- One of the most serious chronic complications
of diabetes mellitus is a condition
known as diabetic nephropathy.
Which, if you break down the term
into nephro and pathy literally means
kidney disease that occurs secondary to diabetes.
And it's actually pretty common
as it eventually affects about 20% to 40% of all individuals
with diabetes, including both type I and type II.
In this tutorial, let's talk about the mechanism
underlying the cause of diabetic nephropathy
and how individuals with diabetes develop the condition.
So diabetic nephropathy is a chronic complication
of diabetes mellitus.
Meaning, it usually has a slow progression over decades
after the initial diagnosis of diabetes.
And to give you an overview of what happens,
an insulin deficiency due to the diabetes
results in hyperglycemia,
which then causes hypertension and kidney dysfunction.
This kidney function is actually then further worsened
by the hypertension.
And ultimately, all of this results in kidney failure,
which can have very severe and potentially even
life threatening complications, such as anemia,
electrolyte imbalances, such as metabolic acidosis,
and heart arrhythmias.
Now, before we dive into the mechanism
of diabetic nephropathy, let's briefly review the structure
of the glomerulus in the kidney,
by bringing in a diagram here.
So, the glomerulus is the portion of the kidney
where blood is initially filtered.
So blood enters the glomerulus over here,
through this afferent arterial, and then
leaves the glomerulus through the efferent arterial.
And you can remember this,
that it leaves through the efferent arterial
for E for exit, or efferent.
And while the blood is within the glomerulus,
there's this advanced filtration system,
which we'll talk about more in a minute.
And the filtered fluid that exits the blood
is known as a filtrate
and it collects in Bowman's space
before it enters into the tubules of the nephron
where further reabsorption and secretion occurs
before it exits the kidney into the ureters as urine.
Now, one last structure to point out in this diagram
is this vessel coming off the efferent tubule, here.
Now, this vasculature actually wraps around the tubules
of the nephron, and contributes
to the reabsorption and secretion of solutes.
Now, to add to this diagram,
let's imagine we took a cross section of this glomerulus,
and looked at it on its end.
And it would look a little bit something like this.
Now, we can use this diagram here to better depict
some of the important structures
within the glomerulus.
So here you can see the capillary vessels,
and each of them I've drawn in here a little red blood cell
to help remind you that it's a blood cell.
And as you can see, these vessels are surrounded
by a few additional structures
that we couldn't really appreciate in that first diagram.
So these are the structures that contribute
to the three layered filtration system of the glomerulus.
The first layer is that of the vascular endothelium.
So the endothelial cover, the inside of the blood vessel,
so the capillary wall, there.
And then the second layer
is the glomerular basement membrane, or GBM for short,
which is a specialized basement membrane
that surrounds the vascular endothelium.
And then the last filtration layer
is the visceral epithelium,
which is also known as the podocytes.
Now, in between all these capillaries here
is the mesangium,
which is comprised of cells known conveniently as
mesangial cells.
And they produce a collagen network
that structurally supports all of these capillaries
and it's across this space that filtration occurs
within the glomerulus of the kidney.
So how exactly does diabetes,
a problem with insulin deficiency,
result in kidney damage?
Well, the answer includes multiple compounding factors.
Now, the first component is an increased pressure state
within the nephron.
And this is due to two mechanisms.
And the first is hypertension,
which is a common comorbidity
associated with diabetes mellitus.
So hypertension or high blood pressure
results in an increased pressure throughout
the entire arterial vascular system.
And this includes the afferent arterial of the glomerulus.
So, to think about how this increases the pressure
within the glomerulus,
let's think about a simple garden hose.
So, in the middle of the garden hose, there's a hole.
And as water flows through the hose,
a small amount of water will leak out through this hole.
But if we open up the spigot all the way
this is going to increase the pressure of the water
traveling through the hose,
and intuitively, this change is going to result
in more water leaking from the hole here in the center
and that's because there's increased pressure
forcing it out of the hole.
Now this is similar to what occurs in the glomerulus.
The hypertension increases the pressure,
just like turning on that spigot,
which in return increases the filtration rate
of the glomerulus, which can be thought of
as that leakiness from the hole in the garden hose.
Now, the other mechanism contributing
to this high pressure state, is something known as
vasoconstriction of the efferent arterial.
Which is just a fancy way of saying
that this blood vessel constricts
or gets smaller in diameter.
So, to understand why this occurs,
we need to briefly review the
renin-angiotensin-aldosterone system, or RAAS, for short.
So renin is a hormone that's secreted by the kidneys
in response to decreased renal profusion,
or low blood flow to the kidney.
This is a sign of low fluid volume
throughout the body.
So in the response to a low fluid volume,
renin has a cascade of effects
in order to maintain blood pressure
as well as volume status.
And one of these effects is constriction
of the efferent arterial,
which then maintains this pressure
within the glomerulus in the presence
of a decreased renal profusion.
So once again, let's go back to this garden hose
to understand this a little bit better.
Now, instead of turning up the spigot, as we did before,
what do you think would happen if you were to kink the hose
on the other side of the hole?
Once again, intuitively, this is going to
increase the pressure behind the kink
and subsequently will increase the rate
at which water leaks out the hole.
So once again, this is similar to what occurs
in the glomerulus in response to activation of this
renin-angiotensin-aldosterone system.
There's a constriction of the efferent arterial
to build up pressure within the glomerulus
to maintain the necessary filtration
and therefore, it will increase the filtration rate
even further.
But why exactly is this happening?
If I just said that individuals with diabetes
often have increased renal profusion
due to the hypertension,
then why is a low pressure system
such as the renin-angiotensin-aldosterone system activated?
And this is a good question,
and the answer is not exactly intuitive.
For some reason, the underlying physiology of diabetes,
specifically the hyperglycemia,
results in a direct intrarenal or within the kidney
activation of this renin-angiotensin-aldosterone system.
And subsequently, efferent vasial constriction
independent of the volume status of the individual
and therefore increases the glomerular filtration rate.
So how does this increased pressure
relate to diabetic nephropathy?
Well, as the pressure within the glomerulus increases,
this results in a process known as mesangial expansion.
The increased pressure results in trauma
and damage to the mesangium of the glomerulus.
And in response to this damage,
the mesangial cells respond by secreting cytokines
that produce inflammation,
as well as oxygen free radicals
that result in endothelial dysfunction,
and all of this kind of combines
into hypertrophy and matrix accumulation
within the mesangium, which is known as
mesangial expansion.
And as you can see over here on the right,
as the mesangium expands, the spaces,
or what are known as the fenestrations
between the podocyte foot processes expand.
Now, this has two effects.
First, it decreases the surface area available
within the glomerulus for filtration,
and second, the dilation of the fenestrations
causes the filtration system to be leaky,
and larger molecules such as proteins
are filtered out of the blood in the kidney.
Then, the last factor contributing to diabetic nephropathy
is a combination of the previously mentioned factors.
And this is ischemia.
As I mentioned earlier, the blood vessels
supplying the tubules of the nephron
come off of the efferent arterial,
and vasoconstriction of this arterial
from the intrarenal activation
of the renin-angiotensin-aldosterone system
decreases this blood flow.
And in addition, the cytokines and free radials
produced from the barotrauma to the mesangium
further damage the nephron vasculature.
And over time these processes result in ischemia,
or cell death, and atrophy of the vasculature
that supports the glomerulus,
as well as the tubules.
So this will decrease the kidney's ability to filter blood,
and is ultimately what will lead to kidney failure
in diabetic nephropathy.
So as you can see, there are many different mechanisms
that are going to contribute to the progression
of kidney failure in individuals with diabetes mellitus.
However, it's important to note
that they are all directly associated
with the underlying hyperglycemia,
and therefore the progression towards kidney failure
can be slow or potentially even prevented,
if the underlying diabetes is well controlled.