Lithium and nephrotoxicity: Unravelling the complex pathophysiological threads of the lightest metal

Abstract

This paper elucidated the current evidence pertaining to the pathophysiology of lithium induced nephrotoxicity and nephrogenic diabetes insipidus. The molecular mechanisms behind are the development of alterations in glycogen synthase kinase 3 signalling, G2 cell cycle progression arrest, alterations in inositol and prostaglandin signalling pathways, and dysregulated trafficking and transcription of aquaporin 2 water channels. ABSTRACT:While lithium remains the most efficacious treatment for bipolar disorder, it can cause significant nephrotoxicity. The molecular mechanisms behind both this process and the development of nephrogenic diabetes insipidus still remain to be fully elucidated but appear to involve alterations in glycogen synthase kinase 3 signalling, G2 cell cycle progression arrest, alterations in inositol and prostaglandin signalling pathways, and dysregulated trafficking and transcription of aquaporin 2 water channels. The end result of this is a tubulointerstitial nephropathy with microcyst formation and relative glomerular sparing, both visible on pathology specimens and increasingly noted on non-invasive imaging. This paper will elucidate the current evidence pertaining to the pathophysiology of lithium induced nephrotoxicity.

Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy

“…Furthermore, clomiphene, lomustine, lithium, and cocaine have been reported to exert direct or indirect modulatory effects on calcineurin/calmodulin/nuclear factor of activated T-cell pathways. [46][47][48][49][50][51][52][53] These findings imply that the calcineurin signaling pathway might play a central pathomechanistic role in PTC damage in patients with CINAC. On top of the highly reabsorptive capacity of the PTCs, renal calcineurin phosphatase activity is highest in these cells, likely accounting for the localization of the injury.…”

The Photoinitiator Lithium Phenyl (2,4,6-Trimethylbenzoyl) Phosphinate with Exposure to 405 nm Light Is Cytotoxic to Mammalian Cells but Not Mutagenic in Bacterial Reverse Mutation Assays

“…Lithium ion is a known nephrotoxicant, whose mechanism of toxicity is related to the inhibition of AQP-2 transport to the cell membrane, thereby causing diabetes insipidus [ 39 ]. However, diabetes insipidus isn’t the major concern in this study versus lithium accumulation within the kidney, risk of renal fibrosis, and damage to various organelles; karyolysis and cell fragmentation were observed in the kidneys of rats exposed to lithium chloride [ 21 , 23 , 40 ]. Results in both the Alamar Blue and Neutral Red Uptake assays agree that lithium ion concentrations typically associated with LAP can be mildly cytotoxic; However, 95% viability from 17 mmol/L LiCl exposure (i.e., equivalent to 0.5 wt % LAP) determined with the NRU assay is a generally accepted viability for cells grown in vitro; this effect should be less pronounced in other cell models not as sensitive to lithium.…”

“…Kidney collecting duct cells are a well-known target of lithium, with kidney injury and disease being a common side effect of lithium treatment for psychiatric disorders [ 16 , 17 , 18 , 19 ]. The mechanism of lithium toxicity to collecting duct cells is related to the epithelial sodium channels (passive transport into the cell) having a greater affinity for lithium versus sodium and the sodium efflux ATPase pump having a lower affinity for lithium leading to accumulation within the cell [ 20 , 21 ]. Fibrosis is a late response to acute kidney injury, and is also observed after exposure to lithium chloride; thus, LAP, a lithium salt, may be more cytotoxic to collecting duct cells versus other cell types [ 22 , 23 ].…”

Pax2 and Pax8 Proteins Regulate Urea Transporters and Aquaporins to Control Urine Concentration in the Adult Kidney

“…NDI is also associated with lithium use, 35 routinely prescribed and effective for bipolar disorders. Lithium is also a potent inhibitor of GSK3, which activates NFAT5 (TonEBP), a positive regulator of UTs and AQPs.…”