Transcript
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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e
Chapter 297: The Transplant Patient J. Hayes Calvert
INTRODUCTION
As of the beginning of 2013, there were 76,047 active candidates waiting for solid-organ transplants in the United
States, with the kidney transplant waitlist being the largest at 57,903 candidates.1 The kidney is the mostcommonly transplanted organ (58%), followed by liver (21%), heart (8%), lung (5%), pancreas (5%), and, lesscommonly, combined organ transplants and intestine transplants. Annually, there are around 18,000hematopoietic stem cell transplants in the United States, with about one third of these transplants being allogenic
transplants and two thirds being autologous transplants.2
Most transplant patients require lifelong immunosuppression. Transplant patients can develop a number of acuteto life-threatening emergencies, including (1) transplant-related infection, (2) medication side e�ects, (3) rejection,(4) gra�-versus-host disease, and (5) postoperative complications or complications of altered physiologysecondary to the transplanted organ. Transplant patients may also have common medical problems that requireunique management. Adverse outcomes o�en are directly proportional to increasing age of the recipient and the
donor organ.3
The most common acute disorders prompting ED visits are infection (39%) followed by noninfectious GI/GUpathology (15%), dehydration (15%), electrolyte disturbances (10%), cardiopulmonary pathology (10%) or injury
(8%), and rejection (6%).4,5,6,7 Acute gra�-versus-host disease is an important complication, especially in those
with hematopoietic stem cell transplantation.8 Coronary artery disease, sudden cardiac death, and heart failureare results of premature cardiovascular disease in solid-organ recipients, due to underlying comorbidities and
metabolic e�ects of immunosuppression.9 Preoperative and regular postoperative cardiovascular assessment
identifies risk factors and enables treatment to mitigate risk e�ects.10
GENERAL APPROACH TO EVALUATION
HISTORY AND COMORBIDITIES
Key historical elements for the management of transplant patients are listed in Table 297-1.
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TABLE 297-1
Key Historical Elements Specific to Transplant Patients
Historical Item Significance
Recent temperature increase or decrease from baseline Potential clue to onset of infection or rejection.
Changes from baseline function Decreased urine may signify rejection in renal
transplant patients or acute dehydration.
Decreased exercise tolerance may signify rejection in
heart transplant patients.
Change in skin color (jaundice specifically) may signify
rejection in liver transplant patients or gra�-versus-
host disease.
Date of transplant surgery The date from transplant helps to predict typical
infections and types of posttransplant complications
(i.e., gra�-versus-host disease).
Gra� source for solid-organ transplant, special features
of gra� if any, prior infections; donor living related vs
cadaveric
These details predict the potential for certain
infections and rejection.
Gra� source for hematopoietic stem cell transplant:
autologous, degree of match, related donor
These details predict potential gra�-versus-host
disease.
Rejection history May predict current rejection if similar presentation
and di�iculty in controlling a current episode of
rejection.
Recent changes in dosages of antirejection and other
medications
Although a planned part of transplant management,
rejection is very common when immunosuppression
doses are reduced.
Chronic infections (CMV, Epstein-Barr virus, hepatitis B
and C, other viruses)
History of chronic infections increases the chances
that current presentation is an exacerbation.
Recent exposure to infections (chickenpox, CMV,
tuberculosis)
Increases the chance of current infection.
Recent history of compliance with immunosuppressive
medications
Noncompliance increases chance of rejection.
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Abbreviation: CMV = cytomegalovirus.
Historical Item Significance
Recent travel, exposure to persons arriving from
countries with endemic infections, exposure to potential
foodborne illness or insect vectors
Exposure may predict unusual infections not
commonly considered.
Complete list of all medications, including over-the-
counter medication
Complex drug interactions are common causes of
symptoms in transplant patients and must be
evaluated.
Baseline: blood pressure, body weight, serum creatinine
(for renal transplants), and expected levels of
immunosuppressive medication
Changes in these parameters may predict rejection or
acute illness.
PHYSICAL EXAMINATION
Direct the physical examination to the chief complaint, present illness, and evidence of complications of the
transplant or immunosuppressive medications (Table 297-2).4,5,6,7,8,11,12
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TABLE 297-2
Physical Examination in Transplant Patients
Examination Comments
Volume status Check static vital signs, orthostatic blood pressures, and pulse. Use US to assess inferior vena
cava diameter as a measure of intravascular volume status.
Head, ears, eyes,
nose, and throat
Periorbital edema (glomerulonephritis), retina (CMV or toxoplasmic chorioretinitis, Listeria
endophthalmitis), sinuses (Staphylococcus aureus, mucormycosis, and invasive fungal
disease), mouth (Candida, HSV), neck (meningismus, retropharyngeal abscess),
lymphadenopathy (CMV, EBV, hepatitis, posttransplant lymphoproliferative disorder).
Lungs Pneumonia is a common source of infections in transplant patients. Streptococcus
pneumoniae and other community-acquired agents are still common sources, but
opportunistic infections, such as Pneumocystis jiroveci pneumonia, Aspergillus, tuberculosis,
coccidioidomycosis, and viral pneumonias should be suspected. Noninfectious pulmonary
infiltrates may also cause dyspnea.
Heart Pericardial friction rubs as a complication of uremia and a wide range of viral infections. New
heart murmur can represent infection.
Abdomen Peritonitis without a defined source is one of the most common sites for infection in transplant
patients. Right upper quadrant tenderness associated with hepatitis B and C, CMV, and EBV.
Varicella-zoster virus causes pancreatitis. If le� in place, peritoneal dialysis catheters can be
sources of infection.
Flank and
suprapubic area
The urinary tract was the most common site of infection identified.
Gra� Renal gra� usually placed in abdominal flap; inspect (look for signs of wound infection),
palpate (gra� tenderness and swelling are o�en seen in acute rejection, outflow obstruction,
and pyelonephritis), and auscultate (bruits suggest renal artery stenosis and AV malformation
or AV fistula). Deep tenderness over liver gra� could indicate abscess.
Rectal Perirectal abscess is a common, yet o�en overlooked, source of infection in transplant
patients.
Extremities Access sites for hemodialysis can be sources of infection. Peripheral edema in the transplant
patient can represent a number of di�erent etiologies: recurrent versus de novo
glomerulonephritis, renal gra� failure, liver gra� failure, cirrhosis, nephrotic syndrome (from
native kidneys), renal vein thrombosis, malnutrition, hypoalbuminemia, and heart failure.
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Abbreviations: AV = atrioventricular; CMV = cytomegalovirus; EBV = Epstein-Barr virus; HSV = herpes simplex virus.
Examination Comments
Skin Rashes are commonly seen in gra�-versus-host disease, viral syndromes (hepatitis B and EBV),
cellulitis from indwelling catheter sites, nocardial cutaneous lesions, and drug reactions.
Mental
status/neurologic
examination
Cyclosporine/tacrolimus neurotoxicity, steroid psychosis, HSV encephalitis, Listeria
meningitis/encephalitis, and cryptococcal meningitis.
DIFFERENTIAL DIAGNOSIS
Consider complications of immunosuppressive medication, infection, solid-organ rejection, and gra�-versus-hostdisease (Tables 297-3 and 297-4). Chronic immunosuppressant medications, including corticosteroids, cause awide range of physical changes evident on physical examination. Medication changes should be made by, or inconsultation with, the patient's transplant team. Outpatient or inpatient management depends on the severity ofillness; the need for ongoing immunosuppression o�en requires admission when symptoms interruptmaintenance of medication.
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TABLE 297-3
Adverse Reactions to Immunosuppressant Medications
Body System Adverse E�ects
Constitutional Fever, rigors, malaise, dizziness, anorexia
Ophthalmologic Blurred vision, conjunctivitis, cataracts, papilledema, blindness
Mouth/ears Gingival hyperplasia, stomatitis, hearing loss, tinnitus
Respiratory Cough, dyspnea, interstitial lung disease, pneumonitis, pleural e�usion, noncardiogenic
pulmonary edema
Cardiovascular Hypertension, tachycardia, bradycardia, cardiomyopathy, congestive heart failure, hypotension,
syncope
GI Nausea, vomiting, diarrhea, epigastric pain, esophagitis, gastritis, hiccups, constipation,
hepatotoxicity, ascites, pancreatitis, colonic necrosis, bleeding
Musculoskeletal Myopathy, osteoporosis, tendon rupture
Hematologic Neutropenia, lymphopenia, anemia, thrombocytopenia, bleeding, thrombosis
Renal Nephrotoxicity, oliguria, dysuria, renal failure
Neurologic Headache, vertigo, paresthesias, tremors, convulsions, agitation, neuropathy, confusion,
generalized weakness, leukoencephalopathy, encephalopathy, cerebral edema
Skin Alopecia, hirsutism, thickening, thinning, necrosis, edema
Metabolic Electrolyte disturbances (sodium, potassium, calcium, magnesium, phosphorus), fluid
retention, hypercholesterolemia, hyperlipidemia, hyperglycemia, hypoglycemia
Endocrine Adrenal suppression
Immunogenic Susceptibility to infection, acute allergic reactions, anaphylaxis
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TABLE 297-4
Physical Examination Clues to Complications of Medications and Gra�-versus-Host Disease
Concern Signs and Symptoms
Edema and other
swelling
Assess symmetry, pain, color, temperature, and active range of motion. Suspect infection,
orthopedic conditions, deep vein thrombosis (due to immobility).
Skin breakdown The back, pressure points, heels, elbows, and leg ulcers (due to corticosteroid-induced
weakness).
Joint range of
motion
Shoulders, elbows, fingers, wrists, and knees (may be limited due to steroid-induced weakness
or sclerodermatous skin changes).
Thoracic
constriction
Relatively noncompliant edema like swelling on the chest wall. If present, ask about
associated dyspnea on exertion.
Abdominal
constriction
Firm skin. History of bloating, gas, constipation, diarrhea, nonspecific pains.
Sclerodermatous
skin
Sclerodermatous skin changes can a�ect joint mobility and GI and respiratory function. Note
the firmness of edema and skin, especially on the thorax and around joints. A firm, so� leather
consistency of swelling, tougher than cardiogenic pitting edema, can be a serious problem.
Assess for recent-onset dyspnea on exertion.
Dehydration Increased thirst, loss of appetite, chills, fatigue, weakness, skin flushing, dark or decrease
volume of urine, dry mouth, tachycardia, weight loss.
Electrolyte
disturbance
Signs and symptoms of dehydration above, hypotension, headache, bradycardia or
tachycardia, irregular heartbeat, tremor, muscle weakness, increased urination, constipation,
altered tendon reflexes, mood changes, abdominal pain, weight loss, muscle cramping.
Solid-organ rejection and gra�-versus-host disease are immune-medicated inflammatory reactions that maypresent with fever, signs and symptoms, and laboratory and radiographic findings that resemble infection.Infection and rejection (or an exacerbation of gra�-versus-host disease) can occur simultaneously, and treatmentshould be started for both. When suspecting acute rejection or acute gra�-versus-host disease, consult thetransplant team about treatment. Typically, high-dose corticosteroids are given, but the steroid, the dose, and theduration of therapy should be confirmed.
POSTTRANSPLANT INFECTIONS
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Infections account for a large number of deaths in transplant patients, with many undiagnosed until autopsy. Viraland bacterial illnesses may occur concurrently. Febrile episodes in the early phase a�er allogenic stem celltransplantation are likely related to infections secondary to neutropenia. Immunosuppression-induced blunting ofthe inflammatory response may mask the classic signs, symptoms, and laboratory markers of infection if thepatient presents early in the course of the illness. Later in the course of infection, patients may present with moreadvanced ominous signs such as seizure, obtundation, coma, and cardiac arrest.
CLINICAL FEATURES
The most common reason for an ED visit by a transplant recipient is fever.4,5,6,7 Fever may be masked byimmunosuppressive agents and other factors such as steroids, uremia, and hyperglycemia, and may be absent in
half of those with infection.5 Fever may be due to factors other than infection, such as drug e�ects,hypersensitivity reaction, rejection, or malignancy. Fever in a transplant patient should prompt an aggressiveworkup, even if low grade.
Signs and symptoms of infection depend on the type of infection and can, in part, be predicted by the time frame
since the transplant (Table 297-5).13 Combining all posttransplant period groups, urinary tract infections (43%)
and pneumonia (23%) are likely to be the most common infections.11 In contrast, a study of 238 ED presentationsof febrile pediatric heart transplant patients found pneumonia in 24%, bacteremia in 3%, cellulitis in 2%, and
urinary tract infection in 1%; the majority had a negative workup.12
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TABLE 297-5
Infections Stratified by Posttransplant Period
Period a�er
Transplant/ConditionsInfection Comments
<1 mo: resistant
organisms
MRSA
Vancomycin-resistant
Enterococcus faecalis
Candida species
(including non-
albicans)
Opportunistic infections are generally absent during this
period as full e�ect of immunosuppression not complete.
MRSA important in HSCT patients.
<1 mo: complications
of surgery and
hospitalization
Aspiration
Catheter infection
Wound infection
Anastomotic leaks and
ischemia
C. di�icile colitis
Clostridium di�icile common during this period. Early gra�
injuries may abscess. Unexplained early signs of infection such
as hepatitis, encephalitis, pneumonitis, or rash may be donor
derived.
<1 mo: colonization of
transplanted organ or
HSCT neutropenia
Aspergillus
Pseudomonas
Klebsiella
Legionella
Microbiologic analysis of aspirates or biopsy from surgery
essential for therapeutic decisions.
<1 mo: HSCT-specific
infections
Additional bacterial
pathogens:
Streptococcus
viridans and
enterococci
Viral infections
include respiratory
syncytial virus and
HSV
Neutropenia and mucocutaneous injury increase risk for HSCT
patients. Lungs, bloodstream, and GI tract most commonly
a�ected sites.
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Period a�er
Transplant/ConditionsInfection Comments
1–6 mo: in patients
with Pneumocystis
jiroveci pneumonia
and antiviral (CMV,
HBV) prophylaxis
Polyomavirus BK
infection,
nephropathy
C. di�icile colitis
HCV infection
Adenovirus infection,
influenza
Cryptococcus
neoformans infection
Mycobacterium
tuberculosis infection
Anastomotic
complications
Activation of latent infections, relapse, residual, and
opportunistic infections occur during this period. Viral
pathogens and allogra� rejection cause the majority of febrile
episodes during this period. Polyomavirus BK, adenovirus
infections, and recurrent HCV are becoming more common.
1–6 mo: in patients
without prophylaxis
Pneumocystis
Infection with
herpesviruses (HSV,
varicella-zoster virus,
CMV, Epstein-Barr
virus)
HBV infection
Infection with Listeria,
Nocardia,
Toxoplasma,
Strongyloides,
Leishmania,
Trypanosoma cruzi
Discontinuation of prophylaxis at the end of this period may
prompt active infection, especially CMV. Gra�-versus-host
disease and mucocutaneous injury increase risk for HSCT
patients.
>6 mo: general Community-acquired
pneumonia and
urinary tract
infections
Infection with
Aspergillus, atypical
molds, Mucor species
Infection with
Nocardia,
Rhodococcus species
Community-acquired organisms dominate during this period.
Transplant recipients have a persistently increased risk of
infection due to community-acquired pathogens.
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Abbreviations: CMV = cytomegalovirus; HBV = hepatitis B virus; HCV = hepatitis C virus; HSCT = hematopoietic stem cell
transplant; HSV = herpes simplex virus; MRSA = methicillin-resistant Staphylococcus aureus; PTLD = posttransplantation
lymphoproliferative disorder.
Period a�er
Transplant/ConditionsInfection Comments
>6 mo: late viral
infections
CMV infection (colitis
and retinitis)
Hepatitis (HBV, HCV)
HSV encephalitis
Community-acquired
viral infections (severe
acute respiratory
syndrome, West Nile)
JC polyomavirus
infection (progressive
multifocal
leukoencephalopathy)
Skin cancer,
lymphoma (PTLD)
In some patients, chronic viral infections may cause allogra�
injury (e.g., cirrhosis from HCV infection in liver transplant
recipients, bronchiolitis obliterans in lung transplant
recipients, accelerated vasculopathy in heart transplant
recipients with CMV infection) or a malignant condition such as
PTLD or skin or anogenital cancers.
DIAGNOSIS AND TREATMENT
The evaluation should include routine testing as well as additional tests based on complaint, history, and physical
examination (Table 297-6).14
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TABLE 297-6
Diagnostic Tests to Consider in the Evaluation of Infections in the Transplant Patient
Test Comments
CBC Leukocytosis or le� shi� of the WBC count may be blunted by immunosuppressive
agents.
Renal function tests:
BUN, creatinine
Essential in the evaluation of renal transplant patients, may help determine dosing of
antibiotics in all transplant patients.
Liver function tests May show mild transaminase elevations with cytomegalovirus and Epstein-Barr virus
infections, and much higher elevations with hepatotropic viruses such as hepatitis B and
C viruses. May be elevated in Legionella infections.
C-reactive protein Significant elevations more likely in infections versus noninfectious infiltrates.
Procalcitonin level Significant elevations more likely in infections versus noninfectious infiltrates.
CT of the brain Focal infections in the brain are much more common in this population, but CT should
be used only as clinically indicated.
Cyclosporine or
tacrolimus level or
other levels of
immunosuppressants
These levels may be deliberately low depending on the desired level of
immunosuppression. Bioavailability may be variable.
Cultures of mouth,
sputum, urine, blood,
stool, vascular access,
and wound sites
Collect as indicated by history and physical. Urine Legionella antigen should be
considered before treatment of patients with pneumonia with GI complaints. Bacterial
and fungal cultures of blood and urine should be obtained on all patients.
Cerebrospinal fluid
cultures and antigen
tests
Collect as indicated by history and physical.
Serology:
cytomegalovirus,
Epstein-Barr virus,
hepatitis,
toxoplasmosis,
cryptococcosis
Because viral and fungal cultures are not very sensitive, clinicians should rely on their
acumen to order organism-specific antigen assays and antibody titers. When
contemplating viral or parasitic infections, these tests should be obtained to allow
identification of bacterial, fungal, and viral pathogens.
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Test Comments
Chest radiograph Infiltrates on chest radiograph may reflect infectious or noninfectious complications of
hematopoietic stem cell transplant or organ transplant.
CT of the chest Patients with evidence of pulmonary infiltrates on chest x-ray or high-resolution CT, but
without productive sputum, may ultimately require bronchoscopy with bronchoalveolar
lavage and transbronchial biopsy for definitive diagnosis.
CT or US to include the
gra�
These scans can be used to identify likely abscess formation or possible anastomotic
leaks.
Tests a�er admission Beyond the scope of this chapter, but may include biopsy of the transplanted organ,
bronchoalveolar lavage on bronchoscopy, and focused imaging of suspected sites of
infection.
Creatine kinase May have increased levels in infections with certain organisms, such as Legionella.
Leukopenia can represent acute bacterial infection,5 and leukopenia with an increase in atypical lymphocytes iscommonly seen with viral infections, especially cytomegalovirus. Pulmonary infections that are encounteredfrequently include Pneumocystis jiroveci, Nocardia, Legionella pneumophila, and Aspergillus; these requirespecial stains and studies for accurate diagnosis.
Treatment recommendations should be determined by careful analysis of each individual patient for potentialatypical infections requiring specific coverage. Empiric antimicrobial therapy for transplant patients is outlined in
Table 297-7.15,16,17 Empiric treatment prior to confirmatory studies centers first on antibacterial agents, and then,especially if there is concern for meningitis/encephalitis, on antiviral agents such as acyclovir. Discuss treatmentof suspected fungal infections or atypical infections with the transplant team.
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TABLE 297-7
Empiric Antimicrobial Therapy
Condition Antimicrobial Agent Comments*
All patients Discuss agent(s) with
transplant team.
The transplant team caring for the patient should always be consulted as
soon as possible; however, in certain life-threatening situations, empiric
broad-coverage therapy may be indicated immediately.
Suspected
infection
site based
on history
and physical
examination
Site-specific agents
are preferable if
predicted by initial
findings, balanced by
known pathogens as
listed in Table 297-5.
The urgency for treatment should be based on the patient's presenting
condition; bacterial infections are the most aggressive organisms
requiring coverage, but some fungal infections may yield sepsis. In
general, broad coverage for any suspected site infection is recommended
initially pending cultures and further workup to define noninfectious
causes of fever.
Neutropenia
in the
absence of
symptoms
suggesting
site-specific
infection
Third-generation
cephalosporin such
as ce�azidime or a
carbapenem plus
coverage for MRSA
below.
Multiple alternative agents used, including an aminopenicillin plus a β-
lactam inhibitor such as piperacillin-tazobactam or cefepime.
Monotherapy has fewer complications, but concern for MRSA remains
high. Addition of antiviral and antifungal agents should be at the
discretion of the transplant team.
Suspected
MRSA
Vancomycin In the majority of patients, MRSA infection should be seriously considered
as a potential cause of infection, pending cultures. Linezolid is an
alternative antibiotic.
Parasitic
infections
Trimethoprim-
sulfamethoxazole
a�er discussion with
transplant team
Consider Toxoplasma gondii, Pneumocystis jiroveci.
Viral
infections
Ganciclovir or
valganciclovir for
CMV, acyclovir for
herpes simplex and
varicella-zoster
Consider treatment for CMV pneumonia, CMV chorioretinitis, CNS or
disseminated herpes simplex or varicella-zoster.
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Abbreviations: CMV = cytomegalovirus; MRSA = methicillin-resistant Staphylococcus aureus.
*Standard doses apply but may be altered by transplant team recommendations.
Condition Antimicrobial Agent Comments*
Fungal
infections
Discuss with
transplant team;
agent depends on site
and severity of illness
Consider Aspergillus, Candida albicans, Cryptococcus neoformans.
GRAFT-VERSUS-HOST DISEASE
Gra�-versus-host disease is a major cause of morbidity and mortality a�ecting approximately 50% of allogeneic
hematopoietic stem cell transplantation patients,18 but it also occurs a�er small bowel or liver transplantation.19
Hyperacute gra�-versus-host disease is an unusual and severe form of acute gra�-versus-host disease. Onsetoccurs in the first week a�er hematopoietic stem cell transplantation and is characterized by fever, generalized
erythroderma, severe hepatitis, fluid retention, widespread inflammation, and shock.20
Acute gra�-versus-host disease is classified as appearance of the disease up to 100 days a�er transplant. A well-appearing hematopoietic stem cell transplantation recipient with a nonspecific rash (most common symptom) ordiarrhea (second most common symptom) should be suspected of having new-onset or an exacerbation of gra�-
versus-host disease.20 The most widely used gra�-versus-host prophylaxis includes a combination of a calcineurin
inhibitor (e.g., cyclosporine, tacrolimus) with methotrexate.20 In patients who recover from acute gra�-versus-hostdisease, later long-term complications from chronic gra�-versus-host disease are common.
Chronic gra�-versus-host disease is a late complication characterized by immune dysregulation.21 It results insevere morbidity, with complications a�ecting skin (sclerodermatous contractures), muscles (myopathy), bone
(osteoporosis), nerves (peripheral neuropathy), and the cardiopulmonary system (physical deconditioning).22
ACUTE GRAFT-VERSUS-HOST DISEASE
Consider gra�-versus-host disease in any patient with a rash. Rash is o�en misattributed as a drug reaction. Thetypical rash is maculopapular, frequently demonstrating a brownish hue and slight scaling (Figure 297-1). The rashcan be pruritic and painful. The distribution varies greatly but o�en a�ects palms and soles initially, and laterprogresses to cheek, ears, neck, trunk, chest, and upper back. In the more severe forms, erythroderma or bullae
develop.8 Mucositis has been reported to occur in 35% to 70% of patients.
FIGURE 297-1.
Rash of acute cutaneous gra�-versus-host disease. The maculopapular lesions have acquired a brownish hue, andthere is slight scaling. [Reproduced with permission from Wol� KL, Johnson R, Suurmond R: Fitzpatrick's Color
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Atlas & Synopsis of Clinical Dermatology, 6th ed. © 2009, McGraw-Hill, New York.]
Diarrhea, GI bleeding, or hepatic dysfunction can occur. Diarrhea, with or without upper GI symptoms such asanorexia, nausea, and emesis, is common. Symptoms include painful cramping, ileus, and, sometimes, life-threatening hemorrhage from the colon. Hepatic involvement is characterized by increase in liver function studies.GI hemorrhage in the early posttransplant period may be a result of coagulation abnormalities, especiallythrombocytopenia. The di�erential diagnosis of GI bleeding in this setting includes all the usual causes of GIbleeding in addition to bleeding due to acute gra�-versus-host disease–related damage to colonic tissues and
infection (viral, fungal, or bacterial).18,23 Diagnosis requires endoscopy.
Treatment is directed by the transplant team, typically PO prednisone or IV methylprednisolone, at 1 to 2
milligrams/kg daily, and possibly adjustment of other immunosuppressant doses.8
Disposition and interval for follow-up are also determined by the transplant team.
TRANSFUSION-ASSOCIATED GRAFT-VERSUS-HOST DISEASE
Most living cells that are in transfused blood survive for no more than a few days or weeks. However, in somepatients, transfused cells engra�, expand, and circulate. When immunocompetent T lymphocytes engra� in animmune-suppressed patient, transfusion-associated gra�-versus-host disease may occur and is almost always
fatal.24,25 It is possible to avoid transfusion-associated gra�-versus-host disease by irradiating blood productsbefore transfusion. Patients with immunocompromise or other risk factors (Table 297-8) should receive irradiatedblood products.
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TABLE 297-8
Significant Risk Factors for the Development of Transfusion-Associated Gra�-versus-Host Disease
Congenital and acquired immunodeficiency syndromes
History of bone marrow (stem cell) transplantation, whether allogeneic or autologous
Transfusions from blood relatives ("directed donation")
Transfusions with fresh whole blood
Premature infants receiving any sort of transfusion
Human leukocyte antigen–matched platelet transfusions
Hodgkin's disease, even when in remission
Leukemia not in remission
Patients treated with purine analogs; the e�ects of fludarabine and cladribine (2-CdA) persist for a year
SPECIFIC TYPES OF TRANSPLANTATION
RENAL TRANSPLANTATION
Renal transplantation is the preferred treatment for end-stage renal disease. Vascular complications that occurfollowing renal transplantation include renal artery stenosis, allogra� infarction, arteriovenous fistulas,pseudoaneurysm, and renal vein thrombosis. Nonvascular complications include ureteral obstruction, urine leak,periallogra� fluid collections (hematomas, lymphoceles, and abscesses), neoplasms, GI complications, and
posttransplant lymphoproliferative disease.26 The major causes of renal transplant loss are death from vascular,malignant, or infectious disease, and loss of the allogra� from chronic renal dysfunction associated with thedevelopment of gra� fibrosis and glomerulosclerosis. Medication changes, as well as imaging contrast agent usethat may a�ect renal function (including gadolinium-based contrast agents), should be discussed with thepatient's transplant team.
DIAGNOSTIC TESTING
Table 297-6 lists recommendations on diagnostic testing in transplant patients, including renal transplantpatients. The serum creatinine level is the most valuable prognostic marker of gra� function at all times a�ertransplantation and should be obtained whenever renal failure or infection is suspected. The urinalysis providesimportant clues to acute changes in gra� viability. Red blood cell casts and proteinuria are commonly seen inrecurrent or de novo glomerulonephritis. The presence of WBCs, bacteria, and nitrites is helpful in diagnosingurinary tract infections. Proteinuria may signal rejection, drug toxicity, glomerular disease, or other gra�nephropathy, although proteinuria from a remaining native kidney should also be considered. Obtaincyclosporine or tacrolimus blood levels for all patients on these medications. Contact the patient's transplantteam regarding abnormal drug levels, because low drug levels are sometimes deliberately used to reduce sidee�ects.
IMAGING
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Ultrasonography is the best test to detect urinary obstruction. Renal gra� ultrasonography can also be useful inpatients suspected of having pyelonephritis, vascular abnormalities (stenosis, thrombosis, pseudoaneurysm, andarteriovenous fistula), perinephric abscess, urine leak, wound infection, or an episode of rejection.
MRI can be helpful in evaluating hematomas and other fluid collections, vascular abnormalities, and small infarctscaused by medication-induced vasculitis. Magnetic resonance angiography has the advantage of requiring eitherno contrast material or a gadolinium chelate that is less nephrotoxic than other agents. However, gadolinium-based contrast agents can cause acute renal failure in up to 3.5% of patients with underlying chronic renal
insu�iciency.27 Therefore, the patient's transplant team should be consulted before using gadolinium-basedcontrast agents.
GRAFT DYSFUNCTION AND FAILURE
Chronic renal dysfunction precedes the majority of gra� failures. Acute renal failure in transplant patients isdefined as a 20% rise from baseline serum creatinine levels, as opposed to a 50% rise in other patients with acuterenal failure. Consider the conditions described in Table 297-9 when evaluating possible gra� dysfunction or even
a small increase in serum creatinine.28,29
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TABLE 297-9
Di�erential Diagnosis of Renal Allogra� Dysfunction
Deferential Disorder Comments
Mechanical At ultrasonography, a urine leak (i.e., urinoma) appears as a
well-defined, anechoic fluid collection with no septations
that increases in size rapidly. Complications of surgery
Ureteral obstruction
Urine leak: urinoma, ascites, or abscess
Vascular The transplanted kidney is usually placed extraperitoneally
in the right iliac fossa. End-to-side anastomosis to the
external iliac vasculature provides circulation. Color duplex
imaging of the renal artery and vein is helpful in assessing
renal vascular stenosis or thrombosis.
Renal artery stenosis or thrombosis (12%)
Renal vein thrombosis
Renal artery and renal vein thrombosis are
uncommon; they usually occur in the first month
a�er transplant.
Glomerulonephritis
Infection Urinary tract infections are the most common source of
bacteremia in renal transplant recipients, and infectious
diseases are the second leading cause of death in this
population. See "Posttransplant Infections" section.
Urinary tract infection
Interstitial nephritis from polyoma BK virus,
cytomegalovirus, herpes viruses 1 and 2, and
adenovirus
Rejection Most common presentation of rejection in renal transplant
patients is hypertension and falling urine output.
Comparison of creatinine at the time of presentation to
prior levels is critical. Fever may be a presentation for
rejection.
Hyperacute
Acute
Late (recurrent acute)
Chronic cellular
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Deferential Disorder Comments
Chronic humoral
Recurrent pyelonephritis/vesicoureteral reflux —
Nephrotoxic agents Drug serum levels do not correlate well with the degree of
renal damage. Nonsteroidal anti-inflammatory drugs are
contraindicated in this group. Avoid contrast agents if
possible.
Aminoglycosides, fluoroquinolones, cidofovir,
foscarnet, sulfonamides, calcineurin inhibitors
(cyclosporin A and tacrolimus), nonsteroidal anti-
inflammatory drugs, gadolinium-based and some
other contrast agents, herbal preparations
Noncompliance with Diabetes o�en follows transplantation; marked
exacerbations in hypertension are frequently associated
with gra� failure. Medications
Management of risk factors such as diabetes and
hypertension
Chronic allogra� nephropathy —
LIVER TRANSPLANTATION
The most common reasons for ED visits are fever and abdominal pain.6 Complications include bleeding, rejection,and infection, as well as biliary, vascular, and wound complications. Bacterial infection may accompany acute
rejection.30 Specific complications of liver transplantation are listed in Table 297-10. Obtain a CBC with plateletcount and di�erential; serum chemistries, including electrolytes, BUN, creatinine, basic coagulation studies, liverfunction tests, amylase, and lipase levels; and cultures of blood, urine, bile, and ascites. Radiographic testing asindicated may include chest x-ray and abdominal ultrasonography with Doppler flow studies. US with Doppler canidentify fluid collections, thrombosis of the hepatic artery or portal vein, and dilatation of the biliary tree(although the absence of biliary dilatation does not exclude obstruction or other posttransplantation pathology).With partial obstruction, the intrahepatic ductal system o�en does not appear to be dilated appreciably by US.With complete obstruction, duct dilation is usually seen. Patients o�en require cholangiography for completeevaluation. Patients with choledochocholedochostomy may be best evaluated by endoscopic retrogradecholangiopancreatography because it permits both a radiographic diagnosis and the potential for nonoperativeintervention. Patients with a Roux-en-Y hepaticojejunostomy or those who cannot have endoscopic retrogradecholangiopancreatography must undergo percutaneous cholangiography. Early, broad-spectrum prophylacticantibiotics should be administered before any biliary tract manipulation. Discuss treatment and disposition withthe transplant team.
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TABLE 297-10
Complications of Liver Transplantation
Complication Comments
Bleeding
complications
GI bleeding should be managed in the usual fashion but may signal gra� dysfunction.
Biliary
complications
Bile leaks present early and biliary strictures present late (>2 mo from transplant). In both cases,
cholestatic liver enzymes are elevated, typically with right upper quadrant pain (more
pronounced with bile leak).
Bile leak
Biliary
stricture
Hepatic artery
complications
CT with contrast (if renal function adequate) or US is helpful in the evaluation of these conditions.
Hepatic
artery
thrombosis
Hepatic
vein
thrombosis
Portal vein
complications
Rejection Early alkaline phosphatase and bilirubin levels rise, followed by a rise in aspartate
aminotransferase and alanine aminotransferase.
Neurologic
complications
Causes include hemorrhage, cerebrovascular infarct, cerebral abscess, hypertensive
encephalopathy, osmotic demyelination syndrome, and sinus thrombosis. MRI is best for
evaluation.
Malignancy Increased risk for squamous cell carcinoma, lymphomas, and posttransplant lymphoproliferative
disorder.
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LUNG TRANSPLANTATION
Fever, cough, and increasing dyspnea are common reasons for ED visits in lung transplant patients. Importantclinical features to note are the respiratory rate, pulse oximetry measurement, and physical findings of cyanosis,diaphoresis, use of accessory muscles, signs of congestive heart failure, and adequacy of peripheral perfusion.Obtain a chest radiograph and arterial blood gas analysis when adequacy of ventilation is in question. Give β2-
agonists and anticholinergics as indicated. Signs of infection o�en overlap with the signs and symptoms ofrejection, and the management of infection is quite di�erent from that of rejection. A drop in the forced expiratoryvolume in 1 second of >10% warrants clinical investigation, but pulmonary function testing cannot distinguishbetween acute rejection, infection, and nonimmunologic causes of respiratory dysfunction such as airway
stenosis.31 Therefore, bronchoscopy is required for specific diagnosis. Lung transplant patients can deterioratevery quickly in the absence of the proper therapy. Thus, it is common practice to cover both infection and rejection
until additional histopathologic and culture results are obtained.32
COMPLICATIONS OF LUNG TRANSPLANTATION
Complications occur most frequently in the first year but can occur at any time starting from the first few weeks
a�er transplant and continue throughout the lifetime of the patient (Table 297-11).32,33 Indications for hospitaladmission are listed in Table 297-12.
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TABLE 297-11
Time Course of Lung Transplant Complications
Days a�er
TransplantComplications Most Commonly Seen in Each Time Period
0–3 d Hemorrhage from technical/mechanical problems
Reperfusion injury
Dysrhythmia
3 d–1 mo Infection: bacterial, mycoplasma, community respiratory viruses
Rejection
Anastomotic failure
Pulmonary embolism
Muscle weakness
Dysrhythmia
Starting at
1 mo
Rejection
Obliterative bronchiolitis
Infection
Bacterial, fungal, community respiratory viral (can occur at any later time)
Mycoplasma 0–4 mo
Mycobacteria a�er 4 mo
Other Cytomegalovirus infection and Pneumocystis jiroveci pneumonia may occur any time, but are more
common when prophylaxis is not being given, especially when such treatment has been recently
discontinued.
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TABLE 297-12
Indications for Hospital Admission for Lung Transplant Patients
Pretransplant patients
Respiratory failure
Infiltrate
Systemic infection
Decompensated congestive heart failure or pulmonary edema
Pneumothorax
Posttransplant patients
Respiratory failure
Acute rejection
Rapidly progressive airflow limitation (forced expiratory volume in 1 second decreases >10% over 48 h)
Infiltrate
Systemic infection
Febrile neutropenia
Pneumothorax
Acute rejection is common and may occur three to six times in the first postoperative year. A�er the first year, thefrequency of acute rejection decreases, but it can occur for several years a�er transplant. Signs of rejection includecough, chest tightness, increase or decrease in temperature from baseline of >0.28°C (0.5°F), hypoxemia, decline inforced expiratory volume in 1 second (10% or more), and infiltrates on the chest radiograph. Radiographicabnormalities are less common >6 weeks a�er transplant, and an acute rejection episode actually may be"radiographically silent" a�er this. Discuss treatment with the transplant team. If the maintenanceimmunosuppressant regimen has been tapered, it can be very helpful to return to pretaper dosages. In addition,high-dose corticosteroids are o�en used to treat acute rejection. The usual dosing regimen is 15 milligrams/kg ofIV methylprednisolone each day for 3 consecutive days. A�er the corticosteroid bolus, if the maintenanceprednisone had been tapered, increasing the prednisone to 1 milligram/kg/d and tapering over the next 10 days
may be helpful.31 Clinical response to treatment is gauged by improvements in oxygenation, spirometry, andradiographic appearance and typically occurs within 24 to 48 hours a�er treatment is initiated. Failure to improveshould suggest infection as an alternative diagnosis. A�er clinical improvement, the maintenance dose ofprednisone is increased, with a slow taper back to baseline.
Pulmonary infections from bacteria, fungi, or viruses are the most common causes of morbidity and mortality in
lung transplant patients34,35 (Tables 297-5 and 297-11). Lung transplant patients are at risk for pneumoniabecause of colonization of the recipient's airway in the setting of transplantation for bronchiectasis and cystic
fibrosis and at risk of aspiration in the presence of gastroesophageal reflux disease.33 Antibiotic selection is bestle� to the lung transplant specialist.
CARDIAC TRANSPLANTATION
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Cardiac transplantation has been applied successfully to patients of all ages, from newborns through persons intheir late 60s. Heart transplantation is indicated for patients with end-stage heart failure not remediable bystandard medical or surgical therapy. Many in the latter group will have undergone previous coronary arterybypass or valve surgery or been bridged on mechanical assist devices. The leading causes of death in those age 60
to 69 are gra� failure and infection.36
The success of a heart transplantation operation depends on the ability of the denervated heart to support thenormal circulation. The lack of sympathetic and parasympathetic innervation does, however, induce an alteredphysiologic state. The denervated heart has a normal sinus rhythm with a heart rate between 90 and 100beats/min. Denervation results in the absence of the initial centrally mediated tachycardia in response to stress orexercise, but the heart remains responsive to circulating catecholamines. Thus, the cardiac response to stress orexertion is blunted. With proper conditioning, patients are able to resume normal activity levels, includingvigorous exercise, following transplantation.
The donor heart is implanted with its own sinus node intact to preserve normal atrioventricular conduction. Thetechnique of cardiac transplantation also results in preservation of the recipient's sinus node at the superiorcavoatrial junction, and the two sinus nodes remain electrically isolated from each other. Thus, ECGs frequentlywill have two distinct P waves (Figure 297-2). The sinus node of the donor heart is easily identified by its constant1:1 relationship to the QRS complex, whereas the native P wave marches through the donor heart rhythmindependently. The presence of the two separate P waves may lead to confusion about the patient's rhythm,mistakenly interpreting sinus rhythm as second-degree heart block. The ECGs may also be interpreted erroneouslyas showing atrial fibrillation, atrial flutter, or frequent premature atrial complexes. Some patients may haveevidence of "cardiomegaly" related to the transplantation of a heart from a donor who was larger than therecipient (Figure 297-3). Clinical evaluation is based on the reason for the ED visit. Chest x-ray, ECG, and furtherevaluation are based on complications of cardiac transplantation (Table 297-13) and underlying patientcomorbidities, especially in elderly transplant recipients.
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TABLE 297-13
Complications a�er Cardiac Transplant
Complication Comments
Altered
physiology
See text in Cardiac Transplantation section.
Dysrhythmias Dysrhythmias a�er transplantation are frequently due to rejection. Treat the unstable patient
presenting in extremis with 1 gram of methylprednisolone IV; delay rejection therapy in the
stable patient for consult with the transplant team and biopsy. Atropine has no e�ect due to
denervation.
Sinus node
dysfunction
Pacemaker usually required.
Pulmonary
complications
Diagnosis may require CT or more invasive diagnostic procedures.
Pneumonia
Thromboembolic
disease
Exercise-
induced
hypoxemia
Pneumothorax
Interstitial
fibrosis
Cardiac ischemia Patients do not experience pain due to denervation; symptoms typically occur with
complications such as congestive heart failure.
Rejection Treat the patient presenting in extremis; withhold treatment for biopsy if possible.
Infection See section "Posttransplant Infections"
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Complication Comments
Congestive heart
failure
Echocardiography can help to determine etiology and therefore ideal treatment.
Ischemic stroke
and intracranial
hemorrhage
Increased risk a�er heart transplant.
Complications
specific to
ventricular assist
devices
Increased risk of infection and thromboembolism.
Cardiac
allographic
vasculopathy
Pediatric heart transplant recipients are at risk for gra� coronary artery disease and ischemia.
May require retransplantation.
FIGURE 297-2.
ECG in a heart transplant patient. ECG demonstrates donor and recipient P waves (arrowhead = donor P wave;arrow = recipient P wave).
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FIGURE 297-3.
Chest radiograph of healthy post–heart transplant patient with typical postoperative changes, including"cardiomegaly" due to transplantation of a heart from a donor who was larger than the recipient.
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1.
2.
3.
4.
CORNEAL TRANSPLANTATION
Corneal transplantation (penetrating keratoplasty) is the most common form of human solid tissuetransplantation. Unlike other tissue and organ transplants, corneal allotransplantation usually does not requiresystemic or permanent immunosuppression. Reasons for gra� failure include corneal gra� rejection (30.9%),
corneal endothelial cell failure (21.0%), glaucoma (8.5%), and other causes (26.2%).37,38 Ophthalmologyconsultation is required for any change in visual acuity or other ocular signs or symptoms in a patient with acorneal transplant.
Corneal gra� rejection is a specific process in which a gra� that has been clear suddenly develops gra� edemawith anterior segment inflammatory signs. Rejection can occur at any time starting at 10 days a�er transplant. Theinflammatory process starts at the gra� margin nearest to the most proximal blood vessels and then moves
toward the center to involve the entire gra�.37 Signs and symptoms include eye pain, photophobia, corneal orscleral injection, or decreased visual acuity. Examination may reveal unilateral anterior chamber reaction withkeratic precipitate or corneal edema in a previously clear gra�. Late gra� failure can present with gradual onset ofgra� edema with no associated inflammation or keratic precipitates. Treatment includes topical or systemicsteroids, cycloplegics, and immunosuppressive drugs such as local and systemic cyclosporine A and tacrolimus.
Wound dehiscence can occur early or late a�er corneal transplantation, as a result of infection or a�er eye trauma.Trauma may be unrecognized or be a result of events such as motor vehicle airbag deployment or a fall with thepatient's glasses impacting the eye. There may be globe rupture, slight separation of part of the suture line, or justbroken sutures.
Viral,37 bacterial,39 or fungal40 infection can threaten the transplanted cornea. In patients with a history ofherpetic keratitis, consider recurrence and examine with fluorescein for characteristic corneal staining and signs of
anterior chamber inflammation.37 Ophthalmology consultation is needed for diagnosis and treatment.
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