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Renal tubular disorders

Last updated: December 9, 2020

Summary

Renal tubular disorders are a heterogeneous group of diseases that involve dysfunctions of transporters and channels in the renal tubular system. These dysfunctions may cause fluid loss and abnormalities in electrolyte and acid-base homeostasis. The disorders are either primary (genetic) or acquired (e.g., drug adverse effects, renal disease). In renal tubular acidosis (RTA), there is normal anion gap (hyperchloremic) metabolic acidosis in a patient with normal or almost normal renal function. Types of RTA include distal tubular acid secretion (type 1), proximal tubular bicarbonate wasting (type 2), very rarely carbonic anhydrase deficiency (type III), and aldosterone deficiency/resistance (type 4). Type 2 can be further classified into isolated proximal tubular bicarbonate wasting and generalized proximal tubular wasting, known as Fanconi syndrome. X-linked hypophosphatemic rickets, the most common form of hereditary hypophosphatemic rickets, is caused by phosphate wasting and manifests with hypophosphatemia and symptoms of rickets. Bartter syndrome, Liddle syndrome, syndrome of apparent mineralocorticoid excess, and Gitelman syndrome are inherited disorders of tubular function characterized by hypokalemia and metabolic alkalosis. Because renal tubular disorders manifest in heterogeneous ways, diagnosis is often challenging; it is based on a combination of clinical features (e.g., rickets, impaired growth, symptoms of electrolyte deficiencies), laboratory analysis of blood and urine, and the results of investigations aimed at determining an underlying cause. The diagnosis of hereditary conditions is usually confirmed with genetic testing. Treatment of type 1 and type 2 RTA involves alkali therapy, while the treatment of type 4 RTA consists of furosemide therapy. X-linked hypophosphatemic rickets requires the supplementation of phosphate and vitamin D, while the mainstay of therapy for Bartter syndrome, Liddle syndrome, syndrome of apparent mineralocorticoid excess, and Gitelman syndrome involves lifelong oral potassium substitution with potassium-sparing diuretics.

Renal tubular acidosis (RTA)

Overview of types of renal tubular acidosis
Type of RTA Distal RTA (type 1) Proximal RTA (type 2) Mixed RTA (type 3) Hyperkalemic RTA (type 4)
Incidence
  • Rare
  • Very rare
  • Extremely rare
  • Common
Cause
Pathophysiology
  • The α-intercalated cells of the distal tubule are unable to secrete H+.
Serum potassium levels
Urine pH
  • ≥ 5.5
  • ≥ 5.5
  • < 5.5

Urine anion gap

  • Positive
  • Negative
  • Positive
  • Positive
Calcium excretion
  • Increased
  • Normal
  • Normal or decreased
Bone involvement
Nephrolithiasis
  • Usually present
  • Absent
  • Absent
  • Absent
Treatment
  • Alkali therapy with orally administered potassium citrate
  • Alkali therapy with orally administered sodium citrate (Shohl's solution) or potassium citrate

Patients with uremic acidosis (metabolic acidosis due to renal failure) have a decreased glomerular filtration rate (increased serum creatinine) and increased anion gap metabolic acidosis. Patients with renal tubular acidosis have relatively normal glomerular filtration rates and normal anion gap metabolic acidosis!

References:[1][2][3][4]

Distal renal tubular acidosis (type 1)

Pathophysiology

The α-intercalated cells of the distal tubule are unable to secrete H+ (apical) → ↓ intracellular production of HCO3- HCO3-/Cl- exchanger activity (basolateral) → decreased concentration of HCO3- in the blood → metabolic acidosis

Etiology

Clinical features

Diagnostics

Treatment

Alkalinization therapy with orally administered sodium bicarbonate or sodium citrate (Shohl solution)

Renal tubular acidosis type 1 causes kidney stONEs.

References:[1][2][3]

Proximal renal tubular acidosis (type 2)

Type 2 renal tubular acidosis is characterized by a dysfunctional proximal convoluted tubule (PCT) that is unable to reabsorb HCO3-. The defect can either be isolated, affecting only the reabsorption of HCO3- or, more commonly, the PCT has a generalized dysfunction of the PCT, in which case the condition is referred to as Fanconi syndrome.

Isolated proximal RTA Fanconi syndrome
Pathophysiology
  • Only HCO3- reabsorption is impaired.
  • Impaired reabsorption of HCO3- and other compounds (e.g., potassium, glucose, phosphate, and amino acid reabsorption) in the PCT
Etiology

Clinical features

Diagnostics

Treatment

  • Alkali therapy with orally administered potassium citrate
  • Thiazide diuretics if alkali therapy is not tolerated or effective

Renal tubular acidocis type 2 has two variants (isolated proximal RTA and Fanconi syndrome).

References:[1][2][3][4][5]

Mixed renal tubular acidosis (type 3)

A combination of type 1 and type 2 RTA.

Etiology

Pathophysiology

Clinical features

Diagnostics

Treatment

  • Alkali therapy with orally administered sodium citrate (Shohl solution) or potassium citrate

Hyperkalemic renal tubular acidosis (type 4)

Etiology

Pathophysiology

Aldosterone deficiency and/or resistance in the distal convoluted tubules hyperkalemia; and metabolic acidosis inhibition of ammonia (NH3) synthesis in the proximal convoluted tubules → decreased urinary ammonium (NH4+) excretion

Clinical features

Diagnostics

Treatment

Renal tubular acidosis type 4 leads to decreased NH4+ excretion.

References:[1][2][3]

X-linked hypophosphatemic rickets

Etiology

X-linked dominant disease caused by a mutation in the PHEX gene

Pathophysiology

Mutation in the PHEX gene → increased levels of fibroblast growth factor 23 (FGF23) → indirect inhibition of the sodium-phosphate cotransporter in the proximal renal tubule → impaired reabsorption of phosphate → chronic hypophosphatemiavitamin D-resistant rickets/osteomalacia

Epidemiology

Clinical features

Diagnostics

Treatment

References:[6][7]

Bartter syndrome

Definition

A group of rare genetic disorders (autosomal recessive); that affect chloride reabsorption in the thick ascending limb of the loop of Henle

Epidemiology

Pathophysiology

Defective Na+-K+-2Cl- cotransporter in the thick ascending loop of Henle results in

Clinical features

Diagnostics

Treatment

The Na-K-2Cl cotransporter that is defective in Bartter syndrome is a target for loop diuretics!


References:[8][9]

Gitelman syndrome

Epidemiology

  • Prevalence: 1/40,000
  • Age of symptom onset: ≥ 6 years; diagnosis is usually made in adolescence or adulthood

Etiology

Autosomal recessive; defect in the SLC12A3 gene on chromosome 16p → impaired function of the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule → impaired Na+ and Cl-reabsorption mild natriuresis mild volume depletion → mild RAAS activation

Clinical features

Diagnostics

Treatment

The effects of Gitelman syndrome are similar to those of a thiazide diuretic!


References:[9]

Liddle syndrome

Epidemiology

  • Extremely rare
  • Age of symptom onset: childhood

Etiology

Autosomal dominant gain-of-function mutation; in the SCNN1B and SCNN1G genes on chromosome 16p → structural alteration in the β and γ subunits of the epithelial sodium channel (ENaC) in the collecting duct

Pathophysiology

Structural alteration in the ENaC subunits → inability of these subunits to bind with an intracellular ubiquitin-protein ligase (Nedd4) decreased degradation of ENaC channels by ubiquitin proteasomes; increased number of ENaCs in the collecting duct increased reuptake of water and sodium (pseudohyperaldosteronism)hypertension with low renin production and hypokalemia

Clinical features

Diagnostics

Treatment

Lifelong oral potassium substitution with potassium-sparing diuretics that directly block ENaCs in the collecting duct (e.g., amiloride, triamterene)

The clinical features of Liddle syndrome are similar to those of hyperaldosteronism, except that Liddle syndrome manifests with decreased renin and aldosterone levels!

Syndrome of apparent mineralocorticoid excess

Epidemiology (hereditary disorder) [10]

  • Extremely rare
  • Age of symptom onset: infancy

Etiology

Pathophysiology

Clinical features

Diagnostics

Treatment

Spironolactone (an aldosterone receptor antagonist) is effective in treating the syndrome of apparent mineralocorticoid excess but not Liddle syndrome!

In Syndrome of Apparent Mineralocorticoid Excess, cortisol has the SAME action as aldosterone.

References

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