Infections in Kidney Transplantation
David A. Pegues
Bernard M. Kubak
Cynthia L. Maree
Aric L. Gregson
Kidney transplantation is associated with lower risk for infection than other solid organ transplantations, reflecting the elective nature of kidney transplantation and clinical and nutritional status of recipients. Infection however, remains a significant cause of morbidity and mortality in renal transplant recipients. Infections related to transplant surgical complications, acquisition of health care-associated pathogens, and reactivation of latent disease can affect graft function and transplant outcome. Graft dysfunction or chronic rejection leads to augmented immunosuppression, increasing the risk for infection with immunomodulating viruses. Infectious syndromes encountered in the kidney transplant recipients include device-associated infections, genitourinary infections, pneumonia, and disseminated or organ-specific viral diseases.
This chapter highlights the infectious disease issues in kidney transplant recipients, post-transplantation infection prophylaxis, and the recognition and treatment of common and emerging infectious syndromes with appropriate antimicrobial therapy to minimize allograft toxicity. As an invaluable resource document, readers are also referred to Green and colleagues (see “Selected Readings”).
GENERAL GUIDELINES FOR INFECTION RECOGNITION
Table 11.1 summarizes the risk factors for infection in the pretransplantation and post-transplantation periods. Recognition of the following factors may assist in the identification of the causative pathogen and the initiation of appropriate empiric antimicrobial therapy before laboratory confirmation:
1. The timing of an infectious episode after transplantation is critical. Most infections occur in the first month after transplantation and are typically related to technical complications of the surgery or invasive medical devices and most commonly involve the genitourinary infection.
During months 1 to 6, infections associated with postoperative complications or with enhanced immunosuppression can develop, persist, or recur. Augmented immunosuppression is associated with an increased risk for infection with immunomodulating viruses such as cytomegalovirus (CMV), human herpesvirus (HHV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV), that enhance susceptibility to opportunistic infections by altering the expression of inflammatory mediators and cytokines by a complex interrelated cascade. This leads to a permissive environment for opportunistic pathogens such as Pneumocystis, Aspergillus, Cryptococcus, and other fungi; bacteria including Listeria monocytogenes; and Nocardia, Toxoplasma, and other viruses. CMV and other HHVs also exert an immunomodulating effect that has been implicated in allograft rejection, obliterative transplant arteriopathy, and post-transplantation lymphoproliferative disorder (PTLD).
TABLE 11.1 Risk Factors for Infection in Renal Transplant Recipients | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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After post-transplantation month 6, patients generally can be categorized as those with successful graft outcome and minimal long-term maintenance immunosuppression, those with poor graft function because of chronic rejection who require intensified immunosuppression, and those chronically infected with immunomodulating viruses
such as CMV. Infections in patients with long-term successful allografts are typically similar to those that develop in persons in the community, whereas the latter two patient groups are at ongoing risk for opportunistic infections.
such as CMV. Infections in patients with long-term successful allografts are typically similar to those that develop in persons in the community, whereas the latter two patient groups are at ongoing risk for opportunistic infections.
2. The net state of immunosuppression is a semiquantitative assessment that reflects the complex interaction of the following factors:
▪ The dose, duration, and temporal sequence of immunosuppressive therapy, including augmented immunosuppression for episodes of rejection
▪ Quantitative immunodeficiency, including leukopenia, thrombocytopenia, and low immunoglobulin levels
▪ Breach of tissue barriers by foreign bodies (e.g., urinary and venous catheters, ureteral stents), open wounds, fluid collections, and devitalized tissues
▪ Metabolic abnormalities such as hyperglycemia, uremia, liver failure, and malnutrition
▪ Infection with immunomodulatory viruses
3. The infectious history of the donor, specifically any infectious syndromes and pathogen that can be directly transmitted with the allograft.
4. Recipient history of infections and exposures, such as tuberculosis, hepatitis viruses, human immunodeficiency virus (HIV), varicella-zoster virus (VZV), CMV, or EBV; immune-altering conditions, such as surgery or functional asplenia; and pretransplantation medical conditions including rheumatologic disorders, such as systemic lupus erythematosus, that require immunosuppressive therapy, diabetes mellitus, substance or injection drug use, liver dysfunction, malnutrition, and potential risk for exposure to geographically restricted endemic mycoses, toxoplasmosis, tuberculosis, and Strongyloides species.
5. The acquisition of community and health care-associated pathogens, such as Streptococcus pneumoniae, Enterobacteriaceae, and Pseudomonas species, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). Pretransplantation dialysis patients and kidney recipients may harbor bacteria and yeasts on their skin and sinopulmonary and gastrointestinal tracts related to frequent contact with health care settings and antimicrobial exposure. In the setting of graft dysfunction, postoperative surgical complications, or rejection, these colonizing organisms have the potential to cause invasive infection. Identifying these colonizing organisms and, when appropriate, determining antimicrobial susceptibility may help to direct empiric antimicrobial therapy if clinical infection develops.
6. Factors that delay or confound the diagnosis of infection in the recipient include an impaired host inflammatory response; the delay in clinical diagnosis because of the lack of classic clinical and radiologic signs associated with infection and inflammation compared with the immunocompetent host; the rapid progression of infections in this context, particularly with altered transplant anatomy; the failure to recognize high-risk patient characteristics (e.g., diabetes, enhanced and prolonged immunosuppression, multiple antibiotic courses); and delays in laboratory diagnosis and limited rapid diagnostic assays for fungal, mycobacterial, and viral diseases.
PRETRANSPLANTATION SCREENING: DONOR AND CANDIDATE
Untreated or unrecognized infections in the recipient can become clinically apparent in the post-transplantation period. These can include intravascular
device infection, pneumonia, periodontal abscess, intra-abdominal, hepatobiliary, or genitourinary tract infection. During pretransplantation screening, the identification of latent or active infections in the recipient can lead to a reappraisal of transplant candidacy or to alterations in standard post-transplantation antimicrobial therapy. For the living related donor, a careful history of potential latent infections should be ascertained, and any active infection should be treated when appropriate. Donation should be deferred until the respective infection resolves.
device infection, pneumonia, periodontal abscess, intra-abdominal, hepatobiliary, or genitourinary tract infection. During pretransplantation screening, the identification of latent or active infections in the recipient can lead to a reappraisal of transplant candidacy or to alterations in standard post-transplantation antimicrobial therapy. For the living related donor, a careful history of potential latent infections should be ascertained, and any active infection should be treated when appropriate. Donation should be deferred until the respective infection resolves.
It may be difficult to differentiate among an infection acquired from the allograft, from an exogenous source, or from reactivation of latent disease in the recipient. The following infectious agents have been implicated in transmission from the donor allograft: aerobic gram-positive and gram-negative bacteria, anaerobic bacteria, Mycobacteria species, Toxoplasma species, and Strongyloides species; HIV, CMV, HBV, HCV, herpes simplex virus (HSV), VZV, EBV, and West Nile virus; and fungi including Candida species, Histoplasma capsulatum, Coccidioides immitis, Cryptococcus neoformans, Aspergillus species, and Scedosporium apiospermum. Serious complications of donor allograft-transmitted infections include bacteremia, fungemia, disruption of the vascular anastomoses, formation of “mycotic” (microbial) aneurysms, and infective endocarditis. The risk for donor-transmitted infection can be reduced by careful screening and epidemiologic evaluation (see Chapter 7).
Donor Screening
Postoperative infections can arise from inadequate donor screening. The donor’s medical and social history should include information on high-risk behaviors such as prior hospitalizations and blood transfusions, injection drug use, incarceration histories, and tuberculosis exposures. These exposures may be associated with an increased risk for acute HIV, HBV, and HCV infection where screening serologies may be negative. The organ procurement agency should provide results of donor microbiology cultures, serum serologies, and history of infections, including upper and lower urinary tract infection and bacteremia that may not be confirmed by the laboratory until after transplantation in some cases. Because many deceased donor kidneys may be recovered from patients in intensive care units, occult bacteremias or genitourinary tract infection should be excluded by appropriate cultures. In the case of donor-associated bacteremia, appropriate antimicrobial therapy should be administered to the recipient typically for 14 days, and follow-up blood cultures should be obtained to exclude endovascular infection of the vascular anastomosis. Although rare, this complication has been associated with donor-derived bloodstream infection with S. aureus, Pseudomonas aeruginosa, other gram-negative bacilli, and Candida and Aspergillus species. During the allograft harvesting and transplantation, microbial contamination of the preservation media can occur. In such cases, appropriate antimicrobial therapy should be administered to the recipient, typically for 14 days. Syphilis has been transmitted in solid organ transplantations but is not a contraindication to organ donation. The recipient should receive treatment appropriate to the presumed stage of donor syphilis infection. Deceased donor kidneys have been transplanted successfully from donors with localized, nongenitourinary infections, including pneumonia and meningitis. However, donors with active fungal infection, especially bloodstream and genitourinary infections, unspecified viral infections, suspicion of encephalitis, or ambiguous causes of infectious death should be avoided. A nucleic acid amplification technique (NAT) is now being used more commonly to screen donor blood for HBV, HCV, and HIV-1 and -2 and should reduce the risk for transmission of these viral agents during the “window” period to negligible.
Transplant Candidate Screening
Evaluation of the transplant candidate for infection risk should include a history of antibiotic allergies and nature of reaction, a dental examination, and assessment for remote or active infection, including a urine culture and chest radiograph (Table 11.2). Patients with polycystic kidney disease who have been treated for infected polycystic kidneys should have repeatedly negative urine cultures. Pretransplantation polycystic nephrectomy is occasionally required (see Chapter 7).
The candidate should be evaluated for potential risk for exposure to Mycobacterium tuberculosis or endemic mycoses, including history of prior residence or travel to high-risk areas, PPD skin test, blood interferon-gamma release assay, and, if indicated, serologic testing for C. immitis or H. capsulatum, especially if the chest radiograph demonstrated calcified or noncalcified granuloma. Living donors should have a PPD skin test, and urine acid-fast bacillus (AFB) stain and mycobacterial cultures should be obtained if there is a history compatible with disseminated tuberculosis. The higher incidence of cutaneous anergy in patients with end-stage renal disease may confound the tuberculosis risk assessment, so it is critical to assess for a history of latent or active tuberculosis or compatible chest radiograph and to administer isoniazid prophylaxis, if indicated. The 2000 American Thoracic Society and Centers for Disease Control and Prevention (CDC) guideline recommends treatment of latent tuberculosis with isoniazid (5 mg/kg per day, maximum of 300 mg daily for adults) for 9 months. Patients who previously completed an adequate treatment course for latent or active tuberculosis typically do not require additional antituberculous therapy after transplantation.
TABLE 11.2 Transplant Candidate Screening | ||||||||||||||||||||||||||||||||||||||||||
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Preoperative antibody testing, when appropriate, should include CMV, VZV, EBV, HSV-1 and -2, HIV-1 and -2; anti-hepatitis B virus surface antibody (anti-HBsAb), surface antigen (HBsAg), and core antibody (HBcAb); and HCV antibody (see Chapter 12); and testing for endemic mycoses when appropriate.
Specific Serologic Testing
Cytomegalovirus
The seroprevalence of CMV ranges from 40% to 97%, depending on the population screened, and increases with age. Most adult dialysis patients have detectable immunoglobulin G (IgG) antibody to CMV. The CMV antibody status of the donor and recipient should be ascertained. A CMV-seronegative recipient (R-) of a CMV-seropositive donor (D+) is at the highest risk for developing subsequent CMV infection and disease. After transplantation, these recipients require preemptive antiviral therapy, typically for 100 days, and careful clinical and laboratory monitoring for evidence of CMV viremia. Recipients receiving antilymphocytic therapy may require prolonged preemptive antiviral therapy. Although CMV-seropositive recipients (D+/R+, D−/R+) have a lower risk for CMV disease, a similar prevention strategy should be employed, based on the individual patient risk factors and net state of immunosuppression. The clinical implications of the CMV infection are discussed in “Viral Infections” and summarized in Table 11.3.
TABLE 11.3 Risk for CMV Infection and Disease without CMV Prophylaxis by Donor and Recipient CMV Serostatus | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Epstein-Barr Virus
Both EBV-seronegative recipients of grafts from EBV-seropositive donors and EBV-seropositive recipients may be at increased risk for PTLD, particularly if they receive prolonged or repeated courses of antilymphocytic therapy (see Chapter 10). EBV mismatch occurs more commonly in pediatric kidney recipients. In high-risk patients, the quantitative EBV viral load can be assayed by polymerase chain reaction (PCR).
Other Human Herpesviruses
Other HHVs of significance to organ transplant recipients include HSV-1 and -2, VZV, and HHV-6 and HHV-8. HHV-6 has been implicated as a cofactor for CMV and other infections; no treatments are available. HHV-8 may cause transplant-associated Kaposi sarcoma and EBV-negative lymphoproliferative disease. Generally, screening for HHV-6 and -8 is not performed before transplantation.
Hepatitis B and C
The detection of chronic HBV and HCV infection in both transplant donors and recipients has improved with newer laboratory methods to detect viral-specific antibodies, antigens, and nucleic acids. The impact of latent or active HBV and HCV infection on transplant candidacy and kidney donation is discussed in Chapter 12.
Human Immunodeficiency Virus
All potential transplant donors should be tested for HIV-1 and -2 antibody. A history of any high-risk behaviors must be obtained, because transplant-derived HIV infection has been associated with acute infection in the seronegative “window” period or associated with massive blood transfusion and false-negative donor HIV antibody test results (see Chapter 4). Routine donor HIV antibody testing routine donor HIV testing and rejection of organs from donors with a high-risk history have reduced the risk for infection to an almost negligible degree. However, in January 2007, four transplant recipients acquired HIV infection from a self-identified high-risk donor, the first instance of HIV transmission through organ donation in the United States since 1985. Routine NAT testing of donor blood would have detected acute HIV infection in this donor with acute HIV infection.
Human T-Lymphotrophic Viruses
Human T-lymphotrophic virus I (HTLV-1) is more common in individuals from the Caribbean and Japan. Blood products, organ transplants, and intimate contact can transmit HTLV-1. Clinical syndromes include HTLV-1-associated myelopathy or tropical spastic paraparesis and adult T-cell leukemia and lymphoma virus. HTLV-1 myelopathy has been reported after transplantation from an infected donor. HTLV-2 is serologically similar to HTLV-1, but disease association is under investigation. Donors with HTLV-1 seropositivity are generally not used.
West Nile Virus
West Nile virus (WNV) is a vector-borne flavivirus transmitted from the bite of an infected mosquito, and much less commonly through blood and transplanted organs. In late 2002, the CDC confirmed the transmission of WNV to organ recipients from a single donor with serious consequences to the recipients. First-generation serologic and PCR assays are available. The epidemiology of WNV has changed rapidly, so the extent of risk to the donor pool and recipients remains under investigation. During summer months, it is prudent to avoid organs from donors from an area with active WNV infection who have symptoms of a viral illness, especially encephalitis or meningitis.
Coccidioidomycosis and Histoplasmosis
Candidates who have resided in at-risk geographic areas should be tested for C. immitis IgM and IgG antibody by enzyme immunoassay (EIA) or H. capsulatum antibody by immunodiffusion during transplant evaluation. Because of the substantial risk for reactivation, recipients with a history of prior infection with endemic fungi or who have detectable antibodies should receive prophylactic azole antifungal therapy following renal transplantation typically for the life of the allograft.
Transplant Candidate and Recipient Immunization
Vaccine-preventable infections are a major source of morbidity following solid organ transplantation. During the transplant evaluation, the candidate’s immunization history should be carefully reviewed and immunizations updated. Current adult and pediatric immunization schedules are available at http://www.cdc.gov/vaccines/recs/schedules/default.htm, and updated recommendations for vaccination of solid organ transplant recipients were published in 2007 and are summarized in Table 11.4.
Unless there are contraindications, VZV-seronegative transplant candidates should receive two doses of live varicella vaccine, and seropositive candidates 60 years or older should receive a single dose of live zoster vaccine to decrease the risk for varicella disease. Other live attenuated vaccines, such as measles, mumps, and rubella (MMR) and varicella, should be administered no later than 4 to 6 weeks before transplantation to minimize the possibility of vaccinederived infection in the post-transplantation period. Ideally, household contacts of transplant recipients should be fully immunized to protect the transplant recipient. Live vaccines should be avoided before transplantation in candidates receiving immunosuppressive therapy and following solid organ transplantation. Other live attenuated vaccines, including bacille Calmette-Guerin, oral polio, and live attenuated influenza vaccine, should also be avoided.
Inactivated vaccines are safe to administer to transplant recipients and include hepatitis A and hepatitis B, intramuscular influenza A and B, 23-valent unconjugated and 7-valent conjugated pneumococcal, Haemophilus influenzae B, inactivated polio, diphtheria-acellular pertussis-tetanus (Tdap), and polysaccharide or conjugated meningococcal vaccines. Annual influenza vaccination is recommended for transplant candidates and recipients. The anecdotal risk rejection with influenza immunization has not been substantiated in randomized trials of solid organ transplant recipients, whereas influenza infection in these patients is associated with higher morbidity and mortality, graft rejection, and prolonged viral shedding. Immunization with meningococcal and inactivated polio vaccines may be appropriate for special risk situations, including travel or occupational risk. An accelerated schedule for hepatitis B immunization can be used before and following transplantation, especially if the organ is from a donor with anti-HBsAb. Following hepatitis B immunization, anti-HBsAb levels should be measured to document seroconversion.
PATHOGENESIS AND DIAGNOSIS OF INFECTION IN KIDNEY ALLOGRAFT RECIPIENTS
About 80% of infections in kidney transplant recipients are bacterial. Tables 11.5 and 11.6 summarize the syndromes and microbial pathogens commonly encountered in kidney transplant recipients. Infections occurring during the first month are typically associated with technical complications of the surgery or indwelling medical devices and most commonly include genitourinary tract infection, bacteremia, surgical site infection, pneumonia and intra-abdominal infection.
TABLE 11.4 Recommended Immunizations for Pediatric and Adult Transplant Candidates and Recipients | ||||
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