Lithium and Nephrotoxicity

Abstract

Despite the availability of so many alternative agents, lithium continues to be a commonly prescribed and effective agent used in acute and maintenance treatment of bipolar affective disorders. The concern on  lithium-induced renal toxicity began with a renal biopsy based study in 1977  showing biopsy abnormalities in some  lithium-treated patients. Lithium clearance may change with the change in glomerular filtration rate, when there is activation of sodium-retaining or sodium-excreting mechanisms, and when there is reabsorption of lithium in the distal nephron. Lithium appears to exert the majority of its toxic effects at the distal tubules and collecting ducts region. Increased lithium concentration leads to a reduction in cyclic adenosine monophosphate (c-AMP) by inhibiting its formation , possibly by acting on the inositol and protein kinase C pathways. Reduced c-AMP concentration results in impaired phosphorylation of protein kinase A (PKA) and subsequently less phosphorylation of aquaporin 2 (AQP2). Lithium also acts through cell division cycle 25 (cdc25)- checkpoint kinase 1 (Chk1) mediated pathway and causes G2 arrest of principal cells. The end result is decreased number of principal cells. Long term lithium use leads to upregulation of profibrotic Transforming growth factor beta 1 (TGF-?1) . Probably lithium causes overexpression of ?-catenin ( which is a component of the Wnt/?-catenin signalling pathway) leading to fibrotic process. Ultimately this fibrotic processes results in chronic interstitial fibrosis. The most common renal side effect of lithium is urinary concentrating defect with or without polyuria. Multiple studies have shown that long-term lithium treatment is associated with increased risk of CKD. A longer duration of lithium therapy, total cumulative lithium dose, high serum level of lithium prior episodes of lithium toxicity, a lower initial e-GFR value, women gender, increasing age are important risk factors for development of chronic kidney disease in patients on lithium therapy. In a good responder of lithium, cessation of lithium treatment may lead to affective deterioration. In such case the therapeutic efficacy of lithium may outweigh the nephrotoxicity risk.