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
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Antibacterial drugs (outdated tetracyclines, aminoglycosides) | |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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