Metabolic syndrome an emerging threat to renal function

Eberhard RitzHeidelberg (Germany)

Metabolic syndrome :an emerging threat to renal function

• History

• The concept of metabolic syndrome

• The role of visceral obesity

Venus ofWillendorf4000 BC

• Renal function and renal diseasein the metabolic syndrome

• Renal morphology in the metabolic syndrome

• Pathomechanisms linking visceral obesity to renal damage

Venus of Laussel(Gravettien period,

25,000 years,25,000 years,found 1911)

Obesity –a longstanding German tradition

Venus of “Hohler Fels“female mammoth ivory figurine; 35,000 years old (Aurignacien)

Conard, Nature (2009)460:737

Evolution of body mass index –historical perspective

changing relation of body mass between adorer and a doree

Evolution prepared humans

well for surviving fasting ,but poorly for combating fast foodbut poorly for combating fast food

Bagby, J.Am.Soc.Nephrol.(2004) 15:2774

Metabolic syndrome :an emerging threat to renal function

• History

• The concept of metabolic syndrome

• The role of visceral obesity

Venus ofWillendorf4000 BC

• Renal function and renal diseasein the metabolic syndrome

• Renal morphology in the metabolic syndrome

• Pathomechanisms linking visceral obesity to renal damage

• Hitzenberger K.Ein Beitrag zum Stoffwechsel bei vaskulärerHypertonie

• Kylin E.Hypertonie -Hyperglykämie -Hyperurikämie Syndrom

Hitzenberger, Wien.Arch.Klin.Med.(1921)2:189

Hypertonie -Hyperglykämie -Hyperurikämie Syndrom

• Reaven 1988 (Banting lecture)Syndrome X = insulin resistance

Kylin, Zentralblatt für Inn.Medizin (1923) 44:105

Reaven, Diabetes (1988) 37:1595

Definition of the metabolic syndromeNCEP criteria

(National Cholesterol Education Program; Adult Treatment Panel /// (ATPIII)

JAMA (2001) 285: 2486

Diabetes Care (2005) 28:2289

• Insulin resistance as the unifying aetiology uncertain

• Criteria arbitrary ; no clear basis for including/excluding CVD risk

factors and rationale for thresholds ill defined

Voices of dissent

factors and rationale for thresholds ill defined

• the CVD risk associated with ‘syndrome’ is no greater than sum of

parts

Kahn R, Diabetes Care ( 2005) 28: 2289

The “father” of syndrome X :

Justification for the concept of themetabolic syndrome

► counselling tool for promoting public awareness (gaining momentum in public discussion)

► the prize one has to pay: not a good predictor of CV disease or diabetes(poor to resolve scientific issues)

Grundy, Clin.Chem.(2005) 51:1352

Is the link between obesity and ESRD fully explained by the high prevalence of diabetes and hypertension in obesity?

Bakker,Nephrol.Dial.Transpl.(2007) 22:15

indirect

indirect

direct via alternative mechanisms ►

hyperfiltrationglomerulomegalyglomerulosclerosisproteinuria…

Metabolic syndrome :an emerging threat to renal function

• History

• The concept of metabolic syndrome

• The role of visceral obesity

Venus ofWillendorf4000 BC

• Renal function and renal diseasein the metabolic syndrome

• Renal morphology in themetabolic syndrome

• Pathomechanisms linking visceral obesity to renal damage

waist circumference

♂ 102 cm, ♀ 88 cm

narrow waist:

(visceral obesity)

Android (apple) vs.gynoid (pear) obesityNot all obesity is created equal

A tribute to a pioneer: Jean Vague (1947)

I am female,I am young,

I am not pregnant

Low B.S.Why sex matters: aDarwinian look at human behaviour

Princeton University Press(2000), p.80

J.Vague, La différentiation sexuelle.Facteur determinant de l’obesité

Press.Med.(1947) 30:339-340)

Obesity and kidney

# kidney problems other than parenchymal renal dis ease, (kidney cancer, nephrolithiasis)

# a specific form of primary kidney disease relate d to obesity

Ritz, Semin.Nephrol.(2009) 29:504

Adams, Am.J.Epidemiol. (2008)168: 268Obligado, Am.J.Hypertens.(2008) 21:257

# a specific form of primary kidney disease relate d to obesity(focal segmental glomerulosclerosis FSGS)

# impact of obesity on primary kidney disease(IgA-GN, kidney allograft, (pre)diabetic nephropathy , uninephrectomy …)

Weisinger, Ann.Int.Med.(1974)81:440Kambham, Kidn.Internat,(2001)59:489

Gonzales, Kidn.Internat.(2005)68:263Bonnet,Am.J.Kidn.Dis.(2001)37:720Meier-Kriesche, Transplantation (2002)73:704Altiparmak, Netherl.J.Med.(2002)60:260

Obesity and non -neoplastic kidney disease894 576 participants, 61% male, recruitment age 46±11 years

hazard ratio per 5 kg/m 2 higher BMI

15-25 kg/m 2 25-50 kg/m 2

Prospective Studies Collaboration, Lancet (2009) 373:1083

kidney disease : 1.14 (0.74-1.77) 1.59 (1.27-1.99)

diabetes : 0.96 (0.59-1.55) 2.16 (1.89-2.46)

Body mass index (BMI) at age 20 years –important determinant of CKD in adult life

Risk of advanced CKD (S-creatinine > 3.4 mg/dl) Swedish nationwide case control study

BMI (kg/m 2) odds ratiomen women

< 25 1.0 1.0> 25 3.1 (2.1-4.8) 3.0 (1.4-6.1)

Ejerblad, J.Am.Soc.Nephrol. (2006) 17:1695

BMI – an independent predictor of endstage renal disease in USA

1.00 1.87 3.576.12

RR 7.07

Adj

uste

d re

lativ

e ris

k E

SR

D

1.0

100

Hsu, Ann.Int.Med.(2006) 144:21

BMI (kg/m2)

<18.5 18.5-24.9 25.0-29.9 30.0-34.9 35.0-39.9 >40.0

RR0.44Adj

uste

d re

lativ

e ris

k E

SR

D

1.0

0.1

Risk of ESRD attributable to obesity higher in young than in older subjects

(underestimate - at higher age competing CV risk? )Because of high CV mortality the old individuals have not had sufficient time to

develop ESRD

Hazard ratioBMI

(kg/m2)

<18.5 18.5-24.9 25.0-29.9 30.0-34.9 35.0-39.9 >40.0

< 40 years 0.2 1.0 1.8 4.4 7.3 11.6

> 40 years 0.8 1.0 1.9 3.1 5.5 4.8

Hsu, Ann.Int.Med.(2006) 144:21

<18.5 18.5-24.9 25.0-29.9 30.0-34.9 35.0-39.9 >40.0

cardiovascular death – competing risk factor ?

IgA glomerulonephritisrisk of renal function deterioration as a function of BMI

1.0

0.8

0.6

0.4

< 25 kg/m2

> 25 kg/m2

Bonnet, Am.J.Kidn.Dis.(2001) 37:720

duration of disease(years)

0 2.5 5 7.5 10 12.5 15 17.5 20

0.4

0.2

0

> 25 kg/m2

Correlation between BMI and filtration fraction ( FF)[index of glomerular hypertension]

even within the normal range of BMI

FF (%) r2=0.205

Bosma, Kidn.Internat.(2004) 65:259

BMI (kg/m 2)

Body weight reduction in morbid obesity by bariatric surgeryreduction of GFR, RPF and albuminuria

BMI 48±2.4 → 33±1.5 kg/m2

Indirect evidence for causality

GFR RPF

Chagnac, J.Am.Soc.Nephrol.(2003) 14:1480

Albuminuria 16 → 5 µg/min

CKD in obese patients weight loss with diet reduction of proteinuria

“prospective controlled study”

Morales, Am.J.Kidn.Dis.(2003) 41:319

months months

weight reduction program dietary advise

• Stabilisation of CKD after bariatric surgery

• Focal-segmental glomerulosclerosis of 16-year old p atientwith extreme obesity –

Alexander, Surg.Obes.Rel. Dis (2009) 5: 237

with extreme obesity –normalisation of proteinuria after “bariatric surg ery“

• Oxalosis (± uremia) after bariatric surgery

Fowler, Ped.Nephrol. (2009) 24:851

Montagnac, Nephrol.Ther. (2011)7:38

ARIC and CHS studies;21,258 participants with normal creatinine at baseline;

observation 9.3 years- 1 SD increase in waist-hip ratio

22% higher risk of CKD

Waist-hip ratio superior to BMIas predictor of chronic kidney disease (CKD)

22% higher risk of CKD- 1 SD increase in BMI

no significant increase

Elsayed, Am.J.Kidn.Dis.(2008)52:29

waist- hip- ratio assesses visceral fatBMI comprises both subcutaneous and visceral fat,

and also muscle, bone, ECC fluid

Ritz, Am.J.Kidn.Dis.(2008)52:1

Visceral obesity microalbuminuria

Bonnet, Journal Hypertension (2006) 24:1157Pinto-Sietsma, American Journal Kidney Disease (2003) 41:733

Glomerulomegaly, reduced podocyte number, segmental glomerulosclerosis

Renal pathology in visceral obesity

Chen, American Journal Kidney Disease (2006) 48:772

Glomerulomegaly, increased mesangial matrix, mesangial cell proliferation, podocyte hypertrophy

Serra, Kidney International (2008) 73:947

Tubular atrophy, interstitial fibrosis, arterial sclerosis

Alexander, American Journal Kidney Disease (2009) 53:759

Hyperfiltration of young men with metabolic syndrome

Tomaszewski, Kidn.Intern.(2007) 71:816

1572 young men (mean age18 years)risk of hyperfiltration (Cockcroft-Gault Ccr >2SD above median) →

6.9 times elevated

Visceral obesity and the kidney(“normal weight obesity”)

even when corrected for body mass index (BMI)central fat distribution ( waist-hip ratio ) :

� greater risk of microalbuminuriaRR 1.7 (1.19-3.12)

� greater risk of diminished eGFR

RR 1.9 (1.19-3.12)

2.0 (1.19-31.9)

2.7 (1.46-4.85)

lean

overweight

obese

Pinto-Sietsma, Am.J.Kidn.Dis.(2003) 41: 733

Visceral obesity predictor ofmicroalbuminuria in type 1 diabetes

men

de Boer, J.Am.Soc.Nephrol.(2007) 18:236

women

Waist circumference –a stronger predictor than BMI

of new onset CKD in type 2 diabetics

Luk, Diabetes Care (2008) 31:2357

Median

Median

Median

Median

Below Below

Above

Above

BMI

waist circumference

Causal role of metabolic syndrome in the genesis of albuminuria :horses with metabolic syndrome develop albuminuria

(apart from hyperinsulinemia, insulin resistance and dyslipidemia)

Frank, Vet.Clin.North.Am.Equine Pract.(2011) 27:73

Metabolic syndrome :an emerging threat to renal function

• History

• The concept of metabolic syndrome

• The role of visceral obesity

Venus ofWillendorf4000 BC

• Renal function and renal diseasein the metabolic syndrome

• Renal morphology in themetabolic syndrome

• Pathomechanisms linking visceral obesity to renal damage

Early renal malfunction / pathology linking

metabolic syndrome with chronic kidney disease

� glomerular hypertension� endothelial dysfunction� vasoconstriction (vas efferens)� matrix proliferation and expansion,

glomerular and interstitial

Lastra, Adv.Chronic Kidney Dis.(2006) 13:365

Metabolic syndrome and de novo CKD9 year observation in nondiabetic individuals

eGFR <60ml/min/1.73m 2 6% 10% 1.69 1.43

Metabolic syndrome odds ratio (95%CI)unadjusted adjusted

(1.42-2.00) (1.18-1.73)

no yes

increased s-creatinine 1% 3% 1.92 1.60(♂ >1.5mg/dl)(♀>1.2mg/dl)

Kurella, J.Am.Soc.Nephrol.(2005) 16:2134

(1.42-2.00) (1.18-1.73)

(1.37-2.68) (1.11-2.30)

even after adjustment for newly diagnosed hypertension and diabetesmetabolic syndrome independent additive risk

prevalence CKD(%)

waist circumference:>102cm (men)

fasting glucose:

Metabolic syndrome risk factors and prevalence of chronic kidney disease or microalbuminuria

Chen, Ann.Int.Med. (2004) 140:167

prevalencemicroalbuminuria

(%)

metabolic syndrome risk factors

fasting glucose:>110mg/dl

HDL-C:<40mg/dl

triglycerides:>140mg/dl

blood pressure:>130/80mmHg

Metabolic syndrome and stage of diabetic nephropathy in type 1 diabetics

40%

60%

80%

62%68%

44%

p<0.001

p=nsp<0.001

prev

alen

ce (

%)

met

ab.s

yndr

ome

0%

20%

40%

NormoN=1261

MicroN=326

MacroN=383

ESRDN=164

28%

44%

Thorn, Diabetes Care (2005) 28: 2019

prev

alen

ce (

%)

met

ab.s

yndr

ome

Metabolic syndrome :an emerging threat to renal function

• History

• The concept of metabolic syndrome

• The role of visceral obesity

Venus ofWillendorf4000 BC

• Renal function and renal diseasein the metabolic syndrome

• Renal morphology in the metabolic syndrome

• Pathomechanisms linking visceral obesity to renal damage

Glomerulomegaly , reduced podocyte number, segmental glomerulosclerosis

Chen, American Journal Kidney Disease (2006) 48:772

Glomerulomegaly … increased mesangial matrix, mesangial cell Glomerulomegaly … increased mesangial matrix, mesangial cell proliferation, podocyte hypertrophy

Serra, Kidney International (2008) 73:947

Tubular atrophy, interstitial fibrosis, arterial sclerosis

Alexander, American Journal Kidney Disease (2009) 53:759

Progressive increase of “ obesity related glomerulopathy ”(Columbia University, New York)

Morbid obesity with “focal segmental glomerulosclero sis“Weisinger, Ann.Int.Med.(1974) 81:440

Kambham, Kidn.Intern.(2001) 59:1498

control

Chen,AJKD (2006)48:772

Glomerularhypertrophy

andpodocyte pathology

in obesity relatedglomerulopathy

obesity

metabolic syndrome

Alexander M. et alKidney pathological changes in metabolic syndrome

Am.J.Kidn.Dis.(2009) 53:751

Beyond the glomeruli

interstitial fibrosis; tubular atrophy arterial sclerosis (arrow)

control

Focal adhesions to Bowman‘s capsule Mesangial matrix increase

Extremely obese individuals despite normal renal fu nction :marked glomerular lesions

hypertrophic podocytes with prominent nucleoli and intracytoplasmic fat droplets

Glomerulomegaly ofextremely obese individual

Glomerulus of normalindividual

Serra, Kidn.Internat.(2008) 73: 947

Obesity related glomerulopathyglomerular gene expression by microarry and real time PCR

microarrayreal time PCR

Wu, Endocrinology (2006) 147:44

LDL receptor

TNFα VEGF TGFβ Glut1 Leptin receptor

rel.ratio(compared to controls)

lipid metabolism inflammatory cytokines insulin resistance

Metabolic syndrome :an emerging threat to renal function

• History

• The concept of metabolic syndrome

• The role of visceral obesity

Venus ofWillendorf4000 BC

• Renal function and renal diseasein the metabolic syndrome

• Renal morphology in the metabolic syndrome

• Pathomechanisms linking visceral obesity to renal damage

Pathomechanismslinking

metabolic syndrome with chronic kidney disease

insulin resistance with compensatory hyperinsulinemia

• sodium retention and hypertension• sodium retention and hypertension• inappropriate activation of the RAS and aldosterone• sympathetic overactivity• oxydative stress• leptin• adiponectin

Lastra, Adv.Chronic Kidney Dis.(2006) 13:365

The insulin resistance paradox

• insulin sensitivity diminished in:

� muscle� adipose tissue� liver� ...� ...• but insulin sensitivity not diminished in :

� kidney → increased sodium reabsorption

� nervous system → increased sympathetic tone

Rocchini, Hypertension (1989) 14:367

Landsberg, J.Hypertens. (2001) 19:523

Normal subjects

Insulin resistance

transient hyperinsulinemia

chronic hyperinsulinemia

sodium reabsorption

vasodilatationNO

vasodilatationNO ����

sodium reabsorption reabsorption NO

no changein BP

NO ����reabsorption

salt sensitivity

BPelevation

Hypertension

→ antinatriuretic effect of insulin preserved→ vasodilatory NO mediated effect abrogated→ (RAS upregulated)

insulin resistance

activated RAS (renal, visceral adipocytes)

Gorzelniak,J.Hypertens.(2002) 20:965

aldosterone secretion independent of classical stimuli (adipocyte derived secretagogue EKODE)

Ehrhart-Bornstein, Proc.Natl.Acad.Sci USA (2003) 100:14211Goodfriend , Hypertension (2004) 43:358

Epidydimal fat-cell-conditioned-medium for incubationwith adrenocortical cells (H295R)

fat cell supernatant of SHR/Ncp (but not of SHR)stimulates aldosterone secretion

Aldosterone secretion

cross-talk –visceral adipocytes

“talking” to adrenals ?

control SHR SHR/Ncpno

metabolic syndrome

metabolic syndrome

Nagase, J.Am.Soc.Nephrol.(2006) 17:3438

• potential role of fat derived factors in podocyte injury in a model of metabolic syndrome

Nagase, J.Am.Soc.Nephrol.(2006) 17:3438

The emerging role of aldosteroneas a perpetrator of podocyte damage

• in hypertensive rats with metabolic syndrome ROS production by podocytes as consequence of aldosterone overprod uction

• Eplerenone → inhibition of podocyte injury and proteinuria

Shibata, Hypertension (2007) 49:355

Nagase, Hypertension (2006) 47:1084

Low plasma adiponectinhigh urine albumin/creatinine ratio

Sharma, J.Clin.Invest.(2008) 118:1645

Globular and full-length adiponectin decrease

albumin permeability across podocyte monolayers

full-lengthglobular

adiponectin

Adiponectin -/- mice

- higher albuminuria- higher oxidant stress(amplified by diabetes)

albuminuria

Sharma, J.Clin.Invest.(2008) 118:1645

oxydative stress

Diabetes

Low water intake –higher risk of new onset hyperglycemia

Daily water intake

< 0.5 L/day 0.5 – 1.0 L/day >1.0 L/day

New onset of

Roussel, Diabetes Care (2011) 34: 2551

New onset ofhyperglycemia

odds ratio 1.0 0.64 0.73

(0.49-0.83) (0.50-0.97)

Quartiles of plasma Copeptin correlated to metabolic syndrome (stable C-terminal arginine vasopressin prohormone)

V1a-R liver glycogenolysis; V1b-R insulin and glucagon secretion

Enhörning, J.Clin.Endocrinol.Metab.(2011) 96:E1065

A polymorphism of the arginine vasopressin receptor gene (AVP-R1a)

is correlated with features of the metabolic syndrome

6065 middle aged individuals in South Swedenfollow-up 1994-2009

carriers of the rs 1042615 variant

Enhörning, Am.J.Clin.Nutr. (2009) 89:400

• triglyceride concentration 1.36 ± 0.77 vs 1.42 ± 0.89 mmol/l (p=0.001)

• fasting blood glucose 5.20 ± 1.44 vs 5.12 ± 1.22 mmol/l (p=0.067)

I thank youfor your invitation

The Japanese commenton the current

obesity epidemic:

Macdonald in Tokyois a terrible revenge for

Pearl Harbourfor your invitation

to discussthe obesity epidemic

and its renal impact

prof.e.ritz@t-online.de

Pearl Harbour