A 2012 update on inflammatory cytokines and adipokines: Revelance for CKD

EURECA-m CME COURSE Cardiovascular Problems and Solutions

in Chronic Kidney Disease

September 7-8, 2-012, Ankara-Turkey

Prof. Andrzej Więcek

Department of Nephrology, Endocrinology and Metabolic Diseases Medical University of Silesia, Katowice, Poland

e-mail: awiecek@spskm.katowice.pl

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 in the USA and in Europe

Flegal K et al. JAMA. 2010; 303: 235-241

Berghöfer A et al. BMC Public Health. 2008; 8: 200

Prevalence of obesity in Poland

Zdrojewski T. et al., NATPOL III Study, 2011

Obesity (BMI > 30 kg/m2)

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

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: 58-59

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

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

Distribution of body mass index (BMI) in dialysis patients (based on USRDS)

Zoccali C., Mallamaci F.,J. Internal Med., 2011, 269, 407-409

White adipose tissue in the lean and obese state

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

Lean state Obese state

Więcek A. et al., Nephrol. Dial. Transplant. 2002; 17; 194-195

• Cardiovascular and reologic effects, sleep apnea

• Renal effects

• Activation of the sympathetic nervous system

• Metabolic effects (dyslipidemia, carbohydrate intolerance)

• Endocrine effects (hyperinsulinism, insulin resistance,

hypercortisolism, increased erythropoietin secretion)

• Increased coagulation/decreased fibrinolysis (↑PAI)

• Haematologic effects

↑NFB

↑PAI ↑Leptin ↓Adiponectin ↑TNF ↑Angiotensin ↑Resistin

Adipocytes

Obesity

Więcek A. et al. Nephrol. Dial. Transplant. 2007, 22:981-988

The major physiological functions of adipose tissue secretory products in 2012

Adamczak M., Wiecek A., Sem. Nephrol., 2012, in press

Shoji T et al.: Metabolism 2005; 54: 330-334

Relationship between body fat mass and plasma adipocytokine levels

Effects of peripheral hormones on hypothalamic regulation of food intake and energy expenditure

+ CKD

Engineer D.R., Garcia J.M., Intern. J. Peptides, 2012, ID 287457

Markers of appetite regulation in various cachectic states

Leptin – a new uraemic toxin?

or

Leptin – marker of nutrition?

Plasma leptin and CRP concentration at baseline

and 12 months after initialion of HD therapy

(BMI)

Leptin is a marker of nutrition:

1. Postive correlation with fat tissue:

a) low BMI = low serum leptin concentation

b) caloric suplemenation increases body fat mass and

median serum leptin concentration

2. Markedly elevated serum leptin concentration does not

suppress appetite in uraemic patients (leptin resistance). Uraemia is

characterised by relative resistance to many hormones (PTH, HGH,

Insulin)

and cytokines:

a) Serum leptin increses and serum CRP decreases in those HD patiens

who gain weight after 12 months after initiation of HD treatment

Circulating adiponectin concentrations

ADIPONECTIN

Scherer Ph. E., Diabetes, 2006, 55, 1537-1545

Shoji T et al.: Metabolism 2005; 54: 330-334

Relationship between body fat mass and plasma adipocytokine levels

Circulating forms of adiponectin

Adamczak M., Chudek J., Wiecek A., Sem. Dial., 2009, 22, 391-395

Adiponectin multimerization – three major forms of adiponectin found in circulation

Scherer Ph. E., Diabetes, 2006, 55, 1537-1545

Adiponectin, adiponectin receptors and intracellular signalling

Hui X. et al., Brit. J. Pharmacol., 2012, 165, 574-590

The pleiotropic role of adiponectin in the cardiovascular system

Hui X. et al., Brit. J. Pharmacol., 2012, 165, 574-590

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 Więcek A. et al. Nephrol Diali Transplant 2007, 22:981-988

Adiponectin synthesis and biodegradation in patients with chronic kidney disease

Adamczak M., Chudek J., Wiecek A., Sem. Dial., 2009, 22, 391-395

Adipokines and HOMA-IR in non-obese PD patients

Yoo D.E. et al. Endocrine J., 2012 in press

HOMA-IR is inversly correlated with plasma adiponectin concentration in PD patients

Plasma adiponectin concentration and insulin, HDL, CRP levels, and LVMI in hemodialysis patients

Abdallah E. et al. Kidney Blood Pres. Res., 2012, 35, 247-253

Survival curves for analysis of time to cardiovacular events in hemodialysis patients

Group 1. Adiponectin <15.1 ug/ml Group 2. Adiponectin > 15.1 ug/ml

p< 0.0412

Abdallah E. et al. Kidney Blood Pres. Res., 2012, 35, 247-253

Kaplan-Meier survival curves for cardiovascular events

(fatal and nonfatal) in patients witch chronic renal failure

Zoccali C. et al., J. Am. Soc. Nephrol., 2002, 13, 134-141

ADPN

ADPN

ADPN

Interventions known to increase adiponectin levels

Barseghian A. et al. J Am Coll Cardiol. 2011 ,57, 761-70

Perivascular white adipose tissue (pWAT) as a paracrine regulator of inflammation and atherosclerosis

Juge-Aubry C.E. et al., Best Practice Res., Clin. Endocrinol. Metab., 2005, 19, 547-566

The adipose renin-angiotensin system

Dorresteijn J.A.N. et al., Obesity Rev. 2012, 13, 17-26

Physiologic/pathophysiologic significance of an adipocyte renin-angiotensin system

Thacher S et al. Mol Cell Endocrinol. 2009; 29: 111–117

Obesity associated adipocyte dysfunction contributes to hypertension by endocrine and paracrine effects of adipokines on

endothelial cells, VSMCs and macrophages

Zhou J. and Qin G., Am. J. Cardiovacular Dis., 2012, 2, 143-149

Ehrhart-Bornstein M et al.:

Proc Natl Acad Sci U S A. 2003; 100: 14211-6

Fujita T. Nephrol. Dial. Transplant., 2007; 22: 3102-3107

Relationship between visceral obesity and both sald dependend hypertesion and chronic kidney disease

Adiponectin inhibits permeability across a podocyte monolayer

Ahima R. J. Clin. Invest. 2008, 118:1619–1622

Role of leptin and adiponectin in glomerulopathies

Mathew et al., Cur. Diab. Rev., 2011 ,7, 41-49,

Bone metabolism regulated by adipocytes, osteoblast and osteocalcin

Cao J.J., J. Orthopedic Surg. Res., 2011, 6,30

Potential mechanisms by which resisitin may mediate cardiovascular dysfunction

Jamaluddin M.S. et al., Brit. J. Pharmacol., 2012, 165, 622-632

Estimated glomerular filtration rate (eGFR) according to quartiles of serum resistin concentrations and the age- and sex-adjusted mean values

of serum resistin levels according to eGFR

Kawamura R et al. Nephrol. Dial. Transplant. 2010;25:3236-3240

© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Hospitalization free survival according to the quartiles of serum resistin levels in hemodialysis patients

Chung W. et al. J. Korean Med. Sci., 2012, 27, 377-388

Serum chemerin concentration and eGFR in healthy controls, patients with ESRD before

and 3 months after kidney transplantation

Rutkowski P. et al. Regulatory Peptides, 2012, 173, 55-59

Survival curves for all-cause mortality among 252 incident dialysis patients according to the chemerin levels

Yamamoto T. et al., Nephrol. Dial. Transplant., 2010, 25, 4017-4023

Association between plasma ometin levels and metabolic risks factors

Shibata R. et al., Diabetology, Metab. Syndrom, 2012, 4, 2-4

Serum omentin 1 levels in normal glucose tolerance group, type 2 diabetes patients without carotid plaque and type 2

diabetes with carotid plaque

Yoo H.J. et al. Cardiovacular Diab., 2011,10, 103

Serum omentin levels in haemodialysis patients

Alcelik A. et al., Kidney Blood Pres. Res., 2012, 35, 511-516

Conclusions: Adipokines, a 2012 up-date

• New adipokines have been discovered

(e.g. chemerin, ometin)

• Role of adipokines in pathogenesis of CKD progression, CV co-morbidities and uraemic toxicity was confirmed

• Still not enough information concerning the therapeutic utilization of this novel information

Andrzej Wiecek

Katowice

Thank you for very much your attention !

Plasma visfatin levels and appetite in CKD 5 patients starting dialysis therapy

Carrero J.J. et al., Nephrol. Dial. Transplant, 2010, 25, 901-906

Adipokines as uremic toxins

Teta D., J. Renal Nutrition, 2012, 22, 81 - 85