Increased risk of solid renal tumors in lithium-treated patients

clinical investigation

http://www.kidney-international.org & 2014 International Society of Nephrology

Increased risk of solid renal tumors in lithium-treated patients Mohamad Zaidan1,2,3, Fabien Stucker4, Be´ne´dicte Stengel5,6, Viorel Vasiliu7, Aure´lie Hummel1,2, Paul Landais2,8, Jean-Jacques Boffa4,9, Pierre Ronco4,9, Jean-Pierre Gru¨nfeld1,2 and Aude Servais1,2 1

Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris Descartes University, Paris, France; 2Paris Descartes University, Sorbonne Paris Cite´, Paris, France; 3INSERM U845, Centre de Recherche ‘‘Croissance et Signalisation’’, Paris, France; 4 Department of Nephrology, Tenon Hospital, APHP, Paris, France; 5INSERM U1018, Centre for Epidemiology and Population Health, Villejuif, France; 6UMRS 1018, Univ Paris-Sud, Villejuif, France; 7Department of Pathology, Necker Hospital, APHP, Paris Descartes University, Paris, France; 8Department of Biostatistics, Necker Hospital, Paris, France and 9UPMC Univ Paris 6, Paris, France

Cystic kidney diseases and toxic interstitial nephritis may be complicated by renal tumors. Long-term lithium intake is associated with tubulointerstitial nephritis and renal cysts but to date such an association with tumors has not been determined. We evaluated this in a retrospective study to determine whether lithium-treated patients were at higher risk of renal tumors compared with lithium-free patients with chronic kidney disease (CKD), and to the general population. Over a 16-year period, 14 of 170 lithium-treated patients had renal tumors, including seven malignant and seven benign tumors. The mean duration of lithium exposure at diagnosis was 21.4 years. The renal cancers included three clear-cell and two papillary renal cell carcinomas, one hybrid tumor with chromophobe and oncocytoma characteristics, and one clear-cell carcinoma with leiomyomatous stroma. The benign tumors included four oncocytomas, one mixed epithelial and stromal tumor, and two angiomyolipomas. The percentage of renal tumors, particularly cancers and oncocytomas, was significantly higher in lithium-treated patients compared with 340 gender-, age-, and estimated glomerular filtration rate (eGFR)-matched lithium-free patients. Additionally, the Standardized Incidence Ratio of renal cancer was significantly higher in lithium-treated patients compared with the general population: 7.51 (95% confidence interval (CI) (1.51–21.95)) and 13.69 (95% CI (3.68–35.06)) in men and women, respectively. Thus, there is an increased risk of renal tumors in lithium-treated patients.

Bipolar disorder is a frequent and severe mood disorder.1 Over the years, lithium has been increasingly recognized as an effective and valuable agent for its treatment and prevention of relapses.1 Although new drugs have recently been developed, lithium is still recommended as a first-line therapy for mood disorders.1 Renal side effects of this treatment, partly due to the narrow therapeutic index of the drug, have given rise to significant concern.2 Indeed, long-term lithium intake may alter the concentrating ability of the kidney, and up to 40% of patients present with polyuria.2 Although serum lithium concentrations are maintained within the therapeutic range, the glomerular filtration rate (GFR) may decline progressively in B20% of patients, potentially resulting in chronic kidney disease (CKD).3–7 In these cases, renal histopathological findings include tubular atrophy and interstitial fibrosis, mixed with tubular dilatations and bilateral, cortical, and medullar cysts that occur in 33% and 62.5% of specimens, respectively.7 Most relevant studies report uncomplicated renal cysts in long-term lithium-treated patients. However, a small number of authors have also described patients with solid renal tumors.7–10 Previously, acquired cystic kidney disease and some other toxic tubulointerstitial nephropathies, due to phenacetincontaining analgesics and to aristolochic acid, have been associated with an increased occurrence of renal and urothelial carcinomas.11–13 The aim of this study was to determine whether lithium-treated patients have an increased risk of renal tumors.

Kidney International (2014) 86, 184–190; doi:10.1038/ki.2014.2; published online 22 January 2014 KEYWORDS: lithium; nephrotoxicity; oncocytoma; renal cancer; renal tumors

Correspondence: Aude Servais, Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris Descartes University, 149 rue de Se`vres, Paris 75015, France. E-mail: [email protected] Received 1 September 2013; revised 14 November 2013; accepted 12 December 2013; published online 22 January 2014 184

RESULTS Baseline characteristics of lithium-treated patients and renal imaging findings

Between 1996 and 2011, 191 patients who were under lithium therapy and followed at two nephrology departments (Paris, France) were eligible for the study. Renal imaging results were available for 170 patients, including 108 women (63.5%) and 62 men (36.5%), who were included in the study (Figure 1). Baseline characteristics are detailed in Table 1. The mean age at the time of renal imaging was 65.1±11.5 years, and the mean age at lithium therapy initiation was 41.1±11.9 years. Kidney International (2014) 86, 184–190

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M Zaidan et al.: Lithium and kidney tumors

Table 1 | Patients’ baseline characteristics

Li2+ patients (n = 191) Li2+ patients with no available renal imaging results (n = 21) Li2+ patients with renal imaging and sCr (n = 170)

No renal lesion (n = 68, 40%)

Atypical renal lesion(s) (n = 17, 10%)

Renal solid lesion(s) (n = 15, 8.8%)

Isolated typical renal cyst(s) (n = 85, 50%)

Atypical renal cyst(s)* (n = 2, 1.2%)

Renal solid lesion(s)** (n = 1, 0.6%) Confirmed renal solid tumor(s) (n = 14, 8.2%)

Figure 1 | Study design and renal ultrasound findings. *Renal cancer was ruled out by further imaging investigation and no histological confirmation was required. **The patient declined further investigations and was lost to follow-up.

The mean duration of lithium exposure was 21.3±10.4 years and the mean estimated glomerular filtration rate (eGFR) at renal imaging was 40.0±17.1 ml/min per 1.73 m2. Renal ultrasound findings are shown in Figure 1. Eighty-five patients (50%) had isolated typical renal cysts. Seventeen patients (10%) had atypical renal lesions on renal ultrasound including two with atypical renal cysts and one with two renal solid lesions. This patient declined further investigation and was lost to follow-up. Fourteen lithium-treated patients (8.2%) were diagnosed with renal solid tumors. Renal solid tumors in lithium-treated patients

The renal solid tumors included seven renal malignant tumors (4.1%) and seven benign tumors (4.1%). The detailed characteristics are shown in Table 2. Pathological analysis was performed in all but two patients who had imaging findings typical of angiomyolipoma (Figure 2). The renal cancers included three clear-cell renal cell carcinoma (RCC), two papillary RCC, one clear cell carcinoma with leiomyomatous stroma, and one hybrid tumor characterized by the association of an oncocytoma and a chromophobe RCC. Benign renal solid tumors included four other cases of oncocytoma, one of which presented with six oncocytomas that were associated with numerous papillary adenomas, one mixed epithelial and stromal tumor, and two angiomyolipomas. The mean age at diagnosis was 64.4±8.6 years. The mean duration of lithium exposure at diagnosis of renal cancer and benign tumor was 23.9±11.7 and 20.2±9.9 years, respectively. The diagnosis of renal tumor was established after lithium withdrawal in four patients, three of whom had renal cancer with a delay between lithium withdrawal and cancer diagnosis of 3, 5, and 18 years. Considering the limited number of cases, no association could be observed between Kidney International (2014) 86, 184–190

Sex ratio (F/M) Age at Li2 þ initiation (yr) Age at renal ultrasound (yr) Duration of Li2 þ exposure (yr) eGFR (ml/min per 1.73 m2)

No renal tumors (n ¼ 156)

All patients (n ¼ 170)

Renal tumors (n ¼ 14)

1.7 (108/62) 41.1±11.9

1.3 (8/6) 37.7±10.0

1.8 (100/56) 0.80 41.3±12.0 0.31

65.1±11.5

64.4±8.6

65.2±11.8 0.65

21.3±10.4

21.3±10.7

21.3±10.4 0.94

40.0±17.1

40.3±20.9

39.9±16.7 0.86

Pa

Abbreviations: eGFR, estimated glomerular filtration rate; F, females; Li2 þ , lithium; M, males; yr, years. Continuous variables are shown as means±s.d. a P-values are given for the comparisons between patients with renal tumors and those without renal tumors, using Mann–Whitney non-parametric test.

age, gender, duration of lithium exposure, eGFR, obesity and ever smoking, and an increased risk of renal tumor in lithium-treated patients. Comparison of the frequency of renal solid tumors between lithium-treated and lithium-free patients

As CKD has been identified as a potential risk factor for renal carcinoma, we investigated whether the frequency of renal solid tumors in lithium-treated CKD patients was increased as compared with lithium-free CKD patients. Lithium-free patients were identified from the active files of the same two nephrology departments using the criteria detailed in the Methods section. Two sex-, age-, and eGFR-matched lithiumfree patients, followed during the same period, were randomly selected for each lithium-treated patient blindly to the result of their renal imaging. Of the 340 matched patients, only one had a renal cancer, none had oncocytoma, and four had angiomyolipoma (Table 3). Three patients had atypical renal cysts that did not require further pathological investigation. The frequency of renal cancer and oncocytoma was significantly higher among lithium-treated patients than among their sex-, age-, and eGFR-matched lithium-free patients (4.1% vs 0.3%, P ¼ 0.002 and 2.4% vs 0%, P ¼ 0.01, respectively). In contrast, the frequency of angiomyolipoma did not differ between the two groups (1.2% in both groups, P ¼ 0.60). Comparison of the incidence of renal cancers between lithium-treated patients and the French general population

Using the French National estimates of renal cancer incidence, we compared the incidence of renal cancer in lithium-treated patients to the general population. The incidence was 10.12 times higher among lithium-treated patients overall than in the French general population (95% confidence interval (CI) (4.06–20.86)) (Table 4). The Standardized Incidence Ratios (SIRs) were highly significant for both men and women (SIR 7.51, 95% CI (1.51–21.95) and 13.69, 95% CI (3.68–35.06), respectively). DISCUSSION

In this retrospective cohort study, we identified 14 of the 170 lithium-treated patients (8.2%) who developed renal solid 185

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Table 2 | Characteristics of lithium-treated patients with renal solid tumor(s)

ID

Age at Li2 þ Age at diag- Duration of eGFR (ml/ initiation nosis of renal Li2 þ exposure Cigarette BMI min per 2 Gender (yr) tumor (yr) (yr) smoking 430 kg/m 1.73 m2)

Renal cyst(s)

Renal tumor Pathological diagnosis

1 2 3 4 5 6

M M M F F F

41 19 52 39 49 30

56 54 69 75 70 71

15 35 17 31 18 41

— — þ — — —

NA — — — NA þ

52 61 48 27 24 55

þ — — þ — —

RC RC RC RC RC RC

7 8

F M

38 37

66 60

10 23

— —

— —

5 10

þ þ

HT RBT

9 10 11 12 13 14

M M F F F F

34 52 28 43 28 NA

66 68 59 46 65 77

32 16 26 3 21 410

— NA — — þ —

— NA — þ — —

33 52 34 71 24 68

þ þ þ þ — —

RBT RBT RBT RBT RBT RBT

Papillary RCC Papillary RCC Clear-cell RCC Clear-cell RCC Clear-cell RCC Clear-cell carcinoma with leiomyomatous stroma Chromophobe RCC þ oncocytoma Oncocytomas (6) and papillary adenomas (21) Oncocytoma Oncocytoma Oncocytoma Mixed epithelial and stromal tumor Angiomyolipomaa Angiomyolipomaa

Abbreviations: BMI, body mass index; HT, hybrid tumor; Li2 þ , Lithium; NA, not available; RBT, renal benign tumor; RC, renal cancer; RCC, renal cell carcinoma; yr, years. a Diagnosis was established on the basis of typical renal imaging findings, including renal magnetic resonance imaging.

Figure 2 | Pathological findings in patients with biopsy-proven renal tumors. (a) Clear cell renal cell carcinoma (RCC) (patient 4); (b) papillary RCC (patient 2); (c) hybrid tumor presenting as an association of oncocytoma and chromophobe RCC within the same lesion (patient 7); (d) clear-cell RCC with leiomyomatous stroma (patient 6); (e) oncocytoma associated with (f) papillary adenomas (patient 8); (g) mixed epithelial and stromal tumor (patient 12).

tumors, including seven cases of malignant and seven cases of benign tumors. The frequency of renal cancers was significantly higher in lithium-treated patients in comparison with sex-, age-, and eGFR-matched unexposed patients with CKD, and with the general population. Similarly, the high frequency of other benign tumors, particularly oncocytomas, also suggests a potential association between lithium exposure and the development of renal solid tumors. Other toxins, notably phenacetin and aristolochic acid, have been identified as risk factors for both chronic interstitial nephritis and RCC or urothelial cancers.12,13 Until very recently, only uncomplicated renal cysts have been reported to be associated with long-term lithium treatment. In our study, cysts were observed in 50% of cases, which is consistent with 186

the 33–62.5% reported in the literature.7,14 These cysts originate from the distal tubules and collecting ducts, and their prevalence generally correlates with the duration of lithium treatment.3,7 Usually, the cysts are multiple and bilateral, localized in both the cortex and medulla, and may be easily detected by renal imaging.14 So far, RCCs have been anecdotally reported in a small number of patients with lithium-induced nephropathy. Markowitz et al.7 described the presence of renal tumors in two of 24 patients with lithium-induced nephropathy. Kjaersgaard et al.8 also reported a lithium-treated patient with RCC. More recently, Rookmaaker et al.9 described six other patients with acquired multicystic kidney disease and renal-collecting duct carcinomas and/or oncocytomas. An additional case of RCC Kidney International (2014) 86, 184–190

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M Zaidan et al.: Lithium and kidney tumors

Table 3 | Comparison between lithium-treated and lithium-free patients Li2 þ -treated patients Li2 þ -untreated (n ¼ 170) patients (n ¼ 340) Age (yr) Women/men eGFR (ml/min per 1.73 m2) Renal solid tumors Renal cancer Oncocytoma Angiomyolipoma

P

65.1±11.5 108/62 40.0±17.1

65.0±11.6 216/124 39.6±16.9

0.93 0.92 0.82

7 (4.1) 4 (2.4)a 2 (1.2)

1 (0.3) 0 (0) 4 (1.2)

0.004 0.02 0.66

Abbreviations: eGFR, estimated glomerular filtration rate; Li2 þ , lithium; n, number; RCC, renal cell carcinoma; yr, years. Continuous variables are shown as means±s.d. and categorical variables are shown as number (percentage). a The oncocytoma associated with chromophobe RCC is not included among the four cases.

Table 4 | Comparison of the Standardized Incidence Ratio of renal cancers between lithium-treated patients and the French general population All patients

Men

Women

Age (years) Observed Expected Observed Expected Observed Expected [15;49] [50;59] [60;69] [70;79] [80;89] Total SIR 95% CI

— 2 2 3 — 7

0.075 0.182 0.242 0.163 0.030 0.692

10.12 (4.06–20.86)

— 0.043 2 0.110 1 0.141 — 0.085 — 0.021 3 0.399 7.51 (1.51–21.95)

— — 1 3 — 4

0.032 0.072 0.102 0.077 0.009 0.292

13.69 (3.68–35.06)

Abbreviations: CI, confidence interval; SIR, Standardized Incidence Ratio. The expected number of renal cancers in this group of patients was estimated using renal cancer standardized incidence rates for 2005, by gender and 5-year stratum in the French population.14

has also been addressed in a patient with acquired cystic disease due to chronic lithium toxicity.10 Collectively, these reports and our study underscore the potential association between long-term lithium intake, renal cysts, and renal solid tumors. Interestingly, the distribution of tumor subtype in the lithium-treated group differed from that in the general population.15–17 In our cohort, 42.9% of the renal cancers were clear-cell RCC and 28.6% were papillary RCC, whereas the corresponding values for the general population are 70% and 15–20%, respectively.16 The tumor subtypes in lithiumtreated patients also differed from those in patients with other cystic kidney diseases. Indeed, patients with end-stage renal disease (ESRD) and acquired cystic kidney disease may develop various types of epithelial neoplasms, notably acquired cystic kidney disease–associated RCC and clear-cell papillary RCC, which are both characterized by specific histological features that have not been observed in lithiumtreated patients.11,18,19 Some genetic cystic kidney diseases are also known to be associated with an increased incidence of Kidney International (2014) 86, 184–190

renal tumors, notably clear-cell RCC, which are reported both in 40–60% of patients with von Hippel–Lindau disease and, to a lesser extent, in patients with the Tuberous Sclerosis Complex.19–21 However, beyond clear-cell RCC and papillary RCC, lithium-treated patients also displayed other rare subtypes of renal cancers, including one case of clear-cell RCC with leiomyomatous stroma, and one case of hybrid tumor, which corresponds to the association of oncocytoma and chromophobe RCC within the same lesion. Rare subtypes of benign renal tumors were also reported. Notably, oncocytomas were diagnosed in four other cases (28.6%) in the lithium-treated group, whereas these lesions represent only 3–7% of renal tumors in the general population.16,17,22 One of the patients displayed multifocal oncocytomas in association with papillary adenomas. Similar multifocal oncocytomas have been described in 5–13% of cases of renal oncocytosis, many of which were associated with papillary adenomas.23 A case of mixed epithelial and stromal tumor, a very rare subtype of benign renal lesion, was also observed.16 It is a complex cystic neoplasm, which contains a cellular stroma in addition to an epithelial component, and combines clustered microcysts, and large and small renal cysts.16 Collectively, these data suggest a potential association between lithium intake, renal cysts, and various types of renal tumors that differ from those reported in the general population and other cystic kidney disease. So far, the molecular mechanisms underlying lithium renal toxicity have not been clearly elucidated.2 Lithium is freely filtered through the glomeruli and reabsorbed, mostly in the renal proximal tubule. A small fraction is reabsorbed in the distal parts of the nephron through the epithelial sodium channel.24 Lithium is known to cause cell remodeling in the collecting duct leading to a decrease in the fraction of principal cells and an increase in intercalated cells.2,7,24 Such remodeling may account for the high proportion of oncocytomas, lesions that originate from intercalated cells,22 in both our cohort and the series reported by Rookmaaker et al.9 Interestingly, proteomic analysis showed that proteins involved in cell death, apoptosis, cell proliferation, and morphology are highly affected upon lithium therapy.25 Members of several signaling pathways are activated by lithium treatment, including the PKB/Akt-kinase and the mitogen-activated protein kinases, such as extracellular regulated kinase c-Jun NH(2)-terminal kinase, and p38.25 Additionally, it has been demonstrated that increased lithium uptake by principal cells can result in inhibitory phosphorylation of the glycogen synthase kinase 3b (GSK3b), as assessed by the positivity for phosphorylated GSK3b of microcystic epithelium from kidneys of lithium-treated patients.8 GSK3b has a central role in the determination of cell survival as a key component in the growth factor- or insulin-stimulated PI-3-kinase/ Akt/mammalian target of rapamycin pathway.26 Increased inhibitory phosphorylation of GSK3b leads to the activation of the Wnt/b-catenin signaling,27 a critical pathway for progression of cystic kidney diseases.28,29 This may be 187

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essential to the dysregulated cell proliferation associated with tubular dilatations and microcysts, and subsequent structural changes. GSK3b is also involved in the maintenance of primary cilia in concert with the von Hippel–Lindau tumor suppressor protein,30 which is mutated in the von Hippel–Lindau disease.20 Other signaling pathways downstream GSK3b may also be activated upon GSK3b phosphorylation, including the nuclear factor of activated T-cell–transcription factor, which drives the expression of a subset of proliferation-related genes.31 Of note, lithium also affects polycystin-2 channel function, a protein that is mutated in autosomal polycystic kidney disease.32 Altogether, lithium seems to interfere with multiple and critical signaling pathways that regulate tubular cell proliferation, differentiation and apoptosis, any of which may explain the onset of tubular dilatations, cysts, and subsequent renal damage. The cystic epithelial proliferation could be considered as the substrate for eventual malignant transformation. However, the mechanisms underlying the transition from benign to uncontrolled malignant proliferation are far from being understood, and may certainly require the activation of some oncogenes and inactivation of tumor suppressor genes, as the final step for malignancy.17,33–35 The fact that the mean duration of lithium exposure at tumor diagnosis was above 20 years may partly explain why such association has been probably missed by short-term prospective studies and has not been investigated so far. Several risk factors for renal cancers have been identified, including cigarette smoking, obesity, and ESRD.36 In our study, only one patient with renal cancer had a history of smoking and only one had a body mass index above 30 kg/m2. CKD could have also been considered as a confounder because some studies reported that decreasing renal function was associated with an increase in cancer mortality.37–39 Nevertheless, none of our lithium-treated patients with renal cancer had ESRD. Moreover, by comparing lithium-treated patients to lithium-free age-, sex-, and eGFR-matched CKD patients, we confirmed that the high prevalence of renal cancers in our lithium-treated cohort was not due to a detection bias or to a confounding effect of any of the matching criteria. The potential at risk population for lithium renal toxicity is very large. Indeed, bipolar disorders affect about 2% of the world’s population,40 and 20–30% of patients are prescribed lithium since this drug remains one of the best established treatment for mood disorders.41,42 Moreover, lithium may be prescribed a lifetime because the switch for other agents is still a difficult task in routine practice with a high risk of relapse. However, similarly to lithium-induced nephropathy, which develops slowly over decades, usually after 10–20 years,5 renal tumor development in lithium-treated patients may also be considered as a late complication, as assessed by a mean duration of 20 years of lithium exposure at diagnosis in our study and other reports.9,10 Thus, lithium-treated patients who have received lithium for more than 10 188

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years and have devolopped CKD would be the most likely to benefit of a screening for renal tumors. The prescription of a renal ultrasound every 3 years may be proposed but the cost-effectiveness of such a recommendation has to be evaluated. Our study has some limitations. Our diagnostic procedure may have caused an unintended detection bias. However, because renal ultrasound is a routine practice in the management of patients with CKD, the indication for renal ultrasound could not have been a source of detection bias in the comparison of lithium-treated patients to matched lithium-untreated patients. It should also be underscored that the interpretation of renal imaging was initially performed by radiologists who were blinded to the objectives of the study. Moreover, incidental renal tumors have emerged as a new entity over the last decades, and this has been associated with an increase in the incidence of renal cancers in the general population, limiting the risk of an overestimation of SIR.43 In summary, our study is the first to provide clear evidence for a potential association between long-term lithium exposure and an increased risk of renal solid tumors, particularly renal cancers and oncocytomas. A regular renal screening should be considered, especially in long-term lithium–treated patients with CKD, and even after lithium discontinuation, to ensure early detection and appropriate management of renal tumors. METHODS Study design, setting, and participants We conducted a retrospective cohort study and considered for inclusion of all patients under long-term lithium therapy referred, between 1996 and 2011, to the Nephrology Departments at Necker and Tenon University Hospitals (Paris, France). The detection of potential renal tumors was based on the analysis of renal ultrasound investigations. Thus, only patients with available renal imaging results were included in the study. Patient care and the conduct of the study complied with good clinical practice and the Declaration of Helsinki guidelines.

Data sources For each patient, demographic, clinical, and biological characteristics at the time of renal imaging were obtained from medical records, and included sex, age at lithium initiation, age at renal imaging, medical history, weight, height, and cigarette smoking. GFR was estimated according to the Modification of Diet in Renal Disease Study equation.44 The result of renal ultrasound performed in the routine management of patients with CKD was reviewed for all patients. Further radiological investigations, including magnetic resonance imaging or computed tomography scan, were also recorded when performed, mostly in case of a suspect lesion found by renal ultrasound. The results of renal imaging were classified as follows: normal, presence of typical renal cyst(s), or atypical renal lesions. Only patients with histologically proven tumors were considered as having solid renal tumors, except for patients with typical images of renal angiomyolipoma. When a biopsy or a nephrectomy was performed, histological specimens Kidney International (2014) 86, 184–190

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were reviewed centrally by a senior pathologist (VV) specialized in renal tumoral pathology.

7.

8.

Statistical analysis Descriptive statistics is presented as the means and s.d.’s for continuous variables, and numbers and percentages for categorical variables. Univariate analysis included the w2 test or Fisher’s exact test to compare categorical variables, and the Student’s t-test or the non-parametric Mann–Whitney test as appropriate to compare continuous variables. To assess whether the frequency of renal tumors was high among lithium-treated patients, we used two different control populations. Comparison of the frequency of renal tumors between lithium-treated patients and lithium-free patients. For each lithium-treated patient, two sex-, age-, and eGFR-matched lithium–free patients with CKD were identified from the active files of the same two nephrology departments using the following criteria: (1) patients with any type of CKD followed during the period of the study; (2) free of lithium exposure; and (3) with available results of renal imaging and serum creatinine measurements. Renal ultrasound was indicated as routine investigation as part of the diagnostic procedure for renal disease. Matched patients were randomly selected blindly to result of the renal imaging. The frequency of renal cancers and benign renal tumors between lithium-treated and matched lithium-untreated patients were then compared using appropriate statistical tests. A value of Po0.05 was considered statistically significant. Comparison of the incidence of renal cancers between lithium-treated patients and the French general population. The number of expected cases of renal cancers in the lithium-treated group was calculated by gender and for each 5-year stratum using the French National estimates of renal cancer incidence provided by the National Institute of Public Health Surveillance cancer registry network, for which the methods are detailed at www.invs.sante. fr/publications/2009/estimation_cancer_1980_2005/estimation_cancer_1980_2005.pdf (accessed on February 2013).45 SIRs, consisting of the ratio of observed-to-expected numbers of renal cancers, and 95% CIs were estimated overall and by gender. Data analysis was performed using the SAS software (version 9.2).

9.

10. 11.

12. 13.

14. 15.

16. 17. 18.

19. 20. 21. 22.

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25.

DISCLOSURE

All the authors declared no competing interests.

26.

ACKNOWLEDGMENTS

27.

We thank Khaled Gaha, Marie Jo Teˆte, Dominique Joly, Bertrand Knebelmann, Philippe Lesavre, Khalil El Karoui, Nathalie Vittoz, and Yves Kodou.

28.

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