metabolic syndrome, obesity, hypertension and chronic ... · metabolic syndrome, obesity,...
TRANSCRIPT
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Metabolic Syndrome, Obesity, Hypertension and Chronic Kidney Disease
xyz
Prof. Andrzej Więcek, FRCP (Edin.)
Department of Nephrology, Endocrinology and Metabolic Diseases
Medical University of Silesia, Katowice, Poland
The 19th Budapest Nephrology School (Nephrology, Hypertension, Dialysis, Transplantation)
26-31 August 2012
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Obesity - the public health problem not only in a Western Countries
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Obese female mammoth ivory figurine produced at least 35000 calender years ago (Aurignacien period) and found
in the „Hohler Fels” cave in southwestern Germany
Conard D.J, Nature, 2009, 459, 248-252
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Obesity in the Paleolithic era The Venus of Willendorf is a superbly crafted sculpture
of a naked obese woman from the stone age
Colman M.D. E. Endocr Pract. 1998, 4(1):58-59
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Epidemiology of obesity
Obesity and survival
Obesity, metabolic syndrome and CKD
Pathogenesis of OR FSGS
Clinical picture of OR FSGS
Differences between OR and I FSGS
Treatment of OR FSGS
Conclusions
Plan of the lecture
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Epidemiology of obesity
Obesity and survival
Obesity,metabolic syndrome and CKD
Pathogenesis of OR FSGS
Clinical picture of OR FSGS
Differences between OR and I FSGS
Treatment of OR FSGS
Conclusions
Plan of the lecture
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In USA:
• the age-adjusted prevalence of obesity (BMI≥ 30 kg/m2) was 33.8% overall, 32.2% among men, and 35.5% among women
• the corresponding prevalence estimates for overweight and obesity combined (BMI ≥25) were 68.0%, 72.3% and 64.1%
In Europe:
• the prevalence of obesity (BMI≥ 30 kg/m2) in men ranged from 4.0% to 28.3% and in women from 6.2% to 36.5%
Prevalence of obesity
Flegal K et al. JAMA. 2010; 303: 235-241
Berghöfer A et al. BMC Public Health. 2008; 8: 200
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1998
Obesity Trends Among U.S. Adults Behavioral Risk Factors Surveillance System (BRFSS), 1990, 1998,
2006
2006
1990
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
U.S Obesity Trends 1985-2006, CDC (www.cdc.gov)
BMI ≥30
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x
Regional variation in prevalence of obesity (BMI ≥ 30 kg/m2) in Europe
MEN WOMEN
Berghöfer A et al. BMC Public Health. 2008; 8: 200.
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x
Prevalence of overweight or obesity in children
Lobstein T et al. International Obesity Task Force , EU Platform Briefing Paper prepared in collaboration with the European Association for the Study of Obesity, Brussels 2005
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Attributions of responsibility for addressing the problem of childhood obesity, according to the political ideology of the respondents
Barry C. L. et al. et al. N. Engl. J. Med., 2012; 5: 389-391
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Epidemiology of obesity
Obesity and survival
Obesity, metabolic syndrome and CKD
Pathogenesis of OR FSGS
Clinical picture of OR FSGS
Differences between OR and I FSGS
Treatment of OR FSGS
Conclusions
Plan of the lecture
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The cluster of co-morbidities associated with and aggravated by obesity
Metabolic syndrome
Diabetes mellitus
High blood pressure
Chronic kidney disease
Cardiovascular disease
OBESITY
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x
Body-Mass Index and mortality among 1.46 million white adults
Estimated Hazard Rati for death from any cause according to BMI for all study participants and for healthy subjects who never smoked
de Gonzales et al. N. Eng. J. Med. 2010; 363: 2211-9
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Estimated hazard ratio for death from any cause according to Body-Mass Index (BMI) among black women who never smoked
Boggs D.A. et al. N Engl J Med. 2011; 365:901-908
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Epidemiology of obesity
Obesity and survival
Obesity, metabolic syndrome and CKD
Pathogenesis of OR FSGS
Clinical picture of OR FSGS
Differences between OR and I FSGS
Treatment of OR FSGS
Conclusions
Plan of the lecture
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Adjusted relative risk for end-stage renal disease (ESRD) by body mass index (BMI)
Model adjusted for multiphasic health checkup period, age, sex, race, education level, smoking
status, history of myocardial infarction, serum cholesterol level, proteinuria, haematuria and serum creatinine evel.
Hsu et al. Ann Intern Med. 2006; 144: 21–28
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Left axis and bar graph: distribution of BMI in the study population of 74986 adults in the HUNT Study in Norway
Right axis: hazard ratio for treated ESDR or CKD-related death by BMI (multiadjusted for age, sex, smoking status, physical activiy, socioeconomic status)
Risk of CKD/ESDR increases with BMI
Hunley TE et al. Curr Opin Nephrol .Hypertens., 2010; 19: 227-234
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Prospective studies of metabolic syndrome and incidence of albuminuria
ACR albumin-to-creatinine ratio
Tanner RM et al.: Curr Hypertens Rep 2012; 14: 152-159
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Metabolic syndrome and risk for development of estimated GFR <60 ml/min per 1.73 m2
Thomas S. et al. Clin. J. Am. Soc. Nephrol, 2011, 6, 2364-2373
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Individual components of metabolic syndrome and their risk for development of eGFR <60 ml/min per 1.73 m2
Thomas S. et al. Clin. J. Am. Soc. Nephrol, 2011, 6, 2364-2373
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Number of components of metabolic syndrome and its associations with development of eGFR <60 ml/min per 1.73 m2
Thomas S. et al. Clin. J. Am. Soc. Nephrol, 2011, 6, 2364-2373
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Odds ratio for chronic kidney disease associated with individual components of the metabolic syndrome
Tanner RM et al.: Curr Hypertens Rep 2012; 14: 152-159
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Wang Y. et al., Kidney Int., 2008; 73 18-23
Association between overweight and kidney disease based on cohort studies in the general populations - overweight (25>BMI<30) vs normal weight.
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Wang Y. et al., Kidney Int., 2008; 73 18-23
Association between obesity and kidney disease based on cohort studiesin the general populations – obesity (BMI>30) vs normal weight.
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Association between the development of CKD (eGFR 64 ml/min per 1.73 m2) and weight change per year
baseline BMI between 18.5 and 23.0 kg/m2
baseline BMI >23.0 kg/m2
Adjustment for age, baseline GFR, BMI, HDL , cholesterol, FBG, uric
acid, and regular exercise.
Ryu S. et al., J Am Soc Nephrol. 2008, 19:1798-805
HR increase even among patients with normal BMI !
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Bonnet F et al., Am. J. Kidney Dis., 2001, 37: 720-727
Overweight significantly increases the risk of IgA nephropathy progression
BMI < 25 kg/m2
BMI ≥ 25 kg/m2
CRF-free survival rate according to the presence of an elevated BMI
at the initial renal biopsy.
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Higher recipient BMI is associated with post-transplant delayed kidney graft function
Molnar M et al. Kidney Int. 2011, 80, 218–224
Multivariate analysis of logistic regression models showing pretransplant body mass index (BMI) and odds ratio of delayed graft function (DGF) in four different models
MICS- malnutrition–inflammation complex syndrome;
Tx- transplanted covariates
BMI
Analysis of 11,836 hemodialysis patients who underwent kidney transplantation
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Allograft survival rates in kidney transplant recipients
with and without metabolic syndrome (MS)
Hricik D E CJASN 2011;6:1781-1785 ©2011 by American Society of Nephrology
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Epidemiology of obesity
Obesity and survival
Obesity, metabolic syndrome and CKD
Pathogenesis of OR FSGS
Clinical picture of OR FSGS
Differences between OR and I FSGS
Treatment of OR FSGS
Conclusions
Plan of the lecture
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renin angiotensin system
aldosterone
sympathetic nervous system
insulin resistance
salt intake
Altered adipokines: leptin, fetuin A, resistin, adiponectin, tumor necrosis factor, free fatty acids
endothelin 1
brain natriuretic protein
plasminigen activator inhibitor 1
Inflitrating macrophage phenotypic switch
Factors implicated in the pathogenesis of CKD in obesity
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Hemodynamic • Effective plasma flow
• /N glomerular filtartion rate
• glomerular filtration fraction
• albuminuria
Structural • kidney weight
• glomerular planar surface
• Mesangial expansion
• Podocyte injury
Pathologic • Glomerulomegaly
• Glomeruloscerosis
• Obesity related glomerulopathy
Effects of overweight or obesity on the kidney
Chronic kidney disease • onset of kidney disease
• progression to kidney failure
• proteinuria
End-stage renal disease • incidence and prevalence
• Survival advantage in hemodialysis
• graft loss in kidney transplant recipiens
Other • renal cell carcinoma
• nephrolithiasis
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Prevalence of glomerular hyperfiltration with or without indexing to body surface area
Marked Association Between Obesity and Glomerular Hyperfiltration: A Cross-sectional Study in an African Population
Wuerzner G et al. Am J Kidney Dis 2010, 56:303-312
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White adipose tissue in lean (A) and obese (B) subjects Adipocytes are shown with yellow triglyceride droplets and blue cytoplasm. In the lean state
the light blue cytoplasm represent a state of normoxia, whereas the dark blue in the obese state represents a hypoxic state. Pre adipocytes are shown in brown, macrophages in green, blood
vessels/endothelial cells in red, and the extracellular matrix as black.
Halberg N et al. Endocrinol Metab Clin North Am. 2008; 37: 753
A B
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Więcek A. et al. Nephrol. Dial. Transplant. 2007, 22:981-988
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Physiologic/pathophysiologic significance of an adipocyte RAS
Thacher S et al. Mol Cell Endocrinol. 2009; 29: 111–117
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Obesity and adipocyte response. Protein factors secreted from white adipose tissue during energy equilibrium and obesity
Vazquez-Vela F et al. Arch of Med Reserch 2008; 39: 715-728
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A role for leptin in glomerulosclerosis ?
• Leptin stimulates glomerular endothelial cell proliferation in vitro and in vivo and transcription and secretion of transforming growth factor b1 (TGFb1), a fibrosis – indicating cytokine
• Leptin administration in rats causes proteinuria and glomerular mesangial matrix expansion Wolf G. et al., Kindey Int. 1999, 56, 860-872
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Wolf G. et al.,Am. J. Kidney Dis.,2002, 39, 1-11
Paracrine TGF-b pathways between glomerular endothelial and mesangial cells mediated by leptin
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Wolf G. et. al., Kidney Int., 1999, 56, 860-872
Leptin induced proteinuria – effect of 3 weeks leptin infusion
Leptin
Control
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Adiponectin ↓scavenger
receptors
↑NO ↑TIMP
↓VCAM-1
↓ ICAM-1
↓ E-selectin
↓TNF-α
↓ lipids accumulation
in monocyte derived
macrophages
↓transformation of
macrophages into foam cells
↓superoxide
↓PDGF-BB
↓FGF
↓HB EGF
↑ glucose
utilization
↑fatty acid
oxidation
↑insulin
signalling
↑glucose
uptake
↓gluconeogenesis
anti-atherogenic actions insulin-sensitizing actions
A. Wiecek, M. Adamczak, J. Chudek: Nephrol Dial Transplant, 2007
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Effects of adiponectin on podocytes
Ahima R. J. Clin. Invest. 2008, 118: 1619–1622
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Ad–/– mice exhibit increased albuminuria, oxidant stress, and podocyte dysfunction
Sharama K J. Clin. Invest. 2008, 118:1645–1656
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Adiponectin inhibits permeability across a podocyte monolayer
Sharama K J. Clin. Invest. 2008, 118:1645–1656
Direct action of adiponectin on podocytes independent of the systemic and/or metabolic effects of adiponectin
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Negative correlation between albuminuria and plasma adiponectin levels in obese adults African Americans
Sharama K J. Clin. Invest., 2008, 118:1645–1656
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Wahba I.M. et al. Clin. J. Am. Soc. Nephrol., 2007; 2: 550-562
Potential mechanisms of renal dysfunction related to inflammatory cytokines and lipotoxicity in obesity and obesity initiated
metabolic syndrome
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Tomino Y et al. Kidney Int. 2011, 80, 133 – 135
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• randomized, crossover clinical trial involving 2 weeks each on a low- and a high-AGE-containing diet, 11 overweight and obese individuals (BMI 26–39 kg/m2)
Targeted reduction of advanced glycation improves renal function in obesity
Harcourt B.E. et al. Kidney Int. 2011, 80, 190–198
Low – low AGE-containing diet High – high AGE-containing diet * p<0.05
Albumin/creatinine ratio Plasma cystatin C
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• randomized, crossover clinical trial involving 2 weeks each on a low- and a high-AGE-containing diet, 11 overweight and obese individuals (BMI 26–39 kg/m2)
Targeted reduction of advanced glycation improves inflammatory parameters in obesity
Harcourt B.E. et al.Kidney Int. 2011, 80, 190–198
Low – low AGE-containing diet High – high AGE-containing diet * p<0.05
Plasma MCP-1 (monocyte chemotactic protein-1)
Urine 8-isopprostane
Plasma MIF macrophage migration inhibitory factor)
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Confirmation of microarray data of gene expresion in the glomeruli of ORG patients by real time PCR
Wu Y et al. Endocrinology, 2006, 147(1):44–50
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The distribution of VEG, TGF a, and GLUT1 in the glomeruli of ORG patients and controls by immunochemistry staining
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Epidemiology of obesity
Obesity and survival
Obesity, metabolic syndrome and CKD
Pathogenesis of OR FSGS
Clinical picture of OR FSGS
Differences between OR and I FSGS
Treatment of OR FSGS
Conclusions
Plan of the lecture
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First description: Weisinger J.R. et al., Ann Int Med. 1974: 81: 440-447
Large series: Kambham N. et al., Kidney Int. 2001; 59:1498 - 1509
2% of renal biopsies compared to idiopathic FSGS:
• Less proteinuria
• Higher S-albumin
• Lower S-cholesterol
• Less glomerular alteration
Obesity associated FSGS (focal segmental glomerulosclerosis)
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Obesity-associated focal segmental glomerulosclerosis (OB-FSGS)
• Proteinuria (frequently in nephrotic range)
• Lack of oedema, hypoalbuminemia, hypoproteinemia and lipds disorders
• Decrease GFR in 50% patients
• Histopathology – Glomerulomegaly
– FSGS
• Treatment:
• loss on weight, ACEI / ARBs
Praga M. et al., Nephrol. Dial. Transplant., 2001, 16, 1790-1798
Praga M. et al., Nephrol. Dial. Transplant., 2002, 17, 1157-1159
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Renal survival- doubling of serum creatinine or end-stage renal disease
Renal survival in patients with obesity related glomerulopathy
Obesity-related vs idiopathic focal glomerulosclerosis
Kambham N et al. Kidney Int. 2001; 59:1498-1509
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Epidemiology of obesity
Obesity and survival
Obesity, metabolic syndrome and CKD
Pathogenesis of OR FSGS
Clinical picture of OR FSGS
Differences between OR and I FSGS
Treatment of OR FSGS
Conclusions
Plan of the lecture
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Per cent of normal glomeruli
Per cent of glomeruli with FSG lesions
Per cent of glomeruli with GGS
Glomerular diameter (µm)
OB-FSG (n=15)
61±24
19±23
18±18
256±24
I-FSG (n=15)
57±20
24±12
18±20
199±26
P<0.001
Praga M. et al.: Nephrol Dial Transplant. 2001, 16, 1790-1798
Renal biopsy findings in OB-FSFS and I-FSGS
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Obesity-Related Glomerulopathy
Serra A et al. Kidney Int; 2008, 73, 947–955
Focal and segmental glomerulosclerosis
Global mesangial matrix increase in both glomeruli
Hypertrophic podocytes that contain intracytoplasmic droplets of fat resorption (arrow) and prominent nucleoli (arrow)
Glomerulus with glomerulomegaly from an extremely obese patient and glomerulus without glomerulomegaly from a control of the same age
Electron microscopy. Large-sized podocyte with intracytoplasmic lipids and focal foot process fusion (uranyl acetate and lead citrate stain, original magnification)
Mild fusion of podocytes and condensations of cytoskeletal filaments with a parallel orientation to the glomerular basement membrane
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HE ×200 Karkoszka H. , Katowice, Pl
Glomerular area: 58567,15 µm2 25056,56 µm2
BMI = 41.8 kg/m2 BMI = 22.3 kg/m2
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Glomerular areas in extremely obese (EO) patients with or without sleep apnea syndrome (SAS) and in controls
Serra A et al. Kidney Internat (2008) 73, 947–955
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Comparison of glomerular density (GD) and glomerular volume (GV) in renal biopsy speciments of health kidney donors, patients with IgA nephropathy
or in patients with obesity – related glomerulopathy (ORG)
Tsuboi N. et al., Clin. J. Am. Soc. Nephrol., 2012, 7, 735 -741
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Tsuboi N. et al., Clin. J. Am. Soc. Nephrol., 2012, 7, 735 -741
A) Kidney transplant donor (36-year-old normotensive woman with estimated GFR of 109 ml/min per 1.73 m2 and body mass index of 24.8 kg/m2).
(B) Patient with obesity-related glomerulopathy (23-year-old normotensive man with estimated GFR of 79 ml/min per 1.73 m2 and body mass index of 32.5 kg/m2).
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Epidemiology of obesity
Obesity and survival
Obesity, metabolic syndrome and CKD
Pathogenesis of OR FSGS
Clinical picture of OR FSGS
Differences between OR and I FSGS
Treatment of OR FSGS
Conclusions
Plan of the lecture
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Obesity - induced renal injury and potential targeted treatments
Agrawal V. et al. Nat. Rev. Nephrol. 2009; 5: 520–528
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One month after the onset of caloric restriction, proteinuria had decreased 26.4 ± 30 % of baseline values (from 2.8 ± 1.4 to 2 ± 1.5 g per 24 h) in spite of a modest weight loss (2.8 ± 2.1 % of the baseline values)
Reduction in proteinuria in a group of obese patients subjected to a low-calorie diet
Morales E et al. Am J Kidney Dis 2003; 41: 319– 327
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Morales E. et al., Am. J. Kidney Dis., 2003, 41: 319-327
Relationship of proteinuria and weight changes in diet-group patients
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GFR and renal plasma flow in obese subjects before and after weight loss (48 kg after gastroplasty)
GFR RPF
Chagnac A. at al., J. Am. Soc. Nephrol., 2003, 14,1480-1486
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Study results for obese patients before and after bariatric surgery
Abouchacra S et al.: Int Urol Nephrol, Published on line 03 March, 2012
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Straznicky N.E. et al., J. Hypertens., 2011, 29, 553-564
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a) Resting muscle sympathetic nerve activity expressed as burst incidence before and
after 12 weeks lifestyle intervention with weight loss by caloric restriction (WL), weight loss by caloric restriction and aerobic exercise (WL+EX,) or no treatment (Control).
b) Individual and average changes in MSNA burst incidence
Straznicky N.E. et al., J. Hypertens., 2011, 29, 553-564
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Individual and average changes in serum creatinine (a) and eGFR (b) after
12 weeks lifestyle intervention with weight loss by caloric restriction (WL)weight loss by caloric restriction and aerobic exercise (WL+EX) or no treatment (Control)
Straznicky N.E. et al., J. Hypertens., 2011, 29, 553-564
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Bariatric surgery has shown benefit in treating type 2 diabetes, hyperlipidaemia and obesity
Ahmed M H , Byrne C D Nephrol. Dial. Transplant. 2010; 25: 3142-3147 ©
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The incidence of type 2 diabetes mellitus per 1000 person-years in the bariatric surgery and control groups, according to deciles of baseline glucose levels (A), serum insulin levels (B) and BMI (C)
Carlsson L.M.S. et al., N. Engl. J. Med., 2012, 367, 695-704
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Changes of the glycated hemoglobin (A), fasting plasma glucose (B), average number of diabetes medications (C) and BMI (D) in obese patients with diabetes mellitus who received bariatrc surgery or
intensive medical therapy only
Schauer Ph. R. et al. N. Engl. J. Med., 2012, 366, 1567 - 1576
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Effect of surgical interventions on glomerular hyperfiltration
Navaneethan S.D. et al. Clin. J. Am Soc. Nephrol., 2009, 4 , 1565 - 1574
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Potential adverse impact of bariatric surgery on renal function, exacerbated by postoperative renal failure and renal calcium oxalate
precipitation
Ahmed M H , Byrne C D Nephrol. Dial. Transplant. 2010;25:3142-3147 ©
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Evolution of proteinuria after ACE-I treatment in obesity associated FSGS
Praga M. et al., Nephrol. Dial. Transplant., 2001, 16: 1790-1798
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Ramipril markedly attenuates the risk of ESDR in overweight and obese patients
Mallamaci F et al. JASN 2011; 22: 1122-28
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Anti-proteinuric effect of ramipril
Mallamaci F et al. JASN 2011; 22: 1122-28
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Epidemiology of obesity
Obesity and survival
Obesity, metabolic syndrome and CKD
Pathogenesis of OR FSGS
Clinical picture of OR FSGS
Differences between OR and I FSGS
Treatment of OR FSGS
Conclusions
Plan of the lecture
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The increased incidence of obesity-related glomerulopathy (ORG) is plotted as a percentage of total native renal biopsies received over a
15-year period.
Kambham N. et al., Kidney Int., 2001, 59, 1498-1509
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Obesity and kidney Pathogenic factors
Hypertension
RAA and SNS activation
Insulin resistance / diabetes mellitus
Hyperlipidemia (mesangium proliferation)
Hyperleptinemia
Hypoadiponectinemia
Increased abdominal pressure
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Obesity and kidney Pathogenic factors
Glomerular hyperfiltration
Endothelial proliferation in glomeruli
Increase TGF-β1 production by endothelial cells in glomeruli
Overexpression TGF β receptors on mesangial cells
Increase collagen type IV deposition in glomerular matrix
Increase angiogenesis
Increased AGE and RAGE
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Wahba IM H et al. Clin J Am Soc Nephrol 2007; 2: 550-562
Hyperfiltration and hypertension- hemodynamic consequences of obesity
HTN, hypertension; Na, sodium; AA, afferent arteriole; EA, efferent arteriole
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Obesity and kidney Clinial and therapeutical aspects
Proteinuria (up to nephrotic range)
No symptoms of nephrotic syndrome
Kidney biopsy not recommended
Treatment:
reduction of body weight
bariatric therapy?
blockeres of the RAS
cessation of cigarette smoking
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Hypertension – Obesity – Metabolic Syndrome – Kidney Disease
The Morbid Pathway
Hypertension
Obesity
Glomeruloscerosis
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Metabolic syndrome
Obesity
Glomeruloscerosis
Hypertension – Obesity – Metabolic Syndrome – Kidney Disease
The Morbid Pathway
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Obesity
Glomeruloscerosis
Hypertension – Obesity – Metabolic Syndrome – Kidney Disease
The Morbid Pathway
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Metabolic syndrome
Hypertension
Obesity
Glomeruloscerosis
Hypertension – Obesity – Metabolic Syndrome – Kidney Disease
The Morbid Pathway
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Katowice
Thank you for your attention !
Andrzej Wiecek