title: Acute kidney injury during therapy with an antisense oligonucleotide directed against PCSK9.
abstract: Antisense oligonucleotides have been explored widely in clinical trials and generally are considered to be nontoxic for the kidney, even at high concentrations. We report a case of toxic acute tubular injury in a healthy 56-year-old female volunteer after a pharmacologically active dose of a locked nucleic acid antisense oligonucleotide was administered. The patient received 3 weekly subcutaneous doses of experimental drug SPC5001, an antisense oligonucleotide directed against PCSK9 (proprotein convertase subtilisin/kexin type 9) that is under investigation as an agent to reduce low-density lipoprotein cholesterol levels. Five days after the last dose, the patient's serum creatinine level increased from 0.81 mg/dL at baseline (corresponding to an estimated glomerular filtration rate [eGFR] of 78 mL/min/1.73 m(2)) to 2.67 mg/dL (eGFR, 20 mL/min/1.73 m(2)), and this increase coincided with the presence of white blood cells, granular casts, and minimal hematuria on urine microscopy. The patient's serum creatinine level peaked at 3.81 mg/dL (eGFR, 13 mL/min/1.73 m(2)) 1 week after the last oligonucleotide dose. Kidney biopsy showed multifocal tubular necrosis and signs of oligonucleotide accumulation. Upon conservative treatment, the patient's serum creatinine level gradually decreased and reached her baseline level 44 days after the last oligonucleotide was administered. The patient recovered fully and kidney function was normal at every follow-up visit.
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Eveline P
authors.initials: EP
authors.lastname: van Poelgeest
authors.forename: Reinout M
authors.initials: RM
authors.lastname: Swart
authors.forename: Michiel G H
authors.initials: MG
authors.lastname: Betjes
authors.forename: Matthijs
authors.initials: M
authors.lastname: Moerland
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Weening
authors.forename: Yann
authors.initials: Y
authors.lastname: Tessier
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hodges
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Levin
authors.forename: Jacobus
authors.initials: J
authors.lastname: Burggraaf
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D005260:Female; D006801:Humans; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000009:adverse effects* / Q000627:therapeutic use; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000009:adverse effects* / Q000627:therapeutic use; D012697:Serine Endopeptidases / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D016376:Oligonucleotides, Antisense; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Clinical kidney injury; PCSK9 (proprotein convertase subtilisin/kexin type 9); oligonucleotide