بسم الله الرحمن الرحيم

بسم الله الرحمن الرحيمبسم الله الرحمن الرحيم

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

Kidney Transplantation: Objectives

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

ESRD: Incidence PMP

61

98

212

139

0

50

100

150

200

250

Australia Canada USA KSA

1992

Incidence of ESRD: KSA

0

50

100

150

200

250

SCOT Medina Gizan Asir

PMP

Fourth Urology Course KAUH, 2004

ESRD: Modality of Treatment in USA

60%

27%

10.60%

0.60%0%

10%

20%

30%

40%

50%

60%

Center HD Renal Tx PD Home HD

USRDS 97

Modality of Renal Replacement Therapy in KSA

HD: 7004 patients

57%

RTx: 486540%

PD: 379 patients

3%

2001

Performed Cadaveric Renal Transplant in KSA

2 0

5974

65

154

83 84

59

89

57

0

20

40

60

80

100

120

140

160

84 86 88 90 92 94 96 98 2000 2001 2002

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

ESRD: Mortality

25 24

7.7

4.2

0

5

10

15

20

25

Dialysis AllESRD

CAD

Deaths/100 Pt. Year

USRDS 97LRD

ESRD: Risk of Death

1

0.32

0.21

00.10.20.30.40.50.60.70.80.9

1

Alldialysis

CAD LRD USRDS 97

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.

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

ESRD: HCV-Ab Status in HD Patients in KSA

Positive70%

Negative 30%

SCOT. 97

HCV in HD Population in KSA

HCV among 7004 dialysis patients

Positive Negative

SCOT 2003

Kidney Transplantation: Types

• Living-related

• Cadaveric

• Emotionally-related

• Living-non-related

Allograft

• (homograft)– Genetically

disparate individuals of the same species

Hx Background:• In 1933: the 1st Renal allograft by

Voronoy in Ukraine

Transplant Immunology: Components of Immune SystemAntigen presenting cells (APC)

Macrophages & dendritic cells, Langarhan’s cells & vascular cells

T lymphocytesCD4+ (helper T cells)CD8+ (suppressor or Cytotoxic T cells)

B lymphocytes (antibody-forming)

What can happen ?

Ab-dependent cell-mediated

cytotoxicity

Complement-dependent cell-mediated cytotoxicity

IFN-g & TNF-a: up-regulating HLA molecules & co-stim (B7) upon graft & APCs

Graft destruction:

Ag specific & graft-destructive

T-cell

Effector T-cell & NK cell stimulated by granzyme B & perforin

IL-2 & IL-10 plays important role

• In 1954: the 1st long term renal transplant in Boston

HOW ?

Isograft

Then….

• 1958: 1st histocompatibility Ag was described

• 1969: radiation was used

What is this coming drug?

Azathioprine(Imuran)

?

Became available for human use in 1951

Immunosuppressants:Azathioprine

Imidazole analogue Purine antagonist thus inhibiting cellualr

proliferation Poorly selective (suppress all cells

population)Dose 1-2mg/kg/day Allopurinol blocks its catabolism


Immunosuppressants:Azathioprine, Complications

Bone marrow suppression : usually one cell line (especially with allopurinol)

GranulocytopeniaRed cell aplasia Isolated thrombocytopenia


Prednisone

?

Became part of therapy w AZA in 1962

Immunosuppressants:Corticosteroids

Maximal effect on macrophages & lymphocytes Inhibits cytokines gene transcription

Inhibit IL-1, IL-2, IL-6Inhibits INF-gamma & TNFThis will lead to inhibition of T cell proliferation

Used as maintenance therapy (PO) and as a treatment for acute rejection (IV)


• 1962: tissue matching

• 1966: direct cross match

Then ….

Many Ag can serve as histocompatibility Ag:

ABOXenografts

• 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

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

• Can be detected on the cell surface of almost all nucleated cells

• The best trigger of the proliferation of allogenic lymphocytes

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

HLA: Major Histocompatibility Complex (MHC)

A B C

DP DQ DR

A B C

DP DQ DR

Class I

Class II

Class I

Class II

Chromosome 6

HLA: Mendelian Transmission

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

A31,B22,C10DR5, DP12,DQ3

A14, B8, C24DR1,DP43,DQ7

A14, B8, C24DR1,DP43,DQ7

A03, B14, C28DR5, DP12, DQ3

A18, B53, C11DR20, DP19, DQ31

Father Mother

1 5432

T-cell Activation

APC

T Cell

IL-2R

IL-2

Nucleus

B7MHC/Ag

TCR/CD3

CD28

CD

APC

T Cell

IL-2R

IL-2

Nucleus

B7

MHC/Ag

TCR/CD3

CD28

Calcineurin

IL2 gene

G0

G1

SImuran

Simulect

MMF

RapCyA

FK

Steroid

M M

OKT3

B-cell stimulation:

• T-cell derived IL-2, IL-4

• Physical contact w T-cell

Immunosupression protocol

Repeated transplant

Living related (HLA identical)

-Cadaver-LRD (non-identical)

First transplant

First Cadaveric & LRD (non-identical)• Intra-op

– Methylprednisolone – CyA

• Post-op– CyA--> Neoral– MMF– Prednisone

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

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.

First Living related (HLA identical)

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

Therapy of rejection

• Prednisone pulse therapy – 500 mg--10 mg / 9 days

• Sever or Steroid resistant– Monoclocal OKT3 for 14 days– Polyclonal ATG, ALG

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

• Immune factors

• Non-immune factors

2-Overcoming chronic rejection

Immune factors

• Multifactorial

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

Rapa

?

Sirolimus (Rapamycin): Side Effects

•Hyperlipidemia •Impair wound healing •More potent Immunosuppression when combined

with CNI•Pneumonitis •Thrombocytopenia •Hypokalemic•Early vascular thrombosis


Rapamycin

• It is a macrocylic ABx produced by Streptomyces hygroscopicus

• binds to– FKBP– TOR1 & TOR2

APC

T Cell

IL-2R

IL-2

Nucleus

B7

MHC/Ag

TCR/CD3

CD28

Calcineurin

IL2 gene

G0

G1

SRap

M M

FKBP

P70 S6 pr kinase

RAPA

Immunosuppressants:rapamycin (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

Non-immune factors

• It’s 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

3-New Therapeutic Targets

• Tolerance

• Gene therapy

• Complement inhibition

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

Donor B.M. infusion in renal Tx

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

Xenograft• (hetrograft)

Between different species (animal to human)

Ethical issues

• Potential recipient

• Psychological stress

• Risk of xenozoonoses

1-Achieving optimal immunosuppression:

?

AntilymphocyteALG

ATGAM

Thymoglobulin

?

OKT3

?

Antibody Therapy:

• Types:– Monoclonal : e.g. OKT3– Polyclonal: e.g. ATG

• M/A• Indications

– Induction– Steroid-resistant rejection

• Side effects

Hybridoma

Myeloma

B-cell

Cloning

Mono Clonal Abx

Ag

APC

T Cell

IL-2R

IL-2

Nucleus

B7

MHC/Ag

TCR/CD3

CD28

Calcineurin

IL2 gene

G0

G1

S

M M

OKT3

e CD3

a B TCR

TCR/CD3

CyA KK

?

Immunosuppressants:Cyclosporine 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

activityThis will lead to inhibition of IL-2 gene

transcription & subsequently IL-2 production


Cyclosporine

• The introduction of CyA in 1980s established Tx as a routine procedure.

• Fungal peptide

• M/A

• Effect: reversible & specific for T-lymphocyte

• Side effects:

Achieving optimal immunosuppression

APC

T Cell

IL-2R

IL-2

Nucleus

B7

MHC/Ag

TCR/CD3

CD28

Calcineurin

IL2 gene

G0

G1

SCyA

FK

M M

FK 506(Tacrolimus)

KK

MMF

?

Immunosuppressants:FK506 (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


Immunosuppressants:Cyclosporine A & FK506 Use

CSA :Maintenance Immunosuppressants for all organ

transplant Dose 4-8mg/kg/day in divided doses

Tacrolimus (FK506): 0.15-.3mg/kgFor female patients Rescue therapy for renal transplant High immunogenicity


Immunosuppressants:differences Between Cyclosporine A & Tacrolimus

Cyclosporine More gingival

hyper-plasiaMore hirsuitismMore Hepato-toxic

TacrolimusMore potent than CSA More neurotoxicityAllopecia Hyperglycaemia (25%

Vs 4% for CSA)


APC

T Cell

IL-2R

IL-2

Nucleus

B7

MHC/Ag

TCR/CD3

CD28

Calcineurin

IL2 gene

G0

G1

SCyA

FK

M M

MMF(Cellcept)

?

APC

T Cell

IL-2R

IL-2

Nucleus

B7

MHC/Ag

TCR/CD3

CD28

Calcineurin

IL2 gene

G0

G1

S

MMF

M M

Immunosuppressants

Site of action Classifications Immunosuppressants and their

side effects Adjuvant therapy

Sir Roy Calne

Tom Starzl

Sollinger

Immunosuppressants: Classification

Inhibitors of transcription Corticosteroids (IL-1, IL-2, IL-3, IL-6, TNF-

alpha, gamma-interferon)CSA: IL-2FK506 (tacrolimus): IL-2

Inhibitors of growth factors signal TransductionRapamycin (sirolimus): IL-2

Inhibition of Gene Transcription

• Azathioprine• Broad myelocytic suppressant (poorly selective)

– Inhibit T-cell proliferation

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 ?

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

Transplant Workup of the Recipient

-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

History & Physical

RadiologicalAssessment

Laboratory Tests

Consultations

Kidney Transplantation: Contraindication to Tx .

• Active infection: Bacterial, TB, HCV, CMV

• Malignancies

• Active auto-immune disease

• High cardiac risk

• High operative risk

• Pregnancy

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

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 (donor’s class-i HLA) cause hyperacute rejection

Kidney Transplant: Complications

• Hypertension• Metabolic abnormalities

– DM and hyperglycemias

– Hyperlipidemia

– Hyper & hypokalemia, hypomagnesaemia

– RTA

– Hyperuricemia

– Hypophosphatemia

– Osteoporosis

Transplant Complications:

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

• Polycythemia

Transplant Complications:(Continued)

Long and short term complications

• Malignancies

• Cardiovascular: CAD• HTN , DM & Immunosuppressants

• Renal artery Stenosis

• Obesity

Infectious Complications of Transplantation

-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

0-3 weeks Usual infections

1-6 months Opportunistic

6 monthsCommunity-acquired

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.

• Caposi’s sarcoma.• Others: kidney, GU etc...

Renal Transplant Rejection

• Hyperacute rejection

• Acute Rejection• Cellular • Vascular

• Chronic rejection

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

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

Future of Transplantation

• “Individualization and Minimization”

• Immune tolerance – New agents– Gene therapy

• Xeno-transplantation

بسم الله الرحمن الرحيم

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