Fluindione-induced immuno-allergic interstitial nephritis

Drug-induced acute interstitial nephritis (AIN) is an established cause of acute kidney injury (AKI). Antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequent offending drugs [1]. Only a few vitamin K antagonist-induced AIN cases have been reported. Some publications describe AIN associated with fluindione (Previscan®), an anticoagulant of the antivitamin K family, derived from indanedione, exclusively marketed in France. We present an additional case of AIN secondary to fluindione and review the available literature. A 70-year-old woman was hospitalized for AKI. Her treatment list included amlodipine and atenolol. In December 2007, the serum creatinine (SCr) level was 70 μmol/L and an asymptomatic atrial fibrillation was detected. Fluindione was hence initiated. SCr rose to 220 μmol/L (04/08). On admission, her SCr level had reached 3.4 mg/dL and fluindione was stopped. Blood pressure was 110/ 80 mmHg, and neither cutaneous rash nor peripheral lymphadenopathy was found. Laboratory tests showed SCr 299.2 μmol/L, proteinuria 2 g/24 h (1 g albumin and low-molecular-weight proteins, each) and negative urine sediment. A renal ultrasound revealed reduced-sized (10 cm) kidneys without obstructive uropathy. Immunological analyses were negative. A transjugular renal biopsy was performed. The renal biopsy included 11 glomeruli; 5 were sclerotic and 6 were normal. A diffuse infiltrate of lymphocytes, eosinophils and monocytes was found in the interstitium associated with severe tubulitis (Figure 1). Immunostains demonstrated CD3-positive lymphoid cells in the interstitium (Figure 2) compared to CD20 immunohistochemical staining (Figure 3). Immunofluorescence was negative. Electron microscopy was not performed. The diagnosis of fluindione-induced AIN (FI-AIN) was made. Despite withdrawal of the offending agent replaced by acenocoumarol, and oral corticosteroid therapy (1 mg/kg/day), renal function did not return to baseline values after 1 month (SCr, 259.6 μmol/L) but improved to 199.8 μmol/L 6 months later. Renal biopsy specimen showing expansion of the renal interstitium by large lymphocyte inflammatory cell aggregates and severe tubulitis. Masson's trichrome stain; original magnification ×40. Immunophenotyping analysis showing positive CD3 + T cells. Original magnification ×400. Immunophenotyping analysis showing few CD20 + lymphocytes. Original magnification ×400. About 15% of the renal biopsies performed on patients with AKI demonstrate drug-induced AIN as the cause of the renal insufficiency. Only 13% of these patients showed the classic triad of rash, fever and eosinophilia. Discontinuation of the offending drug remains the first therapeutic step. Nevertheless, a considerable part of the affected patients may develop ESRD (23.4%). An important clinical prognostic factor is the average duration of the renal dysfunction; a cut-off point of 2–3 weeks seems relatively determining [1–3]. Few cases of vitamin K antagonist-induced AIN have been reported with warfarin, phenindione and fluindione [4]. Hypersensitivity reactions occur in 0.2–2% of cases [5]. Review of the literature revealed 16 biopsy-proven FI-AIN [5–11], including this case (Table 1). AKI appeared 7.5 ± 6.9 weeks (range 2–20) after introducing the offending drug. The average baseline SCr was (102.08 ± 35.2; range 62.5–149.6 μmol/L) obtained 7.5 ± 4.6 (range 0.5–16) months before the onset of FI-AIN. Fifty percent of patients showed proteinuria (0.3–19.7 g/24 h) associated with microscopic haematuria (12.5%) and leukocyturia (12.5%). The highest SCr reached between 135.52 and 824.56 μmol/L with a mean of 425.04 ± 243.76 μmol/L. Two patients (12.5%) required several sessions of haemodialysis [9]. Thirty-one percent (5/16) presented the classical triad of drug-induced AIN: fever, maculopapular rash and eosinophilia. The renal biopsy was obtained in 14 out of the 16 patients. In all cases, a diffuse inflammatory infiltrate composed of lymphocytes, eosinophils, monocytes and plasma cells invading the interstitial compartment was observed. Fluindione was withdrawn in all patients. Eleven patients (68.75%) were treated with steroids. Steroid doses and the duration of treatment were not uniform. The most common scheme consisted of oral prednisone (0.5–1 mg/kg/day) tapering off over 8–12 weeks. Intravenous pulses of methylprednisolone (250–500 mg daily for 3 days) were occasionally used. In 3 out of these 11 steroid-treated patients (27.3%), SCr never reached baseline values. The five patients who did not receive steroids had a complete recovery of baseline renal function 10 days to 3 weeks after withdrawal of the offending drug. However, the largest study to date by González et al. demonstrated the beneficial effects of steroids for the treatment of drug-induced AIN, especially when initiated soon after withdrawal of the offending agent [1]. Characteristics of patients with fluindione-induced acute interstitial nephritis M, men; W, women; MI, myocardial infarction; ARF, acute renal failure; CRF, chronic renal failure; IN, interstitial nephritis; NA, not available; AVR, aortic valvular replacement; HT, hypertension. *Not published. Characteristics of patients with fluindione-induced acute interstitial nephritis M, men; W, women; MI, myocardial infarction; ARF, acute renal failure; CRF, chronic renal failure; IN, interstitial nephritis; NA, not available; AVR, aortic valvular replacement; HT, hypertension. *Not published. Fluindione must be considered amongst drugs that induce AIN. Conflict of interest statement. None declared.

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