Reena Gurung, MD reviews some of the therapeutic choices and landmark trials for kidney disease. She also shares common complications encountered and how to mitigate risks.
All right. So our next presenter is It Rina. Yes. Doctor Rina Gang earned her medical degree at Kathmandu University School of Medicine, Medical Sciences in Nepal. Then she completed her residency at Saint Luke's Hospital in Chesterfield, Missouri and her fellowship at Washington University School of Medicine in Saint Louis where she is currently an assistant professor of medicine in the division of Nephrology. Doctor Gurung sees patients at Christian Hospital and Village Square in North County as well as Barnes Jewish West County Hospital. So, thank you so much for speaking with us today and telling us more about chronic kidney disease. Thank you, Nicole. Um Hi, everyone. Um I, I'm very pleased to be uh here today and I picked the topic of SGOT two inhibitors in kidney disease for discussion today. It seems to be everybody's favorite um at the current state of uh you know, sort of treatment modalities we have for kidney disease. And I thought this discussion would be worthwhile and well served to everybody. Um So for in the next one hour, what I would uh like to focus on is the um sort of the unmet needs that we have in therapeutic choices for treatment of diabetic kidney disease. Uh We'll go through some of the landmark trials that's uh has uh that's available out there, which led to the practice changing um, guidelines we have in terms of treating diabetic kidney disease. We'll go through the indications of scod two inhibitors and the complications that frequently arise and how to mitigate them. Um So just going through the um sort of the epidemiology of kidney disease, um it is a well known fact and we um as nephrologist and obviously PC PS and everybody, we know the uh the urgency of the matter here with rising incidence of kidney disease um over time and it's very worrying that one in 10 people um do have kidney disease of some extent at the present time, especially common in patients with diabetes in hypertension, racial minorities, women and the elderly. And in 2040 it's predicted that it will be the fifth leading cause of death of. And um it is uh certainly quite worrying and just for um information, it's the, it's the top 10 causes amongst the middle and low income countries um as published in this kidney international paper. So what choices do we have and what, what are we going to do in order to hopefully uh di divert this fate of kidney disease and, and it's uh devastating consequences. Looking at the timeline and the history of the treatment we have for kidney disease. Unfortunately, there, there isn't much. Um There were a couple of studies back in 2001 and those were the first studies that showed uh the, that A RBS were um a good preventative measure for kidney disease patients. It looked particularly the herb sartan. Um and Losartan proved that it is associated with decreased risk of kidney disease progression. And that's which led to the uh subsequent uh change in practice and are using so much of the A RBS and then not much happened until the last decade. Um The blue boxes are the SGLT two trials that uh that uh has emerged over time and the um pink ones are the Children know studies that you must have heard about and maybe uh using your practice too. I'm going to focus on obviously, the STLD two inhibitors today and particularly I'd focus on the Empire reg um the AG glyphs in study the DPA CKD Dags in and the credence the cano glyphosate. So as you can see, uh not essentially nothing for diabetic kidney disease until 2015 when these studies emerged. And um I, I think we are at a better for sure in terms of um our treatment choices. So I'm gonna switch gears and talk about sort of honing at the molecular level. Now, at the um level of the single neph, what actually happens in a healthy situation and in a, in a, in a diabetic uh circumstance of diabetic indi diabetic kidney disease. Um So in a, in a hilly glomerulus, um we have the blood flowing in through the artery and gets filtered through the basement membrane. The uh glomerulus, the capillaries gets filtered through and the urine comes out um from the tubal over here. In normal individuals, the patency of the blood vessels, the Afrin ephrine artery is preserved, the wall is preserved. The basement membranes are preserved the sort of the thickness of the glome or basement membrane. This is a chamber of the glomerulus where you know the proteins are kept in the un unneeded electrolytes are filtered through. It's all well preserved, um especially the food process are nice and intact. Um The diaphragms are intact as well and the there is there's no float uh album in being filtered out. Whereas in diabetic patients, the uh some of the pathology that happens is that uh the architecture of the it's not shown here, but there's a lot of hyaline deposition in the blood vessels. There is a lot of mis angel deposition and the foot process. There's a lot happening in the basin membrane too. There's thickening of the basement membrane. The food process gets distorted, detached. Um The which is the cause for albuminuria, the the the negative um the negative um sorry blanking out on the words, there is less negative chart in the a lot of album and leak as well and a lot of album gets filtered out and what does album tubes are not used to getting so much album and it actually leads to downstream damage in the tubular epithelial cells. And um over time causes scarring, fibrosis, atrophy, um and so on and so forth in terms of the classes. Um So initially, there is base memory thickening alone, mis angel expansion, nodular sclerosis and the ultimately would be diabetic glomerular sclerosis. When there is, these gloms are just full of scar and they are nonfunctioning and essentially leads to decrease in the total number of functioning nephrons in the kidneys. And that's what happens when they ultimately end up in renal failure. Um Just some images. Uh This is a silver Jones image uh of the glomerulus. This is a healthy glomerulus and you can see these um capillaries. These are nice and open here happening here. But in comparison to the diabetic meus here, there's a lot of mis angel matrix deposition. This is all highline mostly. Um in the earlier stage, the artery, the blood vessel wall is thickened as well. Um A lot of hyaline deposition. This is the chemo steel Wilson nodule, um damage to the Bowman's capsule here, more hyalinosis here that, that you can't even see the inside of the tubal. And in the electron microscope just wanted to highlight here how the basement membrane is thick and unhealthy. The food process are all used attached which is called a food process at face. Um and the foot process is detached as Well, it's a lot of damage at so many different levels um in patients with diabetes. Um so sorry, the transition is probably not smooth here. But so I'm gonna go back to SGLD two inhibitors with that sort of knowledge of diabetic disease in mind. Um Scod two inhibitors were first discovered in the 19th century and it was found in the bark of apple trees. They found the chemical fluorescent um hence the, you know, kolya zine uh dagli. And initially it was used to treat malaria. Um However, it was discovered later that it actually in, in it actually decreases inhibits the reabsorption of glucose in the kidneys as well, which led to um the trials that we have in current time, its indications uh commonly are I'll go through this later too. But in kidney disease, diabetic and non diabetic in cardiovascular disease and in diabetes. So uh I'm gonna talk, there are so many trials like you saw in that timeline slide, but I'm gonna talk just uh the three major um studies that uh was so helpful in the spectrum of kidney disease, diabetic kidney disease. The first pre trial um this was around 2017, 2019, uh first double blinded randomized controlled trial and they collected good cohort of patients around 4000. Um the stage of C they all were diabetic. So this is a, this is a one distinguishing feature. They were all diabetic. So this was only diabetic kidney disease patients. GFR was pretty not so bad, 30 to 90 ML. So I would say stage you know, 2 to 3 and they were all maxed out on the ace and Arbs before randomization and uh randomization was either the Kozin, sorry, the brand name is Invoca invoca or placebo. And what they were trying to look at was the doubling of serum creatinine, the onset of end stage kidney disease or death cardiovascular or kidney cause. And the outcome was fairly in favor of the Invokana group and the incidence of end stage kidney disease was also favorable for the invoca group. They actually ended the study early because of the treatment. Uh because the primary outcomes were achieved uh within two years. Time of note, this is of note, there was no increased risk of amputations or fractures in the Kano Glyphosate group just to give you a background, Kolya was initially a bit of a worry for everybody because of this. So uh because of increased risk of amputation, but that was in the earlier study canvas that was not duplicated on on this trial and the subsequent trials turns out. So that is this is credence favorable in favorable towards Koly was the second study is CKD. Um The drug Dag Ghos brand name is the Fara this was multinational Multicentric study. One step ahead this studies studies, a step ahead of the other one because they involved patients without type two diabetes as well. And they went a little further with the stage of CKD, they went down to 25. The first one was 30 a little bit sicker patients, more uh sort of variety of kidney disease. And the randomization was patients with dapagliflozin and placebo. Um And the mean follow up was 2.5 years and in that duration, what they found was statistically significant um favorable outcome in terms of, again, similar risk of decline in GFR onset of kidney disease and death from cardiovascular renal cause less of those parameters. Less in DALY is in group, if you remove the cardiovascular factor, still less in depo glyph in group. And um all cause mortality also less in tagine group. Of note, the incidents of DK A, there were two in placebo group and non in DPO glyphs. So again, a a really good outcome and since they did not, since, since there were patients without diabetes. And of course, this was in the early days they use SGLD two inhibitors in patients without diabetes. And naturally, one would ask whether there was hypoglycemia, but there was no severe hypoglycemia in patients without type two diabetes. So just of note here and the last time I'm going to talk about the most recent one is the impact glyphosate LYP. Brand name is Jardines. This was similar to the uh the Multi center, uh multiple countries double blind. Again, this is another step ahead of the last one in that they included, they went further down in the GFR down to 20. So anybody with a severe CKD, I would say this is stage 4338 to see uh stage four, any degree of album Inia would be qualified. And if it was a milder stage, they had to have at least 200 mg of album Inia. Um randomization involved um lysine 10 mg or placebo and their primary outcome uh was similar to prior study, security progression and death. Uh They added hospitalization from any cause hospitalization from heart failure or death from cardiovascular and death from any cause. The first two parameters, especially uh security progression and hospitalization. There was a statistically significant um out was in and the hospitalization and death from all cause was not significant. This is another uh sub analysis of the same studies, polypus in uh r the other was um impact kidney. This is empire the they, they were primarily looking at the cardiovascular outcome, cardiovascular outcome and mortality. But I just wanted to bring this up to show you that the reduction in HB A one C was very mild, very mild uh upon initiation of 10 mg of jardines. Uh 2025 they were, they were subgroups of 10 and 25. The reduction was only 0.5% after three months um and 0.6% respectively. So it's, it's not, it's not a main um it's gonna reduce the HB one. So I just wanted to highlight that and the the reduction in blood pressure was about five M mh G. So just to recap the studies that I uh briefly highlighted here, Creedence Stacy in emacs kidney um just wanted to highlight the empire is the one that went with the most severe CKD patients. And both DC KD and is looked at patients without diabetes and all three of them had favorable outcomes in terms of re re re postponing the onset of kidney failure and delaying the onset of um sort of retarding the progression of kidney disease. So, that's a lot of kidney disease discussion here. But um overall other indications of CS CL two inhibitors are in congestive heart failure and uh type two diabetes. Although as I explained to be a one C reduction is only 0.6 to 0.9%. There's some uh weight loss, 2 to 3 kgs. But it platos after that uh reduction, atherosclerotic vascular cardiovascular disease, um diabetic kidney disease and non diabetic kidney disease. Um and, and when I say non diabetic kidney disease, these were ischemic nephropathy. Um IG and nephropathy, FSGS, chronic pyelonephritis and interstitial nephritis, not the primary glomerular disease like lupus nephritis and vasculitis. Those were excluded from uh these trials and also not recommended in general, especially not in the acute proliferative phase. Um So I'm going to step into the physiology of proximal tule before um transitioning to the mechanism of action of sco due to inhibitor, proximal tubule is almost like I would powerhouse of the of the ephrine. Um There is a lot of glucose absorption happening here. 90% a lot of uh electrolytes absorption happening. So there's, it's a lot of ox ox oxygen consumption as well. And it is where the sgld two channels are present in the apical side of the um proximal tubes, tubules. Um and it is upregulated. Those channels are upregulated in diabetes, diabetes due to just this constant influx of glucose in the urine. Um because of hyperglycemia, there is a negative feedback causing hyperfiltration. Um So there's a lot of pressure on the proximal tubal in diabetics at any given day. The filtered glucose load in the kidney is about 1 80 g per day. PZ stands for the fluorescent, the main component in inhibitor, most of the glucose gets absorbed reabsorbed, but in the presence of florin, most of those are inhibited and it goes downstream in the urine. So there is very less absorption happening. So this this these are very potent drugs here in in the setting of normal kidney function as the urine just uh a graph showing as the urine passes from the glomerulus down to the tubal to the collecting duct. The concentration of glucose falls and the most the sharpest fall is in the first few millimeter which coincides with the proximal tule because it's all reabsorbed. So moving on to the mechanism of action of SGLT two inhibitor. This is a diabetic nephron and um just wanna run you through here. Step by step, the affluent artery brings the and gets filtered here through the woman's capsule and urine is formed. This pink squares are uh are the um sort of glucose molecule for this diagram. And the green are the chloride. In any case, a lot of glucose and sodium and chloride are being filtered at any given time. Assuming this patient is hyperglycemic and the proximal tubule tries to reabsorb it all. So that's a lot of work going on. There are a lot of a TP a lot of oxygen and um what passes on distally is not a whole lot. So what is called dis decreased distal delivery of the sodium and glucose? And this in turn causes reduced feedback to the macular denser. And it's as if the tubal are saying we're not getting enough fluid, not getting enough blood supply. And the, and the next step is ephrine artery starts to dilate because of negative reduced feedback to the macula denser. And this is not a good thing because then more uh filtration is happening. This is called hyperfiltration injury will set in after a certain time. There's a lot of intra increase in interglobular pressure which will just damage the basement membrane. And you know, just, just a lot of whatever we see we saw earlier, it will be just enhanced and at at the proximal tubal level. Also, like I said earlier, there's just increased burden, increased work burden here, increased hypoxia and over time, it will just scar and fibros. When you throw in SGLT two inhibitor. In the picture, the change that sets in is that the inhibitor will block the SGLT two channels. And it's almost like a loop diuretic that there is increased distal delivery of sodium and glucose. And this time the macular denser will sense this increased flow of these glucose and sodium and will tell the artery to constrict. As a result. There is not much filtration that is forced upon in that Nephron. Hence, reduction in the pressure within the glomerulus and reduction in the subsequent damages that would have set in. So that is um the key um mechanism of action of scld two inhibitor zooming out at a whole system level. Um As you can see, there is a lot of sodium that gets past distally, a lot of glucose. As a result of that, there is a diuretic effect, uh almost an osmotic diuretic effect. And as a result, there is reduction in blood pressure, uh reduction in the whole process of arterial stiffening atherosclerosis, improve c although not a whole lot, but there is still a small improvement. A one C um because in itself it acts like a diuretic, there's decreased need of loop diuretics in these patients. Although um um concomitant use is not, is not a bad idea either. But there's decreased risk, um decreased polypharmacy sort of um decrease in the intra glomerular pressure, which is key to the longevity of this nephrons. So there is that there is decreased passing of the, when there's so much album going downstream, it da it is damaging to the tubal. So there is not much tubular atrophy happening. Um and uh and subsequently um sorry, these are not so important but these are the blood pressure, weight, preserving the neph and the die effects are the key advantages of this drug. I just wanted to highlight that what they've also found is interestingly, the fluid mobilization because this acts as a diuretic is actually from the interstitial space rather than intravascular space. The common diuretics, you know, furosemide, hydrochlorothiazide, they, they uh mobilize the food from intravascular volume. So I think this is a win win situation because you are able to, we're able to diurese them without compromising their blood pressure, their intravascular space. Um just briefly going through. Um because uh besides kidney disease has uh prominent advantages in the cardiovascular uh realm of things as well. And especially in terms of left ventricular remodeling or with a similar concept where there is because of the reduction in blood pressure, there's reduced preload, there's reduced afterload and the left ventricle doesn't have to heart. So there is less need for hypertrophy. Um there's decreased inflammation, necrosis and um and um reduce remodeling, effectively reducing the uh preserving the ejection fraction. Um and um atherosclerotic coronary artery disease as well. The um sgot two inhibitors that we frequently encounter in our practice are the three kinds, the invoca far ziga jardines and there are other types too. But I, I feel like these are the three, these three are the ones we mostly use. Uh bio is really good on these, all these agents. And although the studies were very, they did not, the three trials I discussed were very specific to each drug class. But the benefits are uh throughout all commercial classes. And um I would, I would, you know, I would, the, the only I, I would not prefer one over the other unless the insurance uh chooses to. So any of these would be a good agent to go for um as needed as as and when needed. So, um since we have so many good things about SGDLD, two SGLD two inhibitors, we should also be aware of the safety concerns that it brings uh mainly the Egfr tip uh hypertension. I mean, I, I added this, it's not necessarily, but I think it's a practical concern we encounter in these patients hypoglycemia, euglycemic DK, a genital mycotic infection, ut I and amputation. Let's go through them one by one. So the EGFR dip um or the creatinine bump happens the first few weeks after initiation of the uh SGL to do anything better. And this is mostly hemodynamic mediated as you can imagine what the nephrons are going through. Once the SGO 22, he started mainly, I would say there is volume shift for volume depletion and it just needs time to stabilize. So just because the GFR dipped or create it bumped is not an indication to stop the drug. But how, how far are you gonna wait? If the, if the uh let me just go through here in order the, the GFR did more than 10% was mostly seen. There was mostly common in patients with who are also in other agents, other diuretics um also in, in seen also in individuals with lower EGFR to start with and patients more than 65 years of age. This was the finding in the Empire reg uh analysis. But this is the rise in creat is not necessarily associated with, you know, earlier onset of kidney failure or uh cardiovascular adverse effect. This was, this was not associated in the post hoc analysis of the Java CKD. So what, what do we do for these folks? Um My practical recommendation would be to follow up physical, follow up, not virtual, physical follow up in 2 to 3 months after initiation of scod two inhibitor to go through their overall health status, their appetite, their hydration status and to clinically examine their volume status. If the GFR dip or the creatinine bump is more than 30% then I would advise being cautious with those folks maybe a frequent follow up advise hydration and gotta be careful in patients with hef ref but um increase hydration than their baseline um and adjust other antihypertensives as needed. Um Look at the blood pressure and if it is, you know, already 1 10/80 or what, maybe we should peel off that hydrALAZINE or the cloNIDine um here and keep going with the SGOD two inhibitors and last but not the least. Um in kidney patients, when you start the scot two inhibitors, please start with the lower dose. Um that I showed over here, the renal dose, it does not, it's always beneficial to start low and go up as they tolerate rather than the other way around. The other concern is the hypoglycemia. It is not very common, but uh it can be of concern because especially in those folks who are already on other hypoglycemic agents like insulin and sulfon area. And the way to get around this is perhaps reducing the dose of insulin by 10 to 20% if you're going to um SCLD two inhibitors and keeping an eye on the HB A one C closely again, in patients with those risk factors such as advanced CKD, more than 65 years of age perhaps start with a lower dose of SCLD two inhibitor because we don't know how they're gonna respond. And anyway, in CKD patients, the insulin requirement is less because it's not metabolized as fast as in normal kidney patients. So they automatically there a once it starts to improve in kidney patients. So all the more reason to cut back on the insulin um in, in, in those patients, um the euglycemic DK A is I think the very popular uh popular in terms that we are always very vigilant about this. Um So what, what this is is when there is the blood glucose is normal but there is still ad K A. Um the process of DK A happening, it is mostly seen in patients where there's abrupt withdrawal of insulin and insulin dependent diabetes. Patients are starving, they are not eating healthy diet or keto diet or consuming keto diet, acute illness and in alcohol consumption. So, uh we can get we the way to fix, this is not to stop the insulin abruptly, yes, reduced by 10 to 20% but not to stop abruptly, especially if they've been insulin dependent for a long period of time. Um On that fall first, follow up visit, maybe get a urine dipstick to see assess for ketone bodies. Um and also just on that physical exam, talking to them and finding out if they've been eating healthy, if they've been hydrating, um would be a good way because Dkaedk will not have the, you know, symptoms may be vague, uh tiredness, uh lack of appetite, those may be the vague symptoms. So trying to go through that would perhaps be helpful to the patients. Hydration is uh important as I said, uh advice, I would advise against keto diet um altogether in patients on SCL due to inhibitor. And if they become ill, if they are in DK A perhaps holding the medicine for a week or two until they are back to their baseline state of health would be advised advisable. So just the process of DK I think is a little bit interesting here as you can, as you know, the SGOD two inhibitor will call glycosuria natural uresis. And um because of the, because of the reduced circulating glucose, there is decreased need of insulin secretion by the pancreas. And this causes the adipose tissue to undergo lipolysis and free fatty acid is generated which the liver turns into ketones. So there is a lot of um um floating ketone bodies around which causes the ela DK A um final few genital mycotic infection. And UT I most commonly seen in type two diabetes. Um and but in the randomized control trials, there was no significant like severe form of UT I. That was that was seen, the advice that I came across in uh most of the papers were just routine proper hygiene, perineal hygiene, especially at night, rinsing. Um before bed at night had been shown to reduce the incidence of UT I. Uh fluconazole may may be necessary in some patients with genital yeast. Hydration is important again and termination is not usually necessary. Just a caution is uh in selective folks who have obstructive uropathy um as you can with stones or um or such or maybe malignancy. Um The theory is that this glucose urine uh which is stagnant in the setting of obstruction may be a, you know, favorable environment for the bacterial proliferation. So perhaps it in patients with active obstructive uropathy, uh avoid stod two inhibitors in the, especially in the acute setting until the obstruction is released. Relieved, lower limb amputation was very, again, a very um much of concern initially. But that was only in the canvas trial. It was not reproducing the credence trial. Although both trials use the same drug koly phos in the risk is essentially no, no more than in usual diabetic patients. Look for risk factors, prior amputation, diabetic ulcers, cardiovascular disease, age more than 65 and those with lack of foot care. So just like in any diabetic patients, proper foot care, foot examination would be advised to reduce the risk of amputation because it's not necessarily drug. Um I'd like to emphasize again, this has to be held during sick days. I I don't personally think this is a medicine that should be started when patients are hospitalized with pneumonia or sepsis. Uh We should hold on that on that sort of on that temptation to start them. Um because their hydration status is not good, they're just orienting is not good. Uh Perhaps wait until they are stable and the outpatient um in per operative period also advisable to hold this medicine. We talked a lot about SGL due to inhibitors in uh kidney disease. But I just wanted to um bring you back to the main, the low hanging fruit in reducing, in retarding the progression of kidney disease. However, is always is HB A one C um Every attempt should be made for the HB A one C to less than 76.5 to 7 in order to um lessen the progression of kidney disease. And S CO2, 2 inhibitors are great in reducing the glomerular pressure, all that but not, it does not reduce the HB A one C. So we should make every effort to reduce HBO NC with whatever agents we have out there. Um I know this is primarily endocrine endocrinology focused, but KD go has also a guideline for type treatment of type two types in kidney patients. And um just briefly going through of course physical activity and nutrition, weight loss is advised on all patients. Um but Metformin, I just wanted to bring this up uh when to discontinue Metformin, obviously not in dialysis patients. We cannot if there are stable CKD who's been on Metformin forever. Um And the GFR is stable, OK, to continue with just with utmost caution, but in general, not advisable um to start new on patients, less than 30 GFR and less than 45 should reduce those. And the other first line is SCLD two inhibitor we do not use it in dialysis patients. And the general advice is to not use in GFR less than 30. But if you recall the lysine jardines was used that study. They used it in G for as low as 20. I think I, if you feel uncomfortable, this is where a nephrologist consult, nephrology would be warranted. Um, I have used, I have used, um, SGLT two inhibitor and a brand new patients with GFR 18 to 20. But those were, they were very reliable, young adults who would test every two weeks even if needed. So, it depends on the patient population as well. But I think GFR less than 30 is when a nephrology should be on board um to sort of uh determine the eligibility of SCLD two inhibitor uh other agents. Um GOP one agonist, Trulicity Ozempic. We go v uh Well, that's for weight loss but GP P four, all those in conjunction should be used in concert to reduce the HB A one C. Um just to recap the current uh meds we have at the moment. Um Invokana Kagle was in Fara and Jardines. I have seen Steglatro being used as well by some endocrinology, but I, I've never prescribed again the, the with the recent um approval and it's become easier to prescribe, but I find have their own preference and I just go by whichever the insurance would approve. That's the easiest way to go around. Um I think I already discussed this. But just please check the renal function panel 2 to 3 months after you first start the uh S CO2 2 inhibitor. Keep an eye on the blood pressure volume status. Hb A one C if the blood pressure is low, cut back on the other agents first encourage hydration. Um and be aware of the risks, explain the risks to the patient. Um depending on the severity that it doesn't necessarily need to be stopped, but perhaps um held and restart when they're back to their baseline health because of the numerous advantages it has in the longevity of the kidneys. So I'm coming to the end of the talk um to wrap up. Um Please consider using SCLT two inhibitors in diabetic and non diabetic kidney disease, except except anco vasculitis, polycystic kidney disease, lupus nephritis and type one diabetic. Um I would, I would not use in those people. I have seen endocrinologist use in um type 1.5 the more di diabetics, but I, I wouldn't do that. I don't have the expertise. Um avoid use. I've said that um and please, in kidney patients, renal patients, please don't go full dose. It's very difficult um to come back. We lose their confidence and just more complications, hospitalization. So let's start on the lowest dose. Um and go up if they tolerate the GFR drop is only natural as we discussed. But if the drop is more than 30% and given based on the clinical situation, um you may have to hold the dose or just go through it with closer monitoring and increasing hydration and adjustment of other me. And that is on the end of my talk, please. If you have any questions, feel free. Thank you so much, Doctor Guon. Appreciate your talk today. Thank you. Yeah, I'm not seeing anything yet in the chat or in the Q and A But um if anyone has any questions, uh you can always email me or um, put in real quick, but I can always get those to Doctor Gang and have her respond for you. Well, thank you very much, Doctor Gang. Oh, yes. Somebody said thank you so appreciate your time and enjoy the rest of your day. Thank you so much. Absolutely.
