Review Article

FUNGAL INFECTIONS IN RENAL TRANSPLANTATION

Ashok SarinSenior Consultant Nephrology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.

Fungal infections remain a significant cause of morbidity and mortality in renal transplant recipients. Fungalcolonization is associated with use of broad spectrum antibacterial agents, pre-transplant and post-transplantimmunosuppressive therapy. In the post-transplant period, differentiating between fungal colonization andinfection is often difficult and remains imprecise. The period of 1 to 6 months after kidney transplant is markedby opportunistic fungal infection.

During induction or periods of enhanced immunosuppression oral nonabsorbable or topical antifungal agentssuch as clotrimazole or nystatin are typically administered to prevent mucocutaneous Candida infection. Thelipid formulations of amphotericin B (LFAB) are associated with lower risks for nephrotoxicity.

Voriconazole appears to be superior to conventional AmB for the treatment of invasive aspergillosis. Theechinocandins, including caspofungin are fungicidal for Candida species. The development of any seriousfungal infection in a transplant recipient mandates a critical evaluation of the immunosuppressive regimen.

Key words: Fungal Colonization, Candiduria, Cryptococcal Meningitis, Aspergilus infection, Caspofungin

FUNGAL infections remain a significant cause of morbidityand mortality in renal transplant recipients. Although theincidence of fungal infections in renal transplant recipientsis less than that reported for other solid – organ transplantrecipients, the mortality from fungal infections remains highand is related to the pathogenicity of the organisms, site ofinfection, impaired host inflammatory response andcomorbid diseases such as renal failure and diabetesmellitus.

Colonization with yeasts and molds occurs frequently intransplant candidates with end stage renal disease and aftertransplantation because of ongoing immunosuppression,particularly corticosteroid therapy. Fungal colonization isassociated with use of broad spectrum antibacterial agents,pre-transplant and post-transplant immunosuppressivetherapy, and the presence of urinary catheters andendotracheal tubes. Fungal colonization may heraldinvasive fungal infection, particularly with certain Candidaspecies such as C. tropicalis.

In the post-transplant period, differentiating betweenfungal colonization and infection is often difficult andremains imprecise. Candida spp., Aspergillus spp., andC.neoformans are the most common fungal pathogensreported in renal transplant recipients. P.carinii,Zygomycetes (Mucor, Rhizopus).

Donor transmitted fungal infection is uncommon amongkidney transplant recipients. All donors should be evaluatedfor evidence of active or occult fungal infection, particularly

of the blood and urine.

Candida infections occur most commonly during thefirst month following transplant and are usually associatedwith complications of the renal transplant surgery or withearly rejection and enhanced immunosuppression. Candidainfection is most commonly associated with an endogenoussource of colonization, but lack of hand washing ofhealthcare workers may contribute to acquisition from anexogenous source. C.albicans is the most commonlyisolated species.

The spectrum of Candida infections includesmucocutaneous candidiasis and esophagitis: woundinfections: cystitis, pyelonephritis and ureteral obstruction(by Candida elements or “fungal ball”), intraabdominalinfections including infected peritonitis.

Candiduria may be asymptomatic but may associatedwith cystitis or upper tract infection. Recurrent candiduriashould be treated with an antifungal agent to avoid thesecomplications. The risk of fungal infection aftersimultaneous pancreas kidney (SPK) and pancreas afterkidney (PAK) transplants is comparable to liver transplantrecipients.

The period of 1 to 6 months after kidney transplant ismarked by opportunistic fungal infection. The type dose,time, duration and intensification of immunosuppressionare important determinants of ongoing risk. Pneumocystisoccurs most commonly during this period, especially

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Review Article

among patients receiving increased doses of corticosteroidsor inadequate prophylaxis.

Other fungal infections in renal transplant, recipientsinclude cryptococcal meningitis and space occupying brainlesions, pulmonary, dermatologic, skeletal, organ specificdisease, aspergillosis pneumonia and other tissue invasiveforms including genitourinary, central nervous system,gastrointestinal with Mucor species, Coccidioidomycosispneumonia, meningitis, musculoskeletal and skininvolvement: histoplasmosis pneumonia, mediastinal,disseminated disease, cutaneous diseases pneumocystosispneumonia and rarely extrapulmonary infection. Thediagnosis of fungal infection remains problematic andfrequently leads to delays in clinical recognition.

Isolation of yeast (e.g. Candida species) from cultures ofstool, respiratory and urine samples occurs commonly inkidney transplant recipients receiving corticosteroids andbroad spectrum antimicrobials and does not necessarilyimply infection. However repeatedly positive fungalcultures from single sites or from multiple sites may heraldinvasive candidiasis in the appropriate clinical setting.Patients with genitourinary tract stents and recurrent urinaryfungal isolates often require removal of foreign body toeradicate fungal infection. The isolation of Aspergillus fromrespiratory cultures (particularly A. fumigatus and Aterreus) should prompt a search for invasive diseaseincluding by high resolution chest CT with biopsy ofsuspected pulmonary lesions. Patients at risk ofaspergillosis include those receiving repeated courses ofenhanced immunosuppression for rejection, or with chronicgraft dysfunction diabetes comorbid and CMV infection.Diagnosis of aspergillus infection depends upon anisolation of Aspergillus from a sterile body site or repeatedisolation from the respiratory tract, and typical radiographicfindings. Radiologic appearances of pulmonaryaspergillosis in kidney transplant recipients includenodules, diffuse or wedge shaped opacities, empyema,cavitary forms, tracheobronchitis or combination ofparenchymal lesions.

PROPHYLAXIS

During induction or periods of enhancedimmunosuppression oral nonabsorbable or topicalantifungal agents such as clotrimazole or nystatin aretypically administered to prevent mucocutaneous Candidainfection. These agents are ineffective in preventingsystemic fungal infection Although prophylaxis with asystemic antifungal agent is not recommended routinelyafter uncomplicated renal transplantation, it may beindicated in patients receiving prolonged broad spectrumantibacterial therapy or enhanced immunosuppression orwith persistent candiduria.

TREATMENT

Historically, invasive candidiasis, cryptococcosis,coccidioidomycosis, histoplasmosis, and aspergillosis weretreated with amphotericin B deoxycholate (AmB). Becauseof inherent toxicities and intolerance, especially at the highdoses required for invasive aspergillosis, (e.g. 1 to 1.5 mg/kg per day) newer agents have increasingly been used inrenal transplant recipients. The lipid formulations ofamphotericin B (LFAB) are associated with lower risks fornephrotoxicity, metabolic derangements and infusionassociated side effects. These agents include amphotericinB (AmB) (AmBisome)

Voriconazole appears to be superior to conventionalAmB for the treatment of invasive aspergillosis and also hasin vitro activity against Fusarium and Scedosporium.Available in both IV and oral formulations, the drug isgenerally well tolerated, but some patients experiencevisual hallucinations or severe photosensitivity.Althoughitraconazole has good in vitro activity against Aspergillusspecies, its use is generally reserved for treatment of less-severe aspergillosis or maintenance therapy followinginitial response to AmB or voriconazole. Fluconazole is thefirst line agent of the treatment or prevention of reactivationcoccidioidomycosis in renal transplant recipients.Ketoconazole, fluconazole and itraconazole are useful fortreating mucocutaneous fungal infection and infection ofthe genitourinary tract gastrointestinal system. All of theazole antifungals impair calcineurin inhibitor metabolism tosome degree and increase blood levels. This effect is mostconsistent with ketoconazole and its use may permit areduction in cyclosporine or tacrolimus dose of up to 80%.

The echinocandins, including caspofungin and arefungicidal for Candida species, including fluconazoleresistant species. Available only as an IV infusion,caspofungin is well tolerated and increasingly is being usedto treat serious infections associated with non-albicansCandida species in transplant recipients. The developmentof any serious fungal infection in a transplant recipientmandates a critical evaluation of the immunosuppressiveregimen. The corticosteroid dose should be minimized, theblood levels of cyclosporine and tacrolimus should be keptin the low therapeutic range. Failure of clinical response toan antifungal regimen may require discontinuation ofimmunosuppression, even at the cost of abandoning thegraft.

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