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TRANSPLANT MEDICINE IN THE EMERGENCY DEPARTMENT AND BEYOND…

LT Monaco

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OUTLINE

Basics

Anatomical problems

Infection

Rejection

Drug Toxicity

Organ Specific

References

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BASICS

1 Year survival rate

Solid organ > 80%

Transplanted organs lack innervation

Subtle signs and symptoms can be harbingers of severe disease

Complications

Anatomy
Infection
Rejection
Drug Toxicity

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ANATOMICAL PROBLEMS

Vascular

Non-Vascular (Bile ducts, bronchi, ureters)

Surgery

Arterial and Venous Thrombosis

Arterial Stenosis

Pseudoaneurysms and Rupture

Leaks

Obstructions

Hematomas/swelling

(in liver xplant hepatic artery is the sole source of blood flow)

Hepatic us often performed immediately after transplant to ensure good hepatic artery flow

Obstructions= due to scar tissue, stent migration, stone development

Prolonged leaks can lead to abscess

Images:

Random pic of a clot

https://thrombosis.org/patients/what-is-thrombosis/

Hepatic artery stenosis

https://www.cureus.com/articles/29558-liver-transplant-complications-radiologist-cant-miss

Hepatic artery pseudoaneurysm

https://www.heraldopenaccess.us/openaccess/hepatic-artery-pseudoaneurysm-after-hepatic-transplant-endovascular-treatment-with-graft-stenting

Figure 1: Antegrade nephrostogram post RT showing urine leak�A- Arrow shows site of urine leak�B- Arrow showing large urinoma

https://symbiosisonlinepublishing.com/urology-nephrology/urology-nephrology41.php

Figure 2. Multisection CT with 3D reconstruction showing a stenosis distal to right bronchial suture in double-lung transplantation.

https://www.journalpulmonology.org/pt-postoperative-surgical-complications-after-lung-articulo-X0873215915856142

Plain CT scan showing subcapsular hematoma over anteromedial surface of transplanted kidney (arrow).

https://www.researchgate.net/figure/Plain-CT-scan-showing-subcapsular-hematoma-over-anteromedial-surface-of-transplanted_fig1_275216694

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BONUS QUESTION #1

A 57 year old female with a history of renal failure now 43 days status post right renal transplant presents to the emergency department with fever, generalized weakness, cough, and diarrhea. She has been taking tacrolimus, mycophenolate, and prednisone as prescribed. Her vital signs are notable for a hr of 101, temperature of 101.1 F. Her labs show a creatinine that has elevated to 1.3 from a prior baseline of 1.0. Based on her presentation which infection is most likely?

Staphylococcus Aureus
Cytomegalovirus
Streptococcus Pneumoniae
Pseudomonas Aeruginosa

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INFECTION

Lifelong immunosuppression is generally required

Impaired Immune response 🡪 minor complaints can signify severe disease

Aggressive ED management 🡪 increased patient survival and graft function

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LIKELY INFECTIONS STATUS POST TRANSPLANT

Often related to transplant procedures
Typical hospital acquired infections

< 1 month

Immunomodulating viruses (CMV, Hep B+C, BK polyomavirus, HHSV6, EBV)
Opportunistic Infections (Pneumocystis, listeria, fungal species)

1-6 months

Healthy w/ functioning graft, slight increase in normal infection risk
Chronic viral disease, susceptible to various viral diseases
Chronic rejection, on high doses of immunosuppression

>6 months

First month= usually related to transplant procedures, stents, catheters, intubation. Hospital acquired pathogens are prominant

CMV in particular is a bad guy, can cause disease in multiple systems especially pneumonitis, and hepatic dysfunction and acute cardiac dysfunction and atherosclerosis, and glomerulopathy

Can be primary or due to reactivation

Typically occurs median 40 days after xplant

Cmv infection risk improving bc aggressive bronchoscopy leads to earlier dx and tx of cmv with ganciclovir and reduces cmv specific immunoglobulin

Active cmv infection can trigger or exacerbate organ rejection

EBV similar to CMV and contributes to immunosuppression and can cause mono like syndrome

EBV is implicated in B cell lymphoproliferative syndrome

6 months

- With healthy functioning graft at over 6 months only slight increase in normal community acquireds like Flu, UTI, pna

Varicella infections can lead to rapid dissemination with pna, pancreatitis, hepatitis, encephalitis, DIC. Those who are varicella-zoster negative will need high doses of varicella zoster immune globulin after any exposure, this can be life saving

The pts over 6 month with chronic rejection on high dose immunosuppression are at some of the highest risk for the life threat infections like candida, crypto, coccidioides, blastomuces, histo, listeria, nocardia, parasites

Fungal infections distinct to geographic areas, typically manifest as subacute respiratory complaints associated with fever and focal, disseminated or miliary infiltrates on cxr

Diverticulitis is the principal GI infection in transplant pts with chronic rejection often lacking peritoneal signs because inflammation is suppressed

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REJECTION

Immune response to allograft waxes and wanes

Ongoing surveillance is required

Infection vs Rejection difficult in ED

Typically requires cultures and biopsies

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HYPERACUTE REJECTION

Rare with matched donor

Timing: immediate perioperative period

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ACUTE REJECTION

Timing: first months or any time if immunosuppressants stopped

Clinical: constitutional symptoms & signs of transplant organ insufficiency

Diagnosis: Labs, allograft biopsy

Treatment: Adjustment of immunosuppressants

Acute rejection can occur from first week to 6 months after transplant as cellular rejection or acute humoral rejection..I guess at a basic level the two ways it occurs are either cellular via T cell mediated or a humoral B cell response…possibly less than 15% of transplant pts these days

Acute celluler

Immuno response in host/recipients lymphoid tissue due to lymphocytes stimulated against donor antigens. The donors dendritic cells enter the recipients circulation 🡪 act as antigen presenting cells

Acute humoral

Also acute vascular rejection
Severe organ injury medicated by antibodies and complement
Antibodies can be pre-exisint or represent anti-donor antibodies shortly after grafting

https://www.cureus.com/articles/123080-classic-and-current-opinions-in-human-organ-and-tissue-transplantation

Acute Cellular Rejection

This is an immunological response in the host's/recipient's lymphoid tissues due to lymphocytes stimulated against donor antigens. The donor's dendritic cells enter the recipient's systemic circulation to function as antigen-presenting cells (APCs) [50,61]. It is common in renal grafts. Acute cellular rejection detection involves biopsy, B-lymphocyte antigen CD20 staining in cases not responding to treatment, negative kidney C4d staining, positive activating lymphocyte markers test, and proteomic study [62]. The first rejection instance is treated with pulse intravenous steroids and may be repeated in cases of recurring or refractory rejections. The second line of treatment (Thymoglobulin and a murine monoclonal antibody, OKT3) may be used for deteriorating grafts. The prognosis depends on the number of rejection episodes, potent drugs, time of rejection from transplantation, and response to treatment [62].

Acute Humoral Rejection

This is also called acute vascular rejection. It is a severe organ transplant injury mediated by antibodies and complement. The antibodies may be pre-existing or represent anti-donor antibodies developing shortly after grafting [63,64]. Willicombe et al. [65] demonstrated that even low donor-specific antibodies titer not detectable with flow cytometry or complement-dependent cytotoxic cross-matches is linked to lower-ranking renal allograft outcomes. Such patients will likely need augmented immunosuppression. Loupy et al. [66] posited a significant swing in the first-year post-graft in the C4d Banff scores, thus proving the humoral process's changing and painless nature of C4d is not a sufficiently sensitive marker. Still, inflammations in the microvessels and spotting of donor-specific antibodies are better markers of humoral rejection.

Chronic Graft Rejection (CGR)

This is also called chronic transplant rejection (CTR). The allograft function is lost several months to years after grafting. Although the graft may still be in place, graft function loss is due to persisting immune system attacks on the allo-MHC. CGR is mediated by humoral as well as cellular immunity. Although immunosuppressants and tissue-typing methods are helpful in the first-year post-graft, CGR is almost always not preventable. It appears to be fibrotic scarring in the grafted organs, although the specific histopathology image depends on the grafted organ [67].

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CHRONIC REJECTION

Timing: Years

Clinical: Gradual failure of transplanted organ

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IMMUNOSUPPRESSION DRUG TOXICITY

Immunosuppressive therapies are carefully balanced

Regimens are center specific

Typically includes: Calcineurin Inhibitor, Anti-metabolite, steroid

Specific drugs and their interactions requires careful consideration

Discuss with transplant team, pharmacy

Calcineurin inhibitors includes tacrolimus and cyclophosphamide

Anti-metabolites includes mycophenolate and azathioprine

Steroids

Cyclosporine

MOA: inhibits cellular and humoral immunity. Binds to cyclophilins 🡪 blocks cytokine transcription 🡪 inhibits lymphocytes 🡪 immunosuppression of helped induced T cells

Toxicities

Dose related nephrotoxicity via renal tubular damage and renal artery vasospasm (which can lead to systemic htn)

Hyperuricemia + gout

P450 inhibitors lead to elevated levels and vice versa

Tacrolimus

MOA: macrolide compound binds to lymphocyte proteins 🡪 inhibits cytokine synthesis

Favorable side effect profile, used as primary or rescue therapy for allograft rejection

Toxicities

Nephrotoxicity

Neurotoxicity

See also: hyperglycemia with steroids, diarrhea, dyspepsia…

Azathioprine

MOA: An antimetabolite derivative of 6-mercaptopurine it inhibits deoxyribonucleic acid and ribonucleic acid synthesis 🡪 lymphocyte suppression

Generally used with other agents, isn’t being used as much because of the calcineurin class

Toxicities: bone marrow toxin, hepatic dysfunction

Mycophenolate Mofetil (MMF)

MOA: selective inhibition of lymphocyte proliferation

Reduces incidence of acute rejection but with no sig changes in long term survival or transplant recipients or their allografts

Side effects: relatively favorable can cause GI side effects and hematologic tox (leukopenia and thrombocytopenia)

Corticosteroids

MOA: suppress immune system specifically T lymphocytes

Long term use side effects: Osteoporosis, cataracts, GI bleeding, glucose intolerance, skeletal myopathies

Acute use: glucose and electrolyte abnormalities

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COMMON AGENTS

Calcineurin Inhibitors

Cyclosporine

Tacrolimus

Antimetabolites

Azathioprine

Mycophenolate Mofetil

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DEFINITIONS

Operational tolerance- long term acceptance of a transplanted organ without definite immunosuppression. Allogeneic bone marrow transplant from the solid organ donor could facilitate operational tolerance

Accommodation- acquired resistance of an organ to immune-mediated damage

Improvement in long term transplantation outcomes may depend on new agents with novel mechanisms of action devoid of toxicities

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CALCINEURIN INHIBITORS

Cyclosporine

MOA: inhibits cellular and humoral immunity. Binds to cyclophilins 🡪 blocks cytokine transcription + production 🡪 inhibits lymphocyte signal production🡪 inhibits lymphocyte signal transduction 🡪 immunosuppression of helped induced T cells (helper T cells enhance antibody recognition and production by B cells)

Toxicities

Dose related nephrotoxicity via renal tubular damage and renal artery vasospasm (which can lead to systemic htn)
Hyperuricemia + gout
P450 inhibitors lead to elevated levels and vice versa

Tacrolimus

MOA: macrolide compound binds to lymphocyte proteins 🡪 inhibits cytokine synthesis
Favorable side effect profile, used as primary or rescue therapy for allograft rejection
Toxicities

Nephrotoxicity
Neurotoxicity
See also: hyperglycemia with steroids, diarrhea, dyspepsia…

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ANTIMETABOLITES

Azathioprine

MOA: An antimetabolite derivative of 6-mercaptopurine it inhibits deoxyribonucleic acid and ribonucleic acid synthesis 🡪 lymphocyte suppression
Generally used with other agents, isn’t being used as much because of the calcineurin class (use recued because cyclosporine's improved side effect profile)
Toxicities: bone marrow toxin, hepatic dysfunction

Mycophenolate Mofetil (MMF)

MOA: selective inhibition of lymphocyte proliferation
Reduces incidence of acute rejection but with no sig changes in long term survival or transplant recipients or their allografts
Side effects: relatively favorable can cause GI side effects and hematologic tox (leukopenia and thrombocytopenia)

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CORTICOSTEROIDS

MOA: suppress immune system specifically T lymphocytes
Long term use side effects: Osteoporosis, cataracts, GI bleeding, glucose intolerance, skeletal myopathies
Acute use: glucose and electrolyte abnormalities

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ANTILYMPHOCYTE MONOCLONAL ANTIBODY PREPARATIONS

OKT3 and antilymphocyte globulin are used to reverse allograft rejection

MOA: monoclonal Ab to T cells
Adverse: chills, fever, hypotension, pulmonary edema, HA, HIGH risk of infection and opportunistic pathogens such as CMV, risk of lymphoproliferative disease

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BONUS QUESTION #2

Which of the following is a false statement regarding cardiac transplant patients?

Atherosclerosis is often accelerated in there patients secondary to viral infections like CMV and drugs like prednisone and cyclosporine
Atropine is not effective in bradycardia due to de-innervation of the vagus nerve
On EKG it is possible to see two p- waves because the native SA node is often left intact
chest pain is the predominant presenting symptom of acute coronary syndrome

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CARDIAC TRANSPLANT PEARLS

Denervation

Denervation of vagus 🡪 baseline tachycardia (100-110) / atropine ineffective
Ischemia presents as CHF, dysrhythmia, hypotension, syncope, arrest

Posterior right atrium with intact native sinus node 🡪 possibly two P waves on EKG

Beta adrenergic receptors are upregulated in the graft

Even without a pericardium, tamponade can occur due to scarring and adhesions (Do not perform blind pericardiocentesis)

Scarring and adhesions can allow build up of pericardial fluid or blood

3000 procedures annually

5 year survival for adults and children is 72% and 80% respectively

Lifelong immunosuppression is required: most centers use three drug regimen (cyclosporine, prednisone, azathioprine

Pred and cyclosporine aggravates hyperlipidemia in many pts

Infection: most vulnerable period for infection is first 3 months when immunosuppression is maximal, in first month nosocomials predominate with usual gram negative and gram positive after first 3 months pts experience overall 20% per year infection, most common is zoster treated with high dose acyclovir. Nausea, vomiting, diarrhea should prompt search for CMV by culture and serologic testing

Any new HA with or without visual changes may be first symptom of meningitis or brain abscess and CT and LP should be done

All hearth transplant pts with fever should e aggressively evaluated unless a minor source of infection such as URI is obvious

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BONUS QUESTION #3

A 6-year-old boy presents to your community ED in Colorado while on a skiing trip with his father with the rash to the right. While performing your HPI the father who is 44 casually mentions he had a cardiac transplant 3 years ago. After treating the boy what do you do?

Nice meeting ya’ll enjoy your ski trip
Recommend the father check in to receive the varicella vaccine and acyclovir
Recommend the father to check in to receive varicella immunoglobulin
Tell the father he needs to monitor for signs of infection and return for treatment if symptomatic

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OTHER CARDIAC NOTES….

Accelerated atherosclerosis caused by CMV, drug tox such as being on pred and cyclosporine

Rejection used to be more obvious now frequent biopsies are performed to monitor success of immunosuppressive therapy throughout patients' life…

Transplanted HR can increase with exercise or stress through exogenous catecholamines up to 70% max for age

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LIVER TRANSPLANT PEARLS

Survival: 1 year 86%, 3 years 76%

Anastomoses

Vessels first, hepatic artery stenosis most common vascular issue occurring early in course
Biliary system reconstructed, often stented with a T tube

Rejection

Is the norm
Commonly 1-2 weeks post op (fever, RUQ pain, elevated bili and transaminases)

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RENAL TRANSPLANT

Survival: 1 year 96%, 3 years 91%

Infection

Pyelo in 45% of pts within 4 months
admit pts with pyelo

Rejection

Acute: lymphocyte driven
Chronic: Nephrosclerosis
Clinical: fever, swelling, tenderness, decreased UOP, increasing creatinine (even subtle increase)
Dx: color flow doppler

Better long-term survival than dialysis! The most successful of the solid organ transplants

Early transplant rejection

US helps rule out obstruction, abscess, vascular thrombosis, perirenal collections of fluid, pus, blood, lymph

Kidney is typically moved into the retroperitoneal area of the anterior pelvis where is may be at risk from direst blows and seat belt injuries, risk if reported as being rare

Infection:

Pyelo in first month…increased risk of sepsis gram post oragnisms associated with wound infections and gram negative are predominant causes

Hep C is most common cause of hepatitis in renal traplsnt pts may be transferrd by blood transfusion or donoro organ because pretransplant ab testing is poor predictor of latent HCV

Rejection: see next slide, routinely long term immunosuppression with azathioprine, prednisone, cyclosporine needed

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RENAL TRANSPLANT REJECTION PATH

Early: t lymphs against donor tissues including cytotoxic cd8 and cd4 cells. Laos b lymphs, NK cells, macrophages infiltrate foreign tissue. B cells make abs that impair perfusion
Chronic rejection: occurs after several years and result of nephrosclerosis. Proliferation of vascular intima of renal vessels 🡪 decrease in lumen size 🡪 systemic hypertension as graft fails from ischemia 🡪 tubular and glomerular atrophy

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LUNG TRANSPLANT

Survival: 1 year 76% alone, 56% with heart

Chest tubes more difficult, more adhesions

Rejection

Expected
Clinical: cough, dyspnea, fever, rales/rhonchi
When occurring over 1 mo 75% of CXR are normal/unchanged

Data does show it benefits functional status, hemodynamics, quality of life. 800 annual in US

Usually unilateral except for cystic fibrosis

Pneumocystitis uncommon due to prophylaxis with Bactrim

There is no published experience with lung injury after transplantation comparison of cxr with preinjury studies is critical in trauma

Rejection: most pts have early rejection and 25-40% hace chronic rejection

Suspected acute rejection is treated with high dose methylprednisolone 500-1000mg/day, this reverses most cases

Infection: transplanted lung highly susceptive to pna bacuase they can be colonized by bacteria during ventilator stage of brain dead donor after transplant – diminished mucociliary clearance, decreased cough reflex due to decreased innervaion, and defective macrophages are present

Predominant bacteria are pseudomonase, staph aureus. Abx should be directed towards culture from tracheobronchial tree. PCP uncommoun due to routine Bactrim prophylaxis

Cmv is most common opportunisitic pulmo infection after lung transplant . Pts highest risk between 3 weeks and 4 months. It closely mimic rejecition. Tissue bx and rial cx required

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LUNG TRANSPLANT ADDITIONAL

Acute rejection tx’ed wit high does methylprednisolone 500-1000mg/day.

Chronic leading cause of morbid/mortality. Path shows vascular sclerosis and limitation to airflow from obliterative bronchiolitis

Transplanted lungs with decreased mucocilliary clearance, decreased cough reflex, defective function of alveolar macrophages more susceptible to bacteria

Cmv infection resembles transplant rejection

Candida colonization common, asperigillus also possible. They are invasive and can cause bronchiolitis obliterans syndrome by inflammation and obstruction of bronchioles

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PANCREAS TRANSPLANT

Singly or with kidney usually secondary to DM

1 year graft survival is 72%

Anatomical and Physiologic changes

Exocrine functions of the pancreas are drained into the bladder
Pancreas is placed in pelvis overlying iliacs = trauma concern
Bicarb is drained in urinary system = chronic non anion gap acidosis

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BONUS QUESTION #4

A 49 year old male with a history of renal transplant on immunosuppression presents to the emergency department with fever and cough. His symptoms have worsened over the past week and he is now short of breath at rest. His temperature is 102 F, BP 135/98, HR is 122, RR is 22, and oxygen saturation is 89% on room air. Which of the following medications will treat the most likely etiology of his symptoms?

Trimethoprim-Sulfamethoxazole
Rifampin, Isoniazid, Pyrazinamide, and ethambutol
Amphotericin
Vancomycin

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SUMMARY

Differential diagnosis includes anatomical complications, rejection, infection, drug toxicity

Carefully consider drug interactions and toxicity

Clinical signs and symptoms of failure can subtle requiring careful and broad work-ups

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QUESTIONS, COMMENTS?

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REFERENCES

Marx, John, Robert Hockberger, and Ron Walls. Rosen's Emergency Medicine-Concepts and Clinical Practice E-Book: 2-Volume Set. Elsevier Health Sciences, 2013.

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Quiz

https://docs.google.com/forms/d/e/1FAIpQLScofUjlTyf6gkOevtVz39tYmYzs_8E7Gr9KH5xAfGWLozrS5Q/viewform?usp=sf_link