Nowadays obesity is a worldwide epidemic. Apart from the worrying figure in the States, where the prevalence of obese people isc33%% , in Europe the figures of this new epidemic are a matter of great concern for the health organizations in these countries. The prevalence of obesity is relatively low ind Italy……..The main concern about this epidemics is that several epidemiologic studies recently showed that obesity is associated with CKD and ESRD.
Obesity was long cosidered a risk factor for the heart. In reality it is now well established that it is also a risk factor for the kidney…
Hemodynamic alterations in the kidney appear well before individuals develop frank obesity. Indeed there is an important decline in renal plasma flow with increasing body mass within a range of values excluding frank obesity. This decline is not paralleled by simultaneous down-sloping of the GFR and as a consequence Filtration Fraction (the ratio of these two measurements) increases linearly with higher BMI values. Higher glomerular pressure (i.e., a potentially unfavorable renal hemodynamic profile) is evident also in overweight subjects. In micro-hemodynamics terms the only way to explain the maintenance of the GFR in the face of a declining ERPF is efferent vasoconstriction and/or afferent vasodilatation, changes that increase Glom pressure and trigger albuminuria.
Evidence supporting the Glomerular Hypertension/hyperfiltration hypothesis: Interventions reducing efferent vasoconstriction (l ACEi) transiently reduce the GFR . In fact in American African Study of Kidney disease. ACE inhibition by Ramipril causes efferent vasodilatation and reduces glomerular pressure. Accordingly in AASK there was an early , steep fall in the GFR, 4 ml/min in 6 months, which was followed an attenuation in renal function loss over the subsequent 3 years of follow up
If we would like to find the causal risk factors for Glomerular Hypertension and glomerular damage we should interrogate the adipocyte. The adipocyte in the obese produce a variety of factors that disturb the control of renal micro-hemodynamics, Angiotensinogen, the precursor of angiotensin II, Leptin a cytokine which induces insulin resistance and that directly and indirectly , via insulin R, triggers high sympathetic activity. Furthermore the adipose tissue produces ADMA, the most important inhibitor of NO synthase and therefore causes NO inhibition. These factors activate macrophages that produce excess IL6 and TNF alpha. Thus …these risk factors on one side cause glomerular hypertension and on the other side trigger inflammatory mechanisms.
The fact the glomerular hypertension triggered by angiotensin II and inflammation are inter-related phenomena is well documented in an animal model of obesity like the Zucker rat. These rats have mesangial matrix expansion. Furthermore this model showed a high expression of IL6 and monocyte chemoattractant protein MCP1.
On the other hand in a Agnes Fogo group in a model of obesity by high fat intake documented glomerular accumulation of macrophages. Notably bothe mesangial matrix accumulation and macrophage infiltration in these two models were almost abolished by angiotensin II blockade
In man we have a clear documentation that abdominal obesity as measured by waist circumference is strong predictor of incident CKD. Indeed in the Framingham heart study the risk of developping KD closely paralleled abdominal obesity
We remarked that the adipocyte synthesises various inflammatory cytokines..another product of the adypocyte is procalcitonin a protein that we use for the diagnosis of sepsis and that is probably the most powerful biomarker of innate immunity. This peptide is made up by thyroid C cells and by cells derived from the neural crest. Recently we and other documented that PCT is highly expressed in adipocytes and that circulating PCT levels increase accordingly with waist circumference quartiles
Furthermore by the SAME STRATIFICATION of waist circumference we found that the risk of incident renal events associated with a 100 pg/ml increase in PCT is minimal in CKD patients wioth small (I quartile) waist but by the 30% higher in patients with large waist, those in the 4° quartile. Thus Obesity is a risk factor for renal diseases by several mechanisms. Alterations in renal hemodynamics and inflammatory mechanisms largely overlap.
In order to prove that obesity is directly implicated in CKD we need a randomized trial. Because obesity is an established strong risk factor for the CV system this trial will never be done.
Because conventional wisdom equates high BMI with excessive fat, the nephrology community has long considered the inverse link between BMI and survival in patients at all stages of CKD as a clinical research conundrum. BMI is a summary measure of body size that has 2 main components, the osteomuscular/parenchymal (or lean body mass) and the fat component, and within this compartment, visceral fat is of utmost relevance for the regulation of insulin sensitivity and lipid metabolism.
La resistenza insulinica é un fattore di rilievo in questi aggiustamneti emodinamici. Questo é dimostrato in un elegante esperimento di fisiologia clinica di circa 10 anni di un gruppo di ricercatori clinici di Baltimora che fanno capo a Matteuw Weir. Questo ricercatori hanno effettuato studi di misura simultanea della resistanza insulina con la tecnica dell’Insulin Clamp e delle misure dell’emodinamica renale cioé il filtrato glomerulare e il flusso plasmatico renale. Questi studi sono stati effettuati in un gruppo di 10 obesi con normale funzione renale. Vediamo il risultato principale di questo studio. Mettendo in rapporto la frazione di filtrazione , cioè un indice dell’iperfiltrazione ipertensione glomerulare, con la velocità di rimozione del glucosio che è un indice di sensibilità insulinica, é emerso che le due variabili erano fortemente correlate in maniera inversa, in altri termini, tanto più bassa era la velocità di rimozione del glucosio, cioé tanto maggiore la resistenza insulinica, tanto più alta era la frazione di filtrazione, cioé l’iperfiltrazione/ipertensione glomerulare. Pertanto questo elegante esperimento accredita almeno in un esperimento acuto l’ipotesi che la resistenza insulinica abbia effetti negativi sull’emodinamica glomerulare.
In the CREDIT study BMI and the waist to hip ratio, which is a clinical surrogate of visceral fat, were measured in a dialysis population, in Italy. According to previous studies in dialysis patients, BMI was inversely associated to mortality: the higher the BMI the better the survival.
At variance with BMI, Waist Circumference was associated directly with increased risk of death and cardiovascular events in this population. In fact those dialysis patients with a larger waist to hip ratio had the worst survival such as in the General Population. These data for dialysis patients show that stratification by waist circumference is fundamental for studying the link between fat and clinical outcomes. Does this imply that we shouldn’t use BMI any more in ESRD?
Moreover the worst antropometric profile was that combining a large waist and a low BMI, “obese sarcopenia” . In other words dialysis patients with a large addominal circumference and a low BMI had the worst survival.
Per partecipare al Corso di Formazione a Distanza è necessario:
Se sei già registrato fai la login con utente e password.