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Case Report: A 56-year-old male patient with terminal renal insufficiency received a living donor kidney transplant from his wife in June 2007. Initial immunosuppression consisted of prednisolone, tacrolimus, and mycophenolate mofetil (MMF). 4 months after transplantation, the serum creatinine increased to 192 micromol/l and urinary analysis revealed the presence of decoy cells. A biopsy showed a focal interstitial nephritis and SV40 antigen was detected in tubular nuclei. Polymerase chain reaction (PCR) in serum and urine showed high titers of BK virus. Tacrolimus was stopped, MMF was reduced, and leflunomide (20 mg/day) was started. The patient was readmitted because the serum creatinine further increased to 262 micromol/l. Leflunomide concentrations were in the target range, but renal biopsy still revealed the presence of BK virus nephropathy. MMF was stopped. Serum creatinine stabilized at 233 micromol/l and PCR for BK virus in serum was negative. In April 2008, a deterioration of renal function occurred (serum creatinine 308 micromol/l) and renal biopsy revealed signs of acute interstitial rejection without the presence of SV40 antigen. A methylprednisolone pulse therapy for 5 days was performed and cyclosporine was added. After a few weeks serum creatinine increased to 444 micromol/l and a new biopsy revealed the reoccurrence of BK virus nephropathy. Since the tubulointerstitial injury was > 80%, no further therapy was performed and soon after dialysis therapy was initiated., Conclusion: BK virus nephropathy is a still rare, but increasing complication of renal transplantation, presumably mediated by intensive immunosuppression. The disease can induce graft dysfunction and may ultimately lead to graft failure. BK virus nephropathy can trigger acute rejection. Unfortunately, therapy of BK virus nephropathy and acute rejection is just the opposite: BK virus nephropathy requires a reduction of immunosuppression whereas acute rejection calls for intensification. A potential therapeutic approach may be leflunomide, an immunosuppressive substance with antiviral properties, but potential severe side effects. The described case demonstrates the frustrating course of a graft from a living donor despite initial successful therapy with leflunomide and illustrates the problems choosing between intensive and moderate immunosuppression.