Clozapine-induced acute renal failure and cytochrome P450 genotype

To the Editor

Clozapine-induced acute renal failure (ARF) in a 25-year-old Caucasian non-smoking male with a 10-year history of schizophrenia (Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition [DSM-5]) and trialled on several different antipsychotics has been described. The patient was admitted to hospital on the context of increasingly dangerous behaviour in response to command hallucinations, including running at speed headfirst into walls or windows, trying to pull off his genitals and gouge his eyes out with his fingers. Monotherapy clozapine 12.5 mg was commenced with gradual titration according to protocol. At day 20 (300 mg/daily), the patient complained of feeling physically unwell (normal physical examination): white blood cell (WBC) 12.8 × 10⁹/L and neutrophils 8.5 × 10⁹/L. Some 4 days later, abnormal tests peaked: erythrocyte sedimentation rate (ESR) (105 mm/hour), C-reactive protein (CRP) (130 mg/L), creatinine (246 µmol/L) and estimated glomerular filtration rate (eGFR) (28 mL/min/1.73 m³). The renal team diagnosed clozapine-induced ARF; clozapine was ceased and the patient treated conservatively. A renal ultrasound (US) showed no abnormality; the very acute psychotic symptoms prevented biopsy and computed tomography (CT) scan. Over the following 7 days, all the indices returned to within normal parameters.

In our case, as well as in several published cases (Kanofsky et al., 2011), the temporal relationship between the start of clozapine and the development of ARF, as well as the return to normal kidney function after cessation of clozapine, is indicative that clozapine (or norclozapine) is the culprit. Clozapine-induced ARF meets most of the criteria to secondary hypersensitivity immune reactions: (1) it occurs only in a small percentage of individuals taking the drug, (2) it is not dose-dependent and (3) it usually recurs after re-exposure to the drug or closely related agents. The mechanism would be a modification of the immunogenicity of native renal proteins or mimics of renal antigens (Rossert, 2001).

Clozapine is metabolised by cytochrome P450 1A2, 2D6, 3A4 and 1A2 and is responsible for about 70% of this metabolism (Linnet and Olesen, 1997). Patient genotype revealed CYP1A2 rs35694136 (c.-1635delT) and CYP1A2 rs762551 (c.-9-154C>A) polymorphisms. Although these variations may interfere with clozapine metabolism and hence clozapine serum level, clozapine hypersensitivity immune reactions seem to be dose independent. Alternatively, these genotypes might increase the risk of ARF, or this association could just be fortuitous. Further investigation is required to determine the specific relationship between clozapine-induced ARF and cytochrome P450 genotypes.

Only few cases of clozapine-induced ARF have been reported. This may indicate that this hypersensitivity reaction is very rare, but may also indicate that it has not been duly recognised/reported.