Fatty Kidney and Obesity

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Hi everyone, I'm Volkan Yumuk, I'm a clinical endocrinologist and today I'm representing the European Association for the Study of Obesity. As you see, this is a joint meeting with a sister society that is the European Renal Association and the topic we chose is fatty kidney, which is a very interesting topic open to clinicians and for researchers. Our first speaker is Trond Jensen from Norway.

Professor Jensen is a senior consultant in the Department of Transplantation Medicine section of Nephrology, University Hospital of Oslo, Riksjov-Pitalet Hospital. He's a professor in kidney disease, Faculty of Medicine, University of Oslo, Professor of Internal Medicine, Department of Health Science, Arctic University of Norway, Tromsø. His recent contribution to practice, occurrence of diabetic nephropathy after renal transplantation despite intensive glycemic control.

Trond, the floor is yours. Thank you very much Volkan and thank you also to the association for inviting me to this meeting. I have the pleasure of talking about adiposity and overweight kidney disease, actually, and this is part of a discussion that we had in the diabetes group, which is part of the European Renal Association back in September this year.

So before I proceed with my slide deck, I just want to give you my conflicts of interest that may be relating to this talk. The next slide, unfortunately, is with Norwegian text, but it gives you just the outline of what we are talking about in terms of kidneys, kidney disease. Each kidney actually consists of about 1,000,000 or 750,000 micro kidneys, the so-called nephron with the glomeruli here and the tubular system or distal to the glomerulus.

Each kidney with about 750,000 or 1,000,000 nephrons, two kidneys altogether, 1.52 million nephrons. And every time you see a patient which, a patient who has declining renal function, that is because there are nephrons disappearing and the other nephrons will have to take over the work. So the main part of my talk is going to be related to the, in terms of obesity and kidney disease, is going to be relating to the phenomenon of hyperfiltration.

This is just a drawing of the nephron, the glomerulus to the left. And here you can see the proximal tubulus with a now, nowadays very famous SGLT2 reabsorption system of glucose and sodium, and then the more distal tubular system. We are in a position that even if glucose is filtered from the glomerulus, most of it is reabsorbed proximally in the proximal tubules.

So we actually produce no glucose in the urine. There are at least three instances where hyperfiltration in the glomerulus can take place. One is, as I just said, that nephrons are falling apart, they are disappearing, and maybe 60% or 50% or 40% of the nephrons will have to take over the work.

That will naturally lead to hyperfiltration in the remaining glomeruli. The other reason which may complicate this and even increase hyperfiltration will be diabetes with hyperglycemia. If you have hyperglycemia, you filtrate more glucose into the tubular system, more glucose is reabsorbed to go in together with sodium in the proximal tubules, and that makes changes in the sodium flux in the Hennell's loop, which actually leads to dilation of the afferent arteriole in the glomerulus and also hyperfiltration.

So not only few nephrons, but also hyperglycemia by itself will lead to hyperfiltration. The third reason could be that the body mass increases. With obesity, there will be an increased filtration challenge for the remaining glomeruli.

This of course will be deteriorating and even more expressed if the patient not only has obesity, but also diabetes and maybe even falling GFR, which means loss of nephrons. That is the picture that we are going to talk about. If you want to have some insight into the concept of hyperfiltration, this is the famous paper by Barry Brennan and co-workers back in 1996, which actually presented the concept of hyperfiltration as a cause of kidney disease, at least when kidneys are failing and GFR is falling.

Now, there's another important paper I want to focus on, and just to mention this paper in the beginning of my talk, a review paper back in 2016 by Delgatti and co-workers in Nature Reviews Nephrology. This is a very detailed and very good paper describing what can happen in obese persons with damage or deteriorating kidney function. The main thing is actually that when you have obesity in a patient, not overweight, but rather obesity, there's an increased filtration challenge in the glomeruli.

So these are actually biopsy pictures from obese and non-obese persons, taken for some other reason. But you can see that in the obese person, the glomerulus looks enlarged, it's hypertrophic as compared to a non-obese person with a more normal size glomerulus. You can even see here down at the bottom of this glomerulus from the obese person, it looks like there's some hypertrophy in the arterial wall.

And the changes may be even more expressed inside the glomerulus with segmental sclerosis when glomerular changes take place when this hyperfiltration stands over time. And to the right, you have also an enlarged glomerulus from an obese person, and you can see a dilated arterial with hypertrophic walls that may indicate that hyperfiltration, hyperplasma flow is taking place. What is the mechanism behind this? Well, we know also in the kidneys that there may be ectopic fat deposition, but these are mainly studied in animal models because we do not really have any non-invasive method of studying lipid deposition in kidneys in real life in humans.

But this paper actually presents some interesting mechanism that I will come back to during my talk and by the end of the talk. They discuss the probability that lipid toxicity and maybe lipid effects may take place also in the kidney, not only in the fatty liver and other places with ectopic fat deposition. Triglycerides may actually be a common denominator here.

Increased triglycerides in epithelium of the tubulus or even in the podocytes that epithelial cells of the glomerulus and also in the mesangium surrounding the capillary vessels. Increased deposition of triglycerides into the kidney may be caused either by increased fatty acid synthesis, increased fatty acid uptake, decreased fatty acid oxidation or decreased lipolysis. And this is part, as I will come back to, probably to as a picture in the metabolic syndrome where hypertriglyceridium may take place as a rule of the thumb.

Now, going back to obesity as total body obesity, the original notion was, as you can see, already back in 2006, that BMI may be detrimental. At least it's associated with increased risk of end-stage renal disease. This is a huge population study from Kaiser Permanente in the United States.

Altogether, 320,000 persons studied for a total of more than 8 million person-years, which means an average follow-up of about 20-25 years. And they could record 1,471 cases of end-stage renal disease during follow-up. And as you can see here on this x-axis, with a reference for the risk of end-stage kidney disease being with a BMI between 18.5 and 25, there is a progressive increase in the occurrence of end-stage kidney disease with increased body mass index.

So that sort of supports the notion that increased body mass as a whole could be detrimental for the kidney function over time. We do not believe, I think, that obesity itself will cause kidney disease, but obesity itself could sort of be progressive for kidney damage that is there already, maybe because of hypertension, diabetes, or other kind of kidney diseases. However, not all studies can confirm this finding that body mass index is a major factor being associated with decreased renal function and end-stage kidney disease.

In the Framingham study, for instance, they could not confirm these findings. Fewer persons, I admit, but they studied the risk of developing stage 3 kidney disease, which means GFR less than 60, meaning that kidney function is reduced by at least maybe 40% in these persons. And as you can see here, in several subgroups, in the overall group to begin with, there was no clear association with overweight or obesity in these patients.

And even if you studied subgroups like those without hypertension, those without diabetes, those without cardiovascular disease, same phenomenon. There was not an association with body mass index and the risk of developing stage 3 kidney disease. Later on, not later on, but a bit earlier, but this is a cross-sectional study, the PREVENT study from Holland by Pinto Sitzmeidt co-workers, come up with a concept that maybe it is not the peripheral obesity that is detrimental for the kidneys, but maybe it's primarily the central obesity, not distinguishing, of course, between subcutaneous adipose tissue and visceral adipose tissue, but the central obesity seems to be more predictive of diminished real function over time.

So here you can see the correlation between increase in waist-hip ratio and the relative risk of diminished filtration among quarters of waist-hip ratio. So this was a cross-sectional study in patients without diabetes, and it made some of us believe that maybe it's not the obesity itself, the peripheral obesity, but maybe more obesity related to the central part of the body. And this was also confirmed in a follow-up study, a rather large follow-up study published from Boston in the United States back in 2008, the so-called atherosclerosis risk community study, studied 30,000 persons with a mean follow-up of nine years, and they looked at the incident decrease of EGFR of at least 15 mLs per minute corrected for body surface or developing stage 3 kidney disease.

And as you can see from these two graphs, there is no relationship between body mass index and the risk of developing decreased GFR, but there is a linear relationship between waist-hip ratio and the phenomenon of decreased real function. And this leads me to a paper that is standing on its own feet, but has been forgotten by many endocrinologists. Personally, I'm an nephrologist, but with a special interest in diabetes and metabolism.

And what this paper says is that they studied actually altogether 1,146 white men and women, a study published in General Clinical Investigation in 1997, and all these 1,136 persons underwent state-of-the-art hyperinsulinemic euglycemic glucose claps. They collected data from altogether 20 clinical research centers in Europe and put them all together. And the conclusion here in this paper is, if you look at more or less healthy persons, but with overweight or obesity, you will find if you use as reference those with the most insulin sensitivity, the 10% most insulin-sensitive persons, you can see that there is, of course, increased occurrence of insulin resistance with increased body mass index.

But as a whole, only 26% of all obese subjects were insulin resistant. And in this paper, 60% of subjects with BMI above 35 were insulin resistant, meaning that 40% of these persons were not insulin resistant. So, BMI is, of course, and you may know that from before, but it is rather good, rather useful in the nephrology colleagues that I have, that BMI itself does not determine that the person is insulin resistant.

We had to look other places. These are the graphs of the same phenomenon. It's the plasma insulin concentrations in black columns, and it is insulin sensitivity in the light columns here.

And you can see that it increases with increased body mass index, but even at body mass index above 35, only 60% of the persons will be insulin resistant. And this has, of course, to do with the type of adipose tissue that you are looking at, not what we tend to call the healthy, in brackets then, healthy obese persons with subcutaneous deposit of fat with normal fat cells. We are talking about those with visceral obesity and inflamed pathological fat cell metabolism.

I don't want to go into more detail into this, but you know the whole story, of course. So, primarily, we also in kidney disease, we may be looking at these persons rather than these persons. And I will go further into detail on this with new information.

But I start off with this paper from 2007. This is a study on young persons, on average 18 years of age, 1,500 persons studied with estimated GFR, creatinine clearance formula, Cockcroft Gold, and they looked at the correlation between increases in metabolic risk factors, 1, 2, 3, 4, blood pressure, HDL, cholesterol, triglyceride, glucose, increases in the occurrence of these four risk factors compared to creatinine clearance estimated by the Cockcroft Gold formula. And these, all these persons have normal renal function or above renal function.

And you can see here from the graph that with increasing numbers of risk factors that we have to the left, with increased numbers of risk factors, there is a true increase in GFR. The more metabolic risk factors you have, the more you will filtrate. And this is what we call hyperfiltration because the reference group has a normal creatinine clearance rate.

So, metabolic risk factors are associated with the degree of hyperfiltration, not only the body mass itself. And this is a study from my home university, University of Tromso that I originally was affiliated with and I was part of this group. This group had the ability to follow 1,600 persons with measured GFR, not only estimated GFR, but more accurately measured GFR over time.

And in the Tromso Health Service, this is just one of the waves of the Tromso Health Service, a study taking place between 2006 and 2007 and 2009 in altogether 1,555 adult persons measuring GFR with a hyohexal clearance technique and looking at the relationship between measured GFR and waist-hip ratio. And I can tell you that there was no relationship to BMI, but there is a true relationship to the waist-hip ratio and the degree of filtration rate. So, this is more a hyperfiltration tendency that you can see here.

Those people at the left end of the scale may be sort of borderline nephropathic, I guess, but this is true hyperfiltration to the right. And the same group published later on a follow-up study, 5.6 years follow-up in persons who had also measured it according to metabolic risk factors. This study was studied after exclusion for several reasons of persons in the same – this is the same survey, actually.

They ended up following or assessing 1,261 persons after 5.6 years and looking at what could be associated with the GFR in these patients after 5.6 years. There was certainly no real relationship between body mass index and even Nelston waist-hip circumference here, but even with those different models here for adjustments, you could see here that what really tended to sort of predict glomerular filtration rate decline in this population was actually metabolic risk factors establishing the metabolic syndrome and especially the triglycerides. So, this leads us back to the original paper by the Garty and co-workers who looked at animal experiments.

Even in human cohort studies, we can find that there may be a relationship between metabolic risk factors and triglycerides more than to body mass index itself in terms of predictive decline in renal function. This is another paper more recently, a huge paper from Austria, a huge population base, I would rather say. 1,176,420 persons, half of them women, mean age 43 years, followed for a mean of 22 years, and they looked at the risk of Ent-Kidney disease in this population, which occurred among 454 of the participants.

They constructed and evaluated a triglyceride glucose index, which is sort of an insulin resistance index calculated as a logarithmic value, so the triglyceride times the blood glucose values in milligrams per deciliter. What they found was that the risk of Ent-Kidney disease was actually pretty much determined by the triglyceride glucose index. You can see here from the quarter with the lowest triglyceride glucose index to the increased levels that you have a real tendency, a risk of developing Ent-Kidney disease, even if you correct not only for age and sex and smoking status, but also BMI itself.

So this was sort of a paper that was published in JAMA in 2021, and the same group looked at a subgroup of these 170 persons in a study published just this year in the Journal of American Society of Nephrology, and this paper included 100,269 subjects, being age 46 years, followed for a mean of 23 years, and what they wanted to look at with all these differences in BMI, how could overweight, obesity, BMI be related to the development of Ent-Kidney disease? They corrected for age, sex, smoking status, socioeconomic status, and they looked at three factors that may relate it to the metabolic syndrome, insulin resistance determined by the triglyceride glucose index, hypertension, hyperuricemia, and also a cholesterol index, so a measurement that they performed, and what they found in this study was that what could determine the development of Ent-Kidney disease was not the BMI itself, did not have an impact of the development of Ent-Kidney disease, but rather the triglyceride glucose index, a surrogate index for insulin resistance, blood pressure had an effect, or was actually associated with, I should say, also uric acid, but not total cholesterol. So, again, it is sort of more or less the metabolic components of central obesity, visceral fat, rather than body mass index itself, that may contribute or predict loss of renal function. Again, I cannot say that these factors make up or produce kidney disease by itself, but for certain they will be detrimental and more progressive for kidney failure, nephron loss, if you have a kidney disease already from other reasons.

Finally, my third last slide would be that it is not unimportant when in life you develop your obesity or your overweight. This is a study on overweight, actually, not obesity, but on overweight from England. They looked at a certain cohort that was born during one week in 1946.

We had follow-up complete data from 1,800 participants, but they used imputation to expand the numbers to 4,500 participants, and they looked at how did overweight, meaning BMI between 25 and 30, predict decrease in renal function, estimated GFR less than 60, or increased urine albumin creatinine ratio above 3.5 at age 60 to 64 years. What you can see is that the risk is really largest if you develop your overweight in your young age, when you're 26 years, also when you're 36. This is all compared to if you produce or get your overweight at the age of 60 to 64, or you are lean.

Being overweight at age 26, being overweight at age 36, and maybe less so in the mid-age, will sort of predict that your GFR will be lower in the long run. The durability of overweight is also important, of course, not only the degree of overweight by itself. Let me just summarize to you with some conclusion, that obesity is associated with glomerular hypertrophy and segmental glomerulosclerosis, and hyperpigmentation may certainly be one mediating mechanism.

However, central obesity, and I should probably say visceral obesity, is more closely related to glomerular decline than whole body obesity itself. Whole body obesity is not necessarily related to the insulin resistance syndrome, and certain components of the metabolic syndrome, such as blood pressure, uric acid, and also surrogate measures of insulin resistance, for example, triglycerides, may predict glomerular decline more strongly than overweight itself. My final conclusion is, in terms of kidney disease, you should also be aware of your triglycerides.

That concludes my small talk here. This is Bob Dylan back in 64. It's not the picture of Bob Dylan, but the times, they are changing.

We are looking at central obesity these days more than we did in the old days. Thanks a lot for your attention. Toronto, thank you very much for this excellent presentation.

I think we would have some questions for you. Okay. I think you can also see the chat area.

The first question from Abdulhamid. He says, is it obesity or metabolic syndrome related kidney disease that we should be talking about, or both? Yeah, it's a good question. From what I've been presenting and my own thought, given that I went through the literature this summer, is that obesity may be detrimental in some circumstances, but actually the mechanisms, I think, rely more or less in a metabolic syndrome.

What you can see if a person undergoes extensive, or at least significant, body weight loss being obese, let's say more than 10% loss in body mass index, is that the degree of proteinuria decreases significantly, which is a measure, actually, of improved renal health. At the same time, you also improve the same person's metabolisms. If you look at animal studies and what I presented from these cohort studies, it seems to be the metabolism related to obesity, and especially the central obesity, that is more important than total body mass itself.

Maybe I could comment on the SCLT2 inhibition as well from the same questioner, because I think that SCLT2 inhibition will be beneficial for obesity-related nephropathy. We do not have studies on this. We only have studies on kidney disease in general, and especially diabetes, but what SCLT2 inhibition does is that it sort of reduces the glomerular hyperfiltration, which I think is detrimental and a working mechanism in this kind of nephropathy.

So, I would suggest that SCLT2 inhibition will work beneficially in these persons. We know it works in diabetes at least, and it seems from sub-studies in these trials that it works at all different degrees of BMI. His third question is whether we should be looking for incident resistance parameters, like measuring HOMA-IR in non-diabetic people living with obesity.

Yeah, I've been thinking the same question myself, and I come to my own conclusion that it's a very important thing to look at in studies in groups of persons, but I don't think it's so accurate on an individual basis that you could use it in a daily clinic on an individual patient. Personally, I think the most sensitive parameter of incident sensitivity resistance that you have in the clinic is actually the level of fasting triglycerides. If you have an otherwise non-diabetic person, the fasting triglycerides are elevated without any obesity, at least at present, then I think you have an incident resistant person in front of you, just by looking at the triglycerides.

Sandra asked a question, what is the effect of the bariatric surgery on the hyperfiltration and end-stage kidney disease? I don't know if we have studies on end-stage kidney disease at the outcome, but studies show that if you undergo bariatric surgery with extensive weight loss, more than 10 percent, more than maybe 15-20 percent, you sort of decrease your hyperfiltration extensively, maybe to a normal range. The degree of proteinuria reverses, and GFR tends to stabilize. You may not cure the patient, but that may be in some circumstances a delay of the need of dialysis and transplantation for up to 15-20 years, I guess, provided you start with a GFR above 40-50.

Hema asked a question that I was going to ask, and that is, aside from the incident resistance and the role of, she's asking the role of fat, which is period renal fat or renal sinus fat, yeah, the role of this accumulation, ectopic accumulation. It is an exciting question, and I don't really have the answer of the role of it, but tend to hypothesize that it has a role that may be quite similar, at least resemble what you can see in non-alcoholic fatty liver disease. Again, to get access of this fatty acid and its renal-related fatty tissue, you need to do biopsy studies, and we don't do that in native kidneys.

We do them in transplanted kidneys because transplanted kidneys are easily accessible with the loin, but we don't do them in a protocol, in a research protocol situation. So, for the time being, we know from animal studies that this is an ectopic kind of fat tissue that presents, that produces inflammatory substances and other factors that may relate to incident resistance syndrome, as we can see with ectopic fat elsewhere in the abdomen, but human studies are lacking on the phenomenon. This question is also related with the ectopic fat mass in kidney, and that is how can we pick up, are there any imaging techniques, efficient imaging techniques that we can use? Yeah, I think you can pick it up by MRs, but we do not use them in the daily clinics, but there are MR studies performed looking at this, and they are related to, it looks like in small groups of patients, this is related to kidney damage, but then again, in terms of GPR and albuminuria, but again, you don't know how it started.

It may be, as I said, that this is more or less provocative or permissive for a progressive kidney disease that starts with something else, but it is of importance, I think. MR technique is probably the most invasive technique that we have, non-invasive technique we have today. And the last question is in regards to GLP-1 receptor analogs, receptor agonists versus, possibly this is sleeve gastrectomy, bariatric surgery on long-term cardiac and kidney outcomes.

I'm not aware, I mean, the effect of GLP-1 analogs or receptor agonists on the kidney itself in huge trials is that they tend to reduce the degree of proteinuria. They do not to the same degree tend to stabilize GFR or prevent loss in GFR, but they do reduce the degree of proteinuria. It could be partly due to body weight loss because, and central obesity, because if you reduce body weight, you will have less hyperpigmentation, that's for sure.

I have to say that we do not have good studies on GLP-1 receptor agonists in GFR less than 60, so there are GFR studies going on now to see if it could be protective on renal function in patients with GFR less than 60. I think the similarity between GLP-1 receptor agonists and sleeve operation, gastric sleeve operation is the body weight loss. We have started figuring out just GLP-1 receptor agonists have a particular effect on the kidneys.

Yes, it has. It has an effect of sodium transport across the tubules, just like the SGA2 inhibitor does, but on different places in the tubular system. This is not present with the gastric sleeve operation.

Bottom line, body mass reduction is the same, the same degree of body mass reduction or central obesity reduction in those two initiatives. It will be the same benefit for the kidneys, but it could be that GLP-1 receptor agonists also additional kidney-specific defects that are related to the tubular system and the venal tissue itself. We don't know that yet.

Okay, Trump. I think we need to go to the second session due to the time Thank you. that we have.

Thank you very much for your presentation and the answers to all the questions and the rest of the questions, if there are any, could be answered by the speakers that will be talking next to you. Thank you very much, Trump, and I think we'll see each other in the future in another meeting. Yeah, you can come to Istanbul for another congress or a meeting and we'll see each other.

Thank you very much. I'd be happy to. Thank you.

So you, Kati, sharing is on me, okay. All right, so the second speaker would be Enrique Morales. He's a professor of nephrology and he's from Madrid, Spain.

Enrique is the coordinator of a unit for complex adult glomerular pathology at the University Hospital, 12th of October. He's a board member of the European Renal Association Diabesity Working Group. His area of research, areas of research are hyperkalemia, obesity, renal diseases, glomerular pathology, glucose nephritis, malignant hypertension, and acute thrombotic microangiopathy.

Okay, I'm sorry to interrupt. It's you in here. I think when you share your screen, you have to click a button that says share sound so that you can then hear the presentation as well.

So I think you might need to unshare and then share again, and it's before you click the file, there's a button that says share sound. Well, you want this is. Yes, it's as soon as you press share screen at the very bottom left hand corner, it's there's a little tick box that says share sound.

Yes. And then you select and then you select the file after that. Thank you very much for inviting me to participate in this interesting meeting.

In this presentation, I'm going to talk about the link between Nafl-formafil and CKD. This is my discloser. And this is a common case report of our consultancy.

She's a female, 53 years old, with obesity. And with this type 2 diabetes, hypertension, hyperpigmentation, and the patient with chronic disease with 45-54 and proteinuria 1.2. The imaging tests, so with liver stethosis, this is the score for 2.5. The question is, what is the relationship between two entities? Chronic kidney disease and Nafl-formafil. I'm trying in this talk to explain different aspects of this entity.

First, I would like to talk about the importance of nuance in medicine. This is three painters, three pictures. They use different colors to the same aspect skin.

And this is very important in our patients because we need to individualize the treatment on the diagnosis in our patients. And there are some mistakes between this, the relation between two entities. Nafl-formafil is the most common cause of chronic liver disease in the world.

Around 25% of the general population, an increased dispersion in different populations, such as metabolic syndrome or type 2 diabetes. Nafl-formafil includes different types of liver damage, from stethosis to hepatocellular carcinoma. Nafl-formafil is the diagnosis by the presence of more than 5% fat accumulation in the liver cells.

During the last decade, the main investigators are changing the concept of Nafl-formafil to Mafl-formafil because it includes the metabolic syndrome with liver disease. Due to a variety of metabolic comorbidities, such as hypertension, insulin resistance, type 2 diabetes, disdependence, and obesity, they decided to change the name to Nafl-formafil because it includes the wide aspects of metabolic syndrome. In this picture, you can see the diagnosis.

This is how we do non-invasive tests for a score or imaging test. Also, you know that the gold standard diagnosis is the liver biopsy. Hepatic steatosis patients will exclude the secondary cause of hepatic steatosis.

And finally, the diagnosis is Nafl-formafil on patients with obesity, or patients with type 2 diabetes, or patients with a normal weight, and the present of these two metabolic risk factors is the diagnosis of Nafl-formafil. You can see that the two entities, Nafl-formafil, in the majority of the cases, is the same aspect, but you can see in other patients, we have some patients with a diagnosis of Nafl-formafil or not. As you know, there are different comorbidities in the relationship between the two entities.

Nafl-formafil is 20-30% of the adult population, and the patients with CKD, the percent of the population that affects this condition, is higher than 25%. This is the different comorbidities that are common between two illnesses, hypertension, dyslipemia, obesity, and insulin resistance. You can see in the literature, some studies have confirmed that the presence of Nafl increases the risk of CKD, and the degree of liver fibrosis is related to CKD.

While other studies have found that incidence of CKD is not affected by Nafl. Liver biopsy, as you know, is the most definitive approach, is the gold standard diagnosis of Nafl, fibrosis in our patients, but we need to use other techniques to diagnosis of this entity, non-invasive biomarker, different scores, as you can see, or non-invasive imaging, MRI, ultrasound-based, or different techniques of the imaging to diagnosis of Nafl. What is the interconnection between Nafl and CKD? The key questions regarding the link between these two conditions are, first, whether circardio-metabolic risk factors are the basis of the association, or Nafl itself may, independently of circardio-metabolic risk factors, contribute to CKD development, or third, the CKD development is dependent on the degree of liver disease in patients with Nafl.

In this slide, you can see the relation between Nafl and CKD, this is the different stages of chronic kidney disease, and these conditions compare between two entities, obesity, hypertension, diastolephemia, diabetes mellitus, metabolic syndrome, and other aspects with cancer contribute to entities. The next slide, I try to show the different studies that show the interconnection between Nafl and CKD. In this slide, you can see the different studies that show the relationship, or non-relation, between two entities.

This aspect is very important because it depends on the biomarker that you use to diagnosis of Nafl on the number of patients. This allocation, no association between Nafl and CKD, in other occasion, increase the CKD in relation with the liver fibrosis in these patients. For example, this is a study about a cohort of patients, 80 patients, proving Nafl with a liver biopsy on the control patients.

You can see on the left, the patients with CKD and abnormal aglutinuria was a relationship with Nafl, and the degree of liver fibrosis was a relationship with GFA, which increase the fibrosis of the liver, decrease of GFA. In other study, the patients with chronic kidney disease, the prevalence of Nafl was around 18%, and the prevalence was much higher, near to 30% of the patients, diabetic patients. The authors saw the relationship between Nafl and the cardiovascular events.

There was no relationship between endosteroidal disease and Nafl. This is a prospective study on the authors with an important number of patients. They found relationship between Nafl and increase of risk of chronic kidney disease during the follow-up of these patients.

Recently, it has been published this manuscript of the Danish group of the patients, 290 patients with this cohort, compared with the control group. In this study, they found a similar prevalence with the CT, the diagnosis of Nafl with a CT in the cohort of patients with chronic kidney disease, in the cohort of controls for patients without chronic kidney disease. For this reason, they observed a normal prevalence of moderate and severe hepatic stenosis in patients with CKD, and nor appeared to be a risk factor for Nafl.

In another cross-sectional study, they selected different groups, four groups, depending on the existing two variables, or the presence of metabolic disease, or the presence of fatty liver disease. The most important aspect of this study was the patients with non-fatty liver disease with metabolic dysfunction found a relationship with the risk of chronic kidney disease, and in patients with metabolic dysfunction and fatty liver disease, the relationship was higher than the group of only fatty liver disease without metabolic syndrome. For this reason, the conclusion of this study was Nafl was associated with the risk of CKD, whereas fatty liver disease without metabolic disbalance was not a risk factor for CKD.

In summary, this different cohort study, Nafl is also a driving force for the development and progression of CKD in men under 30. This is two meta-analysis studies with an important number of patients. Eleven core studies were included in this meta-analysis, and the conclusion of this first meta-analysis was that Nafl is associated with the increased risk of incidence of CKD, independent of the established cardiovascular risk factor.

In other meta-analysis, with 13 observational longitudinal studies of different countries, indicates that the long-term risk of developing chronic kidney disease states was increased in patients with Nafl, especially in patients that present liver fibrosis. In conclusion, this updated meta-analysis confirmed that Nafl detected by Serum Liver & Science Fatty Liver Index, or IMIGIN, was associated with nearly 40% increase in the long-term risk of incidence of CKD. But the majority of this study has some limitations.

The first, not allow us to establish a causal association with Nafl, a risk of CKD, was uncertain with advanced fibrosis carrying a higher risk of incidence of CKD than simple stethoscopes. Now, studies use the gold standard, the liver biopsy. The majority of these studies use BMI, but only a few of these studies are using it, and use their results for body fat distribution.

This is a normal problem, a common problem, was the use of NGRED or CKD-AP equations to calculate the GFAR, neither of which are available in the presence of severe obesity or cirrhosis. Majority of this study was ASEAN studies and no large prospective studies. But what are the mutative mechanisms linking Nafl with CKD? We are going to talk about different aspects, from RAS defects to cystine chronic inflammation.

This is the relation of different mechanisms to atheropathyogenic between Nafl and chronic kidney disease. Type 2 diabetes and metabolic syndrome, as you know, the centrally obese individual patients with type 2 diabetes and insulin resistant are the most important risk factors to Nafl and CKD. Nafl has a metabolic liver disease under pro-inflammatory cytokines, or the increase of activity of renin and lutecin in the osteosome system under CKD stress, mediated by pro-inflammatory prophylabiotics mediators in relation with these two entities.

This is a very interesting study, four phenotypes of a patient with or without obesity, and patients with or without metabolic health. You can see the patients with metabolic abnormalities, metabolic syndrome and obesity, where the patients have showed an increase of development of chronic kidney disease compared with the patients with obesity, but metabolically healthy patients. This is a retrospective study of our group with patients with type 2 diabetes and chronic kidney disease.

This is the baseline characteristics, patients with obesity and chronic kidney disease and protein group. We divide in three groups, according to the Nafl score and dividing test. You can see the different groups.

It's very interesting, this aspect of GFAR of this patient at the baseline, you can find the patients with group 2 and group 3 with fibrosis, the patients had lower GFAR compared with the group 1, and the proteinuria was increasing in this group 3. The evolution of proteinuria in GFAR in three groups during the follow-up, around seven years, you can see that there is very similar control of leucemia in this patient, was very similar. The control of proteinuria was RAS inhibitors, but the problem was the renal function. The group 1 increased 20 milliliters, the percent was 20 percent, and the group 3 was 47 percent.

The number of patients in group 2 and group 3 was higher, the percent of patients who developed end-stage renal disease compared with the group 1. Only the fibrosis was the only risk factor to develop chronic kidney disease in patients with diabetes and the similar condition with the control of proteinuria in this group of patients. This is the Kaplan-Meyer, and you can see this aspect about what is the survival of patients with decreased 50 percent of the GFAR from baseline. In conclusion, this study asks the degree of hepatic fibrosis is a main factor to the progression of CKD, and probably this will be included in the global evaluation of our patients with type 2 diabetes, and the presence of an awful diabetic patient is a risk factor for renal progression.

This is another study in our groups. These are patients with obesity, undergone the bariatric surgery, and we analyzed only 54 patients, but the results were very significant clinical for us. This is the baseline characteristics of these patients.

The majority was metabolic syndrome, and the patient with a normal GFAR and the percent of patients with diagnosis with IMAGINE was 70 percent, and non-invasive biomarker was the result. In this occasion, we could show you the results of the liver biopsy and the fibrosis, and 35 percent of these patients had fibrosis in the liver biopsy. We compared the group of metabolic syndrome and non-metabolic syndrome, and it was very similar conditions in relation with the AIDS, BMI, GFAR, proteinuria, non-invasive IMAGINE, and the liver biopsy.

In both groups, and the patients with liver fibrosis, you can see the different aspects, and the metabolic syndrome was very similar in both groups, and no significant results between the patient with the liver fibrosis or no liver fibrosis. This is a preliminary result of our study that compares patients with the gold standard, which is liver fibrosis. Another aspect is the diet.

You know that fructose is used in our diets, and this is the the effects of the fructose, which is metabolic to uric acid, and is the main factor of the metabolic disease, and this is the relation with the hypertension, fatty liver, and adrenal disease. Another aspect is the dysbiosis, and this balance of the different groups of bacteria in the intestinal of our population, and these bacteria so which produce the different pro-inflammatory toxins or acids that contribute to the chronic kidney disease and the liver disease. Another situation is the platelet activation as a mediator of the link between NAFLD and CKD, and the platelets are activated, different gamuts and pro-inflammatory cytokines, hemokines, and growth factor play a main factor to develop two entities.

Now, as you know, the premature aging and the age really change. The old people, it's a risk factor for NAFLD, but also for CKD, and the decrease of clotoprotein, of course, with aging. For this reason, this is a near correlation between age-related changes in NAFLD and CKD.

Other aspect is the relation between fetrin A and adiponectin. Fetrin A is a glycoprotein produced by the liver and in humans higher than fetrin A levels associated with obesity and insulin resistance. On the other hand, adiponectin is a protein secreted for adipose tissue.

This is receptor adiponectin in the podocyte, and with six disbalance between fetrin and adiponectin increase the proteinuria in the patients with the disbalance, and the patients show with fibrosis and inflammation. And finally, this is the relation between the renal function and different genetic tests. PNPLA3 is a gene that encoding and is being recognized as a major common genetic variant associated with the NAFLD.

And as you know, PNPLA3 is also high expressed in the kidney and may lead to lipid accumulation. One step more is very important relation to diagnosis. Patients with NAFLD, recently I talked with the pathologists, and in a small number of patients, the patients had a proteinuria in the diagnosis or during the follow-up.

And for this reason, it's very important to obtain urine of this patient to know the value of a proteinuria. And patients with CKD, we need to know the nephrologist, which is the condition of the liver in the patients with type 2 diabetes or chronic disease. This is the natural history of the liver.

This is NAS and fibrosis, and we need to establish different therapeutic treatment. What is the possibility to treat this entity? We talk about a bariatric surgery, the decrease of weight of this patient, or GDP1, receptor agonist, or SLT2 inhibitors. When we decided to change the diet of this patient, this is a good correlation with the decrease of grade of fibrosis of this patient.

This is a very interesting study, with the decrease or resolution of NAS of this patient, and the increase of GFAR with the patients changing the lifestyle of the diet or exercise in patients with this condition. This is other study of our group of patients with CKD, of busy patients, undergone through bariatric surgery. This is the difference during the follow-up of this patient, the decrease of total FAP of this patient after bariatric surgery.

This is the change of GFAR. This is a limitation of different studies. In this occasion, our group designed this study to calculate the GFAR, the real GFAR, with different techniques by UXO.

This is the real GFAR of our patients. From baseline, the patient decreased GFAR, and after the follow-up, recover the GFAR. This is their relation with the high infiltration of this patient with obesity and chronic illnesses, and decreased their protein volume.

What happened with the older parameters? This is the leptin decrease after the bariatric surgery. That you remember, the leptin increased the side renal effects, and the adiponectin increased after bariatric surgery. The evolution of NAPL score in patients, at the end of the study, the chain of the score was 53-54 in one patient, from four patients, and four patients decreased of fibrosis in seven patients, at the end of this study.

The reduction of fibrosis from 4.3 to 1.4. The decrease of inflammatory cytokines, the interleukin, or older inflammatory parameters after the bariatric surgery. This is the end of results before the bariatric surgery of our patients, of different aspects of the baseline, and so we change the colours, the red colours to green, after the bariatric surgery in our patients. SLT2 is the new drugs about the relation to the cardio and nephropotective studies, and our group of obesity working groups, this is a on review of the different aspects of GLP-1 and SLT2 inhibitors.

Recently, it has been published the effects of SLT2 inhibitors in the two heart outcomes, the effects of the renal function, and the cardiovascular event, and decrease of mortality, decrease of cardiovascular events. This is the effects of SLT2. SLT2 inhibitors have some effects of a decrease of nerve flow in these specific sinus studies about this relationship.

And GLP-1, a bonus receptor, has a direct effect, nephroprotective and cardioprotective effects, and finally, have a beneficial effect on the cardiovascular disease in this group of patients. This is the future on the different molecules, on different targets to develop the beneficial effects in the two entities, the nerve flow and the chronic kidney disease. And finally, this is the take-home message.

Recent study has suggested that Nafl or Mafl is associated with increased risk of CKD, but we need more confirmation on prospective studies. Increased body evidence to talk about Mafl, because it included metabolic syndrome in this study, and the inflammatory cytokines, oxidative stress, activation of vasc, insulin-resistant intestinal microbiota, dysbiosis, were reported as potential pathogenesis. It's very important to screen it based with CKD-Nafl, and based with Nafl, screening of CKD, for this reason, there is an interrelation between two entities.

The way those GBB1 receptor agonists or SLG2 inhibitors may benefit both liver and the kidney in this patient with two entities, Mafl and chronic kidney disease. For this reason, it's very important to work together in these multidisciplinary teams. Thank you very much for your attention.

This is a Spanish singer in the last tour about the end of the single life. Thank you very much for your attention. Professor Morales, thank you very much for this excellent talk.

We added now fatty liver into the session, and the talk reminded me of adipocyte kidney and liver crosstalk. Well, I'm going to the third talk now, and the third talk will be given by Professor Muskojuri, the professor of endocrinology at University of Naples, Federico Secundo, and she works as a member of an EASO collaborating center for obesity management at the same university. Her main research interest is obesities, including monogenic obesity and syndromic obesity.

Good morning, I am Giovanna Muskojuri, and I am assistant professor at University Federico Secundo of Naples. My title speech is fatty kidney and obesity. So, as you know, obesity is a chronic relapsing progressive disease, and it is a multifactorial disease.

But mostly obesity is a social disease involving the overcoming of stigma, discrimination, and generalization. As you can see here, there are the definitions of obesity made by different scientific societies. And as you can see here, the most reported word was chronic.

So, this, in order to highlight that obesity is a global chronic disease requiring long-term management. And obesity is also responsible of the increased risk of mortality. And there is also an estimated effects of the BMI that would be reached by about 60 years of age on survival from age 35 years, identifying European union mortality rates in 2000s with those for BMI 25 to 30 kilograms square meter and combining the disease specific EU mortality rates with disease specific relative risks.

The absolute differences in median survival should be robust to changes in mortality rates and for generalizable decadence in three main and two higher BMI categories. The two higher BMI categories account for just 2% of PSH participants, and so are indicated by dashed lines. Excess adiposity typically evolves slowly over time.

Some of the pathways leading to the genesis of excess adiposity by which the mechanical, metabolic, and physiological effects of excess adiposity led to coexisting chronic diseases. Elevated levels of free fatty acids, inflammatory cytokines, and lipid intermediates in non-adipose tissues contribute to impaired insulin signaling and insulin resistance state that is present in many patients who are overweight or obese. With excess adiposity, liposomes in hepatocytes can increase in size steatosis, forming large pathways that are accompanied by a series of pathological things, including narcolepsy, steatohepatitis, and cirrhosis.

Heart diseases, stroke, and chronic diseases all add as their main pathophysiological mechanisms high blood pressure and the cluster of findings associated with insulin resistance, obesity-associated dyslipidemia, and type 2 diabetes. Obesity is often accompanied by an increase in pharyngeal soft tissues, which can block airways during sleep and lead to obstructive sleep apnea. Excess adiposity also imposes a mechanical load on joints, making obesity a risk factor for the development of osteoarthritis.

An increase in intra-abdominal pressure accounts for the elevated risk of gastroesophageal reflux disease, Barrett's esophagus, and the esophageal adenocarcinoma in all persons who are overweight or obese. Obese individuals can present with a wide range of medical and psychosocial problems, which can promote weight gain, provide important indications for treatment, but in some cases, also pose significant barriers to management. To ensure a complete assessment and consideration of these factors, I propose the use of a simple mnemonic consisting of four MS or M, M, M, and M that stand for mental, mechanical, metabolic, and monetary respectively, and may help the PC practitioner navigate it through a true assessment of clients presenting with excess weight.

However, there are no mentions on kidney, so what about kidney? There are studies examining the association between obesity and chronic disease. As you can see here, subjects with obesity are more prone to develop microalbuminuria and at an elevated risk of developing kidney disease. The need for enhanced energy storage in expanded adipose tissue depots results in adipocyte stress, which triggers a local inflammatory response and cause adipocyte dysfunction.

The release of factors associated with the sodium retention in the kidney, such as leptin and angiotensinogen, led to hypertension. Sodium retention in the kidney is further augmented by local increases in cortisol, which binds to mineral corticoid receptors in the kidney, and by the mechanical effects of increased perirenal and renal sinus fat accumulation, which results in compression of the renal vein and reduction in the tubular flow rate. Increases in adipocyte lipolysis due to progressive insulin resistance results in ectopic lipid deposition in insulin-target tissues, such as skeletal muscle, thereby increasing insulin resistance and impaired glycemia.

Ectopic lipid storage in the kidney, alongside glucotoxic stimuli due to impaired glucose tolerance, promotes glomerular and tubular injury. This hypertensive lipotoxic and glucotoxic stimuli coincide with the reductions in the adiponectin release from adipocytes, a factor implicated in podocyte-mediated tonic maintenance of glomerular peritoneal selectivity. Hyperfiltration and defects in glomerular permeability promote kidney cell stress and inflammation, which results in tubular dropout, glomerulosclerosis, tubular interstitial fibrosis, and ultimately lead to a decline in kidney function.

So, as you can see here, weight loss may improve obesity-related comorbidities and benefits there are for 5 to 10 percent weight loss. And this small reduction of weight is also accompanied by improvements in blood pressure that, as you know, has also a beneficial effect on the kidney. So, there are several current obesity treatment guidelines and clinicians that treat patients for overweight and obesity have a variety of guidelines that are available to them to guide and inform their practice.

The guidelines presented here represent the recommendations of a number of different societies and associations from the U.S. These are the EASO European Guidelines for Obesity Management in OUDS 2015, and as you can see here, there are different treatments for different range of BMI, and the use of drugs are recommended for men when there is a BMI range from 30 to 35, and for both women and men, for BMI from 35 and also higher than 40. However, drugs are always recommended when there are obesity-related complications. Here there are the EASO European Guidelines for Obesity Management in OUDS, and there is, this is the algorithm, you should assess symptoms, psychosis, complications, lifestyle, motivation to lose weight, set goals that usually are 5 to 10 percent body weight loss or 0.51 kilograms per week, manage weight loss, consider specialist referral if complex disease states, present conventional treatment fails, or bariatric surgery is being considered, and emphasize long-term follow-up because obesity is a chronic disease.

In particular, the pharmacological treatment in patients is recommended when BMI is higher than 30 or is higher than 27, and it is accompanied by obesity-related disease. Pharmacotherapy should be evaluated after the first three months, and continued if weight loss achieved is satisfactory or discontinued in non-responders. Lifestyle modification or very low calorie diets can lead to modest weight losses of up to 10 percent, but with a great chance to weight regain.

Evidence suggests that intensive behavioral therapy can deliver the weight loss of 4 to 6 percent, and approved and available pharmacotherapeutic options can deliver weight loss in range of 3 to 10 percent. In contrast, bariatric surgery induces very large and sustained weight losses of 10 to 40 percent. However, only few patients are candidates for these invasive procedures.

Therefore, there has been a treatment gap for the majority of patients requiring a clinically relevant weight loss. A newly approved pharmacotherapist together with lifestyle modification may be a suitable treatment option for these individuals. And as you can see in this trial, after 52 weeks, mean weight loss in the IBT alone group was 6.1 percent.

The IBT liraglutide and the multi-component intervention groups achieved significantly greater weight loss than the IBT alone group, with 11.5 and 11.8 percent weight loss respectively. There was no significant difference in weight loss between the IBT liraglutide group and the multi-component group. There are currently a limited but growing number of pharmacotherapy options available for weight management, and they are shown here.

In Urofoli, orally-stuffed naltrexone, bupropion, and liraglutide 3.0 milligrams are approved for weight management. In the U.S., there are six approved therapies. Orally-stuffed fentermin for short-term use, fentermin topiramate, lorcaserine, naltrexone, bupropion, and liraglutide 3.0 milligrams.

C-puteramine is not approved for weight management in the EU or the U.S., but might be used in some other countries. The therapies are listed as adjunct to diet and physical exercise in people with a BMI of at least 30 kilograms per square meter or 27 kilograms per square meter with one or more comorbidities. A series of very potent derivatives of the 30-amino aspeptide hormone GLP-1 is described in this cartoon.

These compounds were all derivatized with fatty acids in order to protect their action by facilitating binding to serum albumin. GLP-1 had a potency of 55 pm for declined human GLP-1 receptors. And many of the compounds have similar or even higher potencies despite quite large substituents.

Microvascular events was lower in the liraglutide group than placebo group. And this difference was mostly explained by the lower rate of nephropathy events in the liraglutide group. And this is because GLP-1 is also able to have a direct action on kidney because kidney expressed the GLP-1 receptor.

But also we can see that in the scale trials the treatment with liraglutide was accompanied by a reduction of blood pressure. And this was another highly indirect mechanism that could explain the improvement of nephropathy after the treatment with the liraglutide. Another nutritional approach that is commonly used for the treatment of obesity is represented by the very low calorie ketogenic diet.

And in this study, the authors aimed to investigate the efficacy and safety of Abwell's CKD in patients with obesity and mild kidney failure. This prospective observational real-life study was carried out in 92 patients following Abwell's CKD protocol for approximately 3 months. 38 subjects had mild kidney failure and 54 subjects had no renal condition and no clinical relevant variation regarding liver and kidney function.

And upon certification based on kidney function, no differences in efficacy and safety outcomes were found. Interestingly, 27.7% of patients with mild renal failure reported normalization of glomerular filtrate after dietary intervention. The need for enhanced energy storage in expanded adipose tissue depots results in adipocyte stress, which triggers a local inflammatory response and causes adipocyte dysfunction.

And as you can see here, there is a protective effect also of the bariatric surgery that is able to act on the kidney through different mechanisms. We have bariatric effects with the reduction of visceral fats, but there are also metabolic effects that are mediated by their reduced hepatic glucose production, the increasing effects related to bariatric surgery, the increased peripheral insulin sensitivity, intestinal gluconeogenesis, intestinal glucose disposal, and improved lipid status. But there is also a reduction of lactin and insulin, a reduction of sympathetic drive, a direct natriuretic effects of GLP-1, decreased necrosis, increased NAP, and decreased RAS activity.

In this study, the authors investigated the effect of bariatric surgery on the functional patients with morbid obesity and CKD. And you can see here in this prospective studies that included 13 of these patients with the CKD, median GFR did not change significantly after bariatric surgery, although there was a significant decrease in the protein excretion rate at six months. An improvement in the TICO CKD risk category was seen in 30.7 patients.

In addition, there is this other study that was carried out in order to analyze the evolution of renal function, adipose tissue, derived molecules, and inflammatory parameters in patients with CKD after bariatric surgery. Observational and prospective study was carried out in 12 subjects with severe obesity, and there was a 24-month follow-up. And the main results of this study was that measured GFR significantly niched from before surgery to months 24 after surgery.

So, my take-home messages are that obesity is a risk factor for kidney complications, which loss is able to potentially partially reverse obesity-related kidney alterations. Miraglutide while seeking the bariatric surgery has been demonstrated to be a renal safe tool for the treatment of obesity. And thank you for your attention.

Well, Giovanna, thank you very much. I think we need to close due to the fact that we passed the planned closure time. It was a very interesting, significant, and stimulating session.

I think there are lots to do for the clinicians, clinical and basic scientists. I would also like to thank the EASO and the European Renal Association for their work in organizing this meeting. Thank you very much.

The answers, I think, Sherry, Ewan, and Kati will be forwarded to the participants as soon as they are taken from the speakers. Thank you very much.