Renal aspergillosis

Aspergillosis limited to the urinary tract is a rare disease, often occurring in immunocompromised patients. Approximately 20 cases of renal aspergillosis including 3 with AIDS, 4 cases of isolated prostatic aspergillosis and 1 case of concomitant renal and prostatic aspergillosis in a non-immunocompromised patient have been reported. Not surprisingly, Aspergillus fumigatus was the most common isolate. Three different patterns of renal Aspergillus infection have been described (Flechner, 1981): disseminated aspergillosis with hematogenous renal involvement, aspergillosis of the renal pelvis with bezoars formation, and ascending panurothelial aspergillosis. Extrarenal aspergillosis of the urinary tract is sparse, with few cases of testicular and adrenal involvement being described.

 

Although the kidney is the most frequently involved part of the urinary tract in invasive aspergillosis (Wise and Silver, 1993), both bladder and prostate aspergillosis are described. Five cases of  prostatic aspergillosis have been reported (Karayannopoulos and Stylianea, 1981, Khawand 1989, Campbell 1992, Abbas, 1995, Hemal, 1999). An additional case of Aspergillosis of a renal allograft, as a result of ascended infection secondary to subacute prostatic aspergillosis, leading to allograft removal has also reported ( Shirwany, 1998). Outflow obstructive symptoms, similar to those due to benign prostate hypertrophy (BPH) are predominant. Other related symptoms could be dysuria, perineal or suprapubic discomfort and hematuria. The prostate fungal infection is indistinguishable from BPH, bacterial and tuberculus prostatitis or malignancy of the gland. Prolonged courses of antibiotics, steroid intake and an indwelling bladder catheter have been identified as presumed predisposing factors in these cases. Of note, among the cases of prostatic aspergillosis none yielded a positive urine culture, while 1 sample of prostate fluid was positive for A. flavus(Karayannopoulos and Stylianea, 1981).

Renal involvement is usually silent if the disease is localised to the cortex of the kidney and is a relatively frequent finding at autopsy in the context of disseminated disease. The typical host group is the leukaemic, organ and bone marrow transplant patient. Although  advances in chemotherapeutic regimens and immunosuppressive therapy have led to increased survival, these have increased the candidates for fungal infections. Aspergillosis occurs as a complication of transplantation in up to 15% of patients. Despite the increased incidence of invasive aspergillosis in transplant recipients, urinary tract infections caused by Aspergillusspecies are uncommon and usually as a consequence of a systemic haematogenous dissemination, characterized by multiple parenchymal microabscesses (Young, 1970, Rinaldi, 1983) although isolated cortical abscesses of the kidney have been described in leukemias and chronic granulomatous disease ( Ippolito, 1978). Renal involvement in disseminated aspergillosis is far less common than in systemic candidiasis -12 versus 85% (Young, 1970, Gerle, 1973). The origin of Aspergillus infection in transplant patients, although not well defined in many cases, is usually the immunosuppressed transplant recipient . Transmission from an immunosuppressed and subclinically infected donor has been reported (Keating, 1996, Hadaya, 1998), although iatrogenic contamination during preservation or perioperatively could not be excluded in the latter case. Renal transplant recipients have been thought to be at low risk for fungal infections compared with other transplant recipients; however, in the era of longevity a 80-90 times higher annual rate of fungal infection have been noted in this host compared to general population. Aspergillus infection of the renal allograft is associated with allograft loss, anastomotic complications due to thrombosis and infarctions. Several reports of primary urinary tract aspergillosis in renal transplants have been published (Hadaya, 1998, Shirwany, 1998, Guleria, 1998, Maranes, 1996, Katz, 1996). Of note, in one of these cases (Guleria, 1998), the transplant patient with ureteric obstruction, underwent ureteroscopic resection of the fungal mass (debulking of the bezoar); no allograft removal was performed.

More common, although still rare, is renal pelvis involvement. Involvement may be unilateral or bilateral. Typical host groups include diabetics and intravenous drug abusers. Fungal masses (bezoars) fill the pelvis of the kidney causing hydronephrosis (insert hyperlink to image on the site).  Aspergillus bezoars are notably more problematic than ones caused byCandida spp. (Irby, 1990). These masses may be passed in the urine as `balls' and may cause renal colic (insert hyperlink to image on the site). Anuria due to bilateral ureteral obstruction with mycelial clumps, although rare, has been recently reported (Kueter, 2002). Aspergillus is usually cultured from the urine and can be cultured and visualised in the fungal balls. Cultures drawn by either a percutaneous nephrostomy tube or transurethral ureteral catheters are useful in case of negative routine cultures. Multiple large volume urine cultures should be useful to identify Aspergillus, but experience is limited. Moreover, even in cases of a classic pyelonephritis with repeat positive urine cultures for bacteria, refractory to antimicrobials, fungal infection might coexist, especially in diabetic patients (Mitchell, 1990). Ultrasound or CT scan of the kidneys demonstrate hydronephrosis with filling defects in the renal pelvis. Retrograde pyelography shows the fungal bezoars clearly and may be useful in placing a ureteral catheter in the renal pelvis for treatment. False negative imaging is reported however (ref).Therefore, in cases of high risk patients for Aspergillus infections, presenting with ureteral obstruction of unknown etiology, imaging should be repeated, even if recent normal studies are available (Kueter, 2002). Careful urinalysis, fungal cultures, and cystoscopy should be performed in these cases. Multiple large volume urine cultures may be necessary to identify Aspergillus, since a single culture is insufficient and provide false negative results.

The management of these challenging infections is a problematic issue. Renal parenchymal disease requires systemic antifungal therapy (amphotericin B, itraconazole, voriconazole or caspofungin), as for any other infected organ, although the efficacy of antifungal agents not proven. A combined medical and surgical approach is required for pelvic disease. Topical and systemic antifungal agents and endourological access for extraction, lavage and debulking, or nephrectomy are required, depending on the anatomy, clinical judgment and the response to an initially 'conservative' approach. Most patients require nephrectomy. This is not a welcome option for patients with bilateral disease.

Amphotericin B can be administered either parenterally or as a urinary irrigant. Intravenous amphotericin B is not useful as less than 5% is excreted in the kidneys.

It should be pointed out that progressive renal impairment during Amphotericin B treatment may be due to the infection process, rather to a toxic effect of Amphotericin B, and these situations need to be distinguished. Flucytosine coadministration is desirable because it is excreted in large amounts in the urine and there is a synergistic effect combined with amphotericin . However flucytosine has only moderate activity against Aspergillus spp., in contrast to better activity against Candida species. Lipid formulations of amphotericin are less nephrotoxic and appear to be equally efficacious but no more so than amphotericin B, although there is no data in this setting. Direct instillation of amphotericin B into the urinary pelvis through a ureteral catheter or nephrostomy tube has been the most successful approach to therapy. For topical instillation a solution of 50mg/l in sterile water is prepared and infused at 40ml/h and instillated through a retrograde ureteral catheter. Prolonged exposure of the irrigant to light for more than 24 hours has shown deleterious effect and should be protected. Pressure in the system should be controlled by a manometer with a pop-off mechanism at 20 cm water to prevent extravasation, pyelovenous or pyelolymphatic reflux of agents or organisms. Toxicity with instillation is minimal, since absorption via the urothelium is negligible (Wise, 1982). Oral itraconazole is occasionally successful combined with local irrigation with amphotericin B (Guleria, 1998), perhaps because the hydroxymetabolite is excreted in the urine, unlike the parent compound.

However, for obstructing lesions or bezoars not resolving with instillation, early surgical debulking should be performed. Systemic amphotericin B should be administered before and after the procedure to avoid fungemia. The optimum time to make a decision for debulking depends on clinical judgment. In cases refractory to the above 'conservative' endourological procedures, an open operation may be necessary. Open pyelotomy and/or nephrectomy may be required if despite instillation and medical therapy the disease persists. Failure in one such patient was attributed to a nidus of Aspergillus around a nylon suture remaining in the pelvis from a prior pyelolithotomy (Davies, 1987).

For prostatic aspergillosis, in cases of involvement as part of a systemic multi-organ disease, management with combined medical and surgical interventions is required; however in isolated prostatic aspergillosis, there is evidence that cure with a surgical procedure alone (transurethral prostate resection or open prostatectomy) could be achieved, based on the reported cases.

In the era of new azole antifungals and echinocandins, treatment options should be changed and probably improved. Experimental data with these regimens have shown an impressive accumulation of drugs in kidney tissues and reduction of fungal burden; however the data is limited to Candida renal infections.

Prepared by:
Dr Helen Sambatakou
Senior Registrar in the Infectious Diseases Unit
The General Hospital "G Gennimatas"
Athens, Greece

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