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Kidney Transplant 101:
A practical approach to the management of kidney transplant patients
Cindy Luo, BSc(Pharm), PharmD, ACPR, BCPSClinical Pharmacy Specialist – Solid Organ Transplant, Vancouver General Hospital
CSHP-BC Fraser Chapter Event (Virtual)– June 17th, [email protected] Twitter @cindyyluo
Presenter disclosure
§ Presenter’s name: Cindy Luo
§ I have no current or past relationships with commercial entities.
§ I have received no speaker’s fee for this learning activity.
2
Commercial support disclosure
§ This program has received no financial or in-kind support from any commercial or other organization
3
Learning Objectives
By the end of this session, you will be able to:§ List the common immunosuppressive medications used in kidney
transplant.§ Describe the mechanism of action, formulations and monitoring
parameters for the most common immunosuppressive medications.§ Describe the spectrum of cytomegalovirus infection.§ Identify locally available transplant-related resources.
5
Kidney Disease
CIHI, Annual Statistics on Organ Replacement in Canada; 2019. [cited 2020 June 5]. Available from https://www.cihi.ca/sites/default/files/document/corr-snapshot-2019-en.pdfBC Transplant 2019 Organ Donation and Transplantation 2019. [cited 2020 June 5]. Available from http://www.transplant.bc.ca/Documents/Statistics/BCT-2019-Stats-FINAL.pdf
> 40 000 Canadiansliving with end stage renal
disease
2018
Dialysis
42.8%
Transplant
> 80%
5-year survival
6
Number of Kidney Transplants
CIHI, Canadian Organ Replacement Register 2016; 2016. [cited 2020 June 5]. Available from https://www.cihi.ca/en/canadian-organ-replacement-register-2016CIHI, Annual Statistics on Organ Replacement in Canada; 2019. [cited 2020 June 5]. Available from https://www.cihi.ca/sites/default/files/document/corr-snapshot-2019-en.pdfBC Transplant 2019 Organ Donation and Transplantation 2019. [cited 2020 June 5]. Available from http://www.transplant.bc.ca/Documents/Statistics/BCT-2019-Stats-FINAL.pdf
Canada British Columbia2014 1430 2052018 1706 335
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Action:
Antibiotics
Medicationreconciliation
Patient:
67 y.o male
2015 KTxKidney transplant
8
Diarrhea
Fever
AKIAcute kidney injury
SOBShortness of
breath
Symptoms:
What transplant medicationsshould this patient be on?
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Most common combination
Calcineurin inhibitors Anti-metabolite
MycophenolateAzathioprine
+/- Steroids
PrednisoneTacrolimusCyclosporine
Class
Drug
10
Calcineurin inhibitors:Tacrolimus and Cyclosporine
MOA
T cells
Metabolism
CYP 3A4/3A5
Levels
Tacrolimus
Cyclosporine
C0
C0, C2
11MOA = Mechanism of ActionC0 = concentration at 0 hoursC2 = concentration at 2 hours Tacrolimus. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https:/https://online.lexi.com.
Cyclosporine. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https://https://online.lexi.com.
Calcineurin inhibitors:Tacrolimus and Cyclosporine
Metabolism
CYP 3A4/3A5
Please check for drug interactions!
Examples:
↑ Tacrolimus Levels ↓ Tacrolimus LevelsErythromycin, Clarithromycin
Phenytoin
Azole Antifungals RifampinDiltiazem
12Tacrolimus. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https:/https://online.lexi.com. Cyclosporine. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https://https://online.lexi.com.
Tacrolimus Formulations
Oral formulation Available strengthsImmediate-release (IR)
§ PrografÒ (BID), generic brands*
§ SL administration: (PO àSL 2:1)§ content placed under tongue
§ NG administration: § content mixed with water and flushed
down NG, clamp NG for feeds
§ 0.5 mg, 1 mg, 5 mg capsules
*Generic brands: (on Canadian market June 2020)
• Ach-Tacrolimus• Apo-Tacroilmus• Jamp-Tacroimus• Ran-Tacrolimus• Sandoz-Tacrolimus
Extended-release § AdvagrafÒ (daily) § IR à AdvagrafÒ 1:1 total daily dose
§ 0.5 mg, 1 mg, 3mg, 5 mg capsules
§ Envarsus PAÒ (daily)§ IR à Envarsus PAÒ 1:0.7
§ 0.75 mg, 1 mg, 4 mg capsules
13Tacrolimus. In: Lexi-drugs online. [cited 2020 June 14]. Available from https:/https://online.lexi.com. Tacrolimus. Government of Canada Drug Product Database. [cited 2020 June 14]. Available from: https://health-products.canada.ca/
Government of Canada. Recalls and Safety Alerts; 2019 July. [cited 2020 May 10]. Available from https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70511a-eng.php#:~:text=Health%20Canada%20has%20received%20reports,the%20wrong%20formulation%20of%20tacrolimus.
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Intravenous Tacrolimus
§ Hypersensitivity/anaphylaxis risk – castor oil content
§ Administration: over 4 to 6 hours or 24-hour infusion, special tubing required
§ Monitoring: more difficult to monitor, greater risk for toxicity
§ Dosing: PO:IV 4:1 (with tacrolimus IR dosing)
Transplant Proc. 2010;42(10):4331-7.15
Adverse Drug EventsCalcineurin inhibitors
Neurotoxicity(tremors, headaches)
HypertensionDyslipidemia
CNS
CVS
RenalNephrotoxicityElectrolyte abnormalitiesMetabolic
Hyperglycemia
16Tacrolimus. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https:/https://online.lexi.com. Cyclosporine. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https://https://online.lexi.com.
Most common combination
Anti-metabolite
MycophenolateAzathioprine
+/- Steroids
Prednisone
Calcineurin inhibitors
TacrolimusCyclosporine
Class
Drug
17
Anti-metabolites:Mycophenolate (MPA) and Azathioprine
MOA Metabolism Levels
T cells and B cells
Clinical monitoring
Mycophenolate: levels are notroutinely done
Hepatic and GI tract
18Azathioprine. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https:/https://online.lexi.com. Mycophenolate. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https://https://online.lexi.com.
Mycophenolate (MPA) Formulations
Oral AvailabilityMycophenolate mofetil (Brand name - Cellcept®)
§ 250 mg, 500 mg
Mycophenolate sodium (Brand name – Myfortic®)
§ 180 mg, 360 mg
Mycophenolate mofetil 1000 mg = Mycophenolate sodium 720 mg Intravenous Mycophenolate mofetil IV to PO: 1:1 with mycophenolate mofetil
19
Mycophenolate. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https://https://online.lexi.com.
Adverse Drug EventsAnti-metabolites
NeutropeniaAnemiaThrombocytopeniaHeme
GIMPA: Diarrhea, heartburnAzathioprine: Hepatitis
20Azathioprine. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https:/https://online.lexi.com. Mycophenolate. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https://https://online.lexi.com.
Medication reconciliation:§ Mycophenolate mofetil 1000 mg PO BID
§ Tacrolimus 3 mg PO BID§ Prednisone 5 mg PO daily
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Scr comes back at 250 µmol/L
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22 Scr = serum creatinine
Renal Impairment
§ Does not affect elimination or serum concentration of tacrolimus
§ Not removed by hemodialysis or peritoneal dialysis
§ No empiric dose adjustments necessary
24
Tacrolimus. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https:/https://online.lexi.com.
Adverse Drug EventsCalcineurin inhibitors– dose related
Neurotoxicity(tremors, headaches) CNS
RenalNephrotoxicityElectrolyte abnormalities
25Tacrolimus. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https:/https://online.lexi.com. Cyclosporine. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https://https://online.lexi.com.
How do we monitor tacrolimus?
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Tacrolimus monitoringFor k idney transplant
Time Post-Transplant Tacrolimus trough concentration (µg/L)Less than 1 month 9 - 121 to 3 months 8 - 104 to 6 months 6 - 8Greater than 6 months 5 - 7
Published in the BC Transplant Medication guidelines- Note: Tacrolimus levels listed above are in draft form
BC Transplant. Medication guidelines; 2020 [cited 2020 May 10]. Available from http://www.transplant.bc.ca/Documents/Health%20Professionals/Clinical%20guidelines/Clinical%20Guidelines%20for%20Transplant%20Medications.pdf
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Tips for tacrolimus monitoring
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Tacrolimus level comes back at 28 µg/L (Target 5-7 µg/L)
29
Tacrolimus level comes back at 28 µg/L (Target 5-7 µg/L)
Poll 2
Tacrolimus can cause nephrotoxicity
The patient’s Scr comes back at 250 µmol/L
Question
Should we stop the tacrolimus?
a) Yesb) Noc) Need more
information
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Tacrolimus levels
§ Half life: variable (between 3-36 hours)§ Tacrolimus levels > 20 µg/L à AKI
Glomerulus
efferentafferent
Tacrolimus causes vasoconstrictionof the afferent arteriole à reduced blood flow and ↓ GFR
31Clin J Am Soc Nephrol. 2009;4(2):481-508.
Tacrolimus. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https:/https://online.lexi.com.
AKI = acute kidney injuryGFR = glomerular filtration rate
How do you manage this high tacrolimus level?
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• Plan: Consult transplant team
• Hold tacrolimus• Restart at lower dose
• Increase frequency of tacrolimus levels
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Why is the tacrolimus level so high?
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35
Action:
Antibiotics
Medicationreconciliation
Patient:
67 y.o male
2015 KTxKidney transplant
36
Diarrhea
Fever
AKIAcute Kidney Injury
SOBShortness of
Breath
Symptoms:
Diarrhea
§ Increased tacrolimus trough levels
§ Result of:§ ↓ CYP 3A4 drug catabolism§ ↓ P-glycoprotein drug efflux
§ Careful monitoring and dose adjustment required
Transplant Proc. 2014;46(2):592-4.Am J Transplant. 2005;5(6):1383-91.Transpl Int. 2001;14(4):230-3.
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CYPmetabolism
↓ CYP metabolism
↑ Tacrolimus levels
Diarrhea
§ Increase in tacrolimus levels but not cyclosporine levels during diarrhea
§ WHY?
§ Not clear§ Different affinity for P-glycoprotein § Whether gut metabolism is more important with Tacrolimus than Cyclosporine
Am J Transplant. 2002;2(10):989-92.38
What is the cause of diarrhea?
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What is the cause of diarrhea?
§ No travel history§ Negative Clostridium difficile and Ova/Parasite
§ ? Side effect of mycophenolate§ ? Another cause
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Adverse Drug EventsAnti-metabolites
NeutropeniaAnemiaThrombocytopeniaHeme
GIMPA: Diarrhea, heartburnAzathioprine: Hepatitis
20Azathioprine. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https:/https://online.lexi.com. Mycophenolate. In: Lexi-drugs online database. [cited 2020 June 14]. Available from https://https://online.lexi.com.
Cytomegalovirus (CMV)
§ In herpes virus family
§ Seroprevalence rates: 45-100% adults
§ Severity of illness dependent on host
§ Significant morbidity and mortality in immunocompromised patients
42PLoS One. 2018;13(7):e0200267.Transplantation. 2018;102(6):900-931.
CMV Risk in Transplant Recipient
Risk Donor/Recipient Comments
High D+ / R- Immunosuppression induction agent importantI.e. Lymphocyte depletionModerate R+
Low D- / R-
43
BC Transplant. Medication guidelines; 2020 [cited 2020 May 10]. Available from http://www.transplant.bc.ca/Documents/Health%20Professionals/Clinical%20guidelines/Clinical%20Guidelines%20for%20Transplant%20Medications.pdf
Clinical Presentation
System InfectionCNS Encephalitis
HEENT Retinitis
CVS Pericarditis, Myocarditis
Pulmonary Pneumonitis
GI Gastroenteritis, Hepatitis
MSK/Derm Rash
Heme Leukopenia
RetinitisEncephalitis
GastroenteritisHepatitis
PericarditisMyocarditisPneumonitis
44
Infect Chemother. 2013; 45(3): 260–271.
Spectrum of Illness
C M V I n f e c t i o n
Asymptomatic viremia
Viral syndrome Tissue invasive disease
45
Infect Chemother. 2013; 45(3): 260–271.
Spectrum of Illness
C M V I n f e c t i o n
Asymptomatic viremia
Diagnosis§ Preferred testing: CMV PCR in blood§ <35 IU/mL considered not detectable
§ In BC, PCR done at St Paul’s Hospital virology lab
§ In active infection, serology not useful
46
Infect Chemother. 2013; 45(3): 260–271.PCR = polymerase chain reaction
Spectrum of Illness
C M V I n f e c t i o n
Viral syndromeDefinition: symptomatic viremia in absence of tissue-invasive disease
Presentation:§ Fever§ Malaise§ Leukopenia
47
Infect Chemother. 2013; 45(3): 260–271.
Spectrum of Illness
C M V I n f e c t i o n
Asymptomatic viremia Tissue Invasive
Disease
Transplant recipients:§ Enteritis/Colitis§ Pneumonitis (especially lung
transplant)• HIV: Retinitis
48
Infect Chemother. 2013; 45(3): 260–271.
Is this CMV??
Order CMV PCR
49
Diarrhea
Fever
AKI
SOB
• CMV PCR 60 000 IU/mLNormal <35 IU/mL
Suspect CMV tissue invasive disease
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How do you manage CMV?
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Treatment of CMV
§ Drug of choice: Ganciclovir (IV) or Valganciclovir (PO)§ Dosing based on renal function§ Standard dosing (for CrCL >60 mL/min):
Valganciclovir PO Ganciclovir IVProphylaxis 900 mg PO daily 5 mg/kg IV q24hTreatment 900 mg PO BID 5 mg/kg IV q12h
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BC Transplant. Medication guidelines; 2020 [cited 2020 May 10]. Available from http://www.transplant.bc.ca/Documents/Health%20Professionals/Clinical%20guidelines/Clinical%20Guidelines%20for%20Transplant%20Medications.pdf
CrCL = creatinine clearance
IV Ganciclovir vs PO Valganciclovir
§ 1o outcome: eradication of CMV viremia Day 21
§ 46% patients had tissue invasive disease
§ Valganciclovir 900 mg PO BID vs Ganciclovir 5 mg/kg IV q12h
A!
sberg et al.
Table 2: Analysis of efficacy
Response Valganciclovir Ganciclovir Difference (95% CI)
(A) Intention-to-treat population n = 164 n = 157viremia eradication at Day 21 74 (45.1%) 76 (48.4%) !14% to +8%viremia eradication at Day 49 110 (67.1%) 110 (70.1%) !13% to +7%Clinical resolution of CMV disease at Day 21 127 (77.4%) 126 (80.3%) !12% to +6%Clinical resolution of CMV disease at Day 49 140 (85.4%) 132 (84.1%) !7% to +9%
(B) Per-protocol population Valganciclovir (n = 133) Ganciclovir (n = 126)Median baseline viral load1 (copies/mL) 19 750 (3470–84 500) 16 675 (3520–83 500)Time to viral eradication ("600 copies) (days) 21 (95% CI: 19.3–22.7) 19 (95% CI: 16.8–21.2)Time to viral eradication ("200 copies) (days) 21 (95% CI: 17.1–24.9) 21 (95% CI: 17.2–24.8)Calculated decay slope (log copies/day)2 –0.060 (–0.084 to –0.042) –0.067 (–0.088 to –0.048)Calculated viral load half-life (days)2 11.5 (8.3–16.5) 10.4 (7.9–14.5)
1Inter-quartile range is shown in parentheses.2Range is shown in parentheses.
presence of tissue invasive disease, previous anti-CMVtherapy and type of organs transplanted or number of HLA-A or HLA-B locus mismatches had no significant influenceon treatment success. The only factor predictive of viraleradication was the baseline viral load (Figure 3). Patientswith a baseline viral load of <10 000 copies/mL had a uni-variate relative chance for eradication of viremia (cutoff:600 copies/mL) at Day 21 of 6.41 (95% CI 3.61–11.36; p <
0.001) and at Day 49 of 2.56 (95% CI 1.29–5.08; p = 0.001),compared to those with a viral load of #10 000 copies/mL.
Discussion
This is the first randomized controlled trial comparing oralvalganciclovir to i.v. ganciclovir for the treatment of CMVdisease in solid organ transplant recipients. The currentAmerican Society of Transplantation recommendation for
Figure 2: Reduction in CMV vi-ral load with time in patientstreated with oral valgancicloviror i.v. ganciclovir. There wasno difference in viral load reduc-tion rate between the treatmentgroups (200 copies/mL as assaycutoff; per-protocol population).
the treatment of CMV disease is i.v. ganciclovir and thiswas the chosen comparator (5). The results of this trialshow that 900 mg of oral valganciclovir twice daily is non-inferior to 5 mg/kg of i.v. ganciclovir twice daily for thetreatment of CMV disease. This was confirmed by bothintention-to-treat and per-protocol analyses at Day 21 andDay 49. In the per-protocol population viral clearance byDay 21 was almost 60%, increasing to about 85% at theend of treatment (Day 49). Viral clearance kinetics basedon plotting best-fit decay curves for each patient was al-most identical in the two arms. In addition, clinical pa-rameters such as resolution of fever and clinical resolu-tion of CMV disease (as assessed by the investigator)were the same in both arms, with very high clinical suc-cess rates observed by Day 49 (valganciclovir, 85.4%; gan-ciclovir, 84.1%). Thus, both clinical and viral parameterswere equivalent for valganciclovir- and ganciclovir-treatedpatients at all time points until Day 49.
2110 American Journal of Transplantation 2007; 7: 2106–2113
Am J Transplant. 2007;7(9):2106-13.
Bottom Line:PO valganciclovir can be used for tissue invasive disease
53
Plan: § ↓ Mycophenolate mofetil to 750 mg PO BID
§ Valganciclovir 450 mg PO BID (renally dosed)
54
5 PMFriday
Medications on admission:§ Mycophenolate mofetil 1000 mg PO BID
§ Tacrolimus 3 mg PO BID§ Prednisone 5 mg PO daily
Medications for discharge:§ Mycophenolate mofetil 750 mg PO BID
§ Tacrolimus 2 mg PO BID§ Prednisone 5 mg PO daily
§ Valganciclovir 450 mg PO BID
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How do you manage these discharge prescriptions?
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Outpatient transplant prescriptions in BC
Community Pharmacy(in BC)
BC Transplant Pharmacy
58
BC Transplant. Transplant Centres, Clinics & Pharmacies; 2020 [cited 2020 May 10]. Available from http://www.transplant.bc.ca/our-services/transplant-centres-clinics-pharmacies 60
Who can I call for help?
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Transplant Centers in BC
Vancouver General Hospital(VGH)
St. Paul’s Hospital(SPH)
KidneyLiverPancreasHeartLung
62
Transplant Resources
§ Contact transplant team:§ VGH, SPH, peripheral sites
§ BC Transplant website:
63
BC Transplant. Medication guidelines; 2020 [cited 2020 May 10]. Available from http://www.transplant.bc.ca/Documents/Health%20Professionals/Clinical%20guidelines/Clinical%20Guidelines%20for%20Transplant%20Medications.pdf
Learning Objectives
By the end of this session, you will be able to:§ List the common immunosuppressive medications used in kidney
transplant.§ Describe the mechanism of action, formulations and monitoring
parameters for the most common immunosuppressive medications.§ Describe the spectrum of CMV infection.§ Identify locally available transplant-related resources.
64
Icon credits(by s l ide number)
§ 6: Dialysis icon: https://pngio.com/images/png-a269986.html
§ 6: Kidney Transplant icon: https://www.kidneyfund.org/kidney-month/images/km-icons3a.png
§ 8, 36, 49: Diarrhea icon & Kidney Injury Icon: designed by Freepik from Flaticon https://www.flaticon.com
§ 11, 18: T cell icon: http://www.clker.com/cliparts/9/F/k/5/Y/9/naive-t-cell-md.png§ 11, 12, 18: Liver icon: https://stock.adobe.com/ca/search?k=%22graphic+organ%22§ 18: B cell icon: https://www.clipart.email/clipart/b-cells-clipart-239297.html
§ 18: GI tract icon: https://www.kindpng.com/imgv/iohRxbJ_digestive-system-cartoon-png-transparent-png/§ 58: BC Transplant icon: http://www.transplant.bc.ca/_layouts/15/CUSTOM/EWI/assets/img/bctransplant/logo.png
§ Images created on Piktochart: Slides 9, 22, 26, 28, 29, 32, 34, 35, 39, 51, 56, 61
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