Advancingdialysis.org 2017 ASN Sponsored Symposium Presentation

AdvancingDialysis.org
Addressing Unmet Needs
in Dialysis
Cardiovascular Care and Volume Control

Disclosures
Mike Kraus, MD,
FACP
Allan J. Collins, MD,
FACP
Peter McCullough,
MD, MPH, FACC,
FACP, FCCP, FAHA,
FNKF
Paul Komenda, MD,
MHA, FRCPC
Bill Davis
Scientific Advisory
Board Member:
NxStage Medical, Inc.
Unrestricted
Educational Grants:
Keryx
Biopharmaceuticals,
Inc.
Satellite Healthcare
Inc.
Fresenius Medical
Care
Chief Medical
Officer NxStage
Medical
Consulting
Epidemiology:
FibroGen
Dialysis Providers:
Executive Director
Peer Kidney Care
Initiative with 7 NPO
and 6 FP CMO
provider groups
Scientific Advisory
Board Member:
Consulting
Epidemiology:
Fresenius
Scientific Advisory
Board Member:
NxStage Medical,
Inc., Boehringer
Ingelheim, Otsuka,
Alexion
Paid Speaker:

Important information
All forms of hemodialysis, including treatments performed in-center and at
home, involve some risks. In addition, there are certain risks unique to
treatment in the home environment. Patients differ and not everyone will
experience the reported benefits of more frequent hemodialysis.
Certain risks associated with hemodialysis treatment are increased when
performing nocturnal therapy due to the length of treatment time and
because therapy is performed while the patient and care partner are
sleeping.

Addressing a
Case in Unmet
Need
Case in Unmet Need
Discussion Lead:
Michael Kraus, MD, FACP
Indiana University School of Medicine
1. The DOPPS Practice Monitor. http://www.dopps.org/DPM/. Accessed May 20, 2015.

Where it all begins
• Mr. B.D.
‒ 52 yo bm
‒ APKD
‒ Prior PD, transplant times 13 years
‒ Transplant with acute failure due to Renal vein thrombosis, initiates
thrice weekly HD (Texas)
‒ PD cavity is full of adhesions on laparoscopy
‒ Continues on in-center dialysis
‒ Transfers to your dialysis shift

Hemodialysis
• IHD 4 hours daily, 3x/week
• Hypertension controlled on 3 drugs
• Increased PO4
• Post dialysis fatigue
• On transplant list – no partner
Due to dialysis he abruptly “retired”
Lives in Florida 6-months a year and wants to be more active
Increased frequency home hemodialysis

After training and going home
• Afib
• Echo – LVH (1.4 cm septum and PW thickness), Decreased LVEF 30%,
diastolic dysfunction
• Pulmonary Hypertension
• Minimal diffuse valvular changes
• Cardiac Catheterization with normal coronary anatomy

Cardiovascular
Clinical
Considerations
Discussion Lead:
Peter McCullough, MD, MPH, FACC, FACP, FCCP, FAHA, FNKF
Baylor University Medical Center
2. Kotanko P, Garg AX, Depner T, et al. Effects of frequent hemodialysis on blood pressure: Results from the
randomized frequent hemodialysis network trials. Hemodial Int. 2015;19(3):386-401. doi:10.1111/hdi.12255.

Outline
• Blood pressure
• Left ventricular hypertrophy
• Myocardial stunning
• Clinical outcomes

AUDIENCE POLL:
Which choice discloses the three major mechanisms of
left ventricular failure?
1) Pressure overload, volume overload, and cardiomyopathy
2) Atrial fibrillation, reduced ejection fraction, mitral regurgitation
3) Excess salt intake, hypertension, and myocardial infarction
4) Viral infarction, alcohol intake, and B-vitamin deficiency
5) Erythropoietin toxicity, left ventricular hypertrophy, and tachycardia
10

Effective Fluid Management
Associated with Better
Cardiovascular Outcomes
VOLUME
OVERLOADPRESSURE
OVERLOADINTRADIALYTIC
MYOCARDIAL
STUNNING
CARDIOVASCULAR
RELATED DEATH
CARDIOMYOPATHY

AUDIENCE POLL:
The pre-hemodialysis systolic blood pressure range with
the lowest hazard ratio for mortality is:
1) 90-120 mm Hg
2) 120-140 mm Hg
3) 130-160 mm Hg
4) 160-180 mm Hg
5) >180 mm Hg
10

1-year Cumulative
Systolic Blood
Pressure and
Mortality1
1.Carmine Zoccali et al. Chronic Fluid Overload and
Mortality in ESRD. JASN 2017;28:2491-2497. doi:
10.1681/ASN.2016121341

AUDIENCE POLL:
After 12 months of home hemodialysis, what percent of
patients will require no antihypertensive therapy?
1) <1%
2) 5%
3) 17%
4) 34%
5) 42%
10

Antihypertensive Medications
Needed in Home HD Patients
Statistically Significant Decline in Utilization
Nair S. et al. New European evidence with Home HD Patients: 12 months follow-up in KIHDNEy cohort.
Presented at 54th ERA-EDTA conference 2017, Madrid.
Mean
Agents/day
% using
No Rx
% using
≥2 Rx
Baseline 1.51 27% 42%
Month 6 1.12 36% 34%
Month 12 0.91 42% 25%
p for trend <0.001 <0.001 <0.001

Clinical Consequences of
Increased Left Ventricular
Mass
Thickening of the LV wall (left
ventricular hypertrophy) can
stimulate a vicious cycle
• Lead to more LVH progression
• Complicated by ESRD uremic
risk factors
• Lead to heart failure
• Lead to arrhythmias and
sudden death

AUDIENCE POLL:
With home hemodialysis there is a reduction in left
ventricular hypertrophy. With each 10-gram reduction in
LV mass, what is the associated reduction in mortality?
1) 8%
2) 18%
3) 28%
4) 38%
5) 48%
10

More Frequent
Hemodialysis
Regression of Left
Ventricular Hypertrophy
1. McCullough PA, Chan CT, Weinhandl ED, Burkart JM, Bakris
GL. Intensive Hemodialysis, Left Ventricular Hypertrophy, and
Cardiovascular Disease. American Journal of Kidney Diseases,
Volume 68, Issue 5, S5 - S14.
…each 10-point
decrement in percentage
change in left ventricular
mass was associated
with 28% lower risk for
cardiovascular death…1

High Ultrafiltration Rates Correlated
to Intradialytic Hypotension
15.4
13.5
3.4
0.6
0
2
4
6
8
10
12
14
16
18
Center
3x/wk
Center
5x/wk
Home
5x/wk
Home
Nocturnal
-41.7
-18.5
-1.5
17.1
-50
-40
-30
-20
-10
0
10
20
30
Center
3x/wk
Center
5x/wk
Home
5x/wk
Home
Nocturnal
1.Jefferies et.al. Frequent hemodialysis schedules are associated with reduced levels of dialysis-induced
cardiac injury (Myocardial stunning). Clin J Am Soc Neprhol 2011 June, 6(6); 1326-1332.
Higher Ultrafiltration Rates Greater Drops in Blood Pressures

Regional Wall Motion Abnormalities
Shown to Increase Mortality Risk1
15.4
13.5
3.4
0.6
0
2
4
6
8
10
12
14
16
18
Center
3x/wk
Center
5x/wk
Home
5x/wk
Home
Nocturnal
4.8 4.6
3.3
3.0
0
1
2
3
4
5
6
Center
3x/wk
Center
5x/wk
Home
5x/wk
Home
Nocturnal
1.Burton, JO et al., Hemodialysis-Induced Cardiac Injury: Determinants and Associated Outcomes. Clin J Am Soc
Nephrol 4: 914–920, 2009. 2.Jefferies et.al. Frequent hemodialysis schedules are associated with reduced levels of
dialysis-induced cardiac injury (Myocardial stunning). Clin J Am Soc Neprhol 2011 June, 6(6); 1326-1332.
Higher Ultrafiltration Rates More Wall Motion Abnormalities2

AUDIENCE POLL:
Regional wall motion abnormalities of the left ventricle
over the course of dialysis are associated with all of the
above except:
1) Use of cinacalcet
2) Intradialytic hypotension
3) High ultrafiltration rate
4) Three times per week dialysis
5) Higher mortality
10

AGGRESSIVE
ULTRAFILTRATION
RATES
HYPOVOLEMIA
INTRADIALYTIC
HYPOTENSION
REGIONAL WALL MOTION
ABNORMALITIES
CARDIAC HYPO-
PERFUSION
2/3 of conventional
hemodialysis patients suffer
from recurrent HD-induced
ischemic injury1
MYOCARDIAL
STUNNING
1.Jefferies et.al. Frequent hemodialysis schedules are associated with reduced levels of dialysis-induced cardiac
injury (Myocardial stunning). Clin J Am Soc Neprhol 2011 June, 6(6); 1326-1332. Graphical summary source: Flythe
JE, Brunelli SM: The risks of high ultrafiltration rate in chronic hemodialysis: implications for patient care. Semin Dial 24(3):259-265, 2011

Over 41% of all deaths were
cardiovascular-related, with
nearly identical percentages in
hemodialysis and peritoneal
dialysis patients.1
CHAPTER 1, FIGURE 2:
Distribution of primary cause of death in
hemodialysis patients, 2011 to 2013.2
1.Saran R, Li Y, Robinson B, et al. US Renal Data System 2014 Annual Data Report: Epidemiology of Kidney
Disease in the United States. 2.Am J Kidney Dis Off J Natl Kidney Found. 2015;66(1 Suppl 1):Svii, S1-305.
doi:10.1053/j.ajkd.2015.05.001
Cardiovascular-related Deaths in
Prevalent Dialysis Patients are
Common

The FHN Trial Group. In-Center Hemodialysis Six
Times per Week versus Three Times per Week. The
New England Journal of Medicine. 010:363;2287-2300.
Frequent
Hemodialysis
Associated with
12-month
Improvements in
Several
Cardiovascular
Markers1
Likely due to improved
control of extracellular
volume excess.
Left ventricular mass
Adjusted mean reduction of
16.4±2.9 g versus 2.6±3.2
(P<0.001)
12%
REDUCTION
FHN RANDOMIZED CLINICAL TRIAL FINDINGS:
Hypotensive episodes
10.9% vs. 13.6% of monitored
sessions with at least one
episode, (P=0.04)
20%
FEWER
Systolic blood pressure
Adjusted mean SPB decrease
9.7±18.2 mm Hg versus 0.9±16.2
mm Hg (P<0.001)
7%
DECREASE
Antihypertensive agents
Change from baseline agents
decreased 0.87±1.85 versus
−0.23±1.35 (P< .001)
32%
LESS

Daily home hemodialysis patients had
20%-25% fewer CV hospital days per patient-
year than in-center HD patients:
↓ 25% lower risk for cerebrovascular disease
↓ 41% lower risk for heart failure, ﬂuid
overload, and cardiomyopathy
↓ 16% lower risk for hypertensive disease
McCullough PA, Chan CT, Weinhandl ED, Burkart JM, Bakris GL. Intensive Hemodialysis, Left Ventricular
Hypertrophy, and Cardiovascular Disease. American Journal of Kidney Diseases, Volume 68, Issue 5, S5 - S14.
Cardiovascular Benefit of
Home Dialysis

58%
5-year survival
+8,000
HHD Patients
More Frequent
HHD*
50%
5-year survival
+45,000
PD Patients
Peritoneal Dialysis
40%
5-year survival
+420,000
Conventional HD Patients
In-center HD
More frequent HHD is
associated with better 5-year
relative survival
5-year patient survival after initiating
treatment
U.S. Renal Data System, USRDS 2015 Annual Data Report: Table 6.3. Adjusted survival (%) by (a) treatment
modality and incident cohort year (year of ESRD onset), and (b) age, sex, race, and primary cause of ESRD,
for ESRD patients in the 2008 incident cohort (initiating ESRD treatment in 2008) Abbreviation: ESRD, end-
stage renal disease. *Data source: NxStage patient data on file

Addressing Unmet Needs
in Cardiorenal Care
Chronic Fluid Overload and
Mortality in ESRD
FO = Fluid Overload
Determined by Bioimpedence
1.Carmine Zoccali et al. Chronic Fluid Overload
and Mortality in ESRD. JASN 2017;28:2491-2497.
doi: 10.1681/ASN.2016121341

Therapy
Prescription:
More Frequent
Home
Hemodialysis
Discussion Lead:
Allan Collins, MD, FACP
University of Minnesota School of Medicine
Chief Medical Officer, NxStage Medical, Inc.
Zoccali C et al. Chronic fluid overload and mortality in ESRD. J Am Soc Nephrol. 2017. (in press)

AUDIENCE POLL:
How do you think of therapy prescription for more
frequent home hemodialysis?
1) Solute removal to achieve target
KT/V
2) Fluid control
3) Patient tolerance to the therapy
4) PO4 control
5) All the above
10

AUDIENCE POLL:
More frequent HD is targeted at which areas of unmet
need?
1) Fluid overload
2) Uncontrolled BP
3) LVH/Heart Failure
4) Patient tolerance to the therapy
5) All the above
10

Pathophysiology and Outcomes
Challenges with Thrice-Weekly Hemodialysis
1.Rocco MV, Burkart JM. Prevalence of missed treatments and early sign-offs in hemodialysis patients. J Am
Soc Nephrol. 1993 Nov;4(5):1178-83.
Fluid
Overload
Uncontrolled
Hypertension
Left Ventricular
Hypertrophy
Heart Failure
Hospitalizations
and Death
“Early Sign-
Offs”
and “No-Shows”
1
High
Ultrafiltration
Rate
Intradialytic
Hypotension
Cramping,
Dizziness,
Nausea, etc.
Long Post-
Dialysis
Recovery Time
Poor QOL
Intervention:
Lower Ultrafiltration Rate,
but Maintain Session
Length

AUDIENCE POLL:
What should be the fluid removal rate target?
1) UFR <13 ml/kg/hr
2) UFR <10 ml/kg/hr
3) UFR <7 ml/kg/hr
4) Unclear which is best
10

Dialysis Recovery
Time is Associated
with All-cause
Mortality
Kaplan- Meier Unadjusted
Chazot et al; Blood Purification 2017; 44:89-97
All-cause Mortality
<6.8 ml/kg/hr
≥6.8 ml/kg/hr

Dialysis therapy prescription
General Concepts: Two Part Approach
(Consistent with John Agar Hemodialysis International Editorial, 2015)
 Set Fluid removal per week
‒ Set desired dry weight
‒ Limit UFR to reduce cardiac/organ system stunning
‒ Limit UFR <10ml/kg/hr for safety and tolerability (reduce recovery time)
 NxStage mean UFR 6-7 ml/kg/hr short daily; 2-3 ml/kg/hr Nocturnal
 Standardized weekly KT/V: normalized volumes cleared of Urea
‒ 2.1 per week of continuous removal (minimum) from Guidelines
‒ Mainly addresses the dietary intake for a week
‒ Provides basic removal of K, adds HCO3, and removes protein uremic toxins
 Large molecules and PO4 take greater time for removal because of large
spaces and slow transport (30+ hours per week)

Fluid Removal Rates and Control of
Volume is a Core Unmet Need
• The range of fluid removal rates has been a subject of
discussion (<7ml/kg/hr, <10ml/kg/hr, <13 ml/kg/hr)
• UFR appears to relate to how patients feel, hypotensive
episodes, recovery time and associated mortality (lower the
rate the better)
• Tolerability of fluid removal is the key element when trying to
achieve a desired target weight to control HTN and treat heart
failure
• Lowering UFR on conventional three times per week HD is very
challenging to implement in a fixed schedule

How should treatment time and frequency be
determined?
1) Whatever we can get the patient to do
2) UF time per week is based on tolerable UFR and total volume to be
removed
3) Set the number of treatment per week to fit minimum UF time per week
4) All the above
AUDIENCE POLL:
10

Therapy Rx Principles: Weekly
CALCULATE RESULT PRESCRIBEINPUT
UF TIME / WEEK
KG gain
/ Week
1500 mL/day x7
10.5 liters/week
QUF limit
<10 mL/kg/h
< 700 mL/h ♂
< 500 mL/h ♀
15
Total Hours
/ Week
Sessions / Week
Hours / Session

High Saturation Dialysate:
Dialysate + UF = Volume Cleared
• The high saturation of dialysate means for each liter of dialysate
used it equals a liter cleared of solutes
‒ Urea
‒ Creatinine
‒ PO4
• Ultrafiltration adds convective clearance removing solutes at the
same concentration as in the blood
• The single pool volumes cleared each treatment is essentially the
volume of dialysate plus the UF divided by the patient TOTAL Body
Water

How do low flow systems deliver enough solute clearance
vs. conventional HD?
1) High dialysate saturation maximizes solute removal similar to PD
2) Total time per week and frequency are used to deliver the weekly total
dose
3) PO4 removal is also improved based on greater dialysate saturation at
lower Qd
4) All the above
AUDIENCE POLL:
10

Weekly Total Normalized Water
Cleared of Urea (KxT)
Based on continuous STD weekly Kt/V
I
II
III
IV
V
eGFRStageContinuous
Clearance
15
eGFR (ml/min)
30
60
90
STD L/wk Urea
80-90 L/wk
80-90 L/wk
128 L/wk
342 L/wk
605 L/wk
1000 L/wk
HD x 3
HD x 6
nocturnal
Transplant
PD x 7
HD x 5
Normal

Prescribing Hemodialysis Therapy
Urine side clearance (dialysate side)
D/P ratio like PET

Dialyzer Urea Clearance
Dialysate Flow (Qd) and Blood Flow Rate (Qb)
When dialysate flow is below 200 ml/min
this determines the basic clearance

0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800
Urea Qb -400 mL/min
Dialysate/PlasmaRatio(D/P)
Dialysate Flow Rate (Qd)
NxStage System
Conventional Hemodialysis
D/P Ratio for Urea*
NxStage Polyether Sulfone Dialyzer
*Urea KoA in vivo 851 ml/min
*Ken Leypoldt kinetics ASN 2017

Comparison of Dialysate Saturation
NxStage – Lower Qd
Conventional – Higher Qd
NxStage Conventional HD
BFR 300 ml/min Qd 200
• Urea Saturation: 85%
• PO4 Saturation: 64%
BFR 300 ml/min Qd 500
BFR 400 ml/min; Qd 200
BFR 400 ml/min; Qd 500

High Saturation Dialysate:
Dialysate + UF = Volume Cleared (KxT)
• The high saturation of dialysate means for each liter of dialysate used it
equals a liter cleared of solutes
‒ Urea
‒ Creatinine
‒ PO4
• Ultrafiltration adds convective clearance removing solutes at the same
concentration as in the blood
• The single pool volumes cleared each treatment is essentially the volume
of dialysate plus the UF divided by the patient TOTAL Body Water

Leypoldt and Collins Dosing Protocol
ASN Abstract/Poster - Based on V: Dialysate Volume rounded*
*Tabulated values are dialysis volumes in L per treatment (obtained by dividing Kt by 0.85) predicted to achieve
a weekly stdKt/V of 2.1 rounded up to the nearest 5 L.
Dialysate Volume needed to nearest 5 liters

In Sum
 Therapy Rx can be addressed in two parts
‒ Volume to be removed per week by addressing UFR
‒ Solute removal based on Normalized Volumes of Total Body Water cleared
per week and per treatment
 UF volume per week is divided by tolerable UFR to obtain hours needed
per week
 STD Weekly KT/V provides the target normalized volumes per week to be
cleared overall
‒ spKT/V is used to determine normalized volume cleared per treatment
‒ Dialysate needed per treatment is computed based on saturation of the
dialysate rounded up to the nearest 5 liters
 The dosing calculator will give alternatives for various schedules

Conclusions
• Therapy prescription for any dialysis is targeted at Volume to be removed
and solute to be cleared
• Volume removal is the first step to address control of CVD areas and
tolerability of therapy
• All dialysis modalities use solute clearance as the basis of therapy Rx:
Blood Side or Dialysate Side
• Conventional HD is based on Blood side clearance
• PD and HHD is based on dialysate clearance
• More frequent HD can deliver comparable, if not superior, therapy
compared to conventional HD

Framing Home
Hemodialysis
Options
Discussion Lead:
Paul Komenda, MD, MHA, FRCPC
Seven Oaks General Hospital
3. Assimon MM et al. Ultrafiltration Rate and Mortality in Maintenance Hemodialysis Patients. Am J Kidney
Dis. Volume 68, Issue 6, December 2016, Pages 911-922.

60%
LIFESTYLE
30%
CLINICAL
10%
ADMINISTRATIVE
Home Hemodialysis Considerations

1972
Medicare
establishes ESRD
Program
1983
Medicare “Composite
Rate for HD”
CAPD
By 1970, 40% of
Hemodialysis
performed at home
1962-1972
Dialysis Death
Panels
Emerging therapy options
1943
First working
dialyzer
1960 Scribner Shunt
1950 1980 199019701960
CCPD
2000

Percentage of
Home Dialysis
Therapy
Utilization
Worldwide
Vol 2, ESRD, Figure 11.15
Distribution of the percentage of
prevalent dialysis patients using in-center
HD, home HD, or peritoneal dialysis
(CAPD/APD/IPD), 2015

 Improved LVM
 Better BP
 Lower PO4
N=245 (2010)
Randomized Control Trials
JAMA, September 19, 2007—Vol 298, No. 11
 Improved LVM
 Better BP
 Lower PO4
N=52 (2007)
? Improved LVM
(p=0.09)
 Better BP
 Lower PO4
N=82 (2011)

“Sunk Costs”
Komenda P et al. An economic assessment model for in-center, conventional home, and more frequent home
hemodialysis. Kidney International. Volume 81, Issue 3, Pages 307-313 (February 2012). DOI:
10.1038/ki.2011.338
• If Intensive Home
Hemodialysis unlikely to last
more than 12-24 months, not
a cost effective option
• Not taking into consideration
PATIENT time for training.

Conventional Machine Limitations
Portability Renovations
Water Quality User Interface

The Cycler and Cartridge
Simple interface using shapes, colors,
and diagrams to aid in operation of system
Color coded cartridge clamps to match
fluid pathways

Increased
Frequency
Home
Hemodialysis
Results
4. Rayner HC, Zepel L, Fuller DS, et al. Recovery time, quality of life, and mortality in hemodialysis patients:
the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2014;64(1):86-94.

Significantly reduced post-dialysis
recovery time
Study of Medicare patients starting more
frequent home hemodialysis with NxStage
System One Key Findings:
• 87% improvement in time to
recovery and significant
improvement in quality of life
measures
1Jaber BL, Lee Y, Collins AJ, et al. Effect of daily hemodialysis on depressive symptoms and postdialysis
recovery time: interim report from the FREEDOM (Following Rehabilitation, Economics and Everyday-Dialysis
Outcome Measurements) Study. Am J Kidney Dis. 2010;56(3):531-539.

Purported Benefits
Clinical
• Blood Pressure
• Volume Control
• LVH Regression
• Ca/PO4 balance
Lifestyle
• QOL Metrics
• Flexibility
Economic
• Lower Operating
Costs
• Cost Utility

Increased
Frequency
Home
Hemodialysis
Results
Discussion Leads:
Michael Kraus, MD, FACP
Indiana University School of Medicine
Bill Davis
Current Home Hemodialysis Patient

B.D.
• BP normal and no meds
• Activity increased
• Serial Echo with improved LVEF (60%) No wma or Valvular disease
• No recurrence A Fib
His story

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