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Year 3 - Clinical > 30 - Renal Transplantation > Flashcards

30 - Renal Transplantation Flashcards

1
Q

Why choose kidney transplantation over lifelong dialysis?

A
  • Improves quality of life and prolongs life

- Cheaper than dialysis (1st year is about the same cost, but subsequent years are much cheaper)

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2
Q

Difference between living and deceased donors

A
  • Living donors = graft survival ~20-25 years; possibility of transplant before ever starting dialysis
  • Deceased donors = graft survival ~13-15 years; wait time
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3
Q

Types of living kidney donors

A
  • Direct donation
  • Kidney paired exchange
  • Altruistic/non-directed
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4
Q

Types of deceased kidney donors

A
  • Neurological determination death
  • Donation after cardiac death
  • Medical assistance in dying (MAID)
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5
Q

What is used to assess donor quality?

A
  • Standard criteria donor (SCD)
  • Extended criteria donor (ECD)
  • High infectious risk donor (IRD)
  • Exceptional distribution donor (ED)
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6
Q

Describe closed chain and domino chain kidney exchanges

A
  • 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
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7
Q

What is the difference between standard kidney transplant recipients and highly sensitized recipients?

A
  • 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?
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8
Q

What is evaluated in a potential donor recipient?

A
  • 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
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9
Q

Describe HLA (human leukocyte antigens)

A
  • 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)
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10
Q

What is the importance of sensitization?

A
  • “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
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11
Q

Describe cross-matching

A
  • 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
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12
Q

What happens if HLA antibodies develop after transplant?

A
  • Often result of non-compliance

- Causes 6x increased risk of graft loss

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13
Q

How to achieve immunosuppression?

A
  • 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
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14
Q

Describe induction therapy of immunosuppressants

A
  • Intense immunosuppressive therapy at time of transplant to reduce risk of acute rejection
  • Thymoglobulin (anti-thymocyte), basiliximab (IL-2 receptor), prednisone & methylprednisolone (corticosteroids)
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15
Q

Describe maintenance therapy of immunosuppressants

A
  • Calcineurin inhibitors
  • Corticosteroids
  • Antiproliferatives
  • Rapamycins (sirolimus) – rarely used
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16
Q

Goal of maintenance regimens

A

Prevent acute and chronic rejection while minimizing drug-related toxicity

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17
Q

What determines the combination for a maintenance regimen?

A
  • Type of transplant
  • Match between donor & recipient (renal)
  • Underlying disease
  • Pt history
  • Co-morbidities
  • Medication tolerance
  • Pt age
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18
Q

For maintenance therapy, want 1 drug from each category, which are…?

A
  • T-cell communication (cyclosporine or tacrolimus)
  • Anti-proliferatives (azathioprine, mycophenolate, or sirolimus)
  • Corticosteroid (prednisone)
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19
Q

What is the standard therapy for adult kidney transplants?

A
  • Tacrolimus (inhibits early T-cell activation and clonal expansion)
  • Mycophenolate mofetil (works to decrease T-cell proliferation)
  • Prednisone (sequesters and inhibits lymphocytes)
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20
Q

What determines dose of calcineurin inhibitors?

A

Individualized based on blood levels

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21
Q

Adverse drug reactions w/ calcineurin inhibitors

A
  • 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)
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22
Q

What can be caused by too high of a dose of calcineurin inhibitors?

A

Increase vasoconstriction and cause increased sCr, causing nephrotoxicity in the short term

23
Q

What can cause additive nephrotoxicity w/ calcineurin inhibitors?

A
  • 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
24
Q

Describe the relationship between calcineurin inhibitors and CYP 3A4 and P-gP

A
  • Substrate and inhibitor of both

- Cyclosporine > tacrolimus for 3A4 inhibitor

25
Q

What effect does diarrhea have on P-gP pumps?

A

Diarrhea causing sloughing of intestinal endothelium -> loss of P-gP -> increased drug levels

26
Q

Which condition is common in transplant px? The tx for this condition is contraindicated w/ which immunosuppressant?

A
  • Gout

- Colchicine contraindicated w/ CN inhibitors

27
Q

Drug interactions w/ tacrolimus

A
  • K+ sparing diuretics
  • Metoclopramide
  • Antacids
  • Statins
28
Q

Can NOACs be used w/ CN inhibitors?

A

Use w/ caution; apixaban likely the safest

29
Q

Rapamycin derivatives - example, dose, are they used?, ___ substrate

A
  • 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
30
Q

Summary of drug intearctions w/ cyclosporine/ tacrolimus/ sirolimus

A
  • 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
31
Q

Which drugs are anti-proliferatives?

A

Azathioprine and mycophenolate; mycophenolate (MMS) preferred b/c better for preventing rejection

32
Q

Dosing for anti-proliferatives?

A

MMS generally BID but can be TID or QID to lessen GI upset

33
Q

SE and drug interactions of anti-proliferatives

A
  • 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
34
Q

Dosing of corticosteroids

A
  • High dose at time of transplant

- Slow taper down after surgery

35
Q

Drug interactions and SE w/ corticosteroids

A
  • 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
36
Q

Immunosuppressant monitoring

A
  • 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
37
Q

Target concentration strategy

A
  • 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)
38
Q

Cyclosporine monitoring

A
  • Rarely used for new transplant recipients
  • Linear dose proportionality assumed
  • High variability of trough levels; target is individualized based on time since transplant
39
Q

Tacrolimus monitoring

A
  • 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
40
Q

Sirolimus monitoring

A
  • Long t1/2 (62 h) – time to steady state = 7 days

- Same notes regarding trough level are tacrolimus (last 3 points)

41
Q

Mycophenolate monitoring

A
  • Drug levels not routinely done b/c doesn’t correlate w/ better tx response
  • Generally, adjust dose based on SE
42
Q

Post-transplant complications

A
  • 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)
43
Q

Rejection - when can it occur and what are the different types?

A
  • 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
44
Q

Describe PJP infection, prophylaxis, and tx

A
  • 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
45
Q

Describe cytomegalovirus (CMV) infection and prophylaxis

A
  • 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)
46
Q

Describe BK virus infection and tx

A
  • 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
47
Q

Describe Epstein-Barr virus infection and tx

A
  • Routine screening if EBV mismatch at time of transplant

- Mainstay tx = loweing immunosuppressive therapy

48
Q

What is the relationship between UTIs and renal transplants? What are some risk factors? What is the prophylaxis and when is it initiated?

A
  • 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)
49
Q

Which vaccines are contraindicated in renal transplantation?

A

Live vaccines

50
Q

Mycophenolate & fertility

A
  • 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
51
Q

What is delayed graft function?

A
  • Requiring dialysis w/in 1 week of transplant or creatinine not decreasing by 25%
  • Directly related to graft survival
52
Q

Statins & immunosuppressants

A
  • 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
53
Q

Goals of transplant

A
  • Prolong graft survival
  • Prevent rejection episodes (assess adherence on a regular basis)
  • Minimize long-term complications

Year 3 - Clinical (30 decks)

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