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