Long-Term Lithium Use and Risk of Renal and Upper Urinary Tract Cancers

Abstract

Lithium induces proliferation in the epithelium of renal collecting ducts. A recent small-scale cohort study reported a strong association between use of lithium and increased risk of renal neoplasia. We therefore conducted a large-scale pharmacoepidemiologic study of the association between long-term use of lithium and risk of upper urinary tract cancer, including renal cell cancer and cancers of the renal pelvis or ureter. We identified all histologically verified upper urinary tract cancer cases in Denmark between 2000 and 2012 from the Danish Cancer Registry. A total of 6477 cases were matched by age and sex to 259,080 cancer-free controls. Data on lithium use from 1995 to 2012 were obtained from the Danish Prescription Registry. We estimated the association between long-term use of lithium ($5 years) and risk of upper urinary tract cancer using conditional logistic regression with adjustment for potential confounders. Longterm use of lithium was observed among 0.22% of cases and 0.17% of controls. This yielded an overall nonsignificant adjusted odds ratio (OR) of 1.3 (95% confidence interval [95% CI], 0.8-2.2) for upper urinary tract cancer associated with long-term use of lithium. Analyses stratified by stage and subtype of upper urinary tract cancer revealed slight but nonsignificant increases in the ORs for localized disease (OR, 1.6; 95% CI, 0.8-3.0) and for renal pelvis/ureter cancers (OR, 1.7; 95% CI, 0.5-5.4). In conclusion, in our nationwide case-control study, use of lithium was not associated with an increased risk of upper urinary tract cancer.

Lithium in the Kidney: Friend and Foe?

“…[5][6][7] Recently, two studies also reported an increased incidence of solid renal tumors in chronic lithium users compared with the general population. 8,9 However, because of several limitations of these studies as outlined by Licht et al 10 and contradictory findings in the study from Pottegård et al, 11 which included many more patients, we will not regard renal tumor development as a side effect of lithium treatment at this point. 10,11 In contrast to these adverse effects of lithium treatment, accumulating evidence suggests that the administration of low lithium amounts (,0.6 mM in blood) improves kidney function in different animal nephropathy models.…”

“…8,9 However, because of several limitations of these studies as outlined by Licht et al 10 and contradictory findings in the study from Pottegård et al, 11 which included many more patients, we will not regard renal tumor development as a side effect of lithium treatment at this point. 10,11 In contrast to these adverse effects of lithium treatment, accumulating evidence suggests that the administration of low lithium amounts (,0.6 mM in blood) improves kidney function in different animal nephropathy models. Single-bolus injections or short-term treatment (,1 week) of lithium reduced adriamycin-, LPS-, cisplatin-, gentamicin-, and ischemiainduced AKI, [12][13][14][15][16][17][18] whereas prolonged treatment ($1 month) alleviated kidney damage because of ischemia-reperfusion, hypertension, and the autoimmune disease lupus erythematosus.…”

Lithium and renal and upper urinary tract tumors – results from a nationwide population‐based study

“…Lithium has been the main mood stabilizing treatment for bipolar disorder for more than 60 years and the evidence for its prophylactic effect is strong and still increasing . However, recently, clinicians and researchers were alarmed by findings from a small case‐series study suggesting an up to tenfold increased prevalence of renal cancer among long‐term lithium users . By contrast, the results from a subsequent Danish nationwide, population‐based case‐control study found no increased risk of renal or upper urinary tract cancer associated with lithium .…”

Considerations for Pharmacoepidemiological Studies of Drug–Cancer Associations

“…Such misclassification is of particular importance when a carcinogenic effect of limited exposure needs to be assessed. Conversely, when only distant or very long-term drug use is anticipated to influence cancer risk, restriction to new users may hinder a meaningful evaluation [7].…”

“…Clear associations have been established for a number of drugs, for example, the preventive effect of aspirin use against colorectal cancer [1,2] or the increased risk of renal cancer with use of phenacetin [3,4]. Further, new hypotheses often arise, such as the recent concerns about carcinogenic effects of lithium [5][6][7] and pioglitazone [8][9][10][11][12]. A significant challenge in the elucidation of drug effects on cancer development is that the effects typically first become manifest several years after drug initiation.…”