Renal Tubular Acidosis

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:

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.

Laboratory Tests Useful in Diagnosis of RTA

• Urea-splitting UTI (which raises urine pH)
• Hypokalemia (which stimulates NH₃ production, buffering free protons)
• Avid salt retentive state

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^- (FE_HCO3):  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 FE_HCO3 will increase to 15%.  In other patients, the FE_HCO3 will remain about 3% indicating good reabsorbtion.

 

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