What we need to know about the effect of lithium on the kidney

Abstract

Lithium has been a valuable treatment for bipolar affective disorders for decades. Clinical use of lithium, however, has been problematic due to its narrow therapeutic index and concerns for its toxicity in various organ systems. Renal side effects associated with lithium include polyuria, nephrogenic diabetes insipidus, proteinuria, distal renal tubular acidosis, and reduction in glomerular filtration rate. Histologically, chronic lithium nephrotoxicity is characterized by interstitial nephritis with microcyst formation and occasional focal segmental glomerulosclerosis. Nevertheless, this type of toxicity is uncommon, with the strongest risk factors being high serum levels of lithium and longer time on lithium therapy. In contrast, in experimental models of acute kidney injury and glomerular disease, lithium has antiproteinuric, kidney protective, and reparative effects. This paradox may be partially explained by lower lithium doses and short duration of therapy. While long-term exposure to higher psychiatric doses of lithium may be nephrotoxic, short-term low dose of lithium may be beneficial and ameliorate kidney and podocyte injury. Mechanistically, lithium targets glycogen synthase kinase-3β, a ubiquitously expressed serine/threonine protein kinase implicated in the processes of tissue injury, repair, and regeneration in multiple organ systems, including the kidney. Future studies are warranted to discover the exact "kidney-protective dose" of lithium and test the effects of low-dose lithium on acute and chronic kidney disease in humans.

Keywords: focal segmental glomerulosclerosis; glycogen synthase kinase 3; nephrotoxicity; podocyte; renal interstitial nephritis.

Copyright © 2016 the American Physiological Society.

Figures

Fig. 1.

Paradoxical effects of lithium on the kidney. Lithium has been reported to confer both detrimental (black area and panels onleft) and protective (white area and panels onright) effect on the kidney. At psychiatric doses, lithium quickly elicits polyuria and in some patients causes nephrogenic diabetes insipidus (NDI), which may uncommonly result in distal renal tubular acidosis (dRTA). Long-term lithium treatment in psychiatric patients occasionally causes chronic lithium nephrotoxicity, characterized by kidney dysfunction and interstitial nephritis with microcyst formation, and, occasionally, focal segmental glomerulosclerosis (FSGS). A number of molecular mechanisms have been implicated in the genesis of lithium nephrotoxicity, including the suppression of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) signaling, inhibition of glycogen synthase kinase (GSK)-3α, competition with magnesium ions (Mg2+), overactivity of cyclooxygenase (COX)-2, and more. In contrast, short-term low-dose lithium has beneficial effects in diverse experimental kidney diseases, including acute kidney injury (AKI) and glomerulonephropathies (GN). In experimental AKI, lithium protects against renal tubular death, suppresses kidney inflammation, and promotes renal repair. In animals with glomerular disease, lithium therapy reduces proteinuria, ameliorates podocytopathy, and glomerular damage. Mechanistically, the kidney-protective effect of lithium has been attributed to GSK3β inhibition.