Renal tubular acidosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Pathophysiology

Normal Physiology of Acid-Base balance

• Normally kidneys reabsorb the filtered bicarbonate and excrete acid to maintain acid-base balance.
• HCO3 reabsorption is facilitated by Na-H and proton pumps.
  • Na-H reabsorbs about 80-90% of the filtered HCO₃ at the proximal tubule.
  • Proton pumps (H-ATPase and H-K ATPase) in the distal nephron reabsorbs remaining 10 percent of HCO₃.
  • There is no HCO₃ in the final urine.
• Collecting tubules serve the function of excretion of acid.
  • Hydrogen ions need a buffer to get excreted.
  • The principal buffers in the urine are ammonia and phosphate.
    • Acidosis stimulates ammonia production in renal tubules.
    • While ammonia can freely diffuse across membranes, ammonium cannot.
    • The secretion of hydrogen ions into the tubular lumen trap ammonia as ammonium which can easily flush out along with .
    • Increased production of ammonium is required in cases of acidosis to maintain near-normal balance.

Source:By Haisook at English Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2945979

Potassium

• Potassium is the most common electrolyte abnormality that can be noticed with renal tubular acidosis.
• It can be either hypokalemic renal tubular acidosis or hyperkalemic renal tubular acidosis.
• Almost all of the filtered potassium is reabsorbed passively in the proximal tubule and loop of Henle.
• The potassium excreted in the urine is derived from secretion into the tubular lumen by cells in the distal nephron.
• Distal potassium secretion is primarily influenced by two factors, both promote sodium reabsorption:
• Depending upon the site of the defect and the mechanism responsible for the various forms of RTA, can result in hypokalemia or hyperkalemia:
• Hypokalemia frequently develops in patients with distal RTA.
  • Usually improves with alkali therapy in contrast to to hypokalemia in proximal RTA which is exacerbated by alkali therapy.
• Hyperkalemia occurs frequently with hypoaldosteronism (type 4 RTA) and in patients with other defects in distal nephron sodium reabsorption (voltage-dependent RTA).

Distal (type 1) RTA

• It is characterized by impaired hydrogen ion secretion in the distal nephron.
• If severe, this defect leads to an inability to excrete the daily acid load resulting in progressive hydrogen ion retention and a normal anion gap metabolic acidosis.
• Distal RTA is commonly associated with hypokalemia due to renal potassium wasting.
• Impaired hydrogen ion secretion in patients with distal RTA can be caused by several defects:
  • Decreased net activity of the proton pump.
  • Increased hydrogen ion permeability of the luminal membrane.

Incomplete distal RTA

• Incomplete distal RTA is a variant in which patients cannot acidify their urine, resulting in a urine pH that is persistently 5.5 or higher.
• The low rate of citrate excretion and relatively high rate of ammonium excretion are believed to the inciting factor for a reduced intracellular pH within the cells of the proximal tubule .
• Persistent hypo-citraturia is a consistent feature of incomplete RTA.

Proximal RTA

• Proximal (type 2) RTA is characterized by a decrease in proximal bicarbonate reabsorptive capacity.
• Hydrogen ions and bicarbonate are generated from carbonic acid within the proximal tubule cells.
• The reaction is accelerated by the intracellular isoform of carbonic anhydrase. The hydrogen ions are secreted into the proximal tubule lumen, mainly via the sodium-hydrogen ion exchanger in the luminal membrane. The movement of sodium down the electrochemical concentration gradient from the lumen (where its concentration is similar to plasma) into the cell (where its concentration is much lower and the electrical charge is negative) drives hydrogen ions in the opposite direction (from the cytoplasm into the lumen). The Na-K-ATPase pump in the basolateral membrane of proximal tubule cells indirectly "drives" this exchange by maintaining the low intracellular sodium concentration.

●Hydrogen ions that enter the proximal tubule lumen react with filtered bicarbonate to generate carbonic acid. The carbonic acid that is formed is then rapidly dehydrated to water (H2O) and carbon dioxide (CO2); this dehydration reaction is catalyzed by the membrane-bound luminal enzyme, carbonic anhydrase IV.

●Within proximal tubule cells, hydrogen ions and bicarbonate are generated simultaneously. For every hydrogen ion secreted from the cell into the lumen, an intracellular bicarbonate must also exit the cell across the peritubular membrane. The bicarbonate exit step occurs via a sodium-bicarbonate cotransporter. The net effect of this process is that, for every hydrogen ion molecule secreted into the lumen, a bicarbonate molecule enters the peritubular capillary. Because each hydrogen ion that enters the lumen combines with one bicarbonate ion to form carbonic acid, the net effect of this process is the disappearance of one bicarbonate ion and one sodium ion from the lumen and the appearance of one bicarbonate ion and one sodium ion in the peritubular capillary. This process of bicarbonate reclamation is equivalent to bicarbonate reabsorption.

Abnormalities of one or more of these proximal tubule transporters, pumps, or enzymes can impair sodium bicarbonate reabsorption and cause the bicarbonate wasting found in proximal RTA

Type of RTA	Primary defect	Plasma HCO3 mEq/L	Urine pH	Plasma potassium	Urine anion gap	Urine calcium/creatinine ratio	Risk for nephrolithiasis
RTA type 1	Impaired distal acidification	< 10	>5.3	Hypokalemic	Positive	↑	↑
RTA Type 2	Reduced proximal HCO3 reabsorption.	12 to 20	<5.3	Hypokalemic	Negative	Normal	-
RTA type 4	Decreased aldosterone secretion  Aldosterone resistance	>17	Variable	Hyperkalemia	Positive	Normal	-
Voltage-dependent RTA	Reduced sodium reabsorption	>17	Variable	Hyperkalemia	Positive	Normal	-