to ongoing bicarbonate wastage 2
• Monitoring for and treating rickets with vitamin D supplementation in patients with chronic hypophosphatemia 1
• Treatment of the underlying cause when possible, especially in drug-induced cases 4

In patients with tyrosinemia type I, the proximal tubular dysfunction (including Type II RTA) may take weeks to normalize even after appropriate treatment 1.