Fever

Management of fever in posttransplant patients should be approached similar to that of fever in other immunocompromised patients.⁵ Because of suppressed immunologic and inflammatory responses, posttransplant patients may not exhibit the common findings of acute infection. Fever may or may not be associated with clinically significant infection.

Acute rejection is one cause of fever that may develop at any time. Decisions regarding appropriate diagnostic testing and disposition of a posttransplant patient with fever should be made in consultation with a transplant service.

Infections

The incidence of infection in the first posttransplant year has been reported to be as high as 25% to 80%. Expected infections vary according to posttransplant time (Box 117.3). Infections in the first posttransplant month are typical postoperative infections—pneumonia, sepsis from central lines or urinary catheters, and wound infections.^3,5 Atypical or opportunistic infections are uncommon.

After the first month through the end of the first posttransplant year, opportunistic infections reach their peak incidence. A variety of atypical bacterial, viral, fungal, protozoal, and parasitic infections may occur. Individual transplant services maintain current information on the opportunistic infections seen in their institution. Cytomegalovirus is one of the most common opportunistic infections and occurs in up to 25% of renal transplant recipients.⁵ It can cause systemic or invasive disease and is associated with acute rejection.

After the first year, the incidence of opportunistic infections decreases and typical community-acquired pathogens predominate.

Leukocytosis is a poorly sensitive and inconsistent indicator of the source of the fever, and therefore a normal white blood cell count should not be used to exclude a potential infectious illness in a transplant patient. Peritoneal findings may be minimal or absent in the presence of an acute intraabdominal catastrophe. As a result of the degree of immunosuppression, infections may follow a fulminant course.

Cardiovascular Emergencies

Because the majority of renal transplant recipients in the United States have diabetes or hypertension (or both), the risk for concomitant cardiovascular disease is high. Furthermore, the combination of cyclosporine and corticosteroids worsens dyslipidemias and atherogenesis.⁶ Cardiovascular disease accounts for 30% to 50% of deaths in the first posttransplant year, and the incidence of atherosclerotic vascular disease is up to five times greater in transplant recipients than in other hospitalized patients.⁷

The approach to diagnosis and management of suspected cardiac ischemia in the posttransplant population is similar that in the general population; however, higher-risk stratification for these patients is critical.

Varying degrees of hypertensive urgencies or emergencies may be seen in posttransplant patients. Likewise, patients may have acute or chronic dysrhythmias (e.g., chronic atrial fibrillation) unrelated to the transplant. Although no single antihypertensive or antidysrhythmic agent is contraindicated, care should be taken to avoid drug interactions (Box 117.4).

Pulmonary Emergencies

Pneumonia remains the most common pulmonary emergency in transplant recipients.⁸ The causative organisms vary depending on the timing after transplantation. Chest radiograph findings may be nonspecific; immunosuppressive medications blunt the appearance of infiltrates.^3,8 Additionally, sirolimus has been noted to cause interstitial pneumonitis.⁹ Chest computed tomography may be required to help delineate the cause of abnormal findings on chest radiography.

The threshold for hospital admission of posttransplant patients with pneumonia is lower given the potential for rapidly progressive disease and opportunistic infections. Appropriate effort should be made to obtain sputum for Gram stain and culture because of the potential for unusual organisms. Antimicrobial choices need to be tailored to the most likely organisms based on the clinical findings, time after transplantation, and history of recent hospitalization.

Fluoroquinolones and macrolides may increase levels of cyclosporine and tacrolimus; these antibiotic classes should not be used as first-line agents for the treatment of patients with posttransplant pneumonia. Discussion with the transplant service may be beneficial in determining the preferred choice of antibiotic.

Gastrointestinal Emergencies

Abdominal pain in renal transplant recipients may be due to a variety of causes. Diagnostic imaging studies should be used liberally given the potential for patients with serious intraabdominal processes to have relatively minimal findings on physical examination.^3,10

Mortality from cholecystitis is high in renal posttransplant patients. Diverticulitis is the most common bacterial gastrointestinal infectious process.¹⁰ Diarrhea may be due to any number of infectious organisms, including Salmonella, Listeria, cytomegalovirus, and Cryptosporidium.

Abdominal pain in the area of the allograft should prompt consideration of acute rejection.

Opportunistic infections may affect any area of the gastrointestinal tract, from the mouth to the anus. Common opportunistic infections include candidiasis, cytomegalovirus, and herpes simplex.^10,11 Cytomegalovirus and Epstein-Barr virus can cause acute hepatitis.

Various immunosuppressive drugs can cause stomatitis, ulcerations, or acute hepatitis.¹⁰ Renal transplant recipients have an increased incidence of acute pancreatitis that may be related to immunosuppressive agents.¹⁰

Genitourinary and Renal Emergencies

Renal transplant recipients are prone to the same genitourinary and renal disorders as the general population. The one truly unique renal emergency in this population is rejection.

Urinary tract infections are more severe in transplant recipients.¹² Pyelonephritis may follow a fulminant course and necessitate inpatient management. These patients often require two broad-spectrum antibiotics for adequate treatment. Aminoglycosides are nephrotoxic and should be avoided if possible.

Hematuria in renal transplant recipients may be due to infection or obstruction in the allograft or in the native kidneys; imaging studies are recommended. Hemolytic-uremic syndrome is a cause of hematuria and acute renal failure in posttransplant patients that may be related to infection (cytomegalovirus), rejection, or medication toxicity (cyclosporine and tacrolimus).¹³

Common causes of renal insufficiency normally observed in nontransplant patients should be considered when evaluating acute renal failure in posttransplant patients; rejection is a later consideration, after other, more likely causes have been excluded.

If hydronephrosis is present, ultrasound studies should be ordered to look for ureteral obstruction. Arterial Doppler imaging may be needed to evaluate the adequacy of blood flow to a graft. Obstruction of an allograft is a true surgical emergency that generally requires placement of a percutaneous nephrostomy tube.

Rejection can be acute, chronic, or acute on chronic. Acute rejection occurs in the early posttransplant period. Chronic rejection is the most common cause of renal allograft dysfunction after the first posttransplant year.

A common cause of acute renal failure in renal transplant patients is nephrotoxicity from cyclosporine or tacrolimus.^3,14 Rejection may not be able to be distinguished from nephrotoxicity without a biopsy. Fever and tenderness over the graft site suggest the presence of rejection, whereas elevated trough levels of cyclosporine or tacrolimus suggest drug-induced nephrotoxicity.

If acute rejection is the most likely diagnosis, the transplant service should be consulted for inpatient management and high-dose methylprednisolone therapy begun at 500 to 1000 mg daily.

Endocrine and Metabolic Emergencies

Transplant recipients receiving corticosteroid therapy have functional adrenal insufficiency and require pulse doses of corticosteroids when they encounter physiologic stress. Stress-dose hydrocortisone should be administered to transplant patients with unexplained or refractory hypotension unless they have not been taking corticosteroids for more than 6 months.

Electrolyte disorders, especially hyperkalemia, are common in posttransplant patients as a result of cyclosporine- or tacrolimus-induced impairment of potassium excretion.¹⁵ This impairment may be exacerbated by the use of potassium-sparing diuretics and angiotensin-converting enzyme inhibitors.

Cyclosporine and corticosteroids both contribute to an increased incidence of new-onset diabetes in transplant recipients.¹⁶

Neurologic Emergencies

Cryptococcal meningitis and central nervous system lymphoma are seen with greater frequency in posttransplant patients because of the immunosuppression.¹⁷ Patients with fever of unknown origin, headache, or altered mental status should undergo intracranial imaging and lumbar puncture as appropriate. Computed tomography scanning of the brain with and without contrast enhancement is preferable in this population to more readily identify space-occupying lesions. The risk for contrast-induced nephrotoxicity must be weighed against the benefit of diagnostic accuracy when brain lesions are suspected. Similarly, use of gadolinium-enhanced magnetic resonance imaging may be contraindicated given the risk for nephrogenic systemic fibrosis in patients with abnormal creatinine clearance.¹⁸

Adverse Drug Reactions

Immunosuppressive medications cause illness through the direct toxic effects of these drugs or through interaction with other common medications. Medication reconciliation is critical as new drug regimens become more complex.

Initial posttransplant regimens typically consist of three agents: a corticosteroid, a calcineurin inhibitor (cyclosporine, tacrolimus, sirolimus), and a purine synthesis inhibitor (azathioprine, mycophenolate mofetil).¹⁹ Most patients are weaned off corticosteroids in 6 months, and maintenance is continued with only two drugs.

During the initial induction phase of immunosuppression, other agents such as antithymocyte monoclonal and polyclonal antibodies are used. Because these medications are generally reserved for inpatient use, it is unusual for patients to be seen in the ED with an acute complication from these agents.

Corticosteroid therapy has many well-recognized complications. In addition to functional adrenal suppression, corticosteroids can induce diabetes, steroid psychosis, gastric ulceration, pancreatitis, changes in body habitus, and avascular necrosis.

Azathioprine is one of the oldest agents used to treat rejection. It is an alkylating agent similar to other chemotherapeutic drugs, and thus its primary toxicity is bone marrow suppression (particularly leukopenia). When given with allopurinol, increased levels of azathioprine may result in myelosuppression. Azathioprine and mycophenolate mofetil demonstrate an additive risk for myelosuppression. The hepatotoxicity from azathioprine is less than that with other agents.

Cyclosporine interacts with multiple other medications and demonstrates significant nephrotoxicity. Increased serum creatinine levels are observed in up to one third of patients taking cyclosporine.¹⁵ As these levels rise, cyclosporine excretion decreases and renal failure worsens. Trough measurements of cyclosporine (3 hours before the next scheduled dose) differentiate drug-induced nephrotoxicity from other causes of renal insufficiency.

Tacrolimus and sirolimus both carry a risk for multiple drug interactions and worsening nephrotoxicity. Drugs that increase the metabolism of these agents may decrease their effective serum levels and thus result in acute rejection because of inadequate immunosuppression.