Acute Tubular Necrosis: Pathophysiology and Causes – AKI

00:01 So, again we're gonna be focusing on acute tubular necrosis.

00:06 This is, hands down, the most common cause of acute intrinsic kidney injury that we see.

00:12 And it's significant because it's associated with a 4 to 6 fold increase in mortality.

00:19 Pathophysiologically, what's going on when our patients enter ATN is that there's patch necrosis of the S3 segment of the proximal tubule and the medullary thick ascending limb in the loop of Henle.

00:29 Why is there patch necrosis? Because if you think about what's happening, these portions of the nephron function at near maximum energy dependency because of their high metabolic demand and activity and their location in the outer medulla where there's lower oxygen.

00:42 So they're really quite sensitive to any changes in renal perfusion.

00:47 So when our patients have ATN, there's some things that can guide us in terms of risk factors that may put them at risk for developing this and this includes: volume depletion, a patient who has underlying chronic kidney disease, a patient who is using NSAIDs, these are those non-steroidal anti-inflammatory drugs.

01:07 Remember I mentioned initially how these were dangerous because they can impair autoregulation This is another situation where they're causing harm because again, if I don't have auto regulation, and I can't control my GFR then this becomes problematic.

01:22 And diabetes mellitus Diabetes mellitus is a risk factor because of the fact that most patients with diabetes do have subclinical renal disease.

01:32 And by having a toxin such as ATN, it really puts them at risk for developing tubular necrosis.

01:39 So when we think about pathophysiologically what's happening, it's multi-factorial - there's endothelial and epithelial cell injury, we also have intratubular obstruction from cast.

01:51 So when we have those tubular epithelial cells that are apoptosing and necrosing, remember they're getting picked off from that underlying basement membrane, they then collect into that tubule, combined with that Tamm-Horsfall protein and they can actually obstruct the outflow of urine.

02:07 We also have changes in the microvascular blood flow.

02:10 We have ischemic, ongoing ischemic hits as well as with reperfusion injuries that cause problems and extending ongoing injury.

02:17 And we also have immunological factors that are playing a role.

02:22 So before we move on, I would like to mention something that happens from a physiologic standpoint when we develop ATN.

02:28 So remember, our bodies are always trying to do the right thing and conserve and preserve life.

02:33 One of the things that you'll notice is that patients who develop tubular injury oftentimes become oliguric, meaning that they don't make very much urine.

02:41 And this is in part because of tubuloglomerular feedback.

02:44 So if you reach back to kind of those first days of medical school and you remember what tubuloglomerular feedback is, these are really alterations in GFR that are induced by changes in tubular flow rate.

02:55 So cells in our macula densa at the end of the cortical thick ascending limb of the loop of Henle sense changes in the delivery and reabsorption of sodium chloride.

03:04 The damage, if you think about what's happening in ATN are damaged proximal tubular epithelial cells and those cells in the thick ascending limb of the loop of Henle cannot reabsorb sodium because of the fact that they're damaged.

03:17 So now, we have an increase in sodium chloride delivery to that macula densa and because of that, we end up with this paracrine signal releasing adenosine that causes renal afferent arteriolar vasoconstriction in order to reduce intraglomerular hydraulic pressure and filtration.

03:35 So essentially, what we're trying to do is shut down GFR because we're sensing that there's so much sodium chloride there.

03:41 And that becomes very important for a couple of reasons.

03:43 Number 1 by shutting down our GFR, that's just going to limit our ATP-dependent tubular reabsorption and that in a sense, will protect against intracellular ATP depletion and augmentation of renal injury.

03:55 We also don't want to have a lot of sodium chloride not being reabsorbed because we need that in order to expand our vascular space.

04:03 So in this sense, tubuloglomerular feedback is actually serving a purpose although it does make our patients oliguric.

04:10 So, when we think about the causes of acute tubular necrosis, there's two main categories that we need to think about.

04:15 The first is ischemia.

04:17 So just as we talked about in pre-renal disease, we can see this with a decrease in renal artery perfusion and that could be because of an acute drop in mean arterial pressure.

04:26 So it might be that my patient is going to the OR and they are on cardiac bypass pump and their pressures are actually dropped for a sustained period of time so they don't have renal artery perfusion Or any sense, it could be septic physiology that decreases that mean arterial pressure.

04:42 Anybody who's been in a state of prolonged volume depletion, so somebody who may have started out pre-renal because they've had decreased PO intake, they're not feeling well but if it's sustained overtime, that's going to become ischemic and damage the tubules.

04:55 And finally, sepsis as I mentioned.

04:59 The other big category is toxin-mediated tubular toxicity or ATN and this is caused by a number of different factors.

05:08 One is radiocontrast media.

05:10 So this is typically an iatrogenic cause, this is something we do to our patients.

05:14 So if our patients are undergoing a CT scan or anangiogram, we are administering iodinated contrast in order to see what we're doing.

05:24 So that iodinated contrast is actually a tubular toxin in certain situations.

05:29 The risk factors in where we see this kind of injury are gonna be people who have underlying chronic kidney disease.

05:35 So it's critical for you to really know what that serum creatinine is and what that kidney function is prior to administering contrast.

05:43 Again, diabetes mellitus is showing up.

05:45 Why is that? Because as we mentioned a lot of times even though somebody appears as if they have preserved renal function.

05:51 Subclinically, they likely do have alterations and subclinical kidney injury.

05:58 And finally, concurrent hypotension if my patient is already hypovolemic.

06:03 And then on top of that, I'm actually administering radiocontrast and I could really augment an injury from this tubular toxin.

06:12 There's also drugs that are nephrotoxic to the kidney.

06:15 These traditionally are aminoglycosides and you may see this in your pediatric population when we give a lot of this to our cystic fibrosis population.

06:24 Amphotencin B, an anti-fungal which is a very broad spectrum agent.

06:29 And Cisplatin which is an excellent chemotherapeutic agent but at the same time it does cause tubular toxicity.

06:35 Interestingly, these 3 entities or these 3 medications tend to cause nonoliguric renal failure so patients oftentimes have preservation or their urine output.

06:46 The last category that we'll talk about is heme pigment.

06:50 So heme pigments can actually cause tubular toxicity as well where we see this most commonly is rhabdomyolysis.

06:56 So again, this is breakdown of skeletal muscle and we could see this with a crush injury.

07:01 Some of these have been found down for a long period of time and they've actually crushed parts of their muscles and they begin to necrose.

07:07 It could be from a burn or from any type of injury that's going to damage to muscle.

07:11 Those heme pigments are released, they then go to the tubule and cause tubular toxicity.