Renal tubular acidosis: Pathology review

Definitions & Key takeaways

Renal tubular acidosis is a medical condition in which the kidney is unable to secrete acids or reabsorb bicarbonate from the body. When blood is filtered by the kidney, the filtrate passes through the tubules of the nephron, allowing for the exchange of salts, acid equivalents, and other solutes before it drains into the bladder as urine. The metabolic acidosis that results from renal tubular acidosis may be caused either by failure to recover sufficient bicarbonate ions from the filtrate in the proximal tubule or by insufficient secretion of hydrogen ions into the distal tubule. If left untreated, acidemia can cause peripheral vasodilation and shock. Treatment may include alkali supplements like potassium citrate or sodium bicarbonate to neutralize the acid in the blood.

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Case Study0:00–1:33

In the emergency department. Two people came in with rapid shallow breathing and tachycardia.
The first one is 45 year old Olga who also has systemic lupus erythematosus. And the second one is 39 year old Fred and arterial blood gas was taken along with electrolytes.
Results showed that Olga had low ph low bicarbonate and P CO2 levels and her potassium level was also low, Fred also had low ph low bicarbonate and P CO2 levels.
But his potassium level was high based on the ABG results. The diagnosis of normal anion gap.
Metabolic acidosis was made in order to identify the cause of their normal gap. Metabolic acidosis.
More investigations were done and the urine anion gap showed that both individuals had a low urinary anion gap which suggests that the cause was renal.
All right. Now, a normal anion gap, metabolic acidosis can have renal causes like when a lot of bicarbonate is lost through the urinary tract, which happens in type two renal tubular acidosis.
A normal anion gap. Metabolic acidosis can also happen when too many hydrogen ions are retained like in type one and type four renal tubular acidosis.
Now, there's also a type three renal tubular acidosis where both the proximal and distal tubules are affected. This is a pretty rare situation and the causes are not well understood.
So it's unlikely to be tested. All right.

Physiology1:33–4:09

Now, let's review the physiology of the tubules. The proximal tubule is affected in RTA type two.
It's lined by brush border cells which have two surfaces. One is the apical surface that faces the tubular lumen and is lined with microvilli and the other is the basolateral surface which faces the peritubular capillaries.
Now, a lot of bicarbonate is reabsorbed here. When bicarbonate approaches the apical surface, it binds to hydrogen to form carbonic acid which will be split into water and carbon dioxide by carbonic anhydrase, the water and carbon dioxide diffuse into the cells where carbonic anhydrase facilitates the reverse reaction and combines them to form carbonic acid which dissociates in the carbonate and hydrogen.
Then carbonate will get into the blood with the help of a sodium bicarbonate cotransporter on the basolateral surface. Now, the proximal tubule is also responsible for reabsorbing glucose as well as amino acids, sodium chloride, potassium phosphate, water and uric acid.
All right. So now let's look at the distal tubule and collecting duct which are affected in type one and type four RTA.
First. They're lined with alpha intercalated cells which also move bicarbonate and hydrogen from the tubule into the cell with the help of carbonic anhydrase.
The alpha intercalated cells also secrete hydrogen across the apical surface and into the tubule with the help of a hydrogen ATPase and a potassium hydrogen apa ase.
Once in the lumen, hydrogen binds to phosphate or ammonia to form relatively weak acids like di hydrogen phosphate or ammonium, which then get peed out in the urine.
This allows protons to get removed without making the urine too acidic and damaging the cells lining the tubules and the rest of the urinary tract.
The other group of cells in these regions are the principal cells. These cells have a potassium channel that allows potassium into the lumen and an epithelial sodium channel that allows sodium into the cell.
The flow of positively charged sodium ions into the cell helps drive the positively charged potassium ions out of the cell against their concentration gradient.
There's also a sodium potassium ATPase pump on the basal lateral surface that again moves two potassium ions in for every three sodium ions out.
All three of these channels are stimulated by aldosterone. And the combined effect is reabsorption of sodium and loss of potassium in type one RTA or distal renal tubular acidosis.

Type I Renal Tubular Ac4:09–5:58

The main issue is that alpha intercalated cells of the distal tubule and collecting duct are unable to secrete hydrogen.
This leads to a buildup of hydrogen in the blood resulting in acidemia which will eventually lead to metabolic acidosis.
With type one RTA. There's also increased potassium excretion to maintain electroneutrality in the renal tubules.
So there will also be hypokalemia. The underlying cause of type one RTA could be a genetic mutation in the hydrogen ATPase pump or the hydrogen potassium ATPase pump of alpha intercalated cells.
Alternatively, it could be due to an acquired defect from a medication like amphotericin B which can allow hydrogen to simply diffuse from the tubule right back into the cell.
Other causes include analgesic nephropathy, congenital anomalies of the urinary tract and autoimmune disease like systemic lupus erythematosus.
All of which can damage the distal and collecting tubules and decrease hydrogen secretion. On lab tests.
Type one RTA leads to a normal gap. Metabolic acidosis, meaning that blood ph will be low and levels of serum bicarbonate potassium and PCO two will be low but the anion gap will be normal.
The urine ph is above 5.5 which is higher compared to other types of renal tubular acidosis. Since hydrogen ions aren't excreted.
Furthermore, metabolic acidosis increases urine calcium excretion without increasing calcium absorption. In order to get more calcium bone turnover increases, this increases the risk for developing calcium phosphate kidney stones, which is the type of stone that forms in more alkaline urine in type two RTA or proximal renal tubular acidosis.

Type II Renal Tubular Ac5:58–7:39

The main issue is that brush border cells of the proximal tubule are unable to reabsorb bicarbonate. As a result, bicarbonate gets lost in the urine and it means that there's nothing to counterbalance the hydrogen ions in the blood resulting in acidemia and eventually metabolic acidosis.
Now, since bicarbonate isn't reabsorbed in the proximal tubule, there'll be a lot of bicarbonate in the urine as a result.
And the high concentration of bicarbonate in the lumen leads to osmotic diuresis. This in turn causes mild hypovolemia which activates the renin angiotensin aldosterone system leading to sodium reabsorption and potassium excretion.
So, levels of potassium will fall leading to hypokalemia. One known cause for type two RTA is Fanconi syndrome or there's generalized proximal tubule dysfunction, meaning that the entire proximal tubule is damaged and won't be able to reabsorb things like bicarbonate, sodium glucose, phosphate, uric acid, et cetera and they're lost in the urine.
On lab tests. Type two RTA causes normal gap, metabolic acidosis.
Ph is low and levels of serum bicarbonate and P CO2 are also low. But the anion gap will be normal.
Potassium levels will also be low since they cannot be reabsorbed. Unlike RTA type one, the distal intercalated cells are still functional and can secrete hydrogen ions and can therefore generally still acidify the urine.
So the urine ph will be below 5.5. Finally, there's type four RTA or hyperkalemic acidosis and it's classically due to aldosterone deficiency or aldosterone resistance in the collecting ducts which would affect both the principal and alpha intercalated cells.

Type IV Renal Tubular Ac7:39–9:29

An example of aldosterone deficiency is Addison's disease where the adrenal gland doesn't produce enough of it. Other causes include certain medications like ace inhibitors and ARB S both of which can inhibit the release of aldosterone by blocking the renin angiotensin aldosterone system.
Other causes include diabetic nephropathy and the use of nsaids. Both of which can inhibit renin release aldosterone resistance can happen with the use of potassium sparing diuretics because they can antagonize the aldosterone receptors.
Sulfamethoxazole trimethoprim can also cause aldosterone resistance but the mechanism isn't clear whatever the cause. The aldosterone resistance can decrease the function of the sodium potassium ATPase.
In principle, cells making sodium levels fall and potassium levels rise in the blood causing hyperkalemia, reduced effect on the hydrogen ATPase in the alpha intercalated cells decreases hydrogen excretion causing acidemia.
Also, since hydrogen usually combines with ammonia in the tubule to form ammonium with less hydrogen. There'll be less ammonium excreted in the urine.
So type four RTA leads to normal gap metabolic acidosis where Ph is low and there's also low levels of serum bicarbonate and low P CO2.
Due to aldosterone resistance, there's decreased potassium excretion leading to hyperkalemia. The urine ph in this case is usually below 5.5 but it can be normal if enough aldosterone is produced.
All right. As a quick recap RTA is a cause of normal gap metabolic acidosis.

Review9:29–10:24

It can develop in either the proximal tubule or the distal tubule in the nearby collecting duct. With type one RTA.
The alpha intercalated cells of the distal tubule and collecting duct are unable to secrete hydrogen leading to metabolic acidosis hypokalemia and the urine ph will be above 5.5 with type two RTA.
The brush border cells of the proximal tubule are unable to reabsorb bicarbonate leading to metabolic acidosis and hypokalemia.
But this time the urine ph is below 5.5. Then there's type four RTA which is due to aldosterone deficiency or aldosterone resistance in the collecting ducts.
This leads to metabolic acidosis, hyperkalaemia, decreased ammonium excretion and the urine PH is below 5.5 but it can vary.
All right. Coming back to our cases, both Olga and Fred came in with a normal gap metabolic acidosis.

Summary10:24–11:02

The urine anion gap was calculated and this showed that the normal gap acidosis was of renal cause. Further investigations showed that Olga's urine ph was above 5.5 and she had hypokalemia, both of which suggest type one RTA, which is probably caused by her lupus bicarbonate is given to correct the acidosis.
Now, Fred has a normal gap acidosis with hyperkalaemia which suggest type four RTA. But more investigations are needed to determine and correct the cause.