Renal refers to the kidney, tubular refers to the portion of the nephron containing the
tubular fluid, 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 due to failure
of the renal tubules to get rid of protons.
The kidneys contain millions of nephrons, each of which has a renal corpuscle, and a
renal tubule that eventually ends in a collecting duct.
The renal corpuscle filters large amounts of solutes that go from the blood into the
filtrate and eventually 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 removed or retained by the body.
Now, renal tubular acidosis can develop in three different parts of the nephron: the
proximal part of the renal tubule, the distal part of the renal tubule, and in the collecting
ducts.
All of these parts of the nephron play a key role in acid-base homeostasis, which is the
balance between acids and bases to regulate the body's pH.
Functionally, acid-base balance can be broken into two parts - the reabsorption of bicarbonate
and the excretion of acids or free hydrogen ions.
The reabsorption of bicarbonate mostly takes place in the proximal convoluted tubule, and
the excretion of hydrogen ions mostly take place in the distal convoluted tubule and
some parts of the collecting ducts.
The proximal convoluted tubule is lined by brush border cells, that act like a sponge,
because they help with the reabsorption of water, salt, and most of the bicarbonate.
The brush border cells have two sides: one side is the apical surface which faces the
tubular lumen and is lined with microvilli.
Microvilli increase the luminal surface area and help with solute reabsorption.
The other side of the cells - is the the basolateral surface - which faces the blood vessels - known
as the peritubular capillaries, which are tiny blood vessels that run alongside and
around the nephron.
The cells lining the proximal tubule have specialized transporters and pumps, that help
move ions, like sodium, chloride, and potassium, out of the lumen and into the blood.
These ion transporters are antiporters because they move an ion out of the lumen in exchange
for pushing another one into the lumen.
They can be located in the apical or basolateral surface.
In total, there is 1 pump, 1 group of enzymes, and 2 ion transporters that help regulate
pH in the proximal tubule.
The pump is the Na/K ATPase pump, which is found on the basolateral surface, and it pushes
three sodium ions out of the cell while pulling two potassium ions into the cell.
The pump uses ATP and to help keep it running the cells are packed with mitochondria.
When bicarbonate reaches the proximal tubule it binds to hydrogen ions to form carbonic
acid and an enzyme called carbonic anhydrase type 4 brakes carbonic acid into water and
carbon dioxide, both of which happily diffuses across the membrane into the cells.
Once water and carbon dioxide are inside the cell, carbonic anhydrase type 2 combines them
once again to form carbonic acid, which then dissolves to form hydrogen and bicarbonate.
There is a sodium bicarbonate cotransporter located on the basolateral surface that moves
sodium and bicarbonate from the cell to the blood.
And there's also a sodium-hydrogen exchanger on the apical surface, that allows 1 sodium
ion to enter the cell and 1 hydrogen ion to enter the lumen.
This allows for a net movement of sodium and bicarbonate from the lumen to the blood.
As the filtered fluid travels through the nephron, it eventually reaches the distal
convoluted tubule.
There are special tubular cells that play an important role in acid-base physiology
called alpha intercalated cells, and they're responsible for secreting hydrogen ions via
the H+/ATPase into the lumen, which acidifies the tubular fluid.
The alpha intercalated cells also reabsorb the remaining bits of bicarbonate that remains
using the same carbonic acid carbonic acid trick that was used in the proximal convoluted
tubule.
Ultimately, there's the collecting duct which is lined by 2 types of cells: principal
cells and intercalated cells.
The principal cells are aldosterone-responsive, and are also ENac-expressing cells, which
means they mediate water and sodium reabsorption.
And then there are the intercalated cells, which are categorized into two types: alpha-intercalated
cells, which secrete acids, and beta-intercalated cells, which secrete base.
The alpha-intercalated cells are tall, columnar epithelial cells which contain an H+ ATPase
pump in their apical surface, which allows hydrogen ions to exit the cell and acidify
tubular fluid.
In contrast, the beta-intercalated cells are shorter and have an apical chloride-bicarbonate
exchanger in their apical surface, known as pendrin, which allows bicarbonate to be absorbed
into the blood in exchange for chloride.
Subsequently, chloride is then reabsorbed back into the blood passively due to a concentration
gradient or actively as it can be pumped back into the blood with potassium by the potassium
chloride pump, which is located in the basolateral surface of intercalated cells, enabling the
cell to secrete base.
The hormone aldosterone -- a steroid hormone that helps control sodium and potassium levels--
plays a super important role in the control of Na+ and K+ ions along the principal and
intercalated cells within the distal and collecting ducts, which are essential for pumps and transporters
to function properly.
Aldosterone allows more sodium to flow from the blood into the principal or intercalated
cells through sodium channels (ENaC).
Aldosterone also activates the sodium-potassium ATPase (Na+K+ATPase) on the basolateral surface
of principle cells, pumping sodium into the blood and potassium into the cell.
On the apical surface of the principal cells, there's also an ATP-dependent potassium
channel pump that pushes potassium out of the cell and into the lumen.
[AMMONIUM] Finally, in the lumen of the collecting duct, hydrogen ions bind to phosphate to be
excreted in the form of weak acids, like dihydrogen phosphate - which functions as a urinary buffer-
meaning that it helps to keep the urine's pH regulated--.
Additionally, hydrogen ions also bind to ammonia which is responsible for carrying hydrogen
ions to form ammonium, so that they can be disposed in the urine.
In the presence of an increased acid load, the phosphate ions are used up and the kidney
then increases its production of ammonium.
In RTA type I or distal renal tubular acidosis, the distal tubule and collecting duct are
unable to secrete hydrogen ions.
There are three ways in which RTA type I can develop, the first, and most common way, is
a dysfunction of the H+ATPase pump, which results in fewer hydrogen ions getting secreted
into the lumen.
The buildup of hydrogen ions in the cell leads to a subsequent buildup of hydrogen ions in
the blood - resulting in acidemia.
The second most common mechanism is dysfunction of the H+K+ATPase pump, which also leads to
acidemia as well as hypokalemia because fewer potassium ions are able to make it into the
blood.
The third, and least common, mechanism is a defect in the Cl-HCO3 antiporter, which
causes a decrease in bicarbonate reabsorption, which leads to a decrease in bicarbonate levels
in the blood and results in acidemia.
The reason that these pumps and transporters don't function properly are typically because
of either genetic mutations or acquired defects from medications like lithium and amphotericin
B or autoimmune diseases like Sjogren's disease --where there is autoantibodies against carbonic
anhydrases type II which impairs the distal tubule capacity to generate hydrogen.
In RTA type II or proximal renal tubular acidosis there is a defect in bicarbonate reabsorption
within the proximal tubule, which leads to urinary bicarbonate wasting.
There are 2 ways by which RTA type II can develop, the first is a dysfunction of the
Na+H antiporter located in apical surface of brush border cells, which results in a
decrease of sodium reabsorption and hydrogen secretion.
Therefore, decreased hydrogen secretion causes a decrease in hydrogen reabsorption, and bicarbonate
is wasted in the urine--causing the urine the be alkaline, and the blood's pH to be
acid--.
The second defect, is caused by the faulty Na HCO3 cotransporter which impairs the exit
of hydrogen ions from the brush border cell into the lumen in exchange for sodium, as
they would normally get reabsorbed with bicarbonate.
By decreasing bicarbonate reabsorption hypobicarbonatemia sets in, and acidosis occurs.
Over time, as there's less bicarbonate getting filtered out, so the proximal tubule is able
to reabsorb what little bicarbonate is there, and the urine becomes acidic once more.
The underlying cause of an RTA type II can be the presence of carbonic anhydrase type
II and IV inhibitors, as well as, Fanconi syndrome -where there is an acquired on inherited
defect in the function of the carriers that transport substances across the luminal membrane
of the proximal tubule, or toxicity from metals like lead, which binds to lead-binding proteins
in proximal tubular cells of the renal tubules, and disrupts the normal flow of ions.
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, therefore a deficiency would cause a problem with bicarbonate reabsorption
in proximal tubule and acid excretion in the distal tubule and collecting ducts.
RTA type IV is sometimes called hyperkalemic acidosis is related to aldosterone deficiency
or resistance in the collecting ducts.
Aldosterone deficiency usually results from low renin levels due to destruction of the
juxtaglomerular cells in the kidney --which normally produce the renin--.
Other causes of adrenal insufficiency include Addison's disease as well as medications like
ACE inhibitors or potassium sparing diuretics.
In contrast, aldosterone resistance results from XXXXXX.
Within principal cells a lack of a
The loss of aldosterone leads to a loss of Na+ and retention of K+ in the blood, which
causes hyperkalemia or increased levels of potassium in blood.
This high concentration of potassium affects the H/K+ ATPase pump which exchanges potassium
with hydrogen ions at the basolateral surface of principal cells in the collecting ducts.
This leaves few hydrogen ions in the cells resulting in an intracellular alkalosis.
This intracellular alkalosis, occurs due to the cell-to-cell exchange of potassium for
hydrogen resulting in the exit of hydrogen ion from the cell.
This consequently inhibits NH3 synthesis from glutamine, which creates an increased acidity
in urine, because there are lots of hydrogen ions but nothing to buffer them.
The most common cause of aldosterone deficiency.
But can also be caused by aldosterone deficiency or resistance within principal cells.
An example of an acquired defect would be when an illness like systemic lupus which
can cause a H+ channel dysfunction or when a medications like amphotericin B and lithium
cause increased permeability of distal tubule cells to H+.
The ROMK channel is an ATP-dependent potassium channel that transports potassium out of cells,
and it plays a major role in potassium secretion in the collecting duct of the nephron.
However, if there is no hydrogen there is no formation of ammonium, and there will be
all these hydrogen ions hanging around so acidosis will occur.
in the ammonium secretion and therefore a decrease in urine buffering capacity that
occurs in collecting duct lumen.
Symptoms of renal tubular acidosis which is a type of metabolic acidosis include vomiting,
abdominal pain, and decreased appetite.
Some types of RTA like RTA type I, can be particularly distinguished by causing urine
to be alkaline, which causes hypercalciuria and leads to the precipitation of calcium
oxalate which can cause painful kidney stones.
If left untreated, severe metabolic acidosis can lead to multi-system organ failure, in
which acidemia causes vasodilation of peripheral arterioles.
Renal tubular acidosis is a cause of metabolic acidosis, and therefore, symptoms include
shortness of breath, hyperventilation, - specifically called Kussmaul breathing-- which occurs in
response to low partial pressure of CO2 and low bicarbonate because of a forced increased
respiration, blowing off the carbon dioxide
[DIAGNOSIS] Renal tubular acidosis is diagnosed based on high levels of hydrogen ions in the
blood, low bicarbonate, and pH below 7.35.
Renal tubular acidosis is a metabolic acidosis with a normal anion gap, which means that
the difference between measured anions --Cl- and HCO3- and cations -- Na+ and Cl+-- is
between 8 mEq/L and 12 mEq/L. To identify the differences between renal tubular acidosis,
lab tests like blood potassium and urine pH are typically done, which differ among different
types of RTA.
A detection of a low serum bicarbonate concentration and negative base excess.
If respiratory compensation has been inadequate, systemic pH will be reduced.
Type of RTA Where the defect is?
pH Potassium
Additional Findings RTA Type I
Distal Convoluted Tubule Urine pH >6
Salts are more likely to precipitate at higher pH.
Hypokalemia Decreased H+ in the lumen
High urine Ca+2 Stones
RTA Type II Proximal convoluted tubule
Initially: excess bicarbonate excretion Urine >6 (high)
After: Bicarbonate loss Urine pH low
< 5.5
Hypokalemia Bone demineralization and multiple myeloma
RTA Type III Mixed
Urine pH <5.5 Hypokalemia
- RTA Type IV
Distal (DCT/CD) Aldosterone
Urine pH < 5.5 Hyperkalemia
Hypoaldosteronism
[TREATMENT] 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 thiazides that act by producing volume depletion
and increasing the reclaiming threshold of bicarbonate.
For RTA type IV, the goal is to treat hypoaldosteronism with fludrocortisone or loop diuretics, which
increase sodium delivery to the collecting duct and increase the exchange between hydrogen
and potassium.
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.
Type I, Type II, Type III, Type IV.
High levels of hydrogen in blood lead to issues that result in multisystemic organ failure.
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