Renal tubular acidosis

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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With renal tubular acidosis, renal refers to the kidney, tubular refers to the main tube-portion of the nephron, and acidosis refers to having too many protons or increased acidity in blood, so renal tubular acidosis or RTA describes increased acidity in the blood because the renal tubules can’t get rid of protons.
The kidneys contain millions of nephrons, each of which has a renal corpuscle, and a renal tubule that ends in a collecting duct.
The renal corpuscle filters large amounts of solutes that go from the blood into the filtrate and eventually the urine, and the renal tubule and collecting duct are responsible for fine tuning the reabsorption and secretion of solutes to adjust the amount that ultimately gets retained by or removed from the body.
Broadly speaking, renal tubular acidosis can develop in either the proximal convoluted tubule, sometimes called just the proximal tubule, or the distal convoluted tubule, or distal tubule, and the nearby collecting duct.
The proximal tubule is lined by brush border cells which have two surfaces. One is the apical surface that faces the tubular lumen and is lined with microvilli, which are tiny little projections that increase the cell’s surface area to help with solute reabsorption.
The other is the basolateral surface, which faces the peritubular capillaries, which run alongside the nephron. Now - when a molecule of bicarbonate approaches the apical surface of the brush border cell it binds to hydrogen to form carbonic acid.
At that point, an enzyme called carbonic anhydrase type 4 which lurks in tubule among the microvilli like a shark, swims along and splits the carbonic acid into water and carbon dioxide.
The overall equation looks like this: The water and carbon dioxide happily diffuse across the membrane into the cells where carbonic anhydrase type 2 facilitates the reverse reaction - combining them to form carbonic acid, which dissolves into bicarbonate and hydrogen.
A sodium bicarbonate cotransporter on the basolateral surface snatches up the bicarbonate and a nearby sodium, and shuttles both into the blood.
Meanwhile, a sodium-hydrogen exchanger on the apical surface, pulls sodium into the cell, while pushing hydrogen back into the tubule.
So at the end of the day, there’s a movement of bicarbonate from the tubule to the blood. Okay - so now let’s shift over to the distal tubule and collecting duct which we’ll talk about together.
First off, one type of cell these are lined with are the alpha-intercalated cells. Like the brush border cells, the alpha intercalated cells move bicarbonate and hydrogen from the tubule into the cell using carbonic anhydrase.
The alpha intercalated cells have two major ways to get rid of that hydrogen across the apical surface. First, they have a H+/ATPase which simply pushes hydrogen into the tubule.
Second, they have a hydrogen potassium ATPase (H+K+ATPase) which pushes hydrogen into the tubule in exchange for potassium.
With regard to bicarbonate, there is a bicarbonate/chloride antiporter which moves bicarbonate into the blood in exchange for chloride.
To prevent chloride from piling up within the cell, there’s a potassium/chloride symporter on the basolateral surface that moves both of these ions into the blood.
In addition, there’s a chloride channel on the basolateral surface that allows chloride to passively move down its concentration gradient into the blood.
Finally, it’s worth mentioning that like all cells - sodium and potassium levels are controlled by Na/K ATPase pumps on the basolateral surface which move two potassium ions into the cell and three sodium ions out of the cell.
So overall, there’s a net movement of sodium, chloride, and bicarbonate into the blood, while hydrogen is pushed into the tubule.
Once in the lumen, hydrogen binds to phosphate or ammonia to form relatively weak acids like dihydrogen 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 are the principal cells. They have two pumps on the apical surface, an ATP-dependent potassium channel pump that pushes potassium into the tubule, and an epithelial sodium channel pump called ENaC that pulls sodium into the cell.
There’s also a Na/K ATPase pump on the basolateral surface that again moves 2 potassium ions in for every 3 sodium ions out.
All three of these are stimulated by aldosterone, and the combined effect is resorption of sodium and loss of potassium.
In RTA type I or distal renal tubular acidosis, the main issue is that alpha intercalated cells of the distal tubule and collecting duct are unable to secrete hydrogen.
The buildup of hydrogen in those cells leads to a buildup of hydrogen in the blood - resulting in acidemia. The underlying cause could be a genetic mutation in the H+ATPase pump or the H+K+ATPase pump of alpha intercalated cells.
Alternatively it could be due to an acquired defect from a medication like lithium or amphotericin B, both of which can make cells permeable, allowing hydrogen to simply diffuse from the tubule right back into the cell.
A less common mechanism, is a defect in the bicarbonate/chloride antiporter, which causes a decrease in bicarbonate reabsorption, and less bicarbonate in the blood, also leads to an acidemia.
In RTA type II or proximal renal tubular acidosis, 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 is nothing to counterbalance the hydrogen ions - resulting in acidemia.
One known cause is a genetic mutation in the sodium bicarbonate cotransporter on the basolateral surface that makes it less functional.
Being able to move less bicarbonate out of the cell, alters the intracellular bicarbonate concentration and makes it imore difficult for bicarbonate to get brought across the apical surface into the cell.
As a result, less bicarbonate gets reabsorbed by the brush border cells, and more is left behind in the lumen of the tubule.
Eventually losing bicarbonate in the urine, means that there’s less bicarbonate in the blood - resulting in an acidemia.
Unlike RTA type I, the distal intercalated cells are still functional and can produce hydrogen ions, and can therefore can generally still acidify the urine.
RTA type II can happen independently or can be part of a broader disfunction of the proximal tubular cells called Fanconi syndrome.
In Fanconi syndrome, in addition to the loss of bicarbonate, there is also phosphaturia, glycosuria, aminoaciduria, uricosuria, and proteinuria - the loss of phosphate, glucose, amino acids, uric acid, and protein in the urine.
Fanconi syndrome can be inherited, but can also be acquired, for example, it can be a side effect of taking certain medications like tetracycline class antibiotics.
In RTA type III there is a defect in both the distal and proximal tubule, a fairly uncommon situation. The causes are not well understood, but some cases have been associated with congenital carbonic anhydrase deficiency, this is because carbonic anhydrases are present in both distal and proximal tubule.
Finally, there’s RTA type IV, sometimes called 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.
Aldosterone has an important role in the regulation of sodium, potassium,, and hydrogen levels. An example of aldosterone deficiency is Addison’s disease, where the adrenal gland doesn’t produce enough of it.
An example of aldosterone resistance is a mutation in the epithelial sodium channel (ENaC), so that it doesn’t respond well to normal levels of aldosterone.
Either way - a reduced effect of aldosterone can decrease the function of the Na+K+ATPase, making sodium levels fall and potassium levels rise in the blood.
A reduced effect of aldosterone on the H+/ATPase in the intercalated cells, means that more hydrogen gets retained in the cells and eventually in the blood, causing the acidemia.
Overall, this causes high potassium, hyperkalemia, and high levels of hydrogen ions, acidemia, in the blood. Also, since hydrogen usually combines with ammonia in the tubule to form ammonium, with less hydrogen there’ll be less ammonium formed and excreted in the urine.
There are some other causes of RTA type IV as well. One of them is severe hypovolemia.
Or low fluid, which means less sodium is available for reabsorption in the principal cells. The result is lower sodium levels in the cell, which alters the ion exchange between sodium and potassium - resulting in low sodium and high potassium levels in the blood, and the hyperkalemia contributes to the acidosis.
Another cause of RTA type IV is systemic lupus or medications like lithium and amphotericin B, all of which can make the distal tubule and collecting duct cells more permeable to hydrogen ions, allowing them to diffuse into the blood and causing acidosis.
Initially, symptoms of renal tubular acidosis include gastrointestinal problems like decreased appetite, vomiting, and abdominal pain.
But, if left untreated, severe metabolic acidosis can lead to vasodilation of peripheral arterioles which can cause shock.
Like other causes of metabolic acidosis, there is a compensatory pattern of breathing called Kussmaul breathing-- where a person initially takes rapid shallow breaths that become more deeper over time - in order to blow off the carbon dioxide.
Also, the urine tends to be more alkaline than normal, typically greater than a pH of 6; this especially happens in RTA type I and sometimes in the acute setting for RTA type II.
This causes hypercalciuria and leads to the precipitation of calcium oxalate which can cause painful kidney stones. Renal tubular acidosis is a metabolic acidosis - a pH below 7.35 and a low bicarbonate level - with a normal anion gap.
That means that the difference between measured anions --Cl- and HCO3- and cations -- Na+ and K+-- is between 8 mEq/L and 12 mEq/L.
In addition, blood potassium and urine pH are typically done to identify the exact type of RTA. Low levels of HCO3- in the blood also lead to elevated levels of chloride, so hyperchloremia is a classic finding in RTA.
In RTA type I and II, the main goal is to replenish bicarbonate and correct hypokalemia with potassium citrate. In RTA type II, this can be achieved with thiazide diuretics which cause water loss and increased reabsorption of bicarbonate.
For RTA type IV, the goal is to treat hypoaldosteronism with fludrocortisone or loop diuretics, which increases sodium delivery to the collecting duct and increases potassium hydrogen exchange.
Alright, as a quick recap, renal tubular acidosis describes a condition in which the kidney is unable to secrete acids or reabsorb bicarbonate from the body.
And this most commonly results in metabolic acidosis with a normal anion gap. If left untreated, the acidemia can cause peripheral vasodilation and shock.