Post on 15-Feb-2018
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