Introduction

Infections are a significant cause of morbidity and mortality after kidney transplantation and have been implicated in allograft dysfunction, rejection, and loss. Both opportunistic and traditional organisms are important causes of infection. The risk for specific infections varies with timing posttransplant, exposures, and the degree of immunosuppression. Because the array of pathogens is diverse, the risk factors not necessarily modifiable, and the causative exposures not consistently anticipated, prevention of infection is a complicated and imperfect process. Moreover, the clinical presentation of infection may be atypical in the setting of immunosuppression, making diagnosis more difficult. Concurrent coinfections with multiple organisms can occur, and in some cases, it is difficult to differentiate infectious from noninfectious causes of patient presentations. Because transplant recipients are chronically maintained on immunosuppression, they are at especial risk for more severe presentations of infection, even with organisms traditionally associated with more benign courses. Prompt and accurate diagnosis is imperative to ensure optimal outcomes.

Infections in kidney transplant recipients can be viewed as the balance of the host interaction with the environment as mediated by prophylactic strategies. Transplant recipients may have underlying conditions associated with depressed host immunity before the administration of the exogenous immunosuppression required to maintain allograft function. The choice of immunosuppression plays an important role in specific infection risks. For example, T-cell depleting therapies, including antithymocyte globulin, increase the risk for opportunistic infection, and mammalian target of rapamycin (mTOR) inhibitors have been associated with skin and soft tissue infections ( Table 40.1 ). The risk for infection also reflects a recipient’s exposures. This includes pretransplant infections that have the potential for latency (e.g., herpesvirus infections, tuberculosis [TB]) as well as infections associated with the transplant including donor-derived and hospital-acquired infections. In the posttransplant setting, new exposures related to environmental and community interactions need to be considered. In some cases, these exposures can be anticipated based on predictive risk periods posttransplant and appropriate prophylaxis can be administered during the highest risk period to reduce the risk for infection; antivirals directed against cytomegalovirus (CMV) are an example of risk mitigation. A thorough evaluation of all potential recipients and donors is critical to manage infection risks.

Pretransplant Recipient Evaluation

All potential transplant candidates should undergo screening to identify both active infections that may have an effect on transplant eligibility and latent infections that may reactivate after transplant and affect patient outcomes ( Table 40.2 ). The screening process should include a thorough history of prior infections, environmental exposures associated with infection risks (including current and prior locations of residence, occupations, hobbies, and pets), and close contacts with communicable diseases such as TB. A careful physical examination should be performed. Laboratory testing should include serological testing for herpesviruses (CMV, herpes simplex virus, varicella zoster virus, and Epstein-Barr virus [EBV]), human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, and Toxoplasma gondii . In situations where window period infections for HIV, HBV, or HCV may be suspected or if there is concern regarding underlying immunodeficiency that may reduce the sensitivity of serological testing, nucleic acid antibody testing should be obtained. Tuberculin testing is especially important; either interferon gamma release assays (IGRAs) or intradermal tuberculin purified protein derivative (PPD) placement can be performed. Since both tests have reduced sensitivity in patients with end-stage renal disease, a detailed history focusing on common risk factors and radiography are important components of this evaluation. For patients with a history of birth or prolonged residency in places where there are increased risks for geographically associated infections (e.g., strongyloidiasis, Chagas disease, coccidioidomycosis, and histoplasmosis), additional serological testing for the specific organism should be considered. During the pretransplant evaluation, immunization histories should be reviewed and vaccines updated as appropriate (see immunization section; Table 40.3 ).

Donor Evaluation

Donor-derived infections occur rarely. Nevertheless, both living and deceased organ donors have been implicated in donor-derived infections; transmissible pathogens are diverse and include bacteria (e.g., pyogenic organisms and Mycobacterium tuberculosis ), fungi (especially endemic mycoses and Candida), viruses (most commonly herpesviruses), and parasitical organisms (including strongyloides). Standard evaluations of both should include a thorough history of past infections and exposures associated with transmissible infections. Because deceased donor histories are provided by surrogates, they are generally less detailed; however, the increased use of paired kidney exchange has led to increased numbers of evaluations being obtained outside the recipient’s center. Whether this impacts on the quality of donor information is unknown. In both cases, laboratory testing should mirror that of the transplant candidate with specific attention to active infections at the time of deceased donation and infections that may reactivate in an immunosuppressed transplant recipient (including herpesviruses, endemic mycoses, and parasitical infections) in both living and deceased donors (see Table 40.2 ). Live donors may be evaluated for latent TB using either intradermal tuberculin PPD testing or IGRA. Given the limitations of TB testing in the setting of deceased donor evaluation, it is especially important to obtain historical information and radiography to assess the potential for deceased donor latent infection. The presence of potentially transmissible donor infections may not exclude a donor from transplantation. Donors with bacteremia, meningitis, or other bacterial infections that do not involve the kidney have been successfully used and may be considered, assuming that the donor has been appropriately treated for 24 to 48 hours and there are acceptable antimicrobial treatment options. Latent infections in the donor including TB and endemic mycoses may be treated with appropriate antimicrobials after transplantation. Donors who are actively infected with organisms that do not have effective treatment options should be excluded. Special attention should be paid to deceased donors with undiagnosed central nervous system (CNS) processes as these donors have been implicated in severe and fatal donor-derived infections, including West Nile Virus, rabies, and Cryptococcus ; consequently the risks associated with using these donors must be balanced with the need for transplantation.

Recent publications have focused on donors who pose an increased risk for blood-borne viral disease transmission because of behaviors associated with recent acquisition of HIV and HCV ( Table 40.4 ). Depending on the screening methodology used (serological vs. nucleic acid testing), there is a window of variable duration during which infection may be present but cannot yet be detected. The Public Health Service (PHS) increased risk donor (IRD) criteria attempt to identify donors at risk for window period infections and disease transmission. The absolute risk for disease transmission overall is quite small, but varies based on the risk behavior, the infection in question, and the testing methodology; for example the risk for HIV transmission from a donor who was incarcerated with negative nucleic acid testing (NAT) and antibody testing is 0.9 per 10,000 but the risk for HCV infection from a donor with active intravenous (IV) drug abuse and antibody testing alone is 300 per 10,000. The prevalence of PHS IRDs is increasing and IV drug users represent the largest proportion of this group of donors. Compared with deceased donors overall, PHS IRDs are more likely to be young and male and less likely to meet expanded donor criteria ; despite the better organ quality afforded by these donors, these organs are more likely to be discarded (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.61 to 0.74). However, for recipients who accept these organs, outcomes are equivalent to those observed with non-PHS IRDs.

The updated guidelines and Organ Procurement and Transplantation Network policies require NAT testing for all IRDs as well as specify testing for living donors to be performed within the 28 days before the transplant surgery. There was also greater emphasis placed on the informed consent process for recipients and clarification regarding the assays and intervals for posttransplant testing; recipients of PHS IRDs should have serological and NAT testing for HIV, HBV, and HCV performed between 1 and 3 months after transplant and testing for HBV at 1 year.

As the opioid epidemic continues to affect large parts of the United States, and PHS IRDs continue to contribute a substantial number of organs to the donor pool, it is important that patients are counseled about the acceptable posttransplant outcomes as well infectious risks associated with these organ offers, compared with the risk for death and disease transmission on dialysis; in recognition of the high prevalence of HCV infection among the population with end-stage renal disease (ESRD), hemodialysis patients themselves are considered PHS IRDs. It has been shown that patients will consider these organ offers. In one study, younger donor age, exposure to dialysis, and longer wait times for an organ were associated with increased acceptance of PHS IRD.

Timeline of Infection

Infection risks may be anticipated based on the net state of immunosuppression, patient exposures (defined as active and latent infections in donor and recipient, and healthcare and community environmental and personal contacts), and prophylactic measures ( Fig. 40.1 ). Standard immunosuppression protocols have allowed for the development of a timeline of anticipated infection that provides a starting point for infection assessment ( Table 40.5 ). Infections in transplant patients may be more severe, especially during periods of more intense immunosuppression. They also may be more difficult to recognize due to the absence of typical features of infection (e.g., fever) in patients on immunosuppressive agents, and noninfectious syndromes occasionally mimic infections. Consequently, this timeline should be regarded as a starting point and individual patient circumstances should be carefully considered to determine the optimal patient evaluation.

The timeline of posttransplantation infections. (Adapted from Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357(25):2601–2614.) HBV, Hepatitis B virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; LCMV, lymphocytic choriomeningitis virus; MRSA, methicillin-resistant staphylococcus aureus; PCP, pneumocystis jiroveci pneumonia; PML, progressive multifocal leukoencephalopathy; PTLD, posttransplantation lymphoproliferative disorder; SARS, severe acute respiratory syndrome; VRE, vancomycin-resistant Enterococcus faecalis; and VZV, varicella-zoster virus.

Months 1 to 6

This intermediate period posttransplant is typically considered to be the highest risk period for the occurrence of opportunistic infections. During this time, the effects of exogenous immunosuppression required to prevent rejection are maximal, enhancing the net state of immunosuppression. Further immune modulation may occur in the setting of coinfection with immunomodulating viruses, such as CMV, or related to metabolic derangements (especially diabetes) that are common during this period. Reactivation of latent infections and acquisition of new infections from the environment, other individuals, and the donor may occur; the resulting infections may be more severe in the immunosuppressed host.

The pathogens seen during this intermediate period are diverse and in the absence of prophylaxis, include bacteria (e.g., Nocardia species, Listeria monocytogenes , and mycobacteria, especially TB), fungi (e.g., Aspergillus species, Cryptococcus , and Pneumocystis jirovecii ), viruses (e.g., CMV, EBV), and parasites/protozoa (e.g., toxoplasmosis). Infections with geographically restricted pathogens including Strongyloides stercoralis , Trypanosoma cruzi , and endemic mycoses ( Coccidioides immitis , Blastomyces dermatitidis , and Histoplasmosis capsulatum ) also may occur. It is important to recognize that exposures both before and after transplantation may result in infections during this period.

Because some infections may be predictably anticipated, several of the more common opportunistic infections may be prevented by the administration of prophylactic antimicrobials ( Table 40.6 ). The use of trimethoprim sulfamethoxazole to prevent Pneumocystis jirovecii pneumonia and valganciclovir to prevent CMV are examples of successful prophylactic strategies. However, prophylactic antimicrobials may not completely eradicate the risk for infection; in some cases, the onset of the disease is merely delayed until after the prophylaxis is discontinued. The changing nature of immunosuppressive strategies and treatment of rejection also may affect the timing and presentation of common opportunistic infections. Consequently, the risk period for opportunistic infections may extend beyond this intermediate risk period.

TABLE 40.6

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