Infectious Complications of Kidney Transplantation

Timing of Infectious Complications in Kidney Transplantation

Infectious complications typically occur in one of three time periods posttransplant: early posttransplant, during peak immunosuppression, and late onset. A number of donor- and recipient-specific factors impact the timing of infections, including preexisting infection or immunity, the use of antimicrobial prophylaxis, and the net state of immunosuppression. Of these, the net state of immunosuppression requires the closest consideration as there are no direct measures to assess the impact of various factors on risk of rejection or infectious complications. Instead, the clinician must assess a variety of factors including current and past immunosuppression; underlying immunodeficiency; neutropenia; lymphopenia; complex metabolic conditions, such as presence of uremia, malnutrition, poorly controlled diabetes mellitus, and cirrhosis; and replication of immunomodulatory viruses, including HIV, CMV, Epstein-Barr virus (EBV), hepatitis B, and hepatitis C. Review of immunosuppression must keep in mind both medications that may not be readily apparent on the patient’s medication list (i.e., alemtuzumab for induction or rituximab for the treatment of antibody-mediated rejection as such antibody-based immunosuppression may have longstanding impacts of components of the immune system) as well as the impact of recent immunosuppression, such as recent rejection treatment, high plasma levels of tacrolimus, or recent conversion from one immunosuppression agent to another. For example, with many immunosuppression conversions, the patient is effectively exposed to multiple agents with effective immunosuppression as one agent is titrated off and another is titrated on. Taken together, these inform the net state of immunosuppression for an individual patient.

Early posttransplant infections are infections that occur in the first 30 days after transplantation. The majority of such infections (∼98%) are those one would see in any surgical patient, but they may be more severe or more common. The most common postsurgical infections include deep and superficial surgical site infections, hospital-acquired pneumonias as a consequence of mechanical ventilation, urinary tract infections due to bladder catheterization, bacteremia secondary to use of intravenous catheters, and Clostridium difficile colitis as a complication of perioperative antimicrobial utilization. Management approaches for such infections are consistent with the local epidemiology and susceptibility of predicted pathogens and published guidelines. Rarely, donor-derived infections may present during the first 30 days posttransplant, as discussed in greater detail below. Finally, recipient-origin infections may manifest in the first 30 days. These include respiratory viral infections, such as influenza, or occult bacteremia that were incubating in the candidate at the time he or she presented for the transplant procedures.

Infections during peak immunosuppression are typically opportunistic infections or pathogens that reactivate from latent infection in the recipient; these generally occur between 30 days and 6 months posttransplant, or within 3 months of treatment of rejection. Use of prophylactic antimicrobials may delay the onset of such infections, resulting in later than typical onset. For example, high-risk CMV donor seropositive, recipient seronegative (D+/R−) patients frequently will be given 6 months of anti-CMV prophylaxis, and, as a result, CMV incidence peaks 1–3 months after such prophylaxis is discontinued. Examples of infections that typically occur during the period of peak immunosuppression include BK virus, CMV, HSV, VZV, HBV, HCV, tuberculosis, Listeria, Strongyloides, and Chagas.

Late-onset infections are infections that typically present greater than 6 months posttransplant, or greater than 3 months after treatment for a rejection episode. Most late-onset infections are community-acquired infections, such as community-acquired pneumonia, respiratory viral infections including influenza, and urinary tract infections. Such infections may lead to hospitalization or require aggressive antimicrobial therapy for treatment. Patients may acquire infections from exposure to the environment or travel, which increases over time as the patient returns to normal function. Examples of environmental exposures include endemic mycoses, including histoplasmosis, blastomycosis, and coccidiomycosis, West Nile Virus, and travel-associated malaria. Some opportunistic infections notoriously present late, including Nocardiosis, mucormycosis, and JC virus-mediated progressive multifocal leukoencephalopathy (PML). Lastly, some infections such as CMV, EBV-positive and EBV-negative posttransplant lymphoproliferative disorder (PTLD), hepatitis, and TB may present in this late period. Pneumocystis jirovecii (PCP) historically was an infection complicating the period of peak immunosuppression, although, with universal prophylaxis, most cases of PCP occur late posttransplant in the current era.

Donor-Derived Infections and Risk Mitigation Strategies

Donor-derived infections are defined as any infection present in the donor that is transmitted to the recipient with the transplanted organ or vessels. Donor-derived infections can be categorized as either expected disease transmissions, where the pathogen is known to be present in the donor at the time of procurement and steps are taken to mitigate the disease transmission, or unexpected disease transmissions, when the donor is not recognized to have an infection that is identified after resulting in clinical disease in one or more of the transplant recipients. Examples of expected disease transmissions include CMV or EBV, in which the donor is recognized to have an infection and the recipient is either monitored for evidence of disease or given prophylactic medications to prevent clinical diseases. Examples of unexpected disease transmissions include bacteria ( E. coli , Mycobacteria tuberculosis, and S. aureus ), fungi (Candida, Cryptococcus, and Histoplasmosis), parasites (Chagas, Strongyloides, and Acanthamoeba), and viruses (lymphocytic choriomeningitis virus (LCMV), rabies, HIV, and HCV). In the United States, any documented or suspected unexpected donor-derived disease transmissions need to be reported to the Organ Procurement and Transplantation Network (OPTN) as soon as possible, but not greater than 24 hours after initially suspecting transmission (OPTN Policy 15.4); the report is made through the Patient Safety Portal. Timely reporting of suspected transmissions is essential to facilitate communication and rapidly allow screening and treatment of recipients of other organs from the same donor. Data on such disease transmissions have been collected and categorized based on standardized methodologies.

There are several ways in which potential living and deceased donors can be screened to mitigate the risk of disease transmission. All prospective donors should undergo a careful review of their medical and social history, have a physical examination of the donor and the potential organs, and receive a thorough testing of blood. The donor medical and social history should be reviewed for history of documented infection or exclusion from blood donation. The donor’s social history should be reviewed for residence or travel to regions of endemicity for potentially transmissible infections, including Chagas, Coccidiomycosis, Mycobacteria tuberculosis , Strongyloidosis, Toxoplasmosis, and West Nile Virus. Patients with evidence of prior exposures to such potentially transmissible diseases should be screened for latent infection, and such screening is required for living donors (OPTN Policy 15.3). The social history should also be reviewed for risk factors that place the donor at increased risk of transmission of HIV, HBV, and HCV, as defined by the US Public Health Services, as summarized in Table 62.1 . Recently, OPTN policy markedly changed the approach to categorizing donors at increased risk of infection transmission and how they are handled. Historically, these donors required special informed consent and focused posttransplant testing. With the most recent revisions, the period of risk in the donor was reduced to 30 days, education about risks was incorporated into standard education on all patients, and all patients are to have HIV, HBV, and HCV polymerase chain reaction (PCR)-based testing at 4-6 weeks posttransplant; liver transplant patients are also required to have HBV testing at 1 year. There is no longer a requirement for special informed consent.

Donors with recognized infections require additional attention ( Table 62.2 ) . While full discussion of relevant risk and prevention strategies are available elsewhere, three unique situations warrant review here: HBV infection in the donor, bacteremic donors, and donors with meningitis or encephalitis. Required screening of donors includes hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb); many donors may also have HBV nucleic acid testing (NAT) available. Donors with detectable virus by positive HBV NAT or HBsAg have active infection and can transmit infection to kidney recipients. As such, these are typically reserved for recipients with preexisting HBV infection, typically with the use of HBV-active antivirals to prevent replication. Transplant of HBV-infected donor kidneys in select hepatitis B surface antibody (HBsAb)-positive recipients has been described with typically excellent outcomes, but in the setting of careful monitoring, antiviral medication, and informed consent. Donors with HBcAb positivity alone have a history of infection with HBV, which remains latent. Since these individuals account for up to 15% of the donor population, there is a greater body of evidence on the outcomes of recipients of such donors. Typically, HBcAb+ donors are utilized in recipients with prior HBV vaccination and positive HBsAb titers of >10 IU/L (although optimal protection is with ≥100 IU/L). Outcomes of such transplants are generally excellent without the need for antivirals with a low rate of HBV transmission, typically 4% or lower. Such patients should be monitored for HBV replication posttransplant. If HBcAb+ donors are used in HBsAb-negative recipients, antivirals can be considered until vaccination is given to the recipient.

Donors with bacteremia are another group that requires careful consideration as they compromise up to 5% of organ donors. Donors with active bacteremia pose a clear risk of disease transmission, and use of these organs requires careful consideration, informed consent of the recipient, and posttransplant antibacterial therapy. Most cases of transmission have involved resistant bacteria or recipients who receive inadequate therapy. Generally, it is recommended that the bacteremic donor receives effective antimicrobial treatment (targeted at the causative bacteria with known susceptibility patterns) for at least 24–48 hours and that the donor has ideally some degree of clinical response (improved white blood cell count, improved hemodynamics, defervescence). The donor should be carefully assessed for the presence of metastatic infection, particularly in the organ to be transplanted, and for endocarditis when there is more than transient bacteremia or risk factors (i.e., intravenous drug use, recent dental work). Use of donors with gram-negative bacteria producing carbapenemases, which usually exhibit extended drug-resistant phenotypes and remain susceptible to only a few antibiotics, must be done with caution and with active engagement of Transplant Infectious Diseases experts as these pose the highest rates of disease transmission and active agents may be associated with nephrotoxicity. Recipients are typically treated for at least 14 days of active antibiotic posttransplant and then monitored closely for evidence of recrudescent bacteremia.

Organs from donors with documented bacterial meningitis, with or without bacteremia, can generally be safely utilized with little risk of disease transmission. Generally, donors are treated for 24–48 hours with antibiotics directed at the identified bacteria prior to procurement, optimally with evidence of clinical improvement. The recipient is typically treated for 7–14 days posttransplant with antibiotics directed at the cultured bacteria. Meningitis caused by highly virulent or intracellular organisms such as Listeria species or Mycobacteria are considered a contraindication. Donors with a clinical diagnosis of bacterial meningitis but without positive bacterial cultures have been known to transmit infections and malignancies, and should generally be avoided. Donors with encephalitis, particularly with fever, without a documented cause are frequently associated with disease transmission. Transmission of rabies, parasitic infections, lymphomas, and leukemias has occurred when donors with encephalitis without a proven cause were accepted as organ donors. As such, donors dying of encephalitis without a proven cause should likely be avoided. The one exception are donors with documented Naegleria fowleri meningitis/meningoencephalitis in which the risk of disease transmission is low and such donors can generally be safely used.

Infectious Disease Prevention Strategies

While available therapies have improved the outcome of infectious complications of kidney transplantation, prevention remains the key to optimize care of these patients. Prevention strategies include thorough recipient screening, optimization of vaccination of recipients and their contacts, and use of selected antimicrobial prophylaxis. All recipients should be screened pretransplant for HIV, HBV, HCV, CMV, EBV, VZV, measles, mumps, rubella, tuberculosis (with either a PPD or interferon-gamma release assay), and relevant latent endemic infections, including Chagas disease, Coccidiomycosis, and Strongyloides. Patients who plan to travel to underdeveloped regions of the world posttransplant should be seen by travel medicine experts for consideration of protective vaccines prior to transplant and at least 30 days prior to any such travel. Candidates should have a thorough screening to ensure their vaccine status is up to date prior to transplant. Special attention should be paid to candidates with negative VZV serology, who should receive pretransplant varicella vaccine, patients with negative measles, mumps, or rubella titers, who should receive the MMR vaccine, and patients with negative HBsAb who should receive the three-dose HBV vaccine series. Pre- and posttransplant, candidates and their family members should have up-to-date influenza (annually), tetanus-diphtheria-acellular pertussis (Tdap, once every 10 years), and pneumonia vaccine ( Table 62.3 ).

Selected antimicrobial prophylaxis should be given to patients beginning at the time of transplantation. Published guidelines recommend cefazolin or vancomycin plus either aztreonam or a fluoroquinolone given no more than 60 minutes before the skin incision as a single dose. Pneumocystis jirovecii prophylaxis consists of trimethoprim-sulfamethoxazole (TMP-SMX) single or double strength daily to three times per week for the first 6–12 months posttransplant; for sulfa-allergic patients, atovaquone 1500 mg daily, dapsone 50–100 mg daily (must not be used with G6PD deficiency), or pentamidine 300 mg nebulized every 4 weeks are alternatives. Prophylaxis for CMV is discussed below, although CMV D-/R- recipients need prevention of VZV and HSV with acyclovir, valacyclovir, or famciclovir for 3-6 months posttransplant. Kidney recipients benefit from UTI prophylaxis while ureteral stents are in place; TMP-SMX daily or cephalexin 500 mg daily is adequate.