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Diabetic nephropathy - Mechanisms

Video transcript

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 Neph row 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 1 and type 2 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 do 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 a heartbeat rhythm yes 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 efferent arteriole and then leaves the glomerulus through the efferent arteriole and you can remember this that it leaves through the efferent arteriole 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 the filtrate and it collects in Bowman's space before it enters into the tubules of the nephron we're 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 tube you'll hear 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 clematis 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 3 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 Poteau sites now in between all of these capillaries here is the mesangium which is comprised of cells known conveniently as ms and jail cells and they produce a collagen Network that structurally supports all of these capillaries and it's across the 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 efferent 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 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 clam areolas which can be thought of 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 arteriole 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 arena angiotensin aldosterone system or Ras for short so reiden is a hormone that's secreted by the kidneys in response to decrease renal perfusion or low blood flow to the kidney and this is a sign of low fluid volume throughout the body so in the response to a low fluid volume Rina 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 arteriole which then maintains this pressure within the glomerulus in the presence of a decreased renal perfusion so once again let's go back to this garden hose to understand this a little bit better now instead of turning 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 of the hole so once again this is similar to what occurs in the glomerulus in response to activation of this rena and angiotensin aldosterone system there's a constriction of the efferent arteriole to build a pressure within the glomerulus to maintain the necessary filtration and therefore it will increase the filtration rate even for but why exactly is this happening if I just said that individuals with diabetes often have increased renal perfusion due to the hypertension then why is a low pressure system such as the rhenium angiotensin aldosterone system activated and it's 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 intra renal or within the kidney activation of this ring and angiotensin aldosterone system and subsequently efferent vasoconstriction independent of the volume status of the individual and therefore increases the glomerular filtration rate so how does this increase 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 responses to 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 in 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 Poteau site 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 arteriole and vasoconstriction of this arteriole from the intra renal activation of the Rena and angiotensin aldosterone system decreases this blood flow and in addition the cytokines and free radicals produced from the Barrow trauma to the mesangium further damage the nephron vasculature 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 kidneys ability to filter blood and is ultimately what will lead to kidney failure in diabetic nephropathy 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