Dr. Theresa Henke assesses statistics, data, drug trials, and technological breakthroughs regarding Chronic Kidney Disease.
we have with us today. Dr Theresa hanky that is going to tell us a little bit more about the future of chronic kidney disease management. Um, Theresa comes to us, she's an adult uh, nephrologist and she comes to us from Cedars Sinai Medical Center. She's got a busy clinical practice, their full scope of nephrology, including um, many different kinds of dialysis, transplantation, chronic kidney disease, kidney stones, metabolic disease and hypertension. She's pioneered a robust vaccination program for chronic kidney disease patients and has given multiple invited talks throughout L. A. Community. Um, Teresa, we are very curious to hear what is in the future of kidney disease with a nod to the president. Thank you. I like that. Thank you for the wonderful introduction. I really appreciate it and I appreciate everyone here inviting me. I will say that's quite a talk to follow. So I'll do my best. So, um, I will be speaking about the future of kidney disease with a nod to today just so we're all kind of starting on the same page, admittedly you may see that some of the data and um, medications I discuss are similar to the ones that you just heard about. And I think, um, that just speaks to really the game changer type of drugs that have come out really just in the last couple years and we for decades use ace inhibitors pretty much exclusively. And now these drugs have come out that have really changed the landscape and I, so people like me and nephrology can't stop talking about them. So, um, I think that it really speaks to how important these medications are. So chronic kidney disease we know is a very important and prevalent disease. It's not a sexy disease that gets talked about very often in the general medical community but it affects 30 million Americans that's about the size of Texas. Which is why I highlighted it there. It's 15% of people above the age of 20 and 35% of diabetics and it's important. And I think as some of the other physicians alluded to as these patients, they die sooner. It's not just a number that is different. It's really a mortality predictor. The life expectancy in these patients compared to the normal curve here. And blue is quite a bit reduced worse in the worst stage of CKD. So the lower your G. F. R. Is, the lower you're likely that your life expectancy is transplantation. The green curve here improves it quite a bit a bit better than stage three CKD. Not quite up to normal though most of these patients are dying of cardiovascular disease, especially in the dialysis patients. You can see across races they have a much significant risk of cardiovascular death in the transplant group. You can see you get a little improvement but still does not normalize. These patients also have an increased risk of hospitalizations. Maybe getting a little bit better through time but still significantly different than the non chronic kidney disease patients. These are also very expensive patients if you're into the finances of medicine. These patients, especially in the later stage. Ckd very expensive just in the medical care costs. These are the non dialysis patients. Um dialysis also a very expensive treatment. America's obsession with in center hemodialysis is very expensive upwards of $100,000 per year per patient. Um Home modalities like peritoneal dialysis a little bit cheaper. Still very expensive transplant after the initial cost of the medications and surgery. It's quite a bit cheaper. So chronic kidney disease is, I think we all know it's very important. It's a mortality predictor. They have cardiovascular death. It's also very expensive. It's a lot of strain on the american health care system and I as has been alluded to earlier. Unfortunately not only is it a a disease that Kills them, it gets worse with time. Um we lose about one mil per uh per minute per year for most patients. The album in New York patients, especially those over 300 do much worse. They lose up Upwards of three in some of the older studies, I saw even upwards of five. So it's bad and it gets worse with time. The hypertensive patients also tend to do worse to so they have more declined per year than those with controlled blood pressure. You can see two. And I think that I liked this graph a lot. This is from a couple years ago that just showed over time 10 years. So you can have a patient in a diabetic patient let's say type two who's starting with the G. F. R. Of 60 which when I get these referrals I say okay that's not that bad. But really if you do a prediction 10 years later, You know many of them are already near 30 or approaching stage four kidney disease and their complication rate gets much higher. Their mortality goes up. It's much harder to treat. They start getting anemic and hyper parathyroid ism and all these other complications. And so it's a really progressive disease. And I the part of my one of my biggest goals in treating these patients is to plateau this curve. I don't very rarely am I able to turn it into a U. Shape and get G fr recovery. But what we want to do is take this slope and and flatten it out and make it more of a plateau. And that's where these medications really come in. And I started with the ace inhibitors and we've all seen this data. This is old data, it's from the nineties, we've all seen this that the ace inhibitor is very clearly have shown a huge benefit in stabilizing G fr reducing the risk of um in stage kidney disease or need for transplant or dialysis. And what everyone said is absolutely right accepting a G fr decline up to 30% is completely okay you have to push through it, you have to warn the patients. and the other physicians just the benefit that you get on the flip side of it is completely worth it. So don't be afraid of that. I can't reiterate that enough. Um similar data. You can see this was um remote PERL study from the 90s and study in the Lancet that just really I think showed help in the stabilization of the G fr. So we love ace inhibitors. I spent all my training using its inhibitors and Arbs and that's it. And I can't tell you how many conversations we had about. We you we basically use ace inhibitors um control your diabetes and your blood sugars and reduce your other cardiovascular risks and the conversations about lifestyle. Don't smoke, don't be overweight, control your lipids, avoid toxic drugs, don't take ibuprofen, that was kind of it. And then outside of that I'd say well I don't know, good luck I'll see you in a few months and next year you're G. F. R. Will be one less no matter what we do. And it's really been unsatisfying. And I I think it's led to more and more dialysis patients and transplant patients and there's organ shortage and who has the money for dialysis and they have to quit work. It's just this nightmare. And I think this approach has resulted in obvious residual renal and cardiovascular risk. So there's a huge gap to improve the outcomes in these patients and that's kind of where the new drugs have come in. And there have been studies over the years that I think some of the other physicians alluded to. That have been completely disappointing. The Bardack salon trial Dallas kieran when they looked at the S. A. S. It never really made a difference and then they added a game changer. The SGL T two's came and I will tell you when I first learned about these drugs as a as a diabetic drug. I was kind of skeptical like what we're going to induce glucose syria. Isn't that part of the pathology of D. K. A. Isn't that what I try to avoid? Isn't that how they get U. T. I. S. And hyperbole mia. So I thought I was worried that would have adverse renal outcomes. And I love when I'm wrong when the patient's benefits. I've been proven over and over again that these drugs are really game changers. And I think I've been the mechanism of this is is interesting trying to understand how it has a real protective effect as you know this quick physiology reminder sorry the SGL T. Two's will inhibitors will block the SGL T to transporter in the proximal tubules cell that is responsible for 1 to 1 stoking metric ratio of reabsorption of sodium and glucose about 80% is re absorbed with the S. G. L. T. Two. Um When this is blocked you get increased sodium and glucose into the urine which is urinated out glucose Syrian nature recess. Um And the cool part of this is by increasing distal sodium delivery. You can increase sodium delivery to the macula denso which has a feedback mechanism and constricts the a Faron arterial which is the cause likely of the G. Fr drop. Um And probably at least part of the reason that they lead to a reduction of the hyper filtration injury and some of the renal protective effects. If you're getting decreased pressure here you will have decreased at the level of the glamour. Realist and protection against hyper filtration. It's a different spot than where the ace inhibitors are that's here at the parent material. So I think there's more to this story than this because Lasix or furosemide for example that blocks in the loop of Henle E also increases distal sodium delivery but you don't get the same renal protective effects. So there's more than just the nature reserves that leads to the beneficial effects here. But regardless as we've seen these slides over and over today that it's completely undeniable The long term benefit that the SGL T two inhibitors provide in renal protection so you can see it in the epochal flows in in de pago flows in it just over and over and I don't want to belabor this since we've already gone over it. I will note on this slide though this is the G fr drop that you may see when you initiate the SGL T. Two inhibitors do not be afraid. And I warn the patients about this because they're really plugged in CKD patients are obsessive about their creatinine because that's all I ever talk about. Well maybe not all but a lot of what I talk about. And so they when they see their crowning go up, they freak out. And so I warned them that this may happen. And I use the analogy that this is a short term payment for a long term benefit. And yes your bank account may go down at the beginning but a year and a half for 14 months later you get to catch the check of the investments. That's really when when these curves diverge and you really get a benefit. So These are game changers and I know we've talked about him a lot today so I won't go crazy. But there really have been very exciting. And the first drug that we've had in 20 years more that really has changed the outcome for these patients. And because they you have patients doing the right thing every day and they still get worse and it's just it's disappointing. So what else is on the docket? Um This drug the GLP agonist was mentioned briefly earlier. The F. F. P. Glenna Tide, which is an investigational GLP agonist has shown some benefit to. It's a phase three international double blinded trial that looked at adult diabetics with either a known history of cardiovascular disease or risk factor and they admittedly look at out composite outcomes and that is defined as any of these. So it's an or not an end incident new macro argument area greater than 300 mg. An increase in the Albany area a decrease in the G. F. R. So that you can notice they use 40% not 30 and then renal failure. So either requiring dialysis or a G. F are under 15 and they just haven't started yet. And in that composite outcome they had a real benefit um in reducing the incidence of any of these in the treatment group. There have been other studies of the GLP different GLP agonists that where the data is a little bit more all over the place. Um And so and usually the renal outcomes in those studies are secondary outcomes. They're usually cardiovascular studies. So this has kind of been the first one where the data looked um impressive to me. So I think this will likely be in our future prescribing this more. We'll see it's an investigational drug still. Um and finery known is a non steroidal mineral glucocorticoids receptor antagonist and it kind of is used um harnessing the concept of Valdosta own escape. And I realized I'm speaking to a group of endocrinologists so I probably have to explain it too much. But um in despite with treatments with the angiotensin um, ace inhibitors or angiotensin receptor blockers, there's still incomplete blockade of the rent an angiotensin cascade. Many of the patients will have increasing Aldo levels despite therapeutic doses not the baby 2.5 dose but real dose. And this Aldo Stallone escape is thought to likely contribute to the progression of chronic kidney disease. So the thought idea of blocking that is a way perhaps to slow progression of CKD. So um to remind you where the mineral accord accord receptor is, it's here is this distal in the tube you'll in the collecting duct in the principal sell it is when Aldo Stallone binds here, it's responsible for sodium reabsorption through the neck channel with and then you get increasing or increasing negative electro negativity and the urinary space which drives potassium excretion. So you get a net effect of sodium absorption and potassium excretion when this receptor is blocked that gets turned off so you can seemingly get hyper colima and you get decrease sodium reabsorption which um in the other um an Alcor decoy receptor antagonists you'd have the anti hypertensive effect as we heard earlier. The Fanara. No not not as much. Um so in this drug was just approved in july by the FDA Brand new. It's very expensive. It's hard to get in my experience personally my Medicare patients, It's $20 a pill. Um those without commercial insurance that a little bit of trouble. But um hopefully things get easier for these patients but and George really I encourage you to jump in if you're listening if you have anything to say about this. Um So this study was just published in december of last year. It was a phase three double blinded multi center trial and diabetic chronic kidney disease. Adults mostly stage three um who are already on a sore arm. So this is an additive um medication, not an oar. And they looked at a few outcomes and they were pretty impressive. The first one primary composite outcome, which is the incidence of kidney failure or a sustained decrease in four of 40% or more in the G. F. R. You'll note that wasn't 30 but 40 or death from renal causes. You can see in the treatment group you had improvement additionally in the isolated, just sustained decrease the G. F. R. Improvement in the treatment group and in the secondary outcome which was either a doubling of the creatinine for a month or more or death from renal causes also improved this. This one. Um See they looked at the incidence of kidney failure and you can see these lines are pretty similar and I think some of the critics of this data would say, well, you know, sure, maybe the um G. F. R looks better four years later. Before, years later, the similar amount of people are on dialysis than in the placebo group. And I think the argument that I would make is that this is only a four year study and most these patients are CKD stage three And so they would lose maybe one mil per minute per year of G fr. So in four years your average CKD three patients wouldn't be on dialysis anyway. So I think to really see the benefit of this drug in keeping people off dialysis. If you're looking in CKD three patients you need longer than four years to really see the benefit. So don't let that discourage you from this drug. I think there's a lot of potential here and I've started prescribing it for the right patients. The it also decreases albumin excretion. These are seen in some of the other mineral accord accord receptors antagonists to like al dark tone or spironolactone that you can get a reduction in the albumin excretion. So that's great. I don't know if that's the only benefit that's happening from the phenomenon and there's probably some additional beneficial effects outside of just this. Um we worry about hyper khalidiya anytime a mineral according. Coid receptor antagonist is initiated and especially in these patients have CKD so they already have a predilection to hyper colonia. They have metabolic acidosis at the same time there these patients are already on an Acer and are they have decreased k excretion. Many of them also hyperglycemia Mick. So they have transferable shifting of k. Many of them have type four RTs as well. That limits case reasons they have a million reasons to have hyper Columbia. And then I'm adding a second drug that can cause hyper colima, it makes people very nervous. Um in this study, the Fanara known group, yes, had a little bit elevated potassium compared to placebo group. But was pretty minor. Really under five. Most of the time. The hitches the exclusion criteria in this drug with the patients had to have a potassium I think less than 4.8 in order to enter this study. So if they had baseline hyper khalidiya, they weren't allowed to to participate in this trial. So your patient that has a history of hyper colima with ace and inhibition initiation or dietary indiscretion. I don't know what will happen with them but I would encourage you to try um and monitor the potassium after initiation and if it's really a problem and you really want to push through it, you can use the binders, you can use patera more or cancel it. Or any of the other ones that can be administered to control the K to let you get the benefit of these drugs because if if we don't do anything, these patients all they'll end up on dialysis and their life expectancy goes down. And so really we have to try to push through the side effects to get the benefit long term for these drugs. Okay, so innovations and ideas that's kind of medications, some of that you've heard before, maybe I put a different spin on it. Um so the real future I think no matter what we do, unfortunately, some of these patients will leak through and end up on dialysis or within stage kidney disease G.F. are less than 10 or 15. And that that can happen because the drugs aren't 100% or patients present late as we know. CKd as a relatively silent disease until it's quite progressed. People aren't always plugged in with doctors. You can make up, you can come up with a million reasons why this may happen. And so I think trying to improve the quality of life and quantity of life and people who have srd is also a major initiative and doing in center hemodialysis is hard. It's hard on the lifestyle, it's hard on the body. So I'm I'm absolutely a home modality first type of nephrologist. So doing home peritoneal dialysis or home hemo is always better. It's a way to stay home and stay out of the dialysis unit and avoid exposure to infections and a million arguments. But I think what even that is still problematic. People have a hard time still going to work or school or taking care of their families and being productive. And so there's still research happening on what can be done otherwise. And there's another nephrologist here at cedars in a different group than me named Dr victor Gura who's if you go to his website, he's part of a study that's um, looking at the wearable artificial kidney and you can see in this picture here? This young man wearing this giant thing? Belt thing is basically a CRT machine that you wear. Um it's admittedly big and people probably don't want to wear that now but and I think it's more of a proof of concept that these things can be done and as engineering improves and technology improves, there's a potential that people could just wear their dialysis machine on there, belt or on their suspenders and go day to day. The current, the one I have a photo of here can in at least in a porcine model was able to get the G. F. R 2 27 which is pretty darn good actually. I mean you can live a long time at 27 not have many complications as a in center hemodialysis patients. So there's some proof of concept there on kind of excitement. UCSF our colleagues up north also, I've had a long, long standing project, the kidney project looking at an implantable bio artificial kidney. This is still just investigational. You can see the little device here is the proof of the idea, the prototype. It's about the size of a cup of coffee where you get it implanted surgically permanently and it would be a bio filter present. Uh there's all kinds of logistic questions I have. Like do you have to replace the filter? Like I do with the dialysis machine or how do I access it? What what if it breaks? I'm sure these are all in in works. But I think that's where people are thinking now or what are alternatives to your standard dialysis. Additionally, if you read in the new york times, it was it this week or last week, it was after I created these slides. There was an article discussing a xeno transplantation of uh genetically engineered pig kidney where they were able to transplant the kidney and it worked for, I think it was four or five days. This was in a a patient who was had brain death but had consented for this um study. So it's at least there wasn't hyper acute rejection. So it worked for a few days. I think there's some excitement there as well. If there is a potential for xeno transplantation and getting organs from other species to help alleviate the transplant desperation need. And maybe I think there's a lot more to transplant and rejection than just hyper acute in the first couple of days. But there's at least a proof of concept there that it's worthwhile thinking about. I'll tell you my father in law. I read that article and he said, well, terry are you seeing these pig kidneys in your practice now? And I said, oh my God, give me a few years. We'll see. So, any way that I think to summarize a lot has happened and changed in chronic kidney disease and diabetic kidney disease management in the last few years? It's been very exciting to be a young pathologist at this time to kind of be witness to this and help our patients. And my summary don't be afraid if the creating Goes up under 30% when you initiate these drugs don't panic, it'll be okay. The long term benefit is worth it. So I'm happy to answer questions and I thank you for your time. Thank you so much Teresa. That was a great summary and really bring us up to speed on a few of the newer agents that are available out there George is not available. So it's going to be on you now to answer any questions about the scenario known. And I actually do have one that I'd like to ask you and maybe it came up also one of the questions with the audience members asked at what point would you recommend? A PCP really referred to a nephrologist for co management of this disease. And and and my question around Fanara known is is that an agent that you think could should be started in a primary care environment. And if yes, at what point, you know, what should the physicians be thinking about that's going on with their disease and say, okay, maybe I've started my ace and ARB maybe I've started a few other things, they're not working. When does Finneran own fit in? Yeah, that's a fair question. I think this study that I showed there was really just in ckd stage three patients. So that means G fr under 60 but greater than 30. So sometime within that range and I think that same range is the sweet spot when adding a nephrologist to your team, your care team for the patient really makes a difference. And there's evidence that has shown that that they can they stay off dialysis longer. They have better anemia, better blood pressure when you get the nephrologist in earlier. They also are less likely to end up with a central catheter and an emergent dialysis start if they get started early. So it's not just me saying that because I love seeing patients that there's some data with that. So I would say I would say to answer your first question once the G F. R. Is under 60 or if the protein area is bad if they have diabetes and they have really profound protein urea, even if they're G fr is preserved, send them over because they could easily have a secondary member in this process or another process causing protein urea that isn't diabetes and maybe a biopsy would be recommended or other treatments. So I would recommend doing that. Um The the phenomenon I think would be the same answer would be once you're getting to the point of G fr under 60 and you're pretty sure this is diabetic kidney disease use it. I don't think you have to be a nephrologist to prescribe it. I think it's a mineral accord accord receptor antagonist. We've been using this type of drug for years. It's perhaps a bit different, definitely monitor for hyper colonia. But I think a PCP could prescribe it, but I'm sure you're the pathologist in your community would also be happy to help. It's expensive. That's that's been my trouble has been the finances of it and actually getting paid for. Yeah. I feel like it's an interesting dilemma with all of these um talks we've had today because We somehow need to intervene a little bit earlier to prevent the later stages. Many of these studies were done in later stages. We don't want people to get to those later stages. So we'll be thinking about things a little bit earlier. Should initiate when they're when they're g fr is 70. I don't know, maybe, I don't know. I don't know how I don't know without evidence, I wouldn't promote anything at this. Yeah, that's how I feel in the same way. Especially drug, you know, I'm I err on the side of caution. So let me ask you if a PCP were to start this, what do you do for the potassium monitoring? Because I have to admit that might be one of the things that someone might be asking about. Oh, I'm going to start this. How should I monitor for? What do I do? So I would it's 10 mg once a day dose. I would do that, counsel them on watching the potassium in the diet and then I would check it a week to 10 days later, somewhere around there and then if stable then again a month later and then routinely just routine. So if you do every three month lab or every six months labs so I'd be on about week one and then week four and then routine unless it's abnormal. So if it's high and you want to try to push through it then you have to intervene on the potassium and then probably check it monthly, something like that. Okay. And if it does go up, are there any recommendations about backing off restarting anything of that sort? I you know, I think if it's severe hyper Khalidiya like greater than 665 you're getting to the seven. That's pretty scary. I would stop it and send to your nephrologist and see if there's anything that can be done. If it's a little elevated. If it's 5557 I would I would usually do some dietary counseling and ask them to avoid potassium containing foods if possible. So bananas, tomatoes, avocados, that kind of stuff and recheck it. And then if if it's still not working then start a binder like petit rumor local MMA any of these other ones that are available pretty readily now that are much easier to take than around the clock KXL it I would do that and see if you can push through it interesting and maybe one last question on this one. You know we've talked a lot about the benefit of SGL T two inhibitors and you did as well. Do we use all three of these agents? If we need to do we start with first the ones that are we have a little more experience with the ace Arbs and STLD two inhibitor or I don't know how do you think about this whole thing? The way I look at it is I use the ones with the most evidence first and then step wise after that. So Ace and our Ace or ARB not an excuse me, Ace or ARB First always unless Angelo demora allergy or something that has decades of data. We know that that is by that standard of care. Not a question after that I would move to the S. G. L. T two inhibitors because there's more years of data it's been shown across the class of drugs that paige workflows and Conagra foods and they all have similar effects. So I would use that next and then I would add probably the Fanara known its patients will see my God these doctors give me a lot of drugs but it really makes a difference. And these studies are additive. These are additive studies that they have additional benefits. So I would use in that order. That would that's just my my preference. I don't think that's a guideline yet but it probably will be seen. That's great. Thank you. There was one other question. Um It might have been related to one of the previous talks but I don't know just a quick answer if you can it says calcium channel blockers can cause a Dema what other choices of medications besides A. R. Bs. And spironolactone would you consider? I don't know if there's just like a one or two? Oh like for the management of hypertension. Sure. Ace or are of course is priority. So I would try to do that or you already Besides that. I would I would do it based on their other clinical scenarios. So you could use the beta blockers if they have especially if they have low ejection fraction heart failure. Um You can use long acting nitrates especially if they have angina hydrology. And at that point, once you're kind of past what the um guidelines are, I try to tailor it based on what side effect I want the patient to have. And don't forget by sides. Either cloth alone for example has been around a really long time and has data and so don't be afraid to use 12.5 for 25 of cloth a lot. Um Okay great. You know one last one just came in while we have you. What cut off of urine albumin would you use for a referral to a neurologist. Um I think that's a fair question in a diabetic. I would expect may up to maybe a gram a gram and a half a day on a spot urine. If you're getting up 2345 g, it's definitely possible from diabetes absolutely can do it. But that's when I start to question other things. Um, And that's when I would consider doing a serological biopsy work up. So maybe somewhere around there in the necrotic range. Yeah, that's pretty. I mean, even a gram a day. I know I think I would probably refer at that point. It's totally reasonable and maybe even a little bit lower if I if I depending on how many medications they're on in other co morbid condition. Yeah. All right, Teresa, thank you so much. It's been great having. It's been a pleasure.