- Clinical science
Renal tubular disorders are a very heterogeneous group of hereditary and acquired diseases that involve singular or complex dysfunctions of transporters and channels in the renal tubular system. The disorders may lead to fluid loss and abnormalities in electrolyte and acid-base homeostasis. Renal tubular acidosis (RTA) refers to normal anion gap (hyperchloremic) metabolic acidosis in the presence of normal or almost normal renal function. The various types of RTA include proximal tubular bicarbonate wasting (type II), distal tubular acid secretion (type I), very rarely carbonic anhydrase deficiency (type III) , and aldosterone deficiency/resistance (type IV). X-linked hypophosphatemic rickets, the most common form of hereditary hypophosphatemic rickets, is caused by phosphate wasting and presents with hypophosphatemia and symptoms related to rickets. Bartter syndrome, Liddle, and Gitelman syndrome are inherited disorders of tubular function that are characterized by hypokalemia and metabolic alkalosis. Renal tubular disorders are suspected when characteristic clinical features and/or laboratory findings are present. The diagnosis of hereditary conditions is usually confirmed by genetic testing. Treatment options vary depending on nature of the renal tubular disorder.
- The term renal tubular acidosis refers to hyperchloremic (normal anion gap) metabolic acidosis in the presence of normal or almost normal renal function.
- Renal tubular acidosis arises as a result of defects in the tubular transport of HCO3- and/or H+.
- Most forms of RTA are usually asymptomatic; rarely, life-threatening electrolyte imbalances may occur.
|Overview of various forms of renal tubular acidosis|
|Type of renal tubular acidosis||Type 1 RTA (distal RTA)||Type 2 RTA (proximal RTA)||Type 3 RTA||Type 4 RTA (hyperkalemic RTA)|
|Incidence|| || || || |
|Pathophysiology|| || |
|Serum potassium levels|| || || || |
|Urine pH|| || || || |
|Urine anion gap|| || || || |
|NH4+ excretion|| || || || |
|Calcium excretion|| || || || |
|Citrate excretion|| || || || |
|Bone involvement|| || || |
|Nephrolithiasis|| || || || |
|Treatment|| || |
Patients with uremic acidosis (metabolic acidosis due to renal failure) have a decreased glomerular filtration rate (↑ serum creatinine) and elevated anion-gap metabolic acidosis. On the other hand, patients with renal tubular acidosis have a relatively normal glomerular filtration rates and normal anion gap metabolic acidosis!
- Pathophysiology: inability of the intercalated cells of the distal tubule to secrete H+
- Sporadic type 1 RTA (idiopathic)
- Familial type 1 RTA (inherited genetic defects)
- Autoimmune diseases; (e.g., Sjögren's syndrome, rheumatoid arthritis, SLE, primary biliary cirrhosis, autoimmune hepatitis, Hashimoto's thyroiditis)
- Nephrocalcinosis (e.g., hyperparathyroidism, vitamin D toxicity, sarcoidosis)
- Medullary sponge kidney
- Chronic obstructive uropathy
- Sickle cell nephropathy
- Wilson's disease
- Renal transplant rejection
- Drugs: ifosfamide, amphotericin B, lithium, NSAIDs
- Polyuria → polydipsia, dehydration
- Bone demineralization usually without overt rickets or osteomalacia
- Impaired growth
- In some cases, features of hypokalemia (e.g., muscle weakness, hyporeflexia, paralysis, U waves and flattened T waves on ECG)
- Autosomal recessive causes of type 1 RTA may present with sensorineural deafness.
- Treatment: alkanization therapy with orally administered sodium bicarbonate or sodium citrate (Shohl's solution)
|Isolated proximal RTA||Fanconi syndrome|
- Vitamin D-resistant rickets/osteomalacia
- Stunted growth
- Polyuria → polydipsia, dehydration
- In some cases, features of hyporeflexia, paralysis, U waves and flattened T waves on ECG) (e.g., muscle weakness,
- The autosomal recessive form of type 2 RTA may be associated with glaucoma, cataracts, band keratopathy, and intellectual disability.
- Etiology: carbonic anhydrase II deficiency (autosomal recessive disease)
- Pathophysiology: impaired H+ secretion by the distal convoluted tubule and HCO3- wasting by the proximal convoluted tubule
Clinical features: Gauibad-Vainsel syndrome
- Cerebral calcification
- Mental retardation
- Treatment: alkali therapy with orally administered sodium citrate (Shohl's solution) or potassium citrate
- Pathophysiology: aldosterone deficiency and/or resistance
- Aldosterone resistance
- Clinical features
- Etiology: X-linked dominant disease caused by a mutation in the PHEX gene
- Pathophysiology: : mutation in the PHEX gene → increased levels of FGF23 (by an unknown mechanism) → indirect inhibition of the sodium-phosphate cotransporter in the proximal renal tubule → impaired reabsorption of phosphate → chronic hypophosphatemia → vitamin D-resistant rickets/osteomalacia
- X-linked hypophosphatemic rickets (XLH) accounts for ∼ 80% of all familial causes of hypophosphatemia.
- Age of onset: typically < 3 years
- Clinical features
- Laboratory tests
- X-ray of the wrist, knees, ankle, and long bones such as the femur (also see “Diagnostics” in )
- Definition: : a group of rare genetic disorders; (autosomal recessive or dominant) that affect chloride reabsorption in the ascending limb of the loop of Henle
- Prevalence: 1/1,000,000
Type of Bartter syndrome
|Mode of inheritance||Genetic defect||Result of the genetic defect||Age of onset|
|I||Autosomal recessive||Inactivation of NKCC2 on chromosome 15q||Failure of Na+/K+-2Cl- cotransporter → impaired reabsorption of chloride||Neonatal|
|II||Inactivation of ROMK gene on chromosome 11q||↑ K+ concentration gradient within the tubular cell → failure of Na+/K+-2Cl- cotransporter → impaired reabsorption of chloride||Neonatal|
|III||Inactivation of CLCNKB on chromosome 1p||↑ Cl- concentration gradient within the tubular cell → failure of Na+/K+-2Cl- cotransporter → impaired reabsorption of chloride||Classic|
Type IVa: Inactivation of BSND
Type IVb: Inactivation of CLCNKB and CLCNKA
|V||Autosomal dominant||Activation of CaSR||↑ K+ concentration gradient within the tubular cell → failure of Na+/K+-2Cl- cotransporter → impaired reabsorption of chloride||Classic|
Pathophysiology: failure to reabsorb Cl- from the ascending loop of Henle →
- Failure to reabsorb Na+ → natriuresis (salt and water loss) → volume depletion → activation of the renin-angiotensin-aldosterone system (RAAS) →
- ↓ Paracellular reabsorption of calcium → hypercalciuria → hypocalcemia, nephrocalcinosis, renal stones
- Antenatal symptoms: polyhydramnios, preterm delivery
- Severe polyuria and polydipsia; → life-threatening volume depletion and hypotension
- Muscle atrophy, weakness, cramps, carpopedal spasm
- Failure to thrive, developmental delay
- Dysmorphic facies , strabismus, and sensorineural deafness
- Symptoms of renal colic may occur during as a result of calcium stones.
- Antenatal diagnostics
- Laboratory diagnostics
- Confirmatory test: genetic testing
- Mainstay of therapy: : lifelong oral potassium substitution with potassium-sparing diuretics (spironolactone, amiloride)
- ACE inhibitors may be used to counteract the effect of hyperreninemia and hyperaldosteronism.
- NSAIDs such as indomethacin
- Strenuous exercise should be avoided.
- Renal transplantation is indicated in patients with severe electrolyte imbalances or those with chronic renal failure as a result of nephrocalcinosis.
- Prevalence: 1/40,000
- Age of onset: usually late childhood and 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
- Fatigue, muscle weakness
- Muscle cramps and/or tetany
- Mild polyuria
- Possibly, mild hypotension
- Extremely rare disease
- Age of onset: childhood
- Etiology: autosomal dominant; mutation in the SCNN1B and SCNN1G genes on chromosome 16p → structural alteration in the β and γ subunits of the ENaC channel in the collecting duct
- Pathophysiology: structural alteration in the ENaC channel → ENaC cannot be degraded by ubiquitin proteasomes → increased number of ENaC channels in the collecting duct → increased reuptake of water and sodium ( ) → hypertension with low renin production and hypokalemia
- Clinical features
- Treatment: lifelong oral potassium substitution with potassium-sparing diuretics that directly block ENaC in the collecting duct (e.g., amiloride, triamterene)