Drs. Ambruso, Young and Urra discuss the mechanism of action of NSAID use, how they affect GFR and the populations at risk of developing AKI with NSAID use.
Sophia Ambruso DO @Sophia_Kidney, Sarah Young MD @kidneycritic, Judy Blaine MD, Parisa Mortaji, MD
Drs. Ambruso, Young and Urra discuss the mechanism of action of NSAID use, how they affect GFR and the populations at risk of developing AKI with NSAID use.
Sophia Ambruso DO @Sophia_Kidney, Sarah Young MD @kidneycritic, Judy Blaine MD, Parisa Mortaji, MD
Welcome to kidney essentials, a podcast for medical students, residents, and advanced practitioners at the university of Colorado and beyond. We have a guest host today. Manny, do you want to introduce yourself? Yeah. Hey everybody. My name is Manny year. I'm one of, one of the recent graduates from the internal medicine program here at the university of Colorado and an aspiring nephrologists. Very excited. And a chief resident, whoo. Chief and house. So if a Sophie misbehaves he'll get her in line, I think he still has to come see us in clinic on occasion. So other way around, Hey Manny, are you on Twitter? I pull a Dr. Blaine. I do have a Twitter. I don't tweet, but I like to follow some good nephrology pages. Um, but I'm at man. Hey, you're not pulling a blame blame. He doesn't, she doesn't touch it. So she just has one. Yeah, you're a lurker. I'm alert. She's absentee. All right, Sophie, do you need an introduction, Sophie? Well, I hope so. I'm Sophia Amoruso. I am. I'm a nephrologist. I am based out of the Denver VA and on faculty at the university of Colorado. And I tweet at Sophia underscore kidney, and I have no conflicts of interest. Manny, do you have any conflicts of interest? I do not have any conflict of interest. You don't own stock and ibuprofen or something like them. All right. So, and I'm Sarah Young. I am a nephrologist at the university of Colorado. I practice in R and shoots campus and I tweaked it at kidney critics. So a few housekeeping notes before we move on, can you, essentials is available on podcast and we could really use some good reviews so that people can find us. And so if you want to tell us about our mission, all right, our mission is to make nephrology more accessible, less intimidating, provide concise nephrology, pearls, and each episode to help listeners understand renal pathophysiology. And to make nephrology sexy one episode at a time. That's why we have Sophie do that one part. All right. And for our legal disclaimer, Manny. So this podcast is for educational purposes. Only the views and statements expressed on this podcast are solely those of the hosts. Excellent. So today we are going to discuss how much ibuprofen is too much ibuprofen, and I'm going to thank my father-in-law. How Sporn for giving me this idea. We, this is also a question we get a lot of in nephrology clinic. So, um, how much I propose it is too much ibuprofen. Well, it really depends on who you are. And when we say ibuprofen, we really mean all end sets. Not all nonsteroidal. Anti-inflammatories not just ibuprofen when we're discussing it. Well, I'm just gonna pipe in here really quick and tell you that I'm on a steady 600 milligrams of ibuprofen a day right now because of some pain I am having. And I'm really hoping my beans are hanging in there. I think they're probably okay. But I think I sound like a little bit of, I mean, this is I'm going on maybe seven to eight days. Manny, do you take. I, my wife gives me a lot of grief over this. It doesn't matter how sick I am or how much pain I am. I take no ibuprofen. Um, it's like this irrational fear that I have. Um, so today maybe we'll tease out if it's, if it's safe for me, at least. Well, yeah, maybe on a future podcast, we'll discuss healthy people, take ibuprofen. Um, but to know we're actually, you know, for most people for most healthy subjects, um, it's really good to cause any adverse effects, but in elderly patients and patients with certain COVID co-morbidities, it's going to cause a lot of problems. And in approximately two and a half million people a year experienced some major, um, renally renal complication of IB. So to focus our discussion tonight on the patient population that we're going to talk about, we'll bring up a case. And I named the case after my father-in-law, since he gave me the idea for this podcast. Oh, how so? How is a 70 year old? I, I decreased disease a little bit. That how you noticed that. So how has the 70 year old with hypertension and heart failure who presents to your office? Asking if he can take ibuprofen for his degenerative joint disease in his knees and backs knees and back, he just has one. He's on lisinopril, 20 milligrams a day and Lasix 40 twice a day. He walks his dog regularly, but this aggravates, his osteoarthritis, and he really would like to take ibuprofen. Sophie, can you start us out by just telling us what ibuprofen does and how it works? Sure. So just to remind you guys, so, you know, this. New my ibuprofen stuff a lot better when I was a med student and I get to relearn my INSEAD mechanism of action for this, but anyways, ibuprofen or other non-steroidal anti-inflammatories are non-selective reversible inhibitors of the cyclooxygenase enzymes, both Cox one. And Cox two. Here we go, guys. It's going to get a little bit more. So before we move on, I just wanted to add Sophie tonight. We're talking about non-selective inseds like ibuprofen, but the risk for adverse renal effects probably applies to both non-selective end sets and Cox two selective inhibitors. Um, Cox who's actually also expressed in the kidney nanny. You're a natural. I know he, like, I feel like it just schooled me. We're going to have to have him on again. Well, Manny. Absolutely. All right. So Cox one and Cox two, uh, catalyze the first step in the synthesis of our prostanoids and specifically we're referring to our prostate Glennon's PGE two and PGI two as they're the most relevant for this discussion. And then of course, there's, thromboxane a two, which is from arachidonic acid. So PGE two and PGI two are pro-inflammatory prostanoids that? Cause a DEMA increased vascular permeability. And promote leukocyte infiltration. I feel like this is a mouthful, but we're going to keep moving. They also reduce the threshold of nociceptor sensory neurons to stimulation. So basically by decreasing our prostate gland and production, ibuprofen decreases inflammation and. So moving on, um, PG two is also a mediator of fevers or also known as PI recess and it spins it's synthesized, excuse me. And it, since at that. And I think that the, and its synthesis is triggered in the mind. You have to start that all over again. Dash rewind. All right. It's synthesis is triggered in the hypothalamus by pirate genes, such as cytokines in the toxin and products from activated leukocytes. So inseds in addition to decreasing inflammation and pain, also reduce fever and re uh, by reducing PG to production in the hypothalamus. Great. Thank you so much for that, Sophie, uh, Manny, any additional actions of ibuprofen you want it? Yeah, just a quick word on throne box and a two. So this is another, uh, product of Cox, one in platelets, and specifically it causes vasoconstriction and promotes platelet activation aggregation. So it can lead to thrombus formation. Interestingly ibuprofen, because of this mechanism of action has a transient mild anti-platelet effect through reversible inhibition of platelet specific Cox. Yeah. And so this is why we are always told to stop ibuprofen ibuprofen before a procedure, although the risk is pretty small. Um, but you know, when you're sticking the big needle into the kidney, you don't want them on ibuprofen prior, if you can avoid it. Nope. Okay. So there are some additional mechanisms by which N CEDS work that are sort of beyond the scope of this podcast, because we really want to focus the prostate gland and production or the reduction in prostate glands that occurs because of the inhibition of Cox one and Cox two. So many. Why do we nephrologists care about prostate gland and production and its inhibition by. Yeah. So I will tell you what I think nephrologists care about. Um, so I think the inhibition of, uh, production of these vasodilatory prostanoids in the kidney basically lead to unopposed vasoconstriction of the AFL and terrain arterials, um, resulting in a reduction in renal blood flow and activation of the renin-angiotensin system and fluid retention, and specifically PGE to regulate sodium and chloride transport in the loop of Henley and modulates water, transport, and renal. Megillah your blood. PGI to regulates renal vascular tone, GFR and Reen release. Interestingly, in a person with normal renal hemodynamic parameters, prostoglandins, don't play a dominant physiological role in maintaining renal blood flow in GFR. Yeah. So that's why most, for most of us, including you, probably Sophie taking ibuprofen's not a big deal, but what about in our patient? Our prostate gland is important in this patient. We described here on ACE inhibitors. Yeah, absolutely. So inhibition of prostaglandin synthesis in this patient could actually lead to renal decompensation as this patient's at high risk for volume depletion from his Lasix and his artery may already be clamping down, not having prostate glandons in the setting of taking inseds can result in even more resistance in the afferent, arterial, and a decline in GFR. In addition, because this patient's also on an ACE inhibitor, the normal increase in resistance to maintain GFR when blood flow to the kidney is reduced, is going to be inhibited. So this is going to result in a further decline in his GFR. So many basically what you're saying is a pipe leading to the glomerulus is being squeezed. And then the pipe leaving the glomerulus is loose and dilated. I think so. So, yeah. And so if you, how many times do you think you see acute kidney injury from N in this setting in a week? I mean, I'm at the VA. I mean, we've got diabetics, we've got everybody on a diuretic. We've got everybody with heart failure and almost everybody's on an ACE, not to mention our SGLT two. Right. Which would increase your risk further. Okay. So to summarize, we should be extremely careful, careful about the use of insets in patients on a diarrhetic and an AC. As their GFR is extremely prostate gland and production, uh, dependent. Excuse me. So what would you counsel this patient about the use of ibuprofen? I think I would recommend zero to minimal use of N sets for this patient. Yeah. I would say, um, zero to minimal. If possible, as Manny said, there are times where it is a quality of life thing for patients, which is a little bit of a different setting, but basically I'll say, um, instead sparing. At, you know, and try and limit it as much as possible. Yeah. I completely agree the lowest possible dose that we can get away with. And if that's zero, that would be preferable to the kidney by all means. So let's explore some other clinical situations in which prostoglandins are really important to maintaining GFR. Sophie, can you think of another clinical scenario in which insides get patients into trouble? I mean, I would say any setting of salt depletion from any car. Uh, prosecute linens are necessary to oppose the excessive renal afferent, arterial, vasoconstriction. Yeah. Another, uh, patient group that I think about our patients with nephrotic syndrome and these patients they're hypoalbuminemia, um, which results in a decrease in their plasma oncotic pressure. This leads to a kind of loss of fluids into the interstitium and results in a decrease in, um, effective blood volume, reaching the case. Under normal circumstances, prostate glands would help visa dilate the a in arterial and maintain renal blood flow. But like we've discussed and says block prostate gland in production. And therefore these patients ability to maintain adequate renal blood flow would be impaired. Yeah, that's excellent. So anybody who has decreased effective arterial perfusion and diff you know, a decrease in effective renal perfusion is going to get into. So another population that I think about is our LV elderly patients with compromised renal function and says, can cause further reductions in GFR and a reduction in urinary sodium excretion, leading to H um, AKI or hospitalization. I also think about this in our cirrhotic patients. Yeah. That's a great patient population. They are so dependent on prostoglandins and we see a lot of that at the university. So another population that I think is at risk are transplant patients who were on calcineurin inhibitors, calcineurin inhibitors include tacrolimus and cyclists scoring. And one of its adverse effects is it can cause, um, a parent vasoconstriction. So in the setting also of unopposed prostoglandins from INSEAD, uh, from inseds these patients can also have, have decreased GFR. Yeah. That's a really important combination insights and tacrolimus are a nightmare. You know, we're using tech Alina's more and more in as immunosuppression for auto-immune renal disease. And so we really need to make sure those patients aren't taking headsets too. Okay. So let's summarize our teaching points for tonight. So we talked about several patient populations that are particularly vulnerable to even low doses of inseds because they are reliant on prostoglandins to maintain renal blood flow and shift. And so our teaching points tonight is to be extremely careful of the use of any insights in the following patient populations. So patients on diuretics, ACE inhibitors, ARBs, and or calcineurin, and, uh, patients with nephrotic syndrome, heart failure, cirrhosis, and the elderly with CKD, the risk of inseds in these patient populations is precipitating, AKA. All right. I have one issue to discuss before we close this up out. Sophie's say, say the word, the medicine that I abbreviated as C S a in this say that medicine. Oh, now cyclist boring, cyclists boring. Who says that? Me boring. We're going to have to check this cyclist sports. oh my God, wait, wait, wait, hold on. I have to look at how it's spelled. We have this there's no, N E at the end, right? Well then why would it be in it should be no, no, but that's how it's pronounced. We are going to go down this rabbit hole again. Did I tell you I was totally mortified when I was an intern, when I did a surgery or back in the day. And I was taught where I went to medical school. It was Liva flock CSUN. Right. And my attending was like, what did you just say? And he wrote it up on the board surgery room and said, and it stayed up there the entire year. Hence, I learned how to pronounce it. Correct. I still say Depak life. This epic life is in a category and it's never going to be out of my brain. All right. Thank you to all of you for joining us tonight. And we are going to cover additional risks of insights, the future podcasts, including the risk of CKD, exacerbating, hypertension, and the problems with disease. So certainly come back and check those out. Thank you to Manny for joining us tonight. He was awesome. We'll have to have him back. I know there was a mic drop moment. Did you notice that when he like went off script and like blew us away? It was good. I tried channeling a Judy Blane as much as I could. I hope I did. Okay. You did awesome. Um, and thank you to Dashel clinks porn. Who's going to edit our podcast, hopefully to Josh strong for the graphics. And of course, the university of Colorado division of nephrology for giving us our jobs and Manny. Well, I guess it's the department of medicine forgiving you, your job.