Diabetic nephropathy - Mechanisms

- 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.