Diabetic nephropathy – Mechanisms | Endocrine system diseases | NCLEX-RN | Khan Academy

– 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.

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