What are the key differences between proximal (type 2) and distal (type 1) renal tubular acidosis regarding pathophysiology, laboratory findings (including serum potassium and urine pH), and recommended treatment?

Proximal (Type 2) vs Distal (Type 1) Renal Tubular Acidosis: Key Differences

Proximal RTA (Type 2) is characterized by defective bicarbonate reabsorption in the proximal tubule with hypokalemia and ability to acidify urine below pH 5.5, while distal RTA (Type 1) involves impaired hydrogen ion secretion in the distal nephron with inability to acidify urine below pH 5.5, hypokalemia, and high risk of nephrocalcinosis and kidney stones. 1, 2, 3

Pathophysiology

Proximal RTA (Type 2)

• The fundamental defect is impaired bicarbonate reabsorption in the proximal convoluted tubule, resulting in urinary bicarbonate wasting when serum bicarbonate is normal or near-normal 1, 2
• The distal nephron's acidification capacity remains intact, allowing urine pH to fall below 5.5 once serum bicarbonate drops and filtered bicarbonate load decreases 2, 4
• Ammonium excretion is reduced despite acidosis and low urine pH, possibly due to more alkaline intracellular pH in proximal tubular cells 5

Distal RTA (Type 1)

• The primary defect is failure of hydrogen ion secretion by intercalated cells in the distal nephron and collecting duct 1, 3
• This results in persistently elevated urine pH (typically >5.5) even during severe systemic acidosis 2, 3
• Both ammonium excretion and titratable acid excretion are impaired 3

Laboratory Findings

Serum Chemistry

• Both types present with hyperchloremic, normal anion gap metabolic acidosis (anion gap 8-16 mEq/L) 2
• Proximal RTA: Hypokalemia is present but typically less severe; serum bicarbonate usually 12-18 mEq/L 1, 2
• Distal RTA: Hypokalemia is more striking and severe, often requiring aggressive potassium replacement; serum bicarbonate typically <12 mEq/L 1, 3

Urine pH

• Proximal RTA: Urine pH can be acidified to <5.5 when serum bicarbonate is low (below the reabsorptive threshold) 2, 4
• Distal RTA: Urine pH remains inappropriately alkaline (>5.5) despite severe systemic acidosis 2, 3

Urine Anion Gap

• Proximal RTA: Negative urine anion gap (Cl⁻ >> Na⁺ + K⁺) when acidotic, indicating preserved ammonium excretion capacity 2
• Distal RTA: Positive urine anion gap (Cl⁻ < Na⁺ + K⁺), reflecting impaired ammonium excretion 2

Fractional Excretion of Bicarbonate

• Proximal RTA: Fractional excretion of bicarbonate >15% when serum bicarbonate is normalized with alkali therapy 2, 4
• Distal RTA: Fractional excretion of bicarbonate <5% even when serum bicarbonate is normalized 2

Urine PCO₂

• Proximal RTA: Normal urine-to-blood PCO₂ gradient (>20 mmHg) after bicarbonate loading 2
• Distal RTA: Reduced urine-to-blood PCO₂ gradient (<20 mmHg) after bicarbonate loading, indicating impaired distal acidification 2

Clinical Manifestations

Proximal RTA (Type 2)

• Growth retardation in children due to chronic acidosis 1
• Bone disease (rickets in children, osteomalacia in adults) 1
• Nephrocalcinosis and nephrolithiasis are NOT typical features 2
• May present as part of Fanconi syndrome with glycosuria, phosphaturia, and aminoaciduria 6

Distal RTA (Type 1)

• Severe growth retardation and bone abnormalities in children 3
• Nephrocalcinosis and nephrolithiasis are hallmark features, developing from hypercalciuria, hypocitraturia, and alkaline urine 6, 3
• Recurrent kidney stones or history of stone surgery is a common presenting feature 6
• Muscle weakness from severe hypokalemia 3

Diagnostic Workup

For Suspected Distal RTA

• Measure urinary calcium-creatinine ratio to evaluate hypercalciuria 6
• Obtain 24-hour urine collection for calcium, citrate (typically low), and pH 6
• Perform renal ultrasound to detect medullary nephrocalcinosis and nephrolithiasis 6
• Check serum intact parathyroid hormone if hypercalcemia is present 6
• Monitor serial renal function to detect progression of kidney disease 6

For Suspected Proximal RTA

• Measure fractional excretion of bicarbonate during bicarbonate loading (>15% confirms diagnosis) 2
• Assess for features of Fanconi syndrome (glycosuria, phosphaturia, aminoaciduria) 6
• Check urine pH when patient is acidotic (should be <5.5 in proximal RTA) 2

Treatment

Proximal RTA (Type 2)

• Alkali therapy with sodium bicarbonate or sodium citrate is required, but much higher doses are needed (10-20 mEq/kg/day) compared to distal RTA due to ongoing bicarbonate wasting 1, 4
• Potassium supplementation with potassium chloride (not potassium citrate or bicarbonate, which worsen alkalosis) 1
• Thiazide diuretics may be added to induce mild volume depletion, which enhances proximal bicarbonate reabsorption 4

Distal RTA (Type 1)

• Alkali therapy with sodium bicarbonate or sodium citrate at lower doses (1-3 mEq/kg/day) is usually sufficient 1, 4
• Potassium supplementation with potassium chloride is essential due to severe hypokalemia 1, 3
• Monitor serum electrolytes, acid-base status, and renal function regularly 6
• Serial renal ultrasound to monitor for nephrocalcinosis development 6

Critical Diagnostic Algorithm

1. Confirm hyperchloremic metabolic acidosis with normal anion gap 2
2. Check urine anion gap: Negative suggests proximal RTA or GI losses; positive suggests distal RTA 2
3. Measure urine pH during acidosis:
   • If <5.5 → likely proximal RTA or GI bicarbonate loss 2
   • If >5.5 → distal RTA 2, 3
4. If proximal RTA suspected: Perform bicarbonate loading test and measure fractional excretion (>15% confirms) 2
5. If distal RTA suspected: Check for nephrocalcinosis on ultrasound and measure urinary calcium 6

Common Pitfalls

• Do not use potassium citrate or potassium bicarbonate for potassium replacement in either type of RTA, as these worsen metabolic alkalosis; use only potassium chloride 7
• Do not assume absence of nephrocalcinosis rules out distal RTA in early disease, but its presence strongly supports the diagnosis 6
• Do not confuse proximal RTA with Fanconi syndrome; Fanconi presents with additional features of glycosuria, phosphaturia, and aminoaciduria 6
• Do not overlook Bartter syndrome in the differential diagnosis of hypokalemic metabolic alkalosis, which presents with metabolic alkalosis (not acidosis), elevated fractional chloride excretion >0.5%, and history of polyhydramnios 6, 8