Overview of renal tubular acidosis

• RTA or renal tubular acidosis is a rare kidney disease. It has four subtypes— proximal RTA, distal RTA, hyperkalemic RTA, and mixed RTA. 

• In proximal renal tubular acidosis, there is a decrease in the proximal reabsorptive capacity of bicarbonates. This leads to the release of bicarbonate in the urine until the level of bicarbonate in the serum has decreased to the extent that all the filtered bicarbonate starts to get reabsorbed. 

• On the other hand, the primary defect in distal renal tubular acidosis is improper distal acidification. As proximal and distal types of renal tubular acidosis have different pathogenetic mechanisms, their clinical manifestations are also different. 

• The common clinical manifestation of proximal and distal renal tubular acidosis is the presence of a certain degree of hypokalemia.

Pathophysiology of renal tubular acidosis

Type 1 Distal RTA pathophysiology

• New bicarbonate is generated in the distal tubule under the impact of aldosterone. If the alpha-intercalated cells of the distal tubule are damaged, no new bicarbonate ( and hydrogen ions) is generated.

• As a result of the inability to remove acid from the body and the generation of acidic urine in the distal tubule, urine pH is increased, even in metabolic acidosis states. Additionally, as the H+/K+ ATPase pump fails, hypokalemia occurs. 

• Other mechanisms leading to distal renal tubular acidosis include reduced functioning of the H+/ATPase pump, enhanced proton leak to the lumen from the lumen (as seen in cases of amphotericin B toxicity) and decreased reabsorption of sodium ( secondary to damage of the alpha- intercalated cells of the distal tubule). 

Type 2 Proximal RTA pathophysiology 

• About 85-90% of bicarbonate is generally reabsorbed at the proximal end of the tubule. Only 10% of it is reabsorbed at the distal end. 

• If there is a bicarbonate leak, the bicarbonate reabsorption at the proximal tubule is impaired, leading to the excretion of excess bicarbonate in the urine. This results in a condition called metabolic acidosis. 

• Type 2 renal tubular acidosis is rarer than type 1 renal tubular acidosis and is often associated with a condition called Fanconi’s syndrome. 

• Due to decreased bicarbonate reabsorption, the distal tubule has an increased flow rate. This causes increased K+ excretion, osmotic diuresis, and hypokalemia. 

• The urinary pH in proximal renal tubular acidosis is variable and depends on whether the patient has received treatment with alkali therapy. 

• In adults, proximal renal tubular acidosis may also occur due to excess use of carbonic anhydrase inhibitors as they impair the reabsorption of proximal bicarbonate. They do not affect the reabsorption of other solutes at the proximal tubule. 

Type 3 Mixed RTA pathophysiology 

• Type 3 or mixed renal tubular acidosis is an extremely rare variant of renal tubular acidosis and is a combination of types 1 and 2. Its inherited type occurs due to mutations of CA II (chromosome 8q22) that lead to carbonic anhydrase II deficiency.

Type 4 Hyperkalemic RTA pathophysiology

• Ammonia and phosphate are the main buffers present in the urine. The excretion of ammonia requires its synthesis by the kidney. It also requires the release of H+ into the tubular lumen from the collecting tubule cells, where they get trapped as ammonium (NH4+).

• Hyperkalemia and metabolic acidosis result from hypoaldosteronism. The ammonia genesis in the proximal tubule is hampered as a result of hyperkalemia. The availability of ammonia to buffer urinary H+ ions is also reduced. This decreases the excretion of H+ in the urine. 

• The availability of NH3 for buffering of protons in this type of renal tubular acidosis is inadequate, rather than being completely absent. This is why the urine is acidified. 

• Even if only a few H+ ions are secreted distally, there is a fall in urinary pH. This is why there is a fall in the urinary pH of these patients to less than 5.5. 

• The most common cause of hyperkalemic renal tubular acidosis in adults is hyporeninemic hypoaldosteronism. It is common in patients with mild to moderate CKD (due to diabetic nephropathy). 

Effect of renal tubular acidosis on potassium balance

• Type 1 and Type 2 renal tubular acidosis manifest with hypokalemia or low levels of potassium in the blood. This is because the kidney excretes too much potassium into the urine instead of sending it back to the blood. Low potassium levels in these patients lead to extreme weakness, irregular heartbeat, paralysis, and in extreme cases, death.

• Type 4 renal tubular acidosis patients have hyperkalemia or high blood potassium levels. This can lead to muscular weakness, abdominal pain, heart problems (irregular heartbeats), decreased appetite, and weight changes.