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

Abstract

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.

Genomics of Lithium Action and Response

“…ACCN1 encodes a member of the ENaC superfamily, but it is not known if this plays a role in the collecting duct pathology. Once lithium enters the duct cells, there are many and, in some instances, hotly debated routes of pathological action, including increased cyclooxygenase-2 expression generating prostaglandin E 2 , inhibition of GSK3β/vasopressin action, decreased urea transporter expression, increased cell-cycle activity leading to cellular remodeling, and reduced inositol monophosphate/cyclic adenosine monophosphate signaling [13–15]. Ultimately, there is reduced induction and expression of the aquaporin-2 channels in the duct cell wall, preventing the passive reuptake of water from the duct and therefore leading to the production of excess, dilute urine.…”

Endogenous Notch Signaling in Adult Kidneys Maintains Segment-Specific Epithelial Cell Types of the Distal Tubules and Collecting Ducts to Ensure Water Homeostasis

“…3,[24][25][26] The underlying mechanism by which lithium alters collecting duct cell types remains unclear. 27 Here, we test the hypotheses that loss of Notch signaling, or lithium treatment, can independently trigger PCs in adult kidneys to lose their identity. We have determined that in the adult kidney connecting tubule (CNT) and collecting duct segments, where different types of epithelial cells coexist intermingled within segments, Notch signaling maintains epithelial cell type diversity by preventing transdifferentiation of the majority cell type into the neighboring minority cell type.…”

Continuation of lithium after a diagnosis of chronic kidney disease

“…However, the underlying pathologies are different. Lithium‐associated tubular damage is more common, and concerns the distal tubuli and collecting ducts . Valproate‐associated tubular damage is less common and concerns the proximal tubulus (Fanconi syndrome) .…”