Lithium and nephrotoxicity: a literature review of approaches to clinical management and risk stratification

Abstract

BackgroundDespite lithium being the most efficacious treatment for bipolar disorder, its use has been decreasing at least in part due to concerns about its potential to cause significant nephrotoxicity. Whilst the ability of lithium to cause nephrogenic diabetes insipidus is well established, its ability to cause chronic kidney disease is a much more vexing issue, with various studies suggesting both positive and negative causality. Despite these differences, the weight of evidence suggests that lithium has the potential to cause end stage kidney disease, albeit over a prolonged period.MethodsA search strategy for this review was developed to identify appropriate studies, sourced from the electronic databases EMBASE, PubMed (NLM) and MEDLINE. Search terms included lithium with the AND operator to combine with nephrotoxicity or nephropathy or chronic kidney disease or nephrogenic diabetes insipidus or renal and pathophysiology.ResultsThe risks for the development of lithium induced nephropathy are less well defined but appear to include the length of duration of therapy as well as increasing age, as well as episodes of over dosage/elevated lithium levels. Whilst guidelines exist for the routine monitoring of lithium levels and renal function, it remains unclear when nephrological evaluation should occur, as well as when cessation of lithium therapy is appropriate balancing the significant attendant mental health risks as well as the potential for progression to occur despite cessation of therapy against the risks and morbidity of bipolar disorder itself.ConclusionThis paper will elucidate on the current evidence pertaining to the topic of the clinical management of lithium induced nephrotoxicity and provide a guide for clinicians who are faced with the long-term management of these patients.

Relationship between serum lithium concentration and kidney damage in a preclinical model

“…In contrast, although compared to controls, HighLi group did not show differences in laboratory data during the first month of treatment, they had higher values of serum creatinine and decreased creatinine clearance at 3 months. This finding suggests a time‐dependent effect of lithium treatment on the development of renal damage, which agrees with previous data from preclinical and clinical studies . In addition, compared with the LowLi group, the HighLi group had a lower creatinine clearance and more histopathological damage characterized by greater dilatation of the cortical collecting tubules, hyperplasia, and hypertrophy with the presence of binucleated cells and macronuclei and focal tubular atrophy.…”

“…In this context, knowledge of the risk factors for the development of CKD associated with long‐term lithium treatment is challenging, and could contribute to a more rational use of this therapeutic agent. There is some convergent evidence that the risk of developing CKD could be associated with the duration of treatment (often more than a decade), old age, prior episodes of lithium toxicity, medical comorbidities (ie, diabetes or hypertension), and the concomitant use of other medications with nephrotoxic potential (such as angiotensin converting enzyme inhibitors or non‐steroidal anti‐inflammatory agents) . On the contrary, the risk associated with serum lithium concentrations—when they are within the therapeutic range—is controversial.…”

The toxicity of lithium to human cardiomyocytes

“…Importantly, the effects of lithium are long-duration accumulation. For instance, lithium-induced nephropathy seems to be a very slowly progressive disease, and the average period from the initiation of lithium to the presence of end-stage kidney disease is a least 20 years [21]. The toxicity of lithium on the central nervous system and renal has been studied extensively.…”

“…The epithelium lining of renal tissue was injured, and some significant changes were observed in the glomerular region in the corticomedullary region [20]. Besides, high concentrations of lithium could cause severe damage to humans, including the nervous system (including coarse tremor and hyperreflexia), kidney (including sodium-losing nephritis and nephrotic syndrome), and endocrine system (including hypothyroidism) [21][22][23][24]. However, the effects of lithium on the cardiovascular system have not been studied yet.…”

Lithium Use in a Patient With Bipolar Disorder and End-Stage Kidney Disease on Hemodialysis: A Case Report

“…Lithium is one of the first-line treatments for the manic and depressive phases of bipolar disorder (1,2). It protects against both depression and mania as well as being the only therapy known to reduce suicide risk in this patient population (3)(4)(5), with a composite measure of suicide plus deliberate self-harm lowered in patients receiving lithium (5).…”