Overview of Renal Transplantation - ssom.luc.edu · PDF fileOverview of Renal Transplantation...
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Overview of Renal Transplantation
Ravi Parasuraman MD, MRCP
Medical Director, Kidney Transplant Program
Associate Professor of Medicine
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Objectives
• History of transplantation
• Incidence and prevalence of ESRD
• “Renal Transplant” the Optimal Choice for ESRD
• Immunosuppression therapy and outcomes
• Barriers / Limitations in renal transplantation
• Future of Renal transplantation
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The History of Transplantation
Hindu’s god of wisdom, Ganesh
The minotaur in Greek mythology
The Egyptian Gods bearing heads of animals
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The Patron Saints of Transplantation
Saints Cosmos and Damian, identical
twin physicians in the 4th century AD
Their most miraculous surgery was
transplantation of the lower extremity of
a dead Ethiopian gladiator to a custodian
of a Roman basilica (gangrenous leg)
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Imagination to Reality - Early 20th Century
• 1902 - Prof. Ullmann: 1st Experimental kidney transplant in a Dog
• 1933 - Prof. Voronoy: 1st Human-to-human kidney transplantation
• 1933-1944: Six additional transplants performed – all failed
• A successful Kidney Transplant would require:
Medical support for Kidney failure (Dialysis, HTN)
Blood group and tissue “Matching”
Preservation of the donor kidney
Overcoming the immunologic barrier
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The First Successful Kidney Transplant
December 23, 1954 at Brigham Hospital by Dr. Joseph Murray between Herrick brothers (Monozygotic twins)
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Kidney Transplantation: Today
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~ 17,000 ~ 170,000
The experimental, risky, limited treatment option 50 yrs ago,
Has become a routine clinical practice in > 80 countries
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Victim of its Own Success: Wait List
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>92,000 patients are waiting for about 12,000 deceased donor
kidneys available each year
Kidney Transplant is considered the major advancement of
modern medicine
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Demand-Supply Crisis
• Number of new patients added to the waiting list:
> 30,000 patients are added to the list each year
• Death rate on the waiting List: ~8%
>4500 patients waiting for kidney transplant die each Year
• Number of deceased donors available remains unchanged:
> 12,000 potential organ donors/year
< Less than 50% of them become actual donors.
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INCIDENCE AND PREVALENCE OF ESRD
ESRD
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Burden of ESRD In US
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The incidence of ESRD in 2010 ~ 120,000
The Prevalence of ESRD~ 600,000
ESRD on therapy has increased 10 fold in 30 yrs
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Global Burden of ESRD
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March 8th is the “World kidney day”
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MODALITY OF THERAPY OF ESRD
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Incident ESRD patients Prevalent ESRD patients
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Transplant –The Optimal Choice
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Alonzo Mourning
Restores Health to near Normal in most Patient
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Renal
Transplantation
Long term survival
Better
Quality of life
Better
Cost-effective
$12000 vs. $60,000
(Tx vs. HD)
Renal Transplantation “The Optimal Choice”
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Renal Transplant: Survival Benefits
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Comparison of Mortality: Transplant vs. Dialysis
NEJM, 341:1725, 1730, 1999
Annual death rate: 2.6 x
Patients on dialysis vs. waiting for a transplant
Annual death rate: 1.7x
Patients on the wait list vs. transplant recipients
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Economic Benefits
• Cost of therapy:
Annual cost of hemodialysis: $60,000-$80,000
Cost of transplant during first year ~$120,000
Thereafter: $10,000-12,000 per year.
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Transplantation: Quality-of-Life Benefits
• Relatively unrestricted diet
• Freedom to travel • Restoration of fertility (in some)
• Return to Employment
• Lifestyle free of dialysis constraints
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Immunosuppression and Outcomes in
Transplantation
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Immunosuppressive Regimens
1. Induction immunosuppression
Intense IS during and immediately after Tx
2. Maintenance immunosuppression
Two or three drug regimen as long as the allograft functions
3. Treatment of Rejection
Immunosuppression for rejection (ACR and AMR)
4. Tolerance Regimen - still a dream
Selective unresponsiveness to donor antigen
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Immunosuppression: Most commonly used
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Induction Maintenance
Thymo or Campath
Simulect
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LUMC Immunosuppression Protocol Recipient Risk Profile
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Mechanisms of Action
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Immunosuppression: Vigilance
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• Monitor for:
Drug toxicities
Drug Interactions
Over Immunosuppression – infection and malignancy
Under Immunosuppression - Rejection
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Monitor for Drug Toxicities
Tacrolimus
•Nephrotoxicity
•Neurotoxicity
•Hypertension
•Hyperglycemia
•GI toxicity
CSA
• Nephrotoxicity
• Neurotoxicity
• Hypertension
• Hyperlipidemia
• Hirsutism
Sirolimus
• Hyperlipidemia
• Cytopenias
• GI toxicity
Steroids
• Osteoporosis
• Weight gain
• Hyperglycemia
• Body changes
• Others
MMF
• Cytopenias
• GI toxicity
PTDM
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Monitor for Drug Interactions (CNI)
• CNIs metabolized - CPY 450 3A4 or gp 170 (MDR1- gene)
• Commonly encountered drugs that interacts with CNI:
Increase CNI (Cyclosporine or Tacrolimus) levels:
Azole antifungals: fluconazole, clotrimazole
Macrolide antibacterials: erythromycin, clarithromycin
Calcium channel blockers: verapamil and Cardizem
Protease inhibitors
Decreases CNI levels:
Anticonvulsants: phenobarbital, carbamazepine
Antitubercular drugs: INH, Rifampicin.. Mignat C. Drug Saf. 1997;16:267-278.
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Transplant Outcomes
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You can’t possibly account for every
possible treatment outcome
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Rejection Rates
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In Early 90s – Rejection rates were >50 %
Now – Less than 10 %
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Short-term Outcome
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Outcomes In Renal Transplantation
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Complications
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Goal Post-transplantation
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Major complications Post Transplantation
• Early complications
Surgical complications
• Urinary leak
• Vascular thrombosis
• Bleeding complications
Medical complications
• Delayed Graft Function – 22%
• Acute Rejection -10-15%
• Late Complications
Chronic Allograft Nephropathy
Death with Functioning Graft
Infections
Malignancy
Metabolic complications
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Common Causes of Graft Dysfunction
Immediate:
1. DGF/ATN
2. Rejection (Hyperacute
or Accelerated)
3. Urinary leak
4. Obstruction
5.Vascular occlusion
6. Athero-embolism
Late (> 3 months):
1.Rejection
2.GN (Rec/ De Novo)
3.CNI toxicity
4. Obstruction
5.Viral Infections
6.RAS
7.CAN
Few days – 3 months:
1. Volume depletion
2.Acute CNI toxicity
3.Obstruction/lymphocele
4.Rejection (ACR/AMR)
5.TMA
6.Infections (e.g.: BKV)
7.Recurrent GN
DGF: Delayed Graft Function, TMA: Thrombotic Microangiopathy
GN: Glomerulonephritis, RAS: Renal artery Stenosis, CAN: Chronic allograft
nephropathy
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Acute cellular rejection
T cell mediated rejection
Incidence <15% in the first year, Early diagnosis is Absolutely Essential Banff I: Tubulointerstitial – Steroids
Banff II. Endothelialitis –Thymoglobulin
Banff III. Vasculitis – Fibrinoid necrosis ATG & revise immunosuppression
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Acute Humoral rejection
A:Fibrinoid necrosis B: Neutrophils margination PTC C: Diffuse strongly positive C4d
Diagnostic Criteria for Acute humoral Rejection 1. Allograft Dysfunction with Evidence of Tissue injury
2. C4d Immunostain Positive
3. Donor Specific Antibody Positive
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Treatment of Rejection
Acute Cellular Rejection
• Corticosteroids (Grade I)
• Anti-thymocyte globulin (Grade>II)
Acute Humoral Rejection
• Intravenous Immunoglobulin (IVIG)
• Rituximab
• Plasmapheresis
Site of action, adverse effects and Drug interactions
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Major Causes of Death in Kidney Transplantation
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Linares et al Transplant Proc. 2007 Sep;39(7):2225-7. N=1200, 1995-2004
38%
29%
12% 10.50% 10.50%
0%
5%
10%
15%
20%
25%
30%
35%
40%
%
CVD Infection Malignancy Others Unknown
Mortality after Renal Transplantation
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Infectious causes for mortality
Post-Transplantation
Linares et al Transplant Proc. 2007 Sep;39(7):2225-7. N=1200 (1995-2004)
35%
24%
18% 18%
4%
0%
5%
10%
15%
20%
25%
30%
35%
40%
Sepsis Vir. Infection Bac.Pneumonia Fung. Infection Abd. Infection
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BK Virus Nephropathy
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Post-Transplant Malignancies
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Skin and Lip Lymphoma
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Malignancy
Recipient of organ transplants are at higher risk for malignancy
Related to impaired immune surveillance as a result of
immunosuppression.
Skin cancer most common: sun protection.
Routine cancer screening.
Specific malignancies:
Kaposi sarcoma – HHV 8
Post-transplant lymphoproliferative disorder (PTLD) - EBV
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Individualizing Immunosuppression Therapy
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Barriers /Solutions for Transplantation
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1. Organ Shortage Barrier : Demand –supply Crisis
2. Immunological barrier: Highly Sensitized status
3. Socio-Economic Barrier
4. Co-morbidity Barriers
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Demand-Supply Crisis
Demand supply crisis
Kidney Waiting list candidates > 90,000
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Impact of Demand-Supply Crisis
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Number on the wait list is >90,000
Time on the wait list is increasing >5 yrs
Longer the waiting time, poorer the outcome
Mortality on the waitlist is increasing
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Increase in Deceased Donor Renal Transplantation
SCD: Standard Criteria Donor -76%
ECD: Extended Criteria Donor 7%
DCD: Donation After Cardiac Death 16%
15%
50%
726%
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Sensitization and Crossmatch (CXM)
• ABO compatibility & Negative CXM - is Essential (Not absolute)
• Sensitization:
Presence of cytotoxic Abs against donor HLA class I or II Ag (PRA- CDC or FLOW cytometry)
• High risk for sensitization
Multiparous, previous transplant, blood transfusions
• 30% on the Waiting List are sensitized (>20% PRA)
Waiting time is at least twice longer
• Positive XM (Cytotoxic Abs) virtually excludes Tx.
80 – 90 % experience hyperacute or accelerated antibody rejection
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Desensitization Protocol
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Higher cumulative immunosuppression
Resource consuming – Manpower and money
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Paired Kidney Donation
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Future :Tolerance
X
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