Lithium in the Kidney: Friend and Foe?

Abstract

Trace amounts of lithium are essential for our physical and mental health, and administration of lithium has improved the quality of life of millions of patients with bipolar disorder for >60 years. However, in a substantial number of patients with bipolar disorder, long-term lithium therapy comes at the cost of severe renal side effects, including nephrogenic diabetes insipidus and rarely, ESRD. Although the mechanisms underlying the lithium-induced renal pathologies are becoming clearer, several recent animal studies revealed that short-term administration of lower amounts of lithium prevents different forms of experimental AKI. In this review, we discuss the knowledge of the pathologic and therapeutic effects of lithium in the kidney. Furthermore, we discuss the underlying mechanisms of these seemingly paradoxical effects of lithium, in which fine-tuned regulation of glycogen synthase kinase type 3, a prime target for lithium, seems to be key. The new discoveries regarding the protective effect of lithium against AKI in rodents call for follow-up studies in humans and suggest that long-term therapy with low lithium concentrations could be beneficial in CKD.

Keywords: acute renal failure; cell and transport physiology; cell signaling; diabetes insipidus; drug nephrotoxicity; end-stage renal disease.

Figure 1.

Lithium is reabsorbed in different segments of the renal tubule and in the collecting duct. Lithium is freely filtered in the glomerulus and subsequently reabsorbed by different nephron segments. In the proximal tubules, lithium is, to a minor extent, reabsorbed through the transcellular pathway, which likely involves NHE3 at the apical plasma membrane and NHE1 at the basolateral plasma membrane. In the distal tubules and collecting duct, transcellular lithium uptake from the prourine occurs through the ENaC, whereas NHE1 likely mediates the cellular efflux to the interstitium. In both the proximal tubule and thick ascending limb of Henle (TAL), lithium is reabsorbed in a paracellular fashion, which is driven by the generated transcellular luminal–positive electrical gradient. In the TAL, this gradient is accomplished by luminal K⁺ efflux by renal outer medullary K⁺ 2 (ROMK2); K⁺, Na⁺, and Cl⁻ influx b Na⁺/K⁺/2Cl^– cotransporter 2 (NKCC2); and basolateral extrusion by the Na⁺/K⁺-ATPase and ClC-Kb chloride channels (as indicated).

Figure 2.

Lithium-induced GSK3 inhibition confers renoprotection via different mechanisms. Upon AKI–induced cell death, an inflammatory response, or increased oxidative stress of proximal tubule cells, activated GSK3 prevents tubular repair and induces proinflammatory gene transcription and apoptosis/necrosis. By inhibiting GSK3, lithium intervenes and reduces activation of these nephrotoxic pathways. Details are in the text. PTP, permeability transition pore.