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It has also been implicated as a cause of a kidney tubular injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      For the final analysis, we retained 36 articles: 28 case reports documented 48 individuals with epilepsy on valproic acid for 7\u00a0months or more and presenting with features consistent with an overt kidney tubular injury. The following disturbances were noted: hypophosphatemia (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200946), normoglycemic glycosuria (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200946), total proteinuria (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200945), metabolic acidosis (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200936), hypouricemia (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200927), tubular proteinuria (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200927), hypokalemia (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200923), and hypocalcemia (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u20098). 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\u00a0months or more, an isolated tubular proteinuria, mostly N-acetyl-\u03b2-glucosaminidase, was often noted.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Valproic acid may induce an overt kidney tubular injury, which is associated with a proximal tubular mitochondrial toxicity. Treatment for 7\u00a0months or more is often associated with a pauci- or oligosymptomatic kidney tubular injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00467-022-05869-8","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T08:03:25Z","timestamp":1673856205000},"page":"1725-1731","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Kidney tubular injury induced by valproic acid: systematic literature review"],"prefix":"10.1007","volume":"38","author":[{"given":"Giulia","family":"Anguissola","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Leu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo D.","family":"Simonetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara Goeggel","family":"Simonetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8391-5462","authenticated-orcid":false,"given":"Sebastiano A. 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