Introduction
Since the first transplantation of a kidney from one human to another in 1954, renal transplantation has evolved from the realm of experimental medicine to the commonplace. It is now the preferred treatment for end-stage renal disease, and, to date, more than 250,000 kidney transplants have been performed in the United States alone.
Emergency department physicians encounter transplant patients at two critical stages. First, they may be the initial physicians to identify potential cadaveric organ donors from the pool of critically ill patients admitted to the hospital. Second, they care for patients once they have been transplanted and need to be aware of the unique problems related to the renal graft as well as those that arise from immunosuppression.
Organ Procurement
At the time of this writing, more than 75,000 people are on the kidney transplant list in the United States and many of them will die before receiving a kidney. It is hoped that a heightened awareness on the part of emergency physicians (EPs) to the task of identifying potential donors can begin to meet the escalating need for solid organ transplantation.
Role of the ED physician in identifying patients
The wet ischemia time—that is, the time from cessation of circulation to removal of the organ and its placement in cold storage—should be no longer than 30 minutes. This reality and other practical and logistical factors prevent "code victims" in the ED from becoming solid organ donors, although keep in mind that these patients should be considered for donation of other tissues such as bone, skin, veins, heart valves, and ocular components.
The role of the EP is to identify moribund patients who are appropriate candidates for transplant and to set into motion the process of acquisition by contacting the local organ procurement organization (OPO), a list of which can be found at the AOPO Web site.
The task of discussing organ donation with a patient's family is best left to the OPO representative, who is highly trained for such discussion, is not involved in the acute care of the patient, and therefore does not have to weigh competing obligations. The ED physician should focus on providing the family with a realistic prognosis for the patient.
Donor selection
Increasing demand for donor organs and improvements in transplant immunology have greatly expanded the pool of patients eligible to donate organs. Absolute contraindications for organ donation include HIV, sepsis, and non-CNS malignancy.
Advanced age is a relative contraindication; most OPOs do not harvest solid organs from individuals older than 75 years. However, EPs should defer rejection of questionable transplant donations to an OPO representative.
The pretransplantation workup of a potential donor should include screening for transmissible infectious agents such as herpesvirus (cytomegalovirus [CMV], herpes simplex virus [HSV], Epstein-Barr virus [EBV]); HIV; hepatitis viruses A, B, C, D and E; and the human T-cell lymphotropic virus type 1.
Brain death determination
The Uniform Determination of Death Act provides guidelines outlining neurological criteria for brain death, which is defined as complete and irreversible loss of brain and brainstem function. Criteria include cerebral unresponsiveness, brainstem areflexia, and apnea in the absence of hypothermia and drug intoxication. Because of the lengthy process required for actual organ procurement, the EP should not wait for the formal declaration of brain death before involving the transplant team. A transplant coordinator should be called early for any patient who may meet brain death criteria in the near future.
Potential donors with brain death and preserved cardiovascular function who are identified in the ED should be quickly admitted to an intensive care unit. Only in this setting can their cardiorespiratory status be maintained against the onslaught of physiologic insults that ensue once neurologic function has ceased. Once stabilized, the organ donor may officially be designated brain dead and transferred to the operating room for organ harvesting.
Donor management
Following brain death, a number of physiological changes occur that require intervention if donor organ perfusion is to be preserved. Increasing cerebral edema after a trauma or stroke initially results in elevated catecholamine release and hypertension. With brainstem necrosis, catecholamine levels drop rapidly to a fraction of normal values, causing hypotension. Such hypotension should be corrected with fluids and vasopressors.
Approximately three fourths of organ donors develop diabetes insipidus due to pituitary necrosis. If this condition is untreated, significant hypovolemia may result. Systemic thermal control is often lost because of hypothalamic ischemia. This occurs in most donors and results in detrimental effects on potential donor organs, including coagulopathy, hypoxia, hepatic dysfunction, and cardiac dysfunction.
Patients who are brain dead require invasive hemodynamic monitoring and aggressive fluid and pressor management to keep mean arterial pressure (MAP) above 60 and urine output over 0.5 mL/kg/h.
Posttransplantation Morbidity and Mortality
Graft prognosis
Graft prognosis is directly related to the source of the donor kidney: recipients of cadaveric kidneys generally have more episodes of rejection and lower graft survival rates. The graft survival rate for kidneys from living donors is approximately 95% at 1 year and 76% at 5 years, whereas the graft survival rate for kidneys from cadaveric donors is 89% at 1 year and 61% at 5 years.
Morbidity
In addition to complications of transplantation such as infection and graft failure, the major causes of morbidity after renal transplantation are hypertension (occurring 75-85% of all renal transplant recipients), hyperlipidemia (60%), cardiovascular disease (15.8-23%—a 10-fold increase over the general population), diabetes mellitus (16.9-19.9%), osteoporosis (60%), malignant neoplasm (14%).
Cardiovascular disease is increased 10-fold compared with the general population, and the rate of malignancies appears to be related to the degree of immunosuppression. Diabetes is more likely to be present prior to transplantation, and new-onset diabetes is related to corticosteroid use after transplantation.
Mortality
Predictably, recipients from living related donors have lower mortality rates than recipients from cadaveric donors. This is likely related to fewer rejection episodes and thus lower immunosuppression requirements. The survival rate of patients after transplantation from a living donor is 98% at 1 year and 91% at 5 years; the survival rate after cadaveric donation is 95% at 1 year and 81% at 5 years. Common causes include coronary artery disease (30.4%), sepsis (27.1%), neoplasm (13%), and stroke (8%). During the first year posttransplantation, most deaths are due to infectious causes. Long-term mortality rates are more closely related to the development of coronary artery disease.
Important History in Transplantation Complications
When taking a history from a patient with an organ transplant, many elements vary from the routine patient. The following are of particular importance in the history of any patient with an organ transplant presenting to the ED:
- Current symptoms, especially fever
- Transplant age (ie, interval since transplant)
- Living or cadaveric organ source
- Previous episodes of rejection (may have necessitated an increase of immunosuppression)
- Current medications, including over-the-counter drugs
- Recent medication changes
- Immunosuppressive therapy
- Compliance with therapy
- Previous infections
- Recent exposure to ill patients
In patients with renal transplants, many of the specific etiologies of infections can be correlated to the age of the graft. Most opportunistic infections occur after the first month post transplant up through the first year but especially between months 1 and 6 when immunosuppression is maximized.
As previously noted, patients with cadaveric grafts have significantly lower graft survival rates and increased infectious complications.
Patients with multiple rejection episodes requiring more aggressive immunosuppression are at significantly higher risk for infectious complications than patients who have experienced little or no rejection. Noncompliance with antirejection medications is the leading cause of late acute rejection. A complete medication history must include all over-the-counter medications. Cyclosporine is especially important to note because of its wide range of drug interactions.
Also important to note are recent exposures to patients with infections (eg, chickenpox, cytomegalovirus [CMV], tuberculosis) and history of chronic infections (eg, CMV, EBV, hepatitis). Reactivation of chronic infections and exposures is the most common source of infections in transplant patients.
Other information necessary in evaluation of any illness is blood pressure, body weight, serum creatinine level, and cyclosporine level. Patients with renal transplants or their families usually are very knowledgeable about their baseline status and are valuable sources of important clinical data.
Examination Points
Fever is the most common presentation of an infection in patients with a transplant. Be aware that uremia, hyperglycemia, and immunosuppressants (including steroids) commonly suppress or mask fever.
In patients with a renal transplant, assessment of volume status is paramount. Hypotension and tachycardia are obvious clues to hypovolemia. Edema is a less reliable finding owing to chronic hypoalbuminemia from malnutrition, nephrotic syndrome, and chronic liver disease common in these patients. Often, invasive hemodynamic monitoring is the only reliable means of determining volume status in patients with renal transplants.
The renal graft generally is placed in the right or left iliac fossa in an extraperitoneal position and is most often anastomosed to the internal or external iliac artery. It should be inspected, palpated, and auscultated. The graft insertion site should be inspected for signs of wound infection. Graft tenderness and swelling often are observed in acute rejection, outflow obstruction, pyelonephritis, and renal vein occlusion. A bruit often can be heard in cases of renal artery stenosis and arteriovenous malformation.
Renal Transplantation Complications
Allograft dysfunction and rejection
Failure of renal allografts is now one of the most common causes of ESRD, accounting for 25% of all patients awaiting renal transplants. Renal transplants can fail for all the same causes as native kidneys, as well as for causes unique to transplant patients. Complications of surgery as discussed below are common causes of graft failure within the first 12 weeks after transplantation. Recurrent renal disease results in fewer than 4% of graft failures but may be an important concomitant etiology of renal failure.
Rejection is related primarily to activation of T cells, which, in turn, stimulate specific antibodies against the graft. Various clinical syndromes of rejection can be correlated with the length of time after transplantation.
Hyperacute rejectionoccurs immediately in the operating room, when the graft becomes mottled and cyanotic. This type of rejection is due to unrecognized compatibility of blood groups A, AB, B, and O (ABO) or a positive T-cell crossmatch (class I HLA incompatibility).
Acute rejectionappears within the first 6 post-transplant months and affects approximately 15% of transplanted kidneys. Roughly 20% of patients with transplants experience recurrent rejection episodes. Patients present with decreasing urine output, hypertension, and mild leukocytosis. Rising creatinine level may be delayed in acute rejection. Fever, graft swelling, pain, and tenderness may be observed with severe rejection episodes. Rejection is secondary to prior sensitization to donor alloantigens (occult T-cell crossmatch) or a positive B-cell crossmatch. The final diagnosis depends upon a graft biopsy. Acute rejection is treated with a 3- to 5-day course of high-dose intravenous steroids.
Late acute rejectionis correlated highly with scheduled withdrawal of immunosuppressive therapy 6 months after transplantation.
Chronic rejectionoccurs more than 1 year after transplantation and is a multifactorial process involving both immunologic and nonimmunologic factors leading to graft fibrosis and tubular atrophy. These patients present with a progressive loss of renal function over time. Diagnosis is by renal biopsy, and treatment depends on the identified cause, if any.
Anatomic complications
Renal artery thrombosisis generally a complication of the immediate post-transplant hospitalization, though it may present later. It is caused by a low flow state from hypotension or vascular kinking due to surgical error. The presenting symptom is sudden cessation of urine output, and the likely outcome is graft loss. This is diagnosed by color flow Doppler ultrasonography.
Renal vein thrombosistypically an early complication presenting as graft tenderness and edema. The patient develops pain and swelling over the graft site, as well as dark hematuria and diminished urine volume. It is diagnosed by color flow Doppler ultrasonography.
Renal artery stenosisusually is a later complication. It presents as uncontrolled hypertension, allograft dysfunction, and peripheral edema. It is diagnosed by color Doppler ultrasonography or magnetic resonance angiography (MRA).
Urine leak: Urine leak results from disruption of the anastomotic connection of the ureter to the graft; this generally occurs within the first 2 months post transplant. Symptoms include fever, pain, abdominal swelling, and graft dysfunction. Ultrasonography demonstrates perigraft fluid collection.
Ureter obstruction: Late post-transplant obstruction can be due to hematuria or chronic fibrotic changes at the anastomosis site or due to extrinsic compression from urinoma, hematoma, or lymphocele. The graft becomes distended and edematous, and ultrasonography reveals hydronephrosis.
Perinephric lymphocele: This can occur in up to 15% of patients as a result of operative trauma to lymphatic vessels. This presents as a mass at the graft site that can occasionally impinge on and obstruct the ureter.
Infection
Infection is the most common cause of first-year post-transplantation mortality and morbidity. During the first posttransplantation year, 40-80% of transplant recipients experience at least one infection; however, these numbers are decreasing as more transplant recipients receive preoperative immunizations and take post-transplantation antibiotic prophylaxis.
Infection most commonly occurs in mucocutaneous areas (41%), the urinary tract (17.2%), and the respiratory tract (13.9%). The most common infective agents were bacterial (45.9%), viral (40.6%), fungal (12.5%), and protozoan (1%). CMV (31.5%), herpes simplex (23.4%), and herpes zoster (23.4%) were the most frequent viral illnesses. Infection (32%) was the most common cause of death; pneumonias accounted for 50% of the patient deaths from infection.
Infectious agents can often be identified by the time interval from transplantation to presentation. The first post-transplantation month is dominated by infections directly related to the surgery. These entities include urinary tract infections (Escherichia coli), line infections (Staphylococcus aureus, Streptococcus viridans), wound infections (S aureus, S viridans), and pneumonia (Streptococcus pneumoniae).
The initial 6 post-transplant months are associated with the highest levels of immunosuppression and therefore carry the greatest risk of viral and opportunistic infections. CMV is responsible for more than two thirds of febrile episodes during this period. These patients often present with fever, malaise, lymphadenopathy, arthralgias, and myalgias. Laboratory studies may show leukopenia with atypical lymphocytes and mild hypertransaminasemia. Diagnosis is based upon isolation of virus or antibody titers. Untreated CMV has been associated with a mortality rate as high as 15%. Other opportunistic infections include Pneumocystis carinii pneumonia, listeriosis meningitis, and sepsis with the organism Aspergillus fumigatus.
After the first 6 months, patients with renal transplants are divided into the following 3 subgroups:
- Patients with good graft function on minimal immunosuppressants, who have the same risk of infection as the general population
- Patients chronically infected with latent viruses (eg, CMV, EBV, hepatitis B and C), who often have significant and ongoing end-organ damage (eg, cirrhosis) due to such infections
- Patients with poorly functioning grafts who have sustained multiple episodes of rejection and who require large dosages of immunosuppressants (These patients commonly have bouts of acute and chronic opportunistic infections (eg, P carinii pneumonia, candidal infections).
Malignancy
Transplant recipients are at significantly higher risk for cancers than the general population because of (1) chronic immunosuppression, (2) chronic antigenic stimulation, (3) increased susceptibility to oncogenic viral infections, and (4) direct neoplastic action of immunosuppressants. Transplant recipients have a significant overall 2- to 5-fold higher risk in both sexes for cancers of the colon, larynx, lung, and bladder and in men for cancers of the prostate and testis. Especially high risks, 10- to 30-fold, exist for cancers of the lip, skin (nonmelanoma), kidney endocrine glands, non-Hodgkin lymphoma, and, in women, cervix and vulva-vagina.
Liver disease
Chronic liver disease is an important cause of morbidity and mortality for patients with renal transplants. Etiologies of hepatic dysfunction include viral hepatitis and antirejection therapy. Of the viral infections, CMV is the leading cause of hepatic dysfunction, followed by hepatitis C and B. Of antirejection medications, azathioprine and cyclosporine are known to cause cholestatic jaundice.
Cyclosporine toxicity
Cyclosporine and tacrolimus (FK-506) nephrotoxicity is related to hemodynamic factors. Acute cyclosporine toxicity (serum level >300 ng/mL) causes vasoconstriction and renal ischemia, which can be reversed by decreasing drug dosage. Chronic toxicity results in fixed vascular lesions and irreversible renal ischemia. Cyclosporine is noteworthy for its many interactions with other medications.
Calcium channel antagonists (eg, diltiazem, verapamil, nicardipine) and certain antibiotics (eg, erythromycin, doxycycline, ketoconazole) increase levels of cyclosporine and predispose to nephrotoxicity. Certain antibiotics (eg, nafcillin, cotrimoxazole, isoniazid, rifampin) and certain anticonvulsants (eg, phenytoin, phenobarbital, carbamazepine) decrease levels of cyclosporine and thereby predispose the patient to infection. Drugs that enhance the nephrotoxicity of cyclosporine without altering blood levels include amphotericin B, acyclovir, and nonsteroidal anti-inflammatory drugs.
Hypertension
Approximately 50% of all renal transplant patients have hypertension. Possible etiologies of hypertension include graft rejection, cyclosporine toxicity, glomerulonephritis, graft renal artery stenosis, essential hypertension from native kidneys, hypercalcemia, and steroid use.
Cardiovascular complications
Overall, risk of cardiovascular disease after transplant is up to 10 times that for age- and sex-matched controls. Risk factors for such disease include pretransplant cardiac disease, hyperlipidemia secondary to antirejection medications, hypertension, steroid use, type 1 diabetes mellitus, erythrocytosis, smoking history, and multiple previous rejection episodes.
Management Strategies for Common Presentations
Workup of suspected infection
Obtain the following studies:
- Urinalysis
- CBC
- Cultures (ie, mouth, sputum, urine, blood, stool, access sites as appropriate)
- CMV antibody titers
- Chest radiography
- Transplant ultrasonography
- Lumbar puncture (in cases of suspected meningitis, particularly due to Listeria species)
Urinary tract infections from indwelling catheters are the most common source of bacterial infections in this patient population and account for up to 69% of bacterial infections. Leukocytosis with a left shift commonly is observed with bacterial infections unless immunosuppressive agents have suppressed the bone marrow. Leukopenia with an increase in atypical lymphocytes commonly is observed with viral infections.
Patients may present with pneumonia from bacterial or viral agents. Interstitial infiltrates commonly are observed with P carinii and other atypical pneumonias. Tuberculosis may present with typical upper lobe distribution in reactivation forms; however, tuberculosis also may present atypically as a primary infection.
Ultrasonography is performed to identify urinary obstruction as well as fluid collections suggesting urine extravasation, abscess, pyelonephritis, or wound infection.
Workup of acute renal failure
Renal failure in patients with transplants is defined as a 20% rise in serum creatinine level (as opposed to a 50% rise in nontransplant patients). In the workup, estimate the patient's volume status. Hypovolemia should be corrected rapidly in all patients.
Obtain the following studies:
- Urinalysis
- Electrolyte levels
- BUN and creatinine levels
- Cyclosporine level
- Transplant ultrasonography
- Consultation for renal biopsy (if necessary)
Urinalysis showing red cells raises suspicion for glomerulonephritis. White cells raise suspicion for infection and obstruction. Hyperkalemia is a common complication of renal graft rejection and cyclosporine use. Cyclosporine levels greater than 300 ng/mL are associated with increased nephrotoxicity. Transplant ultrasonography is performed to identify urinary obstruction. Color flow Doppler ultrasonography is necessary to evaluate vascular occlusion or stenosis.
Renal biopsy represents the ultimate diagnostic modality and usually is required to diagnose most renal graft dysfunction definitively.
Other Considerations
Blood transfusion
Because of the risk of transmitting infection by transfusion, immunosuppressed transplant recipients should receive CMV-negative irradiated blood.
Stress-dose corticosteroid coverage
Severely ill transplanted patients who are on long-term steroid therapy are at risk of adrenal insufficiency and should be treated with stress doses of hydrocortisone (100 mg IV q8h).
Conclusions
Transplant recipients are among the most experienced patients that are seen in the emergency department. Many of them have dealt with their chronic illness for years, have been treated and examined by innumerable doctors, have undergone dialysis and its attendant intrusions on their lifestyle, have managed a complicated regimen of medications, and often have developed a certain expertise related to their own care. They are invariably grateful for any recognition or acknowledgment of their ordeal, and given their expertise, they should be educated about and encouraged to be active participants in their disease management to whatever extent possible.
That said, their problems are often deceptively complex and decisions regarding their care should be made in conjunction with the appropriate transplant team.
Keywords
renal transplant, renal failure, renal transplantation, kidney transplant, kidney transplantation, organ transplant, organ transplantation, end-stage renal disease, ESRD, kidney disease, kidney failure
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Further Reading
Keywords
renal transplant, renal failure, renal transplantation, kidney transplant, kidney transplantation, organ transplant, organ transplantation, end-stage renal disease, ESRD, kidney disease, kidney failure
