Adefovir dipivoxil-induced acute tubular necrosis and Fanconi syndrome in a renal transplant patient

Hepatitis B virus (HBV) infection is associated with high morbidity and mortality following renal transplantation. Prolonged treatment with lamivudine is associated with an increased risk of developing resistance to the drug [1]. In these cases, treatment with adefovir dipivoxil (ADV) may be considered, even in renal transplant patients and in patients with severe renal insufficiency [2,3]. Mild-to-moderate nephrotoxicity has been associated with ADV at doses of at least 30 mg daily. Nephrotoxicity appears after at least 20 weeks of treatment and usually resolves with dose modification or interruption [4,5]. ADV 10 mg once daily was not nephrotoxic in two large randomized placebo control long-term studies [6,7]. We report a case of a patient in whom Fanconi syndrome and acute renal failure (ARF) developed, although treated with ADV 10 mg daily. A 58-year-old man with end-stage renal disease of unknown cause underwent renal transplantation in April 1997. At the time of transplantation, he had an asymptomatic HBV infection treated by lamivudine 100 mg daily. Immunosuppressive treatment included steroids and mycophenolate mofetil. Other medications included felodipine and furosemide. Liver function tests remained normal until October 2006, when he developed a slight increase in the serum levels of aminotransferases: maximum levels of alanine aminotransferase and aspartate aminotransferase, 64 and 54 U/l, respectively. The HBV DNA reached 8.3 log copies/ml, and a clinical diagnosis of resistance to lamivudine was made. The other serologic and radiologic studies of liver function remained normal. At this time, the patient already had moderate renal insufficiency [serum creatinine concentration (SCr) 1.20 mg/dl; abbreviated modification of diet in renal disease (aMDRD) 66 ml/min per 1.73 m2] without proteinuria, not electrolyte disturbances. It was, therefore, decided to initiate treatment with ADV 10 mg/day on top to lamivudine. A dramatic decrease of serum HBV DNA concentration was observed from 8.9 log10 copies/ml at baseline to 3.8 log10 copies/ml within 3 months. He was hospitalized in June 2007 for fatigue, weight loss, generalized bone pain, especially in the ankles, and progressive worsening in SCr level to 1.86 mg/dl (aMDRD 39.5 ml/min per 1.73 m2). Clinical examination disclosed normal blood pressure (140/80 mmHg) and heart rate (75 beats/min). There was no clinical evidence of edema, inflammatory or infectious processes. Laboratory examination on admission revealed metabolic acidosis (plasma bicarbonate level, 17 mmol/l), anion gap of 10 mmol, sodium of 139 mmol/l, hypokalemia of 3.3 mmol/l, hypophosphoremia (blood phosphate level, 0.30 mmol/l), hypouricemia (uric acid level, 145 μmol/l), normoglycemic glycosuria (urine glucose level, 21.8 mmol/day), aminoaciduria, 1.99 g mixed proteinuria (tubular and glomerular with predominant tubular pattern) and microscopic hematuria. Creatinine phosphokinase level was 43 U/l. Kidney biopsy was performed. Microscopic examination revealed acute tubular necrosis with confluent necrosis of the proximal tubular epithelium and a dramatic vacuolization of these cells with a fading of the brush border. Dystrophic cells with karyomegaly were noted only in the proximal tubules. The distal tubule remained normal. No tubular crystals were observed (Fig. 1). Glomeruli were found to be normally associated with minimal chronic vascular thickening. Immunofluorescence study and Congo red staining were negative. There was no sign suggestive of cellular or antibody-mediated rejection (BANFF score g0 v0 i0 ah1, cv1 cg0 ct0-1 ci0).Fig. 1: Acute tubular injury characterized by swelling and vacuolization of proximal tubular cells. Cells appear large and contain discrete vacuoles of varying size. Note persistence of brush border. Masson's trichrome; original magnification 200×.Bone densitometry demonstrated generalized osteoporosis. ADV was stopped despite a normal drug through plasma level (5–10 ng/ml). Four months later, plasma levels of bicarbonate (28 mmol/l), potassium (3.8 mmol/l) and uric acid (525 μmol/l) had normalized. Urinalysis was negative for glycosuria with a progressive reduction of proteinuria. However, renal function worsened with creatinine clearance decreasing from 66 to 31 ml/min per 1.73 m2. Previous studies indicated that nephrotoxicity was the most important dose-limiting secondary effect of ADV therapy observed when studied in patients with HIV-1 infection at doses of 60 and 120 mg daily. Proximal tubular toxicity was documented in 22–50% of patients treated with ADV more than 30 mg daily for 72 weeks. The median time to resolution of proximal renal tubular dysfunction was 15 weeks among patients assigned ADV, and 16% of patients did not resolve completely 41 weeks after onset of nephrotoxicity. The incidence of these changes appeared to be dose related. Interestingly, we have analyzed the renal data of two randomized, placebo-controlled trials and confirmed that ADV nephrotoxicity is dose related. Mild nephrotoxicity was demonstrated with the dose of 30 mg daily, but not with ADV 10 mg for a median follow-up period of approximately 144 weeks [8]. It is plausible that the dual effects of ADV on mitochondria (carnitine depletion and higher ADV Ki on DNA polymerase γ) and on renal tubular transporter may be involved in the nephrotoxicity [8]. Only one case of severe hypophosphatemic osteomalacia induced by ADV at 10 mg/day has been reported. The patient recovered with discontinuation of ADV and correction of hypophosphatemia [9]. Our patient had been taking ADV for more than 1 year, following a clinical breakthrough due to lamivudine-resistant strain. Renal tubular dysfunction appeared under ADV treatment and disappeared few months after stopping it. There was no overdose found, and we did not identify any predisposing factor to this tubular toxicity. We think that this resulted from a direct toxic effect of ADV on renal proximal tubular cells. In summary, we report a case of ADV-induced ARF associated with Fanconi syndrome in a renal transplant patient. Clinicians should be aware of this complication of therapy with ADV 10 mg daily. Acknowledgements H.I. and I.B. prepared the manuscript with the invaluable assistance of G.D. R.K.-E., P.H. and C.S. participated in the clinical study and the therapeutic management of the patient.