Infectious Complications in Renal Transplant Recipients

Infectious Complications in Renal Transplant Recipients

Infectious Complications in Renal Transplant Recipients G. Splendiani, S. Cipriani, G. Tisone, B. Iorio, S. Condo, A. Vega, S. Dominijanni, and C.U. C...

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Infectious Complications in Renal Transplant Recipients G. Splendiani, S. Cipriani, G. Tisone, B. Iorio, S. Condo, A. Vega, S. Dominijanni, and C.U. Casciani ABSTRACT Renal transplantation has become a well-established therapeutic option for end-stage renal disease, but infectious diseases remain a significant cause of morbidity and mortality. Although a wide variety of pathogens may cause infection, viral ones must be regarded as the single most important class of infections. Progress has been made both in the prevention and the early recognition treatment of infections that are closely linked to rejection. Immunosuppressive therapy is central to the pathogenesis of both. Because of the particular characteristics of transplant recipients, it is desirable to establish a close collaboration between nephrologists, surgeons, and infectious disease specialists for the management of these patients. In this article, we describe the different kinds of infectious disease that may affect patients with kidney transplant and the fundamental principles of clinical management, particularly our experience in Polyoma virus (BK) infection.

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ENAL transplantation has become a well-established therapeutic option for end-stage renal disease. The successful results are partially due to improved surgical and organ preservation techniques, but mainly to progress achieved in immunosuppressant therapy. Unfortunately, increasing immunosuppression leads to a higher risk of developing opportunistic infections, which are associated with organ rejection. Therefore, the good outcome of renal transplants is linked to prevention, early diagnosis, and specific timely treatment of infectious complications. Pretransplantation infection evaluation is fundamental both in the donor and the recipient. It should consist of an accurate history, a complete clinical examination, as well as laboratory and radiological tests to demonstrate active infectious disease.1 In particular, the history should investigate epidemiological exposures during journeys in endemic regions, contacts with carrier insects or affected subjects (for tuberculosis), peculiar hobbies like hunting or camping, and abuse of intravenous drugs. It is essential to investigate every previous infectious disease, from childhood ones to recurrent bronchopulmonary infections, viral hepatitis, and venereal diseases. Compulsory childhood vaccinations and recalls, as well as anti– hepatitis A virus, anti-pneumococcus I, and anti-influenza vaccinations, should be checked. Moreover, it is important to investigate drug intolerance or allergy, particularly as regards antimicrobial drugs, which may be commonly used to manage infectious disease also in the general population, as well as peculiar dietary habits that may favor contamination. Clinical examination should be complete and accurate, aiming to exclude every potentially active infectious disease. Among laboratory

tests performed in pretransplantation screening, we focus our attention on blood cell count, routine biochemical profile with hepatic function indices, viral serology for HIV, VZV, EBV, HHSV, CMV, HHVA, HHVB, HHVC, T. pallidum, T. gondii, and endemic opportunistic microorganisms. Checking exposure to M. tuberculosis by Tine Test or Mantoux reaction could be useful. Among radiological investigations, thorax x-ray scan or CT scan, when indicated, could help diagnosis and management.2 Microorganisms causing infections in transplant recipients can be divided into 3 main categories: true pathogens, that are capable of invading healthy tissues, crossing fascial planes, or producing toxins that cause disease (influenza, typhoid, and so on). Sometimes pathogens may cause pathology if there is a break in the integrity of mucocutaneus surfaces (S. aureus). Nonpathogens rarely cause disease in normal subjects but are capable of causing highly lethal disease in transplant recipients (HHSV8, C. neoformans, Aspergillus, and so on). Another way to classify posttransplantation infections is by microbiological categories: bacterial, viral, and mycotic infections.3 It is worth noting that there is a timetable for posttransplantation infections that can be useful in the differential From the Nephrology and Dialysis Department (G.S., S.C., A.V.) Surgical Clinic Department (S.C., G.T., B.I., S.D.) and Chair of Nephrology (C.U.C.), “Tor Vergata” University, Rome, Italy. Address reprint requests to Silvia Cipriani, Clinica Chirurgica Ospedale S. Eugenio, Piazzale dell’Umanesimo 10, 00144 Rome, Italy. E-mail: [email protected]

© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.06.012

Transplantation Proceedings, 37, 2497–2499 (2005)

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diagnosis and that is the basis for devising strategies to prevent infections themselves; exceptions to the timetable usually connote an excessive environmental exposure that requires correction.4 Particularly in the first month after transplantation, when immunosuppressant therapy is still in titration, the most frequent infectious disease are caused by hospital pathogens, like those originating from perfusion devices, “difficult” germs pulmonitis, surgical wound infections, urinary tract infections, sinusitis originating from artificial ventilation devices, prostatitis caused by prolonged catheterization, and disseminated mycosis originating from central venous catheters. Furthermore, in the lack of an accurate pretransplantation investigation, infections originating from the graft itself can occur, like pyelonephritis, CMV infection, tuberculosis, hepatitis, HIV, as well as previous latent infections reactivated in the recipient (CMV, M. tuberculosis, and S. stercoralis). Between the second and the sixth month after transplantation, the most frequent infections are the opportunistic ones because immunosuppression reaches maximum levels, allowing microorganisms like P. carinii, C. neoformans, Nocardia spp, Legionella, Mycobacteria, S. stercoralis, and Aspergillus spp to produce pulmonary infections. Aspergillus, T. Gondii, and Nocardia spp may give central nervous system infections like meningoencephalitis or abscesses, whereas microorganisms like Listeria, C. neoformans, and other fungi (Mucor and Rhizopus) may cause meningitis. Staphylococcus spp, Streptococcus spp, Candida spp, C. neoformans, HHSV1, HHSV2, VZV, and Papilloma virus may produce cutaneous infections. Urinary tract infections may result from the same microorganisms as those involved in the first month. HHSV and Candida spp may lead to esophagitis and gastrointestinal mucositis; CMV may lead to mucosal ulceration; bacterial gastroenteritis may occur as well as diverticulitis and cholecystitis. Finally, fever of unknown origin may develop, mostly due to CMV infection.5 In particular, as regards urinary tract infections, our group has performed an investigation on the prevalence of polyomavirus BK (BKV) infection and activity in a population of kidney transplant (KT) and liver transplant (OLT) recipients. Because the reactivation of BKV is increasingly recognized as a cause of severe renal allograft dysfunction, we also investigated possible correlation with renal dysfunction. We studied 118 randomly selected patients. We evaluated BK viruria and when present, we assessed BK viremia. We also studied HCV status. We observed 16 patients with BK viruria (5 OLT and 11 KT; mean transplant age, 2.5 years) and 8 showed BK viremia too (1 OLT and 7 KT). Among BK-viruria–positive pts, 3 OLT recipients were HCV-positive. All OLT BK-viruria–positive patients showed normal renal function, with a mean serum creatinine (sCr) level of 0.9 mg% and a mean blood urea nitrogen (BUN) value of about 36 mg%. Regarding KT BK-viruria– positive patients (mean transplant age, 7 years), they showed impaired renal function, which was slightly worse among those who also showed BKV viremia with a mean sCr blood level of 1.7 mg% and a mean BUN value of about

SPLENDIANI, CIPRIANI, TISONE ET AL

80 mg%. Our findings, according to what is reported in the literature, showed that BK viruria is prevalent in renal allograft recipients and BK viremia may be related to nephropathy and lead to allograft rejection.6 Regarding temporal aspects of transplant infectious disease, it is apparent that in the late posttransplantation period (beyond the sixth month) community infections are prevalent, due to the fact that immunosuppression reaches a steady state so that the patient becomes receptive to the same infectious diseases that affect the general population. Thus, we can observe pulmonary infections from M. tuberculosis and atypical mycobacteria, Cryptococcus, Pneumococcus, H. influenzae; central nervous system infections from Aspergillus, T. gondii, Nocardia, or other fungi such as Rizhopus and Mucor; ocular infections from CMV or T. gondii; cutaneous infections from Staphylococcus, Streptococcus, Candida, Cryptococcus, HHSV1, HHSV2, VZV, Papilloma virus, or opportunistic microorganisms; urinary tract infections, as in every period, and finally chronic hepatitis from HHVB, HHVC, and HHVD and gastroenteritis from Salmonella spp.5 The risk of infection in transplant recipients is determined by the interaction of 3 factors: the epidemiological exposures that the patient encounters, both in the hospital and subsequently in the community; the patient’s net state of immunosuppression, mostly depending on the nature of the immunosuppressive therapy, with the additional contribution of important factors like underlying disease, proteinenergy malnutrition, and eventual presence of immunomodulating viral infections; and the preventative antimicrobial strategies.7 Among the main risk factors for infectious complications in transplant recipients, those related to the surgery itself are relevant. Prolonged surgical or ischemia time, anesthesia, eventual organ injury, blood loss requiring transfusions, perfusion fluid contamination, anastomotic dehiscence, fluid collections or necrosis, or need for immediate reintervention are all capable enhancing a severe infectious complication. Regarding the donor, the important risk factors may be sepsis with bacterial blood involvement or nonrecognized infections carried along with the transplant. In the postoperative period, factors that may contribute to infectious complications after renal transplantation8 are: instrumental manevoers related to the presence of central venous catheters, stents, or need for prolongued intubation; eventual leukopenia due to immunosuppression; and hospital infections linked to prolonged antimicrobial therapy with antimicrobial resistance development by particular microorganism species. The cornerstone of clinical management of transplant recipients with infections is based on precise diagnosis. Clinical examination, laboratory tests, and imaging techniques are the basis for an early and precise diagnosis, which makes possible to timely start a specific therapy. Transplant recipients show peculiar clinical signs, which may be nonspecific and not well defined. Laboratory tests may be dubious, because of weak reactions or crossreactions. Radiology may require investigations not indi-

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cated in a “normal” subject, but strictly necessary in the transplanted one. Let us think about the pivotal role of thorax CT scan versus investigations in pulmonary pathology. For these reasons and as a general rule, we must remember that prevention is the best strategy, far better than being obliged to cure an established infectious disease. So, what strategies prevent infectious complications in this kind of patient? First, an accurate pretransplantation investigation must be performed, discovering potentially active infectious pathology. Moreover, it may be useful to vaccinate the patient against the main posttransplantation pathogens, if a natural immunization did not occur. In particular, it is useful to acquire immunity against hepatitis virus A and B, Pneumococcus, influenza, and diphtheria-tetanus (or recalls). Moreover, it is indicated to evaluate the opportunity of vaccinating seronegative patients against varicella-zoster virus. Regarding the posttransplantation period, it is fundamental to avoid as far as possible both hospital and community epidemiological exposures, particularly in the above-mentioned critical periods, to minimize the risk of contamination and establish a standard prophylactic antimicrobial therapy against the most frequent and dangerous pathogens like T. gondii, P. carinii, and M. tuberculosis.9 In the case that, in spite of all prophylactic efforts, infectious complications do occur, it is necessary for the correct management of patients to evaluate and match some important matters like interactions between antimicrobial drugs and immunosuppressants, kinds of therapeutic prescriptions, duration of drug administration, comorbidity factors, and importance of prophylaxis and of specific therapy.7 Antimicrobial drugs as a group have an extremely high incidence of clinically significant interactions with cyclosporine and tacrolimus. They may affect immunosuppressant metabolism acting both as up-regulators or down-regulators by inducing or inhibiting the hepatic cytochromes enzyme system, respectively, thus resulting in a decreased/increased immunosuppression and thus in an increased risk of rejection episodes or further infection. An altered net state of immunosuppression is directly related to rejection risk, so it is extremely important to know these kinds of interactions and to adjust antirejection therapy as a consequence. Moreover, the combination of certain antimicrobial drugs with cyclosporine or tacrolimus may cause idiosyncratic (single-dose), accelerated (cumulative doses), or dose-related (depending on total daily amount) nephrotoxicity. Those interactions must be considered when prescribing antimicrobial therapy for transplant recipients.3 There are 3 different kinds of prescription for such patients: a therapeutic mode (to cure an established infection), a prophylactic mode (to prevent important infections in the whole population), and a preemptive mode (to prevent peculiar infections in high-risk subgroups). It is worth remembering that in such patients fixed, standard therapy courses may not be useful. It is advisable to treat “long enough” to reach a goal, defined by clinical and laboratory evidences that the active infection has been

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eradicated as a whole, taking care that immunosuppression is not such that surviving subdetectable levels of microbes can be amplified to pretreatment levels.10 We must keep in mind some factors that may promote the onset and persistence of infectious complications despite an adequate antimicrobial regimen, such as anatomic alterations due to the surgical technique itself or to difficulties or complications that may present in a specific patient. These factors must be discovered and removed to avoid the failure of both prevention and eradication of the specific infection. In conclusion, when treating an infection in a transplant recipient we must take consideration two peculiar aspects: the therapeutic prescription, which must be such that both immunosuppression and antimicrobial therapy are adequate and effective, resulting in a “safe” prevention of rejection, and the microbial burden, which guides the intensity and duration of antimicrobial therapy and requires effective “proof of cure” measurements to assure adequacy of treatment.7 In conclusion, renal transplantation is associated with a high risk of infectious complications, which may lead to relevant consequences for patients’ morbidity and mortality, with a direct influence on side effects both of immunosuppressant and antimicrobial therapy. Moreover, the microbial capacity of immunomodulation may contribute to the evolution of organ damage and to rejection. For all these reasons and because of the need to consider the individual characteristics of each transplant recipient, it is desirable to establish a close collaboration between nephrologists, surgeons, and infections disease specialists for the management of these patients. REFERENCES 1. Rubin RH: Infection in the organ transplant patient. In Rubin RH, Young L (eds): Clinical Approach to Infection in the Immunocompromised Host, 3rd Ed. New York: Plenum Press; 1994, p 629 2. Fishman JA, Rubin RH: Infection in organ transplant patients. N Engl J Med 338:1741, 1998 3. Tolkoff-Rubin NE, Rubin RH: Recent advances in the diagnosis and management of infection in the organ transplant recipient. Semin Nephrol 20:148, 2000 4. Rubin RH: Temporal aspects of transplant infectious disease. Transplant Infect Dis 5:63, 2003 5. Nicholson V, Johnson P: Infectious complications in solid organ transplant recipients. Surg Clin N Am 74:1223, 1993 6. Splendiani G, Cipriani S, Condo S, et al: Polyoma virus BK and renal dysfunction in a transplanted population. Transplant Proc 36:713, 2004 7. Rubin RH, Ikonen T, Gummert JF, et al: The therapeutic prescription for the organ transplant recipient: the linkage of immunosuppression and antimicrobial strategies. Transpl Infect Dis 1:29, 1999 8. Patel R, Paya C: Infections in solid organ transplant recipients. Clin Microbiol Rev 10:86, 1997 9. Rubin RH, Tolkoff-Rubin NE: Antimicrobial strategies in the care of organ transplant recipients. Antimicrob Agents Chemother 37:619, 1993 10. Rubin RH: The prevention and treatment of infectious disease in the transplant patient: where we are now and where do we need to go? Transpl Infect Dis 6:1, 2004