Inherited Tubular Transport Abnormalities
Introduction to Inherited Tubular Transport Abnormalities
Inherited tubular transport abnormalities are a group of rare genetic disorders that affect the kidney's ability to properly reabsorb or secrete various substances, leading to electrolyte imbalances and other metabolic disturbances. These conditions result from mutations in genes encoding for specific transporters, channels, or regulatory proteins in the renal tubules.
Key features of inherited tubular transport abnormalities include:
- Genetic basis: Autosomal dominant, autosomal recessive, or X-linked inheritance patterns
- Impaired renal tubular function: Affecting specific segments of the nephron
- Electrolyte imbalances: Often presenting with hypokalemia, metabolic alkalosis, or acidosis
- Variable clinical presentation: Ranging from asymptomatic to severe manifestations
- Diagnosis: Based on clinical features, biochemical abnormalities, and genetic testing
- Treatment: Typically supportive, focusing on electrolyte replacement and management of complications
Understanding these disorders is crucial for nephrologists, pediatricians, and medical students, as early recognition and appropriate management can significantly improve patient outcomes and quality of life.
Bartter Syndrome
Bartter syndrome is an autosomal recessive disorder characterized by defective sodium chloride reabsorption in the thick ascending limb of the loop of Henle.
Types and Genetics:
- Type I: SLC12A1 gene mutation (NKCC2 cotransporter)
- Type II: KCNJ1 gene mutation (ROMK potassium channel)
- Type III: CLCNKB gene mutation (ClC-Kb chloride channel)
- Type IV: BSND gene mutation (Barttin protein)
- Type V: CASR gene mutation (Calcium-sensing receptor)
Clinical Features:
- Polyuria and polydipsia
- Growth retardation
- Muscle weakness
- Tetany
- Nephrocalcinosis (in some types)
Laboratory Findings:
- Hypokalemia
- Metabolic alkalosis
- Hypochloremia
- Elevated renin and aldosterone levels
- Normal or low blood pressure
Treatment:
- Potassium supplementation
- NSAIDs (e.g., indomethacin)
- Potassium-sparing diuretics (e.g., spironolactone)
- ACE inhibitors or angiotensin receptor blockers
Gitelman Syndrome
Gitelman syndrome is an autosomal recessive disorder caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive sodium-chloride cotransporter (NCCT) in the distal convoluted tubule.
Pathophysiology:
- Defective NaCl reabsorption in the distal convoluted tubule
- Increased urinary Na+ and Cl- excretion
- Secondary hyperaldosteronism
- Increased K+ and H+ secretion in the collecting duct
Clinical Features:
- Often asymptomatic or mildly symptomatic
- Muscle weakness and fatigue
- Salt craving
- Tetany (less common than in Bartter syndrome)
- Growth delay (in some cases)
Laboratory Findings:
- Hypokalemia
- Metabolic alkalosis
- Hypomagnesemia
- Hypocalciuria
- Elevated renin and aldosterone levels
Treatment:
- Oral potassium and magnesium supplementation
- Potassium-sparing diuretics (e.g., amiloride)
- NSAIDs (in some cases)
- Dietary sodium and potassium-rich foods
Liddle Syndrome
Liddle syndrome is an autosomal dominant disorder caused by gain-of-function mutations in the epithelial sodium channel (ENaC) genes SCNN1B or SCNN1G, leading to increased sodium reabsorption in the collecting duct.
Pathophysiology:
- Constitutively active ENaC channels
- Increased Na+ reabsorption in the collecting duct
- Volume expansion and hypertension
- Suppressed renin and aldosterone levels
Clinical Features:
- Early-onset hypertension
- Hypokalemia
- Metabolic alkalosis
- Suppressed plasma renin activity
- Low aldosterone levels
Laboratory Findings:
- Hypokalemia
- Metabolic alkalosis
- Low plasma renin activity
- Low aldosterone levels
Treatment:
- Potassium-sparing diuretics (amiloride or triamterene)
- Dietary sodium restriction
- Potassium supplementation (if needed)
Pseudohypoaldosteronism
Pseudohypoaldosteronism (PHA) is a group of disorders characterized by resistance to aldosterone action, resulting in salt wasting and hyperkalemia despite elevated aldosterone levels.
Types:
1. PHA Type 1:
- Autosomal dominant form (AD PHA1):
- Mutations in the mineralocorticoid receptor gene (NR3C2)
- Milder phenotype, often improves with age
- Autosomal recessive form (AR PHA1):
- Mutations in epithelial sodium channel subunit genes (SCNN1A, SCNN1B, SCNN1G)
- More severe, systemic form affecting multiple organs
2. PHA Type 2 (Gordon Syndrome):
- Autosomal dominant
- Mutations in WNK1, WNK4, KLHL3, or CUL3 genes
- Characterized by hypertension and hyperkalemia
Clinical Features:
- Salt wasting
- Dehydration
- Failure to thrive (in infants)
- Hypotension (PHA1) or hypertension (PHA2)
- Recurrent respiratory infections (in AR PHA1)
Laboratory Findings:
- Hyperkalemia
- Hyponatremia
- Metabolic acidosis
- Elevated plasma renin activity
- Elevated aldosterone levels
Treatment:
- PHA1:
- Sodium supplementation
- Potassium-binding resins
- Sodium bicarbonate (for acidosis)
- PHA2:
- Thiazide diuretics
- Dietary salt restriction
Dent Disease
Dent disease is an X-linked recessive disorder characterized by proximal tubule dysfunction, resulting in low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, and progressive renal failure.
Types and Genetics:
- Dent Disease 1:
- Mutations in the CLCN5 gene (encoding the CLC-5 chloride/proton antiporter)
- Accounts for about 60% of cases
- Dent Disease 2:
- Mutations in the OCRL gene (also associated with Lowe syndrome)
- Accounts for about 15% of cases
Clinical Features:
- Low-molecular-weight proteinuria
- Hypercalciuria
- Nephrocalcinosis
- Nephrolithiasis
- Progressive renal failure
- Rickets or osteomalacia (in some cases)
Laboratory Findings:
- Elevated urinary low-molecular-weight proteins (e.g., β2-microglobulin, retinol-binding protein)
- Hypercalciuria
- Hyperphosphaturia
- Glycosuria (in some cases)
- Aminoaciduria
Treatment:
- Thiazide diuretics (to reduce hypercalciuria)
- Citrate supplementation
- Adequate hydration
- Dietary modifications (moderate calcium intake, low sodium)
- Management of complications (e.g., nephrolithiasis, renal failure)
Fanconi Syndrome
Fanconi syndrome is a generalized dysfunction of the proximal renal tubule, leading to impaired reabsorption of various substances. It can be inherited or acquired.
Inherited Causes:
- Cystinosis (most common inherited cause)
- Wilson's disease
- Tyrosinemia
- Galactosemia
- Lowe syndrome
- Dent disease
- Mitochondrial disorders (e.g., Pearson syndrome)
Acquired Causes:
- Heavy metal toxicity (e.g., lead, cadmium, mercury)
- Medications (e.g., tenofovir, gentamicin, valproic acid)
- Multiple myeloma
- Sjögren's syndrome
Clinical Features:
- Polyuria and polydipsia
- Dehydration
- Growth retardation in children
- Bone pain and fractures (due to osteomalacia or rickets)
- Muscle weakness
Laboratory Findings:
- Generalized aminoaciduria
- Glycosuria (with normal blood glucose)
- Phosphaturia
- Bicarbonate wasting (causing metabolic acidosis)
- Proteinuria (mainly low-molecular-weight proteins)
- Hypokalemia
- Hypouricemia
Treatment:
- Treatment of underlying cause (if identified)
- Electrolyte replacement (potassium, phosphate, bicarbonate)
- Vitamin D supplementation
- Nutritional support
- Management of complications (e.g., rickets, osteomalacia)
Inherited Tubular Transport Abnormalities
- Q: What is the primary function of renal tubules? A: To reabsorb and secrete solutes and water, maintaining electrolyte balance and acid-base homeostasis
- Q: What is Gitelman syndrome? A: An autosomal recessive disorder characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria
- Q: Which gene is mutated in Gitelman syndrome? A: SLC12A3, encoding the thiazide-sensitive sodium-chloride cotransporter
- Q: What are the typical electrolyte abnormalities in Bartter syndrome? A: Hypokalemia, metabolic alkalosis, and normal to low blood pressure
- Q: How does Bartter syndrome differ from Gitelman syndrome? A: Bartter syndrome typically presents earlier in life and is associated with hypercalciuria, while Gitelman syndrome presents later and has hypocalciuria
- Q: What is the underlying defect in Liddle syndrome? A: A gain-of-function mutation in the epithelial sodium channel (ENaC) genes
- Q: What are the clinical features of Liddle syndrome? A: Early-onset hypertension, hypokalemia, metabolic alkalosis, and suppressed plasma renin and aldosterone levels
- Q: What is pseudohypoaldosteronism type 1 (PHA1)? A: A rare inherited disorder characterized by salt wasting, hyperkalemia, and metabolic acidosis despite elevated aldosterone levels
- Q: What are the two types of PHA1? A: Renal (autosomal dominant) and systemic (autosomal recessive) forms
- Q: What is Dent disease? A: An X-linked recessive disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, and progressive renal failure
- Q: Which gene is most commonly mutated in Dent disease? A: CLCN5, encoding a chloride/proton antiporter
- Q: What is the primary defect in cystinuria? A: Impaired reabsorption of cystine and dibasic amino acids in the proximal tubule
- Q: How is cystinuria typically diagnosed? A: By detecting hexagonal cystine crystals in urine and elevated urinary cystine levels
- Q: What is Fanconi syndrome? A: A generalized dysfunction of the proximal tubule leading to urinary loss of amino acids, glucose, phosphate, and bicarbonate
- Q: What is the most common inherited cause of Fanconi syndrome? A: Cystinosis
- Q: What is renal tubular acidosis (RTA)? A: A group of disorders characterized by impaired acid excretion by the kidneys, leading to metabolic acidosis
- Q: What are the three main types of RTA? A: Type 1 (distal), Type 2 (proximal), and Type 4 (hyperkalemic)
- Q: What is the characteristic feature of Type 1 (distal) RTA? A: Inability to lower urine pH below 5.5 despite systemic acidosis
- Q: What is nephrogenic diabetes insipidus? A: A condition where the kidneys are unable to concentrate urine in response to antidiuretic hormone (ADH)
- Q: What are the two main genetic causes of nephrogenic diabetes insipidus? A: Mutations in the vasopressin V2 receptor gene (AVPR2) or the aquaporin-2 gene (AQP2)
- Q: What is Bartter syndrome type 3? A: A variant caused by mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb
- Q: What is the underlying defect in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)? A: Mutations in the CLDN16 or CLDN19 genes, encoding claudin-16 and claudin-19 proteins
- Q: What is the characteristic feature of proximal renal tubular acidosis (Type 2 RTA)? A: Decreased bicarbonate reabsorption in the proximal tubule, leading to urinary bicarbonate wasting
- Q: What is the genetic basis of X-linked hypophosphatemic rickets? A: Mutations in the PHEX gene, leading to increased levels of fibroblast growth factor 23 (FGF23)
- Q: What is the primary defect in Lowe syndrome? A: Mutations in the OCRL1 gene, affecting phosphatidylinositol metabolism
- Q: What are the main clinical features of Lowe syndrome? A: Congenital cataracts, intellectual disability, and renal Fanconi syndrome
- Q: What is pseudohypoaldosteronism type 2 (Gordon syndrome)? A: An autosomal dominant disorder characterized by hypertension, hyperkalemia, and metabolic acidosis
- Q: What is the underlying defect in renal glucosuria? A: Mutations in the SLC5A2 gene, encoding the sodium-glucose cotransporter 2 (SGLT2)
- Q: What is Hartnup disease? A: An autosomal recessive disorder characterized by impaired neutral amino acid transport in the kidney and intestine
- Q: What is the genetic basis of familial hypokalemic periodic paralysis? A: Mutations in genes encoding voltage-gated ion channels, most commonly CACNA1S or SCN4A
