arterial and valvular disorders

Arterial and valvular disorders: pathophysiology and clinical manifestations

Arterial and valvular disorders: pathophysiology and clinical manifestations

Adrian Covic, Iasi, Romania

Content

1. Arterial disease in CKD:• Endothelial dysfunction• Vascular calcification / Arterial stiffness

EpidemiologyPathophysiologyConsequencesTreatment

2. Valvular disease in CKD• Annular and valvular calcification• Valvular stenosis and regurgitation

Valvulopathies

In patients with CKD: impaired endothelial function

Recio-Mayoral, Atherosclerosis 2011

High prevalence of vascular calcification

Adapted from Kalpakian MR et al. Semin Dial. 2007;20:139-143

Mehrotra, Journal of Renal Nutrition 2006.

Both intimal and medial arterial calcification

CKD: chronic kidney disease; VSMC: vascular smooth muscle cellsProudfoot D. Herz. 2001;26:245-251Giachelli CM. J Am Soc Nephrol. 2004;15:2959-2964London GM, et al. Nephrol Dial Transplant. 2003;18:1731-1740

Intimal MedialConsequences Acute closure (occlusion) Vascular stiffness (non-occlusive)

Occurrence Generalized cardiovascular disease CKD, diabetes, aging (Mönckeberg’s sclerosis)

Factors Lipid, macrophages, VSMC, inflammation Elastin, VSMC

And increase arterial stiffness, from stage 1 to stage 5

Wang AJKD 2005

Arterial stiffness is high in patients on dialysis and in those with advanced CKD

Shinohara K, Kidney Int, 2004

> 9-10 m/s

Arterial stiffness after renal transplantation?Controversial data...

Transplantation Proceedings, 44, 684–686 (2012)

No difference between the two groups was found at the 1-year interval after renal transplantation

Content


Epidemiology

PathophysiologyConsequencesTreatment


Boulanger, C. M. et al. Hypertension 2006;

Mechanisms of Endothelial dysfunction in CKD patients

Mechanisms of vascular calcification in CKD patients

Mechanisms of arterial stiffness in CKD patients

Hydration status

OPG

Collagen turnover

Vascular Calcification

Use of BIA versus Clinical Criteria for Guiding Ultrafiltration in HD Patients: Effects on BP, Hydration Status and Arterial Stiffness

• Mihai Onofriescu, Adrian Covic et al.Mihai Onofriescu, Adrian Covic et al.

Use of BIA versus Clinical Criteria for Guiding Ultrafiltration in HD Patients: Effects on BP, Hydration Status and Arterial Stiffness

• et al.

Mihai Onofriescu, Adrian Covic et al.

DataGroup A (n = 64) clinical Group B (n = 71) - BIA

Baseline End of study Baseline End of study

PWV (m/s) 7.9 ± 2.5 9.2 ± 3.6* 8.2 ± 2.3 6.9 ± 2.3*

AIx (%) 37.5 ± 26.1 35.6 ± 10.7 33.1 ± 11.5 30.9 ± 13.3

NT-proBNP (pg/ml) 5238 (2550-14841) 3883 (2009-10119)* 7552 (3591-15429) 4561 (2815-10269)*

PWV significantly decreased in the “BIA” group, whereas PWV even increased in the “clinical” group.

A Decreased Level of Serum Soluble Klotho is Associated with Arterial Stiffness in Patients with CKD

Kitagawa, PLoS One. 2013

Klotho and arterial stiffness, ED, IMT…i.e. = VASCULAR HEALTH

Alterated collagen turnover and arterial stiffness

Dellegrottaglie S et al. NDT 2011

carboxy-terminal telopeptide of type I collagen (C1TP)

PWV

Alterated collagen turnover and arterial stiffnessDellegrottaglie S et al. 2011

PWV is significantly associated with serum PIIINP, but not with C1TPPIIINP is a marker of collagen synthesis,

C1TP reflects collagen degradation.

Content


EpidemiologyPathophysiology

ConsequencesTreatment


Content

1. Arterial disease in CKD:

Consequences (baseline / progression of the arterial disease)

a. baseline – a lot of studies…

b. progression – MORE IMPORTANT….only few!!!

Verbeke, Cjasn 2011

N - 1084 prevalent dialysis patients recruited from 47 European dialysis centers

Each 1-m/s increase in PWV was associated with a 15% higher risk. AAC scores and carotid-femoral PWV provide mutually independent predictive information

for the occurrence of CV events and mortality in patients

N = 180 patients with CKD (mean measured GFR, 32 ml/min per 1.73 m2); followed for a mean of 3.1 years.

Strong and independent relationship between arterial remodeling, CKD progression, and occurrence of ESRD.

Relation between circumferential wall stress and measured GFR change

after adjustment on CV and CKD progression risk factors

Mortality increases with calcification progression

in dialysis patients

Noordzij, M et al. Nephrol Dial Transplant 2010; Advance access online September 29

log-rank P-value=0.001

Years since last available x-ray

0.0 0.5 1.0 1.5

20

2.5 3.00

40

60

100

80Progression

No progression

2.0

N=237n=166

n=71 n=38

n=115

Per

cen

t su

rviv

al (

%)

Content

1. Arterial disease in CKD:• Vascular calcification / Arterial stiffness• Endothelial dysfunction

EpidemiologyPathophysiologyConsequencesTreatment

2. Valvular disease in CKD• Annular and valvular calcification• Valvular stenosis

Treatment with cinacalcet may attenuate the progression of VC

The median difference (95% CI) between treatment groups in percent change in CAC scores from baseline to Week 52 at four anatomical sites as measured by the Agatston (solid squares) and volume (shaded squares) methods

Raggi, NDT 2011

Left intima media thicknessRight intima media thickness

Magnesium supplementation reduces intima media thickness

Turgut F et al, Int Urol Nephrol., 2008;40:1075–1082

at baseline

• 32 HD patients on magnesium citrate, 12 controls

• Graphs show reduction in intima media thickness after 2 months in magnesium treated group

CIM

T (

mm

)

*P=0.002*P=0.56

CIM

T (

mm

)

*P=0.001*P=0.65

at 2 months at baseline at 2 months

0,00,10,20,30,40,50,60,70,80,91,0

0,00,10,20,30,40,50,60,70,80,91,0

Modified by Fresenius Medical Care

Mg group Control Mg group ControlModified by Fresenius Medical Care

•observational cohort study; 283 CKD patients;2006-2010

Covic A, Kanbay M et al. AJN 2012

Overall mortality rates in CKD higher in patients with serum Mg < 2.05 mg/dl

Cardiovascular event is significantly higher in CKD patients whose serum Mg < 2.05 mg/dl

Content



EpidemiologyConsequencesTreatment

Valvular calcification is more prevalent among individuals with CKD.

High prevalence of valvular calcification in dialysis patients vs. non-dialysis controls

Ribeiro S et al. NDT 1998;13:2037-2040

Prevalence (%)

Mitral valve

Aortic valve

0 50

N=92 patients on dialysisN=92 age-matched controls

4%

P=0.01

P=0.02

The prevalence of multiple cardiac calcifications was higher in subjects with a eGFR < 45 mL/ min/1.73 m2 and increased per quartile of cystatin C

Prevalence of CAC score (EBCT) for patients with and without valve calcification

CAC: coronary artery calcification; EBCT: electron beam computerised tomography

Bellasi A et al. Kidney Int. 2006;70:1632-8

0

20

40

60

80

100

≥30 ≥1000 ≥30 ≥1000

CAC score by EBCT

Pro

po

rtio

n o

f p

op

ula

tio

n (

%)

6874

32

14

78

6

64

39

Valvular calcifcation

Present

Absent

N=140

Mitral valve Aortic valve

Cardiac valve calcification is correlated with CAC

Aortic stenosis – more frequent and severe in CKD +/- CAD

group 1: absence of CKD and CAD, n = 16; group 2: presence of either CKD or CAD, n = 51; and group 3: presence of both CKD and CAD, n = 53

Content




Combination of both CKD and MAC was associated with a three–fold increased risk for death compared with those with neither condition

N = 3047 participants; CKD (GFR < 60 ml/min) was present in 8.6%

Valvular calcification and survival in CKD

Valvular calcification and survival in ESRD

N = 114 pts were studied; MAC occurred in 56 patients (40%)

Sharma, Atherosclerosis 2007

The same prognosis in dialysis

14 patients with both aortic and mitral valves calcified versus 48 patients with either mitral or aortic valve calcified versus 130 patients with neither valve calcified Wang A Y et al. JASN 2003

PD HD

Raggi, cJASN. 2011Wang A Y et al. JASN 2003

Aortic stenosis – a fulminant disease process in individuals with CKD

Zentner D et al. Nephrol. Dial. Transplant. 2011

CKD 5D cohort (n = 27) and a control cohort (n = 27

All CKD 5D patients had either undergone AVR or died; in contrast one-third of the control cohort remained free of either of these endpoints

Content




Renal (hazard ratio, 3.90) OD patients had poorer 30-days and long-term survival

The presence of chronic renal failure most profoundly decreases survival in patients undergoing aortic valve replacement

Even a moderate reduction in GFR is associated with a decrease in long-term survival after ARV

N = 2,408 patients undergoing AVR with or without coronary artery bypass graft; 47.7%) had mild RD (GFR 60 to 90, 26.7% - moderate RD (GFR 30 to 59), 2.5% severe RD (GFR 15 to 30 mL) · and 4.7% with kidney failure (GFR <15) or requiring dialysis

The risk is proportional to the degree of renal dysfunction

Which type? Mechanical or bioprosthetic??

Kaplan-Meier survival estimates overall and by implant type.

Long-term survival is similar among patients receiving bioprosthetic versus mechanical valve replacement

Tourani, Ann Thorac Surg 2011

Another solutionTranscatheter aortic valve implantation

In some small initial studies no interaction between pre-interventional GFR and outcomes (survival, renal replacement therapy, acute renal failure)

retrospectively analyzed pooled data from the prospective TAVI databases of 4 centers (942 patients); N = 109 patients normal GFR (11.6%); 329 (34.9%) had mild, 399 (42.5%) moderate, 72 (7.5%) severe CKD, and 33 (3.5%) were on HD

Patients with CKD who undergo TAVI have a higher-risk profile and

worse 30-day and 1-year outcomes.

Patients with CKD who undergo TAVI have a higher-risk profile and

worse 30-day and 1-year outcomes.

Aortic valve reconstruction has been performed on 404 cases; Among them, 54 cases on haemodialysis were retrospectively studied

Survival rates were 84.6% at 30 months and 79.6% at 50 months

Another solutionAortic valve reconstruction - Medium-term results are excellent

Another solutionAortic valve reconstruction - Medium-term results are excellent

The same results for mitral valve repair

N = 208 patients with advanced HF symptoms (Stage C/D) undergoing mitral valve repair for functional mitral regurgitation into 3 groups: Group 1 - eGFR ≥30 mL/min/1.73 m2 (control group, n=144); Group 2 - eGFR <30 mL/min/1.73 m2, not dependent on HD; n=45), Group 3 - ESRD on hemodialysis (n=19)

Patients with ESRD showed favorable late outcome in terms of freedom from mortality and readmission for HF

Kainuma, Circulation. 2012

Conclusion

• Increased arterial and valvular disease in CKD, from stage 1 to 5

• collagen metabolism in CKD-associated arterial senescence as a measure of

vascular ageing are now explored

• Hydration status – a modifiable parameter associated with improvement in

arterial stiffness

• Attenuation of arterial damage may be associated with a significant

improvement in survival

• The presence of renal dysfunction -most profoundly decreases survival after

valve replacement or implantation;

• Valve reconstruction showed favorable outcome

arterial and valvular disorders

Education

arterial disease

valvular disease

ckd annular

arterial remodeling

cardiovascular disease

ckd kitagawa

calcification progression

ckd progression risk