Adequacy of Hemodialysis
Data from HENNET.
นพ.ธนชัย พนาพุฒิ
อายุรแพทย์ โรคไต รพศ.ขอนแก่ น
5 กค. 2556
HENNET project
HEmodialysis Network of the North-East of Thailand
นพ.ธนชัย พนาพุฒิ นพ.จิรศักดิ์ อนุกลุ กนันต์ ชัย
รพ.ขอนแก่น
รศ.นพ.ทวี ศิริวงศ์ รศ.นพ.ชลธิป พงศ์ สกุล รศ.พญ.ศิริรัตน์ เรืองจุ้ย รพ.ศรีนครินทร์
นพ. พิสิฐ อินทรวงษ์ โชติ
รพ.หนองคาย
นพ. สุรพงษ์ นเรนทร์ พทิ ักษ์
รพ.อุดรธานี
นพ. สัจจะ ตติยานุพันธ์ วงศ์
รพ.ชัยภูมิ
พญ. ลักษมณ ประเดิม
รพ.ร้ อยเอ็ด
นพ. ชวศักดิ์ กนกกัณฑ์ พงษ์
รพ.มหาราชนครราชสี มา
พญ. กรรณิการ์ นิวัตยกุล
รพ.เลย
นพ. ปกรณ์ ตุงคะเสรี รักษ์
รพ.สุ รินทร์
นพ. อมฤต สุวัฒนศิลป์
รพ.มหาสารคาม
พญ. ทัดสะรัง แก้ วบุนมา
รพ.ท่ าบ่ อ
Agenda
• What is Adequacy of HD
• Data from HENNET Project
• Kt/V: Do we really need it ?
Dr. John T. Daugirdas
Dr. Daugirdas is Professor of
Medicine at the
University of Illinois at
Chicago.
What is Adequacy of Hemodialysis ?
Adequacy of dialysis refers to
how well we remove toxins and
waste products from the patient’s
blood, and has a major impact on
their well-being.
How do we know if a Patient is
Adequately Dialyzed ?
Urea Kinetic Modeling
Why can’t I understand it ?
It can’t be that difficult !
WHY UREA ?
MW 60, only slightly toxic per se
a MARKER for small MW uremic toxins
Urea removal < ---> other small toxin
removal
WHY UREA ?
MW 60, only slightly toxic per se
a MARKER for small MW uremic toxins
Urea removal < ---> other small toxin
removal
g = rate of UREA generation
g < ---> protein catabolic rate (PCR)
PCR < ---> dietary protein intake ?
g can be derived from pre and post BUN
Monitoring the patient’s urea
Predialysis BUN or Time-averaged BUN
BAD if HIGH, also BAD if too LOW!
Reflect balance of urea removal vs.
production
BUN
BUNpre
(mg/dl)
BUNpost
Time (hour)
Monitoring the patient’s urea
Predialysis BUN or Time-averaged BUN
BAD if HIGH, also BAD if too LOW!
Reflect balance of urea removal vs.
production
BUN
BUNpre
(mg/dl)
BUNpost
Time (hour)
Monitoring the patient’s urea
Predialysis BUN or Time-averaged BUN
BAD if HIGH, also BAD if too LOW!
Reflect balance of urea removal vs.
production
BUNpre
BUN
(mg/dl)
TAC BUN
BUNpost
Time (hour)
Monitoring the patient’s urea
URR or Kt/V
URR% :
(Upre – Upost) x 100
Upre
Reflect removal of urea and other toxins
PRIMARY monitors of dialysis adequacy
What is Kt/V ?
Kt/V = fractional urea clearance
K = dialyzer clearance (ml/min or L/hr)
t = time (min or hr)
V = distribution volume of urea (ml or L)
Kxt =
V
=
Kt/V =
L/hr x
hr = LITERS
LITERS
LITERS/LITERS = ratio
K = 10 L/Hr
V = 40 liters
BUN = 80
BUN = 0
K.t
Holding Tank Model
V = 40 liters
BUN = 80
URR
BUN = 0
1.0
K.t
0.63
Holding Tank Model
1.0
Kt/V
V = 40 liters
BUN = 80
BUN = 0
K t = 20 L
V = 40 liters
BUN = 80
BUN = 0
K t = 20 L
Kt/V = 20 / 40
= 0.50
V = 40 liters
BUN = 80
BUN = 0
K t = 20 L
Kt/V = 20 / 40
= 0.50
Post BUN = 40
URR = (pre-post) / pre
= (80-40) / 80
= 0.50
V = 40 liters
BUN = 80, 70, 60
BUN = 0
K.t
Dialyzer outlet fluid returned continually during dialysis
Relationship between Kt/V and URR
Kt/V
spKt/V = single pool
eqKt/V = equilibrated (Double pool)
Std Kt/V = weekly standard
Post-Dialysis rebound
Post-Dialysis rebound
Equilibrated Kt/V
Kt/V
spKt/V = single pool
eqKt/V = equilibrated (Double pool)
Std Kt/V = weekly standard
What is the target spKt/V in
2 times/week HD patients ?
K/DOQI 2006: Minimum spKt/V
Schedule
Kr<2
Kr>2
ml/min/1.73m2
ml/min/1.73m2
2x/wk
Not
recommended
2.0*
3x/wk
1.2
0.9
4x/wk
0.8
0.6
6x/wk
0.5
0.4
Dialyzer clearance only
*not recommended unless Kr > 3
K/DOQI CPG for Hemodialysis Adequacy: update 2006.
Am J Kidney Dis 2007; 37: S7-S64.
K/DOQI : Methods for Post Dialysis Blood Sampling
1. Both samples should be drawn during the same session.
2. Predialysis BUN should be drawn before treatment began.
3. Postdialysis BUN, Avoid access recirculation by
Slow flow to 100 ml/min for 15 seconds
K/DOQI CPG for Hemodialysis Adequacy: update 2006.
Am J Kidney Dis 2007; 37: S7-S64.
Data from HENNET.
Exploring Mortality based on Kt/V
among ESRD patients undergoing
Twice-weekly Hemosialysis
HENNET
Setting
Multi-center cohort study
**
• 11 hemodialysis centers
*
*
**
• Accrual period 3 months
*
from Feb. 2011
* *
*
• Follow up period 1 years
*
Part1 Baseline
Part2 Follow up
Part3 Hospitalization note
Part4 Discharge summary
HENNET
HD 2/wk
Study design overview
Lab record 2 monthly
Enrollment
•
•
•
Inclusion
Age 18 – 80 years
HD > 3 months.
•
•
•
•
Exclusion
Pregnancy, Breast feeding
Advance malignancy
Bed-ridden status
1 year
Outcomes:
Disease-related Death
Censor:
Kidney transplantation
Shift to peritoneal dialysis
Refer to other centers
Change frequency
Death from accident
HENNET
Results
HD 2/wk
1 year
Enrollment
Death
504
33
6,928 patients-months were observed.
Mortality rate 4.8 / 1,000 patient-months.
HENNET
Table1. Baseline characteristics
Characters
Survivors
N=471
Non-survivors
N=33
Male
276 (58.6%)
15 (45.5%)
Age, year
54.9 ± 13.8
66.1 ± 10.6
Married
365 (77.5%)
24 (72.7%)
1.2 ± 0.7
1.8 ± 0.9
144 (30.6)
90 (19.1)
31 (6.6)
29 (6.2)
28 (5.9)
6 (1.3)
142 (30.2)
16 (48.5)
8 (24.2)
1 (3)
3 (9.1)
5 (15.2)
Time on HD, month
40.6 ± 31.3
38.4 ± 28.0
Anuria (<100ml/day)
228 (48.4%)
15 (45.5%)
ICED score
Causes of ESRD
Diabetes
Hypertension
Glomerulonephritis
Obstructive uropathy
Gout
Cystic disease
Unknown
HENNET
1.5
1.7±0.3
1
1.7±0.4
.5
ktv_avg
2
2.5
3
Kt/V by Age
20
40
60
age
80
HENNET
Distribution of Kt/V
150
158
100
101
Mean
1.7±0.3
50
80
21
19
5
1
0
Frequency
119
.5
1
1.5
spKt/V
2
Range 0.67 – 2.83
2.5
HENNET
Distribution of Kt/V
150
158
Adequate HD
20.6%
100
101
Mean
1.7±0.3
50
80
21
19
5
1
0
Frequency
119
.5
1
1.5
spKt/V
2
Range 0.67 – 2.83
2.5
Hemodialysis patients with adequate dialysis (URR>65%)
CMS ESRD Clinical Performance Measures Project, 2001-2002.
Centers for Medicare & Medicaid Services, ESRD Clinical Performance Measures Project, 2002-2006.
HENNET
Kt/V among women and men
Kt/V
2.4
2.0
1.6
1.9±0.3
1.6±0.3
1.2
0.8
P < 0.001
0.4
Women
214(42.5%)
Men
290(57.5%)
HENNET
Kt/V by numbers of Dialyzer Reuse
N
200
55.4%
44.6%
150
100
50
127
152
160
65
< 15
15
16-20
Range 0 – 30
> 20
No. of Reuse
HENNET
Kt/V by numbers of Dialyzer Reuse
N
Kt/V
200
2
150
1.5
100
1
50
0.5
< 15
15
16-20
> 20
No. of reuse
HENNET
Prediction of Dead by numbers of Dialyzer Reuse
Log odds of dead
Linear prediction
Log odds of dead
-2.00
-2.50
-3.00
-3.50
10.0
15.0
20.0
Mean of c22 categories
25.0
Assessing Linearity Assumption -- Log Odds
No. of Reuse
< 15
15
16-20
> 20
Dead rate
0.03
0.06
0.08
0.11
Hemodialysis Prescription
Determines Adequacy
• Hemodialysis component:
– Duration of Treatment
– Dialyzer Urea Clearance (KOA)
– Blood Flow
– Dialysate Flow
– Heparinization
Adequacy of Treatment is
– Access
Everyone’s Concern !
Improving Adequacy of Hemodialysis:
It Takes a Team.
Kt/V :
Do we really need it ?
Mortality Risk by Kt/V
Categorical and Linear Estimates, 1991
RR
1.5
1.5
1.0
RR = 0.93 / 0.1 Kt/V
( p < 0.01)
0.5
0.0
1.0
0.8
1.20
1.0
1.2
p=0.11
1.00
(rel)
0.69
p=0.01
0.5
463
1.6
Kt/V
0.87
p=0.26
N=
1.4
0.71
p=0.01
462
462
462
462
0.91-1.05
1.06-1.16
1.17-1.32
1.33 +
0.0
< 0.91
Delivered Kt/V* (Quintiles)
* From the Pre/Post BUN and Pre/Post Weight. N = 2,311,
Thrice Weekly only.
P = 0.53
HENNET
Kt/V among survivors and non-survivors
Kt/V
2.4
2.0
1.6
1.2
0.8
0.4
1.7
1.65
(1.67-1.72)
(1.52-1.77)
P=0.52
Survivors
Non-survivors
HENNET
1.00
Kaplan-Meier survival curves by Kt/V
0.75
Kt/V > 2
0.25
0.50
Kt/V < 2
0.00
Log rank test, P=0.41
0
5
10
analysis time, months
Kt/V >= 2
15
Kt/V <2
20
HENNET
1.00
Kaplan-Meier survival curves by Kt/V
0.75
Kt/V > 2
0.50
Kt/V < 2
0.25
1 year survival 94%
0.00
Log rank test, P=0.41
0
5
10
analysis time, months
Kt/V >= 2
15
Kt/V <2
20
HENNET
1.00
1.00
Survival probability among patients with Kt/V>2 and <2
according to diabetic status
0.50
0.00
10
analysis time, month
15
20
HR 1.64 (0.38-7.13), p=0.5*
0.25
0.25
HR 1.0 (0.28-3.75), p=0.9*
5
Kt/V < 2
0.00
0.50
Kt/V < 2
0
Kt/V > 2
0.75
Probability of survival
0.75
Kt/V > 2
0
5
10
analysis time, month
DM
Non DM
*adjusted for age
15
20
HENNET
Hazard ratio of death
Relative Risk of Death by Kt/V quartiles
2.4
2.0
1.6
1.2
0.8
1.04
0.75
0.62
0.4
Kt/V
HENNET
Figure 15. Cox proportional hazard ratios and their 95% CI, adjusted for age, among women
undergoing twice-weekly HD with
Kt/V < versus > 1.4, < versus > 1.6, < versus > 1.8, < versus > 2.0, < versus > 2.2.
HENNET
Prognostic factors of Deaths
Factors
Unadjusted HR
Adjusted HR
95%CI
P-value*
Kt/V,
per 1 unit decrease
1.7
1.9†
1.2‡
1.4¶
0.5-6.4
0.4-4.1
0.4-4.8
0.32
0.76
0.56
Serum albumin,
per 1 g/dl decrease
Current smoker
3.1
2.5
1.2-5.1
0.01
5.3
19.3
4.8-76.9
< 0.001
Table 9. Unadjusted and adjusted hazard ratio of death using Cox regression model.
*P-value from partial likely hood ratio test, adjusted for age, ICED, time on dialysis and dialysis centers.
†Adjusted HR considering effect of albumin level
‡Adjusted HR considering effect of smoking
¶Adjusted HR considering effects of albumin level and smoking
Kt/V :
Do we really need it ?
May be, there are stronger
predictors of mortality.
Take Home Message !!
1. Adequacy of dialysis is based on Kt/V and URR.
Take Home Message !!
1. Adequacy of dialysis is based on Kt/V and URR.
2. Kt/V and URR are mathematically linked.
Take Home Message !!
1. Adequacy of dialysis is based on Kt/V and URR.
2. Kt/V and URR are mathematically linked.
3. For HD 2/week: Target spKt/V 2, Kr > 2 ml/min/1.73m2
Take Home Message !!
1. Adequacy of dialysis is based on Kt/V and URR.
2. Kt/V and URR are mathematically linked.
3. For HD 2/week: Target spKt/V 2, Kr > 2 ml/min/1.73m2
4. For HD 3/week: Target spKt/V 1.2, URR>65%.
Take Home Message !!
5. Data from
HENNET
– Only 20.6% is adequately dialyzed, Kt/V>2.
Take Home Message !!
5. Data from
HENNET
– Only 20.6% is adequately dialyzed, Kt/V>2.
– Mean Kt/V of women is significantly higher than that of
men.
Take Home Message !!
5. Data from
HENNET
– Only 20.6% is adequately dialyzed, Kt/V>2.
– Mean Kt/V of women is significantly higher than that of
men.
– Increase No. of Reuse related to an increase mortality
in a linear prediction.
Take Home Message !!
5. Data from
HENNET
– Only 20.6% is adequately dialyzed, Kt/V>2.
– Mean Kt/V of women is significantly higher than that of
men.
– Increase No. of Reuse related to an increase mortality
in a linear prediction.
– Higher Kt/V quartiles trend to have lower RR for death.
Take Home Message !!
5. Data from
HENNET
– Only 20.6% is adequately dialyzed, Kt/V>2.
– Mean Kt/V of women is significantly higher than that of
men.
– Increase No. of Reuse related to an increase mortality
in a linear prediction.
– Higher Kt/V quartiles trend to have lower RR for death.
– Suggested target Kt/V > 1.8 for Thai women on
2HD/wk.
Take Home Message !!
5. Data from
HENNET
– Only 20.6% is adequately dialyzed, Kt/V>2.
– Mean Kt/V of women is significantly higher than that of
men.
– Increase No. of Reuse related to an increase mortality
in a linear prediction.
– Higher Kt/V quartiles trend to have lower RR for death.
– Suggested target Kt/V > 1.8 for Thai women on
2HD/wk.
– Predictors of death are SMOKING and ALBUMIN level.
Take Home Message !!
6. spKt/V is a current marker for monitoring
HD adequacy.
Acknowledgements : Grant supports
• The Royal College of Physician of Thailand
• The Medical Association of Thailand
• The Kidney Foundation of Thailand
HENNET
Cox proportional hazard ratios and their 95% CI, adjusted for age, among patients
With Kt/V < versus > 1.4, < versus > 1.6, < versus > 1.8, < versus > 2.0, < versus > 2.2.
HENNET
Kt/V by BMI classes
Percent
100
80
60
40
60
20
15.1
< 18.5
18.5-25
11.9
12.7
25-30
> 30
BMI
HENNET
Kt/V by BMI classes
Kt/V
2
1.9
1.7
1.5
1.5
1.7
P=0.00
1
P=0.00
0.5
BMI
< 18.5
18.5-25
25-30
> 30
HENNET Factors affect spKt/V
BMI, kg/m2
Incidence HD, < 12 mo.
Dialyzer membrane:
Semi-synthetic
Low Flux Dialyzer
Dialyzer Surface area
No. of Dialyzer Reuse
Blood Flow, ml/min
Dialysate flow, ml/min
DM
Current Smoking
P<0.05
Kt/V>1.7
Kt/V<1.7
P
N=245(48.6%)
N=259(51.4%)
20.6±2.9
23 (9.4%)
22.4±3.3
45 (17.4%)
0.00
0.01
99 (40.4%)
82 (33.5%)
101 (39%)
97 (34.5%)
0.75
0.35
1.76±0.2
17.1±5.5
1.8±0.2
15.6±5.1
0.04
0.00
324.2±51
537.9±98.3
297.9±46.9
517.7±64
0.00
0.01
71 (28.9%)
5 (2.0%)
107 (60.1%)
12 (4.6%)
0.00
0.08
HENNET Factors affect spKt/V
BMI, kg/m2
Incidence HD, < 12 mo.
Dialyzer membrane:
Semi-synthetic
Low Flux Dialyzer
Dialyzer Surface area
No. of Dialyzer Reuse
Blood Flow, ml/min
Dialysate flow, ml/min
DM
Current Smoking
Kt/V>1.7
Kt/V<1.7
P
N=245(48.6%)
N=259(51.4%)
20.6±2.9
23 (9.4%)
22.4±3.3
45 (17.4%)
0.00*
0.01
99 (40.4%)
82 (33.5%)
101 (39%)
97 (34.5%)
0.75
0.35
1.76±0.2
17.1±5.5
1.8±0.2
15.6±5.1
0.04
0.00*
324.2±51
537.9±98.3
297.9±46.9 0.00*
517.7±64
0.01
71 (28.9%)
5 (2.0%)
107 (60.1%)
12 (4.6%)
*P<0.05 in Multivariate Analysis
0.00
0.08
HENNET
Factors affect spKt/V
Kt/V < 1.7
Coef.
BMI, kg/m2
No. of Dialyzer Reuse
Blood Flow, ml/min
0.20
-0.06
-0.01
95%CI
P
0.13 to 0.27
0.000
-0.02 to -0.10 0.003
-0.006 to -0.014 0.000
Every 1 increase in BMI will increase 20% of Kt/V<1.7
NIH Hemo Study
URR of about 67% vs. about 75%
spKt/V of 1.3 vs. 17
eKt/V of about 1.05 vs. 1.45
Also will compare small-pore (low-flux)
vs. large-pore (high flux) membranes
Endpoints: mortality, hospitalization,
fall in dry weight
HD adequacy : dose
K: dialyzer clearance
t: duration of HD
V: volume distribution of urea
K/DOQI CPG for Hemodialysis Adequacy: update 2006.
Am J Kidney Dis 2007; 37: S7-S64.
Post-Dialysis rebound
Relationship of eKt/V to spKt/V
eKt/V = spKt/V [(t/(t+C)]
C=35 min if artery, 22 min if vein
Std Kt/V, spKt/V and Dialysis frequencies per week
Associated causes of death
Causes of Death
N %
Cardiovascular
14 42.4
Infection
11 33.3
Cerebrovascular
2
6.1
Malignancy
2
6.1
Other
GI bleeding
Bleeding diverticulosis
Dialysis withdrawal
Car accident
1
1
1
1
3
3
3
3
Outcomes
Outcomes
Death
Refer to other centers
Change frequency
Shift to CAPD
Kidney transplantation
Loss to follow up
N
33
27
13
10
6
6
%
34.7
28.4
13.7
10.5
6.3
6.3
Indices of Urea Removal
Kt/V
Reflects urea removal
NCDS suggested Kt/V must be > 0.90
Population studies suggest Kt/V should be>
1.2
URR
Also reflects urea removal
Current goal is a URR > 65 %
Sample
0.8
1.0
< 0.70
0.88
1.0
1.15
Approximate Kt/V
1.8
1.6
1.4
1.3
>1.4
R (post / pre BUN)
< 0.30
1.2
0.30-0.35
0.35-0.40
0.40-0.45
0.75
0.45-0.50
0.50-0.55
>0.55
Relative Mortality Risk
2.0
HENNET
Incidence and Prevalence Hemodialysis
Percent
100
436
80
1.5
60
(86.5%)
P=1.00
40
20
68
(13.5%)
Incidence HD
<= 12 mo.
Prevalence HD
> 12 mo.
HENNET
Kt/V by Incidence and Prevalence Hemodialysis
Kt/V
2
1.5
1
0.5
1.72
1.54
(1.46 to 1.61)
(1.69 to 1.74)
P=0.00
Incidence HD
<= 12 mo.
Prevalence HD
> 12 mo.