Hyperchloremic Metabolic Acidosis: Renal Tubular Acidosis

Subjects
Amount (mEq) of filtered HCO3 −
Amount (mEq) reabsorbed in the proximal tubule
Amount (mEq) delivered to distal segments
Amount (mEq) of HCO3 − excreted
Urine pH
Normal
4,320
3,456 (80 %)
864 (20 %)
< 3
< 5.5
Proximal RTA
     
 Initial phase
4,320
2,808 (65 %)
1,512 (25 %)a
1,134
> 6.5
 Steady state
3,600b
2,880 (76 %)
864 (24 %)
< 3
< 5.5
aMaximum reabsorption, bCalculated at serum [HCO3 −] of 20 mEq/L

Hypokalemia

Hypokalemia is extremely common because of excess urinary loss of K+. This is due to the increased delivery of Na+ and HCO3 − to the distal nephron, where Na+ and K+ exchange occurs. Also, volume depletion-induced aldosterone may contribute to K+ wastage.

Causes

Proximal RTA can occur as an isolated defect in HCO3 − transport (called isolated proximal RTA) or in association with multiple tubular transport defects (called Fanconi syndrome). Table 29.2 shows the causes of proximal RTA.
Table 29.2
Causes of proximal tubule
Genetic causes
Acquired causes
Isolated proximal RTA not associated with Fanconi syndrome
Dysproteinemic states
Genetic
 Multiple myeloma
 Autosomal recessive
 Light chain deposition disease
 Autosomal dominant
 Amyloidosis
 Sporadic
Tubulointerstitial diseases
 Carbonic anhydrase (CA) II deficiency
 Sjögren’s syndrome
 CA IV deficiency
 Posttransplantation rejection
Proximal RTA associated with Fanconi syndrome
 Medullary cystic disease
Inherited disorders
Secondary hyperparathyroidism with chronic hypocalcemia
 Cystinosis
 Vitamin D deficiency or resistance
 Wilson’s disease
 Vitamin D dependency
 Tyrosinemia
Others
 Hereditary fructose intolerance
 Nephrotic syndrome
 Lowe syndrome
 Paroxysmal nocturnal hemoglobinuria
 Galactosemia
Drugs
 Dent disease
 CA inhibitors (acetazolamide, topiramate)
 
 Anticancer drugs (Ifosfamide, cisplatin, carboplatin, streptozotocin, azacitidine, suramin, mercaptopurine)
 
 Antibacterial drugs (outdated tetracyclines, aminoglycosides)
 
 Anticonvulsants (valproic acid)
 
 Antiviral agents (DDI, adefovir, cidofovir, tenofovir)
 
 Others (fumarate, ranitidine, salicilates, alcohol, cadmium)

Clinical Manifestations

  • Skeletal abnormalities and osteomalacia are common due to chronic metabolic acidosis and vitamin D deficiency. Hypophosphatemia may also contribute to skeletal abnormalities
  • Vitamin D deficiency is due to decreased formation of 1,25(OH)2D3 from 25(OH)D3, as proximal tubular production of 1α-hydroxylase is reduced.
  • Osteopenia and pseudofractures occur in adults
  • Nephrocalcinosis and nephrolithiasis are rather uncommon, except in patients treated for epilepsy with topiramate. This drug inhibits CA and causes hypercalciuria, hypoctrituria, and alkaline urine pH with resultant formation of calcium phosphate stones

Specific Causes of Isolated Proximal RTA

Autosomal Recessive Proximal RTA

  • Caused by mutations in Na/HCO3 cotransporter isoform 1 located in the basolateral membrane of the proximal tubule and eyes. Described initially in 2 and 16-year-old females
  • Clinical manifestations include short stature, mental retardation, cataracts, bilateral glaucoma, and band keratopathy. Low HCO3 −, non-AG acidosis, and acid urine were observed. However, both parents were normal
  • Treatment includes lifelong alkali therapy

Autosomal Dominant Proximal RTA

  • Described only in two brothers belonging to a single Costa Rican family
  • Gene mutation is unknown
  • Clinical manifestations include growth retardation and reduced bone density Both brothers had low serum [HCO3 −] with acid urine
  • Treatment is lifelong alkali therapy

Sporadic Form

  • A transient form of inherited proximal RTA, requiring alkali therapy initially, and then discontinuation after several years

Carbonic Anhydrase (CA) Deficiency

  • Two isoforms of CA have been described
  • CA II is cytoplasmic and found in the proximal and distal tubule
  • CA IV is located in the apical membrane of the proximal tubule
  • CA II deficiency is caused by mutations in CA II gene and inherited as an autosomal recessive disease
  • CA II deficiency patients are usually Arabic in origin
  • Early manifestations include growth and mental retardation, osteopetrosis, cerebral calcification, hypokalemia, proximal muscle weakness, and other features of both proximal and distal (type III) RTAs
  • CA IV deficiency impairs HCO3 − reabsorption in the proximal tubule, but a genetic mutation has not been described

Fanconi Syndrome

Definition

It is defined as a proximal tubular dysfunction, leading to excessive urinary excretion of HCO3 −, glucose, phosphate, uric acid, amino acids, and to a lesser extent Na+, K+, and Ca2+.

Laboratory and Clinical Manifestations

The urinary losses of solutes lead to acidosis, electrolyte abnormalities (hypokalemia, hypophosphatemia, hypouricemia), dehydration with resultant increase in renin-AII-aldosterone production, rickets, osteomalacia, growth and mental retardation.

Causes

Table 29.2 shows both genetic and acquired causes of proximal RTA associated with Fanconi syndrome. The most common genetic cause of Fanconi syndrome is cystinosis in children and adolescents, whereas multiple myeloma and drugs are important causes in adults.

Diagnosis of Proximal RTA

  • Suspect proximal RTA in an adult with chronic hyperchloremic metabolic acidosis, hypokalemia, and urine pH < 5.5 with serum [HCO3 −] < 20 mEq/L
  • Confirmatory tests include:
1.
Positive UAG
 
2.
Fractional excretion of HCO3 − > 15 % (even > 5 % may be sufficient in some patients)
 
3.
HCO3 − titration test (definitive test): A marked increase in urinary excretion of HCO3 − and pH occurs, as serum [HCO3 −] is raised to normal levels (i.e., above renal threshold) by IV administration of NaHCO3
 
  • Glucosuria in the presence of normal serum glucose levels, phosphaturia, or other solute excretion establish the diagnosis of Fanconi syndrome
  • Growth retardation and rickets in children, and osteopenia as well as pseudofractures in adults should alert the physician to consider proximal RTA as one of the diagnoses

Treatment Of Proximal RTA

The physician should address the cause of proximal RTA, and take appropriate steps to improve acidosis and skeletal abnormalities
  • Alkali therapy is indicated in all the patients (Table 29.3)
    Table 29.3
    Alkali preparations
    Preparation
    Amount of HCO3 − or its equivalent
    NaHCO3
    4 mEq/325 mg tablet or 8 mEq/650 mg tablet
    Baking soda (NaHCO3)
    60 mEq/teaspoon (4.5 g) of powder
    K-Lyte (K+ HCO3/K+ citrate
    25–50 mEq/tablet
    Urocit-K (K+ citrate)
    5–10 mEq/tablet
    Kaon (K+ gluconate)
    5 mEq/mL or 1.33 mEq/mL
    Shohl’s solution, Bicitra (Na+ citrate/citric acid)
    1 mEq/mL
    Polycitra (Na+ citrate/K+ citrate/citric acid)
    2 mEq/mL
    Polycitra-K (K+ citrate/citric acid)
    2 mEq/mL
  • In children, the aim is to prevent growth abnormalities. Administration of NaHCO3 or its metabolic equivalent (citrate) to maintain serum [HCO3 −] to near normal levels (22–24 mEq/L) is desirable to reestablish normal growth
  • Maintenance of normal serum [HCO3 −] exacerbates kaliuresis; therefore, high doses of K+ supplements are necessary
  • Alkali therapy restores growth and volume with suppression of renin-AII-aldosterone system
  • In adults, it is not necessary to maintain normal serum [HCO3 −]
  • Adults require between 50 and 100 mEq of alkali daily
  • NaHCO3 and baking soda are inexpensive. Both of them may cause osmotic diarrhea; therefore, small and dividing doses may lower this adverse effect
  • Diuretics such as amiloride may be helpful in some patients by preventing K+ loss
  • Thiazide and loop diuretics also help in lowering HCO3 − requirements by volume depletion and increasing HCO3 − reabsoption in the proximal tubule, but hypokalemia may be aggravated
  • Polycitra-K provides both K and HCO3, and is recommended by many physicians
  • Active vitamin D3 and phosphate supplementation help skeletal growth and acidification in patients with low serum phosphate levels
  • Citrate increases aluminum absorption

Hypokalemic Distal (Classic) or Type I RTA

Characteristics

Distal RTA is characterized by:
1.
Hyperchloremic (non-AG) metabolic acidosis
 
2.
Inability to acidify urine despite severe acidosis (urine pH > 6.5)
 
3.
Hypokalemia
 
4.
Positive UAG
 
5.
Skeletal abnormalities
 
6.
Nephrolithiasis and nephrocalcinosis
 
7.
Intact proximal tubule function
 

Pathophysiology

The pathophysiology of type I RTA is fairly understood. Two mechanisms seem important in causing hypokalemic distal RTA :
1.
Defective H+ secretion
 
2.
Backleak of H+
 
Defective H+ Secretion
Both these defects are due to dysfunction of the type A intercalated cell. Recall that acidification of urine occurs by secretion of H+ via H-ATPase and K/H-exchanger. A functional defect in these transport mechanisms results in positive H+ balance and acidemia. This leads to a decrease in NAE, particularly NH4 + excretion, and HCO3 − wastage with alkaline pH despite severe acidosis.
Patients with distal RTA have low NH3 secretion, because of the failure to trap NH3 in the tubular lumen of the collecting duct which has an alkaline pH. Also, secretion of NH3 is impaired from the medulla due to interstitial disease caused by nephrocalcinosis or hypokalemia. Thus, impaired secretion of NH3 into the tubular lumen results in decreased NAE and alkaline urine.
Also, a defect in the exit of HCO3 − via Cl/HCO3 − exchanger (anion exchanger 1 or AE1) results in intracellular alkalinization, which inhibits apical H+ secretion.
Genetic studies have shown that mutations in B1 and A4 subunit of H-ATPase and AE1 cause distal RTA. These genetic defects cause hereditary forms of type 1 distal RTA (see further).
Backleak of H+
It is believed that type 1 RTA is due to altered apical membrane permeability of the type A intercalated cell. An experimental study with amphotericin B has proven this belief. There is no defect in H+ secretion via H-ATPase transporter. However, the secreted H+ diffuses back into the cells through the permeable apical membrane. As a result, the luminal pH remains alkaline, and excretion of NAE is substantially decreased.

Hypokalemia

Hypokalemia is very common because of increased Na/K cotransporter activity in the distal nephron. Also, dysfunction of H/K-ATPase may contribute to hypokalemia, as inhibition of this transporter by vanadate causes hypokalemic distal RTA. Loss of Na+ and HCO3 − in the urine causes volume depletion, which stimulates the renin-AII-aldosterone system and hypokalemia.

Nephrocalcinosis and Nephrolithiasis

One of the major complications of distal RTA is the development of nephrocalcinosis and nephrolithiasis. The mechanisms are as follows:
1.
Chronic metabolic acidosis causes bone buffering and dissolution of bone minerals, resulting in high Ca2+ excretion
 
2.
In addition, luminal alkalinization inhibits Ca2+ reabsorption, promoting further the excretion of Ca2+
 
3.
Because of high urine pH, solubility of calcium phosphate stones is decreased, thereby causing their formation
 
4.
Citrate excretion is reduced in metabolic acidosis, resulting in reduced chelation of free Ca2+
 

Causes

Distal RTA can be either hereditary (primary) or acquired. Table 29.4 shows some important causes of distal RTA.
Table 29.4
Causes of hypokalemic distal RTA
Hereditary
Associated with nephrocalcinosis
Autosomal dominant
Hyperparathyroidism
Autosomal recessive with deafness
Primary nephrocalcinosis
Autosomal recessive without deafness
Idiopathic hypercalciuria
Acquired
Vitamin D intoxication
Associated with systemic disease
Medullary sponge kidney
Multiple myeloma
Drugs
Amyloidosis
Amphotericin B
Systemic lupus erythmatosis
Toluene
Sjögren’s syndrome
Vanadate (?)
Chronic active hepatitis
Lithium
Primary biliary cirrhosis
Analgesics
Cryoglobulinemia
Cyclamate
Thyroiditis
  
Posttransplantation rejection
  
Balkan nephropathy
  
The hereditary forms are rather rare, but deserve some discussion. Table 29.5 summarizes genetic abnormalities and clinical manifestations.
Table 29.5
Clinical characteristics of hereditary distal RTAs
Form
Genetic defect
Age at onset
Clinical features
Autosomal dominant
Mutations in anion exchanger (AE1 or Cl/HCO3 exchanger
Adults
Mild metabolic acidosis
Mild to moderate hypokalemia
Mild to moderate bone disease
Nephrocalcinosis/lithiasis, hypocitrituria, hypercalciuria
Occasional rickets and osteomalacia
Autosomal recessive with deafness
B1 subunit of H-ATPase
Infancy/childhood
Severe metabolic acidosis
Vomiting
Dehydration
Growth retardation
Nephrocalcinosis
Rickets
Bilateral sensorineural hearing loss
Autosomal recessive without deafness
A4 subunit of H-ATPase
Infancy/childhood
Same as above, but without deafness (although late onset hearing loss in some)

Toluene Ingestion

  • Toluene ingestion causes a high AG metabolic acidosis, if their metabolites (hippuric acid and benzoic acid) are not excreted rapidly due to volume depletion and renal failure
  • When volume is adequate and renal function is normal, these acids are rapidly excreted, and a hyperchloremic metabolic acidosis with hypokalemia develops
  • Possible mechanism includes inhibition of H+ secretion in the distal tubule
  • Treatment is supportive with volume expansion and NaHCO3 therapy. Dialysis is indicated when severe acidosis and renal failure are present

Diagnosis of Hypokalemic Distal RTA

  • Suspect distal RTA in subjects with moderate to severe non-AG metabolic acidosis, hypokalemia, and urine pH > 6.5
  • Confirmatory urinary acidification tests include:
1.
Positive UAG
 
2.
NH4Cl test: In this test, NH4Cl (100 mg/kg) is dissolved in water and given orally. Following ingestion, sequential urine samples are collected for pH over a period of 6 h. At the same time, serum [HCO3 −] before and 3 h after NH4Cl ingestion is determined to document systemic acidosis. The normal response is a decrease in urine pH < 5.5. In patients with distal RTA, the urine pH is always > 6.5. All patients must be screened for urinary tract infection, as urine pH with urease-producing organisms is alkaline. This test is contraindicated in patients with liver cirrhosis

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Jun 20, 2017 | Posted by in NEPHROLOGY | Comments Off on Hyperchloremic Metabolic Acidosis: Renal Tubular Acidosis

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