Dialysis and transplantation Flashcards
Describe how haemodialysis works.
- during dialysis, blood is exposed to dialyse (mixture which passes through the membrane in dialysis) across a semi-permeable membrane
- small molecules such as urea and creatinine and electrolytes pass through pores in a partially permeable membrane
- large molecules such as albumin, IgG and blood cells do not pass through
- concentration differences across the membrane allow molecules to diffuse down a gradient → allows waste products to be removed and desirable molecules or ions to be replaced
- water can be driven through the membrane by a hydrostatic force
Describe how peritoneal dialysis works.
- semi-permeable dialysis membrane of the peritoneum comprises the capillary endothelium, supporting matrix and peritoneal mesothelium
- fluid and solutes move between the fluid-filled peritoneum and blood via the ‘three-pore model’
- large pores (20-40 nm): allow macromolecules to be filtered between compartments (via venular or lymphatic absorption)
- small pores (4-6 nm): responsible for the transport of small solutes (Na+, K+, urea, creatinine)
- ultra small pores (<0.8 nm): transport water alone
What are the different types of haemodialysis?
- Short daily haemodialysis
- In-hospital nocturnal haemodialysis
- Nocturnal home haemodialysis
Describe short daily haemodialysis and its benefits.
- 6-7 days/week
- 1.5-3 hours/session
- benefits:
(i) improved BP control
(ii) reduced LV mass
(iii) variable reports of quality of life
(iv) reduced phosphate
(v) reduced mortality
Describe in-hospital nocturnal haemodialysis and its benefits.
- 3 nights/week
- 8 hours/session
- benefits:
(i) reduced mortality
(ii) reduced hospitalisation
(iii) reduced ESA (EPO stimulating agents) requirements
(iv) reduced intradialytic hypotension
(v) reduced phosphate
Describe nocturnal home haemodialysis and its benefits.
- 5-6 nights/week
- 6-8 hours/session
- benefits:
(i) improved BP control
(ii) reduced ESA requirements
(iii) reduced LV mass
What are the different types of peritoneal dialysis?
- Continuous ambulatory PD (CAPD)
- Automated PD (APD)
- Tidal PD
- Assisted APD
Describe continuous ambulatory PD and its benefits.
- consists of 3-5 exchanges, with dwell times of 4-10h over 24h
- usually performed by the patients connecting and disconnecting the PD catheter to dialyse bags
- at night-time exchange can be performed with a machine
- benefits:
(i) simplicity
(ii) ease of training
(iii) flexibility → timing of exchanges can be adjusted for convenience (dwells ,3h are discouraged)
Describe automated PD.
- uses a machine at night whilst the patient is asleep
- machine is usually programmed to perform at least 4 exchanges over 8h
- machine is programmed to leave the patient ‘dry’ for the daytime
- machine can also perform a ‘last fill’ leaving PD fluid in the peritoneum → patients may then perform a further exchange during the day
Describe tidal PD.
- machine is programmed to only partially drain out PD fluid at the end of any dwell during the nightly cycles
- efficiency of dialysis is reduced → useful for patients whose sleep is disturbed through discomfort experienced when ‘dry’
Describe assisted PD.
- poor strength, limited dexterity, decreased vision, or cognitive impairment may mean that some patients are unable to perform PD
- family member or trained HCA can assist with lifting bags of dialysis fluid and the connection/disconnection of APD
What are the potential complications of haemodialysis?
- Access-related:
- local infection
- endocarditis
- osteomyelitis
- creation of stenosis
- thrombosis or aneurysm - Hypotension (common), cardiac arrhythmias, embolism
- N+V, headaches, cramps
- Fever: infection central lines
- Dialyser reactions: anaphylactic reaction to sterilising agents
- Heparin-induced thrombocytopenia, haemolysis
- Disequilibration syndrome:
- restlessness
- headache
- tremors
- fits and coma - Depression
What are the potential complications of peritoneal dialysis?
- Peritonitis, sclerosing peritonitis
- Catheter problems:
- infection
- blockage
- kinking
- leaks or slow drainage - Constipation, fluid retention, hyperglycaemia, weight gain
- Hernias (incisional, inguinal, umbilical)
- Back pain
- Malnutrition
- Depression
What are the absolute and relative contraindications for peritoneal dialysis?
- Absolute:
- patients, or carer, unable to train adequately in the technique
- inguinal, umbilical, or diaphragmatic hernia (esp pleuroperitoneal leak)
- ileostomy or colostomy
- abdominal wall infections or intra-abdominal sepsis, e.g. acute diverticular disease - Relative:
- abdo surgeries (adhesions_ - the more extensive the surgery, the more likely PD will be unsuccessful
- morbidly obese (inadequate clearance)
- high polycystic kidneys (insufficient peritoneal space)
- severe gastroparesis (worsening vomiting)
- severe lung disease (diaphragmatic splinting)
What is the optimal form of vascular access for dialysis?
AV fistula
Describe how AV fistulas are formed.
- require anastomosis of an artery and a vein (under LA or GA)
- either at the wrist (radiocephalic) or elbow (brachiocephalic, brachiobasilic)
- vascular mapping with USS may be required
- maturation for 6-8 weeks minimum prior to needling
Why might a temporary dialysis catheter be required? What are the possible routes?
- Required: for immediate use, for example int he Aki or unresolved sepsis
- Possible routes: internal jugular, subclavian and femoral
- ideally leave in situ for ≤2 weeks (femoral <5 days)
Where are tunnelled dialysis catheters usually formed?
In a central vein → IJV or subclavian
- using femoral vein is less common
What are the different types of transplant?
- Live donor:
- treatment of choice in ESRD
- better graft functional and patient survival - Donated after brain death
- Donated after cardiac death
What are the roles of Class I and II HLAs?
- Class I:
- present non-self peptides to cytotoxic CD8+ T cells, leading to their activation - Class II:
- present peptides to CD4+ T cells, leading to their clonal expansion
- activated CD4+ cells release cytokines that activate CD8+ cells
How are transplanted HLAs recognised by the recipient?
- Direct:
- donor APCs present foreign peptides to cytotoxic CD8+ T cells, leading to their activation
- responsible for early acute cell-mediated rejection - Indirect:
- donor cells or donor proteins shed from cell surfaces are engulfed by recipient APCs and presented to recipient CD4+ helper T cells
The binding of a T cell to an APC leads to the initiation of an immune reactions - describe the 3 signals involved in this process.
(i) Signal 1:
- TCR activation
- Binding of APC MHC-peptide complex to the T cell receptor (TCR) activates multiple intracellular pathways
- one of these pathways involves calcineurin (when activated results in the activation of nuclear factors and release of IL-2)
- IL-2 release will only occur in the presence of signal 2
(ii) Signal 2:
- Co-stimulation
- Binding of complementary coo-stimulatory pathway molecules present on APC and T cells
- Activation of tyrosine kinase
- Induction of IL-2 and other T cell activation genes (with signal 1)
(iii) Signal 3:
- Signal 1+2
- Induction of cytokine, cytokine receptors, and cell activation genes (including IL-2 and IL-2R)
- Clonal proliferation
Describe the process and consequences of T cell activation.
- involves T cell proliferation and clonal expansion (so all cells express the same TCR)
- then differentiate into effector cells (which no longer require co-stimulation for activation)
- CD4+ effector cells include TH1, TH2, regulatory and memory cells:
1. TH1 → activate macrophages, provide help to B cells, synthesise important cytokines
2. TH2 → provide help to B cells (e.g. immunoglobulin class switching)
3. TH17 → inflammatory responses
4. Regulatory cells → suppress T cell responses
5. Memory cells → component of immunological memory (ability to respond to promptly and intensely, following antigen re-presentation) - CD8+ cells develop into a single cytotoxic effector cell population, involved in the killing of infected and tumour cells
What are some of the early and late complications of transplant surgery?
Early:
- bleeding
- wound infection
- vascular thrombosis/occlusion
- urinary leak
- lymphocele
- early obstruction
Late:
- renal artery stenosis
- ureteric stenosis
- bladder dysfunction
What is hyper acute rejection?
- catastrophic form of rejection that occurs immediately on repercussion of the transplanted kidney
- due to the presence of pre-formed antibodies
- antibodies bind to donor endothelial cells where they activate complement and clotting cascades → vascular thrombosis
What is acute rejection?
- a sudden deterioration in graft function, associated with specific immunopathological changes
- either predominantly T-cell or antibody-mediated
How does acute rejection classically present?
- fever
- painful graft
- oligo-anuria
(this presentation is now very rare → rejection usually presents with an asymptomatic risk in serum creatinine)
Describe the mechanisms that increase a person’s risk of malignancy post-transplant.
- increased risk is more a function of overall immune suppress t burden than of a particular immune suppressive agent
- most immunosuppressants impair the cell cycle and cell growth across many different cell types
- calcineurin inhibitors up regulate both TGF-beta and VEGF → increased angiogenesis + tumour spread (animal models)
- azathioprine interrupts the repair of UV light-associated DNA damage in the skin
- may be aided by the viral-induced inhibition of p53 tumour suppressor gene
- (~100x greater risk of non melanoma skin cancer)
What causes diabetes after transplant?
- impairment of insulin secretion + increased insulin resistance
What are the risk factors for new onset diabetes after transplantation (NODAT)?
- > 60 y/o
- Use of certain immunosuppressive drugs (steroids, CNIs, and mTOR inhibitors)
- Non-caucasian
- BMI >30
- Family history T2DM
- History of gestational diabetes
- HCV +ve patients
What are the most common opportunistic infections to occur post-transplant? When do they most often occur?
Most common infections:
- listeria
- aspergillus
- pneumocystis pneumonia
When:
- 1-6 months post-transplant
List immunosuppressive drugs used in renal transplantation.
- Antithymocyte globulin
- Cyclosporin (CNI)
- Tacrolimus (CNI)
- Azathioprine
- Mycophenolate
- Sirolimus + everolimus
- Corticosteroids
What is the MOA of antithymocyte globulins in immunosuppression?
Blocks T-cell membrane proteins
What is the MOA of cyclosporin in immunosuppression?
Binds to cyclophilin and forms complex that inhibits calcineurin
What is the MOA of tacrolimus in immunosuppression?
Binds to FKBP12 and forms complex that inhibits calcineurin
What is the MOA of azathioprine in immunosuppression?
Inhibits protein synthesis
What is the MOA of mycophenolate in immunosuppression?
Inhibits Inosine monophosphate dehydrogenase
What is the MOA of sirolimus/everolimus in immunosuppression?
Binds and forms complex with FKBP12 complex that inhibits mTOR
What is the MOA of corticosteroids in immunosuppression?
Blocks T cell-derived and APC-derived cytokine expression
What combination of immunosuppressants is normally used after transplant?
- Tacrolimus OR Cyclosporin OR Sirolimus
PLUS - Mycophenolate (either Cellcept or Myfortic)
PLUS - Prednisolone
