Thoracic Transplantation
Scandiatransplant figures: Sahlgrenska 2019, 40 lungs (30 DL, 10 SL), 33 hearts
Acute transplant complications
Immunology
Rejection is usually considered to be antibody mediated, throught HLA mismatch (Clinical guide to heart transplantation)
Pre-transplant (due to pregnancy, blood transfusion, previous transplant) 3-11% or de novo (10-30% of recipients after transplant, worse prognosis)
Risk factor for antibody mediated rejection and mortality
Mean fluorescence intensity (MFI) - Measure of DSA levels. ≥5000 is recognised as a risk factor
- Human Leukocyte Antigens (HLA)
Cell surface proteins that present intracellular peptides to leukocytes (eg viral)
Crucial in differentiating self from non-self
More than 14.000 alleles have been identified, not everybody has the same types of HLA molecules
Mismatch is common, some are serious, some are inconsequential
Class I: HLA-A, HLA-B, HLA-C (Primarily intracellular antigens, present on every nucleated cell)
Class II: HLA-DR, HLA-DQ, HLA-DP (Primarily extracellular antigens, present on lymphocytes and antigen presenting cells)
Antibody production can be stimulated by sensitizing events such as pregnancy, transfusion and previous transplant.
Antibody isotypes show varying capability of activating the complement pathway: IgG3>IgG1>IgG2>IgG4
Non HLA antibodies have also been implicated in rejection
Diagnostics
- Microlymphocytotoxic assay
Developed in 1964, the first standard test for determining antibody types present, A way of testing recipient serum against a panel of HLA-typed lymphocytes.
- Complement-dependent cytotoxicity (CDC) assays - to evaluate the ability of recipient serum to lyse a pool of T or B cells. Can not differentiate between IgG and IgM, nor HLA classes. Only shows HLA-antibodies that activate the complement system.
- Luminex Assay, next gen HLA test, developed in the early 2000s. Luminex beads with a single HLA antigen on different coloured beads. Can differentiate between HLA classes and quantify strength of response (antibody binding), represented by MFI (Mean Fluorescence Intensity). Does not differentiate between complement activating antibodies and those that do not activate the complement system.
The C1q variation introduces the first step of the complement cascade and can differentiate between complement activating antibodies and non-activating.
Virtual Crossmatching:
Solid phase assays identify and measure strength of antibody binding to different HLA antigens, mapping the HLA antibody profile of the recipient and then comparing to the donor HLA profile (HLA typing). The primary benefit as opposed to crossmatching, is that there is no need for recipient blood to be present at the donor hospital.
Calculated PRA (Panel Reactive Antibodies)
The cPRA value represents a percentage of a given population that the recipients anti-HLA antibodies will react with. Only antibodies above a certain threshold (eg >5000 MFI) are included in the calculations.
Patients with cPRA above 50% can be considered for sensitization therapy
1oo-cPRA and then take into account ABO type of recipient as well as ABO prevalence in population
Outputs percentage likelihood of a match between recipient and a single donor. Multiply by annual donor number (500 for scandiatransplant) for mean number of acceptable donors per year.
- Immunosuppression:
Induction therapy with Thymoglobulin and corticosteroids is started before implantation plus a calcineural inhibitor for lung transplants.
Thymoglobuline: Polyclonal antibodies against a variety of lymphocytes. Given as an induction dose to deplete lymphocyte number
Standard maintenance therapy is with triple therapy, with a calcineurin inhibitor, anti proliferative and corticosteroids
Calcineurin inhibitors (Ciclosporin/Tacrolimus): Inhibit the key signalling phosphatase calcineurin. MOA is suppression of T-cell activation via inhibition of calcineurin.
Ciclosporin (Sandimmun): Can cause renal failure, other nephrotoxic medicines should be avoided, NSAIDS are contraindicated. Grapefruit juice can increase serum concentration by inhibition of CYP3A4. Colchicine should also be avoided due to an increase in Colchicine concentration.
Tacrolimus (Advagraf/Adport): Long half-life means dosage should not be adjusted daily, instead waiting 3-5 days. Less nephrotoxic than Ciclosporin. NSAIDS are contraindicated. Voriconazole/Itraconazole therapy mandates a decreased dosage.
Anti proliferatives:
Cellcept-Mycophenolate mofetil is a prodrug of Mycophenolic acid (Myfortic). MPA is an inhibitor of de novo synthesis of the purine GMP (as opposed to the salvage pathway). Lymphocytes rely almost exclusively on de novo synthesis, leading to selective inhibition of DNA replication in T cells and B cells.
Azathioprine (Imurel): Mainly used as an alternative to MPA. Dosage is adjusted based on leukocyte levels (between 4-9 E9/L). Can cause leukopenia, anemia or thrombocytopenia due to bone marrow suppression, as well as liver toxicity.
MTOR inhibitors (Sirolimus\Everolimus):
Everolimus (Certican): Add-on therapy to a calcineurin inhibitor in cases of inadequate rejection therapy, to decrease calcineurin inhibitor dose due to renal impairment and beginning chronic rejection. It has also been shown to reduce coronary allograft vasculopathy.
Main side effect is failure to heal surgical wounds\sternal dehiscence. Everolimus is antiproliferative (and used as a cancer drug) as well as immunosuppressive.
MOA is inhibition of mammalian target of rapamycin. The mTOR is a kinase that serves as a core component of 2 protein complexes, mTOR1 & mTOR2, that regulate different cellular functions, such as cell growth, cell proliferation, cell motility, cell survival, proteins synthesis etc. It inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2.
Primary Graft Dysfunction
Pathogenesis:
Brain death is associated with factors that result in imparied myocardial contractility and sensitization to reperfusion injury
Noradrenaline release results in mitochondrial and and cytosolic calcium overload
Calcium overload can lead to necrosis and contracture of contractile proteins
Exogenous catecholamine administration may contribute to desensitization of myocardial beta-signaling and to activation of pro-inflammatory mediators, including complement
Decreased serum levels of thyroid hormones, cortisol and insulin following brain death likely contribute to decreased myocardial contractility
Older hearts are less tolerant to ischemia, in part due to coronary disease, ventricular hypertrophy and decreased endogenous myocardial protective factors
Anaerobic metabolism during ischemia results in lactic acidosis, Na+/H+ pump activation and high intracellular Na levels, causing cellular swelling, the Na/Ca+ pump is activated in turn, resulting in increased intracellular Ca+
Reperfusion leads to further calcium overload and free radical damage, which in an energy depleted cell can result in mitochondrial leak and subsequent necrosis (Ciclosporine inhibits the mitochondrial leak)
Recipient factors also play a role:
High PVR, increases cardiac stress and PDG
Systemic inflammatory response in the recipient (hostile environment) can cause refractory vasoplegia and through poorly understood factors (pro inflammatory cytokines and inducible nitric oxide synthase) affect the newly transplanted heart
Organ Procurement
Medical Management of Brain-dead Organ Donors (including protocols)
Brain Death and its Implications for management of the potential organ donor
Donor management:
General
Cardiac dyskinesia is normal, when area does not correspond to a single coronary artery
90% of brain-dead donor develop progressive hypotension requiring vasopressors (Vasopressin first line choice)
Catecholamines worsen cardiac transplant outcomes
Brain death results in a rapid decline in cortisol, ADH, thyroid hormones and insulin
Everyone should receive steroids (mainly for attenuating the inflammatory response and decrease vasopressor need)
Also consider ADH (Also for diabetes insipidus prophylaxis), T3 and insulin
Cardiac
Increased ICP -> Cushing reflex -> Bradycardia, hypertension
Early catecholamine storm -> increased afterload, increased vascular tone, visceral ischemia, depletion of cardiac ATP
Progression to spinal cord iscemia results in loss of vascular tone, hypotension and decreased afterload
Other factors contributing to hypotension: DI (loss of ADH), hyperglycemic/hypothermic diuresis and following hypovolemia, inadequate fluid resuscitation, ongoing blood loss, patient rewarming and relative adrenal insufficiency
Pulmonary
Only 10-20% of lungs offered are eligible for transplantation
Sympathetic storm -> Increased afterload (Vasoconstriction) -> Increased LAP/PAP -> Neurogenic pulmonary edema (NPE)
Increased pulmonary capillary pressure can cause structural damage with time
Lung protective ventilation increases lung transplant rate
Assessing borderline lungs in vivo, you may uncouple the ETT and assess compliance by seeing if the lungs deflate normally. If not it is typically a sign of interstitial edema, major atelectasis, pneumonia or obstructive disease
Renal
Main factors of post brain death renal tubular injury are proinflammatory and procoagulant effects of brain death
Endocrine
Brain death can cause ant\post pituitary failure (80% for posterior (Oxytocin and Vasopressin) leading to DI)
The anterior gland is usually at least partially preserved, most brain dead donors show normal levels of TSH, ACTH and Human Growth Hormone
Decreased T3 levels are found in 60-80% of cases, severely so in 15%. The cause is typically the sick euthyroid syndrome that accompanies critical illness, rather than TSH deficiency
Hyperglycemia is common due to reduced insulin concentration and insulin resistance
Misc
SIRS is common and can be very severe
Anemia is common, along with coagulopathy
Isolated head injuries present with coagulopathy in 34% of cases
Necrotic brains release tissue thromboplastin and plasminogen activators, which can cause DIC
Hypothermia is common due to loss of hypothalamic function, reduced metabolism, heat loss or loss of shivering, as well as instillation of cold fluids
Technical points:
Consider extra long sternotomy incision, cephalad, to improve exposure
If a single lung transplantation is planned, strongly consider individual pulmonary venous gases
Kg for Kg, female hearts have 10% less muscle mass than male
Open the interatrial groove, this effectively lengthens the left atrium, increasing available cuffs for both teams
Standard heparin dose is 400 U/kg
Organ Procurement Donor Assessment Checklist
44 patients (36 lungs, 8 hearts) with a measurable viral load
4 week antiviral treatment post-operatively, started a few hours after operation
Viral load in recipients became undetectable at 2 weeks and is undetectable at 6 months follow up
Increased risk of acute cellular rejection ( 54% vs 30 % for lungs, 43% vs 33% for hearts)
No adverse events from antiviral treatment
Heart-Lung Procurement - Technique Steps
Heart Procurement
- Selection
Organ preservation strategy is crucial (Cardioplegia administration, donor ventricular hypertrophy is of particular interest in this regard)
Video for DCD NRP Cardiac explantation
Lung Procurement
- Selection
DCD Lung procurement technique
Heart-Lung Procurement
- Selection
- Technique (1)
Hearl-Lung Transplantation
Cardiac transplantation
- Patient selection
Seattle Heart Failure Model for prognosis of patients with heart failure
- Organ selection
Shah - Oversizing not protective for recipients with moderate pulmonary hypertension, undersizing (>15%) is associated with worse outcomes
Age of donor: Increased mortality based on donor age, 30-39 OR 1,3, 40-49 OR 1,7, 50-59 OR 1,8 (Hong, pre transplant risk factors, observational N:11 703)
- Technique
Bicaval vs Biatrial anastomosis - Meta analysis - N= 3208 vs 3555
Bicaval is better
Long term mortality HR 1,77 with biatrial, long term tricuspid regurgitation HR 2,14 with biatrial
Early pacemaker insertion OR 2,5 with biatrial
Heart transplantation after LVAD
Heart transplantation after congenital heart disease
Pediatric Heart-Lung Transplantation
- Post op
Survival:
Sweden: >90% 1 yr, >80% 5 yr, >70% 10 yr
ISHLT: 86,9% 1 yr, 81,1% 3 yr
Lung transplantation
- Patient selection
Median time on waiting list 54 days, on list mortality 7%
Median time on post op ward 3 weeks
Idiopathic Pulmonary Fibrosis prognosis
3-5 yr median survival at diagnosis, <2 yrs with DLco <35-40%, See also the Du Bois Prognostic Index for 1 yr survival
39 DLTx +16 SLTx = 56 Total lung transplantations (40 in GBG)
60 Heart Transplantations (33 in GBG)
- Organ selection
- Technique
Reconstruction of inadequate donor left atrial cuff
Bilateral sequential lung transplantation
- Post operative
ISHLT: DLTx, 1 yr 83%, 5 yr 60%, 10yr 38%, 20 yr 18%. Median survival 7,6 yr for DLTx, 4,7 yr for SLTx
Sweden: DLTx 1 yr 85%, 5 yr 75%, 10 yr 60%
Rejection:
Restrictive Allograft Syndrome (RAS): A form of Chronic Lung Allograft Dysfunction (CLAD), characterized by fibrosis instead of obstructive and small-airway pathology. Worse prognosis than other CLAD.