Alan S. Kliger MD
Hospital of St. Raphael
Yale University School of Medicine
New Haven CT

Best Opportunities to Improve
Outcomes
Increase Dialysis Dose
Reduce Inflammation
Decrease LVH
Restore fluid balance and BP
Reduce Sympathetic Activity
Reduce Depression

Cardiovascular disease mortality general population vs ESRD patients
100
10
1
0.1
0.01
GP Male
GP Female
GP Black
GP White
Dialysis Male
Dialysis Female
Dialysis Black
Dialysis White
0.001
25-34 35-44 45-54 55-64 66-74 75-84 >85
Age (years)
GP = General Population.
Foley RN, et al. Am J Kidney
Dis . 1998;32:S112-S119.

4

5

HEMO Study: Survival by dose group
1,846 Patients
Eknoyan et al, N Eng J Med 2002

THE DEATH-RATE
WAS THREE TIMES
THAT OF BREAST
CANCER AND HIV,
TWICE THAT OF
PROSTATE CANCER
Slide courtesy of
Dr. Kjellstrand
HIV
BREAST
CANCER
PROSTATE
CANCER
HEMO

Post-Hoc Analysis of HEMO
Study
Limited separation between treatment groups for unified dose measures, such as
Standard Kt/V ≅ [urea generation rate] / [average (C
0
)]
Separation in Std Kt/V in HEMO Trial
Mean = 2.19 Mean = 2.53
2.88
2.59
2.30
Only 16% difference in mean Std Kt/V between dose groups
2.02
Standard
Dose
High
Dose

Effect of increasing length of dialysis
Three sessions per week
7
6
5
4
3
2
1
0
0.0
HEMO: Standard
0.5
1.0
1.5
HEMO: High
Dialysis dose each dialysis (eKT/V)

3
2
1
0
0.0
4
6
5
7
Effect of increasing number of dialysis sessions per week
Daily
Dialysis
6
Hemodialysis sessions/wk
HEMO: High
HEMO: Standard
0.5
1.0
1.5
Dialysis dose each dialysis (eKT/V)
3

Variable
SBP or MAP*
Serum phosphorus or binder dose*
Outcome
Decrease
No change
Anemia (Hb, HCT or EPO dose) Improvement
# studies
10 of 11
6 of 8
7 of 11
Serum albumin
HRQOL
Increase
Improvement
Vascular access dysfunction No change
Suri R. et al. CJASN 1:33-42, 2006
5 of 10
6 of 12
5 of 7
12

Retrospective Analysis of
Survival for 415 Patients Treated with Short Daily Hemodialysis
• 10 year survival: 42+9%
• Compared with matched patients from
USRDS:
– Daily dialysis patient survival was 2-3 times higher
– Predicted survival times were 2.3 -10.9 yrs longer for daily dialysis patients
Kjellstrand et al NDT 23:3283, 2008

I
V
A
L
S
U
R
V
C
U
M
100
75
50
USRDS
CAD TX
2005
SHORT DAILY
HOME HD
N=265
25
USRDS
PD AND HD
SURVIVAL
0
0 5 10
Slide courtesy of Dr. Kjellstrand YEAR
15 20 25

Variable
Outcome # studies
SBP or MAP*
Number of antihypertensives*
Decrease
Decrease
Serum phosphorus or binder dose No change
4 of 4
4 of 4
1 of 2
Anemia (Hb, HCT or EPO dose)* Improvement 3 of 3
HRQOL Improvement Variable+
Walsh M et al. Kidney Int 67:1500-1508, 2005
Walsh M et al Kidney Int 67: 1500-1508, 2006
15

Alberta RCT Nocturnal HD vs
Conventional HD
• Primary Outcome: Change in LV mass
• 52 patients randomized
• 44 had baseline MRI
• 35 had follow-up MRI after 6 months
– No second MRI
• 6 refused
• 2 transplanted
• 1 died
Culleton et al JAMA 298:1291, 2007
16

Baseline
Exit
Change
Conventional
HD
Nocturnal
HD
181.5 (92.3) 177.4 (51.1)
183.0 (84.2) 163.6 (45.2)
1.5 (24.0) -13.8 (23.0)
Estimated Treatment Effect on LV Mass (Gm)
Last observation carried forward (n=44): 15.3, CI (+1.0, +29.6 )
Observed data only (n=35): 19.7, CI (+1.9, +37.4 )
Culleton et al JAMA 298:1291, 2007 17

Nocturnal Home Hemodialysis
(NHHD)
Nocturnal Hemodialysis Improves
Erythropoietin Responsiveness and
Growth of Hematopoietic Stem Cells
– 16 patients switched from conventional HD to NHHD
– Kt/V urea increased from 1.27+0.06 to
2.23+0.09
– Phosphorus and PTH levels fell
– BP and BP medications fell
Chan JASN Express Dec 17 2008

Nocturnal Home Hemodialysis
(NHHD)
– Hb rose from 11.3+0.3 to 12.5+0.4 Gm/dL with no change in EPO or iron
– Cell culture studies and gene profiling showed up regulation of genes responsible for hematopoetic progenitor cells after more intensive HD.
– NHHD increases growth and production of
RBCs.
Chan JASN Express Dec 17 2008

Frequent Hemodialysis Network
2 parallel RCT
1. Comparing in-center 6x/wk dialysis to conventional 3x/wk dialysis
2. Comparing home nocturnal 6x/wk dialysis to conventional 3x/wk home dialysis

FHN Study Designs
Daily In-Center
Patients from 10 regional centers
Nocturnal
Patients from 9 regional centers
250 pts randomized over 46 mo.
12 months
6x/Week
Daily
In-center HD
12 months
3x/Week
Conventional
In-center HD
Compare outcomes after 1 year
90 pts randomized over 27 mo.
1.5 months training +
12 months
6x/Week
Nocturnal HD
12 months
3x/Week
Conventional
Home HD
Compare outcomes after 1 year

4
3
2
6
5
1
0
7
2.46
+55%
3.82
+108
5.12
3X w eek HD Daily HD Nocturnal HD
22

1600
1400
1200
1000
800
600
400
200
0
299
+39%
415
1218
+328%
3X week HD Daily HD Nocturnal HD
23

12
10
8
6
4
2
0
4.73
+ 3%
4.88
+91%
9.03
3X week HD Daily HD Nocturnal HD
24

• Composite of 1-year mortality and change in LV mass by cardiac cine-
MRI
• Composite of 1-year mortality and change in RAND PHC from SF- 36
25

9 Main Outcome Domains
# Domain Main Outcome
1
Cardiovascular structure /
Function

LV mass by cardiac MRI
2
Health related QOL /
Physical function

SF-36 Physical Health Composite
3 Depression / Burden of illness

Beck Depression Index
4 Cognitive function

Trail Making B Score
5 Nutrition/Inflammation
6 Mineral metabolism

Serum Albumin

Serum Phosphorus
7 Survival / Hospitalization
8 Hypertension
Non-Access Hospitalization/Death
Rate
Several outcomes
9 Anemia Several outcomes

Clinical Centers for Daily Trial
RRI and UCSF/Stanford Cores
Univ. of Western Ontario
– Dr. Robert Lindsay
Washington Univ. (MO)
-- Dr. Brent Miller
RRI: New York City (NY)
– Dr. Peter Kotanko
Vanderbilt University (TN)
– Dr. Gerald Schulman
Wake Forest University (NC)
– Dr. Michael Rocco
UCSF/Stanford
– Dr. Glenn Chertow
Univ. California, Davis
– Dr. Thomas Depner
Peninsula Dialysis: (CA)
–
Dr. George Ting
UCLA
– Dr Anjay Rastogi
UCSD

Clinical Centers for Nocturnal
Trial
Univ. of British Columbia
– Dr. Michael Copland
Humber River Hosp
– Dr. Andreas Pierratos
University of Toronto
– Dr. Chris Chan
Univ. of Western Ontario
– Dr. Robert Lindsay
Rubin Dialysis (NY)
– Dr. Christopher Hoy
University of Iowa
– Dr. John Stokes
Lynchburg Nephrology
– Dr. Robert Lockridge Jr.
Wake Forest University
– Dr. John Burkart
Washington University
– Dr. Brent Miller

Daily Nocturnal
Goal
Enrolled
Randomized
250
378
245
90
118
81

Daily Nocturnal
Randomization Ends 3/2009 5/2009
Study Period Ends 3/2010 5/2010
Report Results late 2010-2011

Cost-Effectiveness of Frequent in-Center Hemodialysis
• Monte Carlo simulation model
• Inputs:
– Various frequencies and duration of HD (3-
6x/wk, 2-4.5 hrs/session)
– Outcomes: costs, life expectancy, QALY
– Assumptions on potential effects of frequent dialysis on outcomes –
(ex: 32% reduction in mortality with
6x/wk)
Lee CO et al JASN 19:1792, 2008

Cost-Effectiveness of Frequent in-Center Hemodialysis
• Incremental cost-effectiveness ratio will be at least $75,000/ life year gained
• None of the strategies using 6x/wk HD achieved a cost-effectiveness ratio of
< $125,000/ life year gained
Lee CO et al JASN 19:1792, 2008

Cost-Effectiveness of Frequent in-Center Hemodialysis
How could costs “break even”?
• If the per-session costs were reduced between 32 and 43%
• Reduction in hospitalization rate
– For 4 HD/wk, need to reduce hospitalization to 46% of current rate
– For 5 HD/wk, need to eliminate hospitalizations
Lee CO et al JASN 19:1792, 2008

Cost-Effectiveness of Frequent in-Center Hemodialysis
Conclusions
• More frequent in-center HD strategies would likely increase ESRD program costs considerably.
• Transition to home-based therapies will be required to derive any benefit that might be present without incurring excessive costs.
Lee CO et al JASN 19:1792, 2008

• 16 patients in New Haven switched from conventional to INHD
– Kt/V urea rose from 1.2+0.16 to 2.6+0.65
– UF rate fell from 10.3+4.5 to 5.9+1.7 mL/hr/kg
– Phosphorus fell from 5.3+1.3 to 4.4+1.1mg/dL
– No change in psychosocial assessments (QoL)
Troidle Adv Chronic Kid Dis 14:244,2007

• 39 patients in Toronto switched from conventional to 8 hr INHD
– URR increased from 74% to 89%
– Phosphorus fell from 5.9 to 3.7 mg/dL
– Number of antihypertensive drugs: 2.0 to 1.5
– ESA use fell significantly
– QoL, sleep, intradialytic cramps, appetite, energy level all improved significantly
Bujega CJASN April 2009

• 224 pts in Turkey switched from conventional to 8 hour INHD
– Compared prospectively with matched cohort
224 pts on conventional 4 hour HD 3 days/wk
– INHD patients had
•25% hospitalization rate
•78% reduction in mortality
•Less intradialytic hypotension, lower phosphate, reduced arterial stiffness
•Improved cognitive function
Ok E: ASN abstract F-FC-317 2008

Home
3x/wk
QOD
4x/wk
7x/wk
INHD
PD
5x/wk
6x/wk
Frequent HD in USA:
Current Status
DaVita FMC* Satellite
70
17
50
696
764
5
842
9,207
(O RCG)
163
33
8
6
3
1
785
7,921
88
0
10
648
5
2
6
39

NxStage Growth 2004 to 2008
4000
3100
3000
2223
2000
1000 45
8
295
70
1022
174
334
0
2004 2005 2006 2007 2008
400
NxStage Daily Patients
NxStage HT Centers
Courtesy Dr Lockridge

International Quotidian Dialysis
Registry
• Standard Daily HD: >2 hrs, 5-7x/wk
• Nocturnal HD: > 6 hrs, 3-7x/wk
• Enrollment as of Mar, 2009:
US 1,260
ANDATA 1,210
Canada 225
Total 2,695
Nesrallah GE, on behalf of the quotidian dialysis international working group

• More intensive dialysis is needed to improve ESRD patient outcomes
• Observational trials suggest better anemia care, phosphorus control, fluid and BP management with intensive HD
• Retrospective analysis shows improved survival with intensive dialysis

• Frequent in-center HD (4-6 HD/wk) is more costly - unless per-treatment HD costs fall
• Frequent home HD (4-6HD/wk) is increasing slowly
• NHHD is promising, but utilized by few patients
• INHD is the fastest growing – in US and internationally - with more efficient use of facility space improving financial viability

• RCT of NHHD and daily in-center HD in progress
• International Quotidian Dialysis Registry may give us meaningful information on the effect of intensive HD on mortality and hospitalization