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Transplant Basics for Acute Care NPsAlison Mitchell MSN, ACNP, FAANPAdjunct Clinical professor

Disclosure: Conflicts of Interest

Alison Mitchell has no commercial financial relationships to disclose

This presentation uses a number of slides prepared by

Julie Stanik-Hutt, PhD, ACNP/GNP, FAANP, FAAN

” Managing Transplant Recipients in a Primary Care Setting” presented at 2017 AANP Conference

Learning Objectives

Describe the management of common side effects of immunosuppressant medications

Analyze clinical situations common in solid organ transplant recipients in order to develop an appropriate list of differential diagnoses

Describe the role of the patient and their transplant center providers role in minimizing complications after transplantation

Why transplant?

To prolong recipients life

Decrease morbidity related to their underlying organ failure

Improve quality of recipients life

Transplant OptionsSolid organs

Avascular tissue

Vascular composite allotransplant

Transplant Options

Solid organs

Kidney

Heart

Intestine

Liver

Lungs

Pancreas

Avascular tissue

Cornea

Heart valves

Bone

Teeth

Skin

Vascularized composite allotransplant

-hands/arms/face/penis

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Transplant History

u 1954- 1st successful transplant in North America

u Living related renal transplant between identical twins

u No immunosuppression and graft survived for 8 years

u > 650,000 people in the USA have received a transplant since 1988

u Today, >200,00 Americans live with a functioning organ transplant

So what has improved?

Operative technique and immunosuppressants

Control of complications

Addition organs available for transplant

Liver, Heart, Lung, Pancreas, Intestines(solid organs) and face and hands

Donors expanded to:

-Living Donors that are HLA mismatch

Extended criteria donors- non beating heart

So how long do the grafts survive?(2017 data)

Living related kidney

Cadaver renal transplant

Pancreas

Liver

Heart

Lung

1 yr 98% 3 yr 93% 5 yr 88%

1 yr 93% 3yr 85% 5 yr 74%

1 yr 81% 3 yr 71% 5 yr 60%

1yr 90% 3yr 81% 5 yr 73%

1yr 91% 3yr 85% 5 yr 78%

1yr 88% 3yr 67% 5 yr 53%

ChallengesOrgan shortage

Increased number of minority recipients>50 yrs

>6,700 die waiting( 22 daily)

>33,595 transplants annually

5,975 living donations

Despite living donations there are 144 new listings every day

Long term complications

Rejection

Infection

Cancer

Fractures from long term steroids

Medication effects

Americans waiting…

> 118,786 Americans wait for

Kidneys 82%

Liver 12%

Pancreas 9%

Heart 3%

Lung 1 %

Who qualifies?Eligibility

End stage organ disease despite optimal medical management

Otherwise healthy

No contraindication for immunosuppression

Adequate social supports to comply with post transplant care

ExclusionsActive smoking and drug abuse( livers now being transplanted in ETOH abusers)

Financial

> 75 yrs old

Cancer in the last 5 years

Active infections or colonizations with pan resistant organisms

Foreign nationals

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Vascularized composite allotransplantation VCA

Hand

Arm

Face

Penis

Composite Tissue Allotransplantation CTA

Skin

Soft tissue(muscle, nerve, vessels)

Bone

teeth

Vascular(VCA) & Composite(CTA)

Vascular Composite Allo-transplantation

Upper extremities

First in 1964, first successfully in 1998

12 US hospitals

> 100 patients worldwide, 20 patients in the USA

Bilateral deficit below the shoulder-6 months post amputation and failed myoelectric prosthesis

Face

First in 2005

8 US hospitals

30 pts. worldwide ,10 patients in USA

Loss of >25% facial structure

5 deaths- 2 infections, 1 graft lost to non adherence, 1 cancer reoccurrence, 1 GSW

Hand & Arm RecipientsPost Operative Care

Frequent vascular checks

Position hand at level of heart

Strict use of pressure relieve

Topical & systemic immunosuppression

Post Operative care

Extensive PT/OT

Passive ROM at 24-48 hrs

PT/OT 6 hrs a day 5 days a week

for 3-6 months

Psychosocial support

Face recipientsPost Operative care

Sedation and analgesia

Airway management

Hemostasis

Flap healing- maintain patency of drains and minimize movement

Post Operative Care

Prevent edema by having a neg I/O, Elevate HOB

PT/OT/speech

Enteric feeding

Nerve impulse detection with exercises

Psychosocial and family support

Long term complications

Ischemia-reperfusion

Bleeding vs. thrombosis

Vascular stenosis-renal, pulmonary

Wound Infection

Interrupted lyphatics-lymphocele, chest

Luminal disruption-ureter, smal bowel, bile duct, bronchus

Nerve Injuries/denervation-vagus,phrenic,aspiration,hypotension(orthostatic)

Management of Transplant Recipients

Rejection

Immunosuppression

Drug interactions and drug toxicities frequently checked

Infection

Procedural Complication

Malignancies

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Types of Rejection

Acute-

Abrupt, commonly in the first months of the first year, usually treatable but predisposes to chronic rejection

Major cause of mortality/morbity in 1st year after transplant

Chronic-

Months and years post transplant, diffuse & progressive thickening and fibrosis, poorly understood- antibody related

Microvasculature obstruction and sclerosis of graft

Mechanisms of Rejection

Humoral-

Antibody mediated (Vascular rejection), B –lymphocytes

Presence of donor specific HLA antibodies, vascular endothelium

Cellular-

Cell mediated, T-lymphocytes

Recipient tissue recognized as foreign, activated then proliferative that destroys graft

Immunology 101Human leukocyte antigens ( HLA)

Class I ( A&B) and II (DR)

Panel Reactive Antibody(PRA) serology

DNA testing to match donor to recipient

Cell surface glycoproteins, >histocompatibility antigens, >help body recognize self versus non self

Major histocompatibility complex ( MHC), inherit 1 allele with 6 loci from ca. parent,

MHC I ( on all cells)

MHC H (on Antigen Producing Cells), brain, eyes, articular cartilage, testes, fetus, and placenta

Immunology 101

T- cells activate then bind to MHC if not trained to recognize

Class 1- Natural killer cells- innate

Class I-CD8 recognition ( killer)

Class II-CD4 recognition ( Helper)

Induction-Anti Lymphocytic antibodies or II-2 Receptor

antagonistsProfound immunosuppression

Near total inactivation T cells

Maximize infection control

Increased long term risk for malignancy

Goal-delay onset first acute rejection

At time of initial exposure to foreign antigen-before and during transplant surgery, short term, high dose immunosuppression

70% receive a specific induction agent

Immunomodulation

Induction antibodies

Donor bone marrow transplant

Minimal maintenance immunosuppression

From a therapeutic point of view, immunomodulation refers to any process in which an immune response is altered to a desired level. Microorganisms are also capable of modulating the response of the immune system to their presence, in order to establish or consolidate an infection

www.encyclopedia.com/science/encyclopedias-almanacs.

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Immunomodulation

Immunomodulation by microorganisms is directed at several aspects of the immune system. One target are the small molecules known as cytokines , which function as messengers of the immune system. In other words, cytokines stimulate various immune responses such as inflammation of the manufacture of antibodies. Other cytokines are involved in down-regulating the immune responses.

Immunomodulation

Some microorganisms are able to produce and excrete proteins that mimic the structure and function of cytokines. Often the result is a suppression of the host's inflammatory response. Examples of microbes that produce cytokine-like molecules are the Epstein-Barr virus , poxvirus, vaccinia virus.

World of Microbiology and Immunology. . Encyclopedia.com. 5 Sep. 2017

T- Cell Co-stimulation Blockade

Epstein Barr Virus sero positive renal transplants only

Induction in OR and on day 5

Maintenance doses at 2,4, 8 &16 weeks

Adverse reactions-pancytopenia, infections and increased risk of post transplant liver disease

Belatacept (Nulojix)

IgG immunoglobin fragment- selective T cell co-stimulation blocker, used with steroids,

basiliximab & MMF

Avoid Calcincurin inhibitors

MaintenanceLife long maintenance

What is the goal?

Promote graft survival and prevent rejection

Triple Therapy to prevent rejection

Dosage titration-levels, side effects, clinical status

Balance risks; Rejection vs. Infection

1/Calcinurin Inhibitors-Cyclosporine or Tacrolimus

2/Purine Synthesis inhibitors-Azathioprine or Mycophenolate Mofetil (MMF). Consider Sirolimus or Everolimus

3/Steroids-Prednisone

Belatacept

CyclosporineSandimmune

Neoral

Gengraf

Cyclosporine

Inhibit T Cell activation

Dosage-titrate to target which varies by patient history and organ

Metabolized by liver

Multiple drug reactions

Sandimmune vs. Neoral, Gengraf

Side Effects

Tremors, N/V, hypomagnesia

Nephrotoxicity, headaches

Hypertension, hirtsuism

Dyslipidemia, parathesias

Polycythemia, seizures, hepatotoxicity, gingival hyperplasia

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Monitoring Cyclosporine

CR

Mag

Hg/Hct

LFTs

lipids

Drug level monitoring-12 hr. troughs

Hypertension

Tremors- usually a sign of toxicity

Gums-unusual growth & swelling may occur

TacrolimusPrografHecoria

Monitoring Tacrolimus

Cr-rising

K- Hyperkalemia

LFTS

Glucose

Lipids

Drug Monitoring-12 hr. troughs

Tremors

Hypertension

Cyclosporine & TacrolimusDrug Interactions

Increase levels

Calcium Channel Blockers

-Azole Antifungals

Macrolides antibiotics

Statins

Grapefruit juice

CYP 450 3A4

Decrease levels

Rifampin

Anti Convulsants

Phenytoin

Phenobarbitol

Ticolipidine ( precursor to Plavix) called Ticlid

Monitoring Tacrolimus

Hyperkalemia

Hypertension

Tremors

Hyperglycemia

Nephrotoxicity

Hepatotoxicity

Parathesias

Alopecia

N/V

Headaches

Both drugs-major drug reactions, narrow therapeutic window, hepatic metabolism

Cyclosporine & TacrolimusSynergistic Nephrotoxicity

Amino glycosides

Ampho B

Vancomycin

Bactrim- sometimes every other day, MWF

NSAIDS

Histamine Blockers

Statins

Other Toxicities

HIV drugs- the ‘virs”

Tramadol- not necessarily one you would generally consider

CMV meds;

Foscarnet, Cidofovir- not that common except in transplant patients

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MMF( Cellcept) or Imuran(Azathioprine)

MMF- suppresses T& B proliferation

AZA-inhibits DNA synthesis

Standard dosing IV=PO, no blood levels

MMF dose goal- 1gm BID

Imuran goal-2mg/kg QHS

Metabolized by liver

Side Effects

Bone marrow suppression so slower to make WBCs

N/V/D

Hepatotoxicity

SirolimusRapamune

Sirolimus

Standard Dosing

Loading dose 6mg then 2-5mg qd

Metabolized by liver

Check lab frequently

CBC

Triglycerides

CR

K & Phos

Drug monitoring

Sirolimus

Side effects

Anemia

Leukopenia

Dyslipidemia

Hypophosphotemia

Dyspepsia

Pulmonary Fibrosis

Thrombocytopenia

Hypertension

Hypokalemia

Nausea/vomiting

Diarrhea

Nephrotoxicity

(Standard dosing with drug monitoring, metabolized in liver)

SteroidsCytokine suppression

Suppress T activation & migration

Steroids

Side Effects

Na+H2O retention

Hypertension

Glucose Intolerance

Sleeplessness

Myopathy

Avascular Necrosis

Cataracts

Acne

Appetite Stimulation

Weight Gain

Delayed Wound Healing

Emotional Lability

Osteoporosis

Peptic Ulcer

Glaucoma

Skin Changes

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Therapeutic Drug Monitoring

Organ and Center Specific Protocols

Daily- weekly-monthly-quarterly , especially 1st year

Interpretation:

Timing-draw, dose

Validate with evidence of toxicity e.g. CR

Change in drug interaction, consistent with clinical scenario, medication adjustments

Rejection

Renal- s/s graft tenderness, >u/o, edema

Dx- Rising Creatinine, US-blood flow, hydronephrosis, percutaneous biopsy

Liver-s/s RUQ pain, anorexia, ascites, > bile output

Dx-Rising bili, transaminases, alk.phos, WBCs

US- blood flow, dilated ducts

CT-leak, obstruction,collection,abcess

Percutaneous biopsy

RejectionHeart-s/s SOB, decreased exercise tolerance, JVD, edema & wt. gain, new gallop, rub, crackles, hypotension

Dx-low voltage ECG, dysrhythmias, CXR enlarged heart, echo dysfunction, endomyocardial biopsy

Lung-s/s-SOB, productive cough, 20 % drop home spirometry (FEV1)

Dx-pleural effusion on CXR,transbronchial biopsy

Rescue Med s/ effectsPt and graft survival depend on behavior change, med adherance, self monitoring, medical follow up

76% report increased side effects after transplant

Symptoms-Distress-poor QOL-poor adherance-Rejection-< graft survival

At time of suspected/confirmed rejection

Goal- Arrest active rejection

Pulse steroids vs. Anti-lymphocyte antibodies

Augment or alter maintenance ‘cocktail’

Plasmapheresis-IVIG-photopheresis

Types of medication s/eBiomedical

HTN &DM

Osteoporosis

N/V/D

Renal insufficiency

Psychosocial

Hair & weight

Acne and fragile skin

Tremors and weakness

Fatigue

Headache and decreased concentration

Identifying Risk & Managing

Young woman- body image is big

Older patients- functional capacity is important

Inadequate coping

Look for & listen

Anticipate and prevent

Adjust immunosuppression

Balancing ACT

Rejection

Increase immunosuppression

Infection

Reduce immunosuppression

Then back to rejection

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Major Complications

Opportunistic Organisms

CMV,HSV,VZV

Candida, Aspergillus

Cryptococcosis

PCP,Toxoplasmosis, histoplasmosis, cryptosporidia

TB, MAC, Listeria, Norcardia

1st month- post infections

2nd—6th month opportunistic infections

Relationship to stimulation of immune system- rejection

Relationship to blood products

Colonization vs. Infection

Timeline for Typical Infections

Bacteria-1st month-Wound, UTI, HAP

2nd-month & for life- CAP, Strep, Staph, Legionella, Norcardia, GI Salmonella, Campylobacter

Mycobacterial- 1st month & Life

Viral-2nd month & for life-HSV, CMV, Paravirus, EBV, VZV, Papilloma, Adenovirus

Fungal-1 month & life- candida, PCP, Aspergillus, Crypto, Macro

Parasites– 3months& life-Toxoplasmosis

Gulliford J, Gama D S,(2000) Postgrad Med

Infection Interventions

Infection Control Procedures- hand washing, immunizations, prophylactic anti microbials, transfusions(irradiated, almost all lungs need CMV negblood), self surveillance

Differential always includes the unusaul

Avoid high risk situations- ill individuals, polio, TB, crowds, Foods- salad bard, sushi/sashimi, undercooked foods

Animals-birds, turtles, lizards

Other environmental hazards- gardening

Infection Prophylaxis

PCP Pneumonia- TMP-SMX ( Bactrim) DS 1 tab po MWF

Dapsone, Pentamidine

Fungal Prophylaxis-Valcyte, AmphoB,clotrimazole

CMV-check frequently,GancyclovirvsValganciclovir

Clinical ManagementTransplant coordinator and clinican-consult them

Drug interactions-problems emerge anytime after starting or stopping

Maintain prophylactic protocols

Listen to your patient

Update meds

Trend lab results

Focused exam considering rejection/infection, drug interactions

Consider is it a side effect? Is the patient taking d

Meds as prescribed? Brand change?

Malignancy

Skin cancers-

Maximal SPF, hats, cover ups

Annual skin exams

Post Transplant Lympho-Proliferative Disease (PTLD) B –lymphocyte & EBV related

Rx with radiation/Rituxan/Chemo and reduction of immunosuppression

3-4 fold increased risk

Oncogenic viruses

DNA damage from immunosuppressants

Induction and Rescue with T-Cell antibodies

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Major pointsOrgan shortage demands optimal use

Team approach to management

NEVER hesitate to call Transplant center to advise

Meds constitute major source of comorbities

Manage symptomatic side effects

Nephrotoxic-HTN-DM-Dyslipidemia

Pancotopenia-CNS-GI problems

Multiple interactions-manage therapeytic as well as toxic effects

REJECTION vs. INFECTION plus MALIGNACY

Transplant, coming to a hospital near you!ajmitchell@houstonmethodist.orgCell 713 515 5508

ReferencesWorld of Microbiology and Immunology. . Encyclopedia.com. 5 Sep. 2017

Gulliford J, Gama D S,(2000) Postgrad Med

Wong CJ,Pagalilauan G,(2015)Primary Care of the Solid organ Transplant Recipient.Medical Clinics of North America99(5), 1075-103

Allison TL, (2016)Immunosuppressive Therapy in Transplantation,Nursing Clinics of North America 51 (1) 107-20

ChelalaL,Kovacs CS, Taege AJ, Hanouneh IA (2015) Common infectious complications of liver transplant Cleveland Clinic journal of Medicine 82 (110, 773-84