Zonisamide-induced acute kidney injury.

Abstract

Zonisamide is a new generation anticonvulsant indicated for the adjunctive management of partial seizures in adults [1]. The anticonvulsant activity of zonisamide is predominantly related to the inhibition of voltage-gated sodium action potentials and reduction of T-type calcium-channel currents. Because of its broad mechanism of action, zonisamide is used for many types of epilepsy and in patients whose epilepsy is resistant to other antiepileptic drugs (AEDs) [2,3]. There is insufficient evidence to demonstrate the superior clinical effectiveness of zonisamide compared to other adjunctive AEDs; however, its long half-life of 63 h supports convenient once- or twice-daily dosing. In vitro studies have demonstrated antioxidant and neuroprotective properties at therapeutic doses, suggesting that zonisamide may protect against ischemic damage and recurrent seizure activity [4]. Therapy is generally well tolerated; the most common reported adverse events include somnolence in 17% of patients and dizziness and anorexia in 13% of patients. Zonisamide may be an alternative in some patients over agents associated with weight gain, such as valproate or pregabalin [5,6]. Zonisamide is metabolized by acetylation to N-acetyl zonisamide and reduction to 2-sulfamoylacetyl phenol (SMAP) by cytochrome P450 isoenzyme 3A4. Zonisamide primarily undergoes renal excretion with 62% recovered from urine and 3% from feces following multiple doses [1,7]. The package insert was recently updated to reflect a risk of hyperchloremic, nonanion gap metabolic acidosis due to weak inhibition of carbonic anhydrase and increased renal excretion of bicarbonate. Furthermore, according to the manufacturer's label, zonisamide is not recommended for use in patients with renal failure (defined by the manufacturer as an estimated GFR < 50 mL/min); use of this agent in patients with renal insufficiency, defined as having a GFR < 60 mL/min according to the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative, requires slower titration and more frequent clinical monitoring for toxicities and adverse effects. Avoidance of use of zonisamide in individuals with end-stage kidney disease (e.g., GFR < 15 mL/min or on dialysis) is prudent based on manufacturer recommendations. Zonisamide has been associated with a statistically significant 8% mean increase in serum creatinine and blood urea nitrogen in clinical trials; however, this effect dissipated after therapy was discontinued. Of note, a case report has demonstrated hypersensitivity syndrome with acute kidney injury due to zonisamide; however; acute kidney injury has not been previously reported as an adverse event of zonisamide [7]. We present a case report that suggests that such an association exists as demonstrated by acute kidney injury in a patient on two separate occasions.