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Renal Transplantation . Azim Gangji MD FRCPC FACP McMaster University. Objectives. Overview of Immunology Cross match test Immunosuppressive Medications Rejection Antibody Mediated Rejection Acute Cellular Rejection Causes of Allograft Failure Surgical Complications

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renal transplantation

Renal Transplantation

Azim Gangji MD FRCPC FACP

McMaster University

objectives
Objectives
  • Overview of Immunology
  • Cross match test
  • Immunosuppressive Medications
  • Rejection
    • Antibody Mediated Rejection
    • Acute Cellular Rejection
  • Causes of Allograft Failure
  • Surgical Complications
  • Longterm Medical Complications
what is mhc and what is its role
What is MHC and What is its Role
  • Human Leukocyte Antigen (HLA) system is synonymous with the human Major Histocompatibility Complex (MHC)
  • In humans, it’s called HLA due to expression of gene products on surface of WBC
  • These terms describe a group of genes on chromosome 6 that encode a variety of cell surface markers, antigen presenting molecules and other proteins involved in immune function
  • Inheritance ~ a haplotype from each parent
what is mhc and what is its role4
What is MHC and What is its Role
  • HLA region is subdivided into 3 regions:
    • Class I
      • encodes “classical antigens” HLA A, B, C
      • Expressed on all nucleated cells
      • Class I alpha genes are coded by the MHC whereas the B microglobulin gene is coded on chromosome 15 (non MHC)
    • Class II
      • Encodes HLA- DR, DQ, DP
      • Has both alpha and beta genes both of which are coded by MHC genes
      • DR genes all share the same alpha chain but vary in the beta chain whereas DQ and DP can have polymorphic alpha and beta chains
      • In addition, the number of DR genes can vary among individuals. For example, 2 DR molecules are expressed on a single haplotype: both dimers use the same alpha chain but one uses a beta chain encoded by DRB1 and the other uses a beta chain encoded by a second DR locus called DRB3, DRB4, DRB5, etc. Alleles at this locus are usually expressed at much lower levels on the cell surface.
    • Class III
      • Contains genes for complement, TNF, Heat shock protein
mhc molecules
MHC Molecules

3D structure of MHC Class II Molecule

schematic of mhc
The structure of class I MHC and

class II MHC molecules. The schematic diagrams and models of the crystal structures of class I MHC and class II MHC molecules

Both types of MHC molecules contain peptide-binding clefts and invariant portions that bind CD8 (the 3 domain of class I) or CD4 (the 4 domain of class II).

Schematic of MHC
t cell recognition of alloantigen indirect pathways
Intact donor MHC molecules are also known to be continuously shed into the circulation where they may then be endocytosed by the recipient's antigen-presenting cells.

Within the acidic endosomal compartment, the MHC proteins are fragmented into their constituent peptides. They are then transferred into the endoplasmic reticulum, loaded into the antigen binding cleft of MHC class II of the recipient and finally expressed on the cell surface of recipients APCs. This mechanism has been referred to as the "indirect allorecognition.“

However, this is of course the normal route by which T cells normally encounter antigen ie in context of self MHC.

T Cell Recognition of Alloantigen: Indirect Pathways
t cell recognition of alloantigen direct pathways
T cell activation by the "direct" pathway occurs when T cells encounter intact donor MHC on the surface of donor antigen-presenting cells (APC). Since MHC molecules w/o a bound peptide are unstable & unrecognizable by T cells, endogenous proteins bound to the donor MHC may play a role.

Direct allorecognition of intact surface MHC molecules has only been demonstrated in allogenic transplantation

This pathway is thought to be of dominant importance during early acute rejection as engrafted organs contain a large number of passenger leukocytes.

T Cell Recognition of Alloantigen: Direct Pathways
t cell receptor and apc interaction signal 1
HLA peptide presentation by APC to T Cell

Triggering of the TCR by antigen initiates a signaling cascade started by the signaling complex made up of CD3

T Cell Receptor and APC Interaction: Signal 1
role of costimulation signal 2
Role of Costimulation: Signal 2
  • Naïve T cells require both signal 1 and
  • Memory T cells do not require costimulation through CD28 to become activated. Costimulation through ICOS is sufficient for memory T cell activation. c, Absence of B7 or blocking of B7 with CTLA-4 Ig leads to anergy of the T cell.
b t and nk cells and effect rejection
Fig 2. Classes of lymphocytes. Different classes of lymphocytes recognize distinct types of antigens and

differentiate into effector cells whose function is to eliminate the antigens. B lymphocytes recognize soluble or cell

surface antigens and differentiate into antibody-secreting cells. Helper T lymphocytes recognize antigens on the

surfaces of APCs and secrete cytokines, which simulate different mechanisms of immunity and inflammation.

Cytolytic T lymphocytes recognize antigens on infected cells and kill these cells. (Note that lymphocytes recognize

peptides that are displayed by MHC molecules.) Natural killer cells recognize changes on the surface of infected

cells and kill these cells. It should be emphasized that native T cells (CD4 or CD8) are activated by professional

APCs. Effector CD8 T cells, not native T cells, can kill and infected cell expressing the specific peptide-class I

complex.

B, T and NK Cells and Effect: Rejection
immune activation and rejection

Stimulus

Activation

Expansion

Rejection

Memory

T Cells

Divide

Plasma

Cells

Make

Antibody

Effector

T Cells

Attack the

Transplant

Humoral

Rejection

Immune System

Encounters the

Transplant

Hyperacute

Rejection

T Lymphocytes

Are Activated

And Make

Cytokines

Immune

System

Develops

T and B

cell memory

Immune Activation and Rejection

0 0.5 1 2… 24 hours…. 3-4 days… 7 days...

t cell mediated rejection
T Cell Mediated Rejection
  • T cell receptor (TCR) of alloreactive cytotoxic lymphocytes (CTL) recognize allogeneic major histocompatibility complex (MHC) on target cells. CTL mobilize cytotoxic granules containing perforin and granzyme B (Gz B) toward the target cell releasing the cytotoxic molecules into the intercellular space. Perforin inserts into the target cell membrane and Gz B binds to its receptor and both are internalized to induce apoptosis. TCR stimulation increases expression of Fas ligand (FasL) on the CTL surface and binds the Fas receptor, triggering the apoptotic cascade. CTL can produce the cytotoxic cytokine tumor necrosis factor α (TNF-α), which binds the TNF-R on the target cell leading to apoptosis. CTL can also release interferon (IFN)-γ, which will activate the macrophage to release proinflammatory substances. NO, nitric oxide; ROS, reactive oxygen species.
t cell mediated rejection on renal biopsy
T Cell Mediated Rejection on Renal Biopsy
  • Tubulitis
    • Infiltration of tubular epithelium by T lymphocytes (arrows) that have crossed the basement membrane.
  • Endothelialitis
    • Invasion of the endothelium of a large artery by graft-infiltrating lymphocytes (arrow).
antibody mediated rejection on renal transplant biopsy
Antibody Mediated Rejection on Renal Transplant Biopsy
  • Evidence of peritubular capillary C4d staining c/w AMR
complement dependent cytotoxicity cdc crossmatch
Complement Dependent CytotoxicityCDC Crossmatch

Recipient’s serum + Donor lymphocytes (with defined HLA) + Complement, Incubate, add Eosin; remember here lymphocytes are just serving as cells that can be lysed; nil to do with the immune process/function

the phases of immunosuppression

Pre-Transplant Therapy

Antibody Suppression

Late Acute Rejection

Early Acute Rejection

Acute Immune

Desensitization

Immune

Accommodation

Induction

Therapy

Acute Post-Transplant

Immunosuppression

The Phases of Immunosuppression

Chronic Allograft

Dysfunction

Maintenance

Immunosuppression

Graft Failure

immunosuppressant action overview
Three events in T cell activation

Signal 1: Engagement of the T cell receptor with the antigen peptide in the context of self major histocompatibility complex (MHC) class II molecule leads to the activation of the calcineurin pathway and results in the induction of cytokine genes (e.g., interleukin [IL]-2).

Signal 2: The costimulatory signal, involves the engagement of CD28 with members of the B7 family. This synergizes with signal 1 to induce cytokine production.

Signal 3: Interaction between cytokine production and its corresponding receptor leads to induction of cell division, probably through the target of rapamycin pathway. This constitutes signal 3.

Immunosuppressant Action Overview
categories of agents
Categories of Agents
  • Induction agents
    • Monoclonal or polyclonal antibodies
    • Administered intravenously in the perioperative period
    • Induce acute, powerful, short-lived immunosuppression
  • Desensitization agents
    • Pretransplant IVIg can desensitize patients’ immunity to HLA
    • Rituximab is gaining interest as a desensitization agent
  • Primary immunosuppressants
    • CNIs are the cornerstones of immunosuppressive therapy
  • Adjuvant agents
    • 1 or more medications prescribed in addition to a CNI
induction agents
Induction Agents
  • Non Depleting Antibodies
    • Basiliximab
    • Daclizumab
  • Depleting Antibodies
    • Alemtuzumab
    • Muromonab-CD3
    • Equine polyclonal IgG antibody
    • Rabbit polyclonal IgG antibody
primary immunosuppressants calcineurin inhibitors cnis
Primary ImmunosuppressantsCalcineurin Inhibitors (CNIs)
  • Calcineurin inhibition prevents nuclear factor (NFAT) activation.
  • In the absence of cyclosporine, calcium activates calcineurin by exposing its phosphatase site, which, in turn, activates NFAT.
  • Cyclosporine forms a complex with cyclophilin (CP), which binds to calcineurin (CN) and sterically hinders the phosphatase site.
mechanism of action tacrolimus
Calcium-Calmodulin-Calcineurin form a complex to dephosphorylate NFAT

Tacrolimus binds to FK binding protein which binds to calcineurin and inhibits this process

Mechanism of Action: Tacrolimus
cni side effects
CNI Side Effects

1. Gaston RS. Am J Kidney Dis. 2001;38(suppl):S25-S35.

2. Johnson C, et al. Transplantation. 2000;69:834-841.

3. Margreiter R. Lancet. 2002;359:741-746.

cni side effects35
CNI Side Effects

Gaston RS. Am J Kidney Dis. 2001;38(suppl):S25-S35.

metabolic interactions that increase cni levels
Calcium channel blockers

Verapamil

Diltiazem

Nicardipine

Antifungal agents

Ketoconazole

Fluconazole

Itraconazole

Clotrimazole

Metronidazole

Immunosuppressants

Sirolimus increases CsA levels

Antibiotics

Erythromycin

Clarithromycin

Azithromycin

Protease Inhibitors

Saquinavir

Indinavir

Nelfinavir

Ritonavir

Foods

Grapefruit

Grapefruit juice

Metabolic Interactions That Increase CNI Levels
metabolic interactions that decrease cni levels
Antituberculosis drugs

Rifampin

Rifabutin

Isoniazid

Anticonvulsants

Barbiturates

Phenytoin

Carbamazepine

Herbal preparations

St John’s wort

Metabolic Interactions That Decrease CNI Levels
mechanism of action of mycophenolic acid mpa
Mechanism of action of mycophenolic acid (MPA)
  • Lymphocytes use the do novo pathway for generation of purines (guanine).
  • Mycophenolate mofetil (MMF) is converted in the liver by ester hydrolysis to mycophenolic acid which in turn non-competitively and reversibly inhibits IMPDH activity during DNA synthesis in the S phase of the cell cycle.
  • In the salvage pathway, guanine is converted to GMP by the enzyme hypoxanthine-guanine phosphoribosyltransferase
mpa adverse reactions
MPA Adverse Reactions
  • Bone marrow suppression
  • n/v/d
  • Oral and colonic ulcerations
  • Colitis
azathioprine
Is an antimetabolite that is a purine analogue that is incorporated into DNA and halts synthesis

Inhibits proliferation of T and B cells and effect is mediated by AZA metabolites, 6-MP, 6-TU, 6-MMP, 6-TGN

Azathioprine
azathioprine adverse effects
Azathioprine Adverse Effects
  • Bone marrow suppression
  • Hepatotoxicity
  • Alopecia
  • Drug Interactions:
    • Allopurinol
sirolimus everolimus
Sirolimus binds to FK binding protein but does NOT inhibit calcineurin.

Instead Sirolimus inhibits mTOR and blocks IL-2 mediated cell proliferation

mTOR activates protein that trigger cell cylcle G1 to S progression

Sirolimus/Everolimus
sirolimus adverse effects
Sirolimus Adverse Effects
  • Hypercholesterolemia
  • Hypertriglyceridemia
  • Edema
  • Hypertension
  • Rash
  • Bone marrow suppression
  • Interstitial pneumonitis
  • Delayed wound healing
  • Mouth ulcers
  • Myalgia/weakness
  • Drug fever
  • Proteinuria
corticosteroids
Anti inflammatory and immunosuppressive effects

Suppress production of numerous cytokines (IL-1, TNF, IL-2, chemokines, prostaglandins, proteases, NFK-B)

Also affect chemotaxis (neutrophilia)

Corticosteroids Side Effects

Acne

Cushingoid facial appearance

Hirsutism

Mood disorders

Hypertension

Glucose intolerance

Cataracts

Osteoporosis

Growth retardation in children

Corticosteroids
done by your local urologist
Done by your Local Urologist

I always recommend drinking at least 6-8 glasses of fluid for the procedure!”

post surgical complications
Post Surgical Complications
  • Vascular complications
    • Bleeding from vessels in the hilum
    • Anastamosis hemorrhage (more common with multiple arteries)
    • Renal artery thrombosis (due to hypotension in the OR, technical complications, antiphosholipid ab syndrome)
    • Renal vein thrombosis (usually 3-9 days post op and related to technical complications, antiphosholipid ab syndrome)
post surgical complications49
Post Surgical Complications
  • Vascular complications
    • Transplant Renal Artery Stenosis
      • Atherosclerosis of recipient vessel
      • Clamp injury to donor or recipient vascular endothelium
      • Faulty suture technique (primarily seen with end-to-end anastomosis
      • Angulation due to diproportionate length between graft artery and iliac artery
      • Kinking of the renal artery
post surgical complications50
Post Surgical Complications
  • Lymphocele
    • Collection of lymph caused by leakage from several lymphatics that overlie the iliac vessels
    • Usually present weeks after transplantation
    • Can lead to ureteral obstruction, compression of iliac vein and swelling/DVT of leg, incontinence due to bladder compression, scrotal masses
    • Can be avoided by minimizing dissection of iliac vessels and ligating lymphatics
    • Sirolimus increased the incidence of lymphoceles from 18% to 38% therefore not used as an induction agent
post surgical complications51
Post Surgical Complications
  • Urine Leaks
    • Occur within the first few days
    • Due to technical or as a result of ureteral slough due to disruption or ureteral blood supply. Blood supply to distal ureter is the most endangered during harvesting
  • Ureteral Obstruction
    • Technical
    • Blood clots
    • Ureteral slough
    • Ureteral fibrosis
      • Ischemia, rejection or polyoma virus BK
    • Extrinsic compression
      • Kinking or periureteral fibrosis from lymphoceles or graft rejection
post surgical complications52
Post Surgical Complications
  • Wound
    • Infections
    • Healing becomes a problem in obese recipients
  • GI Complications
    • Bowel obstruction, colonic perforation, gastric ulcer
delayed graft function
Delayed Graft Function
  • Poor definition:
    • Need for dialysis in the 1st week post transplant
  • Etiology
    • Immune
      • Hyperacute rejection
    • Non immune
      • ATN, intravascular volume contraction
      • Technical: arterial, venous or ureteric occlusion, urine leak
      • Recurrent disease (HUS/TTP)
delayed graft function54
Delayed Graft Function
  • Factors promoting ischemic injury in Deceased donor renal transplantation
    • Donor Factors (age, h/o HTN, DM, ARF)
    • Donor Management (brain-death stress, ionotropes, nephrotoxins, cardiac arrest)
    • Procurement surgery (Hypotension, traction on renal vessels, flushing solution)
    • Kidney storage (pump vs cold storage, prolonged time)
    • Recipient status (volume status, body habitus, pelvic atherosclerosis, poor cardiac output, hypotension in OR, preformed antibodies, prolonged warm ischemia time)
renal transplant program at mcmaster university
Renal Transplant Program at McMaster University
  • All forms of transplantation
    • Standard Criteria
    • Donation after Cardiac Death
    • Extended Criteria (donors > 60yo, donors 50-59yo with 2 additional RF (h/o HTN, death as a result of a stroke, elevated terminal serum Cr > 132umols/L)
    • Cross Match Positive Transplants
    • ABO incompatible Transplants
rejection and treatment
Rejection and Treatment
  • Acute Cellular Rejection
    • Steroids, Thymoglobulin, CNI
  • Antibody Mediated Rejection
    • PLEX
    • IVIG
    • Rituximab
    • Bortezomib
    • Urgent splenectomy
rejection and treatment57
Rejection and Treatment
  • And of course prayer!

Surgical resident ?

longterm complications
Longterm Complications
  • Allograft Failure
    • On average 50% of DDRT allografts are functioning at the 10-12 year mark
    • On average 50% of living donor allografts are functioning at the 15-17 year mark
    • Etiology of Allograft Failure
      • Immune: Rejection, HLA mismatch, prior sensitization history, medication non compliance
      • Non Immune: donor factors (age, ECD, etc), CNI toxicity, HTN, Hyperlipidemia, Infection (CMV), Proteinuria, renal size mismatch, recurrent disease, BK Nephropathy
longterm complications60
Longterm Complications
  • Renal Tx patients are at high risk of dying with a functioning allograft
    • 40% from CVD
    • 25% infection
    • 10% malignancy
    • 25% other
longterm complications61
Longterm Complications
  • CVD Risk Factors
    • 20% of renal transplant recipients will develop impaired fasting glucose post tx and 10% will develop T2DM
    • Prior ESRD pts
    • HTN
    • Hyperlipidemia
    • Cigarette smoking
    • Inflammation
    • Infections (CMV)
longterm complications62
Longterm Complications
  • Infections
    • CMV
    • BK
    • Hepatitis C
    • Influenza
    • Fungal
malignancy
Malignancy
  • Skin Cancer: 3.5 fold increase
  • Post Transplant Lymphoproliferative disorder
  • GU cancers ~HPV related vulva, vagina, cervical cancers
  • Liver cancer (Hep B, C pts)
  • Cumulative incidence of malignant tumors over 30 years is 33%
summary
Summary
  • Overview of Immunology
  • Immunosuppressive Medications
    • Know pharmacology and adverse effects
  • Rejection
    • Antibody Mediated Rejection
    • Acute Cellular Rejection
  • Causes of Allograft Failure: differentiate immune vs non immune
  • Surgical Complications
  • Longterm Medical Complications
slide68
Causes of Elevated Resistive Index
  • Parenchymal
    • Acute Rejection
    • Acute Tubular Necrosis
    • Pyelonephritis
  • Vascular
    • Renal Vein Thrombosis
    • Hypotension
  • Urological
    • Ureteral Obstruction
  • Technical
    • Graft Compression