Transcript - Rockpointe

Please Help Us with the Following
Prior to the start of the program, check your syllabus to
ensure you have the following printed program materials:
•
Participant Survey and CME Evaluation
– In the front of your syllabus
– Remove from your packet
– Fill out the demographic information at the top
– Throughout the program, please take a moment to answer
the corresponding Activity Survey questions on this form
(slides will be marked as “Polling Questions” throughout the
deck)
CME Information
Please note, all pertinent CME information, statements, and
disclosures can be found in your program syllabus, including:
• Faculty/Steering Committee and Non-faculty Planner/Reviewer
Disclosures
• Educational Objectives
• Accreditation and Credit Designation Statements
• Faculty/Steering Committee Bios
Educational Objectives
• Describe evidence supporting increased use of higher
KDPI kidneys and optimizing allocation of donor kidneys
• Apply current evidence regarding strategies to individualize
and optimize immunosuppressive therapy to prevent
chronic rejection and minimize immunosuppressantassociated toxicity
• Identify patients at risk for non-adherence and implement
strategies to maximize adherence in patients undergoing
kidney transplant
Polling Question 1
Activity Survey
Please rate your level of confidence in your ability to
individualize and optimize immunosuppressive therapy?
A. Not confident
B. Slightly confident
C. Confident
D. Very confident
E. Expert
Case Study
• 65-year-old woman, with polycystic kidney disease (PKD)
and prior mitral-valve replacement, no other coronary
artery dissection (CAD), on waiting list for 2.5 years,
expected waiting time in region is ~4 years for her blood
type (B). Otherwise healthy. She has no living donors.
cPRA = 56.
• Called with a kidney offer.
Polling Question 2
Activity Survey
Which of the following kidneys would you consider
for this patient?
A. KDPI 98, DCD, CIT 28 hours, terminal creatinine 2.5 mg/dL
B. KDPI 87, CIT 12 hours, terminal creatinine 1.1 mg/dL
C. KDPI 40, malignant melanoma
D. KDPI 37, prior heart transplant recipient on CyA for 20 years,
terminal creatinine 3.6 mg/dL
E. KDPI 9, HIV-viremia, terminal serum creatinine 1.1 mg/dL
Case Study (cont)
• Offered a kidney from deceased donor with KDPI 89; 1 DR
match, blood type A2
• Deceased donor: 5’6” 180lb AA woman, PMH of HTN for
<5 years, DBD due to CVA, terminal Cr 1.1 mg/dL; History
of jail time in the past 36 months (no DM, no DCD, HCV
negative)
Polling Question 3
Activity Survey
What advice would you give this patient?
A. Decline the kidney, wait for a blood type O donor
B. Decline the kidney, wait for a blood type A1 donor
C. Decline the kidney, it has a 60% chance of working
at 12 months
D. Decline the kidney, wait for a PHS-increased donor
kidney from a younger donor as national wait times
are about 2.7 years
E. Accept the kidney
Organ Allocation
Major New Components as of December 4, 2014
• Replaced SCD/ECD with KDPI
• Broader sharing for high KPDI kidneys (>85)
• Longevity matching – donor KDPI to recipient expected
post-transplant survival (EPTS)
• Increased priority for sensitized candidates/CPRA sliding
scale
• Included pre-registration dialysis time
• Incorporated A2/A2B to B
Overview of Policy
Recipient
Donor
Allocation to those with
“longest expected posttransplant survival”
Allocation first to pediatric list,
then according to waiting time
Allocation according to waiting
time
Allocation to those who
consent (similar to yesterday’s
“ECD”)
All allocation sequences to be based on KDPI
OPTN kidney allocation system (KAS)
https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_08
Donor and Recipient Factors to Determine
Groups
KDPI
–
–
–
–
–
–
–
–
–
–
Donor age
Race/ethnicity
Hypertension
Diabetes
Serum creatinine
COD CVA
Height
Weight
DCD
HCV
Candidate Estimated Post
Transplant Survival (EPTS)
– Candidate age
– Candidate diabetes
– Prior transplant
– ESRD time
Sequence A
Sequence B
KDPI ≤20%
KDPI >20% but <35%
Highly sensitized
0-ABDRmm (top 20%
EPTS)
Prior living donor
Local pediatrics
Local top 20% EPTS
0-ABDRmm (all)
Local (all)
Regional pediatrics
Regional (top 20%)
Regional (all)
National pediatrics
National (top 20%)
National (all)
United Network for Organ Sharing.
Highly sensitized
0-ABDRmm
Prior living donor
Local pediatrics
Local adults
Regional pediatrics
Regional adults
National pediatrics
National adults
Sequence C
KDPI ≥35% but
≤85%
Highly sensitized
0-ABDRmm
Prior living donor
Local
Regional
National
Sequence D
KDPI >85%
Highly sensitized
0-ABDRmm
Local + Regional
National
Regional
sharing is
prioritized to
optimize
utilization
Kidney Donor Profile Index (KDPI)
KDPI Variables
•
•
•
•
•
•
•
•
•
•
Donor age
Height
Weight
Ethnicity
History of HTN
History of diabetes
Cause of death
Serum creatinine
HCV status
DCD status
United Network for Organ Sharing.
Graft Survival and Discard Rates by KDPI
100%
91.5%
90%
80%
90.0%
89.0% 87.9%
86.6%
2-year graft survival
85.2%
83.7%
81.9%
78.9%
76.3%
71.9%
69.9%
70%
60%
55.0%
50%
46.1%
40%
36.3%
Discard rate
30%
29.5%
24.5%
(Pre-KDPI in DonorNet)
17.8%
20%
12.5%
7.2%
10%
1.6%
0%
Kidney Donor Profile Index (KDPI)
Gradual decline in graft survival, but steep increases in kidney discard rates.
Provided by Alexander Wiseman, MD, FACP.
Projected Results
• >8000 additional life years annually
• Increase in transplants to blood type B, PRA>98
A
AB
B
O
Pre-KAS Estimated
35.2
5.1
12.7
47.0
30.1
5.6
17.7
46.6
Diabetes, <50
Diabetes, ≥50
Hypertension
Glomerular
Polycystic
6.1
25.7
21.1
20.8
7.9
5.8
23.4
21.7
22.7
7.3
AA
Hispanic
White
Other
34.1
14.5
44.3
7.1
35.0
15.2
42.9
7.0
Primary disease
Race/ethnicity
Israni AK et al. J Am Soc Nephrol. 2014;25:1842-1848.
Age Distribution
50
Pre-KAS
Estimated
-4.1%
40
30
-2.7%
20
10
0
<18
18-34
35-49
50-64
65+
Survival Advantage of Kidney Transplant is
Maintained in Elderly ≥70 Years
Mortality RR (95% CI) for 2,078 first deceased donor kidney transplant
recipients vs 5,667 wait-listed dialysis patients ≥70 years of age
Rao PS et al. Transplantation. 2007;83:1069-1074.
The Risk of NOT Being Transplanted is
High in the Elderly
“Almost half (46%)
of candidates >60
years…are
projected to die
before receiving a
DDTx”
“Older candidates
are now at
significant risk for
not surviving the
interval in which a
deceased-donor
transplant would
become available”
Schold JD, Meier-Kriesche HU. Clin J Am Soc Nephrol. 2006;1:532-538.
Schold J et al. Clin J Am Soc Nephrol. 2009;4:1239-1245.
Should You Take a “High KDPI” Kidney or
Wait for a “Better Offer”?
• High-KDPI KTx
• Increased short-term but
decreased long-term
mortality risk
• “Break-even point” of
cumulative survival at 7.7,
18.0, and 19.8 months
post-KTx with survival
benefit thereafter (P<0.01
for each comparison)
Massie AB et al. Am J Transplant. 2014;14:2310-2316.
Should You Take a “High KDPI” Kidney or
Wait for the “Better Offer”?
• Benefit of high-KDPI
KT
• Greatest for those >50
years old and for
patients at centers
with median wait time
≥33 months
Massie AB et al. Am J Transplant. 2014;14:2310-2316.
The Combined Risk of Donor Quality and
Recipient Age: Higher-quality Kidneys May Not Always
Improve Patient and Graft Survival
UNOS analysis of 137,311 primary kidney transplant recipients 1995-2010 with follow-up through 2012
• Donor organ quality (by KDPI) was
divided into quintiles (very high, high,
medium, low, and very low quality)
• Recipients 70 -79 years had
comparable outcomes if they received
low-quality kidneys compared to
medium-quality kidneys. (HR death,
1.03, P=0.51; HR graft loss, 1.11;
P=0.19)
• “Transplanting medium-quality
kidneys into elderly recipients
does not provide significant
advantage over low-quality
kidneys”
Hernandez RA et al. Transplantation. 2014;98:1069-1076.
Peri-operative Risk in Elderly is Dramatically
Reduced with Living Donor Transplant
• Elderly recipients of LD, SCD, and ECD transplants vs all wait listed patients ≥65 yrs
in the USRDS from 1995-2007
• Categorized patients as low, intermediate, or high risk based on presence of
comorbidities (ischemic heart disease, congestive heart failure, stroke, peripheral vascular disease)
• Zero = Low Risk; One = Intermediate Risk, ≥ Two or Diabetes = High Risk
Living Donor
SCD
ECD
Death
rate/100
patient years
in first year
Days to equal
Survival
Death
rate/100
patient
years in first
year
Days to
equal
Survival
Death rate/100
patient years in
first year
Days to
equal
Survival
Low
3
0
8
203
10
264
Inter.
3
0
8
285
14
304
High
6
76
11
368
16
521
Gill JS et al. Am J Transplant. 2013;13:427-432.
First Report on the OPTN National Variance
Allocation of A2/A2B Deceased Donor Kidneys to
Blood Group B Increases Minority Transplantation
• Eligibility: Candidates with at least two
consecutive, quarterly IgG anti-A titer
<1:8.
• Majority of donors were white (86%)
and the majority of recipients (61%)
were non-white
• Rejection rates equivalent, patient
survival equivalent to B to B
transplants
• As of April 23, 2015:
– 30 A2/A2B to B transplants performed (vs.
6 in the 5 months before the new KAS
policy was implemented)
– Only 3.6% of active B candidates were
registered to accept potential A2/A2B
offers
Williams W et al. Am J Transplant. 2015;15:3134-3142.
n=101 A2/A2B to B transplants from 2002-2011
Graft Survival
Public Health Service (PHS) High Risk
Donors: ~10% of Donor Pool
Categories of behavior leading to classification of High Risk Donor:
MSM
IDU
Hemophiliac
men who have had sex with another man in the preceding 5 years
persons who report nonmedical intravenous, intramuscular, or
subcutaneous injection of drugs in the preceding 5 years
persons with hemophilia or related clotting disorders who have
received human derived clotting factor concentrates
CSW
men and women who have engaged in sex in exchange for money or
drugs in the preceding 5 years
High Risk Sex persons who have had sex in the preceding 12 months with any person described
in items 1-4 above or with a person known or suspected to have HIV infection
HIV exposed persons who have been exposed in the preceding 12 months to known or suspected
HIV-infected blood through percutaneous inoculation or through contact with an open
wound, non-intact skin, or mucous membrane
Incarcerated inmates of correctional systems
MSM = men who have sex with other men, IDU = injection drug user,
CSW = commercial sex worker, HIV = human immunodeficiency virus
Seem DL et al. Public Health Rep. 2013;128:247-343.
Risk of Window Period Hepatitis-C Infection
in High Infectious Risk Donors
Systematic Review and Meta-analysis
• NAT testing reduces the the estimated window period (WP) for HCV
and HIV infection to 7-10 days
RISK BEHAVIOR
HIV RISK
% HIV RISK
HEP C RISK
% HEP C RISK
1:2000
0.05% risk
1:313
0.3% risk
1:2500
0.04% risk
1:3333
0.03% risk
1:3333
0.03% risk
1:833
0.12% risk
Incarcerated
1:10,000
0.01% risk
1:12,500
0.008%
Blood transfusion
1:20,000
0.005% risk
1:25,000
0.004% risk
IV drug use
Men having sex
with men
Commercial sex
worker
Kucirka LM et al. Am J Transplant. 2011;11:1188-1200.
HCV Transmission Despite Modern Donor
Screening Practices: Risks and Responses
• 3 clusters (3 organ donors defined as PHS high risk, with negative
NAT testing) resulted in 6 cases of acute HCV infection in transplant
recipients
– 2 with active IDU, one with a history of IDU
• Advisable to screen recipients of PHS high risk donors for HCV and
HIV 1-3 months after transplant
• Recent studies indicate successful eradication of HCV following
kidney transplant with direct-acting antivirals (DAA)
– Need to consider access to DAA
Suryaprasad A et al. Am J Transplant. 2015;15:1827-1835.
Humar A et al. Am J Transplant. 2010;10:889-899.
Sawinski D et al. Am J Transplant. 2015 Nov 25 (epub ahead of print).
Seem DL, et al. Public Health Reports. 2013;128(4):247-343.
Case Study
• Patient accepts kidney offer
• BMI 33, VSS, on BP meds, warfarin, statin, PPI, cPRA 49
• Admitted for transplant, cold ischemia time 21 hours
Polling Question 4
Activity Survey
Based on available clinical trial data, which of the following
de novo regimens has the greatest efficacy (lowest rates of
graft loss, rejection, or death) in the first two transplant
years?
A. Alemtuzumab-Tac-sirolimus-steroid withdrawal (day 5)
B. rATG-Tac-MPA-prednisone
C. rATG-Tac-MPA-steroid withdrawal (day 5)
D. Basiliximab-belatacept-everolimus-prednisone
E. Basiliximab-Tac-MPA-prednisone
Case Study
• Immediate graft function, discharged on day 4 on rATGtacrolimus, mycophenolate (MPA), prednisone
• Month 1: Developed wound infection, tac C0 range
5-10 ng/mL, MPA 720 bid, prednisone tapered to 10 mg
daily, creatinine remained stable (1.2-1.4)
• Month 6: BK viremia on screening, 10K, MPA decreased to
360 bid, prednisone tapered to 2.5 daily
Maintenance Immunosuppression
Use in USA, 1998-2011
SRTR Annual Data Report, 2012
“Gold-standard”
RATG
Tac
MPA
Steroids
Rationale for multi-agent regimen
• Most efficacious
• More immunological targets
• Permits reduced dosing of each drug,
with less drug-specific toxicity
Chapter 1: Induction Therapy
Limitations of induction trials
No double-blind RCT
No long-term outcomes
No approved depleting agent
Alemtuzumab on the way out
Variable maintenance Rx
Factors Influencing Selection of Therapies
• Established efficacy
– RCTs
• Immunological risk
– Highly sensitized
– African-American
• Medical risk
– Comorbidities
– Prior immunosuppressive burden
• Potential drug toxicity
– CNI
– Steroid
Chapter 2: Initial Maintenance
Immunosuppressive Medications
CNI Minimization
SYMPHONY
OPTICEPT
ASSET
CNI Elimination
CTOT-9
ORION
CENTRAL
CONVERT
ZEUS
CNI Avoidance
SYMPHONY
ORION
SYMPHONY:
“Low Dose” Tacrolimus 4-7 ng/mL
12-month randomized open-label multicenter trial (n=1645)
4 arms (IL2R induction in “low” arms, MMF/Prednisone for all)
At 12 months:
Regimen
GFR
(mL/min)
CSA “standard”
57.1
CSA “low”
59.4
TAC “low”
65.4
SRL “low”
56.7
Ekberg H et al. N Engl J Med. 2007;357:2562-2575.
SYMPHONY and CNI Minimization
Drug Trough:
Tac (4-7)
CSA (100-200)
CSA (50-100)
SRL (4-8)
12 months
6.4
142
101
7.5
36 months
6.5
114
103
7.0
Graft survival
Ekberg H et al. Am J Transplant. 2009;9:1876-1885.
Ekberg H et al. N Engl J Med. 2007;357:2562-2575.
“Low-dose”
tacrolimus
GFR
The ORION Study
• Tacrolimus elimination [13 wks]
• Tacrolimus avoidance
• Standard tacrolimus-MMF
RCT (n=443)
1. Tac Srl: 66% withdrawn
2. Srl-MMF: 60% withdrawn (arm terminated)
3. Tac-MMF: 37% withdrawn
Primary endpoint: 1 year GFR: no difference between groups
Adverse events
• SRL arms had higher rates of:
– withdrawal from study
– Acute rejection (15% vs 32% vs 8%)
Flechner SM et al. Am J Transplant. 2011;11:1633-1644.
Tac Withdrawal in Immunologically
Quiescent Recipients (CTOT9)
• Prospective study, nonsensitized, primary live
donor recipients
• rATG-Tac-MMFprednisone for all,
randomized at 6 months to
continue, vs Tac
withdrawal if DSA neg, no
rejection/inflammation on
protocol biopsy
• 14 weaned, 6/14
developed rejection, 5/14
developed DSA
Hricik DE et al. J Am Soc Nephrol. 2015;26:3114-3122.
CNI Elimination Studies with mTOR Inhibitors
Study
Time to
conversion
(months)
CONVERT (Srl)1
6-120
ZEUS (Evr)2
Followup
Baseline
(months)
CNI
CyA or
12
Tac
GFR,
mL/min
Treatment
Failure/
Graft Loss
BPAR
+4.9a
↑
↑
4.5
36
CyA
+7.8a
↑
↑
CENTRAL (Evr)3
2
12
CyA
+8.0a
↑
↑
ORION (Srl)4
3
12
Tac
-
↑
↑
1-6
24
80% Tac
+3.6a
- (but 27%
back to CNI)
-
SPARE THE
NEPHRON (Srl)5
All intent-to-treat
1.
2.
3.
4.
5.
Schena FP et al. Transplantation. 2009;2:233-224.
Budde K et al. Lancet. 2011;2:837-847.
Murbraech K et al. Transplantation. 2014;97:184-188.
Flechner SM et al. Am J Transplant. 2011;2:1633-1644.
Weir MR et al. Kidney Int. 2011;2:897-907.
a
P<0.05
Belatacept and CNI-Avoidance
BENEFIT and BENEFIT-EXT
– Simultaneous studies: Bela vs CyA
– EXT: ECD, DCD, and prolonged cold time
7-year follow-up [BENEFIT]
Acute rejection rates at 1 year
20
17.7
17
18
16
14.1
14
12
CsA
10
8
Bela
7
6
4
2
0
BENEFIT
BENEFIT-EXT
Vincenti F et al. Am J Transplant. 2010;10:535-546.
Durrbach A et al. Am J Transplant. 2010;10:547-557.
Vincenti F et al. N Engl J Med. 2016;374:333-343.
What Are the Concerns about Belatacept?
• Higher rejection rates
• Histologically more severe rejection
• Post-transplant lymphoproliferative disorder risk
• IV administration and cost
• Patient reluctance
• No RCTs with tacrolimus as comparator agent
Pestana JO et al. Am J Transplant. 2012;12:630-639.
Vincenti F et al. Am J Transplant. 2012;12:210-217.
Durrbach A et al. Am J Transplant. 2010;10:547-557.
Vincenti F et al. Am J Transplant. 2010;10:535-546.
Heher et al. N Engl J Med. 2016;374:388-389.
Early Steroid Withdrawal RCT
Summary at 5 Years
60-month randomized controlled, double-blinded, double-dummy, multicenter trial (n=386)
2 arms, RATG-Tac-MMF; steroid withdrawal within 7 days
• Lipids a little better
• No differences in:
CV risk
- weight gain
- new diabetes
- kidney function
-
• Increased
-
acute rejection
-
chronic graft dysfunction
Woodle ES et al. Ann Surg. 2008;248:564-577.
Case Study (cont)
• Month 6 to year 2: BK virus clears; stable kidney function
(Cr 1.2-1.4) (monthly-quarterly follow-up) with tac trough
trending lower (range 3-7 ng/mL)
• Consistent complaints of emotional lability, insomnia,
tremor
• At 2-year visit: she asks if she can decrease tacrolimus
(level is 3.3 ng/mL despite no changes in dose); also
informs you that sometimes she falls asleep before her
evening meds
Polling Question 5
Activity Survey
Clinical studies suggest that which of the following
treatment options would be associated with the lowest risk
of acute rejection after conversion?
A. Change twice-daily tacrolimus to once daily tacrolimus
(MR4 or LCP)-MPA-prednisone
B. Change to everolimus-MPA-prednisone
C. Change to sirolimus-MPA-prednisone
D. Change to belatacept-MPA with steroid elimination
Once-a-Day Tacrolimus
Tac-MR*
LCP-Tac*
Similar
Similar
Cmax
Similar
Lower
Tmax
Similar
Delayed
AUC
Lower
Higher
Higher
Lower
C0
Required dose
*compared to twice-daily tacrolimus
Twice –daily Tac
Provided by Roy D. Bloom, MD.
Tac MR [Astagraf]
LCP-Tac [Envarsus]
Efficacy of LCP-Tacrolimus
• Phase III, RCT, double-blind, double-dummy; primary endpoint: treatment
failure
• 543 subjects receiving de novo kidney transplants were randomized to one
of two treatment arms: daily LCP-tacrolimus, twice daily tacrolimus
• All subjects received basiliximab induction, mycophenolate mofetil;
corticosteroids per local practice
Grinyó JM, Petruzzelli S. Expert Rev Clin Immunol. 2014;10:1567-1579.
Budde K et al. Am J Transplant. 2014;14:2796-806.
Efficacy of Once-daily Tacrolimus
• Phase III, open-label, comparative, non-inferiority study
• 638 subjects receiving de novo kidney transplants were randomized to one of three
treatment arms: daily tacrolimus extended-release, twice-daily tacrolimus, or twice-daily
cyclosporine
• All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids
Silva HT et al. Transplantation. 2014;97:636-641.
Case Study (cont)
• Converted to tacrolimus MR4; month 26: serum creatinine
1.5 mg/dL; Tac level 5.1 ng/mL, despite stable dose; BK
negative
• Month 36: kidney function has declined (Cr 1.9 mg/dL);
urine protein/creatinine 1.6, Tac level 2.3 ng/mL, despite
stable dose
• Also informs you that she stopped her prednisone 9
months ago because of fear of side effects
• New DSA to DQ at 4500 MFI
Polling Question 6
Activity Survey
The most likely diagnosis at this point is:
A. BK nephropathy
B. CNI toxicity
C. Late episode of acute kidney injury
D. Chronic rejection secondary to non-adherence
E. Recurrence of primary disease
Improving Long-term Kidney Allograft
Survival
Progress in graft outcomes is due to improved short-term outcomes
2012 OPTN/SRTR Annual Data Report. Available at: http://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/01_kidney_13.pdf.
Lamb KE et al. Am J Transplant. 2011;11:450-462.
Adjusted Rate of Allograft Failure in the USA
Patients aged ≥18 years at transplant; adjusted by age, gender, and race
United States Renal Data System; 2013 Annual Data Report. Available at: www.usrds.org/2013/slides/vol2_chap07_13.zip.
Graft Survival in DeKAF
Impact of Diagnosis of CAN or CNI Nephrotoxicity
CAN Does not Predict Subsequent Graft Failure: DEKAF Study
• n=440 “troubled grafts”
• Baseline creatinine <2 mg/dL
• Creatinine increase >25%
Gaston RS et al. Transplantation. 2010;90:68-74.
Gourishankar S et al. Am J Transplant. 2010;10:324-330.
Why Do Kidneys Fail? Mayo Experience
1996-2006: 330 of 1317 KTX with graft loss at mean 50-month follow-up
138 (43.4%) due to death
39 (11.8%) due to 1° non-function
153 (46.3%) due to graft failure (biopsies mean 4.7 months prior to graft loss):
• Of “glomerular disease”
• Of “IF/TA”
Med/Surg
(16%)
• 1/4 history of acute
rejection
• 40% “transplant glomerulopathy”
(~HLA Ab?)
Glomerular
disease
(37%)
IF/TA (31%)
Acute
rejection
(12%)
• ONLY 1 GRAFT LOSS ATTRIBUTED SOLELY TO CNI TOXICITY
El-Zoghby ZM et al. Am J Transplant. 2009;9:527-535.
Late Graft Loss: A Changing Paradigm
• Chronic rejection is the most frequent cause of deathcensored graft loss
• Chronic rejection is commonly due to insufficient
immunosuppression
– Inappropriate prescription (minimizing or avoidance
strategies)
– Patient non-adherence
Morath C et al. Transpl Int. 2012;25:633-645.
The Role of Antibody-mediated Rejection
and Non-adherence in Kidney Transplant
Failure
ABMR = antibody-mediated rejection
Sellarés J et al. Am J Transplant. 2012;12:388-399.
Strategies to Optimize Adherence
• Monitoring drug levels
• Tracking pharmacy refills
• Supervised medication administration
• Electronic notification (patient, center, other)
– Bottle caps
– Pill dispensers
– Apps
– Alarms/reminders
• Simplified regimens
Transplant Outcomes and Economic Costs
Associated with Patient Noncompliance to
Immunosuppression
• Use of Medicare claims data to calculate compliance as
medication possession ratio (MPR)
• 15,525 KTx recipients with at least 1 year of graft function
Pinsky BW et al. Am J Transplant. 2009;9:2597-2606.
Transplant Outcomes Associated with
Patient Noncompliance to
Immunosuppression
Medication possession ratio quartile cutpoints:
Y1
Y2
Y3
Overall
25%
0.731
0.816
0.827
0.811
50%
0.896
0.951
0.962
0.951
75%
0.964
0.997
1.000
0.998
Compliance by quartiles:
Graft failure
HR
Excellent
(Ref.)
Good
1.12
Fair
1.63
Poor
1.80
P-Value
0.2514
<0.0001
<0.0001
Pinsky BW et al. Am J Transplant. 2009;9:2597-2606.
Compliance predicts graft and
patient survival
Predictive Patterns of Early Medication
Adherence in Renal Transplantation
MEMS (Medication Event Monitoring System):
A microprocessor embedded in the cap of a medication
bottle records every opening and closing of the cap
195 patients:
• 44 (22.6%) decreased adherence
by 7% or more in month 2 post
treatment
 Acute Rejection
 Early Graft Loss
Nevins TE et al. Transplantation. 2014;98:878-884.
Use of Drug Level Monitoring (Intra-patient
Variability) to Assess
Under-immunosuppression/adherence
• 356 patients, measured tacrolimus variability while on stable dose
(“tacSD”=tacrolimus standard deviation), median follow-up 3.72 years
• Composite end point: late allograft rejection, transplant glomerulopathy, or graft
loss (including death)
tacSD >1.5
tacSD ≤1.5
n=256; P=ns
tacSD >2
tacSD ≤2
tacSD >2.5
tacSD ≤2.5
tacSD >3
tacSD ≤3
n=136; P=ns
n=74; P=0.04
P<0.001;
n=47
• For every 1-unit increase in TacSD, a 27% increase in composite end point
[HR 1.27 (95% CI 1.03-1.56)]
Sapir-Pichhadze R et al. Kidney Int. 2014;85:1404-1411.
Persistence and Adherence in Kidney
Recipients: Effect of Dosing Frequency
• 219 patients randomized to once-daily tacro or
twice-daily tacro 035.
Persistence, 6 mos
Adherence, 6 mos
Once-daily
(n=145)
82%
88%
Twice-daily
(n=74)
72%
79%
• Doses were missed more frequently in the evening
than in the morning (11.7% vs 14.2%; P=0.0035)
Kuypers DRJ et al. Transplantation. 2013;95:333-340.
P
value
0.08
0.0009
Difficulty for Both Prediction and
Intervention
• There is not one single cause for non-adherence
– Examples
•
Lack of understanding of the regimen
•
Forgetfulness
•
Financial problems with co-pays
•
Difficulty with regimen (work schedule/travel)
• Therefore, it is difficult to have a single effective
intervention
Outcomes of Interest to Patients:
The perspectives of kidney
transplant recipients on
medicine taking:
Medication properties
•
•
•
•
Large size
Multiplicity of medicines
Unpleasant taste and smell
Stickiness
(…and acute rejection, graft, and
patient survival)
Tong A et al. Nephrol Dial Transplant. 2011;26:344-354.
Side effects
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Bone disease/joint pain
Skin thinning
Hirsutism
Cancer
Psychological (aggression,
moodiness, memory loss)
Hand tremor/shaking
Gastrointestinal (diarrhea,
nausea, stomach pain)
Puffy face
Weight gain
Fatigue
Infections
Swollen gums
Hair loss
Dry mouth
Conclusions
• Anticipated benefits of the new kidney allocation system include improved equity
and utility
• Compared to remaining on dialysis for better quality organs, high KDPI kidneys
and kidneys from PHS-increased donors are associated with better outcomes in
patients who are older or are residents in regions with longer waiting times
• Among currently used immunosuppressants:
– tacrolimus-based therapy remains the efficacy “gold standard”
– belatacept is an emerging alternative, though trials comparing it to tacrolimusbased therapy are needed
• The leading cause of death-censored graft loss is chronic rejection, typically due to
non-adherence
• Several strategies to improve adherence are entering the transplant arena,
including use of more simplified immunosuppression regimens
CME Credit
•
Post-activity Survey
– Now that the program has completed, please take a
moment to answer the Post-activity Survey questions on
your form
– Your answers are important and will help us identify
remaining educational gaps and shape future CME activities
•
CME Evaluation
– If you’re seeking credit, ensure you’ve filled in your name
and demographic information on page 1 and complete the
CME Evaluation on your form (after the Post-activity Survey)
– Return all forms to on-site CME staff
Thank you for joining us today!