kidney transplant 101 - bccshp.files.wordpress.com · 6/17/2020 · kidney transplant 101: a...

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.

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Commercial support disclosure

§ This program has received no financial or in-kind support from any commercial or other organization

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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.

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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

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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

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Diarrhea

Fever

AKIAcute kidney injury

SOBShortness of

breath

Symptoms:

What transplant medicationsshould this patient be on?

2020-04-23, 6:47 PMCustomer Journey_new - by Cindy Luo [Infographic]

Page 1 of 3https://infograph.venngage.com/view/0b449258-31a8-4f68-a614-21573abec172

Customer Journey_new

Admission Hospitalization Discharge

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Most common combination

Calcineurin inhibitors Anti-metabolite

MycophenolateAzathioprine

+/- Steroids

PrednisoneTacrolimusCyclosporine

Class

Drug

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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


Most common combination

Anti-metabolite

MycophenolateAzathioprine

+/- Steroids

Prednisone

Calcineurin inhibitors

TacrolimusCyclosporine

Class

Drug

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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

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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


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

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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


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)

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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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Action:

Antibiotics

Medicationreconciliation

Patient:

67 y.o male

2015 KTxKidney transplant

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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


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-

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Clinical Presentation

System InfectionCNS Encephalitis

HEENT Retinitis

CVS Pericarditis, Myocarditis

Pulmonary Pneumonitis

GI Gastroenteritis, Hepatitis

MSK/Derm Rash

Heme Leukopenia

RetinitisEncephalitis

GastroenteritisHepatitis

PericarditisMyocarditisPneumonitis

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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

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Spectrum of Illness


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

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Infect Chemother. 2013; 45(3): 260–271.PCR = polymerase chain reaction

Spectrum of Illness


Viral syndromeDefinition: symptomatic viremia in absence of tissue-invasive disease

Presentation:§ Fever§ Malaise§ Leukopenia

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Spectrum of Illness


Asymptomatic viremia Tissue Invasive

Disease

Transplant recipients:§ Enteritis/Colitis§ Pneumonitis (especially lung

transplant)• HIV: Retinitis

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Is this CMV??

Order CMV PCR

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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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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

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Plan: § ↓ Mycophenolate mofetil to 750 mg PO BID

§ Valganciclovir 450 mg PO BID (renally dosed)

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5 PMFriday

Medications on admission:§ Mycophenolate mofetil 1000 mg PO BID


Medications for discharge:§ Mycophenolate mofetil 750 mg PO BID


§ 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

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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

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Transplant Resources

§ Contact transplant team:§ VGH, SPH, peripheral sites

§ BC Transplant website:

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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.

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Questions?

[email protected]

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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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