Renal tubular defects: Pathology review

Definitions & Key takeaways

Renal tubular defects refer to a group of disorders that affect the tubules of the kidneys. These tubules are responsible for filtering waste products from the blood, reabsorbing essential nutrients, and regulating the balance of electrolytes in the body. When these tubules are damaged or malfunctioning, they can lead to a variety of symptoms and complications, such as electrolyte imbalances, acid-base disturbances, and kidney failure. Some examples of renal tubular defects include Fanconi syndrome, Bartter syndrome, and Gitelman syndrome.

In Fanconi syndrome, there is a dysfunction of the proximal convoluted tubule (PCT), which results in the excretion of all substances normally reabsorbed by the PCT, such as glucose, bicarbonate, etc. In Bartter syndrome, there are defects in Na+/K+/2Cl- cotransporter in the thick ascending loop of Henle, which lead to metabolic alkalosis, hypokalemia, and hypercalciuria. Finally, in Gitelman syndrome, there is defective reabsorption of sodium chloride in the distal convoluted tubules (DCT), which leads to metabolic alkalosis, hypomagnesemia, hypokalemia, and hypocalciuria. Treatment options may include medications, dietary changes, and in some cases, kidney transplants.

Chapters:

Watch video only

Case Study0:00–1:00

In the Emergency Department, two people came in. One of them is 40-year-old Sarah, who came in with rapid, shallow breathing and tachycardia.
The other one is 35-year-old Alfred, who came in with slow and shallow breathing. Arterial blood gas was taken, along with electrolytes.
Results showed that Sarah had low blood pH, bicarbonate and pCO2 levels and her potassium level was also low. Alfred had a high pH, bicarbonate and pCO2 levels, but his potassium level was low.
Based on these results, Sarah was diagnosed with metabolic acidosis, while Alfred had metabolic alkalosis. Further investigations were done, like electrolytes and urinalysis.
This showed that Sarah had hypophosphatemia and urinalysis showed phosphaturia, aminoaciduria and glucosuria, while Fred had hypokalemia and urinalysis showed hypercalciuria.
Now, the results from the labs of both individuals point towards some kind of renal tubular defect that’s causing acid-base disorders.

Physiology1:00–2:45

Before talking specifics, let's remember the physiology of the renal tubules. The proximal convoluted tubule or PCT reabsorbs bicarbonate, all glucose, uric acid and amino acids.
Apart from this, it also reabsorbs water, potassium, chloride, phosphate and most of the sodium, as well as most of the calcium.
PCT also secretes hydrogen and phosphate into the urine. The thin descending loop of Henle reabsorbs water and that’s pretty much it.
The thick ascending loop of Henle or TAL, on the other hand, reabsorbs potassium, chloride and sodium. Now, in order to reabsorb sodium, potassium and chloride, there’s a Na/K/Cl cotransporter or NKCC2, that’s only found in the kidney and its role is to snatch these ions from the urine and reabsorb them.
Apart from this, TAL can also reabsorb calcium and most of the magnesium but doesn’t reabsorb water. Now, the distal convoluted tubule or DCT reabsorbs sodium and chloride, through a sodium-chloride cotransporter, as well as calcium and some magnesium.
Again, it does not reabsorb water. Finally, the collecting tubule is regulated by aldosterone and reabsorbs sodium in exchange for potassium and hydrogen.
Now, aldosterone acts on mineralocorticoid receptors and in the principal cells of the collecting tubule, which leads to potassium secretion, while in the -intercalated cells, leads to hydrogen secretion.
Alright, let’s now talk about tubular defects, which are a group of disorders that affect the renal tubules. Tubular defects are usually genetic, but they can also be acquired.

Pathology2:45–3:17

The PCT can be affected by Fanconi syndrome. The thick ascending loop of Henle can be affected by Bartter syndrome, while the DCT can be affected by Gitelman syndrome.
The collecting tubule can be affected by Liddle syndrome. Finally, there’s syndrome of apparent mineralocorticoid excess or SAME which also affects the collecting tubule.
Let’s start talking about Fanconi syndrome which is a generalized reabsorption defect in the PCT. Now, Fanconi syndrome can be hereditary or acquired.

Fanconi Syndrome3:17–6:27

Hereditary Fanconi syndrome can be caused by inherited disorders like Wilson’s disease. With this disease, there’s a defect in the copper-transporting protein and this leads to accumulation of copper in various tissues.
It primarily affects the liver, but other organs, like the brain, cornea and the kidney’s PCT are also affected, the latter can lead to Fanconi syndrome.
Another example is tyrosinemia, which is caused by mutations in some enzymes needed for tyrosine metabolism. There are several mutations involved, but the key fact is that depending on where the tyrosine metabolism is affected, this can result in the accumulation of tyrosine or its byproducts in different organs, like the liver, kidneys and peripheral nerves.
Now, all that tyrosine or byproduct accumulation is toxic for the proximal tubule and this can result in Fanconi syndrome.
Finally, there’s glycogen storage disease, which is a group of genetic conditions that affect either glycogen synthesis or the breakdown of glycogen or glucose.
There are several mutations involved, but when glycogen metabolism is affected, this can result in the accumulation of glycogen in the liver and kidneys.
Just like with tyrosinemia, all that glycogen can be toxic to the PCT and result in Fanconi syndrome. Alright, next there’s acquired Fanconi syndrome that can happen with ischemia.
Now, renal ischemia has a lot of causes, like hypovolemia, which in turn also has many causes, like diarrhea or acute hemorrhage.
Now, hypovolemia leads to less blood flow to the kidneys, and this means that the cells are not getting all the blood supply and nutrients they need, and this can damage the PCT, leading to Fanconi syndrome.
Another condition is multiple myeloma, which can cause proximal tubular dysfunction. Now, multiple myeloma is a monoclonal gammopathy where there’s a proliferation of plasma cells in the bone marrow.
These plasma cells secrete many abnormal immunoglobulins which are then filtered in the kidneys and are pretty toxic for the proximal tubule and as a result, this can lead to Fanconi syndrome.
Then, there are nephrotoxic drugs, like ifosfamide, cisplatin or expired tetracycline and heavy metal exposure, like lead poisoning that can damage the PCT.
Alright, now, since the entire proximal tubule is damaged, it won’t be able to reabsorb things like bicarbonate, sodium, glucose, phosphate, uric acid, etc, and they are lost in the urine.
Now, when bicarbonate isn’t reabsorbed in the proximal tubule it can lead to proximal renal tubular acidosis, or type II renal tubular acidosis, or type II RTA.
Here, a lot of bicarbonate is lost in the urine and as a result, serum bicarbonate levels fall, leading to acidemia and metabolic acidosis.
Another important fact to remember is that since phosphate is lost in the urine, there’s also hypophosphatemia which in turn decreases bone mineralization, so these people often suffer from osteopenia.
Next, let’s move onto the loop of Henle and look at Bartter syndrome, which is an autosomal recessive condition. This is a defect that causes a mutation in the NKCC2 cotransporter in the thick ascending loop of Henle, leading to loss of sodium, potassium, and chloride in the urine.
Even though there’s more sodium lost through the urine, more water is lost with it, so typically, there’s no hyponatremia.

Bartter Syndrome6:27–7:51

However, the potassium lost through urine will lead to hypokalemia. Also, in the thick ascending loop of Henle, calcium is reabsorbed with the help of an electrochemical gradient that’s created by the movement of sodium, chloride and potassium.
Another high yield fact to remember is that when these ions are lost, calcium also can’t be reabsorbed, leading to hypercalciuria.
Now, the loss of all these ions in the urine causes volume contraction or excessive loss of extracellular volume. This in turn triggers the renin-angiotensin-aldosterone system.
As a result, angiotensin II and aldosterone levels rise, and the kidneys start to secrete more potassium and H+ while reabsorbing more bicarbonate in the PCT, and serum bicarbonate levels rise, leading to metabolic alkalosis.
Alright, for your exam, a high yield fact is that loop diuretics also block the NKCC2 cotransporter in the thick ascending loop of Henle, which means that Bartter syndrome presents almost like chronic loop diuretic use.
Okay, let’s continue our journey through the tubules and stop in the DCT. Here we have another autosomal recessive condition called Gitelman syndrome.
This is a defect that causes a mutation in the sodium chloride cotransporter in the DCT and this affects the reabsorption of sodium chloride.
The loss of sodium chloride leads to the loss of water, which results in mild volume contraction. Just like in Bartter syndrome, this activates the renin-angiotensin-aldosterone system, which in turn leads to increased excretion of potassium, causing hypokalemia, and hydrogen, resulting in metabolic alkalosis.

Gitelman Syndrome7:51–9:31

Now, volume contraction can also increase calcium reabsorption in, and this leads to hypocalciuria. That’s because in the PCT, studies suggest that calcium reabsorption is secondary to sodium and water reabsorption, but the exact mechanism is still not clear.
So, when there’s volume contraction, sodium and water reabsorption increases in the PCT to compensate for the losses. And as a result, calcium reabsorption also increases.
Additionally, Gitelman syndrome also decreases magnesium reabsorption. Okay, so, in the distal convoluted tubule there’s a protein that acts as a channel and that allows some magnesium reabsorption.
It’s thought that Gitelman syndrome also causes a mutation in the gene that makes this protein and as a result, there will be magnesium wasting in the kidneys which in turn causes hypomagnesemia.
Okay, remember that thiazide diuretics also block sodium chloride reabsorption in the DCT, so on your test, a person with Gitelman syndrome will present similarly as someone on thiazide diuretics.
Alright, moving on to the collecting tubule, where this time we have an autosomal dominant condition called Liddle syndrome.
Now, this defect causes a mutation in the sodium channel in the collecting tubule that increases their activity so more sodium is reabsorbed.
A key concept is that aldosterone also increases the activity of these channels, so Liddle syndrome clinically presents as hyperaldosteronism with symptoms like high blood pressure, headaches and fatigue.
You can differentiate between the two by looking at the aldosterone levels which are typically very low or even absent in people with Liddle syndrome.

Liddle Syndrome9:31–11:28

Now, normally, aldosterone induces the synthesis of more sodium channels in the distal and collecting duct cells. This allows for more sodium to enter the cells, so there’s more sodium available for the sodium-potassium ATPase, found on the basolateral surface of the tubular cells.
The sodium-potassium ATPase gets two potassium ions inside the cells, and pumps three sodium ions outside the cells. As a result, sodium is pumped out of the cells and eventually into the bloodstream, while potassium enters the cells.
In this way, the intracellular potassium concentration increases and this creates a driving force for potassium to be secreted from the cell into the lumen.
Now, with Liddle’s syndrome, basically the same thing happens, but unlike the renin-angiotensin-aldosterone system, there’s nothing that stops the sodium channel from reabsorbing all that sodium and excreting all that potassium.
As a result, a lot of sodium is reabsorbed and a lot of potassium is lost and this will lead to hypertension and hypokalemia.
Now, the kidneys will try to compensate the loss of potassium by increasing the activity of K+/H+ ATPase in the collecting tubule.
This will reabsorb potassium and will secrete hydrogen ions in the collecting tubule. As a result, the loss of hydrogen ions will lead to metabolic alkalosis.
In order to stop or slow down the sodium channel, a potassium-sparing diuretic, specifically amiloride, is given to block this channel.
Finally, there’s syndrome of apparent mineralocorticoid excess or SAME. This can be hereditary and transmitted in an autosomal recessive pattern or acquired.
With hereditary SAME, there’s 11-beta-hydroxysteroid dehydrogenase deficiency. Normally, aldosterone is the main hormone that binds to the mineralocorticoid receptor in the kidneys.
However, cortisol can also bind to mineralocorticoid receptors but the enzyme 11-beta-hydroxysteroid dehydrogenase in the collecting tubules metabolize cortisol to cortisone, which can’t bind to these receptors.
In SAME, there’s a decrease in the level of these enzymes, so cortisol levels increase and over activate these receptors.
A high-yield fact to remember is that this will basically mimic the effects of aldosterone, so serum aldosterone levels are low, but there are symptoms of hyperaldosteronism.

SAME11:28–13:18

Just like Liddle’s syndrome, a lot of sodium is reabsorbed, leading to hypertension and a lot of potassium is lost, leading to hypokalemia.
The kidneys will try and compensate for the potassium losses using the K+/H+ ATPase to reabsorb potassium and secrete hydrogen, leading to metabolic alkalosis.
Interestingly enough, a person can also get SAME by eating too much licorice! That’s because licorice contains a lot of glycyrrhetinic acid that can inhibit 11-beta-hydroxysteroid dehydrogenase leading to the disease.
The treatment of SAME relies on giving potassium sparing diuretics in order to lower the mineralocorticoid effects, like hypokalemia.
Another option is giving corticosteroids, because exogenous corticosteroids lower the endogenous production of cortisol, meaning that not so much cortisol will bind to the mineralocorticoid receptor.
Alright, as a quick recap... Fanconi syndrome is a PCT dysfunction where there’s increased excretion of all substances normally reabsorbed by the PCT, like glucose, bicarbonate, and so on.
As a result, there’s metabolic acidosis, type II RTA, hypophosphatemia and sometimes even osteopenia. Bartter syndrome is an autosomal recessive disorder that affects the Na+/K+/2Cl- cotransporter in the thick ascending loop of Henle, leading to metabolic alkalosis, hypokalemia and hypercalciuria and it presents similarly to chronic loop diuretic use.
Gitelman syndrome is another autosomal recessive disorder that affects reabsorption of sodium chloride in the DCT, leading to metabolic alkalosis, hypomagnesemia, hypokalemia and hypercalciuria and it presents similarly to chronic thiazide diuretic use.
Then, there’s Liddle syndrome which is an autosomal dominant disorder where there’s increased sodium reabsorption in the collecting tubules, leading to metabolic alkalosis, hypokalemia, hypertension and low levels of aldosterone.

Review13:18–14:50

Treatment here relies on amiloride. Finally, there’s SAME, where there’s 11-beta-hydroxysteroid dehydrogenase deficiency and as a result, cortisol bind to the mineralocorticoid receptor, leading to metabolic alkalosis, hypokalemia and hypertension.
Treatment relies on potassium sparing diuretics or corticosteroids. Alright, coming back to our cases.
Sarah came in hyperventilating and lab tests showed that she had metabolic acidosis, hypophosphatemia and urinalysis showed phosphaturia, aminoaciduria and glucosuria, which indicates Fanconi syndrome.
On the other hand, Alfred came in hypoventilating and lab tests showed that he had metabolic alkalosis and hypokalemia. Urinalysis showed hypercalciuria, indicating Bartter syndrome.
alkalosis hypomagnesemia hypokalemia and hypocalciuria And it presents similarly to chronic thiazide diuretic use Then there's little syndrome which is an autosomal dominant disorder where there's increased sodium reabsorption in the collecting Tubules leading to metabolic alkalosis hypokalemia hypertension and low levels of aldosterone treatment here relies on aMILoride Finally there's same where there's 11 beta hydroxysteroid dehydrogenase deficiency And as a result cortisol binds to the mineralocorticoid receptor leading to metabolic alkalosis hypokalemia and hypertension treatment relies on potassium sparing diuretics or corticosteroids All right Coming back to our cases Sarah came in hyperventilating and lab tests showed that she had metabolic acidosis and hypophosphatemia and urinalysis showed phosphaturia amino aciduria and glucose urea which indicates Fanconi syndrome On the other hand Alfred came in hypoventilating and lab tests showed that he had metabolic alkalosis and hypokalemia urinalysis showed hypercalciuria indicating

Summary14:50–15:15

Renal tubular defects: Video, Causes, and Symptoms | Osmosis