Structural abnormalities of the heart and

vascular system in CKD & Dialysis

-

Thick but weak

Kerstin Amann

Nephropathology,

Dept. of Pathology, University of Erlangen-Nürnberg

Krankenhausstr. 8-10

91054 Erlangen, Germany

Cardiovascular pathology in CKD

LVH

fibrosis

reduction in capillarisation

atherosclerosis

microarteriopathy

arteriosclerosis

calcification

Cardiovascular pathology in CKD - crosstalk

between kidney and cardiovascular system

LVH

cardiac fibrosis

impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system)

accelerated arterio- and atherosclerosis (calcification and inflammation)

Cardiovascular pathology in CKD - crosstalk

between kidney and cardiovascular system

LVH: is very common and develops early on in CKD

cardiac fibrosis

impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system)

accelerated arterio- and atherosclerosis (calcification and (micro-) inflammation)

Prevalence of LV disorders in CKD

16%

16%

28%

40%

normal LV

systolic sysfunction

LV dilatation

concentric LVH

(Parfrey et al, NDT 1996)

time until development

of end-stage heart failure 84% of patients starting dialysis

already show LV alterations

„Uremic cardiomyopathy“ /

cardiomyopathy in advanced CKD

CKD

control

Relative heart weight and left ventricular

weight

0

1

2

3

4

5

6

7

8

9

10

control (n=9) hypertension (n=9) uremia (n=9)

g/kgrel. heartweight (g/kg)

rel. left ventricular

weight (g/kg)*

*

*

*

(*:p<0.05 vs uremia) (Amann et al, JASN 1998)

Morphology of the myocardium in

experimental CKD

sham SNX

→ LVH already present after 3 weeks (20 - 60% increase in LV weight)

→ LV contractility: - 40%

→ prevented and reversed (!) by ACE-i and mTOR inhibition

0

5000000

10000000

15000000

20000000

25000000

30000000

number of myocytesper heart

number ofmyocytes per volume

myocardium

sham (n=10)

SNX (n=8)**

LVH in SNX is accompanied by increased

apoptosis and loss of cardiomyocytes

sham SNX

(Amann Kidney Int 2003)

→ myocyte loss (-25%) in CKD predisposes to cardiac failure !

→ experimentally prevented by ACE-i and mTOR inhibition!

Nakamura et al. 2010:

↑cyclin D2, ↑PCNA, CDK-inhibitor

p27 (as novel markers of LVH)

Cardiovascular pathology in CKD - crosstalk

between kidney and cardiovascular system

LVH

cardiac fibrosis

impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system)

accelerated arterio- and atherosclerosis (calcification and (micro-) inflammation)

Increased volume density of the

myocardial interstitial tissue in CKD

0

5

10

15

20

25

30

35

control (n=9) hypertension (n=9) uremia (n=9)

(%)

*

*

*:p<0.05 vs uremia

(Amann et al. JASN 1998)

→ early and specific activation of myocardial interstitial cells in CKD

→ pathogenetic role of PTH, P, AngII and ET-1 (via TGF-ß)

sham

SNX

TGF- mRNA

Functional consequences of cardiac

fibrosis

reduced LV compliance

altered stress – strain

relationship

arrhythmia

- interposition of fibrous tissue

with high electrical resistance

- local delay in spread of action

potential

- reentry type of arrhythmia sudden cardiac death

Cardiovascular pathology in CKD - crosstalk

between kidney and cardiovascular system

LVH

FGF23, a new kid on the block ?

cardiac fibrosis

impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system)

accelerated arterio- and atherosclerosis (calcification and inflammation)

(JCI 2011)

(JASN 2015)

synergy of high-

phosphate diet,

Klotho deficiency

and aging on car-

diac remodelling

+ cardiac fibrosis

- CKD

Cardiovascular pathology in CKD - crosstalk

between kidney and cardiovascular system

LVH

cardiac fibrosis

impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system)

accelerated arterio- and atherosclerosis (calcification and (micro-) inflammation)

Decrease of myocardial capillarisation

in CKD

control

patient

CKD

patient

0

500

1000

1500

2000

2500

3000

3500

4000

control (n=9) hypertension (n=9) uremia (n=9)

*

mm/mm3

*

*: p<0.05 vs uremia

(Amann et al. JASN 1998)

Myocyte-capillary mismatch in

experimental CKD

SNX sham

→ - 25% reduction of capillary supply

(can be prevented by blockade of the sympathetic nervous system and

the ET system !)

Capillary rarefaction in SNX leads to increased

myocardial damage after coronary artery ligation

(Dikow et al, JASN 2004)

Area of infarction (in % LV) : 18.8 ± 6.6 % in sham

30.6 ± 6.7 % in SNX

(p<0.05)

→ reduced myocardial ischemia tolerance in SNX !

sham

SNX

Vascular maladaption in CKD under ischemic

conditions

sham SNX

-25%

LD

PI-

rati

o

(hin

dp

aw

)

sham vs SNX, p<0.05

0.3

0.5

0.7

0.9

1.1

sham vs. SNX

p=0.014

pre-OP day1 day14

sham SNX (Amann et al. 1992, 1996, 2000, Jacobi et al. 2005)

sham

SNX

Lack of adaptive VEGF-regulation in CKD

under ischemic conditions (LVH and hind-limb)

sham SNX

0

0,05

0,1

0,15

0,2

0,25

0,3

0,35

0,4

0,45

sham SNX

* *

0

5

10

15

20

25

30

35

40

45

sham snx

*

sham sham SNX SNX

VEGF mRNA VEGF-protein

(JASN 2009) → anti-angiogenic effect of CKD serum with ↑apoptosis of EC and NO

Elevated sFLT-1 levels reduce capillary density

in the heart

Cardiovascular pathology in CKD - crosstalk

between kidney and cardiovascular system

LVH

cardiac fibrosis

impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system)

accelerated arterio- and atherosclerosis (calcification and (micro-) inflammation)

Accelerated arteriosclerosis in CKD -

Uremic arteriopathy

fibrous or fibro-

elastic intimal

thickening

Epigastric artery of a 46y old patient at the time of renal transplantation

Wall thickening of coronary arteries in CKD

control

CKD

0

0,05

0,1

0,15

0,2

0,25

Mediadicke Intimadicke

mm2 nierengesund

chron. NI**

(Schwarz et al., NDT 2000)

Control

CKD

media thickness intima thickness

Arterial wall thickening in CKD is acompanied

by ultrastructural changes

Normal morphology of aortic media

(sham)

Media thickening with hyperplasia of

VSMC, increased ECM and reduced

elastic fibre content

(SNX)

(Amann et al., Am J Hypertens 1995)

→ reduced vascular elasticity, increased vascular wall stiffness,

RR ↑, LVH ↑ , calcification ↑

Atherosclerosis in CKD ?

more severe ? more common ?

specific characteristics ?

Atherosclerosis in CKD

0

2

4

6

8

10

12

14

16

18

20

Type I Type II Type

III

Type

IV

Type

V

Type

VI

Type

VII

Type

VIII

number of

casesno renal disease

(n=27)

renal disease

(n=27)

(Schwarz et al., 2000)

X-ray diffraction analysis of

coronary plaques

Ca x P

→ pro-inflammatory phenotype of atherosclerotic plaques in CKD !

Cardiovascular pathology in CKD

LVH

fibrosis

reduction in capillarisation

atherosclerosis

microarteriopathy

arteriosclerosis

calcification

Phenotypic alterations in uremia

(Smith et al. 2009)

Intradialytic hypotension

Glomunculus

Thank you

very much !