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Doctor Cambi, Dear Colleagues I’ve been asked to discuss the renal risk accompanying the metabolic syndrome. The metabolic syndrome, of course, is driven by the Tsunami-like epidemic of obesity.

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Obesity is not completely novel. Here you see the Ancient Austrian ideal of female beauty, the Venus of Willersdorf 4000 B.C. Before the Austrians had a chance to invent culinary delicacies like Sachertorte and Apfelstrudel.

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What has changed with time is the relation between the adorer and the adoree. The one has gotten fatter, the other has gotten thinner.

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As for Britain, let me emphasise that despite the dubious quality of traditional English cuisine even William Shakespeare was familiar with obesity. His Julius Caesar says, ‘Let me have men around me that are fat, sleekheaded and such as sleep o’night’. But today we have a modern "epidemic" namely the high prevalence of renal disease related to obesity. I shall come back to the metabolic syndrome in a minute.

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Here you see in the U.S. Americans from the Kaiser Permanente program in Northern California that the higher the body mass index, the greater the adjusted relative risk to experience end-stage renal disease. Note that the risk starts to increase at a body mass index of 25.

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In Japanese, more strictly the residents of Okinawa, Iseki found also that body mass index was an independent predictor of end-stage renal disease. But note that here the risk starts at a body mass index of 21 kg/ m2.

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Consequently BMI is not BMI across ethnicities. You see here that with an identically low BMI of 22.3 there is a fat man from India, an investigator in London and his fat is much more than in this muscular Caucasian Professor Judkin who runs the marathon.

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From the Framingham study we know that BMI is an independent predictor of reduction of estimated GFR. 23% increase per body mass index higher by one standard deviation, not negligible.

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We also know that obesity is not only an independent predictor of end-stage renal disease but is also correlated to albuminuria. An interesting J related relationship has recently been reported by Ramirez. A causal relationship is suggested by this finding of Praga from Madrid that weight loss causes reduction of albuminuria.

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The interest in obesity started 3 decades ago when, not surprisingly, in the USA a syndrome of focal segmental glomerulosclerosis with proteinuria and rapid progression into renal failure was found in morbidly obese individuals who had no primary renal disease. The syndrome, discovered in 1974, has meanwhile also been observed in Europe. Furthermore Praga in Madrid found more rapid loss of renal function in patients with primary renal disease; such as IgA glomerulonephritis, membranous glomerulonephritis etc. So if you are fat, you have worse chances if you have renal disease.

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In an extended study by Bonnet obesity was an independent risk factor for rapid loss of renal function. Here again you see a dichotomy: the risk stars beyond a body mass index of 25 kg/m2. IgA glomerulonephritis patients with a body mass index above as compared below 25 kg/m2 have a greaer risk to progress to end-stage renal disease.

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The same is true after renal transplantation as Meier-Kriesche in Gainesville reported.

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You see that not only the risk of cardiovascular death, but allograft loss corrected for death with a functioning graft, in other words death censored renal allograft loss, was significantly increased when the subject had a body mass index above 25. So, there seems to be the threshold for the increase in risk.

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If we accept the working hypothesis underlying the pathophysiology of the metabolic syndrome, visceral obesity, that is elevation of the waist-hip ratio, should be more important than global body weight, the body mass index. This has indeed been shown in Groningen where Pinto-Sietsma found that even when corrected for body mass index an increased waist-hip ratio conferred a greater risk of microalbuminuria and a greater risk of diminished eGFR, estimated gomerular filtration rate. Not surprisingly at any given waist-hip ratio the risk was further elevated, the more obese the individual was that is to say the higher his or her body mass index. The recently published French DESIR study is another study where waist circumference was analysed; both in women (and more pronounced in men): the higher the tertile of waist circumference, the greater the incidence of renal malfunction. This is not cross-sectional prevalence, but rather de novo incidence of albuminuria during a 6-year follow up.

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Is there evidence that it makes sense to quantify the 5 individual components of the metabolic syndrome to verify whether a patient has a metabolic syndrome? In other words, is it useful for the nephrologist to evaluate whether a metabolic syndrome is present or not?

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There is little formal evidence but Mulè recently reported that individuals fulfilling the criteria of the metabolic syndrome had not only left ventricular hypertrophy, which was the main item investigated so far, but they had also a higher risk to have microalbuminuria, 36.2 versus 19.3%.

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The cross-sectional study of Leoncini shows one further detail, the greater the number of components of the metabolic syndrome, the greater the urine albumin/creatinine ratio in parallel with a greater left ventricular mass index.

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So, the more severe the metabolic syndrome, the greater the risk of albuminuria as a surrogate marker for renal and perhaps endothelial damage.

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The largest database has been presented by Chen based on the famous NHANES Study (National Health and Nutrition Examination Study). He reported: the greater the number of syndrome components of the metabolic syndrome, the greater the prevalence of microalbuminuria and the greater the prevalence of chronic kidney disease. These are not trivial increases. We talk about a factor of 7 and of 30 respectively, if all components of the syndrome are present.

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Now, the metabolic syndrome does not only play a role in non-diabetic kidney disease but also in diabetes mellitus. In this Finnish study (FinnDIANE study) the presence of a metabolic syndrome (red frame) was found in 38% of men and 40% of women with type I diabetes. Mind that this is not type II!

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The stage of nephropathy was clearly correlated to the metabolic syndrome. The more advanced the stage, the greater its prevalence, 28% in normoalbuminuric, 44% in microalbuminuric, 62% in macroalbuminuric and no less than 68% of metabolic syndrome in those type I diabetics who had reached end-stage renal disease. This is not proving causality but it is very irritating and suggestive.

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Interestingly, there was interaction between glycaemic control reflected here by haemoglobin A1C and the prevalence of the metabolic syndrome (on the ordinate). The higher the haemoglobin A1C, the greater the prevalence, but this effect was more pronounced if the stage of renal disease was more advanced. You see it was greatest, if the patients were in end-stage renal disease. Overall for patients with type I diabetes and the metabolic syndrome, the odds ratio for the presence of diabetic nephropathy was higher by a factor of 3.75.

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Let me close with a comment on the pathomechanisms underlying the relation between the metabolic syndrome and end-stage renal disease.
On the one hand, this is banal, obviously obesity is associated with progression promoters such as hypertension, diabetes, potentially dyslipidemia. But there are also more fascinating causal links. It has been proposed by Barry Brenner that maternal malnutrition and a disturbed prenatal environment, followed by postnatal catch up growth, causes a lower number of nephrons, as we also reported for patients with essential hypertension. This constellation is associated with a greater risk of insulin resistance and obesity. Doctor Barker recently examined in Helsinki women aged 40 who had undergone myocardial infarction and found that their birth weight was lower and their post-natal catch up growth was higher. So, the cardiovascular, as well as the renal risk, begins in part in utero. A second, and possibly complementary, explanation would be high concentrations of the adipocyte hormone leptin.

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In this scheme Wolf enumerated a number of potential mechanisms. Induction of TGF beta, oxidative stress, modulation of growth processes in the kidney, elevated sympathetic nerve tone, increased hypertension, proinflammatory responses, upregulation of TGF beta-receptors. So, there is a whole panoply of factors through which leptin might be injurious to the kidney. I close by stating that independent of known risk factors the presence of the metabolic syndrome increases the risk both of albuminuria (as an early stage of renal malfunction) and of end-stage renal disease (as a late manifestation of kidney damage).

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I thank you for your attention.

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Prof Cambi: Thank you very much Doctor Ritz. The paper is open for discussion. The first question please.

Question: Many thanks to Eberhard for this very exciting presentation. I’m a bit surprised that you didn’t talk about uric acid as a component of the metabolic syndrome with respect to its potential role in utero before the development of hypertension, big chance that you’re probably aware to talk about that.

Prof Ritz: Sure I’m aware of it, I’m not a doubting Thomas, but I’m a scientist who is waiting for the definitive evidence. There are a number of associations, which are very firm. I am impressed by forthcoming evidence that in children high uric acid predicts later onset that of hypertension. In the past we had only the association with cross-sectional studies, so there is certainly a strong case but I didn’t feel the evidence was so solid (like that the in utero syndrome) that it merited to be included. But it’s certainly meritorious that you drew the attention of the audience to this possibility. But let’s say that animals with very low uric acids still get renal disease. So not all is due to hyperuricemia.

Question: Doctor Ritz, you showed that obesity is associated with a higher risk of loss of renal function but what are the data that the intervention losing weight also slows then the risk of declining renal function?

Prof Ritz: The best evidence we can obtain is of course unethical and not feasible, i.e to perform a controlled prospective trial. But Praga in Madrid has very impressive data on the slowing down of progression after weight loss. I am sceptical whether this indicates that you gain renal immortality, if you restore normal weight. I’m still sceptical but certainly weight control helps to reduce progression, there is no doubt about it. Whether this is related to the accompanying factors like hypertension which are improved etc or whether this is unique to obesity per se, leptin or some other circulating factor we do not know. But on a practical level it is very good medical practice to advise the patient to lose body weight with one caveat as soon as he has a creatinine of 3 mg/dL, I no longer advise losing weight because of the disquieting DOPPS data that survival is less in individuals with normal body weight and is best in those with morbid obesity. So, if you are an overweight German Chancellor, you probably would have the best chances on dialysis.

Prof. Cambi: How solid is the Brenner statement about the prenatal environment? Because if this statement is really solid, we may explain several unknown renal diseases that are starting from the prenatal situation.

Prof Ritz: I’m convinced it plays a major role and many other factors that we consider as risk modulators or risk promoters can be linked at least in part to in utero development. As to smoking, for instance, we have beautiful data of Bailin in Perth in Australia. 2 years after childbirth he found that children of mothers that smoked during pregnancy had higher blood pressures. There is also evidence from Katowice, by a collaborator of mine who found that there are kidney abnormalities, if you expose pregnant mothers to smoke extract. This is just one example; there are numerous others, malnutrition for instance. When the British tried to defeat Germany quickly by taking the Ruhr Valley they made an attack on Arnhem. Because this was supported by the Dutch, Hitler interdicted food supply to South Holland and this caused a terrible famine with high mortality. Krediet in Amsterdam and others looked into the offspring of these mothers: if the mother had been exposed to the famine in the second semester when renal organogenesis occurs, the offspring at age 50 had a higher albumin excretion rate. So I think prenatal conditioning is something which we neglected in the past. It doesn’t explain everything, but it is an important thing to look into and has enormous public health implications.

Prof Cambi: Are there any other questions? In this case, thank you very much Eberhard.