Bone Marrow Transplantation (2003) 31, 1173–1176 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt Case report Acute renal failure due to adenovirus-associated obstructive uropathy and necrotizing tubulointerstitial nephritis in a bone marrow transplant recipient K Mori1, T Yoshihara1, Y Nishimura1, M Uchida2, K Katsura3, Y Kawase4, I Hatano5, H Ishida1, T Chiyonobu1, Y Kasubuchi1, AMorimoto 6, T Teramura7 and S Imashuku7 1Department of Pediatrics, Matsushita Memorial Hospital, Osaka, Japan; 2Department of Urology, Matsushita Memorial Hospital, Osaka, Japan; 3Department of Pathology, Matsushita Memorial Hospital, Osaka, Japan; 4Department of Dialysis, Matsushita Memorial Hospital, Osaka, Japan; 5Laboratory of Toxicological Pathology, Department of Safety Research on Biologics, National Institute of Infectious Diseases, Tokyo, Japan; 6Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan; and 7Kyoto City Institute of Health and Environment, Kyoto, Japan Summary: and fatal for transplant recipients.3 Hydronephrosis has also been described as a transplant complication of Management of post-transplant complications caused by adenoviral infection.4,5 Management of adenovirus-induced severe adenoviral infection remains a major therapeutic urinary tract complications remains controversial because challenge. A 17-year-old male who had undergone bone evaluation of disease progression is often difficult and the marrow transplantation for the treatment of acute availability of effective therapeutic agents is still limited. lymphoblastic leukemia developed complete anuria follow- We report here a case of acute renal failure, which ing hemorrhagic cystitis 34 days after the transplant may have resulted from post-transplant adenoviral procedure. The computed tomogram scan revealed bilat- infection-associated obstructive uropathy and necrotizing eral hydronephrosis, indicating acute renal failure because tubulointerstitial nephritis, in a bone marrow transplant of obstructive uropathy. The emergency procedure of recipient. percutaneous nephrostomy caused massive bleeding in the left kidney, which eventually required a nephrec- Case report tomy. Adenovirus-positive severe necrotizing tubulointer- stitial nephritis was the histopathological diagnosis. A17-year-old male with acute lymphoblastic leukemia in Post-transplant acute renal failure because of hydrone- the second remission received an allogeneic bone marrow phrosis, which could be complicated by adenovirus- transplant (BMT) from an HLA-matched unrelated donor. induced renal parenchymal disease, is of great concern The BMT was performed after a conditioning regimen of and may cause significant problems with interventional total body irradiation (12 Gy) and cyclophosphamide treatment. (60 mg/kg  2 days)/mesna. For GVHD prophylaxis, a Bone Marrow Transplantation (2003) 31, 1173–1176. combination of cyclosporine (CyA) and short-term metho- doi:10.1038/sj.bmt.1704077 trexate was administered, but CyAwas replaced with Keywords: allogeneic bone marrow transplantation; methylprednisolone (mPSL) on day 13 because of adverse acute renal failure; hydronephrosis; adenoviral infection; effects. The neutrophil count reached 0.5  109/l and necrotizing tubulointerstitial nephritis; nephrostomy engraftment was confirmed by microchimerism on day 20, when he began to complain of dysuria. On day 22, the patient developed gross hematuria, which was found to be Severe adenoviral infection is a serious complication in positive for adenovirus by rapid enzyme-linked immuno- immunocompromised patients, particularly in recipients of sorbent assay (ELISA). Supportive therapy of hydration hematopoietic stem cell transplantations.1,2 To date, with forced diuresis, intravenous vidarabine6 (600 mg/day, hemorrhagic cystitis, nephritis, pneumonitis, hepatitis, from day 24) and ribavirin7 (5–10 mg/kg/day, from day 26) enteritis as well as disseminated infection have been effectively alleviated his symptoms and resulted in a reported, and the development of these conditions is closely negative ELISAtest. However, on day 32, the acute associated with graft-versus-host disease (GVHD).1,2 GVHD worsened (grade IV: stage 4 for skin and stage 2 for Among adenovirus-induced urinary tract infections, acute gastrointestinal tract, stage 0 for liver) and he required necrotizing tubulointerstitial nephritis is the most critical high-dose mPSL therapy (1 g/day for 3 days). During this period, his urinary N-acetyl-b-d-glucosaminidase (NAG) levels were high, ranging from 13.7 to 106.7 U/g-creatinine (normal o10). On day 34, he abruptly became completely Correspondence: K Mori, Department of Pediatrics, Matsushita Memorial Hospital, 5-55, Sotojima-cho, Moriguchi-shi, Osaka 570- anuric (0 ml of urine/day) with elevated serum levels of urea 8540, Japan nitrogen and creatinine. The computed tomogram (CT) Received 22 July 2002; accepted 13 January 2003 and ultrasonogram showed bilateral hydronephrosis with a Adenovirus-associated nephritis following BMT K Mori et al 1174 Figure 1 Computed tomogram on day 34 shows bilateral hydronephrosis with a fluid level of blood-contrast urine in the dilated renal pelvis. fluid level of blood and contrast contaminated urine in the dilated renal pelvis (Figure 1), markedly thick-walled ureters and bladder showing no urine retention, suggesting acute renal insufficiency because of obstructive uropathy. Percutaneous nephrostomy tubes were promptly inserted into both renal pelvises with interventional ultrasound when his hemostasis/coagulation parameters showed no evidence of disseminated intravascular coagulation except for mildly reduced platelet counts (59 000/ml) and a prolonged APTT (44%). However, the following day, massive bleeding occurred into and around the left kidney as well as down into the sacral cavity. Since the renal arteriogram did not reveal any bleeding spots and because arterial coil embolization8 of the left renal Figure 2 (a) Nephrectomized kidney tissue shows degeneration and artery did not stop the bleeding, an emergency left necrosis of tubular epithelial cells with associated necrotic cell debris and nephrectomy9 was performed. Subsequently, the patient hemorrhage in the lumen (hematoxylin–eosin stain, magnification  25). (b) The three types of inclusion bodies: Cowdry A(long arrow), full-type was maintained on hemodialysis but died on day 56 of (middle-length arrow) and smudge-type (short arrow) are identified in the multiorgan failure. affected tubules (hematoxylin–eosin stain, magnification  100). Laboratory studies known to be specific for adenovirus and is characterized by nuclei with dark basophilic material and blurred margins. Retrospective analysis of adenovirus genome levels in the Adenoviral particles were clearly observed by electron blood by real-time polymerase chain reaction (PCR)10 microscopy of the nuclei of the affected tubular epithelial revealed a positive result for adenovirus 25 days after the cells (Figure 3). Taken together, the diagnosis of necrotiz- transplant procedure (data not shown), suggesting that the ing tubulointerstitial nephritis induced by type 11 adeno- patient actually had systemic adenovirus disease at this virus was confirmed. stage. Adenovirus isolated from the urine on day 22 was later determined to be type 11. Grossly, the resected kidney had a subcapsular hematoma around the nephrostomy tube Discussion and blood clots were noted in the pelvis, the ureter and the surrounding fatty tissues. No large vessel damage from the Common causes of post-transplant acute renal failure tube insertion was identified. Many microscopic foci of include GVHD, adverse effects of immunosuppressive tubular epithelial cell degeneration and necrosis associated agents (CyA, tacrolimus) and adenoviral infection-induced with necrotic cell debris were present and hemorrhaging in urinary tract diseases. Previously, an association between the tubular lumens was apparent (Figure 2a). Besides adenovirus-induced hydronephrosis and necrotizing tubu- edema and hemorrhage, inflammatory infiltration was lointerstitial nephritis has not been clearly described. In the barely present in the surrounding interstitial tissue. The case described here, anuria abruptly occurred on day 36 affected tubular epithelial cells contained intranuclear post-transplantation during treatment for adenovirus- inclusion bodies of three types: Cowdry A, full-type and induced hemorrhagic cystitis. At the time, we believed that smudge-type (Figure 2b). The smudge-type inclusion is percutaneous nephrostomy11 was the best treatment. Bone Marrow Transplantation Adenovirus-associated nephritis following BMT K Mori et al 1175 procedures, as reported by Echavarria et al,13 is crucial. In particular, real-time quantification of the adenovirus genome in the blood10 would help to determine if the infection is systemic and likely to progress into the renal parenchyma. Early detection of disease progression enables prompt reduction of immunosuppression14 or prompt treatment with antiviral agents such as cidofovir, gancy- clovir, ribavirin, or vidarabine.15 Early administration of cidofovir may be effective for adenoviral infection,16,17 if started just after the positive serum PCR results. Donor lymphocyte infusion would be another choice of treatment, although it may worsen GVHD.14,18 In conclusion, post- transplant adenoviral infections should be assessed more extensively in a prospective study employing quantitative PCR approaches in order to