Transplantation:
Dealing with Landmines
Shamkant Mulgaonkar MD
Chief
Transplant Division
Saint Barnabas Health Care System
New Jersey
Death
Death
Dialysis Care
Transplant Care
Death
Renal Disease
Death
Death
Death
Death
Prevention
Halt Progression
Prepare for ESRD
End organ w/u
Death
Nancy 28 year Old
Dialysis nurse
Type I Diabetes age 5
High BP, Proteinuria
age 18
Age: 23, Creatinine 3.5
Creatinine Clearance 25
Healthy Parents 50’s
3 Healthy Siblings
Age: 26, Develops Retinopathy
Starts PD Peritonitis
Hemodialysis.. Access problems
Age: 27, Develops Dyspnea
CHF
Toe gangrene
Age 28,
Referred for Transplant
Issues upon arrival
Abnormal NST
Abnormal ECHO Low EF
Abnormal Carotids
Abnormal PV studies
Age 29, Needs CABG
Carotid Bypass
Stent both femorals
Death
Died at age 29
Nancy 28 year Old
Dialysis nurse
Type I Diabetes age 5
Treatment of newly diagnosed DM
Tight BS control
High BP, Proteinuria
age 18
Diagnosis
Treatment, tight BS+BP control
ACEI ARB
Pancreas or islet cell transplant
Age: 23, Creatinine 3.5
Creatinine Clearance 25
Healthy Parents 50’s
3 Healthy Siblings
Referral to transplant
Kidney or SPK
Explore Living donors
Dialysis preparation
Age: 26, Develops Retinopathy
Starts PD..Peritonitis
Hemodialysis.. Access problems
Team approach to serious problems
Cardiac testing
Vascular w/u
Immediate transplant
Age: 27, Develops Dyspnea
CHF
Toe gangrene
Vasculopathy
Needs aggressive w/u
Age 28,
Referred for Transplant
Issues upon arrival
Arrives alone,
blind in a wheelchair
Support, many problems
Abnormal NST
Abnormal ECHO Low EF
Abnormal Carotids
Abnormal PV studies
Advanced cardiovascular
Ineligible !
Age 29, Needs CABG
Carotid Bypass
Stent both femorals
Death
Died at age 29
What have we learned ?
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Reduce progression to ESRD : 10 years
Surveillance cardiovascular : 10 years
Early referral to transplant
Prepare for dialysis
Adequate dialysis
Avoid cardiac and infection problems
Early transplant with the best kidney : 20 years
Early SPK or PAK transplant : 10 years
Projected life expectancy: 65 years
Jack 54 year old Truck driver
African American
ESRD unknown cause
Permacath
Hemodialysis
Noncompliant from Day 1
5 foot 11 inches
312 lbs
1 ppd smoker
Access clotted 4 times
Transfused 4 units PC
Unemployed
Lost insurance
Remains on dialysis 5 years
Family ?
No car
Uncontrolled BP
Dietary noncompliance
8 lb weight gain bet HD
Referred to transplant center
Leg Graft
59 year old, High PRA
No work up in 5 years
2 brothers healthy
1 daughter
All in Alabama
W/u Renal tumor
Hypernephroma
Abnormal NST stent
COPD
Uncontrolled BP
Dietary noncompliance
8 lb weight gain bet HD
Continues to smoke
Listed after w/u, insurance
and counseling
High PRA 90 %
+ crossmatch family no LD
Died of MI at age 60
Death
Jack 54 year old Truck driver
African American
ESRD unknown cause
Recurrent Nephropathy
Permacath
Hemodialysis
Noncompliant from Day 1
Referral to transplant
Creation of AV access
5 foot 11 inches
312 lbs
1 ppd smoker
Approach to Obesity
Smoking cessation
Access clotted 4 times
Transfused 4 units PC
Unemployed
Lost insurance
Proper assessment of vascular access
Coagulation studies
Psychosocial issues
Assist with insurance
Remains on dialysis 5 years
Family ?
No car
Lost wait time for transplant
Where is the family?
Importance of transportation
Uncontrolled BP
Dietary noncompliance
8 lb weight gain bet HD
Role of MD/RN/Dietitian
Compliance
Referred to transplant center
Leg Graft
59 year old, High PRA
No work up in 5 years
Now an emergency !!
Highly sensitized
? Medical problems of ESRD,
Smoking, obesity
2 brothers healthy
1 daughter
All in Alabama
Willing donors
W/u Renal tumor
Hypernephroma
Abnormal NST stent
COPD
Cancer and transplantation
Stent or CABG and wait time
Sleep apnea, COPD
Uncontrolled BP
Dietary noncompliance
8 lb weight gain bet HD
Continues to smoke
PERFECT PATIENT !!!
Listed after w/u, insurance
and counseling
High PRA 90 %
+ crossmatch family no LD
May never get a transplant
Died of MI at age 60
Death
What have we learned?
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Diagnose cause of ESRD : Recurrence
Surveillance cardiovascular
Early referral to transplant
W/U Hypercoagulation
Aggressive counseling: Dialysis Compliance,
Diet, Meds, Cigarette Smoking, Pot
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Involve family members
Assist in insurance matters
Adequate dialysis
Avoid anemia and transfusions
Early transplant with the best kidney
Who is responsible for the death of
Nancy and Jack?
• Patient and family
• Society
• Internist
• Endocrinologist
• Nephrologist
• Predialysis educator
• Dialysis nurse
• Dialysis social worker
• Transplant center
Projected Years of Life from WL for WL
Dialysis vs. Transplant Patients by Age Group
40
Projected Years of Life
Wait List Dialysis
Transplant
31
22
20
14
11
10
6
0
20-39
40-59
Age Group
60-74
00079
Projected Years of Life from WL for WL
Dialysis
vs. Transplant by DM (Age 40-59)
40
Projected Years of Life
Wait List Dialysis
Transplant
22
19
20
12
8
0
Non-DM
DM
00082
Graft survival in of 2,405 recipients of paired kidneys
78 %
58 %
63 %
29 %
months post-transplant
Take Charge
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Think Death
Think Early intervention
Think Team approach
Think Family
Think Insurance
Think Compliance
Assume responsibility
Think Death
Conclusions
• Renal transplantation is associated with a
survival advantage
• This survival advantage over maintenance
dialysis is maintained even when marginal
kidneys are used for transplantation
• Waiting time on dialysis is associated with an
increased risk for graft loss and patient death
after renal transplantation
Incompatible Renal
Transplantation
or
High Risk Transplantation
High Risk Renal Transplantation
• Demographic : Child or age>60, African American
• Medical : Diabetic, Uncontrolled BP, cardiac problems,
High BMI, + Viral infections, Sickle cell disease
• Surgical : Major abdominal surgery, access, vascular
• Psychosocial : Noncompliance, Lack of family support,
Lack of insurance, alcohol/substance abuse
• Allograft : Imported, DCD or ECD
• Immunologic :High PRA, Sensitizing events, Incompatible
Blood group
Incompatible Renal Transplantation
• ABO Blood Group Incompatible
• HLA (Cross Match) Incompatible
Blood Group: ABO
• O : Universal donor can receive only O or A2
• A : Can receive from A or O
• B: Can receive from B or O
• AB : Universal recipient, Can receive from
A,B,AB or O
Facts
• It is possible that blood group
antigens may be shared by some
bacteria, leaves and seeds of plants.
• Infants have low levels and older
patients have higher levels due to this
exposure.
Jill
• 25 year old type I diabetes age 4.
• Creatinine 5 ( Creatinine clearance 10).
• Blood group O.
• Parents : Medical problems.
• 1 Brother willing donor : Blood group A.
• No other donors.
No BG compatible donors
ABOI
Titers
Plasma exchange
IVIG
Recheck Titers
Retuximab
Thymoglobulin
Transplant
Prednisone
Prograf
Cellcept
PP
IVIG
Outcomes
Short term
Long term
Post transplant
Nonadherance
Introduction
“Drugs don’t work
in patients who don’t take them”
-C. Everett Koop, M.D.
• Non-adherence to transplant medications
– Important and leading cause of transplant
failure
Gaston RS, Hudson SL, Ward M, Jones P, Macon R. Late renal
allograft loss: noncompliance masquerading as chronic rejection.
Transplantation Proceedings. 1999;31(4, Supplement 1):21S-23S.
– Precedes over 1/3 of transplant failures
Butler JA, Roderick P, Mullee M, Mason JC, Peveler RC. Frequency
and impact of nonadherence to immunosuppressants after renal
transplantation: a systematic review. Transplantation. 2004;77(5):769776.
Non-adherence in general nephrology
• Hemodialysis
Newmann JM, Litchfield WE. Adequacy of dialysis: the patient's role and
patient concerns. Semin Nephrol. 2005;25(2):112-9.
Hecking E, Bragg-Gresham JL, Rayner HC, et al. Haemodialysis
prescription, adherence and nutritional indicators in five European
countries: results from the Dialysis Outcomes and Practice Patterns Study
(DOPPS). Nephrol Dial Transplant. 2004;19(1):100-7.
• Peritoneal dialysis
Bernardini J, Piraino B. Compliance in CAPD and CCPD patients as
measured by supply inventories during home visits. Am J Kidney Dis.
1998;31(1):101-7.
Case
• 39 year old Black female
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ESRD due to HTN
s/p deceased donor renal transplant 5/2002
Creatinine 0.8 in 2004
Recent serum Cr in 2.5-3.0 range
Transplant biopsy spring 2005
• Moderate chronic allograft nephropathy
• Immunosuppressive regimen
– Prednisone
– Cyclosporine (Neoral)
– Mycophenolate mofetil (Cellcept)
Case (continued)
• On emergency visit to transplant clinic,
– Complained of SOB and DOE for past week
– Ran out of metoprolol several weeks before
– Serum Cr 8.5
• Admitted to Saint Barnabas Medical Center
– Repeat transplant biopsy
• Severe chronic allograft nephropathy
• Acute cellular rejection, grade 1B
– Treated with high-dose corticosteroids
– Upon further questioning, patient admitted
• Not taking prednisone for past several months
• Not taking mycophenolate mofetil for past 3 weeks
– Awaiting mail delivery of prescriptions
Case (continued)
• Hospital course
– Started on hemodialysis for uremic symptoms
– Immunosuppressive medications changed
• Cyclosporine replaced with tacrolimus
– When dialysis held, transplant failed to show
any function
• Patient returned to maintenance dialysis
Profiles of non-adherent
patients
Greenstein S, Siegal B. Compliance and noncompliance in patients with a
functioning renal transplant: a multicenter study. Transplantation.
1998;66(12):1718-26.
• “Accidental” non-compliers
– Disorganized
– Medication ingestion is not a priority
• “Invulnerables”
– Believe that they do not need to take their
immunosuppressive medications regularly
• “Decisive” noncompliers
– Independent rationales for non-adherence
Reasons for non-adherence:
Complexity of treatment regimen
• Increased dosing frequency
– Leads to decreased adherence
Claxton AJ, Cramer J, Pierce C. A
systematic review of the associations
between dose regimens and
medication compliance. Clin Ther.
2001;23:1296-310.
Reasons for non-adherence:
Side effects of medicines
• Medication side effects are under-recognized by
transplant professionals
Peters TG, Spinola KN, West JC, Aeder MI, Danovitch GM, Klintmalm GB, et al.
Differences in patient and transplant professional perceptions of immunosuppressioninduced cosmetic side effects. Transplantation. 2004;78:537-43.
• Cosmetic changes
– Important cause of non-adherence among adolescents
and young adults
Prevalence of non-adherence
• 22% of transplant recipients were non-adherent
• Median of 36.4% of graft losses are associated
with prior non-adherence
• Probably underestimates the actual incidence
Interventions to increase
adherence
Osterberg L, Blaschke T. Adherence to medication. N Engl J Med.
2005;353:487-97.
• Patient education
• Improved dosing schedules
• Improved communication between
physicians and patients
Why there will not be a Steroid
booth at Meetings ?
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Weight gain
Mood changes
Cataract
Osteoporosis
Avascular necrosis
Hypertension
Diabetes mellitus
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Depression
Peptic ulcer
Infections
Skin friability
Abdominal strae
Hyperlipidemia
Cosmetic changes:
moon face, hirsutism,
acne
SBHCS Protocol :
Immunosuppression
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Thymoglobulin 6 mg/kg over 3-4 days starting intra op
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Solumedrol 500 mg pre-op, then 250 mg bid post-op day 1, 125 mg
bid post op day 2 and 60 mg bid post op day 3
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Tacrolimus:Trough levels 10 for 90 days, 8-10 until 365 days,5-8
after 365 days
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Mycophenolate Mofetil 1 gram bid
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In Sirolimus arm : Levels 10 for 90 days, 5-8 until 365 days and 5
thereafter.
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Suspected ACR: Biopsy and treatment with Thymoglobulin, no
steroids
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Prophylaxis: Bactrim DS, Mycelex, Valcyte
Results
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120 patients March 2003-March 2006
Patient survival 98%
Kidney survival 96%
BP controlled with less meds
Decreased incidence of NOD
No bone fractures
Cosmesis excellent
No psych problems
Improved adherence
Graft Loss
• Acute rejection
• Chronic allograft nephropathy
• Impact of return to dialysis
Treatment of Acute Rejection
Acute Rejection
Hyperacute Rejection
Acute Vascular Rejection
Prevention
Nephrectomy
Prevention
Antibody
Plasma Exchange
Acute Cellular Rejection
Steroid Pulse
Antibody
ATGAM
Thymoglobulin
OKT3
Rescue
Prograf
Cellcept
Rapamycin
Chronic Rejection
Chronic Allograft Nephropathy
[CAN]
•One of the most common causes of CKD
•25 % Patients waiting for TSP have chronic allograft
failure.
•20% Kidneys go to patients who have failed 1 or more
transplants.
Can We Prevent
Chronic Allograft Nephropathy?
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HLA Matching
Acute rejection
Non adherence
Infections
Hypertension
Recurrent disease