The Solid Organ Transplant Patient

Key Concepts

The solid organ transplant recipient’s altered anatomy, denervated allograft, and immunosuppression frequently result in atypical disease presentations both related and unrelated to the transplanted organ.
An understanding of the solid organ transplant recipient’s altered anatomy, including vascular and nonvascular anastomoses, is critical to evaluating early post-transplantation complications.
Rejection can manifest at any point post-transplantation with constitutional symptoms and signs of allograft insufficiency, requiring prompt recognition and augmented immunosuppression to salvage the transplanted organ.
Timing post-transplantation, the net state of immunosuppression, and ongoing antimicrobial prophylaxis should be incorporated into the evaluation of a solid organ transplant recipient with fever and other concerns for infection.
In addition to affecting a specific arm of the immune system, each antirejection agent is associated with unique toxicities which may be independently responsible for a solid organ transplant recipient’s clinical condition.
Cardiac allograft vasculopathy, a form of chronic rejection and similar to coronary artery disease in presentation, has emerged as a common complication of orthotopic heart transplantation as transplant recipients live longer.
Especially in lung transplant recipients with underlying cystic fibrosis or bronchiectasis, prior imaging and culture data should help guide initial management of new respiratory symptoms.
Recurrent allograft pyelonephritis post-transplantation merits thorough evaluation for ureteral stones and strictures, perinephric abscesses, and urinary retention to identify potentially actionable contributors to infection.
Hepatic artery thrombosis is an uncommon but devastating early complication of liver transplantation resulting in allograft dysfunction, biliary necrosis, and sepsis if left undetected and untreated.
Allograft rejection, bacterial or viral enteritis, and altered intestinal transit time can all contribute to diarrhea in the intestinal and multivisceral transplant recipient.
As chronic corticosteroids are incorporated into immunosuppression regimens for the majority of solid organ transplant recipients, adrenal insufficiency should be considered in the differential of transplant recipients presenting with hypotension and fever.
In addition to the organ-specific complications described in the sections above, solid organ transplant recipients experience graft-versus-host disease, malignancy, trauma, and psychosocial distress post-transplantation requiring heightened awareness and assembly of multidisciplinary teams.

Introduction

Solid organ transplantation has undergone significant advancement since the first successful kidney transplant in 1956. In 2019, over 39,000 solid organ transplants were performed in the United States (US). As improvements in medical and surgical treatments allow more individuals to undergo transplantation and increase the life expectancy for transplant recipients, emergency clinicians should expect to encounter patients with illnesses complicated by their history of transplantation. This chapter provides a basic knowledge of organ transplant pathologies and their initial management as well as an appreciation for the utility of consultation with transplant surgeons and other subspecialists.

Pathophysiology

Altered anatomy and ongoing immunosuppression change how transplant recipients present with disease. Allografts are denervated, and thus pain is an unreliable sign of illness. Normal inflammatory and immunologic responses are impaired, limiting the recipient’s ability to mount a fever or elevated leukocyte count. Subtle signs and symptoms may be harbingers of serious complications. Transplant-related illness can generally be placed into one of four categories: anatomy, rejection, infection, and drug toxicity ( Fig. 183.1 ). Rejection and infection may present similarly. Changes in baseline allograft function and time since transplantation guide the differential diagnosis. It is imperative to consider infectious risk and drug toxicity when recipients present with issues not directly involving the allograft.

Fig. 183.1, Evaluation of the solid organ transplant recipient in the emergency department.

Anatomy

Anatomic complications can involve vascular anastomoses, nonvascular anastomoses, or surgical wounds, and typically manifest within the first few months post-transplantation. Vascular anastomotic complications can include arterial or venous structures. Of these, arterial complications are more acutely devastating. Arterial stenosis or thrombosis may lead to fulminant organ failure. Pseudoaneurysms or mycotic aneurysms can precipitate hemorrhagic shock. Nonvascular organ anastomoses can develop leaks or obstructions from scarring or stent migration, which may provoke acute allograft dysfunction or infection. Early identification of these complications by laboratory investigation of allograft function, imaging, and prompt consultation of transplant specialists is vital to salvage the allograft.

Infection

Infection is the primary cause of mortality after transplantation. Timing since transplantation may predict the most likely pathogens and guide empirical antibiotic selection ( Fig. 183.2 ).

Fig. 183.2, Timeline for infectious complications after solid organ transplantation.

Early Period: 0 to 4 Weeks Post-Transplantation

Infections within the first month of transplantation often relate to postoperative intensive care and surgical site complications. Typical pathogens include nosocomial and multidrug-resistant organisms as well as the transplant recipient’s colonizing bacteria identified pre-transplantation. Wound infections, pneumonias, urinary tract infections, and Clostridioides difficile colitis are encountered. Bloodstream infection may present without typical signs of sepsis syndrome.

Both donors and recipients undergo extensive serologic and nucleic acid testing pre-transplantation, but expected and unexpected pathogen transmissions from donor to recipient can occur. Expected transmissions in some donor/recipient pairs include cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis C virus (HCV). Transplant center–specific strategies to monitor and pre-emptively treat such infections effectively prevent end-organ disease. Unrecognized donor infection prior to transplantation can rarely result in unexpected transmissions and lead to tissue-based or systemic illness (e.g., rabies encephalitis, disseminated disease due to fungi, Mycobacterium tuberculosis [MTB], or Strongyloides stercoralis ). While the focus should remain on addressing the more likely postoperative infections in this time period, consideration of donor-derived infections may be instrumental for diagnosis. Unexpected donor derived infections are reported to United Network for Organ Sharing (UNOS) for the safety of other transplant recipients.

Intermediate Period: 1 to 12 Months Post-Transplantation

Infections occurring within the first year of transplantation are generally divided into two categories: reactivation of latent infections and opportunistic infections.

Reactivation of CMV, the most prevalent viral infection observed during this time period, increases the risk of other infections, allograft rejection, and mortality due to CMV’s immunomodulatory properties. ^, As all transplant centers provide valganciclovir prophylaxis or serum CMV deoxyribonucleic acid (DNA) monitoring, symptomatic CMV infection does not usually emerge until after prophylaxis is stopped. Duration of prophylaxis varies based on the type of allograft, donor/recipient serostatus, and transplant center, but typically ranges from 3 to 12 months post-transplantation. Common presentations of CMV reactivation include “CMV syndrome,” characterized by fever, leukopenia, and viremia, and CMV gastrointestinal disease presenting with diarrhea, abdominal pain, or odynophagia with or without viremia. Other tissue-based infections (e.g., hepatitis, pneumonitis) involve their respective allografts, present with viremia, and are differentiated from alternative etiologies by allograft biopsy.

Reactivation of herpes simplex viruses (HSV) 1 and 2 and varicella zoster virus (VZV) can be prevented by valganciclovir or other acyclovir-derivatives. When these agents are stopped beyond the prophylaxis period, transplant recipients may present with localized or disseminated disease including multidermatomal zoster. Facial zoster involving the cornea and multidermatomal zoster require hospital admission. Multidermatomal zoster merits airborne and contact precautions. Timely treatment with acyclovir decreases post-herpetic neuralgia. Some adults may be VZV seronegative at the time of transplantation and are at risk for complications of primary varicella infection, including life-threatening pneumonia and encephalitis with or without classic skin lesions. Treatment includes intravenous acyclovir and sometimes varicella immune globulin.

Effective prophylaxis can also prevent many opportunistic infections post-transplantation. Thus, such infections merit particular consideration in transplant recipients who cannot tolerate prophylactic antimicrobials. For example, trimethoprim/sulfamethoxazole (TMP/ SMX) is the drug of choice to prevent Pneumocystis jirovecii pneumonia (PCP) and concomitantly covers Toxoplasma , Nocardia , and Listeria species. Those with sulfa allergies or significant intolerance may be prescribed alternative agents (inhaled pentamidine, oral dapsone, or atovaquone) for PCP prophylaxis but these alternative agents do not sufficiently protect against these other pathogens.

Pneumocystis typically presents with a subacute, progressive, nonproductive cough and dyspnea and is accompanied by diffuse pulmonary infiltrates on imaging. Diagnosis is best made by molecular testing of induced sputum or bronchoalveolar lavage fluid. Optimal treatment is with 5 mg/kg of TMP/SMX every 6 to 8 hours, based on renal function. There is no proof that adjunctive steroid use is beneficial in patients with PCP but without human immunodeficiency virus (HIV), and high doses of steroids may be harmful, but data are extremely limited.

Mycobacterial infections such as tuberculosis (TB) mostly represent reactivated disease, but can also represent primary disease from a new exposure. Transplant recipients may develop pulmonary TB or disseminated infection, presenting with nonspecific systemic symptoms or evident meningitis, peritonitis, or vertebral infection. Treatment is challenging due to public health concerns, serious drug-drug interactions with immunosuppression, and allograft toxicities.

Lung and liver transplant recipients are at highest risk for fungal infections post-transplantation. Invasive aspergillosis frequently presents as pulmonary nodules but may disseminate to any organ system. Endemic mycoses (histoplasmosis, blastomycosis, and coccidiomycosis) manifesting with fever and respiratory symptoms should be considered based on geographic location and exposure history. These infections are uncommon but are more likely to disseminate from an original pulmonary source. Amphotericin B may be appropriate for disseminated disease but newer azoles can be effective for pulmonary infection and are specifically indicated for certain fungi.

Toxoplasmosis is uncommon in solid organ transplantation. Risk is greatest in toxoplasma seronegative recipients who acquire an organ from a seropositive donor and do not receive TMP/SMX prophylaxis. Toxoplasmosis presents as myocarditis in heart transplant recipients, resembling rejection, but can disseminate to cause pulmonary infiltrates, hepatosplenomegaly, and central nervous system (CNS) disease. Treatment involves intravenous sulfadiazine and pyrimethamine or TMP/SMX.

Cryptococcus neoformans presents as a meningoencephalitis with altered mental status. Serum cryptococcal antigen can diagnose disease. However, lumbar puncture for opening pressure and cryptococcal antigen is required to address CNS involvement. If the opening pressure is greater than 25 mm H ₂ O, relief of cerebrospinal fluid to reduce the opening pressure to less than 20 mm H ₂ O, or by 50% if the pressure is extremely high, is immediately warranted. Repeated lumbar punctures or percutaneous drains may be required over subsequent days. Initial antimicrobial therapy for meningoencephalitis includes the lipid formulation of amphotericin and flucytosine.

Strongyloides stercoralis is an intestinal nematode that can present with hyperinfection syndrome, causing a necrotizing hemorrhagic enterocolitis and hemorrhagic pneumonia. Disseminated strongyloidiasis presents with severe abdominal pain, obstructive symptoms, hemorrhage and secondary peritonitis, sepsis from enteric pathogens, meningitis, and pneumonia. Diagnosis is by stool or bronchoalveolar lavage sample microscopy. Treatment of disseminated strongyloidiasis is with ivermectin and albendazole, although mortality is high if not detected early.

Late Period: Beyond 1 Year Post-Transplantation

One year after transplantation, transplant recipients’ susceptibility to infection is predominantly dependent on their net state of immunosuppression. Healthy transplant recipients have a functioning allograft and can generally be maintained on low doses of immunosuppression such that they achieve immunologic control of CMV and other herpes viruses. They face a mildly increased susceptibility to community-acquired infections, such as influenza and pneumococcal pneumonia, and still develop certain reactivated or opportunistic infections (i.e., VZV, TB, aspergillosis) with aging or environmental exposures. They remain at risk for more severe forms of community-acquired infections and endemic mycoses. In contrast, transplant recipients with chronic immune dysregulation require aggressive immunosuppression for rejection and are unable to develop adaptive immunity to CMV. They face high risk for life-threatening opportunistic infections, as well as standard community-acquired and nosocomial infections, and may require prolonged antimicrobial prophylaxis.

Rejection

Rejection is the process by which T cell receptor–mediated pathways lead to cytotoxic activity and B cell memory and antibody formation lead to allograft cell death. This immune response to the allograft waxes and wanes, mandating lifelong surveillance. Hyperacute rejection occurs in the immediate postoperative period, caused by preformed antibodies against major histocompatibility complex or ABO blood type antigens. This complication is rare with careful donor-recipient matching or with aggressive desensitization strategies. Acute cellular rejection (ACR) and antibody mediated rejection (AMR) are both associated with constitutional symptoms and signs of allograft insufficiency occurring days to weeks after transplantation or any time immunosuppression is deliberately or accidentally decreased. ACR is mediated by T cells whereas AMR is due to circulating donor-specific antibodies, complement deposition, and neutrophilic inflammation of the allograft. Chronic rejection occurs over months to years and results in allograft failure.

Immunosuppressive therapy requires correctly timed drug combinations to establish a balance between rejection and infection. Regimens are transplant center–specific, but most include a calcineurin inhibitor (usually tacrolimus), an antimetabolite (usually mycophenolate mofetil), and steroids. Recognition of the side effects, toxicities, and potential drug-drug interactions of immunosuppressant medications is important for the care of any transplant recipient ( Table 183.1 ). Consultation with a clinical pharmacist trained in transplant pharmacotherapy can help optimize the use of immunosuppressive and antibiotic agents.

TABLE 183.1

Immunosuppression Agents Used in Solid Organ Transplantation

Agent	Mechanism	Metabolism	Drug-Drug Interactions	Toxicities and Other Considerations
Alemtuzumab	CD52 inhibitor	–	–	Lymphocyte depletion for 6–12 months
Antithymocyte globulin	Polyclonal T cell depletion	–	–	Lymphocyte depletion for 3–6 months Serum sickness, fevers with infusions
Azathioprine	Antimetabolite	Hepatic	↑ by allopurinol May ↓ anticoagulant effect of warfarin	Hepatotoxicity Bone marrow suppression, ↑ by valganciclovir
Basiliximab	IL-2Rα inhibitor	–	–	Duration of activity may last 4–6 weeks
Belatacept	CD80/86 inhibitor	–	–	Post-transplant lymphoproliferative disorder
Bortezomib	26S proteasome inhibitor	Hepatic CYP2C19, CYP3A4	↓ by phenytoin, carbamazepine, rifampin ↑ by azoles, CCBs, macrolides, PIs	Peripheral neuropathy
Cyclosporine A	Calcineurin inhibitor	Hepatic CYP3A4 and P-glycoprotein	↓ by phenytoin, carbamazepine, rifampin ↑ by azoles, CCBs, macrolides, PIs, letermovir	Nephrotoxicity, ↑ by AG, AMB, NSAIDs Hypertension Gingival hyperplasia
Eculizumab	Terminal complement inhibitor	–	–	Neisseria meningitides meningitis
Everolimus	Mammalian target of rapamycin inhibitor	Hepatic CYP3A4 and P-glycoprotein	↓ by phenytoin, carbamazepine, rifampin ↑ by azoles, CCBs, macrolides, PIs	Interstitial pneumonitis Nephrotoxicity Poor wound healing
Intravenous immunoglobulin	Antibody replacement	–	–	Serum sickness, fevers with infusions
Mycophenolate mofetil Mycophenolate sodium	Antimetabolite	Hepatic and gastrointestinal	↑ by antacids, cholestyramine	Hepatotoxicity Bone marrow suppression, ↑ by valganciclovir Gastrointestinal distress
Rituximab	CD20 inhibitor	–	–	Reactivation of hepatitis B, JC virus
Steroids	Variable	Hepatic cytochrome P450 (minor)	↑ by PIs	Weight gain and associated glucose intolerance, HLD Poor wound healing ↑ risk gastrointestinal bleeding with NSAIDs
Sirolimus	Mammalian target of rapamycin inhibitor	Hepatic CYP3A4 and P-glycoprotein	↓ by phenytoin, carbamazepine, rifampin ↑ by azoles, CCBs, macrolides, PIs	Interstitial pneumonitis Poor wound healing
Tacrolimus	Calcineurin inhibitor	Hepatic CYP3A4 and P-glycoprotein	↓ by some antiepileptics, caspofungin, rifampin ↑ by azoles, CCBs, macrolides, PIs, CBD	Nephrotoxicity, ↑ by AG, AMB, NSAIDs Neurotoxicity (PRES, Tremor)

CCB , Calcium channel blocker; PI , protease inhibitor; AG , aminoglycoside; AMB , amphotericin B; NSAID , nonsteroidal antiinflammatory; HLD , hyperlipidemia; PRES , posterior reversible encephalopathy syndrome.

Desensitization Regimens and Therapies for Antibody-Mediated Rejection

Desensitization regimens decrease circulating antibodies likely to react with donor antigens in patients sensitized to incompatible donors. These pretransplant regimens include plasmapheresis to remove antibodies, rituximab to deplete B cells, bortezomib to reduce antibody production, intravenous immune globulin (IVIG) to trigger antibody clearance, and eculizumab to target the complement cascade.

Induction Agents

Induction immunosuppression is employed in the pre- or peri-transplantation period. Antithymocyte globulin (ATG) and alemtuzumab are both lymphocyte depleting agents, with ATG targeting T cells and alemtuzumab both T and B cells. ATG is also used to treat steroid-refractory acute cellular rejection. Lymphodepletion can last for 3 to 6 months, conferring increased risk of opportunistic infections and post-transplantation lymphoproliferative disorder (PTLD). Non-lymphodepleting agents include basiliximab and daclizumab, anti-IL-2 monoclonal antibodies used in recipients at lower risk of rejection.

Maintenance Immunosuppression

Calcineurin Inhibitors

The calcineurin inhibitors tacrolimus and cyclosporine have greatly improved patient- and allograft-related outcomes. However, calcineurin inhibitors (CNIs) have narrow therapeutic indices, variable pharmacokinetics, and adverse side effects. Serum trough levels should be checked in patients with worsening renal function, because CNIs are cleared by the kidney and can cause kidney injury. Both CNIs have been associated with gout and pseudogout. CNI concentrations are altered by common post-transplantation medications including antibiotics; the initiation of such medications merits close communication with the transplant team to plan for CNI dose adjustments and prospective drug monitoring.

Tacrolimus is a macrolide compound that binds to lymphocyte proteins and inhibits cytokine synthesis. Adverse effects include dose-dependent nephrotoxicity as well as neurotoxicity, characterized by tremors, headache, and posterior reversible encephalopathy syndrome (PRES). When combined with steroids, tacrolimus can lead to hyperglycemia and diabetes.

Cyclosporine inhibits both cellular and humoral immunity by binding to proteins which inhibit lymphocyte signal transduction between helper-inducer T cells and B cells. Cyclosporine is similarly associated with dose-dependent nephrotoxicity which is enhanced when used with other nephrotoxins, such as amphotericin or aminoglycosides. Renal tubular injury and direct renal artery vasospasm can result in systemic hypertension. Rarely, cyclosporine toxicity can result in a neurologic syndrome of confusion, quadriplegia, and coma if left untreated.

Mammalian Target of Rapamycin Inhibitors

Sirolimus and everolimus are two drugs in the mammalian target of rapamycin (mTOR) class. mTOR is key in the pathway for T cell clonal activation. Adverse effects include delayed wound healing, hyperlipidemia, cytopenias, diarrhea, and sirolimus-induced lung injury.

Antimetabolites

Azathioprine is an antimetabolite derivative of 6-mercaptopurine and inhibits both DNA and ribonucleic acid synthesis to suppress lymphocyte proliferation. Transplant recipients may exhibit dose-dependent neutropenia, hepatic dysfunction, and gastrointestinal upset.

Mycophenolate mofetil (MMF) is an antimetabolite with more potent and selective inhibition of lymphocyte proliferation as well as a relatively low side effect profile. The most common adverse effects are diarrhea and leukopenia. Because magnesium and aluminum antacids interfere with MMF absorption, care should be exercised in treatment of GI symptoms. MMF is usually switched to azathioprine in the setting of pregnancy to reduce risk of teratogenicity.

Corticosteroids

Corticosteroids have a wide range of effects on the immune system. Every effort is made to minimize corticosteroid use to prevent long-term consequences such as gastrointestinal bleeding, diabetes, and osteonecrosis. High-dose steroids to treat rejection may precipitate altered mental status. Acute withdrawal or severe illness may lead to Addisonian crisis, presenting with fevers, hypotension, and metabolic derangements and merit initiation of stress-dose steroids (e.g. hydrocortisone 100 mg IV).

Other Agents: Belatacept, Rituximab, Eculizumab

Belatacept is a fusion protein that blocks T cell co-stimulation at CD28 and is used primarily in kidney transplantation to avoid the nephrotoxicity of CNIs. It is dosed on a monthly basis. It is associated with increased rates of PTLD and is contraindicated in EBV-seronegative recipients. Rituximab is a monoclonal antibody directed against the B-cell surface marker CD20 and results in B cell depletion. It is associated with cytopenias and hepatitis B reactivation. It also carries a black box warning for progressive multifocal leukoencephalopathy, although this is rare. Eculizumab is a monoclonal antibody that acts as a terminal complement inhibitor and is associated with increased risk for meningococcemia.

Organ-Specific Considerations

The following sections delineate organ-specific anatomic, rejection-related, infectious, and pharmacologic complications of transplantation with occasional reference to the general concepts of solid organ transplantation described previously.

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