30 - Renal Transplantation Flashcards
Why choose kidney transplantation over lifelong dialysis?
- Improves quality of life and prolongs life
- Cheaper than dialysis (1st year is about the same cost, but subsequent years are much cheaper)
Difference between living and deceased donors
- Living donors = graft survival ~20-25 years; possibility of transplant before ever starting dialysis
- Deceased donors = graft survival ~13-15 years; wait time
Types of living kidney donors
- Direct donation
- Kidney paired exchange
- Altruistic/non-directed
Types of deceased kidney donors
- Neurological determination death
- Donation after cardiac death
- Medical assistance in dying (MAID)
What is used to assess donor quality?
- Standard criteria donor (SCD)
- Extended criteria donor (ECD)
- High infectious risk donor (IRD)
- Exceptional distribution donor (ED)
Describe closed chain and domino chain kidney exchanges
- Closed chain = 2 different donors have a recipient in mind but they aren’t matches, so donors switch recipients & each is a correct match) (think of X instead of =)
- Domino chains = longer closed chain; registered pair A aren’t a match, so donor on pair A gives to recipient of pair B, B gives to C, and so on
- Generally, starts w/ non-directed anonymous donor & ends w/ individual on transplant waiting list
- Can go on for as long as 10 pairs
What is the difference between standard kidney transplant recipients and highly sensitized recipients?
- Standard recipients = low or high immunological risk based on HLA match, antibody memory
- Highly sensitized recipients = PRA > 95%, but on a highly sensitized patient registry from Minneapolis?
What is evaluated in a potential donor recipient?
- Transplant nephrologist visit
- Blood group, HLA typing, HLA cross-matching, HLA Ab screening
- Infection screening – TB, HBV, HCV, HIV, CMV, EBV, BK
- Cardiac evaluation
- Vascular disease screen
- Psychiatry assessment
- Matching for ABO & HLA
Describe HLA (human leukocyte antigens)
- Markers on most cells that help to identify “self” from “foreign”
- MHC in humans = HLA
- Many types:
- Class 1 (A, B, C) – stimulate T-killer cells
- Class 2 (DR, DP, DQ) – stimulate T-helper cells, marcophages, & B cells
- Typical matching between A, B, DR, & DQ types (each person has 1 haplotype from each parent, thus a “match” is out of 8)
- Lower match (higher degree of HLA disparity) = greater degree of immunologic risk (0 mismatched pairs will have greater percentage of remaining grafts after a time period than 5-6 mismatched pairs)
What is the importance of sensitization?
- “Sensitizing events” can lead to anti-HLA antibody (ex: pregnancy, blood transfusions, previous transplant) = increased difficulty in finding match
- PRA (panel reactive antibody) screening – degree of “transplantability”
- 60% PRA = incompatibility for transplant w/ about 60/100 potential donors (of same blood group)
- 95% or greater = highly sensitized, separate registry
Describe cross-matching
- HLA antibody screening
- Test between donor & recipient
- HLA antibodies can cause severe rejection & graft loss
- Positive cross-match is bad – recipient’s cells are able to recognize & attack the donor cells; increased risk of rejection
What happens if HLA antibodies develop after transplant?
- Often result of non-compliance
- Causes 6x increased risk of graft loss
How to achieve immunosuppression?
- Depletion of lymphocytes (depleting antibodies)
- Blocking of lymphocyte response
- Non-depleting monoclonal antibody IL-2 receptor antagonists (basiliximab)
- Calcineurin inhibitors (tacrolimus, cyclosporine)
- Anti-proliferative agents (azathioprine, mycophenolic acid)
- mTOR inhibitor (sirolimus)
- Corticosteroids
Describe induction therapy of immunosuppressants
- Intense immunosuppressive therapy at time of transplant to reduce risk of acute rejection
- Thymoglobulin (anti-thymocyte), basiliximab (IL-2 receptor), prednisone & methylprednisolone (corticosteroids)
Describe maintenance therapy of immunosuppressants
- Calcineurin inhibitors
- Corticosteroids
- Antiproliferatives
- Rapamycins (sirolimus) – rarely used
Goal of maintenance regimens
Prevent acute and chronic rejection while minimizing drug-related toxicity
What determines the combination for a maintenance regimen?
- Type of transplant
- Match between donor & recipient (renal)
- Underlying disease
- Pt history
- Co-morbidities
- Medication tolerance
- Pt age
For maintenance therapy, want 1 drug from each category, which are…?
- T-cell communication (cyclosporine or tacrolimus)
- Anti-proliferatives (azathioprine, mycophenolate, or sirolimus)
- Corticosteroid (prednisone)
What is the standard therapy for adult kidney transplants?
- Tacrolimus (inhibits early T-cell activation and clonal expansion)
- Mycophenolate mofetil (works to decrease T-cell proliferation)
- Prednisone (sequesters and inhibits lymphocytes)
What determines dose of calcineurin inhibitors?
Individualized based on blood levels
Adverse drug reactions w/ calcineurin inhibitors
- Hyperglycemia (more w/ tacrolimus than cyclosporine)
- HTN (cyclosporine > tacrolimus)
- Hyperlipidemia (cyclosporine > tacrolimus)
- Electrolytes (low Mg/phosphate, hyperkalemia)
- CNS (tremor, headache)
- Nephrotoxicity (dose related)
- Hirsutism (cyclosporine)
- Alopecia (tacrolimus)
What can be caused by too high of a dose of calcineurin inhibitors?
Increase vasoconstriction and cause increased sCr, causing nephrotoxicity in the short term
What can cause additive nephrotoxicity w/ calcineurin inhibitors?
- NSAIDs – not absolutely CI, but don’t recommend use unless need to
- ACEi/ARB, aminoglycosides & amphotericin B – don’t ever use unless absolutely have to
Describe the relationship between calcineurin inhibitors and CYP 3A4 and P-gP
- Substrate and inhibitor of both
- Cyclosporine > tacrolimus for 3A4 inhibitor
What effect does diarrhea have on P-gP pumps?
Diarrhea causing sloughing of intestinal endothelium -> loss of P-gP -> increased drug levels
Which condition is common in transplant px? The tx for this condition is contraindicated w/ which immunosuppressant?
- Gout
- Colchicine contraindicated w/ CN inhibitors
Drug interactions w/ tacrolimus
- K+ sparing diuretics
- Metoclopramide
- Antacids
- Statins
Can NOACs be used w/ CN inhibitors?
Use w/ caution; apixaban likely the safest
Rapamycin derivatives - example, dose, are they used?, ___ substrate
- Sirolimus
- Dose individualized based on blood levels
- Rarely used due to side effects (ex: hyperlipidemia, HTN, GI intolerance, bone marrow suppression, acne) & poorer degree of preventing rejection
- Scheduled 4 h after cyclosporine (but rarely used together)
- CYP 3A4 substrate
Summary of drug intearctions w/ cyclosporine/ tacrolimus/ sirolimus
- CYP 3A4 inducers = decrease concentrations
- Ex: rifampin, phenytoin, St. John’s Wort
- Inhibitors = increase concentrations
- Ex: diltiazem, verapamil (decrease immunosuppressant dose by 25-50%)
- Azoles – avoid if possible (single dose fluconazole has minimal effect)
- Erythromycin, clarithromycin = avoid if possible
- Grapefruit
Which drugs are anti-proliferatives?
Azathioprine and mycophenolate; mycophenolate (MMS) preferred b/c better for preventing rejection
Dosing for anti-proliferatives?
MMS generally BID but can be TID or QID to lessen GI upset
SE and drug interactions of anti-proliferatives
- SE = azathioprine (bone marrow suppression, hepatotoxicity; can use TPMT phenotype to guide dosing – shows whether person can metabolize azathioprine & if they can, less likely to experience SE); mycophenolic acid (GI intolerance**)
- Main drug interaction w/ azathioprine = allopurinol (causes profound neutropenia)
- Interactions w/ mycophenolate = cholestyramine, PPIs, antacids, calcium & iron preparations
Dosing of corticosteroids
- High dose at time of transplant
- Slow taper down after surgery
Drug interactions and SE w/ corticosteroids
- Minimal drug interactions
- General principles of drug interactions – immune stimulants (ex: echinacea), decongestants, PPIs (lowest dose possible), NSAIDs/ aminoglycosides/ amphotericin B (additive nephrotoxicity, avoid when possible)
- Lots of SE (when talking to px, focus on what is short term vs. long term, what will get better w/ time)
- Short term = sleep disturbances, edema, mood changes, weight gain
- Long term = hyperglycemia, hyperlipidemia, HTN, myopathy, osteoporosis, skin thinning, cataracts
Immunosuppressant monitoring
- Managing drug levels of transplant pt is like balancing a scale
- Rejection (efficacy) vs. toxicity
- Each person & each target level is unique
- Within each “reference range”, the appropriate drug level (tighter range) is influenced by – time post-transplant, organ type, use of induction agents, other immunosuppression, & presence of rejection/toxicity
Target concentration strategy
- Objective = maintain concentration w/in a defined range (range w/ greatest probability of therapeutic success – maximize efficacy & minimize toxicity)
- Blood concentration must correlate w/ exposure (AUC) & clinical outcomes (therapeutic & toxic)
Cyclosporine monitoring
- Rarely used for new transplant recipients
- Linear dose proportionality assumed
- High variability of trough levels; target is individualized based on time since transplant
Tacrolimus monitoring
- Linear dose proportionality assumed
- Trough level (w/in 30 min pre-dose) correlates well to AUC/drug exposure
- Target trough level individualized
- Maintenance target range = 6-8 mcg/L
Sirolimus monitoring
- Long t1/2 (62 h) – time to steady state = 7 days
- Same notes regarding trough level are tacrolimus (last 3 points)
Mycophenolate monitoring
- Drug levels not routinely done b/c doesn’t correlate w/ better tx response
- Generally, adjust dose based on SE
Post-transplant complications
- Transplant = highest risk of acute rejection, complications of IS (HTN, hyperlipidemia, diabetes), & highest risk for opportunistic infection
- 1 year + = low risk of acute rejection, chronic complications of immune system (CV disease, malignancy, renal failure), chronic rejection, & recurrent disease (ex: hep C, IgA, DM)
- Increased risk of malignancy (increased risk of cancer – colon, skin)
- *Remember ABCDE
- Anemia, analgesia
- Bone density decrease, BP increase
- Cholesterol increase, cancer risk
- Diabetes, depression
- Px on dialysis don’t require drugs for hyperglycemia b/c insulin stays in the body longer w/ no kidney function; this changes after a transplant
- Eyes (cataracts)
Rejection - when can it occur and what are the different types?
- Take place at any point following surgery
- Classified as:
- Hyperacute – Ab mediated, happens w/in minutes, extremely rare (b/c precautions are taken to prevent it)
- Acute – cellular, Ab mediated, or mixed; most occur w/in first 6 months but can occur anytime
- Chronic – Ab mediated, generally develop late (> 6 months post-transplant); not reversible w/ any immunosuppressive agents currently available
Describe PJP infection, prophylaxis, and tx
- Significant morbidity & mortality in solid organ transplant px
- Associated w/ periods of higher immunosuppression (first 3-12 months post-transplant)
- Prophylaxis = lifelong TMP/SMX daily for first 6 months then MWF
- Tx = TMP/SMX higher dose x 3 weeks
Describe cytomegalovirus (CMV) infection and prophylaxis
- Greatest risk if recipient negative & donor positive; also risk when both are positive b/c use of immunosuppressants can reactivate the infection
- Common opportunistic infection post-transplant
- Prophylaxis = valganciclovir 900 mg daily x 6 months (adjust dose for renal function)
Describe BK virus infection and tx
- Common in general population, mostly asymptomatic in renal tract
- Reactivates & replicates in immunosuppressed state
- May lead to BK nephropathy & graft failure
- No good tx available – reduction in baseline immunosuppression currently used
Describe Epstein-Barr virus infection and tx
- Routine screening if EBV mismatch at time of transplant
- Mainstay tx = loweing immunosuppressive therapy
What is the relationship between UTIs and renal transplants? What are some risk factors? What is the prophylaxis and when is it initiated?
- Most common infection post kidney transplant
- Pyelonephritis can lead to sepsis, graft dysfunction, & failure
- Risk factors = female, advanced age, hx of UTIs pre-transplant, prolonged use of catheter
- Benefit to using UTI prophylaxis especially w/in first 3 months post-kidney transplant (TMP/SMX preferred over cipro)
Which vaccines are contraindicated in renal transplantation?
Live vaccines
Mycophenolate & fertility
- Known to be teratogenic
- Switch to azathioprine if planning for pregnancy
- Health Canada issued warning in Jan 2016 that also teratogenic if men are taking it; no data to support this, but must warn px
What is delayed graft function?
- Requiring dialysis w/in 1 week of transplant or creatinine not decreasing by 25%
- Directly related to graft survival
Statins & immunosuppressants
- Increased lipids & CV disease common in transplant
- Reports of myopathy/rhabdo w/ cyclosporine & statin; few w/ tacrolimus & sirolimus
- Competitive inhibition of CYP 3A4, P-gP, & other transport proteins = increased statin exposure
- Atorvastatin & rosuvastatin generally considered safe at lower doses in combination w/ tacrolimus
Goals of transplant
- Prolong graft survival
- Prevent rejection episodes (assess adherence on a regular basis)
- Minimize long-term complications
