Renal Transplants Flashcards
List some benefits of renal transplantation
- Not life saving (as for liver, lung, heart transplant)
- Kidney transplantation is another means of renal replacement therapy
- The sickest patient does not necessarily get a kidney transplant first
- Survival benefit
- Improved quality of life
- Cost saving (after the 1st year post transplant)
*kidney transplants are an alternative to dialysis
Which patients are high priority?
- Children (need kidneys for normal development)
- People on dialysis but lost line access and can no longer receive dialysis
- Younger kidneys go to younger patients
- People who previously donated a kidney
Living donors:
Grant survival ?
20-25 years
Living donors:
Pre-emptive ?
possible
Deceased donors:
Graft survival ?
13-15 years
Deceased donors:
Have a ____ time
wait
List the 3 types of living kidney donors
1) Direct donation (ex. family or friend)
2) Kidney paired exchange (KPD)
3) Altruistic, non-directed (just want to donate a kidney and help someone out - anonymous)
List the 3 types of deceased kidney donors
1) Neurological determination death (NDD)
- brain dead
2) Donation after cardiac death (DCD)
3) Medical assistance in dying (MAID)
List the 4 parts to describing donor quality
1) Standard criteria donor
2) Extended criteria donor
3) High infectious risk donor
4) Exceptional distribution donor
How many kidney transplants can you have?
The most there is right now is someone with 4 extra kidneys.
Describe standard kidney transplant recipients
Low or high immunological risk based on HLA match, antibody memory
HLA
Human Leukocyte Antigens:
-HLA are markers on most cells that help to identify “self” from “foreign”
MHC in humans = HLA
Describe Class 1 types of HLA
Class 1: A, B, C
Stimulate T-killer cells
Describe Class 2 types of HLA
Class 2: DR, DP, DQ
Stimulate T-helper cells, macrophages, B-cells
A match is out of __
8
What type of donor would give you the best probability for an 8/8 match?
sibling (identical twin is best)
Describe “sensitizing events” that can lead to anti-HLA antibody and make it harder to find a match
- pregnancy
- blood transfusions
- previous transplants
What is a PRA screening
Panel Reactive Antibody screening
- Degree of “transplantability”
- 60% PRA = incompatibility for transplant with about 60 out of 100 potential donors (of same blood group)
- 95% PRA - highly sensitized, separate registry
What is cross-matching?
What result is bad?
- A test between donor and recipient
- HLA antibodies can cause severe rejection and graft loss
- Positive cross match is BAD
- The recipient’s cells are able to recognize and attack the donor cells. This causes an increased risk of rejection
Sometimes a person develops antibodies to the donor after the transplant, often a result of ?
- Often result of non-compliance, under immunosuppression
- 6x increased risk for graft loss
- 56% 10 year graft survival
How do we achieve immunosuppression ?
1) Depletion of lymphocytes (depleting antibodies)
2) 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)
Intensive immunosuppressive therapy at time of transplant to reduce risk of acute _____
rejection
What agents do we use for immunosuppressants (induction therapy)? (3)
1) Depleting antibodies
- Anti-thymocyte: Thymoglobulin
2) Non-depleting antibodies
- IL-2 (CD25) receptor: Basiliximab
3) Corticosteroids (predinosine, methylprednisilone)
What agents do we use for immunosuppressants (maintenance therapy)? (4)
1) Calcineurin inhibitors (CNIs)
- Cyclosporine
- Tacrolimus IR
- Tacrolimus ER
2) Corticosteroids
- Prednisone
- Methylprednisilone
3) Antiproliferatives
- Azathioprine
- Mycophenolate mofetil
- Mycophenolate sodium
4) Rapamycins derivatives
- Sirolimus
Many difference combinations of maintenance regimens. What does the choice depend on?
- Type of transplant
- Match between donor and recipient
- Underlying disease
- Patient history
- Co-morbidities
- Medication tolerance
- Patient age
What is the standard therapy for adult kidney transplant?
1) Tacrolimus (Program or Advagraf)
- Inhibits early in T-cell activation + clonal expansion
2) Mycophenolate mofetil
- Works to decrease T-cell proliferation
3) Prednisone
- Sequesters and inhibits lymphocytes
Describe the usual maintenance regimen?
1) T-cell communication
- Cyclosporine
- Tacrolimus
2) Anti-proliferative
- Azathioprine
- Mycophenolate
- Sirolimus
3) Prednisone
* Usually 1 from each box
Cyclosporine and Tacrolimus are examples of?
Calcineurin Inhibitors (CNIs)
30-40% of ppl after kidney transplant develop _____
diabetes
Adverse drug reactions with CNIs (cyclosporine and tacrolimus)
- increase BG (tacrolimus)
- increase BP
- increases lipids
- increases K+
- decrease Mg+
- decrease P
- increase UA
- tremor
- nephro & hepatoxicity, gingival hyperplasia (CSA)
CNIs are both substrates and inhibitors of ______ and ____
CYP-3A4 and P-gp
Is cyclosporine or tacrolimus a better inhibitor of CYP 3A4?
cyclosporine
How does diarrhea affect cyclosporine/tacrolimus ?
- diarrhea can cause sloughing of intestinal endothelium
- loss of P-gp
- increased CNI levels
*other meds may use P-gp and this can affect them too
List some 3A4 inhibitors that will increase concentrations of cyclosporine or tacrolimus
- Azoles
- Macrolides
- Non-DHP CCB’s
- Grapefruit juice
- Ritonovir/protease inhibitors
List some 3A4 inducers that will decrease concentrations of cyclosporine or tacrolimus
- Rifampin
- Phenytoin
- Carbamazepine
- Phenobarbital
- St. John’s Wort
Describe the drug interaction between cyclosporine & minoxidil
hirsutism (excessive body hair)
Describe the drug interaction between cyclosporine & phenytoin, nifedipine
gum hyperplasia
Describe the drug interaction between cyclosporine & statins, digoxin, caspofungin
decreased clearanceq
Describe the drug interaction between cyclosporine & colchicine
increased myopathy and hepatotoxicity
Describe the drug interaction between cyclosporine & glyburide
increased CSA level
Describe the drug interaction between cyclosporine & repaglinide
increased repaglinide exposure
Describe the drug interaction between cyclosporine & warfarin
decreased INR and CSA levels
Describe the drug interaction between cyclosporine & potassium sparing diuretics
hyperkalemia
Which statins can you use with cyclosporine?
pravastatin or fluvastatin (still caution tho)
Describe the drug interaction between tacrolimus & potassium sparing diuretics
hyperkalemia
Describe the drug interaction between tacrolimus & metoclopramide
increased tacrolimus exposure
Describe the drug interaction between tacrolimus & statins
TAC/atorvastatin might be okay
Which NOAC is the safest with CNI’s?
Apixaban - likely “safer”
slide 41
CNIs cause afferent & efferent ________
vasoconstriction
Which drugs will cause additive nephrotoxicity with CNI’s?
NSAIDS: afferent vasoconstriction
ACEi/ARB: efferent vasodilation
Aminoglycosides, amphotericin B
Which drugs will cause renal sparing?
CCBs: afferent vasodilation
List an example of rapamycin derivatives?
sirolimus
When is Sirolimus dosed in response to cyclosporine?
4 hours after cyclosporine
SE of Sirolimus ?
- increase lipids, proteinuria, delayed would healing, anemia, hypertension
- caution in liver and lung transplant - hepatic artery stenosis, bronchial anastomotic dehiscence
3A4 inhibitors will ______ concentrations of Sirolimus
increase
3A4 inducers with _____ concentrations of Sirolimus
decrease
Inducers of 3A4 will ____ concentrations of tacrolimus, sirolimus and cyclosporine
decrease
List examples of inducers of 3A4
- Rifampin
- Phenytoin, carbamazepine, barbiturates
- St. John’s Wort (avoid with CSA, TAC, SIR)
Inhibitors of 3A4 will ______ concentrations of tacrolimus, sirolimus and cyclosporine
increase
List examples of inhibitors of 3A4
Diltiazem, verapamil: immunosuppressant dose reductions of 25-50%
Azole antifungals: avoid if possible (esp. voriconazole)
-Single dose fluconazole has minimal effect
Erythromycin, clarithromycin: avoid if possible
Grapefruit
Inhibitors of P-gp will ____ concentrations of tacrolimus, sirolimus and cyclosporine
increase
Inducers of P-gp will ______ concentrations of tacrolimus, sirolimus and cyclosporine
decrease
How does diarrhea affect P-gp ?
Diarrhea depletes GI lining with P-gp
-Increased drug levels/exposure (also it’s own cause of GI distrubances)
List examples of Anti-Proliferatives
Azathioprine, Mycophenolate
ADRs of Azathioprine
- bone marrow suppression
- hepatotoxicity
ADRs of Mycophenolate
leukopenia, GI intolerance
What is TMPT phenotype to guide dosing of azathioprine?
TMPT is a genetic test - it’s an enzyme, you check and see if it’s normal levels this enzyme breaks down azathioprine
Describe the drug interaction between:
Azathioprine & Allopurinol
- Avoid using allopurinol while on AZA
- Significantly increases AZA levels
- Profound neutropenia
Describe the drug interaction between:
Azathioprine & ACEi
increased neutropenia
Describe the drug interaction between:
Azathioprine & Warfarin
decreased INR
Describe the interaction between:
Mycophenolate & Antibiotics
may change enterohepatic recirculation (may change trough level but not necessarily overall exposure)
Describe the interaction between:
Mycophenolate & Cholestyramine
- Prevents reabsorption via enterohepatic recirculation
- Significant decrease in MPA concentration
Describe the interaction between:
Mycophenolate & PPIs
Decrease Mycophenolate levels, use lowest dose possible
Describe the interaction between:
Mycophenolate & Antacids
Dose separation by 2 hours minimum
Describe the interaction between:
Mycophenolate & iron preparations
dose separation not required
Why is dose separation not required for iron but it is required for antacids?
**with mycophenolate
Bc we think mycophenolate absorption is pH dependent
- Antacids affect pH
- Iron dose not
List 2 corticosteroids
Prednisone, methylprednisone
Adverse drug reactions of corticosteroids?
-increase lipids, increase BG and BP, sleep disturbances, increase appetite/weight, mood swings, osteoporosis, acne, fluid retention
Drug interactions with corticosteroids?
Minimal but do interact with:
- Immune stimulants
- Decongestants
- PPIs - use lowest possible dose
- Additive nephrotoxicity: avoid when possible with NSAIDs and ahminoglycosides, and amphotericin B
From Case #1:
You are starting phenytoin but they are tacrolimus. What do you do?
No need to pre-emptively lower doses. Take blood levels and adjust accordingly.
Phenytoin = 3A4 inducer so it will decrease TAC level
-Increase TAC level by 25%
Describe the monitoring after a kidney transplant
Managing drug levels of a transplant patient is like balancing a scale:
- Rejection (efficacy vs toxicity)
- Each person and each target level is unique
- Never a textbook case
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 or toxicity
Target blood concentrations must correlate with what?
- Exposure (i.e. AUC)
- Clinical outcomes - therapeutic and toxic
What factors influence pharmacokinetics of CNI?
- Age
- Race
- Type of organ
- Liver dysfunction
- Hep c
- Small bowel length
- Gastrintestinal state
- Infection
- Inflammatory states
- Time post-transplant
- Hematocrit
- Albumin levels
- Diurnal variations
- Drug interactions
- Comorbidities (diabetes, CHF)
- Intestinal CYP 450 and P-gp expression
go over monitoring slides on slide 67
okay
Case #2
What else do you want to know?
- BMI, waist circumference
- Diet and exercise and smoking history
- CVD history (personal and family)
- Abnormal baseline renal function
- Why cyclosporine vs tacrolimus?
- Lipid target ? lol
What are some reasons for dyslipidemia?
- CKD
- Age
- Lifestyle: diet, exercise, smoking
- Prednisone
- Cyclosporine
Which statins can you use with cyclosporine?
pravastatin and fluvastatin (caution tho)
Which statins can you use with tacrolimus?
nothing mentioned
no data vs. no interaction
Which statins can you use with sirolimus?
atorvastatin
lipids and CV disease is common in _____
transplants
Which immunosuppressant and statin combo has the most reports of rhabdomyolysis/myositis?
Cyclosporine
Post-transplant infections:
Describe PCP/PJP
Pneumocystis jiroveci:
- PJP has significant morbidity and mortality in solid organ transplant patients
- Associated with periods of higher immunosuppression in the first 3-12 months post-transplant
Post-transplant infections:
What is the prophylaxis for PCP?
In Mb:
- 3 months
- Co-trimoxazole 400/80 mg daily or 800/160 mg EOD/MWF
Post-transplant infections:
What is the treatment for PCP?
- 3 weeks
- Co-trimoxazole (oral/IV) 15-20 mg TMP/kg/day
- approx 1600/320 mg (2 DS tabs) q8h
Post-transplant infections:
Describe CMV
-CMV is a member of the herpes virus family
Post-transplant infections:
What is the prophylaxis for CMV?
Pre-emptive treatment until 2 negative PCR
Valganciclovir 900 mg daily for 6 months
Post-transplant infections:
Describe BK Virus
- Polyomavirus
- Common in general population, mostly asymptomatic in the renal tract
- Reactive and replicate in immunosuppressed state
- May lead to BK nephropathy and graft failure
- Routine screening for BK viraemia & graft dysfunction
- No good treatments available (reduction in baseline immunosuppression, switch to cyclosporine)
Post-transplant infections: Describe EBV (mono)
- Common virus in general population
- Routine screening if EMB mismatch at time of transplant
- Association with development of post transplant lymphoproliferative disorder
- Mainstay treatment - lowering immunosuppressive therapy
Post-transplant infections:
Describe UTI
- Most common infection post kidney transplant
- Pyelonephritis can lead to sepsis, graft dysfunction and failure
- Risk factors include female, advanced age, history of UTI’s pre-transplant, prolonged use of catheter, indwelling device, polycystic kidney disease
- There is benefit to using UTI prophylaxis especially within first 3 months post kidney transplant
- TMP/SMX is preferred over ciprofloxacin
Post-transplant:
When is it okay to give vaccines and which type?
Avoid live vaccines!
Inactivated vaccines only.
Flu shot is okay 3 months after transplant, should wait 6 months after transplant for other inactivated vaccines.
Post-transplant increases risk for ______
malignancy/cancer
What are some complications of renal transplants?
- Anemia
- Analgesia for pain
- Bone density decrease
- Blood pressure increase
- Cholesterol increase
- Cancer risk
- Diabetes/increased BG
- Depression/mood changes
- Eyes (cataracts)
- Exercise
Describe mycophenolate & fertility
- Known to be teratogenic in females
- Switch to azathioprine if planning for pregnancy
Goals of transplant
- Prolong graft survival
- Prevent rejection episodes
- Assess adherence on a regular basis
- Minimize long term complications
What should you do if you have a transplant recipient at your pharmacy ?
- Find out who their transplant team is
- Remember drug interactions
- The ABCDE list is a great way to look for areas to improve their overall health
- Ask about adherence
KNOW THE TARGET RANGES FOR THE DIFFERENT LEVELS
ok dude
