Molecular mechanisms in lithium-associated renal disease: a systematic review

Int Urol Nephrol. 2016 Nov;48(11):1843-1853. doi: 10.1007/s11255-016-1352-6. Epub 2016 Jun 29.


Purpose: Lithium is an essential treatment in bipolar disorder and treatment-resistant depression; however, its use has been limited by concerns regarding its renal adverse effects. An improved understanding of potential molecular mechanisms can help develop prevention and treatment strategies for lithium-associated renal disease.

Methods: We conducted a systematic literature search using MEDLINE, Embase, and PsychINFO including English-language original research articles published prior to November 2015 that specifically investigated lithium's effects on nephrogenic diabetes insipidus (NDI) and chronic kidney disease (CKD), using molecular markers.

Results: From a total of 3510 records, 71 pre-clinical studies and two relevant clinical studies were identified. Molecular alterations were reported in calcium signaling, inositol monophosphate, extracellular-regulated, prostaglandin, sodium/solute transport, G-protein-coupled receptors, nitric oxide, vasopressin/aquaporin, and inflammation-related pathways in lithium-associated renal disease. The majority of studies found that these mechanisms were implicated in NDI, while few studies had examined CKD.

Discussion: Future studies will have to focus on (1) validating the present findings in human subjects and (2) examining CKD, which is the most clinically relevant lithium-associated renal effect. This will improve our understanding of lithium's biological effects, as well as inform a personalized medicine approach, which could lead to safer lithium prescribing and less renal adverse events.

Keywords: Chronic kidney disease; Lithium; Molecular mechanisms; Nephrogenic diabetes insipidus; Systematic review.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Animals
  • Aquaporins / metabolism
  • Calcium / metabolism
  • Diabetes Insipidus, Nephrogenic / chemically induced
  • Diabetes Insipidus, Nephrogenic / metabolism*
  • Humans
  • Lithium / adverse effects*
  • Prostaglandins / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Renal Insufficiency, Chronic / chemically induced
  • Renal Insufficiency, Chronic / metabolism*
  • Signal Transduction*
  • Sodium / metabolism
  • Symporters / metabolism
  • Vasopressins / metabolism


  • Aquaporins
  • Prostaglandins
  • Receptors, G-Protein-Coupled
  • Symporters
  • Vasopressins
  • Lithium
  • Sodium
  • Calcium