Classification of Immunosuppressants

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Kidney Transplantation

• Dr. Anmar Nassir, FRCS(C)
• Canadian board in General Urology
• Fellowship in Andrology (U of Ottawa)
• Fellowship in EndoUrology and Laparoscopy
  (McMaster Univ)
• Assisstent Prof Umm Al-Qura
• Consultant Urology King Faisal Specialist
  Hospital

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Kidney Transplantation Objectives

• Why transplantation?
• Types of transplantations
• Assessment of transplant recipient and donor
• Transplant immunology
• Immunosuppressants
• Complications
• New advances in transplantation
• Challenges

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ESRD Incidence PMP
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Incidence of ESRD KSA
PMP
Fourth Urology Course KAUH, 2004
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ESRD Modality of Treatment in USA
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Modality of Renal Replacement Therapy in KSA
2001
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Performed Cadaveric Renal Transplant in KSA
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Kidney Transplantation Why?

• Better quality of life
• Restoring healthy productive life
• May restore sexuality and fertility
• Dialysis-associated morbidity
• Access problems and other infections
• Bone disease and dialysis-associated amyloidosis
  
• Lower mortality

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ESRD Mortality
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ESRD Risk of Death
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Kidney Transplantation Why?Special Reasons in
KSA

• Increasing number of ESRD patients.
• Negative image of dialysis.
• High Incidence and prevalence of HCV infection.
• Poor dialysis therapy inadequacy.
• Improper treatment of anaemia and bone disease.

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Causes of Morbidity and Mortality

• Hemodialysis
• Access problems
• Blood Stream Infection
• HCV
• Bone disease
• Dialysis-associated amyloidosis
• Acquired cystic diseases RCC
• IHD

• Peritoneal Dialysis
• CAPD peritonitis
• Loss of Peritoneal membrane
• Hyperglycaemia
• Hyperlipidemia
• Acquired cystic diseases RCC
• IHD

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ESRD HCV-Ab Status in HD Patients in KSA
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HCV in HD Population in KSA
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Kidney Transplantation Types

• Living-related
• Cadaveric
• Emotionally-related
• Living-non-related

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Allograft
Hx Background

• In 1933 the 1st Renal allograft by Voronoy in
  Ukraine

• (homograft)
• Genetically disparate individuals of the same
  species

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Transplant Immunology Components of Immune
System

• Antigen presenting cells (APC)
• Macrophages dendritic cells, Langarhans cells
  vascular cells
• T lymphocytes
• CD4 (helper T cells)
• CD8 (suppressor or Cytotoxic T cells)
• B lymphocytes (antibody-forming)

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What can happen ?
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Graft destruction
Ag specific graft-destructive T-cell
Complement-dependent cell-mediated cytotoxicity
Effector T-cell NK cell stimulated by
granzyme B perforin IL-2 IL-10 plays
important role
IFN-g TNF-a up-regulating HLA molecules
co-stim (B7) upon graft APCs
Ab-dependent cell-mediated cytotoxicity
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• In 1954 the 1st long term renal transplant in
  Boston

HOW ?
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Isograft
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Then.

• 1958 1st histocompatibility Ag was described
• 1969 radiation was used

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What is this coming drug?
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Azathioprine(Imuran)
Became available for human use in 1951
?
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ImmunosuppressantsAzathioprine

• Imidazole analogue
• Purine antagonist thus inhibiting cellualr
  proliferation
• Poorly selective (suppress all cells population)
• Dose 1-2mg/kg/day
• Allopurinol blocks its catabolism

Fourth Urology Course KAUH, 2004
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ImmunosuppressantsAzathioprine, Complications

• Bone marrow suppression usually one cell line
  (especially with allopurinol)
• Granulocytopenia
• Red cell aplasia
• Isolated thrombocytopenia

Fourth Urology Course KAUH, 2004
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Prednisone
Became part of therapy w AZA in 1962
?
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ImmunosuppressantsCorticosteroids

• Maximal effect on macrophages lymphocytes
• Inhibits cytokines gene transcription
• Inhibit IL-1, IL-2, IL-6
• Inhibits INF-gamma TNF
• This will lead to inhibition of T cell
  proliferation
• Used as maintenance therapy (PO) and as a
  treatment for acute rejection (IV)

Fourth Urology Course KAUH, 2004
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Then .

• 1962 tissue matching
• 1966 direct cross match

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• The strongest of the Tx Ag is the expression of a
  single chromosomal region called MHC
• large gene that control traits which influence
  the entire immune response
• located on chromosome 6
• the gene products of MHC were first investigated
  on leukocyte named HLA

Many Ag can serve as histocompatibility
Ag ABO Xenografts
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• Can be detected on the cell surface of almost all
  nucleated cells
• The best trigger of the proliferation of
  allogenic lymphocytes

• Only on the cells of immune system mac. dend.
  B, activated T
• Not as strong

• On each chromosome 6 there are 6 genetic loci ,
  and on each pair there are 12 loci

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HLA Major Histocompatibility Complex (MHC)
Chromosome 6
A B C
Class I
DP DQ DR
Class II
A B C
Class I
DP DQ DR
Class II
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HLA Mendelian Transmission
Father
Mother
DR01 DP43 DQ7
A03 B14 C28
DR20 DP19 DQ31
A14 B8 C24
DR05 DP12 DQ 03
A18 B53 C11
DR22 DP18 DQ20
A31 B22 C10
1
5
4
3
2
A31,B22,C10 DR5, DP12,DQ3
A14, B8, C24 DR1,DP43,DQ7
A14, B8, C24 DR1,DP43,DQ7
A03, B14, C28 DR5, DP12, DQ3
A18, B53, C11 DR20, DP19, DQ31
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T-cell Activation
APC
IL-2
T Cell
Nucleus
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MHC/Ag
APC
IL-2
T Cell
IL-2R
Nucleus
Calcineurin
G0
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B-cell stimulation

• T-cell derived IL-2, IL-4
• Physical contact w T-cell

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First Cadaveric LRD (non-identical)

• Intra-op
• Methylprednisolone
• CyA
• Post-op
• CyA--gt Neoral
• MMF
• Prednisone

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First Cadaveric LRD (non-identical)

• Out pt
• Neoral
• Prednisone
• Taper gradually
• MMF
• Maintain for 1 yr, then D/C
• Switch to Azatioprine if concern about rejection

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Repeated Tx

• (Same protocol as 1st Tx)
• Polyclonal Ab (ALG)
• should be started in RR
• Few days then start Neoral
• Most pts will remain on CyA, MMF, Pred.

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First Living related (HLA identical)

• Same protocol as above w/o MMF (or Azathioprine)

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Therapy of rejection

• Prednisone pulse therapy
• 500 mg--10 mg / 9 days
• Sever or Steroid resistant
• Monoclocal OKT3 for 14 days
• Polyclonal ATG, ALG

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There are 4 key needs which, if not met, could
marginalize Tx as a form of therapy

• 1-Achieving optimal immunosuppression
• 2-Overcoming chronic rejection
• 3-New therapeutic targets
• 4-Increasing the of organ donation

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2-Overcoming chronic rejection

• Immune factors
• Non-immune factors

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Immune factors

• Multifactorial
• Needs more Ix of
• endothelial cell activation
• expression of adhesion molecules
• cytokines
• chemokinse

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Rapa
?
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Sirolimus (Rapamycin) Side Effects

• Hyperlipidemia
• Impair wound healing
• More potent Immunosuppression when combined with
  CNI
• Pneumonitis
• Thrombocytopenia
• Hypokalemic
• Early vascular thrombosis

Fourth Urology Course KAUH, 2004
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Rapamycin

• It is a macrocylic ABx produced by Streptomyces
  hygroscopicus
• binds to
• FKBP
• TOR1 TOR2

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MHC/Ag
APC
IL-2
T Cell
IL-2R
Nucleus
Calcineurin
G0
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RAPA
FKBP
P70 S6 pr kinase
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Immunosuppressantsrapamycin (Sirolimus)

• Macrolide analogue
• It binds to FKBP (TOR) but does not inhibit
  calcineurin
• It has different mechanism of action than CSA and
  tacrolimus
• It inhibits growth factor cell transduction
• No nephrotoxicity

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Non-immune factors

• Its implication concerns clinical groups across
  the world
• Only 25-30 of R.Tx are normotensive
• Causes are multifactorial
• angiotensin system
• can be worse w hyperlipidemia

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3-New Therapeutic Targets

• Tolerance
• Gene therapy
• Complement inhibition

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Tolerance

• specific absence of an immune response to an
  Ag.
• but may also involve active immune response !
• 1-clonal deletion
• 2-clonal ignorance
• 3-active suppression

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Donor B.M. infusion in renal Tx
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4-Increasing Of Organ Donors

• Live donation
• education
• 3yrs f/u of 134 pt revealed
• 1.3 morbidity
• No mortality
• Better results in term of graft survival
• non-heart beating
• Xenotransplantation

Melchor, 1998
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Xenograft

• (hetrograft)Between different species (animal to
  human)

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Ethical issues

• Potential recipient
• Psychological stress
• Risk of xenozoonoses

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1-Achieving optimal immunosuppression

• ?

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Antilymphocyte

• ALG
• ATGAM
• Thymoglobulin

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OKT3
?
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Antibody Therapy

• Types
• Monoclonal e.g. OKT3
• Polyclonal e.g. ATG
• M/A
• Indications
• Induction
• Steroid-resistant rejection
• Side effects

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Ag
Myeloma
B-cell
Hybridoma
Cloning
Mono Clonal Abx
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MHC/Ag
B7
APC
OKT3
IL-2
T Cell
CD28
TCR/CD3
IL-2R
Nucleus
Calcineurin
G0
IL2 gene
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TCR/CD3
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CyA
K
?
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ImmunosuppressantsCyclosporine A

• Inhibit cell growth by inhibiting of gene
  transcription of IL-2
• It binds with cytoplasmic receptor protein
  (cyclophillin)
• CSA-cyclophillin complex binds with Calcineurins
  and inhibits its phosphatase activity
• This will lead to inhibition of IL-2 gene
  transcription subsequently IL-2 production

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Cyclosporine
Achieving optimal immunosuppression

• The introduction of CyA in 1980s established Tx
  as a routine procedure.
• Fungal peptide
• M/A
• Effect reversible specific for T-lymphocyte
• Side effects

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MHC/Ag
APC
IL-2
T Cell
IL-2R
Nucleus
Calcineurin
G0
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FK 506(Tacrolimus)
K
?
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ImmunosuppressantsFK506 (Tacrolimus)

• Inhibit cell growth by inhibiting of gene
  transcription of IL-2
• It binds with cytoplasmic receptor protein (FKBP)
  
• FK506-FKBP complex binds with calcineurin and
  inhibits its phosphatase activity
• This will lead to inhibition of IL-2 gene
  transcription subsequently IL-2 production

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ImmunosuppressantsCyclosporine A FK506 Use

• CSA
• Maintenance Immunosuppressants for all organ
  transplant
• Dose 4-8mg/kg/day in divided doses
• Tacrolimus (FK506) 0.15-.3mg/kg
• For female patients
• Rescue therapy for renal transplant
• High immunogenicity

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Immunosuppressantsdifferences Between
Cyclosporine A Tacrolimus

• Cyclosporine
• More gingival hyper-plasia
• More hirsuitism
• More Hepato-toxic

• Tacrolimus
• More potent than CSA
• More neurotoxicity
• Allopecia
• Hyperglycaemia (25 Vs 4 for CSA)

Fourth Urology Course KAUH, 2004
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MHC/Ag
APC
IL-2
T Cell
IL-2R
Nucleus
Calcineurin
G0
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MMF(Cellcept)
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MHC/Ag
APC
IL-2
T Cell
IL-2R
Nucleus
Calcineurin
G0
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Immunosuppressants

• Site of action
• Classifications
• Immunosuppressants and their side effects
• Adjuvant therapy

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Immunosuppressants Classification

• Inhibitors of transcription
• Corticosteroids (IL-1, IL-2, IL-3, IL-6,
  TNF-alpha, gamma-interferon)
• CSA IL-2
• FK506 (tacrolimus) IL-2
• Inhibitors of growth factors signal Transduction
• Rapamycin (sirolimus) IL-2

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Inhibition of Gene Transcription

• Azathioprine
• Broad myelocytic suppressant (poorly selective)
• Inhibit T-cell proliferation

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Inhibition of Gene Transcription

• Mycophenolate mofetil (MMF) Cellcept
• Selective lymphocyte suppressant
• Down-regulate the expression of adhesion
  molecules
• Mycophenolate salt (MPS) Myofortic
• Selective lymphocyte suppressant
• Less GI symptoms ?
• More potent ?

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Kidney Transplantation Workup of Recipient

• Comprehensive history and physical
• Biochemistry tests
• CBC
• HBsAg, HCV-Ab, HIV, CMV, EBV
• PPD
• EKG, Echo, stress test, coronary catheterisation
• CXR, US abdomen and pelvis , Mammogram, MRI and
  VCUG
• Dental, cardiology, urology, GI and ID
  consultations

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Transplant Workup of the Recipient
History Physical
Radiological Assessment
Laboratory Tests
Consultations
-Full detailed History -The cause of ESRD
-History of TB Examination
-Detailed examination -Examination of
Peripheral blood Vessels
-Cardiopulmonary and CNS assessment

-CBC Differential -PT. PTT
-Urea, Creatinine , And
Electrolytes -Calcium, phosphate
Alkaline phosphate -Liver enzymes,
Bilirubin, protein, alb. -Urine analysis, 24 h
alb. -HCV, HBsAg, HIV -CMV, EBV,HSV,
-Toxoplasma. PPD
-CXR, US abdomen -US Pelvis -EKG,
Echo -Stress test
-Coronary Angiogram -MRA or Angiogram If
indicated -CT scan if indicated -VCUG if
indicated
-Cardiac consultation -Dental check up
-Gynaecologic assessment in
female -ID consultation if Indicated
-Urologic consultation -Psychiatric
consultation if indicated
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Kidney Transplantation Contraindication to Tx.

• Active infection Bacterial, TB, HCV, CMV
• Malignancies
• Active auto-immune disease
• High cardiac risk
• High operative risk
• Pregnancy

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Kidney Transplantation Workup of the Donor

• Same as recipient plus
• Three 24 hour urine collections for protein and
  Creatinine clearance
• Three urine sediment exam
• Renal Angiogram or MRA
• Psychiatric consultation

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Transplantation Pre-Tx. Match

• ABO match
• As preformed natural anti-a, or anti-b abs will
  cause accelerated rejection
• HLA match
• Lymphocyte match
• Circulating preformed Abs against major HLA
  (donors class-i HLA) cause hyperacute rejection

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Kidney Transplant Complications

• Hypertension
• Metabolic abnormalities
• DM and hyperglycemias
• Hyperlipidemia
• Hyper hypokalemia, hypomagnesaemia
• RTA
• Hyperuricemia
• Hypophosphatemia
• Osteoporosis

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Transplant Complications

• Gastro-intestinal tract
• Peptic ulcer disease
• Pseudo-membranous colitis
• CMV colitis
• Pancreatitis
• Polycythemia

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Transplant Complications(Continued)

• Long and short term complications
• Malignancies
• Cardiovascular CAD
• HTN , DM Immunosuppressants
• Renal artery Stenosis
• Obesity

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Infectious Complications of Transplantation
0-3 weeks Usual infections
1-6 months Opportunistic

• 6 months
• Community-acquired

• Wound infections
• UTI
• Line-related infections
• HSV
• Oral candida

• -CMV
• -VZV
• EBV
• PCP
• Hepatitis
• Nocardia
• Listeria
• TB

• - CMV
• -TB
• Papilloma virus
• Other community-acquired infections

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Transplant Complications Malignancies

• Cancer (1.6).
• Skin cancer (squamous cell ca, basal cell ca
  melanoma).
• PTLD.
• NHL.
• EBV-related lympho proliferative syndrome.
• Reticulum cell sarcoma.
• Caposis sarcoma.
• Others kidney, GU etc...

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Renal Transplant Rejection

• Hyperacute rejection
• Acute Rejection
• Cellular
• Vascular
• Chronic rejection

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Causes of Morbidity and Mortality

• Dialysis
• Access problems
• Line-related sepsis
• HCV
• Anaemia
• Bone disease
• Dialysis-associated amyloidosis
• IHD

• Transplantation
• IHD
• DM and hyperlipidemia
• Osteoporosis
• Opportunistic infections
• Malignancies
• PTLD
• Skin cancer
• Osteoporosis

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Kidney Transplantation Challenges

• Over or under-immune suppression
• Individualization and minimization
• Chronic Rejection and Tx Glomerulopathy
• CNI avoidance
• New agents
• Immune tolerance
• IHD
• More aggressive approach to co-morbid conditions
• Hyperlipidemia and DM

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Future of Transplantation

• Individualization and Minimization
• Immune tolerance
• New agents
• Gene therapy
• Xeno-transplantation

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Thank you
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