What is the most likely diagnosis, appropriate diagnostic work‑up, and treatment for a patient presenting with normal anion‑gap metabolic acidosis, persistent hypokalemia, and a urine pH >5.5 despite systemic acidosis?

Distal (Type 1) Renal Tubular Acidosis

The most likely diagnosis is distal renal tubular acidosis (Type 1 RTA), confirmed by the classic triad of normal anion gap metabolic acidosis, persistent hypokalemia, and urine pH >5.5 despite systemic acidosis. 1, 2, 3

Diagnostic Confirmation

Key Laboratory Features

• Normal anion gap (8-12 mEq/L) metabolic acidosis with serum bicarbonate typically <20 mmol/L distinguishes RTA from high anion gap acidoses like diabetic ketoacidosis 1, 4, 2
• Urine pH persistently >5.5 (often 6.0-7.0) despite systemic acidosis is pathognomonic for Type 1 RTA, reflecting the inability of the distal nephron to secrete hydrogen ions 2, 5, 3
• Severe hypokalemia (often <3.0 mEq/L, can be as low as 1.3 mEq/L) results from renal potassium wasting and can cause muscle weakness, paralysis, rhabdomyolysis, and cardiac arrhythmias 1, 2, 3
• Hypercalciuria with low urinary citrate predisposes to nephrocalcinosis and calcium phosphate kidney stones 5, 6

Essential Diagnostic Work-Up

• Serum electrolytes: sodium, chloride, potassium, calcium, magnesium, bicarbonate, and calculate anion gap 7, 1
• Arterial blood gas: confirms metabolic acidosis (pH <7.35) with normal anion gap 1, 3
• Simultaneous urine pH measurement: must be >5.5 in the presence of systemic acidosis (ideally early morning sample) 5, 3
• Urinary calcium-to-creatinine ratio: typically elevated in Type 1 RTA 7, 1
• Renal ultrasound: assess for medullary nephrocalcinosis (common in Types 1 and 2 Bartter syndrome) and kidney stones 7, 1, 5
• Plasma renin and aldosterone levels: to differentiate from Bartter syndrome (both markedly elevated in Bartter) 8
• Urinary chloride concentration: >20 mEq/L indicates chloride-resistant alkalosis, suggesting alternative diagnoses like Bartter syndrome 8
• Fractional excretion of chloride: >0.5% suggests Bartter syndrome rather than RTA 7, 1, 4

Critical Differential: Bartter Syndrome

Bartter syndrome presents with hypokalemic metabolic alkalosis (not acidosis), distinguishing it from Type 1 RTA 7, 1, 8. Key differentiating features include:

• Elevated pH and bicarbonate >25 mEq/L in Bartter syndrome versus low bicarbonate and pH in Type 1 RTA 7, 8
• Fractional chloride excretion >0.5% in Bartter syndrome despite volume depletion 7, 1
• Markedly elevated plasma renin and aldosterone in Bartter syndrome (secondary hyperaldosteronism) 8
• History of polyhydramnios and premature birth may suggest Bartter syndrome 7, 8

Genetic Testing

• Confirm diagnosis with genetic testing for mutations in SLC4A1 (autosomal dominant), ATP6V0A4, or ATP6V1B1 (autosomal recessive with sensorineural hearing loss) 7, 1, 6
• Avoid obsolete and potentially dangerous tests like ammonium chloride loading or furosemide/thiazide tubular function tests, which risk severe volume depletion and worsening acidosis 1

Treatment Approach

First-Line Therapy

Potassium citrate is the drug of choice for long-term treatment of Type 1 RTA, as it simultaneously corrects metabolic acidosis and hypokalemia 1. Treatment goals:

• Maintain serum bicarbonate >22 mmol/L to prevent growth failure, bone disease, and nephrocalcinosis progression 9, 6
• Maintain serum potassium 4.5-5.0 mEq/L to prevent cardiac arrhythmias and muscle weakness 1, 8
• Typical dosing: 1-2 mEq/kg/day of alkali (as potassium citrate) divided into 3-4 doses, with potassium chloride supplementation (20-60 mEq/day) as needed 1, 8, 9

Monitoring Parameters

• Serum electrolytes (potassium, bicarbonate, calcium, phosphorus) every 2-4 weeks initially, then every 3-6 months once stable 7, 1
• Urine calcium-to-creatinine ratio to assess hypercalciuria and nephrocalcinosis risk 7, 1
• Renal ultrasound annually to monitor for nephrocalcinosis progression 7, 6
• Growth parameters in children (height and weight charts) to ensure adequate catch-up growth 7, 3
• Audiometry if autosomal recessive Type 1 RTA suspected (ATP6V1B1 or ATP6V0A4 mutations cause progressive sensorineural hearing loss) 5, 6

Common Pitfalls to Avoid

• Never use potassium citrate or potassium bicarbonate alone without addressing acidosis, as alkalinization worsens hypercalciuria and stone risk 8
• Avoid furosemide or acetazolamide, which worsen hypokalemia and acidosis respectively 1
• Do not overlook urinary obstruction as a secondary cause of Type 1 RTA; relieve obstruction first to prevent permanent nephron loss 1
• Recognize that Type 1 RTA is not benign: untreated disease causes growth failure, rickets, nephrocalcinosis, nephrolithiasis, and chronic kidney disease 3, 9, 6

Expected Treatment Response

• Biochemical correction within 2-3 months: bicarbonate normalizes to >18 mmol/L, potassium to >3.2 mEq/L 3
• Radiographic healing of rickets visible on X-rays within 3 months 3
• Significant catch-up growth in children: 10 cm height gain and 5 kg weight gain possible within 6 months of adequate alkali therapy 3, 9