Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.
-
Upload
jocelin-reeves -
Category
Documents
-
view
222 -
download
5
Transcript of Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.
![Page 1: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/1.jpg)
Renal Transplantation
Azim Gangji MD FRCPC FACP
McMaster University
![Page 2: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/2.jpg)
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
![Page 3: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/3.jpg)
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
![Page 4: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/4.jpg)
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
![Page 5: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/5.jpg)
MHC Molecules
3D structure of MHC Class II Molecule
![Page 6: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/6.jpg)
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).
![Page 7: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/7.jpg)
Comparison of MHC Class I vs II
Comparison of MHC class I and class II molecules
Class I MHC Class II MHC
Structure MHC encoded chain, beta-2 microglobulin
MHC encoded chain, MHC encoded beta-chain
Antigen binding groove* Closed Open
Peptide length 9 to 10 amino acids 12 to 28 amino acids
Source of antigen Intracellular Extracellular
Expression All nucleated cells B cells, macrophages, dendritic cells
Antigen presented to: CD8+ T cells CD4+ T cells
![Page 8: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/8.jpg)
Direct and Indirect Allorecognition
![Page 9: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/9.jpg)
The Processing of Antigens and Presentation to T Cells
![Page 10: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/10.jpg)
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.
![Page 11: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/11.jpg)
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.
![Page 12: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/12.jpg)
The Processing of Antigens and Presentation to T Cells
C
L
A
S
S
I
C
L
A
S
S
II
![Page 13: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/13.jpg)
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
![Page 14: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/14.jpg)
APC and T Cell Interaction: Role of Costimulation: Signal 2
![Page 15: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/15.jpg)
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.
![Page 16: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/16.jpg)
Allorecognition and Stimulation of T Cells and Effect
![Page 17: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/17.jpg)
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.
![Page 18: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/18.jpg)
Immune Activation and Rejection
0 0.5 1 2… 24 hours…. 3-4 days… 7 days...0 0.5 1 2… 24 hours…. 3-4 days… 7 days...
Immune SystemImmune SystemEncounters theEncounters theTransplantTransplant
HyperacuteHyperacuteRejectionRejection
Stimulus
T CellsT CellsDivideDivide
PlasmaPlasmaCellsCellsMakeMakeAntibodyAntibody
Expansion
EffectorEffectorT CellsT CellsAttack theAttack theTransplantTransplant
HumoralHumoralRejectionRejection
Rejection
ImmuneImmuneSystemSystemDevelopsDevelopsT and B T and B cell memorycell memory
Memory
T LymphocytesT LymphocytesAre ActivatedAre ActivatedAnd Make And Make CytokinesCytokines
Activation
![Page 19: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/19.jpg)
Acute Cellular Rejection
![Page 20: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/20.jpg)
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.
![Page 21: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/21.jpg)
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).
![Page 22: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/22.jpg)
Antibody and Complement Mediated Cytotoxicity ie AMR
![Page 23: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/23.jpg)
Antibody Mediated Rejection on Renal Transplant Biopsy
• Evidence of peritubular capillary C4d staining c/w AMR
![Page 24: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/24.jpg)
Complement Dependent Cytotoxicity
CDC 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
![Page 25: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/25.jpg)
Complement Dependent Crossmatch
![Page 26: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/26.jpg)
The Phases of Immunosuppression
Acute Post-TransplantAcute Post-TransplantImmunosuppressionImmunosuppression
Chronic Allograft Chronic Allograft DysfunctionDysfunction
Acute ImmuneAcute ImmuneDesensitizationDesensitization
InductionInductionTherapy Therapy
Early Acute RejectionEarly Acute Rejection
ImmuneImmuneAccommodationAccommodation
Late Acute RejectionLate Acute RejectionPre-Transplant Pre-Transplant TherapyTherapyAntibody Antibody SuppressionSuppression
MaintenanceMaintenanceImmunosuppressionImmunosuppression
Graft FailureGraft Failure
![Page 27: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/27.jpg)
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.
![Page 28: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/28.jpg)
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
![Page 29: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/29.jpg)
Induction Agents• Non Depleting Antibodies
– Basiliximab – Daclizumab
• Depleting Antibodies– Alemtuzumab – Muromonab-CD3 – Equine polyclonal IgG antibody– Rabbit polyclonal IgG antibody
![Page 30: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/30.jpg)
![Page 31: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/31.jpg)
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.
![Page 32: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/32.jpg)
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
![Page 33: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/33.jpg)
Is Tacrolimus Just a Clone of Cyclosporine?
![Page 34: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/34.jpg)
CNI Side EffectsEvent1 Comments
Hepatotoxicity • Tacrolimus = CsA
Cardiovascular • Hypertension• Hypercholesterolemia
• Less HTN and Hyperlipidemia with Tacrolimus
Post Transplant DM • Tacrolimus causes more post transplant Diabetes Mellitus
Neurotoxicity • Tremor• Headache• Insomnia• Paresthesia
• Seen more often with TAC and generally improve with dose reduction
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.
![Page 35: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/35.jpg)
Event Comments
Cosmetic• Gingival hypertrophy• Hirsutism• Alopecia
• Use of corticosteroids may exaggerate development
• Gingival hypertrophy and hirsutism are associated with CsA
• Alopecia can occur with TAC
Malignancy• Skin cancers• Cervical cancer• Lymphoproliferative
disorders
• Incidence appears to be a function of overall amount and duration of immunosuppression rather than any specific agent
CNI Side Effects
Gaston RS. Am J Kidney Dis. 2001;38(suppl):S25-S35.
![Page 36: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/36.jpg)
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
![Page 37: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/37.jpg)
• Antituberculosis drugs– Rifampin– Rifabutin– Isoniazid
• Anticonvulsants– Barbiturates– Phenytoin– Carbamazepine
• Herbal preparations– St John’s wort
Metabolic Interactions That Decrease CNI Levels
![Page 38: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/38.jpg)
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
![Page 39: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/39.jpg)
MPA Adverse Reactions
• Bone marrow suppression
• n/v/d
• Oral and colonic ulcerations
• Colitis
![Page 40: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/40.jpg)
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
![Page 41: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/41.jpg)
Azathioprine Adverse Effects
• Bone marrow suppression
• Hepatotoxicity
• Alopecia
• Drug Interactions: – Allopurinol
![Page 42: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/42.jpg)
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
![Page 43: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/43.jpg)
Sirolimus Adverse Effects
• Hypercholesterolemia• Hypertriglyceridemia• Edema• Hypertension• Rash• Bone marrow suppression• Interstitial pneumonitis• Delayed wound healing• Mouth ulcers • Myalgia/weakness• Drug fever• Proteinuria
![Page 44: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/44.jpg)
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
![Page 45: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/45.jpg)
Done by your Local UrologistI always recommend drinking at least 6-8 glasses of fluid for the procedure!”
![Page 46: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/46.jpg)
Transplant Surgery
![Page 47: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/47.jpg)
Transplant Surgery
![Page 48: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/48.jpg)
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)
![Page 49: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/49.jpg)
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
![Page 50: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/50.jpg)
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
![Page 51: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/51.jpg)
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
![Page 52: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/52.jpg)
Post Surgical Complications
• Wound– Infections– Healing becomes a problem in obese
recipients
• GI Complications– Bowel obstruction, colonic perforation, gastric
ulcer
![Page 53: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/53.jpg)
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)
![Page 54: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/54.jpg)
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)
![Page 55: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/55.jpg)
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
![Page 56: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/56.jpg)
Rejection and Treatment
• Acute Cellular Rejection– Steroids, Thymoglobulin, CNI
• Antibody Mediated Rejection– PLEX– IVIG– Rituximab– Bortezomib– Urgent splenectomy
![Page 57: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/57.jpg)
Rejection and Treatment
• And of course prayer!
Surgical resident ?
![Page 58: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/58.jpg)
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
![Page 59: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/59.jpg)
Longterm Complications
![Page 60: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/60.jpg)
Longterm Complications
• Renal Tx patients are at high risk of dying with a functioning allograft– 40% from CVD– 25% infection– 10% malignancy– 25% other
![Page 61: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/61.jpg)
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)
![Page 62: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/62.jpg)
Longterm Complications
• Infections– CMV– BK– Hepatitis C– Influenza– Fungal
![Page 63: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/63.jpg)
Infection Timeline Post Transplant
Fishman NEJM 2007
![Page 64: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/64.jpg)
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%
![Page 65: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/65.jpg)
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
![Page 66: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/66.jpg)
Thank You For Your Attention
![Page 67: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/67.jpg)
![Page 68: Renal Transplantation Azim Gangji MD FRCPC FACP McMaster University.](https://reader038.fdocuments.in/reader038/viewer/2022102910/56649e005503460f94ae8df4/html5/thumbnails/68.jpg)
• Causes of Elevated Resistive Index
• Parenchymal– Acute Rejection– Acute Tubular Necrosis– Pyelonephritis
• Vascular– Renal Vein Thrombosis– Hypotension
• Urological– Ureteral Obstruction
• Technical– Graft Compression