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Renal Tubular Acidosis

Definition:  Disorders of the renal tubules which result in a normal anion gap (hyperchloremic) metabolic acidosis in the presence of normal glomerular function.

Physiological Basis:  A number of processes take place in the proximal and distal kidney tubules which relate to acid-base and electrolyte balance.  There are three ions of primary interest in RTA:

Bicarbonate:  80-85 percent of HCO3- is reabsorbed in the proximal convoluted tubule and another 5-10% is absorbed in the proximal straight tubule and loop of Henle.  Carbonic anhydrase located in the proximal tubule is important for HCO3- reabsorbtion.
Ammonium:  NH3 is produced in the PCT by metabolism of glutamine to alpha-ketoglutarate and is secreted into the lumen as NH4+.  About 70% is reabsorbed in the thick ascending loop of Henle in a process known as medullary cycling.  Here it is in equalibrium with NH3 and H+.  The NH3 can diffuse into medullary collecting ducts.  Trapping takes place here when a proton converts it to NH4+ which cannot diffuse back out of the lumen and must be excreted.

Protons:  Protons are secreted is the collecting duct by an electrogenic H+/ATPase.  For each proton secreted, an HCO3- is transferred to circulation by the chloride/bicarbonate exchanger located on the basolateral membrane here.

Classification of RTA:

RTA has traditionally been divided into proximal RTA (Type II), distal RTA (Type I) and Hypoaldosteronism (Type IV).  An earlier designation, type III referred to mixed or severe type I disorders and this term is no longer in use.  Type I can be subdivided according to etiology:

Proximal (Type II) RTA:  Associated with loss of bicarbonate (failure to reabsorb HCO3-), or decreased ammonium excretion into the tubule lumen. This type of RTA is often part of Fanconi syndrome (in which there is also proximal tubule loss of glucose, calcium, phosphate, other electrolytes, and organic acids).  Type II is clinically associated with failure to thrive.  At serum HCO3- levels less than 15 mmol, HCO3- is reabsorbed efficiently.  Below this level, urine pH will be below 5.5 indicating efficient reabsorbtion of HCO3-, otherwise urine pH is greater than 6 in the presence of a metabolic acidosis. Inhibitors of carbonic anhydrase also cause Type II RTA.

Distal (Type I) RTA:  There are four subdivisions within Type I RTA, all of which relate to difficulties in maintaining a secretory proton gradient in the distal portion of the tubule system.  Incomplete dRTA is seen only when an acid load exceeds the proton excretion mechanism.  dRTA responds better to oral alkali treatment than pRTA.

Proton pump defects:  the H+-ATPase may be either defective or absent.  This can manifest as a "gradient-limited" defect where the urine pH is always greater than 5.5, or a "rate-limited" defect, where urine acidification is possible.  NH4+ excretion is diminished because there is less H+ to combine with NH3 to trap the NH4+ in the collecting tubules.
Poor electrical gradient:  Proton secretion in the distal nephron is facilitated by cortical Na+ reabsorbtion which creates an electronegative lumen.  Anything which decreases the sodium (or electrical) gradient will impede proton secretion.  Severe volume depletion and drugs such as amiloride or triamterene can decrease Na+ reabsorbtion.  Since K+ secretion is also affected by this mechanism, hyperkalemia may be present.  The urine pH is usually greater than 5.5.
Permeability defect:  If backflow of protons occurs, the gradient cannot be maintained.  Amphotericin forms aqueous channels in the lipid membrane which short-circuits proton secretion.
Insufficiency of NH3: Either decreased synthesis, or defects in reabsorbing and transporting NH3 result in too little NH3 being available in the distal tubule.  As a result, the normal physiological trapping does not occur.  Without NH3, the other buffers, primarily phosphate, are overloaded.  As a result, the urine pH is acidic.
Type IV (Hyperaldosteronism/Aldosterone resistance):  This form of RTA can result from numerous causes of decreased aldosterone, increased renal resistance to aldosterone, or the presence of an aldosterone antagonist such as spironolactone.  It is associated with increased renin activity, hyponatremia, hyperkalemia and volume depletion.

Finding Distal (I) Proximal (II) Type IV
Growth Failure yes yes yes
Serum K Normal to decreased Normal to decreased Increased
Urine pH during acidosis > 6 < 6 < 6
Net acid excretion with
profound acidosis
Increased Normal Decreased
K excretion Increased Increased Decreased
Calcium excretion Increased Normal to increased Normal (?)
Citrate excretion Decreased Normal Normal
HCO3 excretion
with normal serum HCO3
< 5 > 15 < 15
(urine - blood) PCO2 Decreased Normal ?
Glucosuria, aminoaciduria
no yes no
Nephrocalcinosis yes no no
Rickets yes no no
Daily alkali Tx (mEq/kg/day) 1-4 2-15 2-3
Requirement for K no increased no
Adapted from Pediatrics Clinics of North America 42(6):1365-1395

Laboratory Tests Useful in Diagnosis of RTA

Urine pH:  A urine pH greater than 5.5 in the presence of acidosis is diagnostic of a dRTA if the following conditions are excluded:
Net Acid Excretion:  The net acid secretion is the urinary (titratable acid + NH4+) - (HCO3-).  At pH less than 6, bicarbonate is not a term.  In most labs, the ammonia cannot be quantitated, so the urine net charge is used as a surrogate calculation.  The UNC is the "cation gap" of the urine: UNa + UK - UCl.  Since the urine is electrically neutral, if the UNC is negative, the undetermined cation is ammonium.  A positive UNC indicates low (<80mmol/d) NH4+ excretion.  In pRTA, the UNC should be negative, as there is no defect in ammonium production.

Urine Acidification Tests:  The short ammonium chloride loading test consists of measuring urine pH 6-8 hours after administration of  0.1g/kg of NH4Cl.  Failure to acidify to a pH of less than 5.3 suggests dRTA (gradient-dependent, or problems with electrical gradient or membrane permeability).  It will be less than 5.5 in Type II and IV, as well as rate-limited dRTA.

NaSO4 administration:  The patient is made salt-avid by restriction or furosemide treatment and then given NaSO4.  The sulfate is not resorbable, and a steep voltage gradient is created.  Urine pH should be less than 5.5; if not, there is either a defect in proton pump function or distal Na+ reabsorbtion.

Fractional Excretion of HCO3- (FEHCO3):  Urine pH is monitored as the patient is given HCO3 until a level of 30 mmol/L is reached.  In pRTA, as soon as the threshold of 15 mmol/L is exceeded, the FEHCO3 will increase to 15%.  In other patients, the FEHCO3 will remain about 3% indicating good reabsorbtion.

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Last modification: April 30, 1998