14. Mechanisms of arterial stiffness in CKD patients
Hydration status
OPG
Collagen turnover
Vascular Calcification
15. 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.
16. 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.
Data
Group 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.
17.
18.
19. 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
20. Alterated collagen turnover and arterial stiffness
Dellegrottaglie S et al. NDT 2011
carboxy-terminal telopeptide of type I collagen (C1TP)
PWV
21. Alterated collagen turnover and arterial stiffness
Dellegrottaglie S et al. 2011
PWV is significantly associated with serum PIIINP, but not with C1TP
PIIINP is a marker of collagen synthesis,
C1TP reflects collagen degradation.
22. Content
1. Arterial disease in CKD:
• Endothelial dysfunction
• Vascular calcification / Arterial stiffness
Epidemiology
Pathophysiology
Consequences
Treatment
2. Valvular disease in CKD
• Annular and valvular calcification
• Valvular stenosis and regurgitation
23. 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!!!
24. 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
25.
26. 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
27. 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 3.0
0
40
60
100
80
Progression
No progression
2.0
N=237
n=166
n=71 n=38
n=115
Percentsurvival(%)
29. 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
30. 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
CIMT(mm)
*P=0.002
*P=0.56
CIMT(mm)
*P=0.001
*P=0.65
at 2 months at baseline at 2 months
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Modified by Fresenius Medical Care
Mg group Control Mg group Control
Modified by Fresenius Medical Care
31. •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
32. 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
Epidemiology
Consequences
Treatment
34. 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 dialysis
N=92 age-matched controls
4%
P=0.01
P=0.02
35. 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
36. 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
Proportionofpopulation(%)
68
74
32
14
78
6
64
39
Valvular calcifcation
Present
Absent
N=140
Mitral valve Aortic valve
Cardiac valve calcification is correlated with CAC
37. 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
38. 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
Epidemiology
Consequences
Treatment
39. 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
40. Valvular calcification and survival in ESRD
N = 114 pts were studied; MAC occurred in 56 patients (40%)
Sharma, Atherosclerosis 2007
41. 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
42. 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
43. 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
Epidemiology
Consequences
Treatment
44. 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
45. 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
46. 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
47. Another solution
Transcatheter 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.
48. 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 solution
Aortic valve reconstruction - Medium-term results are excellent
Another solution
Aortic valve reconstruction - Medium-term results are excellent
49. 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
50. 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
Hinweis der Redaktion
Mehrotra, Journal of Renal Nutrition 2006
Key points: Vascular and valvular calcification are prevalent in the dialysis population. Mechanisms for calcification include raised serum Ca and P. The two forms of calcification have different etiologies and can lead to different cardiovascular outcomes. Both correlate with morbidity and mortality. Intimal calcification shown with von Kossa stain (silver stain of P deposits) Medial calcification (Mönckeberg ’ s) is shown with H&E stain. There are two types of vascular calcification that occur in distinct areas of the artery wall, the intima and the media. These can be differentiated by histology, consequence, occurrence, and the type of cells and factors associated with them. 1 CKD patients frequently exhibit both types of calcification. 4 Arterial intimal calcification occurs in atherosclerotic plaques. It can result in acute occlusion when the plaque ruptures. 1 It is mainly observed in older patients with a history of diabetes and atherosclerosis and atherosclerotic complications before starting hemodialysis. It is associated with the typical risk factors of atherosclerotic disease. 2 Arterial medial calcification occurs independently of intimal calcification and atherosclerosis. It is a non-occlusive condition. Medial vascular calcification leads to increased stiffness of the arterial wall and disturbances in blood flow, which can be assessed by aortic pulse wave velocity measurements. 2,3 Medial calcification is observed in young and middle-aged CKD patients without conventional atherosclerotic risk factors and is closely associated with duration of hemodialysis and calcium phosphate disorders. 2 References: Proudfoot D, Shanahan CM. Herz . 2001;26:245-251. London GM, et al. Nephrol Dial Transplant. 2003;18:1731-1740. Raggi P, et al. Kidney Int . 2007;71:802-807. Giachelli CM. J Am Soc Nephrol. 2004;15:2959-2964.
With the influence of various factors such as age, high blood pressure, and diabetes, the walls of large conduit arteries undergo intense remodeling processes leading to alteration in the viscoelastic properties. The result is a diffuse process of arteriosclerosis, characterized by stiffer arteries or, in other terms, reduced arterial elasticity or compliance. Clinical consequences of increased stiffness are higher SBP, lower diastolic BP, and widened PP. All three changes are known as major determinants for high CV morbidity and mortality [ 3 ]. As arteries become stiffer, macroscopic and microscopic changes are observed. Macroscopically, the arteries appear tortuous and dilated. Microscopically, there is a loss of the orderly elastic lamellae and disorganized thickening of the media with glycosaminoglycan deposition, fibrosis, and calcification. In the extreme, there is a medial necrosis and aneurysm formation [ 9 ]. The causes and consequences of arterial stiffness are shown in Fig. 1.
Mihai Onofriescu, Adrian Covic et al.
Mihai Onofriescu, Adrian Covic et al.
A total of 101 patients remained at 24 mo. Progressive calcification was seen in 58 of 101 patients. Most (31 of 46) patients with an initial calcification score of zero did not develop calcification. The hemodialysis group demonstrated a greater degree of progression than patients who were on peritoneal dialysis or had stage 4 chronic kidney disease. Progressive calcification was associated with age, male gender, serum alkaline phosphatase, β blockers, and lipid-lowering agents. Increases in vascular calcification correlated with increased arterial stiffness. Vascular calcification was present in 20 of 21 patients who died. Cox proportional hazard analysis identified change in calcification score, calcium intake from phosphate binders, and low albumin as risk factors for death. Hemodynamic variables that were measured at baseline and 12 and 24 mo with significant changes highlighted. ΔCaSc correlated with pulse pressure ( r = 0.216, P < 0.05) and PWV ( r = 0.329, P < 0.05) at 24 mo. It is interesting that ΔCaSc correlated significantly with increased arterial stiffening (ΔPWV) at both 12 ( r = 0.52, P < 0.001) and 24 mo ( r = 0.33, P = 0.003 Our group [ Haydar, Covic et al, Kidney Int 2004] extended the search on the arterial calcification-stiffness relationship using a more precise method for detecting vascular calcifications – electron-beam computerized tomography (EBCT). In a group of 55 patients on renal replacement therapy EBCT was performed for CAD diagnosis, along with subsequent PWV measurement. CAC score = 2551 373.8. PWV = 9.13 0.19 m/s ( r ange 5.9 - 12.3). PWV positively correlated with patient age , dialysis duration, and time-averaged CRP , but not with time-averaged plasma P , plasma Ca , CaxP , total cumulative exposure to calcium-containing oral phosphate binders. Most importantly, we found that PWV strongly correlates with total calcification scores as assessed by EBCT, even after correction for age, dialysis duration, the prescribed dose of calcium-containing phosphate binders, and microinflammatory status (assessed by time-averaged C reactive protein). To further dissect the relationship between calcification and PWV, the group was splitted according to PWV tertiles. Calcification scores were significantly different when compared according to PWV tertiles, so that as PWV increased, calcification scores also increased proportionally (p=0.0001). These findings may be important, as arterial calcifications may be the one of the few preventable factors of arteriosclerosis in ESRD patients .
They include flow-mediated dilatation (FMD) (%), a marker of endothelial dysfunction (A), ankle-brachial pulse wave velocity (baPWV) (cm/sec), a marker of arterial stiffness (B), maximum intima-media thickness (max IMT) (mm), a marker of atherosclerosis (C), and the aortic calcification index (ACI) (%), a marker of vascular calcification (D). The serum Klotho levels were significantly lower in patients with FMD<6.0%, PWV≥1400 cm/s, max IMT≥1.1 mm and ACI>0% compared to patients with FMD≥6.0%, PWV<1400 cm/s, max IMT<1.1 mm and ACI=0%, respectively ( A–D ). ( A ) N=70 and n=40 in FMD<6.0% and FMD≥6.0%, respectively. ( B ) N=60 and n=45 in PWV<1400 cm/s and PWV≥1400 cm/s, respectively. ( C ) N=82 and n=29 in max IMT<1.1 mm and max IMT≥1.1 mm, respectively. ( D ) N=28 and n=75 in ACI=0% and ACI>0%, respectively. The boxes denote the medians and 25th and 75th percentiles. The lines mark the 5th and 95th percentiles
The authors measured serum levels of collagen type III and type I turnover, the and the carboxy-terminal telopeptide of type I collagen (C1TP), and explored their relationship with aortic pulse wave velocity (PWV) and echocardiographically measured left ventricular mass index (LVMI), markers of arterial stiffness and left ventricular hypertrophy, respectively. The population of the study published in this issue consisted of 242 patients with CKD stage 3-5, a subset of the larger Renal Research Institute observational cohort (n=834). The general characteristics were comparable to most European CKD populations with 30% diabetics and 53% males; 80% of patients were Caucasian. it should be noted that PIIINP is a marker of collagen synthesis, while C1TP reflects collagen degradation.
for the first time , also demonstrated an independent relationship between PIIINP and PWV; it should be noted that PIIINP is a marker of collagen synthesis, while C1TP reflects collagen degradation. The negative results regarding C1TP are in line with a recent study in patients with hypertrophic cardiomyopathy, where biomarkers of collagen degradation alone, including C1TP, were not informative
he risk associated with each 1-m/s increase in PWV was less pronounced in patients with moderate to severe calcification. This effect of modification of calcification status on PWV could be because in heavily calcified patients, calcium deposits will also be localized in the medial layer of the vascular wall, thus contributing to an increased stiffness. Conversely, patients without or with only minor calcification still can have stiff arteries because of other mechanisms, including an increased collagen content in the vessel wall (13), accumulation of advanced glycation end products in diabetes (14), and endothelial dysfunction; Another explanation may be that PWV values are underestimated at higher levels of calcification because of an inaccurate path length estimation because of aortic tortuosity, a situation that could occur more frequently in heavily calcified patients. However, in this case, our conclusions regarding the importance of combined measurement of PWV and AAC scores would only be reinforced because a normal value of one parameter does not exclude an increased value of the other.
Death rates were 31% and 46% for progression and no progression, respectively, over length of study. Methods. Three hundred and eighty-four patients who started haemodialysis or peritoneal dialysis between 1997 and 2007 were included (age 61 ± 15 years, 64% male, 61% haemodialysis). Annual chest X-rays were screened for calcification in the aortic arch, and patients were categorized as having no, moderate or severe calcification. Progression was defined as an increase in calcification category during follow-up on dialysis. Results. At baseline, 96 (25%) patients had severe, 205 (53%) patients had moderate and 83 (22%) patients had no aortic calcification. For 237 of the 288 patients with no or moderate calcifications at baseline, X-rays were available for follow-up. During follow-up (mean 2.3 years), aortic calcification progressed in 71 patients (30%). We found that baseline plasma calcium > 9.5 mg/dL and iPTH > 300 pg/mL were associated with progression [odds ratios of 3.1, 95% confidence interval (1.2–8.2) and 4.4 (1.4–14.1), respectively]. Progression of aortic calcification was significantly associated with increased risk of all-cause mortality (hazard ratio: 1.9; 95% CI: 1.2–3.1) and cardiovascular mortality (hazard ratio: 2.7; 95% CI: 1.3–5.6). Conclusions. Aortic calcification progressed in almost a third of the patients during dialysis. Hypercalcaemia and hyperparathyroidism were associated with an increased risk of progression. Progression of aortic calcification was significantly related to an increased mortality risk.
Raggi, NDT 2011
Key messages: Mg may play an important role in the progression of atherosclerosis in dialysis pts. Background information: All patients were treated with calcium acetate phosphate binders for 2 months. One group of patients received magnesium citrate supplementation with approximately 100 mg of elemental magnesium every other day orally. The group taking magnesium supplementation showed reduced intima media thickness after 2 months. Group Magnesium Control n 32 12 P binder Calcium acetate Calcium acetate Intervention 610 mg/2d MgCit - sMg baseline (mg/dL) 2.50 ± 0.36 2.15 ± 0.32 (1.02 ± 0.87) (0.88 ± 0.13) sMg at 2 months 2.69 ± 0.39 2.38 ± 0.40 (1.11 ± 0.16) (0.98 ± 0.16) (Differences in baseline serum Mg levels despite randomization).
Kaplan-Meier survival curves according to median serum magnesium levels (<2.05 mg/dl or ≥2.05 mg/dl). At 38 months, the survival rate was 81 % in the group with serum magnesium levels <2.05 mg/dl compared to 97 % in the arm with serum magnesium levels ≥ 2.05 mg/dl (p < 0 . 001 by log-rank test). significantly higher mortality rates in CKD patients whose serum Mg < 2 .05 mg/dl cardiovascular event is significantly higher in CKD patients whose serum Mg < 2.05 mg/dl
Key points: Patients were evaluated by ECHO. Graph is adapted from Results paragraph 1. In this study mitral calcification was associated more frequently with cardiac rhythm and conduction defects, peripheral VC and valvular insufficiency; aortic calcification was associated with age and longer history of predialysis hypertension. Controls were not on dialysis.
CAC >30 Agatston units (AU) is used here as a cut-off level for the presence of CAC. Patients with higher CAC scores are more likely to have valvular calcification than not.
N = 114 pts were studied; MAC occurred in 56 patients (40%) and was associated with higher mortality ( p = 0.04)
All the CKD 5D patients (100%) underwent surgery or died during the follow-up period. In contrast, 17 (63%) of the controls underwent surgery or died. Of the remaining 10 controls, nine remain alive and free of AVR and one was lost to
