The present case illustrates the risk of potentially life-threatening toxic side effects of isoniazid in patients at risk, including end-stage renal disease patients on dialysis and/or those harboring a slow acetylator phenotype conferred by NAT2 polymorphisms.
More than 2 million people worldwide have end-stage renal disease and require dialysis as a life-saving therapy [
4]. In the dialysis population,
Mycobacterium tuberculosis infection has a high prevalence, ranging between 5 and 25%, and isoniazid is frequently used to prevent reactivation [
5]. Latent tuberculosis is frequently diagnosed in renal transplant candidates, who all should be screened during pre-transplantation evaluation, as the risk of active tuberculosis in transplant recipients is estimated to be 20–74 times higher than in the general population [
6]. Patients on dialysis are at risk for isoniazid toxicity, because of altered pyridoxine metabolism resulting in severe deficiency in pyridoxal phosphate (the active form of pyridoxine), and extensive removal of pyridoxal phosphate (a small molecule of 247 Da) by renal replacement therapies [
7]. While the recommended dose of pyridoxine supplementation in case of isoniazid treatment is usually 10–25 mg per day, [
8] it needs to be increased to >100 mg/day to prevent drug toxicity among patients on dialysis [
7]. Patients on high-flux high-efficiency hemodialysis – as our patient – are particularly at risk of pyridoxal phosphate depletion because of higher clearances during dialysis sessions [
9].
Isoniazid is primarily metabolized by the polymorphic arylamine NAT2. NAT2 activity is genetically determined and basically relies on the number of active alleles in
NAT2 gene (NAT2*4 and *12), thereby providing a molecular mechanism for the large inter-individual variability in toxicity and efficacy of isoniazid [
10]. Individuals are therefore classified as rapid metabolizers if they have one or more NAT2*4 alleles, and slow metabolizers only if they carry two slow metabolizer variants, as our patient (Fig.
1). During treatment with the standard regimen, slow acetylators carry a higher risk of drug toxicity, while rapid acetylators are prone to treatment failure, due to insufficient exposure to isoniazid. As a result, it has been suggested that
NAT2 genotype may help determining the dose of isoniazid in individual patients [
11]. The appropriateness of such a pharmacogenetics-based has been recently validated in a large randomized controlled trial.
NAT2 genotype-guided regimen significantly reduced the risk of both toxicity and treatment failure, in slow and rapid acetylators, respectively [
12]. In our patient, the combination of increased isoniazid and decreased acetyl-ionazid levels pointed towards a slow acetylator phenotype, an hypothesis that was further verified by the identification of NAT2*5B/*6A genotype. Intriguingly, Sub-Saharan populations show a high prevalence (>70%) of slow acetylator phenotype related to
NAT2 polymorphisms, possibly as a consequence of selective pressure related to the chemical environment, climate, biome, and dietary habits [
13].