Kidney transplantation

Historically, kidney transplant recipients have been thought to be at a lower risk for invasive aspergillosis (IA) than other solid organ transplant recipients. In a large retrospective review of 296 kidney graft recipients from 1986-1999, the overall incidence of invasive fungal infection (IFI) was 4% (Altiparmak et al, 2002). Infection with A. fumigatus (n=7) was found in 2.4% of patients. In another study the incidence of positive Aspergillus cultures in kidney transplant recipients was similar at 2.2% (Brown et al, 1996), less than in liver transplant patients (4.5%). The mortality of the kidney transplant patients was 40%, similar to the mortality of the liver transplant patients (41%). A. fumigatus was the most frequently isolated Aspergillus species, occurring in 60% of kidney transplant recipients and 69% of liver transplant recipients. Most cultures in both transplant groups were isolated from the lungs. However, it was felt that the majority of those cultures, particularly those obtained from body fluids, and were not indicative of disease. Interestingly, the predominance of cultures were positive in the early post-transplant period (< 30 days), which is different than majority of cases of IA in hematopoietic stem cell transplant patients which occurs at a mean of approximately 100 days post-transplant.

 

A large retrospective study in the United States of 33,479 kidney transplant recipients foundAspergillus pneumonia as the second leading cause of fungal infection in kidney transplant patients, following Candida esophagitis (Abbott et al, 2001). While data was not presented specifically for IA, 21.5% of patients with IFIs were hospitalized within 2 months post-transplant, and 66% within the first 6 months after transplantation.  Aspergillus infection was associated with a statistically significant longer hospital stay than other fungal infections. Patients who did not experience allograft rejection had their highest risk for IFIs within the first 6 months post-transplantation, while those patients who experienced rejection episodes continued to have a higher risk for a longer duration.

The incidence of fungal infections in general appears to be related to the conditions of the individual transplant center, as there appear to be more infections in less-developed regions of the world (Chugh et al, 1993; Altiparmak et al, 2002; Tharayil John et al, 2003 ). A possible relationship to construction was recently supported by molecular typing (Panackal et al, 2003). The risk factors for the development of IA in kidney transplant patients appears to be similar to the well-described factors in other hosts, such as anti-rejection therapy (i.e., pulse corticosteroids, anti-lymphocytic globulins, etc), prolonged antibiotic treatment, neutropenia, and concomitant infections such as CMV.

IA appears to clinically manifest as pulmonary or CNS infection in kidney transplant recipients, mirroring the incidence in general.  There are not any conclusive studies that depict a separate and distinct incidence of IA in living related donors versus cadaveric donors, and instead the incidence of IA appears to be more dependent on the individual center. Additionally, there is not an extensive evaluation of IA with the use of various immunosuppressive regimens (i.e. calcineurin inhibitors), as there has been in liver transplant patients.

Treatment of IA in kidney transplant recipients appears to be no different than in other patient populations, however one would hypothesize extra care should be exercised in avoiding nephrotoxic medications. To date, there have been no large clinical studies focusing on treatment of kidney transplant recipients with the newer available antifungals, so all treatment decisions must be extrapolated from the larger pool of immunocompromised patients. In the years before the availability of lipid-associated amphotericin B and itraconazole, conventional amphotericin B in doses of 0.5-1.0 mg/kg were often successful in salvaging the patient, if all immunosuppression was stopped and the transplanted kidney sacrificed. Even this strategy was often unsuccessful if the patient had bilateral pulmonary disease or disseminated disease. A preferable alternative is a lipid-associated amphotericin B preparation, to minimize nephrotoxicity, typically in a dose of 4-5 mg/kg daily (White et al, 1997; Ringden et al, 1991). Immunosuppression should be reduced as much as possible, especially the dose of corticosteroids.

Subsequently reports emerged of excellent results with oral itraconazole therapy (Dupont, 1990) although patients with cereberal or disseminated disease fared less well (Denning et al, 1989; Kreisel et al, 1991). Ciclosporin doses should be halved on the first day of itraconazole treatment and then measured frequently. Recently voriconazole has superseded itraconazole in most centres, because of randomized trial results (Herbrecht et al, 2002). However voriconazole interacts with both prednisolone and ciclosporin, and so immediate dose adjustment is necessary with both drugs. As with itraconazole, significant renal dysfunction (clearance <30-50mL/min) is a relative contraindication to intravenous itraconazole and voriconazole because of the carrier cyclodextrin.

Lately the licensure of caspofungin or micafungin allows treatment with fewer toxicity problems and drug interactions. Caution is advised in the use of caspofungin and ciclosporin, although no problems have been seen in some cases (Anttila et al, 2003). Experience is limited in terms of efficacy, but it is clear there is no need for a decreased dose in renal insufficiency as the echinocandins are an extremely safe class of antifungals in renal disease.

David W. Denning FRCP FRCPath FIDSA FMedSci
Professor of Medicine and Medical Mycology
Director, National Aspergillosis Centre
Education and Research Centre
University Hospital of South Manchester (Wythenshawe Hospital)
Southmoor Road
Manchester M23 9LT UK

June 2004