Successful cidofovir treatment of adenovirus-associated hemorrhagic cystitis and renal dysfunction after allogeneic bone marrow transplantation

We present a patient who developed hemorrhagic cystitis and renal dysfunction after unrelated bone marrow transplantation. Polyoma BK virus and adenovirus type 11 were detected in the urine. Vidarabine was administered without effect. Relatively low dose cidofovir was efficacious. Renal function improved, and the urinary excretion of adenovirus stopped. Late onset hemorrhagic cystitis, a common complication after bone marrow transplantation, is mainly attributable to viral infection. Polyoma BK virus (BKV) DNA is frequently detected in the urine of such patients, and it is considered to be the main pathogen of hemorrhagic cystitis. 1–3 Adenovirus is also an important pathogen of hemorrhagic cystitis for bone marrow transplantation recipients. 4 Disseminated adenovirus infection is sometimes fatal in such patients. 5 However, some bone marrow transplantation recipients excrete BKV or adenovirus in the urine asymptomatically. There is no widely accepted treatment for virus-associated hemorrhagic cystitis, but reduction of the dose of immunosuppressive agents or donor lymphocyte infusion is sometimes done. Recently antiviral agents such as ribavirin, ganciclovir, vidarabine and cidofovir have been used to treat virus-associated hemorrhagic cystitis in patients with bone marrow transplantation. 6–17 Among them cidofovir has emerged as a potential antiviral drug for disseminated adenoviral infection, but special attention must be paid to its nephrotoxicity. Here we describe a patient with adenovirus-associated hemorrhagic cystitis and renal dysfunction after bone marrow transplantation who was successfully treated with low dose cidofovir. Adenovirus and BKV excretion in the urine were monitored successively by the PCR method. 18, 19 Case reports. A 15-year-old male youth with acute lymphoblastic leukemia in complete remission received an allogeneic bone marrow transplantation from an HLA-identical unrelated donor from the Japan Marrow Donor Program. The conditioning regimen for bone marrow transplantation consisted of cyclophosphamide and total body irradiation. Prophylaxis of cyclophosphamide-induced hemorrhagic cystitis consisted of mesna and hyperhydration. Graft-vs.-host-disease prophylaxis consisted of FK506 by continuous iv infusion and a short course of methotrexate. He also received acyclovir orally and immunoglobulin iv infusion weekly. Engraftment of neutrophils (≥5 × 108/l) was achieved on Day 12 after bone marrow transplantation, of reticulocytes (≥1%) on Day 17 and of platelets (≥5 × 1010/l) on Day 19, respectively. On Day 11 after bone marrow transplantation, he developed Grade II acute graft-vs.-host-disease of the skin, which responded to corticosteroid therapy (methylprednisolone 2 mg/kg/daily for 4 days and then tapered). On Day 22 micturition pain and gross hematuria with clots developed without renal dysfunction. Simultaneously intranuclear inclusion bodies in the urine sediments appeared and persisted thereafter. We thought that he developed late onset rather than early hemorrhagic cystitis, which usually appears around 3 days after onset of the conditioning regimen and is mainly attributable to cyclophosphamide toxicity. Urine cultures for bacteria and fungi were negative. Adenovirus type 11 was isolated from urine by tissue culture. BKV-DNA and adenovirus-DNA in the patient’s urine were detected by PCR, according to methods described by Arthur et al. 18 and Echavarria et al., 19 respectively (Fig. 1).Fig. 1: PCR for BK virus (A) and adenovirus (B) in urine sediments. Lane M, 100-bp ladder marker; Lane 1, at onset; Lane 2, before cidofovir treatment; Lane 3, after 5 doses of cidofovir; Lane 4, after 7 doses of cidofovir; Lane 5, after 9 doses of cidofovir; Lane 6, after 14 doses of cidofovir; N/C, negative control.Initially hyperhydration, continuous bladder irrigation and reduction of the dosage of immunosuppressive reagents were used. Dysuria and hematuria worsened gradually, and abdominal and pelvic computed tomography on Day 32 showed severe thickening of the bladder wall, bilateral obstructive hydronephrosis and severe swelling of both kidneys. He was then treated with immunoglobulin 150 mg/kg once daily iv and a course of vidarabine 10 mg/kg once daily iv for 5 days. His condition continued to worsen with high fever, renal dysfunction and pneumonia. On Day 42 the serum creatinine concentration and urea nitrogen increased to 229.8 μM and 16.8 mM, respectively. Urinal beta-2-microglobulin increased to 10 575 μg/l (normal range, 30 to 200 μg/l) and N- acetyl-beta-d-glucosaminidase to 18.2 units/l (normal range, 0 to 10 units/l). Creatinine clearance (24 h) decreased to 35 ml/min/1.73 m2. At that time treatment was started with cidofovir (1 mg/kg iv once daily three times a week) and probenecid (1.25 g/m2 orally in divided doses daily) after obtaining informed consent from his parents and approval by the ethical committee of Sapporo Medical University. He complained of mild gastrointestinal signs, particularly nausea, probably caused by probenecid, but the treatment was otherwise well-tolerated. His clinical condition and laboratory renal function data gradually improved. After seven doses of cidofovir, renal function was normal, although mild micturition pain and microhematuria persisted. Adenovirus-DNA in the urine sediments disappeared after nine doses of cidofovir. BKV-DNA excretion persisted after a total of fourteen doses of cidofovir (Fig. 1). Discussion. In this report we present a bone marrow transplantation recipient who developed hemorrhagic cystitis and renal dysfunction with urinary excretion of BKV and adenovirus. There have been reports of effectiveness of vidarabine and cidofovir for BKV- or adenovirus-associated hemorrhagic cystitis after bone marrow transplantation. 6–10, 15–17 Vidarabine, however, had no effect on our patient’s clinical condition and viral excretion in the urine. We attributed the worsening renal function to disseminated adenovirus infection. In a recent report some children experienced nephrotoxicity after a second administration of cidofovir in the standard recommended dosage (5 mg/kg once a week), and the therapy was discontinued. 16 Other investigators have reported that treatment with a decreased dosage of cidofovir (1 mg/kg once daily three times a week) was also effective without nephrotoxicity in adenovirus-associated hemorrhagic cystitis. 17 Our patient had preexisting renal dysfunction; therefore we administered cidofovir in a decreased dosage with probenecid as a concomitant. No cidofovir-related side effects, including nephrotoxicity, were recognized, and his clinical condition and renal function laboratory data improved. Because adenovirus-DNA disappeared from his urine coincident with his clinical and laboratory improvement whereas BKV-DNA did not, we considered adenovirus as the main cause of the hemorrhagic cystitis and renal dysfunction. Because virus-associated hemorrhagic cystitis, especially adenovirus, after bone marrow transplantation is sometimes fatal, 5 prompt initiation of antiviral therapy is important. Although the effectiveness of cidofovir for virus-associated hemorrhagic cystitis needs further evaluation, a reduced dose of cidofovir can be considered for such patients.