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Current time:0:00Total duration:10:05

Diabetic nephropathy - Clinical presentation & treatment

Video transcript

- [Voiceover] Diabetic nephropathy is one of the most common and serious chronic complications associated with diabetes mellitus. In this tutorial, let's discuss how the mechanisms underlying diabetic nephropathy correlate with the clinical presentation as well as the treatment of the disease. Now fortunately the mechanisms underlying diabetic nephropathy, directly correlate with the clinical presentation. And the first clinical finding of the disease is somewhat paradoxically an increased kidney filtration rate or glomerular filtration rate. So, diabetic nephropathy, if you break down the term into nephro and pathy literally means kidney disease caused by diabetes. Now typically kidney disease is marked by a decreased filtration rate, so why is it that the first clinical stage of diabetic nephropathy is that of an increased glomerular filtration rate? Well recall that the earliest mechanism contributing to diabetic nephropathy is an increased pressure state, over here in blue. And this is due to hypertension and efferent vasoconstriction. So let's use a common garden hose to help illustrate how this increased pressure state will ultimately result in an increased glomerular filtration rate. So, imagine you have this garden hose and it has a small hole in the middle of it. So first you're gonna open up the spigot and increase the pressure and flow through the hose. Intuitively, this is going to increase the rate at which water is leaking from the hole in the hose. Next, you partially kink off the end of the hose distal to the hole, and once again this is gonna further increase the rate at which water leaks from the hose. This is essentially what's occurring in the glomerulus with the hypertension representing the opening up of the spigot and increasing the pressure before the glomerulus, in front of the glomerulus, and the efferent vasoconstriction representing the kinking off of the hose, which causes this back pressure. Both of which are going to increase the filtration rate. This stage of diabetic nephropathy is most commonly asymptomatic, so it goes typically unnoticed. However, it's going to set the stage for the next clinical step of diabetic nephropathy; and that is detectable proteinuria. And what proteinuria is is protein in the urine. So this increased pressure state causes trauma on the mesangium, in the middle of the glomerulus here and it results in mesangial expansion, which is this second mechanism of diabetic nephropathy. Now as the mesangium expands, this also increases the size of these fenestrations or spaces between the podocyte foot processes, so let's go back and look real closely at these fenestrations and watch how they increase in size. Now, these podocyte fenestrations are a component of the glomerular filtration mechanism. So, let's think of these podocyte foot processes as a coffee filter. A proper coffee filter is porous enough to allow for the water to flow through, but will retain the coffee grounds within the filter. This is because the molecules of water are much smaller than the size of the coffee ground, so over time the coffee pot is gonna fill just with the coffee but no coffee grounds. Now imagine if the coffee filter was replaced with a cooking strainer, which has considerably larger pores. If you were to try and use a cooking strainer as a coffee filter, when you pour the hot water through, it's not gonna work because the pores of this cooking strainer are much larger. Both the coffee as well as the grounds are gonna start to spill through and you're gonna end up with coffee grounds in your coffee. So in the glomerulus, the fenestrations between these podocyte foot processes are kind of like coffee filters and normally in the filtration of blood no proteins or large molecules are allowed though. However, with mesangial expansion these fenestrations become much larger and when filtration occurs they become leaky, and they allow for molecules, such as proteins, to be spilled out into the urine. So this is what causes the detectable proteinuria in diabetic nephropathy. One of these proteins is albumin. Urine tests are available to detect the presence of albumin in the urine, so frequently individuals with diabetes will have routine screening to test for this albumin or for protein in their urine, which is a sign that they may be developing diabetic nephropathy or kidney disease due to diabetes. Then the next clinical stage of diabetic nephropathy is that of a decreased glomerular filtration rate. So you can see that we've gone from an increased glomerular filtration rate, then to a decreased glomerular filtration rate. So what exactly causes this? Well, recall that part of the reason for this mesangial expansion is the release of cytokines which cause inflammation and oxygen free radicals. Now, these cytokines and oxygen free radicals damage the mesangium, resulting in the mesangial expansion. However, they don't just damage the mesangium. They damage the cells throughout the tubules as well as the vasculature that supports the nephron. Now in addition to the cytokines and oxygen free radicals, this vasculature is further damaged by this efferent vasoconstriction here. Which is one of the causes of that increased pressure state. And this combination of damage from decreased blood flow and cytokines and oxygen free radicals results in ischemia and atrophy of this vasculature. As this vasculature kind of dies off, it no longer can support the tubules of the nephron, so the nephron itself begins to die off as well, and so there's a decreased ability to filter the blood. Now initially this occurs in just a small percentage of the nephrons in the kidney, and the kidney's able to compensate, but eventually over time if this diabetic nephropathy is not treated, a large enough number of nephrons throughout the kidney are gonna die off, and it's gonna be detected as a decreased filtration rate. The kidney's no longer able to keep up with the dying off of nephrons. If this is present, this decreased filtration rate is present for more than three months in a row, then it's known as chronic kidney disease. As it continues to progress, eventually it will become a permanent decrease, which is then known as end-stage renal disease. Now that we have a better understanding of the mechanisms that cause diabetic nephropathy and how they correlate with the clinical presentation, let's just briefly touch on how diabetic nephropathy is treated. This is, once again, gonna be directly correlated to the underlying mechanisms. So, the most important thing in diabetic nephropathy is to treat the underlying diabetes. This is because the hyperglycemia associated with diabetes is the cause of this increased pressure state, so if you can treat the diabetes, you can prevent the increased pressure state, which will then prevent the cascade of effects leading to diabetic nephropathy. However, if this increased pressure state does start to occur, the next step is to treat the pressure. And what I mean by that is treat the hypertension. So if you can decrease the blood pressure, that goes into the afferent arteriole here, you'll decrease this increased pressure state. In addition, one of the most common medications to treat blood pressure are known as ACE inhibitors. Now ACE inhibitors stands for angiotensin converting enzyme inhibitor and angiotensin is one of the hormones in that renin-angiotensin-aldosterone system that results in the efferent vasoconstriction. So by treating the blood pressure with an ACE inhibitor, you're also going to decrease this vasoconstriction to further decrease this pressure state within the glomerulus. These two treatments should be occurring regardless of whether or not an individual with diabetes is in any of these clinical stages of diabetic nephropathy. So these are not only treatments, but they're also good for preventing the progression of diabetic nephropathy before someone even enters this first clinical stage. However, if someone does develop diabetic nephropathy and it unfortunately progresses far enough to have this decreased glomerular filtration rate and they end up in end-stage renal disease, unfortunately then there are only two treatment options. The first is dialysis, in which the blood is filtered outside the body by a machine to kind of replace the effect of the kidney. And the other is a kidney transplant. Fortunately though, like most of the complications of diabetes mellitus, if the underlying disease and its comorbidities, such as hypertension, are properly treated, diabetic nephropathy can be a preventable complication of diabetes mellitus.