Lithium Therapy Associated With Renal and Upper and Lower Urinary Tract Tumors: Results From a Retrospective Single-Center Analysis.

To the Editors

In February, 2015, the European Medicines Agency communicated that the current evidence is sufficient to conclude that long-term use (>10 years) of lithium may induce microcysts, oncocytomas, and collecting duct renal carcinomas.[1] Thereupon, marketing authorization holders of lithium containing medical products were requested to amend the product information accordingly.[1] The currently available epidemiological studies regarding the association between lithium therapy (LT) and renal and urinary tract tumors, however, differ significantly in terms of included tumors, methodology, and results.[2-4] Thus, an adequate evaluation of the relation between (long-term) LT and the risk for renal und urinary tract tumors is currently not possible. The mechanisms underlying lithium-induced nephrotoxicity in general and lithium-associated oncogenesis in the kidney and the upper and lower urinary tract in particular are not completely understood.[2,5] Lithium exerts possible oncogenic effects merely in the intracellular space and primarily enters the cells of the kidney via the amiloride-sensitive epithelial sodium channel (ENaC).[6-8] The urothelium of renal pelvis, ureter, bladder, and urethra also expresses ENaCs,[9-13] thus making these tissues theoretically also susceptible to lithium-associated oncogenesis. However, the aforementioned epidemiological studies have not considered the lower urinary tract (urethra and bladder).[2-4] In addition, the ENaC consists of 3 different subunits (α, β, γ) and a fourth so-called δ subunit, whose function is unknown.[14,15] These subunits are expressed differently in kidneys and the urothelium of renal pelvis, ureter, bladder, and urethra (eg, stronger expression of α, β, and γ subunits in the kidney than in the urothelium of the bladder).[9,11] Therefore, there may be a relation between the tissue-specific expression of ENaCs and the tissue-specific susceptibility regarding lithium-associated oncogenesis. Taking into account these aspects, we performed an exploratory retrospective, single-center analysis of patients with malignant and benign renal and upper and lower urinary tract tumors to (1) determine the prevalence of LT and (2) investigate if the prevalence of LT varies significantly between different tumor entities as an indication of a possible relation between the tissue-specific susceptibility regarding lithium-associated oncogenesis and the tissue-specific expression of ENaCs.

The study protocol was introduced to the local ethics committee/human subjects committee of Ulm University and received approval. All patients receiving treatment in the Department of Urology at the University Hospital of Ulm between January 1, 2006, and December 31, 2015, owing to 1 or more of the following index tumor groups according to International Statistical Classification of Diseases, 10th Revision (ICD-10), were included for further data acquisition: malignant neoplasm of kidney, except renal pelvis (ICD-10 C64), malignant neoplasm of renal pelvis (ICD-10 C65), malignant neoplasm of ureter (ICD-10 C66), malignant neoplasm of bladder (ICD-10 C67), malignant neoplasm of other and unspecified urinary organs (ICD-10 C68), and benign neoplasm of urinary organs (ICD-10 D30). (Because of the high number of cases of malignant bladder tumors treated between January 1, 2006, and December 31, 2015, resulting in overrepresentation of these entity [1712 malignant bladder tumors vs 904 malignant renal tumors], the reference period for this tumor entity was later restricted to January 1, 2010, and December 31, 2015, resulting in 951 malignant bladder tumors.) Patients with age less than 18 years at the time of treatment at the Department of Urology owing to 1 of the previously mentioned index tumors were excluded. The clinic's internal digital patient database was screened for eligible patients by using the previously mentioned ICD-10 codes. Digital files of patients identified in this procedure were checked by hand for the presence of the previously mentioned inclusion and exclusion criteria. The following data were extracted from the digital patient files: age (at the time of diagnosis of the index tumor based on the date of the report on the histopathological findings or the date of the first doctor's report listing respective diagnosis), sex, exposure to lithium (yes/no) and period of exposure to lithium, type of tumor, histological subtype of tumor, and risk factors for the development of renal and upper and lower urinary tract tumors: body height and weight (calculation of the body mass index using these parameters), smoking status, arterial hypertension, estimated glomerular filtration rate (measurement before the surgical procedure due to the respective index tumor, as documented in the digital patient files or calculated based on the Chronic Kidney Disease Epidemiology Collaboration formula[16]), exposure to aromatic amines, use of phenacetin-containing analgesics, chronic urinary tract infection, von-Hippel-Lindau disease, and radiotherapy of the pelvis. Exposure to lithium before diagnosis of 1 of the index tumors was defined as presence of correspondent information in the digital patient files and/or written or oral statements by the patient. Information regarding the period of exposure to lithium was also retrieved from the digital patient files or requested directly from the patient. If the digital patient files did not provide sufficient information regarding prior exposure to lithium, the patients were contacted by mail and asked to complete a brief 1-sided questionnaire that was created for the detection of lithium exposure (yes/no) and duration of lithium exposure; if questionnaires were not returned to the study personnel, the respective patients were contacted by phone and a semistructured telephone interview was performed based on structure and content of the questionnaire.

We identified 2131 cases featuring 1 or more of the previously mentioned tumors, corresponding to 2027 patients. After contacting patients via mail and phone respectively, information regarding exposure to lithium before diagnosis of 1 of the index tumors was available in 471 cases (22.1%), corresponding to 440 patients (21.7%). In the subgroup with information regarding prior exposure to lithium, the prevalence of prior exposure to lithium was 0.85% (4/471; 95% confidence interval [CI], 0.23%–2.16%), and 0.50% (1/202; 95% CI, 0.01%–2.73%) in renal and 1.12% (3/269; 95% CI, 0.23%–3.22%) in urinary tract tumors. Numbers of index tumors in cases with information regarding prior LT and respective prevalences of prior exposure to lithium are indicated in Table 1. We found 4 cases corresponding to 3 patients with index tumors and exposure to lithium before diagnosis of the respective index tumor(s): 3 cases of urothelial cancer of the bladder and 1 case of benign renal tumor, whereas 1 patient featured both tumors. There was no statistically significant difference regarding the prevalence of lithium exposure between patients with renal tumors and urinary tract tumors (P = 0.6385, Fisher exact test). All analyses were evaluated in an exploratory way (using SAS 9.4). Because of very low numbers of cases with prior exposure to lithium, further analyses regarding comparisons between subgroups of tumors and/or to control for covariates (eg, risk factors for different index tumors) were not possible.

TABLE 1

Numbers of Cases of Index Tumors With Information Regarding Prior Exposure to Lithium and Prevalences of Prior Exposure to Lithium

As a result of a very small number of detected cases with index tumors and prior exposure to lithium, our hypothesis of a possible relation between the tissue-specific susceptibility regarding lithium-associated oncogenesis and the tissue-specific expression of ENaCs could not be tested. However, there was no statistically significant difference between cases with renal tumors and urinary tract tumors regarding the prevalence of prior exposure to lithium, which may be a weak point arguing against our hypothesis. Meaningful further comparisons, for example, comparisons between different types of upper and lower urinary tract tumors as initially envisaged, were not possible owing to the low number of cases with prior exposure to lithium. In this regard, further epidemiological studies comprising larger samples of patients with the here defined index tumors and sufficient information regarding prior exposure to lithium should be performed to test our hypothesis. Although our study was not designed to contribute to the question of whether long-term LT may be associated with renal and/or urinary tract tumor formation, the overall prevalence of prior exposure to lithium was low in our sample; this may be interpreted as a possible weak indication of a low risk of renal and urinary tract tumors associated with LT; however, further studies are necessary to adequately address this important safety aspect of LT.