Renal tubular disorders

Generalized Proximal Tubule Defect

• Fanconi Syndrome
  • Pathophysiology: A generalized reabsorption defect in the Proximal Convoluted Tubule (PCT). Impaired transport of glucose, amino acids, HCO₃⁻, phosphate, and other solutes. Leads to significant urinary wasting of these substances.
  • Key Features:
    • Normal serum glucose despite glucosuria is a major clue. (Plasma glucose is tightly regulated by mechanisms (eg, insulin, glucagon) independent of renal reabsorption.)
    • Metabolic Acidosis (Type 2 RTA): Due to urinary loss of bicarbonate (HCO₃⁻).
    • Hypophosphatemia: Leads to rickets in children and osteomalacia in adults.
    • Aminoaciduria, Polyuria.
  • Causes:
    • Hereditary: Wilson disease, cystinosis, galactosemia.
    • Acquired: Multiple myeloma (light chains), lead poisoning, and nephrotoxic drugs (e.g., expired tetracyclines, ifosfamide, certain antiretrovirals).

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Renal tubular acidosis (RTA)

• In RTA, there is a normal anion gap metabolic acidosis in patients with normal or almost normal renal function.
• Basically all present with low pH and hypokalemia (except type 4)
  • Think H⁺ and K⁺ antagonize each other during excretion (due to Na⁺/K⁺ vs Na⁺/H⁺), increased excretion of one leads to decreased excretion of the other.
• Renal tubular acidosis is caused by defects in the tubular transport of HCO₃^- and/or H⁺.
• Most forms of RTA are asymptomatic; rarely, life-threatening electrolyte imbalances may occur.

Remember these alphabetically

Renal Tubular Acidosis (RTA) is a group of disorders causing a non-anion gap, hyperchloremic metabolic acidosis with a relatively preserved glomerular filtration rate (GFR). The core issue is a failure of the renal tubules to properly handle acid excretion or bicarbonate (HCO₃⁻) reabsorption.

Type 1 (Distal) RTA

• Pathophysiology: Defect in H⁺ secretion by α-intercalated cells in the distal tubule/collecting duct. This leads to an inability to acidify the urine.
• Etiology:
  • Autoimmune diseases: Sjögren syndrome, Rheumatoid Arthritis (RA), SLE.
  • Medications: Amphotericin B, lithium.
  • Hereditary causes.
• Clinical Presentation:
  • Hypokalemia.
  • Recurrent calcium-phosphate kidney stones and nephrocalcinosis due to alkaline urine (pH > 5.5), hypercalciuria, and hypocitraturia.
  • In children: failure to thrive, rickets.
• Diagnosis:
  • Hallmark: Urine pH > 5.5 despite systemic metabolic acidosis.
  • Serum: Normal anion gap acidosis, hypokalemia.
• Management: Alkali replacement with sodium bicarbonate or potassium citrate to correct acidosis and prevent stone formation.

Type 2 (Proximal) RTA

• Pathophysiology: Impaired HCO₃⁻ reabsorption in the proximal convoluted tubule (PCT).
• Etiology:
  • Fanconi Syndrome: A generalized PCT defect causing phosphaturia, glucosuria, and aminoaciduria.
    • Plasma glucose is tightly regulated by mechanisms (eg, insulin, glucagon) independent of renal reabsorption. Therefore, serum glucose remains normal.
  • Medications: Carbonic anhydrase inhibitors (e.g., acetazolamide), expired tetracyclines.
  • Multiple myeloma (light chain toxicity to tubules).
• Clinical Presentation:
  • Hypokalemia.
  • Bone disease (osteomalacia/rickets) due to phosphate wasting and chronic acidosis.
  • Symptoms related to Fanconi syndrome if present.
• Diagnosis:
  • Serum: Normal anion gap acidosis, hypokalemia.
  • Urine pH: Initially high (>5.5) due to bicarbonaturia. Once serum HCO₃⁻ is significantly depleted, less bicarbonate is filtered and the distal tubule can still acidify the urine, leading to a urine pH < 5.5.
  • Fractional excretion of HCO₃⁻ >15% during a bicarbonate infusion test.
• Management: Requires large doses of alkali (e.g., sodium bicarbonate) and potassium supplementation. Thiazide diuretics may be used.

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Type 4 (Hyperkalemic) RTA

• Pathophysiology: Aldosterone deficiency or resistance, leading to impaired Na⁺ reabsorption and K⁺/H⁺ secretion in the collecting duct. The resulting hyperkalemia inhibits ammonia (NH₃) synthesis, further reducing acid excretion.
• Etiology:
  • Diabetic nephropathy (hyporeninemic hypoaldosteronism) is a classic cause.
  • Medications: ACE inhibitors, ARBs, NSAIDs, K⁺-sparing diuretics (e.g., spironolactone), TMP-SMX.
  • Adrenal insufficiency (Addison’s disease).
• Clinical Presentation:
  • Usually mild, asymptomatic acidosis.
  • Hyperkalemia is the hallmark finding and can cause cardiac arrhythmias.
• Diagnosis:
  • Serum: Normal anion gap acidosis, hyperkalemia.
  • Urine pH < 5.5 (distal acidification ability is intact).
• Management:
  • Treat the underlying cause and stop offending drugs.
  • Low-potassium diet.
  • Loop or thiazide diuretics can be used to manage hyperkalemia.
  • Fludrocortisone (a mineralocorticoid) may be used in cases of aldosterone deficiency if the patient is not volume-overloaded.

Feature	Type 1 (Distal)	Type 2 (Proximal)	Type 4 (Hyperkalemic)
Defect	↓ H+ secretion	↓ HCO3⁻ reabsorption	Aldosterone deficiency/resistance
Serum K+	Low	Low	High
Urine pH	> 5.5	Variable (< 5.5 once acidotic)	< 5.5
Key Association	Kidney stones, autoimmune dz	Fanconi syndrome, multiple myeloma	Diabetes, ACE inhibitors

Tip

Type 1 (Distal) RTA

• High Urine pH (>5.5): The distal H⁺ pump is broken, so acid (H⁺) cannot be secreted. The urine is always alkaline.
• Low K⁺ (Hypokalemia): The body wastes K⁺ in the urine to try and conserve H⁺. Also, the H⁺/K⁺ pump that reabsorbs K⁺ is impaired.

Type 2 (Proximal) RTA

• Variable Urine pH (<5.5 when severely acidotic): The proximal tubule leaks bicarbonate (HCO₃⁻), initially making urine alkaline. Once serum HCO₃⁻ is very low, there’s none left to leak, and the normal distal tubule can successfully acidify the urine.
• Low K⁺ (Hypokalemia): The lost HCO₃⁻ in the tubule acts as a diuretic, washing K⁺ out into the urine.

Type 4 (Hyperkalemic) RTA

• Low Urine pH (<5.5): The problem is aldosterone failure, not broken H⁺ pumps. However, the resulting hyperkalemia prevents the kidney from making ammonia (NH₃), which is needed to buffer the acid. Urine is acidic, but total acid excretion is low.
• High K⁺ (Hyperkalemia): This is the root cause. Without aldosterone, the kidney cannot secrete K⁺, so it builds up in the blood.

Mixed RTA (type 3)

• Type 1 RTA with HCO₃^- wasting

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Disorders Mimicking Diuretic Use

• Bartter Syndrome
  • Pathophysiology: Defect in the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC) in the thick ascending limb of the loop of Henle. Mimics chronic loop diuretic use.
  • Key Features:
    • Presents in childhood.
    • Hypokalemia, Metabolic Alkalosis.
    • Hypercalciuria (high urine Ca²⁺) because the disrupted ion gra dient impairs paracellular Ca²⁺ reabsorption.
    • Normal to low blood pressure.
• Gitelman Syndrome
  • Pathophysiology: Defect in the Na⁺-Cl⁻ cotransporter (NCC) in the Distal Convoluted Tubule (DCT). Mimics chronic thiazide diuretic use.
  • Key Features:
    • Milder, often presents in adolescence or adulthood.
    • Hypokalemia, Metabolic Alkalosis.
    • Hypocalciuria (low urine Ca²⁺) and Hypomagnesemia. The latter is a key differentiator from most other tubulopathies.
    • Normal to low blood pressure.

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Disorders Mimicking Hyperaldosteronism

Both present with hypertension, hypokalemia, and metabolic alkalosis, but have low aldosterone levels.

• Liddle Syndrome
  • Pathophysiology: Gain-of-function mutation in the epithelial Na⁺ channel (ENaC) in the collecting tubule. Leads to excessive Na⁺ reabsorption and K⁺ secretion, independent of aldosterone.
  • Key Features:
    • Autosomal dominant inheritance.
    • Presents as early-onset hypertension.
    • ↓ Aldosterone and ↓ Renin due to feedback from hypertension and volume expansion.
  • Treatment: Amiloride or Triamterene (ENaC blockers).
• Syndrome of Apparent Mineralocorticoid Excess (SAME)
  • Pathophysiology: Deficiency of 11β-hydroxysteroid dehydrogenase type 2. This enzyme normally inactivates cortisol to cortisone in mineralocorticoid receptor-expressing cells. Without it, excess cortisol activates the mineralocorticoid receptor.
  • Key Features:
    • Presents like Liddle syndrome (hypertension, hypokalemia, metabolic alkalosis).
    • ↓ Aldosterone and ↓ Renin.
    • Can be acquired from consuming licorice (glycyrrhetinic acid), which inhibits the enzyme.
  • Treatment: Corticosteroids (e.g., dexamethasone) to suppress endogenous cortisol production; potassium-sparing diuretics.