Kidney transplantation – brief

overview
• History of Kidney transplantation
• Immunologic Principles of Kidney
Transplantation
• Evaluation of Donor and Recipient
• Kidney Transplant Surgery
• Immunosuppressive Therapy
• Complications of Kidney Transplantation
 History of Kidney transplantation

Dr. Joseph Murray and the medical team at Boston's Peter Bent Brigham Hospital
perform the first successful long-term organ transplant, Dec. 23, 1954
 History of Transplantation

Ten months after the transplant, Ronald Herrick (left) and his identical twin
Richard toast their good health.
History of Kidney Transplantation in
Bulgaria

• First attempts – 1968-1970

• Total number of transplant recipients –
approx. 1300
• Transplant recipients at present - 583
History of Kidney Transplantation in
Bulgaria

Ass.-Prof. Boriana Beleva

1946-2001
Immunologic principles of
kidney transplantation
 Allogenic transplantation

Activation of allogenic T- and B- Lymphocytes

Rejection
Main groups of cells participating in
the immune response
• APC – dendrite cells, macrophages, B-
lymphocytes – activate T-Lymphocytes
• T-lymphocytes – CD 4/+/, CD8/+/
• B-Lymphocytes – antibody production,
presence of specific B- Cell Receptor
 Stages of immune response
• APC – activation
• T-Lymphocyte activation
• B-lymphocyte activation
• Damage of target organ /transplanted
kidney
• End of the immune response
 The MHC
• 3 gene regions - MHCI, MHC II, MHC III
• MHC molecules – class I and class II –
involved in rejection
• Importance – present the antigen to the T-
lymphocytes
• Encoding – HLA – A,B,C/HLA- DR, DP,
DQ
• Expression of the MHC molecules
Structure of MHC molecules
 Activation of APC
• Detection of donor
peptides
• Migration to
secondary lymph
organs
• Presenting the
peptide to T-
lymphocytes
 HLA match/mismatch
• HLA formula donor • HLA formula recipient

HLA 1 13 HLA 1 14
A
HLA 1 13 A
A
HLA 2 11 HLA 5 11
HLA
B 2 11 B
B
HLA 15 23 HLA 15 28
HLA 15 23
DR DR
DR
HLA
HLA 0202 06 06 HLA 02 06
DQ
DQ DQ

mismatches matches
Activation of T-lymphocytes – T-cell
receptor
Activation of T-lymphocytes –
signal 1
 Activation of T-lymphocytes –
signal 1
Activation of CD3

Protein kinase C activation Increased concentration of

Inositol 3P

NFκB activation Activation of calcineurin

NFAT activation
Signal 2 – amplifies the immune
response
Signal 3 – proliferation of activated
cells
NFAT and NFκB
activation

Increased expression
of ILR-2 and IL2

M-TOR activation

Activated T-
Lymphocytes
proliferation
 Effector functions of activated T-
cells

• CD4/+/ - IL-s, cytokines, B-cell activation,

T-cell activation
• CD8/+/ - cytotoxicity, cytokines production
End of immune response –
inhibitory signal
Immunosuppressive agents
 Corticosteroids

How they work

• ↓ IL-1,IL-2 and TNFα
production
• ↓ adhesion of Neu
• ↓ NFkB production
 Antimetabolites - Azatioprine
• Antagonist to purine
metabolism
• Blockade of
lymphocyte
proliferation
• Doses
• Adverse effects
 Mycophenolic acid derivatives

• Blocks de novo purine

synthesis
• Stronger
immunosuppressant
than Azathioprine
• Preparations MMF,
Mycophenolate Na
 Calcineurin inhibitors - CsA

• Peptide molecule
• CsA levels are
monitored
• Side effects
• Dose 5mg/kg
 Calcineurin inhibitors – Tacrolimus
/FK 506/

• Macrolide antibiotic
• Binds to FKBP
• Inhibits calcineurin
• Stronger
immunosuppressant
than CsA
• Dose 0.1mg/kg
 M-TOR Inhibitors
• Binds to FKBP
• Blocks proliferation
of activated T-
lymphocytes
• Preparations –
Rapamune,
Everolimus
• Drug levels
monitored
 Protein molecules

• Antibodies against
Lymphocytes/ Ly-
receptors
• Polyclonal/monoclonal
• Animal – horse,
rabbit,
murine/humanized
 Polyclonal AB

• ATG – Thymoglobulin
• Rabbit/horse Ab
• ↓Ly count
• Indications
• Side effects – Neo, infections
 Monoclonal AB – anti CD25

• CD 25 = IL-2Rα
• Humanized Ab
• Preparations –
Basiliximab,
Diclazumab
• No reduction in Ly -
count
 Monoclonal AB
• Anti-CD3 – OKT3
murine antibodies
• Anti CD20 Rituximab
↓B-Ly proliferation
• Anti CD 52 –
Campath
• Anti CD40L – inhibit
signal 2
 Fusion proteins CTLA4-IgG

• Bind to B7 of the APC

• Blockade of B7 – CD28 stimulation
• Belatacept
 Recipient evaluation
• Histocompatibility
• Cardiovascular disease
• Malignancies
• Infections
• Obesity
• Recurrent disease
• GI and genitourinary evaluation
• Pulmonary evaluation
• Psychosocial evaluation
 Histocompatibility
• Tests – AB0 typing, HLA typing, cross-
match test
• AB0 incompatibility – contraindication
• HLA mismatch more than 3 –
contraindication
• Cross match /+/ - contraindication
 Cardiovascular disease
• Ischaemic Heart Disease – poor LVF –
contraindication for TR
Tests – exercise tests, pharmacological
stress test
• Cerebrovascular Disease – stroke within 6
months – contraindication
• Peripheral VD – claudicatio present –
vascular imaging and consultation
 Malignancies

• ESRD – increased risk for Neo

• Transplantation – increased risk for
Neoplasm and recurrence of the disease
• Active disease – contraindication
• Waiting time after Ca – 2-5 years
 Screening for Infections

• Tests for – HCV, HBV, HIV, TBC, CMV,

EBV and others
• Active disease – contraindication
• HCV, HBV, HIV – no replication – TR can
be performed
• TBC, CMV prophylaxis after TR
 Obesity and Recurrent disease

• BMI > 40 – contraindication

• Recurrent disease – reduced graft survival

MPGN, FSGS, MN, IgAN
 Gastrointestinal and Genitourinary
Evaluation
• GU – not needed in
general
GI
• Native nephrectomy
• Gastroscopy bilateral – indications
• Colonoscopy – if • Unilateral
symptoms are nephrectomy –
present indications
• Active ulcer - • Failed graft
contraindication nephrectomy
 Pulmonary evaluation

• Tests – chest X-Ray , pulmonary function

tests
• Active disease – contraindication
• Bronchiectasias – increased risk
• CESSATION OF SMOKING
 Psychosocial issues

• Capacity for consent

• Ability for treatment adherence and
compliance
Evaluation of Deceased Donors
/DD/
 Types of DD

• Heart beating donors (HBD)

• Non-Heart beating Donors (NHBD)
• Extended criteria donors – plasma
creatinine >1,5 mg/dl, history of
hypertension
• Survival NHBD < HBD
 Conditioning of DD

• HBD – support • NHBD

cardiac function  cooling of organs
after end of life
support
 Cooling of organs in
situ
 Warm ischemia!!!!
 Contraindications to Donation
• Malignancies
• Active hepatitis
• Sepsis, HIV
• CKD
• Donors younger than 6 years
Evaluation of Living Donors
 Is Living Donation Safe

• Generally – YES, esp. after TR

• ↑ risk for hypertension and CKD
 Test in Living Donors - II

• HLA typing, ABO typing

• ECG, Echocardiogram
• Sonography of Iliac arteries and veins
• Radionuclide scintigraphy with 99mTc DTPA
 Important Issues - I
• Renal function – min 80 ml/min/1,73m2
• Hypertension
• Obesity BMI > 35 – contraindication
• Diabetes mellitus
• Nephrolithiasis – recurrent, bilateral, single
stone
• Active infections – viral, bacterial, TBC
 Important issues II
• Maligancies – contraindication
• Venous thromboembolism
• Renovascular disease – contraindication
• Isolated haematuria
• CVD – myocardial dysfunction, ischemic heart
disease, valvular disease – contraindication
• Chronic pulmonary disease
• Psychological evaluation
Kidney Transplantation - Surgery
 Nephrectomy of DD

• NHBD – warm ischemia – Ist and IInd

period
• Cold ischemia period
• Warm ischemia longer than 60 min -
contraindication
 Nephrectomy of LD

• Laparoscopic techniques
• Open incision
 Transplantation procedure

• Vascular anastomosis – end-to-side/ end-

to-end anastomosis of arteries
• Ureteral anastomosis
 Surgical complications
• Vascular • Urologic
 Bleeding in the renal  Urinary leaks
hilum  Ureteral obstruction
 Anastomosis
hemorrhage
 Thrombosis
 Renal artery stenosis
 Lymphocele
 Immunosuppressive protocol
• Induction therapy – prophylaxis of
rejection reaction
• Corticosteroids
• Mycophenolate 1000 mg b.i.d.
• Tacrolimus – 0,1 mg/kg
• Rapamune – 2-5 mg/d
• Everolimus 0,75 mg bid.
 Long term immunosuppressive
treatment
• Standard treatment
CS + MMF/M-Na + Tac
• Rejection
Aza →MMF/M-Na
CsA →Tacrolimus
• Calcineurin-Inhibitor toxicity, Neo
CsA/Tac → Rapamune
Medical complications
 Renal complications
• Rejection

• Recurrent disease

• Urinary tract infections

• Polioma virus nephropathy

• CsA – nephrotoxicity

• Chronic allograft nephropathy

• De novo glomerulonephritits
 Infections

• HCV, HBV, HIV, TBC

• Opportunistic infections – CMV, VZV, EBV,

HSV, fungal infections etc.

• High mortality !!!!!!!!!!

 Other complications

• Diabetes mellitus

• CV disease

• Osteoporosis

• Dyslipidaemia

• Malignancies
Thank You for Your Attention!!!