Prospective monitoring of BK virus load after discontinuing sirolimus treatment in a renal transplant patient with BK virus nephropathy.
نویسندگان
چکیده
To the Editor—The polyomavirus BK may cause progressive renal allograft failure in 1%–5% of kidney transplant recipients [1, 2]. The risk factors for BK virus nephropathy (BKVN) are not well understood but may involve rejection episodes and treatment with antilymphocyte preparations and potent new immunosuppressive drugs such as tacrolimus and mycophenolate mofetil [3]. Diagnosis of BKVN requires the immunohistochemical demonstration of BK virus–infected tubular epithelial cells in the allograft biopsy specimen. We note that detection of BK virus DNA in plasma closely follows the course of BKVN and may serve as a noninvasive tool for diagnosis and monitoring [4]. Recently, Limaye et al. [5] confirmed our findings in a retrospective study of 4 patients with BKVN and showed that the BK virus load decreased when the immunosuppressive treatment was reduced or when the renal allograft was removed. We have independently established a quantitative assay of a similar format (real-time fluorescent probe–based assay [TaqMan, Applied Biosystems]: primer 1, AGCAGGCAAGGGTTCTATTACTAAAT; primer 2, GAAGCAACAGCAGATTCTCAACA; probe, AAGACCCTAAAGACTTTCCCTCTGATCTACACCAGTTT labeled with 6-carboxyfluorescein at the 50 end and 6-carboxytetramethylrhodamine at the 30 end), which allows the detection of BK virus over a linear range of 10–10 copies per reaction. We prospectively followed a 65-year-old renal transplant recipient who developed BKVN in January 2001 while on an immunosuppressive treatment with cyclosporine, prednisone, and sirolimus. The underlying diagnosis of mesangioproliferative glomerulonephritis was made in 1987. He began hemodialysis in 1999 and received a renal transplant from a cadaver in October 2000. As shown in figure 1, initial allograft function was good (creatinine clearance, 55 mL/min). Two months after transplantation, a rise in serum creatinine from 1.52 mg/dL (135 mmol/L) to 2.47 mg/dL (218 mmol/L) was noted. Sirolimus concentrations (mean ^ SD) were 5:8 ^ 2:4 ng/mL (median, 6.4 ng/mL; range, 3.0–6.6 ng/mL), and blood levels of cyclosporine (mean ^ SD) were 242 ^ 108 ng/mL (median, 225 ng/mL; range, 122–324 ng/mL). In the first allograft biopsy, a mononuclear and plasmacytoid interstitial infiltration was seen together with an altered tubular epithelium, and acute rejection was diagnosed. Intravenous methylprednisolone (1000 mg for 3 days) was given, but renal function did not improve. A second transplant biopsy 2 weeks later revealed more-pronounced tubular alterations. BKVN was diagnosed by immunohistochemistry. BK virus DNA was detected in plasma, and the BK virus load was 3 10 copies/mL. Sirolimus therapy was stopped; however, prednisone (15 mg/day) and cyclosporine therapy was continued (blood levels [mean ^ SD], 156 ^ 26 ng/mL; median, 153 ng/mL; range, 76–121 ng/mL). Over the next 12 weeks, the BK virus load decreased until it was no longer detectable (figure 1). In parallel, allograft function improved, with a serum creatinine concentration of 1.74 mg/dL (154 mmol/L). We believe that this case is the first description of BKVN while the patient was undergoing immunosuppressive triple therapy with sirolimus. Of note, the sirolimus concentrations had not been high nor had there been prior treatment with antilymphocyte preparations. BKVN must be distinguished from interstitial rejection, which may coexist at times [6]. In the absence of rejection, treatment with steroids does not result in a functional or histologic improvement [1, 2]. Because specific antiviral treatment is not established, reduction of immunosuppression may be an option if carefully monitored [4]. In our patient, sirolimus therapy was stopped while cyclosporine and prednisone therapy was continued at slightly lower levels. Prospective monitoring of the BK virus load revealed a decrease by 5 orders of magnitude over 12 weeks. This, together with the improving allograft function, supported the critical decision to reduce the immunosuppressive treatment. The patient’s BK virus load was 3–4 orders of magnitude higher than the levels determined by Limaye et al. [5]. This difference in BK virus load cannot be attributed to sirolimus, because we found similarly high BK virus loads in 9 patients undergoing treatment with tacrolimus, a finding that we confirmed independently in 2 cases by limiting-dilution polymerase chain reaction (PCR) [4]. In 2 of 41 control patients without BKVN, we found BK virus loads of 511 and 748 copies/mL [4]. In fact, we have never observed histologically manifest BKVN at BK virus levels of ,5000 copies/mL (authors’ unpublished
منابع مشابه
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عنوان ژورنال:
- The Journal of infectious diseases
دوره 184 11 شماره
صفحات -
تاریخ انتشار 2001