ESRD: State of the Art ConferenceOptimal CV-Renal Therapy
Over the Next 5 Years
William L. Henrich, MDUniversity of Texas Health Science Center
at San Antonio
NEJM 2004;351:1285-1295.
CV Causes
Estim
ated
Eve
nt R
ate
(%)
P<.001
0
10
20
30
40
50
60
Death From Re-infarction CHF Stroke Resuscitation CompositeEnd Point
(mL/min/1.73 m2)
<45 GFR(mL/min/1.73 m2)
60-74.9 GFR(mL/min/1.73 m2)
The Problem – Causes of Death in CKD Patients
*14,527 patients with HF or LV dysfunction post-MI
Courtesy of Allen R. Nissenson, MD, FACP
(mL/min/1.73 m2)
CV
AJKD Vol 45, No 4, Suppl 3, April 2005
Hypothetical CV Risk Factors and Event Rates
in Various Stages of CKD
GFR
Literature
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
Qunibi, Henrich, Berl
CHF
Arterial Stiffness
LVH
MI
CAD
Trad
ition
al R
isk
Fact
ors
Ure
mia
-rel
ated
Ris
k Fa
ctor
s
Modifiable
Non-modifiable
HypertensionDyslipidemiaSmokingHyperhomocystinemiaOxidative stressInflammationLow serum albumin
AgeMake GenderFamily HistoryDiabetes
AnemiaHigh PTHHigh PO4Low GFRIncreased ETHigh CRPAlbuminuria
PVD
Eberhard Ritza. Sudden death accounts for 59% of deaths now— focus on that problem!
b. Lower BP via a reduction in ECF volume
Suggestions and Observations by Experts on Priorities
LeftVentricle
HTNincreasedafterload
Concentric LVH
Uremic cardiomyopathyAltered myocardial metabolism
• Ischemia• Cardiac arrest• CHF• Death
Eccentric LVH
AnemiaHyperparathyroid
Angiotensin II
Myocyte dropoutArteriolar wall thickening
Myocyte/capillary mismatch
Progression of CKD
Increased cardiacoutput
Volume overload
Courtesy: J. Fink, M.D.
Eccentric and Concentric LVH
Ecc LVH Concen LVH
Early CKD* 65% N/A
ESRD – Incident Dialysis**
44% 42%
*Prevalence changes over time** Prevalence of LVH 75%-80%
AJKD 34:125, 1999Sem 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
Diastolic Pressure-Volume Relation in Patients with Diastolic Heart Failure and in Controls
NEJM 350:1953, 2004
Left Ventricular Diastolic Volume (ml)
Left
Vent
ricul
ar D
iast
olic
Pre
ssur
e(m
mH
g)
Controls
Patients with diastolicheart failure
*P= 0.001
Risk of CV Death Related to Systolic Function and LVH in 254 ESRD Patients
JASN 15:1029, 2004
0
1
2
3
4
5
6
7
8
HR
and
95%
CI
No LVH and NormalEjection Fraction
LVH or ReducedEjection Fraction
LVH and ReducedEjection 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]++
Cardiac Arrests Occur Most Often on Monday
Day relative to facility being closed
Num
ber o
f car
diac
arr
ests
Kidney Int’l 73(8): 935, 2008
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 X
2-test.
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 HD
I 8 0 II 40 28III 36 48
IV 16 25
Kidney Int’l 67:333, 2005
A 63 yo Man on HD for 7.3 yearsBizarrely Shaped Myocytes with Irregular
Enlarged Nuclei
Kidney Int’l 67:333, 2005
56 yo Man on HD for 7.1 yearsWidespread 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.
Hypertension 49(6):215, 2007
PNx=UremiaMBG= Mini PumpOPNx-IM-Immunized to MBG
Proc
olla
gen-
1 Ex
pres
sion
(arb
uni
ts)
0.0
1.5
2.0
3.0
2.5
0.5
0PNx-IMMBGPNxSham
Uremia Stimulates Collagen Formation in the Heart Secondary to Marinobufagenin
1.0
Kidney Int 75(8):800, 2009
Rapamycin Prevents Uremic Cardiac Fibrosis Independent of BP
SHAM
NxR
Nx
NxV
Kidney Int 75(8):800, 2009
Rapamycin Prevents Uremic Cardiac Fibrosis Independent of BP
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
50
70
90
110
130
150
170
190
210
LV
MI
(g/m
2)
SDHD CHD
Group
Baseline12 Month
JASN 16: 2778, 2005
p<.01 P=NS
Impaired Systolic Function Pre/Post Transplant
JACC 45:1051, 2005
• 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
Pre -Tx Cx’s of 79 Patients
All Patientsn = 79
Post - Tx EF < 40%
n = 25
Post - Tx EF > 50%
n = 54Age 54 54 55
% AA 59% 60% 60%
% Male 71% 60% 72%
% CAD 51% 52% 50%
Time on HD (mos)
24 39* 17*
% NYHAIV 57% 56% 57%
0
10
20
30
40
50
60L
VE
F%
All
No C
AD
CA
D
No C
AB
G
CA
BG
No P
TC
A
PT
CA
No D
M
DM
Pre LVEFPost LVEF
Pre/Post Tx LVEF in Different Subgroups of Patients
JACC 45:1051, 2005
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 receiveAdditional ultra filtration
50 were assigned to a Control group
9 patients did notComplete the study 5 withdrew consent 3 were hospitalized 1 had high BP
7 patients did notComplete the study 1 withdrew consent 1 was transplanted 5 had high BP
91 completed the study 43 completed the study
Hypertension 53: 500, 2009
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 CheungRenal diplipidemias— Not responsive to statins (↑ TG’s, low LDL, High Lp(a), abnormal LDL, oxidized LDL)
• 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
4D Study
Median Change in LDL in 4D Study
130
110
706050
4030 20
10
6054486 12 18 24 30 36 420
Baseline
8090
100
120
Placebo
Atorvastatin
Med
ian
LDL
Chol
este
rol (
mg/
dl)
No. at RiskPlacebo 636 611 544 493 427 327 264 208 147 105 60 37Atorvastatin 619 597 539 484 413 343 279 218 157 117 74 44
NEJM 353(3):238, 2005
Month
Cumulative Incidence of Primary End Point
NEJM 353(3):238, 2005
20
10
0
30
50
40
60
610 2 3 4 5
Cum
ulati
ve In
cide
nce
of th
e Pr
imar
y Co
mpo
site
End
Poi
nt (%
)
Year
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
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
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 Age
Duration of dialysis Kidney function/Uremia Diabetes
Known coronary artery disease Abnormal boneBiochemical Hyperphosphatemia Hypercalcemia Abnormal parathyroid hormone Low fetuin-A Elevated cytokines Oxidative stress Low pyrophosphate Decreased MGP Decreased BMP-7Medications Calcium-containing phosphate binders High-dose vitamin D Coumadin (decreases active MGP)
Kidney Int’l: 1535, 2006
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
0
1000
2000
3000
4000
To
tal
Ca
lciu
m S
co
re
One Two Three
Number of Vessels Involved
NDT 19:2307, 2004
Importance of CAC Score in Incident ESRD Patients
P=0.02
CAC=0CAC1-400CAC>400
Surv
ival
dis
trib
utio
n fu
nctio
n
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
7.5
8.9
10 10.4
11.6
0
4
8
12
PW
V (
m/s
)
(n=12) (n=24) (n=30) (n=15) (n=21)
Stage of Chronic Kidney Disease
AJKD 45:494, 2005
1 2 3 4 5
p<0.001 for trend
Effect of Vascular Calcification on PWVM
edia
n ca
lciu
m s
core
2000
1200
1000
800
600
400
200
0
1800
1600
1400
Coronary artery calcium score
Thoracic aorta calcium score
PWV < 12 m/sPWV > 12 m/s
161.5
323.3
P – value = 0.307
P – value = 0.002
470.1
1852.0
Kidney Int’l: 802, 2007
• 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
Conclusions
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 Ca-containing 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
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