The risk of kidney cancer in patients with kidney stones: a systematic review and meta-analysis

Transcription

1 Q J Med 2015; 108: doi: /qjmed/hcu195 Advance Access Publication 10 September 2014 The risk of kidney cancer in patients with kidney stones: a systematic review and meta-analysis W. CHEUNGPASITPORN 1, C. THONGPRAYOON 1, O.A. O CORRAGAIN 2, P.J. EDMONDS 3, P. UNGPRASERT 4, W. KITTANAMONGKOLCHAI 1 and S.B. ERICKSON 1 From the 1 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA, 2 University College Cork, Cork, Ireland, 3 SUNY Upstate Medical University, Syracuse, NY, USA and 4 Division of Rheumatology, Mayo Clinic, Rochester, Minnesota, USA Address correspondence to Wisit Cheungpasitporn, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. cheungpasitporn.wisit@mayo.edu Received 2 August 2014 and in revised form 21 August 2014 Summary Background: The objective of this meta-analysis was to evaluate the association between a history of kidney stones and kidney cancer. Methods: A literature search was performed from inception until June Studies that reported odds ratios or hazard ratios comparing the risk of renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) of the upper urinary tract in patients with the history of kidney stones versus those without the history of kidney stones were included. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. Result: Seven studies were included in our analysis to assess the association between a history of kidney stones and RCC. The pooled RR of RCC in patients with kidney stones was 1.76 (95% CI, ). The subgroup analysis found that the history of kidney stones was associated with increased RCC risk only in males (RR, 1.41 [95% CI, ]), but not in females (RR, 1.13 [95% CI, ]). Five studies were selected to assess the association between a history of kidney stones and TCC. The pooled RR of TCC in patients with kidney stones was 2.14 (95% CI, ). Conclusion: Our study demonstrates a significant increased risk of RCC and TCC in patients with prior kidney stones. However, the increased risk of RCC was noted only in male patients. This finding suggests that a history of kidney stones is associated with kidney cancer and may impact clinical management and cancer surveillance. Introduction Kidney stones are one of the most common urological problems. The incidence of kidney stones is increasing with an estimated global prevalence of 10 15%. 1 4 In the USA, approximately 13% of men and 7% women will develop a kidney stone during their life time. 1,4 Similar to the incidence of kidney stones, the incidence of renal cell carcinoma (RCC), the most common type of renal parenchymal tumor, continues to increase with nearly cases annually in the USA. 5 Although transitional cell carcinoma (TCC) of the upper urinary tract involving the renal pelvis and ureter is rare, representing only 5% of all urothelial tumors, 6 the overall incidence of TCC and the rate of in situ neoplasms of upper urinary tract also appears to be increasing over the past 20 years. 7! The Author Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please journals.permissions@oup.com

2 206 W. Cheungpasitporn et al. As the incidences of kidney stones, RCC and TCC are all trending upward, it is possible that a history of kidney stones is associated with these two kidney cancers. Kidney stones have also been proposed to cause chronic irritation, subsequently leading to proliferation and the development of malignant neoplasms. 8,9 The reported risks of RCC and TCC in patients with a history of kidney stones, however, are still conflicting. Several studies have demonstrated that a history of kidney stones is associated with RCC and TCC. 8,10,12 Conversely, a number of studies have shown that a history of kidney stones is not a risk factor for RCC 8 or TCC. 10,16 The objective of this meta-analysis was to evaluate the association between a history of kidney stones and two common kidney cancers, RCC and TCC. Methods Search strategy Two investigators (W.C. and C.T.) independently searched published studies indexed in MEDLINE, EMBASE and the Cochrane database from inception to June 2014 using the terms kidney calculi, nephrolithiasis and kidney stone combined with the terms kidney neoplasms and kidney cancer. A manual search for additional relevant studies using references from retrieved articles was also performed. Conference abstracts and unpublished studies were excluded. Detailed search strategy is available as online supplementary data. Data extraction A standardized data collection form was used to extract the following information: last name of the first author, title of the article, study design, year of study, country of origin, year of publication, sample size, characteristics of included participants, method used to diagnose kidney stones, RCC and TCC, mean duration of follow up and adjusted effect estimates with 95% CI. The two investigators mentioned above independently performed this data extraction. Statistical analysis Review Manager 5.2 software from the Cochrane Collaboration was used for data analysis. Point estimates and standard errors were extracted from individual studies and were combined by the generic inverse variance method of DerSimonian and Laird. 18 Given the high likelihood of between study variances, we used a random-effect model rather than a fixed-effect model. Statistical heterogeneity was assessed using the Cochran s Q test. This statistic is complemented with the I 2 statistic, which quantifies the proportion of the total variation across studies that is due to heterogeneity rather than chance. A value of I 2 of 0 25% represents insignificant heterogeneity, 26 50% low heterogeneity, 51 75% moderate heterogeneity and more than 75% high heterogeneity. 19 The presence of publication bias was assessed by funnel plots of the logarithm of odds ratios versus their standard errors. 20 The post hoc analysis was performed to assess the sex-specific association between kidney stones and kidney cancer. Inclusion criteria The inclusion criteria were as follows: (i) randomized controlled trials or observational studies (case control, cross-sectional or cohort studies) published as original studies to evaluate the association between kidney stones and the two most common kidney cancers, RCC and TCC, (ii) odds ratios, relative risks, hazard ratios or standardized incidence ratio with 95% confidence intervals (CIs) were provided and (iii) a reference group composed of participants without a history of kidney stones was utilized. Study eligibility was independently determined by the two investigators noted above. Differing decisions were resolved by mutual consensus. The quality of each study was independently evaluated by each investigator using Newcastle-Ottawa quality assessment scale. 17 Results Our search strategy yielded 7201 potentially relevant articles articles were excluded based on title and abstract for clearly not fulfilling inclusion criteria on the basis of the type of article, study design, population or outcome of interest. 198 articles underwent full-length article review. 189 articles were excluded (105 articles were not observational studies and 84 articles did not report the outcomes of interest). Nine articles met our inclusion criteria. 8,10 16,21 Seven studies (six case control studies and one retrospective cohort study) with patients with kidney stones were included in the data analysis for the risk of RCC. 8,10 15 Five studies (four case control studies and one retrospective cohort study) with patients with kidney stones were included in the data analysis for the risk of

3 Kidney cancer and kidney stones 207 Table 1 Main characteristics of studies included in the meta-analysis McLaughlin Ross et al. 16 et al. 13 Maclure Talamini McCredie Schlehofer Chow et al. 11 et al. 15 et al. 12 et al. 14 et al. 8 Liaw et al. 21 Chung et al. 10 Country USA. USA. USA. Italy Australia Australia, Denmark, Sweden and USA. Study design Case control Case control Case control Case control Case control Case control Retrospective cohort Year of publication Sweden USA Taiwan Case control Case control Cases All white residents of seven-county St. Paul- Minneapolis who were RCC between 1974 and Cases by reviewing records of all hospitals. Diagnosis of RCC/TCC Review of records. Controls Sex and Los Angeles county who were TCC between 1978 and Cases from the tumor registry of Los Angeles county. Sex, race and Boston Metropolitan area who were RCC between 1976 and 1983 in 37 participating hospitals. Cases by reviewing records of those hospitals. Review of records. Sex and agematched Northern Italy who were RCC between 1986 and 1989 in participating hospitals. Cases were identified by reviewing records of those hospitals. Review of records. Sex and admitted patients the same hospital. New South Wales who were diagnosed with RCC or TCC between 1989 and Cases were identified from the NSW cancer Subjects selected from NSW area. the study areas (Sydney, Denmark, Uppsala and MN) who were RCC between 1989 and Cases from the population-based registry of those areas. Sex and All patients who were admitted with the diagnosis of renal stone from 1965 and Cases using National inpatient national cancer Using Swedish age- and sex-specific general population incidence rates for RCC/TCC as the comparator for Los Angeles, New Jersey and Iowa who were diagnosed with TCC between 1983 and Review of records. Sex and agematched Taiwan who were diagnosed with RCC or TCC between 2002 and Cases were identified from the Taiwan National Health insurance database. Sex and same database. (continued)

4 208 W. Cheungpasitporn et al. Table 1 Continued McLaughlin Ross et al. 16 et al. 13 Maclure Talamini McCredie Schlehofer Chow et al. 11 et al. 15 et al. 12 et al. 14 et al. 8 Liaw et al. 21 Chung et al. 10 Country USA. USA. USA. Italy Australia Australia, Denmark, Sweden and USA. Study design Case control Case control Case control Case control Case control Case control Retrospective cohort Year of publication Sweden USA Taiwan Case control Case control Diagnosis of renal stone Number of cases Number of control Confounder adjusted Quality assessment (Newcastle- Ottawa scale) the calculation of SIRs. registry (prior to the index date of having diagnosis of RCC or TCC) RCC: RCC:780 TCC: 147 TCC: NA Age None None Age, sex, education and area of residence Selection: 3 Selection: 4 Selection: 3 Selection: 2 Age and sex Age, sex, BMI and smoking Selection: 3 0 star Selection: 4 None Age, sex, HTN and smoking Selection: 4 Outcome: 3 Selection: 2 Income, geographic area, HTN, DM, CKD, Obesity, smoking and alcohol use Selection: 4 2 BMI = body mass index, CKD = chronic kidney disease, DM = diabetes mellitus, HTN = hypertension, NA = not applicable, RCC = renal cell carcinoma, TCC = transitional cell carcinoma.

5 Kidney cancer and kidney stones 209 Figure 1. Forest plot of the included studies comparing risk of RCC between patients with a history of kidney stones and those without a history of kidney stones; square data markers represent RRs; horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. A diamond data marker represents the overall RR and 95% CI for the outcome of interest. Figure 2. Forest plot of the included studies comparing risk of RCC in males with a history of kidney stones and those without a history of kidney stones; square data markers represent RRs; horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. A diamond data marker represents the overall RR and 95% CI for the outcome of interest. Figure 3. Forest plot of the included studies comparing risk of RCC in females with a history of kidney stones and those without a history of kidney stones; square data markers represent RRs; horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. A diamond data marker represents the overall RR and 95% CI for the outcome of interest. TCC. 8,10,12,16,21 Table 1 describes the detailed characteristics and quality assessment of the included studies. The risk of RCC in patients with kidney stones The pooled risk ratio (RR) of RCC of with kidney stones versus control was 1.76 (95% CI, ). The statistical heterogeneity was high with an I 2 of 89%. Figure 1 shows the forest plot of the included studies. In addition, a history of kidney stones was associated with increased RCC risk in males (RR, 1.41 [95% CI, ], I 2 = 47%), whereas the association was not significant in females (RR, 1.13 [95% CI, ], I 2 = 0%). Figures 2 and 3 show the forest plots of the included studies in males and females with kidney stones, respectively.

6 210 W. Cheungpasitporn et al. Figure 4. Forest plot of the included studies comparing risk of TCC between patients with a history of kidney stones and those without a history of kidney stones; square data markers represent RRs; horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. A diamond data marker represents the overall RR and 95% CI for the outcome of interest. The risk of TCC in patients with kidney stones The pooled RR of TCC of with kidney stones versus control was 2.14 (95% CI, ). The statistical heterogeneity was high with an I 2 of 86%. Figure 4 demonstrates the forest plot of the included studies. The differences in TCC risk between males and females could not be analyzed due to data limitations. 10,16,21 Evaluation for publication bias Funnel plots were evaluated for publication bias for the risk of RCC and TCC. The plots were suggestive to the presence of publication in favor of positive studies of the risk of RCC and negative studies of the risk of TCC in patients with kidney stones. Discussions Our meta-analysis showed a significant association between a history of kidney stones and the two most common kidney cancers, RCC and TCC, with an overall 1.76-fold increased risk of RCC and a 2.14-fold increased risk of TCC compared with those without a history of kidney stones. In addition, our subgroup analysis found that a history of kidney stones was associated with increased RCC risk only in males but not in females. The analysis of TCC risk in males and females was not performed due to data limitations. The risk factors for kidney cancer including cigarette smoking, hypertension, obesity, acquired renal cystic disease, analgesics, genetic factors and particular occupational exposure have been established Interestingly, our meta-analysis successfully demonstrates the association between kidney cancer and a history of kidney stones. The most likely reason for the increased risk of kidney cancer in patients with kidney stones is stone-induced irritation and infections. It has been proposed that kidney stones may cause changes in the local environment due to chronic irritation and infections, subsequently leading to urothelial proliferation and the development of malignant neoplasms. 8,9 The inflammatory cells secrete cytokines and chemokines in response to chronic recurrent inflammation and infections, which subsequently promote the growth of neoplastic cells and progression of malignancy. 25 In addition, kidney stones have also been demonstrated in animal models to cause neoplastic changes in the adjacent urothelium. 26 Our study also demonstrates the association between a history of kidney stones and increased RCC risk in males in the subgroup analysis. Interestingly, the prevalence of kidney stones is higher in males than females (10.6% vs. 7.1%, respectively). 27 Kidney cancers, both RCC and TCC, are also more common in male gender (RCC is about twice as common in men compared with women, 28 whereas TCC is three times more prevalent in men than in women 29 ). This underlying pathophysiology is unclear. Men with kidney stones may be exposed to dietary or environmental factors that could increase their risk of RCC. For example, men are more likely to be smokers than women and cigarette smoking was also recently reported as a potential independent risk factor for the development of kidney stones. 30 Moreover, males have different eating habits from females that may contribute to both higher risks of kidney stones and RCC, 31 for example females are more likely to report eating fruits and vegetables, which are less lithogenic and carcinogenic. Further studies are needed to identify the potential gender effect on kidney stones and kidney cancers. Five-year survival for patients with RCC has been improved with increased use of nephron sparing surgery (partial nephrectomy) due to the increasing number of incidentally discovered low

7 Kidney cancer and kidney stones 211 stage tumors. 32 Although kidney stones may cause inflammation in the urinary tract and increase risk for developing kidney cancers, patients with kidney stones also require more imaging studies which may detect RCC in early stages. Studies on outcome of RCC in patients with kidney stones are needed. Although most of the included studies were of high quality 8,10,11,13,14,16 (as evaluated by Newcastle- Ottawa scale), there are some limitations. Firstly, five studies 8,10,12,14,16 were conducted using registry-based databases, therefore coding inaccuracies for kidney stones, RCC and TCC may have been presented. Seven studies 11 16,21 used a definition of kidney stones composed of self-reporting, which has been reported as accurate in 97% of cases. 33 Secondly, there is statistical heterogeneity in this complete analysis. The potential sources of this heterogeneity include the difference in diagnosis methodology of kidney stones and RCC and TCC, the duration of the follow-up and the differences in confounder-adjusted methods. This is a meta-analysis of observational studies with its inherent limitations. Therefore, at best it can demonstrate an association but not a causal relationship. Most studies also lacked information regarding potential confounding factors, such as family history of kidney cancer, cigarette smoking, body mass index, dietary and occupational exposures, all of which may have contributed to the development of kidney cancer. 10 Dietary factors may play an important role as a confounding factor in the association between kidney stone and kidney cancer. A high animal protein diet was not only found to be a risk factor for kidney stones, but it has also been demonstrated in a recent large cohort study of participants recently also demonstrated that red meat intake may increase the risk of kidney cancer, especially RCC. 34 Furthermore, these studies may have been vulnerable to a surveillance bias as patients with kidney stones would have been more likely to have follow-up imaging studies and kidney cancer may have been detected more than patients without kidney stones. Future studies which minimized these confounders and bias are required to confirm this potential causal relationship. In conclusion, our study demonstrates a statistically significant increased risk of RCC and TCC in patients with prior kidney stones. However, the increased risk of RCC was noted only in male patients. This finding suggests that a history of kidney stones is associated with kidney cancer and may impact clinical management and cancer surveillance. Supplementary material Supplementary material is available at QJMED online. Acknowledgments All authors had access to the data and a role in writing the manuscript. Conflict of interest: None declared. References 1. Goldfarb DS. Increasing prevalence of kidney stones in the United States. Kidney Int 2003; 63: Long LO, Park S. Update on nephrolithiasis management. Minerva Urol Nefrol 2007; 59: Lopez M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol 2010; 25: Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: Kidney Int 2003; 63: Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, CA Cancer J Clin 2008; 58: Tawfiek ER, Bagley DH. Upper-tract transitional cell carcinoma. Urology 1997; 50: Munoz JJ, Ellison LM. Upper tract urothelial neoplasms: incidence and survival during the last 2 decades. J Urol 2000; 164: Chow WH, Lindblad P, Gridley G, Nyrén O, McLaughlin JK, Linet MS, et al. Risk of urinary tract cancers following kidney or ureter stones. J Natl Cancer Inst 1997; 89: Li WM, Chou YH, Li CC, Liu CC, Huang SP, Wu WJ, et al. Association of body mass index and urine ph in patients with urolithiasis. Urol Res 2009; 37: Chung SD, Liu SP, Lin HC. A population-based study on the association between urinary calculi and kidney cancer. Can Urol Assoc J 2013; 7:E Maclure M, Willett W. A case control study of diet and risk of renal adenocarcinoma. Epidemiology 1990; 1: McCredie M, Stewart JH. Risk factors for kidney cancer in New South Wales, Australia. II. Urologic disease, hypertension, obesity, and hormonal factors. Cancer Causes Control 1992; 3: McLaughlin JK, Mandel JS, Blot WJ, Schuman LM, Mehl ES, Fraumeni JF Jr A population-based case control study of renal cell carcinoma. J Natl Cancer Inst 1984; 72: Schlehofer B, Pommer W, Mellemgaard A, Stewart JH, McCredie M, Niwa S, et al. International renal-cell-cancer study. VI. the role of and family history. Int J Cancer 1996; 66: Talamini R, Baron AE, Barra S, Bidoli E, La Vecchia C, Negri E, et al. A case control study of risk factor for renal cell cancer in northern Italy. Cancer Causes Control 1990; 1:

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