Hello, I am Dr. Sumit Jain. I am a clinical endocrinologist and the Director of Inpatient Diabetes at Rush University Medical Center in Chicago. I've been very impressed over the past week here on the excellent talks we've had on obesity medicine, on diabetic kidney disease, on non-alcoholic fatty liver disease. And I think today's talk will be a great capstone putting together all of those different talks. I have the pleasure of introducing Dr. Christian Mendy. He is a professor of medicine and nephrology at the University of California, San Diego. He is an expert in hypertension and diabetic kidney disease. Without further delay, I will introduce Dr. Christian Mendy. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. I'm very pleased to present this topic. And I also like to point out that this was a cooperation between Dr. Ian Horn and myself. So I'm a nephrologist and he's the endocrinologist. So we tried to put our ideas together. So actually in a perfect way, we both should have been presenting the data, but at this point I will proceed. So the big picture is, as you can see here, is how does obesity cause diseases in so many organs? And are there organ-specific consequences of obesity that actually tell us or gives us opportunities to improve our therapy? There also is a endo-organ-specific pathophysiology that teaches us about disease mechanisms. And is the fat the same in different counterparts and in different organs? And the ABCD, obesity paradigm, is a function of the ectopic fat in organs, or is it the fat itself? So basically I will try to answer some of those questions and the topic is fatty kidney disease. And you can actually say this is akin to what initially fatty liver disease was. And it's proposed to be a new clinical entity because I looked at not just the renal consequences of fat, but also try to combine the systemic consequences and look at fat in its ectopic presentation, what it does to the kidney. And so we know it's present in anybody who is obese with or without metabolic syndrome, but in addition to type 2 diabetes and to metabolic syndrome. So we suggest that the combination of having fat around the kidney, inside the kidney, that means intracellular, as well as having visceral fat, which has major aspects on modulating renal function, that this ectopic fat deposition really deserves to be united, so to speak, and to form a new entity, so-called fatty kidney disease, or FKD. So the objective is to define the disease and then, interesting enough, I said, what does it mean? So why would we just name something FKD if it would not have any implications? And I'm going to show you very excellent data that if your BMI is above 30, not only are you at risk to develop an EGFR of less than 60 or albinoria, which is also a sign of CKD, or actually both, or you can develop hypertension. If you don't have hypertension, fatty kidney disease will certainly make it more difficult to treat. And then uniquely, people are not aware that having infiltration of fat inside the kidney, in the renal cells, the tubular cells, for example, that this actually leads to a worsening of hyperglycemia in metabolic syndrome, as well as in diabetes. Now, to start with, we know that fat isn't all bad. It is very important, let's say, in the cell wall as a structure. It also is very important for intracellular signaling. Fat is one of the key sources of energy by beta-oxidation. And up to a certain degree, the intracellular storage of triglycerides without any obesity being present is a safety for future metabolism. And importantly enough, immunity with inflammatory responses guided by the right amount of fat or fatty acids, the intracellular is also very, very important. So what is bad about fat is the so-called lipotoxicity. And I like to give you the definition that any ectopic deposits of lipids, either intracellular in the form of lipids, droplets, or in the form of infiltrating from the surface of an organ, and it is not inside, the adipocyte really fits the definition of ectopic fat deposition. So fat outside the adipocytes in a major way is ectopic fat deposition, leading to potential significant lipotoxicity. And the cause is clear to us, it's excessive caloric intake. But you also have to realize that the sterile binding protein, we'll get to this a little bit later, is upregulated, for example, in the renal tubules in type 2 diabetes, leading to de novo lipogenesis that also takes place in the liver. And you have increased peripheral lipolysis. So you have multiple other mechanisms to increase your lipotoxicity, leading to dysfunctional signaling and also insulin resistance. So this is just a very plain forward, trying to correlate multiple comorbidities, so obesity and the hyperglycemia and the hypertension and the dyslipidemia with kidney disease. We know in nephrology that adiponectin has major renal actions. We know that people with albinuria and obesity are likely to have a rather low adiponectin level. And you can actually, in animals, very elegantly infuse adiponectin, normalizing the levels, and you actually will reduce albumin, albinuria, because you're improving podocytes, which are, as you remember, the membrane of a glomerulus has an endothelium and basal membrane, and on the outside, towards the bowel and capsule, you have the podocytes, which are key for preventing albinuria, because with their foot prosthesis, they are making a tight net, avoiding the free entry of albumin into the bowel and space and into the urine. So actually, the administration of adiponectin clearly improves the function of the podocytes. We also know that people with obesity have leptin. Yes, they are leptin-resistant, but still, leptin causes the blood-brain barrier, and from a hypertensive standpoint, I find it fascinating that it actually increases your sympathetic tone. The pulse rates in obesity are maybe only three or four beats per minute faster in some individuals more, but it's clearly an increased sympathetic tone, and that is responsible for glomerulus sclerosis. Actually, it's pro-arteriosclerotic in the kidney, in the glomerulus, can lead to albinuria, and also, subsequently, to renal fibrosis and excessive oxidative stress, and, as I already outlined, the increased sympathetic fatigue. Just to give you an idea, from a hypertensive standpoint, a drug like spironolactone has actually an excellent action to reduce the aldosterone levels, which I will mention in a moment, or block it, which actually reduces the hypertension very well, better than many of the commonly used endohypertensive medications. So let's talk about the local RAS system. As you know, the renal angiotensin-aldosterone system is a three-dimensional system. Most of us just are aware that this is a circulating system, but it also has interstitial components, and, very importantly, it has intracellular components. So, for example, the kidney can produce every one of the components. The proximal tubules can produce angiotensin, excuse me. Most of it, of course, is produced by the liver, but the kidney, of course, produces also renin, as well in the major hormones, but also can produce aldosterone. So if you look at the Oedipokines, they have a certain degree of releasing a factor, which we have yet to determine what it exactly is. It has been measured. When the Oedipocytes release that aminoalocorticoid releasing factor, you actually have in the adrenal glomerulosa in the adrenal cortex, it increased the production of aldosterone. So, matter of fact, in hypertension, we know that there's a linear relationship between your BMI and your aldosterone level, and you lose weight, you actually, your aldosterone levels may not be abnormal, that may be high normal, but they come back down to normal. In addition, we know that the Oedipocytes are producing aldosterone synthase, which is actually increased and stimulated by leptin. So you have then an increased release of aldosterone with an increase of aldosterone level as a consequence of a up-regulated renin-angiotensin system. So this so-called hyperaldosteronism caused by obesity is also pro-inflammatory, as you realize recent data on spironolactone and finarinone really show they're impressive on a reduction of inflammatory markers, and their benefits from a renal standpoint are probably highly driven, not by lowering blood pressure with finarinone, for example, but by being anti-inflammatory agents to reduce the production of cytokine IL-6, IL-18, then IL-6-beta, so in addition, the increased reabsorption of sodium leading to hypertension, which we see with aldosterone secretion is an additional factor there. So where do we see ectopic fat outside the Oedipocytes? Well, the best numbers now are from liver disease. We know it's in the muscle with insulin resistance. We, the cardiologists, are very keen now to be concerned about epicardial fat because it mechanically may interfere with the action of the left ventricle, but more importantly, being wrapped around the fat of the coronary arteries, there are cytokines released from the fat tissue directly affecting the endothelium, so there are data now showing there is an accelerated coronary artery sclerosis with increased amount of epicardial fat. And from the kidney standpoint, which is my topic, it is the development and the progression of CKD, and the same is true for hypertension and in a type 2 diabetic, as I mentioned earlier, the aspect of hyperglycemia. So if you look at lipotoxicity and the renal consequences are that the droplets, which are accumulating excessively in the renal tubule or cells, as well as other renal cells, are actually, it's a two-edged sword. If you are obese, your free fatty acids are increased, often by six times, from 0.6 millimole to 10, to six millimole, so it's a 10 times increase, and these free fatty acids are carried from the liver on albumin to the kidney, and there they're reabsorbed from the kidney by diffusion and some by especially a protein which moves the free fatty acids from the albumin into the cell. There's also an issue, particularly in type 2 diabetes, that the intracellular transport of excessive amounts of free fatty acids is impaired, and this is the so-called ABC-1 transporter, which in the last three years has been clearly described to be low, leading to more intracellular fat accumulation, particularly in diabetes. So the bottom line is, the excessive intracellular fat in the kidney enhances inflation. We have a so-called inflammasone that's called NLRP3, which by the way is reduced with the estro-2 inhibitors, just to give you that additional information. That one leads then to a production of IL-18 and also of the IL-1 beta. So there's a whole cascade of cytokine production initiated by abnormal accumulation of intracellular lipids. It increases then oxidative stress because the mitochondria are affected and you have apoptosis, reduced autophagy, so you don't sort of delete the defective DNA and RNA, and basically the combination of the inflammation and the excessive fatty acids intracellular, including, as I'll show you in a moment, ceramide and other products, leads to podocyte injury. And any time you injure a podocyte, you are at risk of developing albinoria and subsequently chronic interstitial inflammation and fibrosis. So what about the epidemiology? What are the human data? The human data show that if you are overweight at age 20, let's say your BMI is 30 at age 20, and you don't have diabetes and you don't have hypertension, you have a increased risk of developing CKD. That means an EGFR of less than 60 or an albumin of 30 or greater. As you know, our new guidelines from Kidego, the kidney guidelines, show that you have CKD if your albumin is elevated of 30 or greater for three months, even with an EGFR of 80 or 90. So there are two ways to look at CKD. One from a standpoint of EGFR and two from a standpoint of albinoria. And of course, many of our patients have both, but you typically start with the albuminuria initially. And so one needs to really pay attention to early albuminuria, even in obesity, even if you don't have diabetes, because that should be treated because it is associated with endothelial dysfunction and a major risk factor if you have albuminuria to have sequential loss of EGFR beyond the 0.7 or one mL per year, which any one of us has who is totally healthy starting age 35, 40. So the normal loss of renal function, courtesy of age without any disease, is about 0.7 mL per year. So obesity clearly is associated with an increased risk of albuminuria. So if I can actually ask all the endocrinologists from now on or healthcare providers who see patients to please do yearly urine albumin creatinine ratios, which we now use as a preferred way to measure. Why do you ACR? Because it's absolute. So whether you take furosemide or your volume is only 500 cc, it is absolute. So it's independent of your urine volume. And this is a risk factor and a component of both the metabolic syndrome and the CKD because they are very strongly linked to each other. So here are some of the data. Pretty impressive, over 3.3 million of U.S. veterans. They all had an EGFR over 60. They were about 60 years old, but their BMI was 29 and many of them was over 30. So they followed them for seven years. Look what happened. 8%, that's 250,000. That's a quarter million of those patients over age 40 who had a BMI over 30, developed a loss of EGFR of five ml per year. This is horrendous loss. This is more than five times the normal loss of renal function. And these were courtesy of obesity. So who had the best outcome? The best outcome was between 25 and 30. So this was the tip off of earlier findings. Then we looked at a elegant Kaiser California study where again, a BMI between 25 to 29 was actually higher than less than 25, but was actually acceptable. But when you got to be above 30, are your risk of developing end stage kidney disease if you had an EGFR below 60? So let's say you were 55 and your BMI is over 30. What is your five, seven year risk of going on dialysis? It actually was three times greater. And I'll show you more data in that respect. So let's just be very specific. Let's look at obesity from a renal standpoint, from the standpoint of how much of a risk is it for you and me to develop an EGFR to less than 60, i.e. new onset CKD. Well, the Eric study is like the Mesa study or the heart study from Framingham. And it showed that if your BMI is over 30 versus being less than 20, you have a 24% risk of your EGFR dropping below 60. And that was in the span of about five years. And we all know the physician's health study, it went 14 years. And if your EGFR was above 60 to start with, you had about a 45% risk if you were, let's say 27 versus 22 BMI. And then we have multiple Kaiser studies. Again, these individuals did not have hypertension. The EGFR was over 60, but they followed them for 25 years. So this is actually one of the really, really quality long-time study. And if your BMI was compared to less than 25, if you are over 30, you have a 3.1 risk. So officially right now, basically, when you teach, I think you can say that if you have a lifelong BMI above 30, in the absence of hypertension or diabetes, you still have about a three times greater risk of your EGFR in your lifetime to drop below 60. So it means that you have a risk of developing CKD just from obesity. So this is a second topic, it looks like, look at people who have an EGFR of less than 60 or albinoia. So what happens to them if their BMI is over 30? In this study called Regards, very nicely looked at this, and they said, if you're 45 and older, and I follow you for four years, and your EGFR, let's say, is around 50, what is your risk of going on dialysis over the four years? And it was essentially two times, particularly if your BMI was above 25, and most of them actually were above 30. And then there was another Kaiser study, lovely done for 24 years, and they compared BMIs of less than 25 with BMIs of over 30, and you can see there was an 80% increase of CKD risk, and over 30 was 3.5. So basically here, that's the number to remember from all these studies. If your BMI is above 30, and even in the absence of diabetes or hypertension, and I don't care whether you have polycystic kidney disease, or you've got just one kidney, or whatever your underlying renal pathology is, if you have an EGFR below 60, you are at risk for progression, and if it's above 60, you are at risk of developing CKD. So this study actually should be 8,500, so the big number is missing, but you always hear these, see these papers on metabolically healthy, that they're pretty safe, so let them enjoy their eating, but you actually, when you look at the data, and this is only three-year data from Korea, and these patients didn't have insulin resistance or hypertension or dyslipidemia, but they had an EGFR above 60, and look what happened. If they compared a BMI with 22, with one which is higher, like a 26, which would be like a 28 in a non-Asian or higher, you did indeed have a 38% greater CKD risk. So in nephrology, we know that being, quotes, unquotes, metabolically healthy, quotes, unquotes, and have obesity still is a risk factor, not only for albinoria, but also for the development of CKD from a standpoint of lowering your EGFR below 60. And so I put together the, from all the literature, and there's about 200 papers actually, all the aspects of renal visceral obesity. So it's like hormonal, the RAS system is elevated, sympathetic system is elevated, leptin goes up, insulin resistance is high, and you have the famous inflammatory cytokines. But something which I found is that if you probe, you put a probe into the abdomen of an obese person, let's say a BMI of 33, their intra-abdominal pressure is actually 40 millimeters higher. So this is, and this is important because it compresses the kidney. In the kidney where the artery, the vein, and the artery go into the kidney, this is what we call the hilum, as you remember, it's a kidney bean-shaped organ, there, there is no capsule. So if you have increased intra-abdominal pressure, at one point, this pressure is persistent on the medulla. It actually is a pressure physically on the distal tubules, and it usually leads not only to increased renin-angiotensin, renin production, it also leads to an increase of sodium reabsorption. So you have a plain physical component. And then, as I'll show you in a moment, that if you are obese, you have to get rid of the extra water, the extra sodium, the extra metabolite. So what you actually do is you're hyperfiltrating. So what is hyperfiltration? We are still arguing in nephrology where it starts. Some say if your EGFR is above 20. For most people, that's probably the right number. But if you're obese, particularly the same for diabetics, type 1 or type 2, in the early phases of the hyperglycemia, in the early phases of obesity, you have hyperfiltration. And the hyperfiltration leads to an increased intraclamerular pressure. We call this clamerular hypertension. Your blood pressure in your glomerulus, if you're totally healthy, is about two-thirds of your arm. So if your systolic is 120, your intraclamerular pressure is 75. The glomeruli are very sensitive to clamerular hypertension. We call it barotrauma. So a pressure of 10 millimeters higher, 85 or 90, that seems only 10, 15 millimeters above normal, is very detrimental. It causes glomerulus sclerosis. It actually expands the size of the glomerulus. Then the podocytes sitting on the lunar periphery are stretched. There's more space between them. The foot processes lose contact, and you start to have albinoia. So you can develop albinoia actually partly also from a physical standpoint by just stretching the glomeruli and creating intraclamerular hypertension. And then, of course, this I already alluded to, the aspect of hyperfiltration. So to summarize, the renal consequences of visceral, i.e. abdominal obesity, is glomerular hypertension leading to hypertrophy, the glomerulus, a decreased density of podocyte because they're moving up, and increased loss, there should be loss of foot processes. So the foot processes are attached to the part of the glomerulus, and as I said, they touch each other, and there's a very fine membrane between them called the slit membrane, and this is where you filter your urine through. So if this slit membrane, like a pore in a simplistic way, gets too wide, then you open the gates for albinoia. It's one of the mechanisms of albinoia. So to summarize, you have a three times risk of CKD if you are obese, and that leads to enlargement of glomeruli. You have albinoia. But then I'm going to tell you a couple of things you're probably not aware of. We have an epidemic of renal cell carcinoma, courtesy of our obesity. I'll show you the data. And of course, everybody knows about the percentage is actually very kind here. It says 60%. There are some studies showing that if you have 10 years or 5 years of obesity, you have an 80, 85% chance of developing hypertension, even without CKD or diabetes. And then, of course, we talked about insulin resistance and the RAS system and leptin, so I don't want to repeat this here. So we have a unique disease. Actually, I saw my first patient in 1980, and that's over 40 years ago. And then I found the article in the Annals. It described obese patients, BMI usually close to 35, who had nephrotic syndrome. And then they biopsied them, and they had a condition which looked very like focal glomerulosclerosis, so minimal changes or minimal disease, and minimal change in the size of the glomeruli and a minimal change in the podocytes. So this was the start of a new diagnosis for obesity called ORG, or obesity-related glomerulopathy. Again, you have hyperfiltration, hypertrophy, and large glomeruli, and you have problems of podocyte dysfunction with albinoia and a loss of a number of podocytes. Here comes the nephrolithiasis aspect. Right now in the U.S., you probably know somebody who has nephrolithiasis, and you're now at one out of 11, so every 11th adult U.S. in their lifetime has a risk of now or has developed nephrolithiasis, and the obesity leads to not more salt intake and intake of phosphates and uric acid or oxalates, but it also leads to insulin resistance. In nephrology, we know if you have insulin resistance, you actually put less ammonia in the urine. So that means your urine pH, if you would wake up in the morning, is 4 or 5, maybe 5.5 or 6. So if you're unlucky that you have some higher uric acid excretion, this is the perfect scenario for precipitation because the lower your pH, the more likely uric acid precipitates out, so you have a very high incidence of nephrolithiasis from uric acid stones, but also from other stones, from oxalate stones, and then in addition, because of the increased food intake, you typically also have a higher intake of salt and calcium absorption, and of course the animal protein. So nephrolithiasis is a real side effect of obesity, and obesity now has become the number three neoplasm associated for renal cell carcinoma. So first by much is colon cancer and breast cancer in women, and I think the third one clearly induced by obesity is renal cell carcinoma. We really don't know the mechanism, but look at the Hawaiian study, which is actually the best. They followed 160 Hawaiians in the Los Angeles clientele from UCLA for 8.3 years, and they saw an increase of the risk of renal cell carcinoma by 76% if your BMI was above 30, so these are the renal carcinoma data. So let's get down to the last couple slides of ectopic fat in the kidney. So where is it? It is retropernil, so it's around the kidney, but let's say it's quite away from the kidney. Then you have it actually on top of the kidney, then it's between the fascia and the capsule, and then you have a large amount of accumulation on the hylum, and that is dangerous because the fat will compress the renal artery, the renal vein, and the sympathetic system, you know, the innervation to the kidney. So you have a physical compression, and then it can extend itself. The fat can actually grow from the hylum along the vascular bundle into the renal sinuses and actually then becomes intracellular visible. So it is both a physical penetration by fat from the outside as well as you heard earlier the intracellular accumulation of fat droplets and free fatty acids. So here are all the pathophysiologies related, so I'm not going to go through all of them, but the obesity-related glomerulopathy is a unique feature of obesity only in kidney disease, and we talked about the leptin and the edible kinds and their importance, and this is just a pathway, if you like, to look at adiposity and the interplay with hypertension and lipids as well as heart failure and hypertension and leading to a risk of albinoia and CKD. So, let's look at the classical pathway of how does actually fat get inside the renal cells. So many, many years ago, particularly from the urine literature, before we really got to fractionate the cholesterol and look at LDL and HDL, some of the clinicians in the 50s and early 60s were actually measuring, believe it or not, free fatty acids. So the data I found was that the normal free fatty acid circulating amount is less than 0.6 millimoles. So if you look at the typical BMI of 30, it's 10 times higher. So their circulating free fatty acids are 6 millimoles and higher, and almost all the free fatty acids are attached to albumin, and that's how they make it get into the kidney. As you know, a small amount of albumin, even in you and me being hopefully healthy, is reabsorbed. So if you have a lot of free fatty acids, the albumin gets reabsorbed, so it gets intercellularly metabolized, and the free fatty acids are there. So this is just one small way of getting there, but most of the free fatty acids are transported to the surface of a cell, the renal tubular cell, for example. There are specific proteins which move the fat via the membrane inside the cell, and there are some other mechanisms we are not so sure of. Some of it is also by diffusion. So what happens? Well, the free fatty acids are a unique source of beta-oxidation and energy. So if you introduce more than what you need, the next step is to make droplets of about 20 mu, and we call them lipid fat droplets. And up to a certain degree, they are wonderful because they're like having them stored in case you need it when you're starving. So basically, a certain degree of triglyceride accumulation in the renal cell is very, very healthy and very physiologic. The issue comes because the renal cell only has a certain fixed size. If too much triglyceride accumulates, it cannot be metabolized, then you start to convert them into potential lipotoxic substances. The first one is thioacylglycerol, and then famously, ceramide. The endocrinologists know that very well because ceramide released is very toxic to the beta cells, but actually is very toxic to most cells too because it causes apoptosis, so the programmed, so to speak, of cell death. So basically, the next step with the ceramide and the abnormal metabolites of fatty acids is to lead to TGF beta, reactive oxygen species goes up, the cytokines and the inflammasomes get upregulated, and you have mitochondrial dysfunction and interstitial renal fibrosis. So basically, that's the pathway of the free fatty acids going into the renal cells, which is totally different from what I told you earlier, that the physical penetration, so to speak, of fat from the hylum into the kidney. So if you want to look at literature, it goes back to Kimmelstill Wilson and to other authors and pathologists from 1883 on, who actually saw by staining fat that several of renal diseases were associated with some fat deposit as you lose, sort of as a scarring-type tissue. But the amounts you see in diabetic lephropathy or focal glomerulosclerosis or whatever disease are rather small. So they by no way compare to the fatty kidney or obesity-associated intrarenal intrinsic fat deposits in the cells. So basically, that needs to be recognized. And now I want to just go specifically and say, okay, how much does fatty kidney, meaning fat outside the kidney at the hylum and excessive fat intercellular in the kidney, contribute to hypertension? You can see from the Framingham study, if you did a CAT scan on the Framingham individuals and you followed them for 10 years, you saw that 30% had higher fat and they were at a higher risk of developing not only hypertension, but they also were at a very high risk of developing CKD, i.e. the EGOR dropping below 60. And then there was another study looking at MRI, which showed that if you were hypertensive, with the higher fat, you either developed hypertension anew or you had hypertension which required two or more drugs. And then other studies I already alluded to is the renal compression of the intra-abdominal pressure by 40 millimeters. But one other thing I found interesting is that if you look at a renal ultrasound or a CT in a diabetic with obesity, and you see a lot of perirenal fat, I'm not talking about visceral fat, but really perirenal fat all the way around the kidney, that that actually predicts your onset of CKD. So it's a very fascinating article. So how much does fatty kidney disease, and this is now intracellular, so it's mostly the intracellular free fatty acids and their metabolites, they actually contribute to hyperglycemia because free fatty acids actually stimulate renal gluconeogenesis. As you know, people talk about it's about a quarter percent when you're fasting, but I want to remind you that after you eat postprandially, the renal glucogenesis is equal to the hepatic glucogenesis. And we know that when you're postprandial, you actually restore the depleted hepatic glycogen stores. So if you say, well, where does the glycogen really come from? Because the kidney postprandially secures half of the gluconeogenesis, allowing the liver to regenerate its glycogen stores. So you have clearly increased glycogenesis converting amino acids, basically, and fatty acids into glucose. But then you also have what many years ago Dr. Randall called the Randall effect or the Randall cycle, that if you offer a renal cell, for example, glucose in an animal setting and you then offer it the fat, it actually prefers fat and then returns the glucose to the circulation. So you actually, with the fatty kidneys, so to speak, you are adding glucose in diabetes and metabolic syndrome to hyperglycemia. So not only does the kidney in diabetes reabsorb 32% more glucose by an overactive SGLT2 receptor, it also adds glucose courtesy of increased free fatty intramenal deposits of fat in insulin resistance. So this is an interesting additional aspect. So how well are we doing with dieting? Well, the initial studies really were short-lived and they couldn't really see much on EGFR. They were only looking at EGFR and if you lose weight, you lose muscle. So you really need to look at a cystatin C or both or combination of both, which is probably the best test. EGFR with creatinine and EGFR with cystatin, you add them up and you divide them by two, you get a much more reliable parameter because you're circumventing some of the interfering components with each other. And of course, the gold standard is thalamates. But the reviews initially clearly showed that weight loss, if you have albinouria, is very important. And the patients we see in nephrology who have nephrotic syndrome, we actually are really trying to get their BMI below 25 because over and over, you can show that the lower the BMI, even if it's 28 or 30 or below 30, that it does reduce your degree of albinouria. So this was an initial study. And then additional studies looked at EGFR. Again, it took a while for them to really start to look. The third study here, the longitudinal study, finally found that there was a reduction of the progression of loss. And as I went along with the literature, we got to more recent bariatric data. And I think they're very encouraging because now the newer bariatric data and looking at this one study was, some studies were going out 14 years. Now we see that if you lose weight, you may actually reduce your GFR loss by one ml, which is huge. So you actually now have less loss. And I'm very sure that additional bariatric surgery studies will clearly not only show a reduction of albinouria, but a preservation of renal function so that you at least level off and only lose the amount, which is courtesy of your aging. So how can we diagnose chronic kidney disease? And Dr. Einhorn reminded me, he said, how poorly 25 years ago, fatty liver was accepted. People didn't know what it was. And if you don't know what it was, you didn't test for it. So you wouldn't be able to make the diagnosis. So we're at the same stage with fatty kidney disease. You should be aware of that. We have albinouria, which you can't explain in a normal intensive non-diabetic obese person. Somebody who suddenly gets an EGFR of less than 60 or loses four or five ml per year, or develops hypertension and is difficult to control. That's probably the key. If you happen to get a CT MRI, I talked to our radiologists here, it's at Scripps and other institutions. Well, they tell me, well, the patient is obese. So I see a lot of fat in the abdomen. They don't make one tittle squat remark about the fat around the kidney. They don't see the fat in the hilum. So I think we need to go down to the radiology department in our obese patient and said, how much fat was there around the kidney? How much fat did you see in the hilum? Because that would be a tip off that your CKD or your albinouria may indeed have to do with the extra renal and indirect intrarenal fatty acids deposits. And I think the Dutch are very good right now. There are multiple studies. Unfortunately, it's very expensive to PMRS. They can actually measure the triglycerides stored in the renal cells, in the renal tubules. So they can actually see for the first time, make a diagnosis of fatty kidney disease by seeing the excessive amount triglycerides. So ultrasound, hopefully in the future, can be evaluated like you do with the epicardial fat. But again, I think awareness is probably the key that anytime you have an obese patient, don't just accept the diabetes or the metabolic syndrome. Think about obesity, particularly if you get any abdominal study, look at the perirenal hylo fat, and then you can actually make the assumption that you likely have increased renal fat. And therefore, you may indeed have diabetes or hypertension and obesity, and also fatty kidney disease. From the animal data, I'm really impressed. There are multiple study on pigs, not on humans yet, and they're all from Europe, and they have a 100% relationship that if they had fatty liver disease, they had fatty kidney disease. So my aim right now is to prove in a study if I get funded, that the patients who have fatty liver disease, if there is a 100% correlation with fatty kidney disease, because that would be actually great, because if you already have diagnosed one, you can then assume or know that you also have fatty kidney disease. Those two, is that in the animals, multiple rats and dogs and pigs, piglets actually, there was a 100% relationship between fatty liver and fatty kidney disease. So what about drugs? TCDs, actually a study, I talked to Dr. DeFranco, and he has lovely studies on the reduction of albinoia. However, none of his studies went beyond a year or two, so we really don't know whether it also preserves renal function. However, nephrology-wise, we know that if you reduce albinoia by more than 30% for six months or longer, you have an impact on EGFR. This was actually for the first time approved as a criterion of renal protection by the FDA in the European nephrology societies and the US societies about two years ago. So I want you to know that if you reduce by whatever method, by losing weight or by using an SJ2 inhibitor, or you're using a mineralocorticoid receptor antagonist, that if you go beyond 30% reduction of albinoia, that you should see some stabilization of renal function just from the albumin standpoint. So the SJ2 inhibitors in animals actually have been pretty impressive, not even reducing fatty liver disease, but also fatty kidney disease. And, you know, it was adabroglyphosin and canaglyphosin. We don't have human data yet. So I'm very encouraged about the dual GLP-1 receptor agonist like Dicepatide and others to come. So if you can lose 15% of weight with any drug, you would have a tremendous reduction of visceral fat, tremendous reduction of fatty liver, and you should also have reduction of hyalur and hopefully intrarenal fat. So that should benefit the albinoia and it should benefit your development of CKD or CKD progression. So in closing early, I wanted to point out that there are major mechanisms from the obesity, which produce not only cardiovascular disease, but also kidney disease, i.e. etiovascular cystic albinoia. And you have direct mechanisms via diabetes, via hypertension, via atherosclerosis, but you also have major indirect renal mechanisms from the aldosterone, renal angiotensin, the intrarenal oxidative stress from intrarenal fatty acid deposits, inflammation, and last but not least, a lower adiponectin and elevated leptin. So at this point, I'd like to finish and close in saying that we suggest to combine all the systemic and the local effects of obesity, a particular ectopic factor position on the kidney and start to call it fatty kidney disease and become aware of it and to integrate this into the spectrum of obesity-related diseases. Thank you very much. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you, Dr. Mende. That was wonderful. I was waiting for you to get to the weight loss data because it's pretty clear that that reduces albuminuria. But as you said, many studies don't document an improvement in EGFR and also might not prevent the predicted decline in EGFR as well. With the exception of that one bariatric surgery paper which a lot of people have kind of glopped onto. Yeah. But if you, when you lose weight like that, you also lose muscle mass and you lose creatinine production. And if you look at all the factors you need to calculate EGFR, you know, that you could explain an improvement in EGFR just by reduced creatinine production. And if you go to the appendix, the supplemental information in that paper, and kind of calculate the degree to which EGFR might be improving because of reduced creatinine, you don't see, you don't really see an improvement in EGFR anymore. Maybe I've got all this wrong because this is not my area of expertise. But I was just wondering what your comments are about that. No, I think everything you said I 100% agree with. I think you need to do a cystatin C because a cystatin C is independent of creatinine. And that's why, you know, I mean, Dan, I actually wrote a paper in the endocrine journal about three years ago saying that if you have major weight loss and you really want to assess, or for multiple other reasons, you really want to assess renal function, do, it's a cheap test, it's another $2, and you use the EGFR formula, and you put down creatinine once, put down the number, put the cystatin C in, and the EGFR formula now from the National Kidney Foundation actually has a box for cystatin. So they finally, about three years ago, added it, and you add them up and divide them by two. Now, of course, if you would do a research paper, you have to do Iothalamate, which is the gold standard. But let me remind you that every drug I've ever seen which made an impact in a positive way by preserving or stabilizing EGFR, it took one year. If you look at ACEs and ARBs, it looks one year. You look at all the estrogen inhibitors, three studies now finished, it took one year to show the difference. You see the albinoria within 60 to 90 days, and then they all stop. So the problem with the old study is they only did creatinine, like you said, and the problem is they didn't go out two years, or one and a half or two years. The problem, anytime you lower albinoria by 30% or more, that's what the estrogen inhibitor, that's what's pheneronone, what spironolactone shows, you lower albinoria, I don't care by what method, if it's over 30% and it's persistent for six months, you have positive renal benefits. So that would, to me, I would say, look, do the cystatin C, do them both, and go out longer. Just go beyond a year and a half and go two years, then you should see the benefits. You won't get it back, that's the problem with CKD. You know, if you have intrinsic CKD, all I can hope for is to level off. Now, if you had uncontrolled hypertension, other aspects, and there was a lot of compression from the fat outside the kidney, you may see improvement. But if you have intrinsic renal disease, lupus nephritis, diabetic nephropathy, you name it, the best you can hope for is to level off, to slow the progression. There is no regression. Okay? I hope that answers. That's a very good comment you made. Thank you, Dr. Mende. I'm Sainthu Reddy from Central Michigan. I have a request and a question. The request is to increase the font size of Dr. Einhorn's name on your introductory slides. And the question is, leptin has been used for lipodystrophic diabetes, where it's at the extreme end of the spectrum, and has beneficial effects on fatty liver. Is there any collateral evidence that there may be benefits on renal fat as well? I'm not aware of it. The only thing I know, these are all animal data. You know, you can infuse in the rats or dogs leptin, and you do the continuous infusion. And I forgot exactly how long it was, but after, it may be a week, or I don't remember the time, you do develop albinuria, okay, from the leptin infusion. And you then, subsequently, the animals develop a nephrosclerosis, so glomerulosclerosis. So there are negative data on leptin, but how much a reduction of leptin by losing 10, 15% of weight has on reduction of albinuria clinically on preservation renal function? I'm not aware of any data, and I really looked into the literature. So the literature is all split up. There's some renal data, there's some diabetes data, there's some in the obesity journals, and there's some in the biology journals from the fatty acids. So you really have to go to four or five different specialties, so to speak, to try to extract this. So nobody has actually put this all together. Go ahead. Yes, fascinating presentation. The question I have is, it's something to show when you have weight loss and that improves in renal function, be it albinuria or CKD. But I would like to see if the improvement in weight in these patients improved the fat deposition in the kidney. So that, because as you know, weight loss has multiple mechanisms which may impact health. That would be a very interesting thing to see. The second thing is, other than the association you are making with fatty liver, are there any imaging studies which would be valid in diagnosing fatty deposition in the kidney? Imaging. You know, I ask, actually I've talked to several, and again, talking to the thyroencephalitis people, I said, look, when they look at abdominal fat, believe it or not, on their CTs, they cut the CT off at the diaphragm because they weren't interested in what the kidney is. So basically, nobody has actually looked whether drug studies which have been done with weight loss, including periodic surgery studies. You know, I listened to the talks before, and I found nothing against the searches. I mean, why should they be looking at renal fat? So basically, one needs to maybe even look at data they have. Or if you do a study, any bariatric study, or you do any weight loss study now when you're north of 10%, you ought to look at the fat in the high lung because we don't have the data. So your point is well taken. I would love to do any company or anybody a study looking at the reduction of visceral fat and correlate how well does it correlate? Because I already was told by one radiologist that visceral obesity has several phenotypes. They actually can see that the fat in some people who have the same BMI with visceral obesity is more concentrated on the liver site, around the liver, or the omentum, and then in others, in another spot, more retroperitoneal. That was complete news to me. So your point is well taken. How do you know that it's equally effective? We don't know. Thank you. So I think we have time for one more question. I think you were first over here. Unfortunately, they're telling us we only have time for one more. I'll be here, I'll be here. So over here. So my question was relating to, you mentioned in the fatty kidney disease, obesity in general that leads to aldosterone excess. And we now say primary aldosterone, once we thought was not as common cause of hypertension, now we say it's 20% of essential hypertension is from primary aldosterone. And I was wondering, have we been just missing these cases? Or was there something else that led to this state where it's more common? And now looking at this, I wonder if the primary aldosterone, many of them is driven by fat in general. You know, I mean, to your point, our aldosterone renal ratio, as you saw from the recent papers in hypertension, is not that sensitive. So here, the way to really go is to salt load somebody for three days. And then your parameters will be, as you said, 10 to 15% or more development. But your point is that if you have elevated aldosterone levels, everybody looks at the adrenal. But if your BMI is 33, you may want to look at the BMI, or maybe it's both. So basically, your point is well taken. I don't have a way to differentiate, but I can tell you from the literature there is a linear relationship between your serum aldosterone level and your BMI. And the renin will be also suppressed. That's right, the renin should be equally suppressed. Absolutely. You can't really tell it apart. No, you can't tell it apart. But I think your point is well taken. So how much is obesity? How much is excessive aldosterone production from other sources? Thank you, good question. I'll come and talk to you. Oh, you wanna, go ahead. Yes, sir. The answer is probably no. The liposuction industry has been around for a while, which results in a redistribution of fat in the body. Do you have any idea of the impact of liposuction on the perinephric fat constantly? I saw one abstract and it was zero. Okay, so, but you know what? This was a very small study of about 12 or 15 patients. So that actually probably needs to be redone, but it showed absolutely zero effect. Very good, thank you for the good questions. Okay, thank you very much for staying on. So. And thank you again, Dr. Mendy, for that excellent lecture.

fatty kidney disease

obesity

fat accumulation

kidney health

clinical entity

intracellular fat

hyperglycemia

inflammation

SGLT2 inhibitors