Okay, now we're here live with Dr. Kittleson after those excellent talks. And your questions are coming in, but please feel free to add more or upvote the ones that are in the queue. You can upvote the ones you're particularly interested in. And we will get to questions we don't cover in the whole chair question and answer session, which follows this. So Dr. Kittleson, thank you so much. Let's talk about transitioning between immunosuppression. You talked a lot about why you might choose one medicine over another. How do you do this? Do you just stop one and start the other? Do you overlap them? Do you down titrate and up titrate? Yes, great question. I think it depends what you're transitioning from to. So for example, you have a patient on standard TAC and MMF, and now they have CAV and you want to get them on a proliferation signal inhibitor, let's just say sirolimus. That's better in the sense that you're transitioning them to a regimen that's going to have them offer increased protection against rejection, right? So in that situation, we generally just start the sirolimus, overlap four days with the MMF, and then stop the MMF. I think it's going to take about four days for some of that sirolimus to work into your system to a reasonable level. Check the level a week later, two weeks later. So that's a pretty reasonable, easy, straightforward transition. You can even do it over the phone with the patient. When you're switching to a CNI-free regimen, that's a much more high stakes situation, right? You're not going to pick a person who's at high risk for rejection. And if you do, because you're worried about the kidneys, but you're less worried about the heart, then you're willing to do that regimen. And if you do it, we generally cut the CNI dose in half. So cut the TAC dose in half, as you add the sirolimus on board, and then check a level in a week or two and only stop the TAC completely when the sirolimus level is therapeutic, because you really want to make sure you've got good immunosuppression on board when you're taking away the quarterstone of the CNI. And then check an echocardiogram about four weeks later, just to document that their function is normal. So that's generally the protocol we follow. And we don't do it over the phone generally, we really want to make sure that the patient understands it's written down, the follow-ups are arranged, because that's not the kind of regimen you want to fall through the cracks. Great. How about using the drug interactions to administer lower doses of calcineurin antagonists to patients? So historically, in the olden days, you know, things like diltiazem were given to transplant recipients early after transplant, so in order to give them less cyclosporine. It's very historic, it's back when cyclosporine was the standard CNI. That's not done anymore, because it's not a cost issue, you don't pay by the milligram. And second, it's not clear that the nephrotoxicity of the calcineurin inhibitors is related to the milligrams you give, it's more likely related to the levels in the blood. So there's really no benefit to leveraging your drug-drug interactions to give diltiazem for hypertension, to also give them less milligrams of their calcineurin inhibitor. And in addition, we actually try to avoid that, because you don't want this unpredictable impact on your calcineurin inhibitor levels, that they may lead to worse nephrotoxicity. The one situation where we'll often leverage the benefit of drug-drug interactions is those Black American patients who are rapid metabolizers of the CNI, and you just can't get those levels up. So you go to 2BID, 3BID, 5BID, nothing, 6BID, 5TID, and you're really having trouble, then add quinoconazole, 100, 200 milligrams, slip that in there, activate your, inhibit your cytochrome P450, and then bring your levels up. So that's one situation where we'll use it. Excellent. How about tolerability of everolimus versus serolimus? Yes, that is what I like to call a data-free zone. So, you know, I tend to like serolimus better because it's once a day, it's older, sometimes cheaper, some drug prescription plans will cover serolimus better than everolimus, it will be cheaper for the patient. That's generally the go-to. There's really no clear evidence one is superior to the other. But if, say, the patient, but 30% of people who start PSI stop them. The mouth ulcers, the edema, the stomach upset, the fatigue, the malaise, the ennui, there's all kinds of weird PSI stuff that people get. If they get something like that, some non-life-threatening but quality-of-life impairing side effects to one PSI, absolutely try another one. But if they get pneumonitis, then all PSIs are off the table. So that's generally how I think about it. And then, again, PSI side effects. If you have someone who you'd like to have on a calcineurin-free regimen, and they develop proteinuria with serolimus, how do you manage that to put them back on? Yeah, I like to phone a friend, a nephrologist in that situation for counseling and therapy, because I think it's a balance of what's actually worse. Is the CNI-related renal dysfunction that's dropped their EGFR less than 50, less than 40, we're really in the danger zone, we're worrying? Or is it just a touch of proteinuria, when their creatinine, their EGFR, has actually gotten better? So I tend to try to balance that counseled by a nephrologist. If it's a little low-level proteinuria, and it's stable, and their EGFR has actually improved, maybe you continue it, and you simply monitor the EGFR. But if they just have rampant proteinuria, then you say, no dice. They are better off on a CNI minimization regimen, where instead of running their attack level standard 5 to 10, you might say 4 to 8, or 3 to 6, something like that. Great. So let's turn to the physiology now. How do you manage chronotropic incompetence after heart transplant when a patient's really bothered? When do you add a beta agonist? When do you put in a pacemaker? Yeah, so early after transplant, there are sometimes patients who have relative bradycardia, the perfect patient coming out of the OR is going to have a heart rate of 110, and a right atrial pressure of 2, and a creatinine of 1.0, no epinephrine. That's the dream patient coming out of the OR. But we never see those patients, because if they were that healthy, they probably wouldn't need a transplant. So more likely, you'll see this relative bradycardia. And there's a lot of reasons for it. It might be that awful scourge of the pre-op amiodarone that's just sitting around in their liver, leeching out slowly over months, or it can be some primary graft dysfunction. So when does relative bradycardia become symptomatic bradycardia early post-transplant? Really, if you see a heart rate in the 50s or 60s, I mean, that's just bad, right? If that persists more than a week or two after transplant, you're pretty much giving the patient a pacemaker. Well, what if the heart rate's 70s, and they walk around the halls, and they feel fine, and their blood pressure's okay, and they're not volume overloaded, and their creatinine's fine, then you probably let them ride. So for me, the cutoff is one fatigue or exertional intolerance. That may be a little hard to parse out early after transplant with everything else going on. But if they're volume overloaded, difficult to diurese, creatinine's rising, that tells you they're not happy at that heart rate, and they often need a pacemaker. Interestingly enough, the renervation happens in almost everyone. By the time they're a year out or even using that pacemaker, maybe not, but you've got to get them through the hump of that early period. You have to do everything you can to preserve their volume status, especially their precious renal function early on. So you talked a lot about medications that may not behave as expected because of the denervation, but you just mentioned that almost everyone does re-enervate to some extent. So how do you judge response to medications? Do you actually truly avoid medications, or do you try them? Yes. So those are three types of nerves, right? There'll be the efferents that go back to the ones that make you give you chest pain. So the ones that give you chest pain probably grow back to some extent because there are patients with CAV who actually have classic angina. So you really only know if those nerves grow back because patients tell you they have chest pain later after transplant. Then there's the parasympathetic, the vagus nerve, which makes the heart rate relatively higher. But by the time they're a year out, most patients are now running in the 80s for their heart, so they must have some re-enervation. And then there's the sympathetic nerves of the post-ganglionic release of the epinephrine, the norepinephrine response to exercise. I mean, there's no way to know that for sure unless you do fancy studies that no one's going to do in clinical practice. So really, how does that matter when you're thinking about medications? Well, number one, if you have someone with unstable bradycardia, are you going to try atropine in them? You probably still will never do that because you'll just feel foolish that you don't understand the vagus nerve. You'll use isoproteinol. The second thing is, what about the beta blockers? What about beta blockers post-transplant? We avoid them because we're going to blunt their exercise response because they already don't have the sympathetic innervation. Well, I think about it another way. When are beta blockers going to be actually useful post-transplant? We know they're very poor anti-hypertensives anyway. So even regardless of the innervation issue, what's my algorithm for managing hypertension in a transplant recipient? Often a calcium channel blocker first, a dihydropyridine like amlodipine or nifedipine because I know it won't hurt the kidneys early when everyone's worried about the kidney function. So often they have the limiting lower extremity edema. Second line is going to be an ARB, ACE inhibitor, or thiazide diuretic. If that doesn't work because their kidneys are bad or their potassium won't tolerate it, then you're going to go more to your clonidine and guanfacine. Hydralazine doesn't work anyway, but probably slip it in there. And then only then and only then are you going to even get to the beta blocker because we know it doesn't work well anyway. So if you've gotten to your fifth line agent, then sure, you're not going to let this concern about exercise, blunting exercise tolerance bother you. You're just going to give them something to treat their blood pressure, probably levatolol, probably more bang for your buck. But you'll be very vigilant for any quality of life related side effects of fatigue and exercise intolerance, recognizing you should pull back if that's likely the culprit. Super. Okay. We have a few minutes remaining. We're going to talk about non-board questions now. None of these will be on the boards, I guarantee it. Okay. So virtual histology Ivis to manage CAV, does this have a role? What's your approach? You know, I don't know. I'm going to be totally honest. I think this is an area in inception. It's a data-free zone. I like to call myself the Andy Rooney of cardiology. Probably most people listening aren't old enough to remember him, but he was the cranky guy at the end of 60 Minutes who hated everything and didn't believe anything. And so I don't know. I don't know where we are yet. I think Ivis in the present age, it's hard to know where it matters. But what I'm really excited about when it comes to CAV is the CAV trajectory score. So disclaimer, two of my colleagues, Dr. Patel and Kobashigawa were the co-authors in this really interesting study that came out in CERC two years ago, where they took a testing cohort and a validation cohort and used six criteria, donor and recipient characteristics, donor age, smoking, recipient LDL, donor-specific antibodies. There were six in total. And you could predict very accurately what CAV trajectory a patient would fall in. There are four trajectories, one with really no CAD up to 10 years, one with a little bit, one with a moderate amount, and then the last was accelerated vasculopathy. And by calculating which trajectory someone falls in, then you can limit the number of surveillance studies you do to assess for CAV. We know we can't rely on symptoms because the heart's denervated. We have to do something. But the question is, how often do you need to do that something? And can you risk stratify to do it in the right person? So I think the future is in the correct application of machine learning models in a clinically relevant way so we can minimize testing on our patients. Super. How about co-stimulation inhibitors like bilaticept to reduce renal toxicity? I am so excited about the concept of bilaticept. And I've seen the case reports here and there, and I'm thrilled by the case reports. But someone out there needs to put together, Dr. Schweitzer needs to put together a clinical trial so that we can figure out the who, what, where, when, why, because I think it would be huge. It's great for kidneys. I think it would be great for hearts. God forbid I ever need a transplant. I plan to switch myself to a CNI free regimen as soon as possible and then get myself some bilaticept. Yes. Excellent. And then how about, where is it? Oh, DCD hearts. Do you immunosuppress them differently? I don't think we know enough to say, but I also don't. So I think when you don't know, you should always err on the side of less is more and do the standard approach. I'm delighted about DCD. I think it's an extraordinary step forward for mankind to widen our donor pool. And I suppose you could say if there'd be some more inflammatory milieu somewhere in that functional ischemic time and waiting for the systolic to fall and the five minute standoff, I don't think we know, at least in our clinical practice, we have treated them exactly the same where you give induction. If there's other reasons like renal dysfunction or sensitization, but otherwise exactly the same management. Great. And a question about propranolol for tremor. Yeah. So again, the right answer is what works. And I think you have to balance with the patient. How bad is the tremor? How bad are the side effects to propranolol? How well is the propranolol actually working to control their tremor? And, you know, this, the CNI related tremor, tachycardia tremor that happens mostly in older people tends to be dose sensitive. So it's really bad for the first three months. Then as you target lower levels, it generally improves. So generally we tell people for those first few months, just hang in there. You will be able to sign your name and eat soup just not right now. And then as time goes on, it often improves to the point they don't need it. But if they have another essential tremor or something else going on, we'll absolutely try it. But then recognizing the patient has to choose what's worse, the tremor or the side effects of the propranolol. Okay. Last couple of minutes. One final question. Talk about when, when you can't get a patient off their CNI, but they have significant CKD, you know, how low can you go? Do you do sort of partial sparing regimens? What's your strategy? Yeah, a hundred percent. So the people who you worry about are the people who have had prior rejection, donor specific antibodies, don't tolerate a lot of cell sept as their buffer, because they're going to be off the CNI. Maybe a previously weaned off predative, no interest in going on five as a placeholder. Issues of non-adherence in the past, we're just not going to come back and check their levels frequently. Those are the kinds of people that even when their kidneys start to go, you'll sacrifice their kidney for their heart. But in that scenario, if you can't go straight to CNI free, you can try a CNI minimization regimen. So in that situation, instead of running five to 10, do you run four to six, three to five, two to, yeah, how low can you go? I think the patient in a way tells you how low you can go. Meaning if I have a multiparous woman who is in her thirties, I'm not going to run her as low as an 80 year old white man, right? So there's many advantages to being an old white man. And one of them is you're at less risk for rejection. And so I think it really matters in that sense. You have to take it into the context of the patient. The other time we do CNI minimization is often to patients who have cancer, who we feel very uncomfortable taking away the CNI altogether. And yeah, we run as low as two to five, but if you pick the right patient, they'll do well with that regimen. Yeah. And as you point out, younger patients, the questioner asked about a 35 year old, it's hard to really minimize in the 35 year old, because their immune systems are robust and they will reject on you. So, you know, you go as low as you can, right? Yeah, treat the patient. Exactly. Awesome. Well, thank you so much, Michelle. Dr. Kittleson's talks are always, you know, you just want to listen to them over and over. We're going to go out to the main question and answer area, but you will be able to watch these videos. It takes us a day or two to upload them, but you can watch these again if you would like. And we'll see you in the question and answers. Thanks, Michelle. Thank you.

immunosuppression medications

transitioning

sirolimus

calcineurin inhibitor

proteinuria