Slide 1

Thank you very much for inviting me to give this lecture. I’m going to talk about obesity as a risk factor for CKD and end stage renal disease and how these things relate.

Slide 2

I want to first talk about the epidemiology of obesity, then about epidemiological studies on obesity and ESRD, renal consequences of obesity both functional and structural and then about potential underlying mechanisms under the functional and structural changes related to obesity.

Slide 3

First the epidemiology of obesity. Obesity is a huge accelerating phenomenon. Here you have a picture of the United States of America in 1990 and it shows what percentage of the people have a BMI, that’s the definition of obesity, above 30 kg/m2 and you see that everything is green still and in some places data are lacking.

Slide 4

In 1995 this changed tremendously, now there are many areas of the country where 15-19% of the people have obesity and more than half of this area is covered in yellow.

Slide 5

In 2000 the regions that were green still in 1995 are now yellow and have more than 15% of obesity and many other regions have now more than 20% of people who are obese.

Slide 6

In 2002 it was even worse with some regions even with more than 25% of people having obesity. So obesity is a huge problem and can well, if it’s related to CKD, underlie the current epidemic of CKD and ESRD.

Slide 7

Epidemiological studies on obesity as a risk factor for ESRD.

Slide 8

Well, we know that the incidence and prevalence of ESRD are growing worldwide and rapidly and in many countries of the world there is now more than 50% of people on dialysis, have a diagnosis attributed to type 2 diabetes and more than 20% to hypertension. So 70% of the people on dialysis suffer from type 2 diabetes or hypertension and has this diagnosis as basic disease. That’s also because of the classic view that we have of development of ESRD, it’s either diabetes or hypertension or vascular disease or another primary renal disease which is underlying the development of ESRD.

Slide 9

So many studies that looked at obesity as a risk factor for ESRD have said, well it’s not really a risk factor because it’s not independent of diabetes and hypertension but in fact, obesity is a cause of diabetes and hypertension partly due to insulin resistance but it’s an important cause in the general population of diabetes and hypertension. So, epidemiological studies should not require it to be a risk factor independent of diabetes and hypertension rather diabetes and hypertension should be risk factors independent of obesity if you want it to turn around.

Slide 10

So the contemporary view should be obesity is a risk factor for diabetes and for hypertension and vascular disease and also for ESRD but obesity could well act through the induction of diabetes, through induction of hypertension and through induction of vascular disease.
Some examples of large epidemiological studies that have looked at obesity as a risk factor for ESRD and you can here see the study by Stengel et al in 2003 and they looked at obesity as a potential risk factor but said obesity risk for ESRD appeared largely mediated by the diabetes and hypertension. So they were reducing their findings that obesity is a risk factor for ESRD. The same was done by Iseki et al in Kidney International in 2004. They looked at a tremendous amount of people and you see here a graded increase of the number of people who develop ESRD over a period of follow up of 15 years. They stated, ‘we found that BMI was associated with increased risk for ESRD in men but not in women although in women you also see a clearly although somewhat less graded increase of development of ESRD with varying decrease of obesity’. They stated this because the association in women disappeared after adjustment for systolic blood pressure and proteinuria but because obesity is an inducer of systolic blood pressure and I will later show of proteinuria as well, you shouldn’t adjust for these things but appreciate the finding that obesity is a risk factor.

Slide 11

A study that had the more contemporary view of Hsu et al in 2006, they also looked at a huge amount of people over 15-35 years and the total of nearly 1500 cases of ESRD in this period and you see here BMI categories, BMI larger than 40 kg /m2 and here the reference category and you see that there is a graded increased in risk health by BMI for development of ESRD and they adjusted for many factors not diabetes and not hypertension so that’s a good thing but they adjusted for myocardial infarction and proteinuria so still some factors that are caused by obesity, myocardial infarction, cardiovascular disease obviously a consequence of obesity in part at least and proteinuria may also be a consequence of obesity and they found it but still they adjusted for these factors and I think that should not have been done.

Slide 12

What are then the renal consequences of obesity? Why is it leading to ESRD?

Slide 13

The early renal phenotype of obesity is one of hyperperfusion, this is the perfusion through the kidney and this is one of a high GFR, so the kidney seems to function abnormally well, the GFR increases with increasing obesity. You have here lean people and here overweight people normotensive, hypertensive, normotensive, hypertensive and you can see that in overweight people compared to lean people there is a larger GFR and there is a larger renal blood flow and only in the people with hypertension the filtration fraction went up so the filtration fraction is a reflection of elevated intraglomerular pressure and these people are probably prone to develop proteinuria.

Slide 14

You can indeed see this in the next slide you can see that renal function is more or less the same as reflected by serum creatinine but urinary albumin excretion is clearly higher in the people with hypertension and overweight and you have to take for granted from me that these people had no diabetes at all that was very carefully investigated so they have a high albumin excretion rate, a tendency for proteinuria.

Slide 15

In fact, this was already known from the 90s from diabetes that if you get diabetes, there is a period where the renal function seems abnormally good, so the GFR increases in first instance and then starts to decline once microalbuminuria has developed and macroalbuminuria starts to appear.

Slide 16

Same thing has been found more or less for the general population the PREVEND study of the city of Groningen and you can here see creatinine clearance and then the rates of urinary albumin excretion and with more urinary albumin excretion probably reflecting renal hyperfiltration you see in first instance a better renal function with more urinary albumin excretion and then later on with even more urinary albumin excretion, renal function starts to decline. This is in the general population.

Slide 17

So what does this obesity do? If you induced obesity suddenly, you would start to hyperfiltrate, so an abnormally good renal function. Probably that’s recruitment of functional renal reserve capacity, so you offset the kidney for starting to decline renal function earlier because you consume the functional renal reserve capacity that you could otherwise use for compensating for, for instance, an accelerated decline of renal function and then maintain renal function at the same level and also for declines due to other causes.

Slide 18

Obesity induces consumption of renal reserve capacity this was theory, this is practice. In our hospital we have a large transplantation programme and also a large living-related donor programme and here we have measured renal reserve capacity by low dose dopamine infusion 4 months before transplantation and 2 months after donor nephrectomy. So one kidney was only left in. Here we have looked at age and BMI adjusted of dependent decrease in renal functional reserve capacity. Here you see the mean change in GFR induced by low dopamine infusion and you can see that here are categories for BMI, it’s about 180 people and if you have both kidneys in, it makes no difference what response is to low dose dopamine infusion and also not for age, you can’t see a difference between the age groups and not between the BMI groups. But if you have removed one kidney, you will suddenly see that the unmasking of the decreased renal function reserve capacity in this kidney probably because it has been growing compository already as a response to the donor nephrectomy that has occurred and you can then see that there is a graded decrease with BMI and a graded decrease with age.

Slide 19

So kidneys, mono kidneys or decreased renal function mass is a risk factor for BMI, for obesity as an inductor of renal decline in function and you can here see a seminal study of Praga et al in 2000 and they looked at the cause of renal function and the cause of development of proteinuria in a cohort of 73 people of which 20 had a BMI larger than 30 and you can here see patients without proteinuria in first instance all of them and the non-obese were slow in developing proteinuria and the obese developed almost all proteinuria in the course of 25 years.
None of the patients or only one as I recall, went onto dialysis but an increase of serum creatinine or decrease in creatinine clearance occurred in many of the patients with obesity.

Slide 20

Those were the functional consequences of obesity, what are then the structural consequences of obesity?

Slide 21

You can here see a study in dogs where in 8 weeks severe obesity was induced and body weight increased from 24-39 and you can see that the changes in function that I have been talking about were induced but also an increase in kidney weight was induced by the induction of obesity so there is induction of nephromegaly.
There are similar human data in a large study in 1986 in which the association between obesity and kidney weight was established.

Slide 22

Potential underlying mechanisms for the functional and structural changes.

Slide 23

I’m now going into somewhat speculation but there is no or little evidence about potential underlying mechanisms. One thing that is many times suggested is intrarenal RAS activation by obesity one way or another. This is a study where they looked at captopril as an inductor giving a better perfusion of the kidney and you can see that there is indeed and this is taken as evidence for renal RAS activation playing a role in the induction of a higher filtration fraction and glomerular filtration rate and it’s indeed so but only in the very severe cases and not in the lower cases, so I don’t think that can be all.

Slide 24

Another thing that could be a factor is hepatocyte growth factor and the transforming growth factor β1 axis. The hepatocyte growth factor is a mitogen which is released by many tissues in response to reduction of mass of these tissues and transforming growth factor β is taking down again the mitogenity of hepatocyte growth factor if it has done its job. Here you can see kidney volumes of children in which uninephrectomy has been performed compared to children with both kidneys in. You can see that there is no difference between children with only one kidney in or two kidneys in because the one kidney in has grown compository to give an equal renal volume as the two kidneys in the control people.

Slide 25

If you then look at hepatocyte growth factor, it is very interesting early after nephrectomy you see very high levels of hepatocyte growth factor and they have gone down to normal levels after a long time after nephrectomy. So hepatocyte growth factor could be an initial stimulus for compository growth.
If you then look at the relation between obesity and hepatocyte growth factor, you see that adipocytes secrete hepatocyte growth factor and that serum concentrations of hepatocyte growth factor are also correlated with obesity, so that could be a factor.

Slide 26

Another thing is lipotoxicity. Doctor Sarafidis has already eluded to that a bit. If you look at tissues other than adipose tissue, you see and it’s well known that in the liver and in the pancreas and in the skeletal muscles triglycerides accumulate and for instance, in the pancreas it’s thought that it’s causing an underlying cause of development of type 2 diabetes and in the liver it’s an inductor of fatty liver and also liver cirrhosis.
This is lipodystrophy. These are the patients where Doctor Sarafidis was talking about who have malfunctioning fat adipose tissues so they are lean but they appear metabolically obese and these are just the normal obese guys.

Slide 27

Here is the only experiment that I have seen that has been looking at potential lipotoxicity in kidneys and it was in a mouse study with diet-induced obesity and you can see that there was indeed an increase in body weight and kidney weight and here you can see the mainly proximal tubular epithelial cell accumulation of fat in response to induction of obesity. So lipotoxicity could play a role.

Slide 28

The conclusions that I would like to draw are that obesity is an independent risk factor for CKD, which frequently acts through diabetes and hypertension, rather than alongside them.
The early renal phenotype of obesity is characterized functionally by renal hyperperfusion and hyperfiltration with stimulation of urinary protein excretion, and structurally by hypertrophy maybe compensatory to the more profound metabolic demands induced by obesity.
As such, obesity “consumes” renal reserve capacity which would otherwise compensate for age-related or disease-related decline in renal function.
Mechanisms may involve renal RAS activation, other growth factors, angiotensin II could also be a growth factor and lipotoxicity probably with varying contributions to functional changes, structural changes and damage. That’s what I wanted to tell you.