US Pharm. 2014;39(8):HS10-HS16.
ABSTRACT: Patients are faced with various infections following kidney transplantation. Thus, transplant patients are routinely provided prophylaxis against common opportunistic infections such as cytomegalovirus and Pneumocystis jirovecii pneumonia. However, other infections such as urinary tract infections, Epstein-Barr virus, and the BK virus may also lead to posttransplant complications. Recognizing which types of infections are likely to occur and when may aid clinicians in selecting appropriate preemptive strategies. This article provides an overview of the common infections that may complicate kidney transplantation along with potential preventive and treatment strategies.
On average, 16,000 kidney transplants are performed each year in the United States.1 Among hospital readmissions in the first year post transplant, approximately 20% are due to infectious complications.1 These complications threaten to increase the risk of morbidity and mortality in transplant recipients. However, the balance of attaining immunosuppression to prevent graft rejection while also providing sufficient immune function to fight off life-threatening infection is unfortunately never perfectly achievable in these patients. It is therefore reasonable to have a basic understanding of the principles of infectious disease in renal trans-plantation in hopes of preventing infection and managing these patients appropriately. Recognizing which infections are likely to occur and when (TABLE 1) helps clinicians to determine preemptive strategies to prevent the infections from taking place.
Pretransplant Immunologic Evaluation
Pretransplant assessment is the first step in preventing infections after a kidney transplant. Many tests are routinely performed across the U.S., while others depend on the transplant center, the region, and the organ donor and recipient. Standard serologic tests performed on living donors and recipients include testing for cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis B and C, HIV-1, and HIV-2.2 Living donors and recipients should also receive a purified protein derivative (PPD) skin test to ascertain tuberculosis (TB) infection status.2 All potential living donors should undergo a comprehensive physical examination and medical history review. Because of the time-sensitive viability of deceased donor organs, the greater the amount of information available from a donor’s medical history, the better. Rapid serologic testing can also be performed in deceased donors. If the status of both donor and recipient is determined pretransplant, the recipient can receive prophylaxis to prevent infections from ever taking place and healthcare providers can gain an advantage over future infections.
Once patients are accepted onto the transplant list, efforts should be made to determine their vaccination status. Live attenuated vaccines are especially important to receive pretransplant, as it is not recommended to receive live vaccines after becoming immunocompromised. Inactivated vaccines are safe post transplant, but protection against possible diseases before the immune system is compromised is preferred. Measles, mumps, rubella (MMR), hepatitis, and varicella serology studies should be performed to determine the need for vaccination, which should be given when appropriate. Inactivated influenza vaccine is recommended for all patients before or after the transplant, depending on the time of year. Family members, coworkers, and healthcare providers should all receive the influenza vaccine as well, with preference given to the inactivated virus due to the possibility of viral shedding with the live attenuated vaccine. Human papillomavirus (HPV) vaccine may be given to patients who meet the indications prior to their transplant, and if the regimen is unable to be completed before surgery, it can be continued 3 to 6 months after it.3
Children who are transplant candidates should continue to receive the recommended vaccines for their age group before surgery including the MMR, pneumococcal, pertussis/diphtheria/tetanus, and influenza vaccines as applicable.3 Careful consideration should be given post transplant to keep children on track with their immunization schedule if possible.
Urinary Tract Infection
Urinary tract infections (UTIs) are the most common type of posttransplant infections, accounting for 45% to 85% of infections in kidney transplant recipients.4-10 UTIs have been shown to significantly increase the risk of mortality and graft loss, highlighting the need for identification and proper therapy selection.11 Kidney transplant recipients share many risk factors for UTIs with the general population, including advanced age, female gender, and prolonged use of a Foley catheter.8 Risk factors exclusive to this population that have been reported are ureteral stent placement, delayed graft function, and high levels of immunosuppression.4,8,12 While most risk factors for UTIs are nonmodifiable, positive hygiene practices should be encouraged because of immunosuppression and the risks associated in transplant recipients.
As with the nontransplant population, the most common infectious UTI pathogen among kidney transplant recipients is Escherichia coli.6,8,12 Other commonly reported pathogens include Enterococcus, Klebsiella, Pseudomonas, and Enterobacter species (spp).4,6,8,12 With the rise in extended-spectrum beta-lactamase (ESBL)–producing and carbapenem-resistant gram-negative pathogens, the patient’s risk factors for multidrug resistance, along with past antibiotic history and local susceptibility patterns, should be considered during empirical antibiotic selection.12 Since sulfamethoxazole-trimethoprim (SMX-TMP) is routinely used for Pneumocystis pneumonia (PCP) prophylaxis post transplantation for up to 6 months, patients coincidently receive some level of UTI prophylaxis during this time.8,10,13 However, should a UTI develop, empirical treatment with an oral fluoroquinolone, amoxicillin-clavulanate, or an oral third-generation cephalosporin is recommended.13
CMV is the most common viral infection in all solid-organ transplant patients. CMV is a herpesvirus commonly found in humans and is transmitted through close contact.14 The clinical presentation of CMV includes fever, malaise, myalgia, arthralgia, pneumonitis, and leukopenia.15 Infections in healthy, uncompromised patients are mostly subclinical and quickly turn into a lifelong latent infection. Due to the elusive nature of the disease, testing prior to transplantation is necessary for both the donor and the recipient of the organ.
Those with the highest risk of CMV infection are donor-seropositive [D+]/recipient-seronegative [R−]; therefore, they should receive antiviral prophylaxis.16,17 For these patients, guidelines recommend valganciclovir as the preferred drug at the standard dosage of 900 mg once daily beginning 10 days post transplantation for 3 to 6 months depending on the extent of immuno-suppression.17 In D−/R+, reactivation of latent infection is possible as a result of immunosuppression. CMV infection can begin in the first 6 months post transplant; therefore, patients in this category should also receive valganciclovir prophy-laxis for 3 months. Patients who are D−/R− are considered low risk and do not require routine prophylaxis for CMV.
Though EBV only affects around 1% of kidney transplant patients, the impact of this virus can be devastating for these individuals. EBV is strongly associated with the development of posttransplant lymphoproliferative disease (PTLD), which includes multiple disorders involving inappropriate B cell transformation.18,19 Patients who are R− and have increased levels of immunosuppression are at greater risk for PTLD. Diagnostic testing for PTLD varies depending on the location of the lesions. While evidence for EBV prophylaxis is lacking, antiviral agents such as acyclovir or valganciclovir may be used.18 The treatment of PTLD is also variable, and further research is needed; treatment should be initiated and monitored by the appropriate specialists.
Polyomavirus is a member of the Polyomaviridae family of viruses and can cause infection post transplantation. The predominant polyomavirus affecting kidney transplant recipients is the BK virus, named after the kidney transplant patient in whom it was first discovered. Primary infection with human BK virus occurs in most healthy children and results in colonization of the renourinary tract in a latent state.20,21 Studies of the rate of latent infection in the general population report ranges from 71% to 91%.22,23 However, reactivation of BK virus in the general population is significantly less common (10%) than in solid-organ transplant recipients (30%-40%), in large part due to immunosuppression post transplant. Reactivation of the BK virus is most likely to occur in the first 3 months following transplantation, and viremia persists throughout the first year.24
A potential complication related to reactivated BK virus is BK virus–associated nephropathy. It is reported that up to 10% of renal transplant recipients develop BK virus–associated nephropathy, with 50% to 80% of these subsequently developing graft failure.20
Because BK virus is often asymptomatic or presentation is nonspecific, screening for reactivation is recommended every 3 months during the first 2 years post transplantation and then annually for the next 3 years.23 No pharmacotherapy specific for BK virus exists at this time. Consequently, a common treatment strategy for BK virus is to reduce immunosuppressive medications by up to 50% or discontinue the immunosuppressants altogether in an attempt to allow the immune system to naturally clear viremia.20,23
Pneumocystis jirovecii is a fungus that is found widespread throughout nature. Similar to BK virus, it is believed to infect children as evidenced by high rates of seroconversion. Colonization in immunocompromised hosts is reported to range from 15% to 59%.25 Active P jirovecii pneumonia is a common coinfection with CMV and other viral respiratory infections.26,27 Patients may present with profound hypoxemia that develops over a few days.27 Opportunistic infections involving the respiratory tract have been shown to have a significantly higher rate of mortality than nonrespiratory tract opportunistic infections.28
Active P jirovecii pneumonia is relatively rare in the first 6 months post transplant due to routine use of prophylaxis in renal transplant recipients. However, prior to routine prophylaxis, incidence ranged from 5% to 15% in solid-organ transplant recipients.29 The American Society of Transplantation (AST) recommends prophylaxis with SMX-TMP usually given as a double-strength tablet three times weekly or as a single-strength tablet once daily for at least 6 months after transplantation. Pentamidine inhalation, dapsone, or atovaquone may be alternative therapies in those with a sulfa allergy.27
Importance of Adherence
Adherence to prescribed medications post transplant is a fundamental preventive measure for infection and organ rejection. Adherence has been shown to be especially decreased in the pediatric adolescent population. Possible causes of lower levels of adherence in this population include lack of understanding of the disease state, low health literacy of adolescents and their parents, and psychosocial issues.30
Methods to improve adherence in all age groups include the use of pill boxes and daily reminders by cell phones, alarm clocks, or e-mail. Establishing rapport between patients and all healthcare providers is vital, as this is a lifelong condition. Education for the transplant patient should not end immediately post transplant, but instead should be revisited as often as possible and by all members of the healthcare team.
The farther away patients are from their transplant, the greater the risk of nonadherence based on the notion that there is less or no risk of complications after an initial period post surgery. No matter the length of time after surgery, the importance of staying vigilant cannot be stressed enough to these patients. Pharmacists in all settings can offer encouragement and support while seamlessly helping to prevent adverse outcomes in these patients.
Household Infection Prevention
General education regarding decreasing infection risk should be encouraged, especially in the 6-month period immediately following transplantation and during other times of increased immunosuppression. Patients should be instructed to wash their hands as often as possible with soap and water, and family members should be encouraged to do the same. Patients should be reminded of foods to avoid, including raw eggs, raw or undercooked meat, raw seafood, and unpasteurized milk or juice.31 Patients looking for additional educational resources can be directed to websites such as the National Kidney Foundation (www.kidney.org), the American Association of Kidney Patients (www.aakp.org), and www.foodsafety.gov.
Prophylactic medication and vaccinations targeted at the most common infections are standard preventive measures for kidney transplant recipients. Even so, no kidney transplant recipient is without risk when it comes to infectious disease. However, understanding the fundamentals of infectious disease in this patient population may help guide appropriate pharmacotherapy and reduce the potential for further complications.
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