Kidney tubular injury induced by valproic acid: systematic literature review

Abstract

Background Valproic acid is prescribed for epilepsy and as prophylaxis for bipolar disorder and migraine headaches. It has also been implicated as a cause of a kidney tubular injury. Methods We undertook a review of the literature to characterize the biochemical and histopathological features of the overt kidney tubular injury and to evaluate the possible existence of a pauci-symptomatic injury. The pre-registered review (CRD42022360357) was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Searches were conducted in Excerpta Medica, the National Library of Medicine, and Web of Science. The gray literature was also considered. Results For the final analysis, we retained 36 articles: 28 case reports documented 48 individuals with epilepsy on valproic acid for 7 months or more and presenting with features consistent with an overt kidney tubular injury. The following disturbances were noted: hypophosphatemia (N = 46), normoglycemic glycosuria (N = 46), total proteinuria (N = 45), metabolic acidosis (N = 36), hypouricemia (N = 27), tubular proteinuria (N = 27), hypokalemia (N = 23), and hypocalcemia (N = 8). A biopsy, obtained in six cases, disclosed altered proximal tubular cells with giant and dysmorphic mitochondria. Eight case series addressed the existence of a pauci- or even asymptomatic kidney injury. In the reported 285 subjects on valproic acid for 7 months or more, an isolated tubular proteinuria, mostly N-acetyl-β-glucosaminidase, was often noted. Conclusions Valproic acid may induce an overt kidney tubular injury, which is associated with a proximal tubular mitochondrial toxicity. Treatment for 7 months or more is often associated with a pauci- or oligosymptomatic kidney tubular injury. Graphical abstract

Valproic Acid-Associated Acute Pancreatitis: Systematic Literature Review

“…Valproic acid (dipropylacetic acid), a branched-chain carboxylic acid, is currently recommended to treat epilepsy, acute mania, and bipolar disorders and to prevent migraine headache [ 5 ]. While generally considered safe, valproic acid is associated with adverse effects such as skin rashes, bone marrow suppression, liver or kidney injury, hyperammonemia, and teratogenicity [ 5 , 6 , 7 ].…”

Combined effects of valproate and naringin on kidney antioxidative markers and serum parameters of kidney function in C57BL6 mice

“…Sodium valproate and valproic acid (valproate further in the text) have long been indicated for the treatment of epilepsy and more recent prophylactic indications include bipolar disorder and migraine. Generally, adverse effects are rare and usually involve dermatological signs, pancytopaenia, an increase in blood ammonia or liver and pancreatic enzymes, or teratogenic effects ( 1 , 2 ). Some epileptic patients receiving valproate over long time develop subclinical tubular injury with a number of symptoms, such as metabolic acidosis, aminoaciduria, decreased 25-OH vitamin D 3 , and the Fanconi syndrome ( 1 – 3 ).…”

“…Generally, adverse effects are rare and usually involve dermatological signs, pancytopaenia, an increase in blood ammonia or liver and pancreatic enzymes, or teratogenic effects (1,2). Some epileptic patients receiving valproate over long time develop subclinical tubular injury with a number of symptoms, such as metabolic acidosis, aminoaciduria, decreased 25-OH vitamin D 3 , and the Fanconi syndrome (1)(2)(3).…”