arterial and valvular disorders
TRANSCRIPT
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
1. Arterial disease in CKD:• Endothelial dysfunction• Vascular calcification / Arterial stiffness
Epidemiology
PathophysiologyConsequencesTreatment
2. Valvular disease in CKD• Annular and valvular calcification• Valvular stenosis and regurgitation
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
1. Arterial disease in CKD:• Endothelial dysfunction• Vascular calcification / Arterial stiffness
EpidemiologyPathophysiology
ConsequencesTreatment
2. Valvular disease in CKD• Annular and valvular calcification• Valvular stenosis and regurgitation
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
1. Arterial disease in CKD:• Vascular calcification / Arterial stiffness• Endothelial dysfunction
2. Valvular disease in CKD• Annular and valvular calcification• Valvular stenosis and regurgitation
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
1. Arterial disease in CKD:• Vascular calcification / Arterial stiffness• Endothelial dysfunction
2. Valvular disease in CKD• Annular and valvular calcification• Valvular stenosis and regurgitation
EpidemiologyConsequencesTreatment
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
1. Arterial disease in CKD:• Vascular calcification / Arterial stiffness• Endothelial dysfunction
2. Valvular disease in CKD• Annular and valvular calcification• Valvular stenosis and regurgitation
EpidemiologyConsequencesTreatment
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