Transcript ESRD: State of the Art Conference Optimal CV

ESRD: State of the Art Conference
Optimal CV-Renal Therapy
Over the Next 5 Years
William L. Henrich, MD
University of Texas Health Science Center
at San Antonio
The Problem – Causes of Death in CKD Patients
Estimated Event Rate (%)
60
75 GFR
(mL/min/1.73 m2)
P<.001
50
60-74.9 GFR
40
45-59.9 GFR
(mL/min/1.73
(mL/min/1.73 m2)
(mL/min/1.73 m2)
30
<45 GFR
(mL/min/1.73 m2)
20
10
0
Death From
CV Causes
Re-infarction
CV
CHF
Stroke
Resuscitation
Composite
End Point
*14,527 patients with HF or LV dysfunction
post-MI
NEJM 2004;351:1285-1295.
Courtesy of Allen R. Nissenson, MD, FACP
AJKD Vol 45, No 4, Suppl 3, April 2005
Hypothetical CV Risk Factors and Event
Rates
in Various Stages of CKD
Literature
GFR
Cheung, 2004
CVD/ESRD Pathophysiology
• Multifactorial
• Traditional factors (Htn, volume overload,
smoking, HDL, oxidative stress)

• Non-Traditional (HCY, ADMA, Ca/P, ET)
• Common pathways:
• Stiff blood vessels
• Ischemia
Modifiable
Uremia-related Risk Factors
Traditional Risk Factors
Non-modifiable
Qunibi, Henrich, Berl
Age
Make Gender
Family History
Diabetes
Hypertension
Dyslipidemia
Smoking
Hyperhomocystinemia
Oxidative stress
Inflammation
Low serum albumin
Anemia
High PTH
High PO4
Low GFR
Increased ET
High CRP
Albuminuria
CHF
LVH
Arterial
Stiffness
PVD
CAD
MI
Suggestions and Observations
by Experts on Priorities
Eberhard Ritz
a. Sudden death accounts for 59% of deaths
now— focus on that problem!
b. Lower BP via a reduction in ECF volume
Concentric LVH
HTN
increased
afterload
Left
Ventricle
Uremic cardiomyopathy
Altered myocardial metabolism
Anemia
Hyperparathyroid
Angiotensin II
Progression of CKD
Myocyte dropout
Arteriolar wall thickening
Myocyte/capillary mismatch
Increased cardiac
output
Volume overload
Courtesy: J. Fink, M.D.
Eccentric LVH
• Ischemia
• Cardiac arrest
• CHF
• Death
Eccentric and Concentric LVH
Ecc LVH
Concen LVH
65%
N/A
ESRD – Incident
44%
Dialysis**
*Prevalence changes over time
** Prevalence of LVH 75%-80%
42%
Early CKD*
AJKD 34:125, 1999
Sem in Dialy 16:85, 2003
Correlation of LV Anatomy and LV Function
in ESRD Patients
n = 41
• % of patients with LVH (defined as PW or IVS  1.2 cm): 62%
• % of patients without LVH, SD or DD: 9.5%
• % of patients with isolated SD (with LVH): 5%
• % of patients with both SD and DD: 24%
• % of patients with isolated DD: 57%
– 58% of this group had LVH
– 42% of this group did not have LVH
JASN 9:275, 1998
Left Ventricular Diastolic Pressure
(mmHg)
Diastolic Pressure-Volume Relation in Patients
with Diastolic Heart Failure and in Controls
Patients with diastolic
heart failure
Controls
Left Ventricular Diastolic Volume (ml)
NEJM 350:1953, 2004
Risk of CV Death Related to Systolic Function
and LVH in 254 ESRD Patients
8
7
*P= 0.001
HR and 95% CI
6
5
4
3
2
1
0
No LVH and Normal
Ejection Fraction
JASN 15:1029, 2004
LVH or Reduced
Ejection Fraction
LVH and Reduced
Ejection Fraction
LVH, Sudden Death and Dialysis
• Abnormalities in coronary microcirculation
(myocyte/capillary mismatch)
• Impaired coronary reserve
• Reduced aortic compliance
•  activity of the SNS
•  activity of the renin-angiotensin system
• Sudden changes in [K]+, [Ca]++, [Mg]++
Number of cardiac arrests
Cardiac Arrests Occur Most Often on Monday
Day relative to facility being closed
Number of cardiac arrests relative to the day of the week of dialysis facility closure. *25
cases versus expected number of 15.7, P = 0.011, significance based on X2-test.
Kidney Int’l 73(8): 935, 2008
Myocardial Ultrasound Tissue
Characterization in Patients with
Chronic Renal Failure
Massimo Salvetti, Maria Lorenza Muiesan, Anna
Pain, Cristina Monteduro, Bianca Bonz, Gloria
Galbassini, Eugenia Belotti, Ezio Movilli , Giovanni
Cancarini and Enrico Agabiti-Rosei
JASN 18(6): 1953, 2007
Objective
To detect ultrastructural changes in myocardium related to
collagen content by U.S. in patients with CKD and
uncomplicated hypertensive patients
Patients
25 ESRD, 25 CKD, 10 HTN matched for age, BP, LVMI and EF
Methods
Key new measurement called integrated backscatter signal (IBS)
analyzed by acoustic densitometry
JASN 18(6):1953, 2007
Results
IBS is a measure of increased myocardial
collagen and was significantly increase in
HD and CKD patients. It correlated
positively with serum creatinine.
JASN 18(6):1953, 2007
JASN 18(6):1953, 2007
Conclusion
Interstitial collagen appears early in
CKD and acoustic densitometry is a
useful tool for detection.
Pathological Characteristics of Cardiomyopathy in
Dialysis Patients
• 40 dialysis patients and 50 “control” patients
with dilated cardiomyopathy had
endomyocardial biopsies
• Both groups had a decrease in EF (34/35%)
• Classification by NYHA (%)
Control
I
8
II
40
III
36
IV
16
Kidney Int’l 67:333, 2005
HD
0
28
48
25
A 63 yo Man on HD for 7.3 years
Bizarrely Shaped Myocytes with Irregular
Enlarged Nuclei
Kidney Int’l 67:333, 2005
56 yo Man on HD for 7.1 years
Widespread Fibrosis Present; Patient Died of
Ventricular Arrhythmia 1.1 Year after Biopsy
KI 67:333, 2005
56 yo Man on HD for 6.8 Years. Small Amount of
Fibrosis Present and No Cardiac Event
3.8 Years After Biopsy
KI 67:333, 2005
Cumulative Survival for Cardiac Death
Stratified by Extent of Fibrosis
Kidney Int’l 67:333, 2005
Conclusions
1. Uremic cardiomyopathy is characterized
by a derangement in myocardial myocyte
organization.
2. Uremic cardiomyopathy associated with
LVH is characterized by an increase in
intermyocyte fibrosis.
3. An increase in myocardial fibrosis is
associated with an increase in cardiac
deaths.
Uremia Stimulates Collagen Formation in
the Heart Secondary to Marinobufagenin
Procollagen-1 Expression
(arb units)
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Sham
PNx
MBG
0PNxIM
PNx=Uremia
MBG= Mini Pump
OPNx-IM-Immunized to MBG
Hypertension 49(6):215, 2007
Rapamycin Prevents Uremic Cardiac Fibrosis
Independent of BP
SHAM
Nx
NxV
NxR
Kidney Int 75(8):800, 2009
Rapamycin Prevents Uremic Cardiac Fibrosis
Independent of BP
Kidney Int 75(8):800, 2009
Effects of Short Daily vs. Conventional
Hemodialysis on Left Ventricular
Hypertrophy and Inflammatory Biomarkers
• Non randomized, controlled trial
• Short daily = 3 hr / HD x 6 d
• 4 hr / HD x 3 d
• n = 26 SD
• n = 51 Conventional
• Follow-up @12 months
JASN 16: 2778, 2005
Change in LVMI over 12 Months
210
190
LVMI (g/m2)
170
p<.01
P=NS
150
130
Baseline
12 Month
110
90
70
50
SDHD
CHD
Group
JASN 16: 2778, 2005
Impaired Systolic Function Pre/Post
Transplant
• 103 ESRD patients with LVEF < 40%,
restudied @ 6 and 12 months post - tx
• Mean LVEF 31.6 (± 7)% pre tx to 52.2 (± 12)%
post - tx; NYHA Class also improved
• No preoperative deaths
• Longer duration of dialysis pre- tx decreased the
likelihood of normalization of LVEF post - tx
JACC 45:1051, 2005
Pre -Tx Cx’s of 79 Patients
Age
All
Patients
n = 79
54
Post - Tx
EF < 40%
n = 25
54
Post - Tx
EF > 50%
n = 54
55
% AA
59%
60%
60%
% Male
71%
60%
72%
% CAD
51%
52%
50%
24
39*
17*
57%
56%
57%
Time on HD
(mos)
% NYHAIV
Pre/Post Tx LVEF in Different Subgroups of
Patients
60
50
LVEF%
40
30
Pre LVEF
Post LVEF
20
JACC 45:1051, 2005
DM
No DM
PTCA
No PTCA
CABG
No CABG
CAD
No CAD
0
All
10
Importance of Dry Weight Reduction for BP
Control
494 Patients were screened
346 were eligible
250 were consented
150 were randomized
100 were assigned to receive
Additional ultra filtration
9 patients did not
Complete the study
5 withdrew consent
3 were hospitalized
1 had high BP
91 completed the study
Hypertension 53: 500, 2009
50 were assigned to a
Control group
7 patients did not
Complete the study
1 withdrew consent
1 was transplanted
5 had high BP
43 completed the study
Importance of Dry Weight Reduction for BP
Control
UF
Control
n
100
50
Age
54
55
% AA
85
92
Pre BP
160/86
159/87
Post BP
143/78
143/78
% DM
40
38
Hypertension 53: 500, 2009
Importance of Dry Weight Reduction for BP
Control
• Ambulatory BP monitoring used in
the study
• Goal UF was 0 – 1 kg per 10 kg in wt
• No deterioration in QOL by survey
Hypertension 53: 500, 2009
Importance of Dry Weight Reduction for BP
Control
The effects of dry-weight reduction on interdialytic ambulatory systolic (A) and diastolic
BP (B) in hypertensive hemodialysis patients.
Hypertension 53: 500, 2009
Importance of Dry Weight Reduction for BP
Control
• Reduction in dry weight is a simple,
efficacious and well-tolerated
maneuver to improve BP in ESRD
patients.
Hypertension 53: 500, 2009
Suggestions/Observations, Con’t
George Bakiris
Lower intradialytic BP
Fosinopril Study
• RCT, n = 397; all had LVH on HD for 24 mos.
• 5 – 20 mg Fosinopril
• End-point= CVE’s
• 196 patients treated with Fosinopril 201
with placebo for 24 months
Kidney Int’l 70: 1318, 2006
ACEI Use in ESRD: Fosinopril of Benefit
Kidney Int’l 70: 1318, 2006
Suggestions/Observations, Con’t
Richard Glassock
a. Euvolemia
b. ACE/ARB
c. Control [Phosphate]
d. Replete Vit D, Pth to <500 pg/ml
e. Monitor LVH by Echo/MRI Q12 to 36 mos.
f. QD/Nocturnal HD
Suggestions/Observations, Con’t
Alfred Cheung
Renal diplipidemias— Not responsive to statins
(↑ TG’s, low LDL, High Lp(a), abnormal LDL,
oxidized LDL)
4D Study
• 1,255 patients, type 2 DM on HD
• 20 mg. lipitor vs. placebo
• Primary end point: composite of death
from cardiac causes, nonfatal MI and stroke
• Secondary end points: death from all
causes and all cardiac and cerebrovascular
end points combined
Median Change in LDL in 4D Study
Median LDL Cholesterol (mg/dl)
130
120
110
Placebo
100
90
80
70
60
Atorvastatin
50
40
30
20
10
0
Baseline
6
12
18
24
30
36
42
48
60
54
Month
NEJM 353(3):238, 2005
No. at Risk
Placebo
Atorvastatin
636 611 544
619 597 539
493 427 327 264
484 413 343 279
208
218
147
157
105
117
60
74
37
44
Cumulative Incidence of the Primary
Composite End Point (%)
Cumulative Incidence of Primary End Point
60
50
40
30
20
10
0
0
1
2
3
Year
NEJM 353(3):238, 2005
4
5
6
Conclusions from 4D
No significant effect of
atorvastatin on primary end point
in ESRD patients.
Rosuvastatin (10 mg) and CVE in ESRD
• RCT, n=2,776, age 50 to 80
• Primary End-Point: CVE’s,
death from CVD
NEJM 360(14):1395, 2009
Changes in Levels of LDL
NEJM 360(14):1395, 2009
Changes in Levels of TG’s
NEJM 360(14):1395, 2009
Changes in Levels of HDL
NEJM 360(14):1395, 2009
No Difference Between R and P Groups
NEJM 360(14):1395, 2009
Conclusion
Two well-done RCT’s
with a negative result.
Should we d/c statin therapy in
ESRD patients? Should we not
start it in ERSD patients who have
not yet been treated?
Suggestions/Observations, Con’t
Ravi Thadhani
A major consequence of renal
calification is the increase in PWV.
Risk Factors for Vascular Calcification
Clinical
Biochemical
Medications
Kidney Int’l: 1535, 2006
Age
Duration of dialysis
Kidney function/Uremia
Diabetes
Known coronary artery disease
Abnormal bone
Hyperphosphatemia
Hypercalcemia
Abnormal parathyroid hormone
Low fetuin-A
Elevated cytokines
Oxidative stress
Low pyrophosphate
Decreased MGP
Decreased BMP-7
Calcium-containing phosphate binders
High-dose vitamin D
Coumadin (decreases active MGP)
Role of Phosphate and Calcium on Vascular
Calcification in CKD
Kidney Int’l 68:429, 2005.
Comparison Between Calcification Score and
the Maximum Degree of Vessel Occlusion in
Coronary Arteries Measured by CT
Angiography
AJKD 43:313, 2004
Calcification Score Does Correlate with
Severity of Disease in ESRD Patients
• 82 patients asked to undergo CA and EBCT
• Patients selected for CA because they were renal
transplant candidates, had symptoms at rest,
exertional CP or recent MI.
• 62 agreed, and 46 had CA w/in 12 months of the CA
• CA before EBCT, n = 36; EBCT before CA, n = 10
• > 50% luminal narrowing “significant”
• 16 HD patients
– 4 CAPD patients
– 8 GFR < 25
– 18 post renal transplant
NDT 19:2307, 2004
Calcium Score and Number of Coronary
Vessels Involved
Total Calcium Score
4000
3000
2000
1000
0
One
NDT 19:2307, 2004
Two
Number of Vessels Involved
Three
Survival distribution
function
Importance of CAC Score in Incident ESRD
Patients
P=0.02
CAC=0
CAC1-400
CAC>400
Months
Kidney Int’l : 438, 2007
Pulse Pressure Increased in Setting of
Increased Vessel Stiffness
AJKD 45:965, 2005
Pulse Wave Velocity Increases as Renal
Function Decreases
p<0.001 for trend
12
11.6
10.4
10
8.9
7.5
PWV (m/s)
8
4
1
2
3
(n=24)
(n=30)
4
5
0
(n=12)
(n=15)
Stage of Chronic Kidney Disease
AJKD 45:494, 2005
(n=21)
Effect of Vascular Calcification on PWV
2000
P – value = 0.002
Median calcium score
1800
1852.0
1600
1400
PWV < 12 m/s
PWV > 12 m/s
1200
1000
800
600
P – value = 0.307
400
200
470.1
323.3
161.5
0
Coronary artery
calcium score
Kidney Int’l: 802, 2007
Thoracic aorta
calcium score
Conclusions
• Vessel calcifications are common in ESRD
• Having calcifications worse prognosis than not having
calcifications
• Vessel calcification in ESRD is located in intima and
medial areas of vessel – unknown correlation with
intimal narrowing
• Badly need studies which:
– Correlate calcification to outcomes/events
prospectively
– Correlate calcification to ischemia and anatomy
prospectively
– Intervene to reduce or retard calcification and then
track CV outcomes prospectively
Management - 1
• Maintain euvolemia (increased use of extra sessions,
nocturnal or quotidian dialysis
• Excellent BP control (pre-dialysis SBP <130/80), using
ACEI/ARB as first line agents where needed
• Monitor for LVH/LVMI with an echocardiogram or MRI
(no contrast) Q 12-24 months
• Manage Ca/P to a low pre-dialysis P, if possible, and a
PTH of less than 500 pg/ml (or 1.5 to 2 times normal);
replete Vitamin D where possible; controversy over Cacontaining vs. non-Ca-containing Phosphate binders at
present.
• Hematocrit to guidelines
Management - 2
• Avoid catheters
• Improved nutrition
• LDL-C to <100 mg/dl, <70 in patients with
documented CAD
• Cautious used of B-Blockers for low EF Systolic
Failure
• Passive resistance exercise where feasible
• Stay tuned for evidence of benefit of aldosterone
blocking agents on myocardial fibrosis/sudden death
“Actionable” Variables in ESRD: Effects on
Mortality
AJKD 53(1): 79, 2009