Obesity and Chronic Kidney. The Catholic University of Korea Cheol Whee Park, M.D.

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1 Obesity and Chronic Kidney Disease The Catholic University of Korea Cheol Whee Park, M.D.

2 Epidemic Obesity and type 2 Diabetes in Asia Yoon KH, et al. Lancet 368: , 2006

3 [1 단계 ] 지방세포가커진다 [2 단계 ] 염증인자가대량분비 [6 단계 ] 당지질호르몬 Adiponectin 분비감소 [3 단계 ] Insulin 수용체를변질 Obesity [5 단계 ] 고혈압이발생한다 [4 단계 ] 식후고혈당이나타난다 From BRIC

4 Obesity --- indirectly initiates a cluster of disorders including insulin resistance, glucose intolerance, dyslipidemia, atherosclerosis, and high blood pressure. --- directly 2 indices of renal damage: (1) albuminuria/ proteinuria (2) Pathological changes podocyte hypertrophy, mesangial expansion, glomerular enlargement ---> 2 nd FSGS

5 Renal Disturbnaces in Obesity Microalbuminuria/proteinuria Glomerular hyperfiltration/hypertension Glomerulomegaly with/wo focal or segmental glomerulosclerosis Enhanced progression of other renal diseases (reduced renal mass, IgAN, and post-kt chronic graft dysfunction) Diabetic nephropathy Reduced renal survival after kidney transplantation Carcinoma of the kidney Increased formation of kidney stones

6 Obesity induced renal problems 1. Hypertension 2. Obesity-related glomerulopathy (ORG)

7 1. Obesity-induced hypertension Obesity GFR elevation -α1-subunit of Na-K ATPase - Thiazide-sensitive NaCl co-transporters -β-enac -- set-point of natriuretic action by AT II Ritz E, et al. Semin Nephrol 29: , 2009

8 Relationship between obesity and pressure-natriuresis Hall JE, et al. Curr Opin Nephrol Hypertens 12: , 2003

9 Obesity-induced cardio-renal changes Hall JE, et al. Curr Opin Nephrol Hypertens 12: , 2003

10 2. ORG-pathology BMI>40 kg/m 2 Serra A, et al. Kidney Int 73: , 2008

11 Obesity-induced glomerular hyperfiltration Metabolic demand Very large natural variability in the glomerular number (4.3-8-fold) Griffin KA, et al. Am J Physiol Renal Physiol 294: , 2008

12 Obesity-induced susceptibility of barotrauma; podocyte against GC pressure

13 Obesity-induced susceptibility of oxidative stress; podocyte against insulin and free radicals Obesity Hyperinsulinemia Generation of free radicals Antioxidant enzymes Oxidative stress NO bioavailability Glycoxidation products Lipid peroxidation products Renal injury; including podocytes

14 Obesity aggravates chronic renal disease

(1980 2006), 25 cohorts, 3 cross-sectional, and 19

15 RR for the association between obesity and kidney diseases From 247 retrieved articles via PubMed ( ), 25 cohorts, 3 cross-sectional, and 19 case control studies. Wang Y, et al. Kidney Int 73:19-33, 2008

16 Cumulative incidence of end-stage renal disease according to quartile of BMI; 1983 Okinawa survey 2000 result N=100,753(M;F, 47,504:53,249), 20 yrs Iseki K, et al. Kidney Int 65: , 2004

17 Cumulative incidence of end-stage renal disease and CKDrelated death by BMI; the HUNT I study N=75,000 for 21 yrs F-U HUNT 1 Study in Norway, prehypertension only factor except BMI Munkhausen J, et al. Am J Kidney Dis 54: , 2009

18 Pathomechanisms linking obesity (metabolic syndrome) with CKD SNS activation Inappropriate activation of the RAS and aldosterone systems Adipokine alteration Renal lipotoxicity Fetuin A-Adiponectin-MAPK relationships Ritz E, et al. Semin Nephrol 29: , 2009

19 1. Obesity-induced SNS activation* Mechanisms of SNS activation in obesity Hyperinsulinemia Increased free fatty acids AT II Increased central chemoreceptor sensitivity Impaired baroreflex sensitivity Hyperleptinemia *Baroreceptor sensitive medullary neurons and nucleus tractus solitarius Hall JE, et al. Curr Opin Nephrol Hypertens 12: , 2003

20 2. Obesity-induced RAS activation Hunley TE, et al. Curr Opin Nephrol Hypertens (in press)

21 3. Obesity-induced adipokine alterations Ritz E, et al. Semin Nephrol 29: , 2009

22 4. Working hypothesis; Renal lipotoxicity (in HF-induced renal damage in SHRs) Fenofibrate Tempol CDRT Na retention Shin SJ, et al. Hypertens Res 32: , 2009 Chung S, et al. NDT 25: , 2010

23 5. Another working hypothesis linking obesity-ckd-fatty liver diease: the role of fetuin-a, adiponecin, and AMPK Ix JH, et al. J Am Soc Nephrol 21: , 2010

24 Mechanisms of obesity (metabolic-syndrome)- induced renal injury and potential targeted treatments Agrawal V, et al. Nat Rev Nephrol 5: , 2009

25 Effects and targets of some metabolic syndrome (obesity) treatment Weight loss, regular exercise, and a low-calorie, low-fat diet (1 ST line Rx) Agrawal V, et al. Nat Rev Nephrol 5: , 2009

26 Changes in median albumin:creatinine ratio 1 year after Bariatric surgery Agrawal V, et al. Clin Nephrol 70: , 2008

27 Key points 1) Obesity (metabolic syndrome; MS) is a constellation of metabolic risk factors that predict increased risks of CVD and diabetes. 2) In cross-sectional and longitudinal studies, obesity is associated with CKD and microalbuminuria. 3) Abdominal obesity and insulin resistance are widely considered to be key mechanisms of obesity-mediated renal damage. 4) Limited studies suggest that treatment of obesity by way of lifestyle changes, pharmacotherapies, or both, can improve markers of renal function. 5) Increased recognition of obesity and early intervention for this condition could improve cardiovascular and renal outcomes.

28 감사합니다. Knowing is not enough, we must apply. Willing is not enough, we must do. ( Es ist nicht genug zu wissen: man muss es auch anwenden; es ist nicht genug, zu wollen, man muss es auch tun. Johann Wolfgang Goethe,

Obesity mediated hypertension and renal dysfunction

Obesity mediated hypertension and renal dysfunction Gergely Bodor Marion Hervouet Nicky Honnef Mariarosaria Malgadi Julie Robert Tutor: Pr Alina Parvu Objectives 1. Introduction 2. Renal structural and