Vitamin C intake and risk of renal cell carcinoma: a meta-analysis

Studies have showed that vitamin C intake is linked to renal cell carcinoma risk, however, the results were inconsistent. Hence, the present meta-analysis was to examine the association between vitamin C intake and RCC risk. We searched the published studies that reported the relationship between vitamin C intake and RCC risk using PubMed and Embase up to January 2015. Based on a fixed effects model, RR and the corresponding 95% CI were used to assess the pooled risk. 3 prospective cohort studies and 7 case-control studies were included. The overall RR (95% CI) of RCC for the highest vs. the lowest levels of vitamin C intake was 0.78(0.69,0.87). Little evidence of heterogeneity was found. In the subgroup analyses, we found an inverse association between vitamin C intake and RCC risk in the case-control studies but not in the prospective cohort studies. Additionally, this association between vitamin C intake and RCC risk was not differed by population distribution. Our study provides evidence that vitamin C intake is associated with a reduced RCC risk. However, our conclusion was just based on ten including studies, so more high-quality of case-control studies or cohort studies which report this topic are needed.

Scientific RepoRts | 5:17921 | DOI: 10.1038/srep17921 C intake of RCC with following search terms: "dietary vitamin C intake", "vitamin C intake" and "vitamin C" in combination with "renal cell cancer", "kidney cancer" and "renal cell carcinoma". Reference lists of the retrieved articles were also reviewed. If necessary, we contacted the authors of the original studies for the required data.
Study selection. The studies that met the following criteria could be included: 1. a prospective cohort design or case-control design; 2. the exposure of interest was vitamin C intake and the kind of intake is only from foods or supplements; 3. the outcome was RCC incidence; 4. the RRs and the corresponding 95% CIs for the highest compared with the lowest levels of vitamin C intake were reported. Data extraction. For data extraction, the following information was extracted: the last name of the first author, publication year, characteristics of study population (age and sex), geographic region, follow-up length, number of cases or size of cohort; RR from the most fully adjusted model for the highest compared with the lowest levels of vitamin C intake and the corresponding 95% CI adjustment from the multivariable model; statistical adjustment for the potential confounding factors. Two authors independently performed the literature search, studies selection, and data extraction, any disagreements were resolved by discussion.
Statistical analysis. STATA version 12.0 was used to conducted all analyses. Based on a fixed-effects model, RR and the corresponding 95% CI were used to measured the association between vitamin C intake and RCC risk. Homogeneity test was performed with the use of Q statistic at the P < 0.05 level of significance and I 2 statistic, which is a quantitative measure of inconsistency across studies 23 . If the Q statistic at the P < 0.05 level of significance and I 2 > 50%, the random effects model was choosed; however, If the Q statistic at the P > 0.05 level of significance and I 2 < 50%, the fixed effects model was selected. Subgroup analyses were performed to identify the source of heterogeneity, if possible, and the effect of the potential factors on the overall risk estimate. Additionally, we conducted a sensitivity analysis to investigate the influence of a single on overall risk estimate by omitting one study in turn. Potential publication bias was assessed by Begg rank correlation test and Egger linear regression test 24,25 . All statistical tests were two-sided and P < 0.05 was considered statistically significant, except where otherwise specified.

Results
Literature search. We initially identified 908 potential articles from Pubmed (n = 147) and Embase (n = 761).
Most were excluded because: 1. most studies from Embase were pharmaceutical research. 2. They were reviews or animal experiments. 3. They were not case-control or cohort studies. 4. The exposure was not vitamin C or the   Meta-analysis. 10 epidemiological studies (7 case-control studies and 3 prospective cohort studies) reported the association between vitamin C intake and risk of renal cell cancer. The multivariable-adjusted RRs for each study and the combined RR for the highest compared with the lowest levels of vitamin C intake are presented in Fig. 1. The RRs from individual studies varied from 0.58 to 1.12. In the 10 included studies, one reported 6 an inverse association between vitamin C intake and risk of RCC, however, others found null associations. Overall, there was a statistically significant inverse relationship between vitamin C intake and the risk of RCC, the pooled RR was 0.78 (95% CI, 0.69, 0.87). Little evidence of heterogeneity was found (P = 0.655, I 2 = 0.0%). Fig. 2 present the results of subgroup analysis according to different populations and design patterns. There was little heterogeneity were observed within any subgroup-analyses. According to different populations, we found an inverse association between vitamin C intake and risk of RCC both in Americans and Europeans, the pooled RR and 95% CI was 0.81(0.67, 0.96), 0.76(0.65, 0.88), respectively. According to study design patterns, a significant inverse association between vitamin C intake and risk of RCC was observed in case-control studies, however, it showed that there was no statistically significant association in prospective cohort studies (the RR and 95% CI was 0.75(0.66, 0.86), 0.91(0.69, 1.20), respectively).
Sensitivity analysis was conducted to assess the influence of a single study on the overall risk estimate by omitting one study in each turn. The combined RRs were all statistically significant and similar with one another, with a narrow range from 0.76 (95% CI: 0.66, 0.87) to 0.79 (95% CI: 0.69, 0.90), it revealed that the result was statistically stable and reliable. The result of sensitivity analysis is presented in Fig. 3.
Begg's and Egger's regression test showed a low probability of publication bias in our study (P = 0.515). The funnel plot of the studies is presented in Fig. 4.

Discussion
The effect of antioxidants on the primary prevention of cancer has raised considerable interest in the recent years. Vitamin C which is one of the most common antioxidants plays an important role in our body metabolism. However, the epidemiological studies have reported inconsistent association of vitamin C intake with the risk    of RCC. The present meta-analysis addresses this point by summarizing the updated evidence from published epidemiological studies and shows that there would exist an inverse association between vitamin C intake and risk of RCC, in other words, vitamin C intake may reduce the risk of RCC.
Heterogeneity is often a concern in a meta-analysis. However, little evidence of heterogeneity was observed across our study, which meant that there was little between-study variation. This could be partially explained by the following facts: all the studies were conducted in western countries, in where populations share much in terms of genetic background, lifestyle and dietary patterns; all the studies were published in English and had a high quality assessment, and the results from each original study was adjusted for a wide range of potential confounders, eliminating the most obvious confounding factors.
In the subgroup analyses, the pooled risk estimate of 7 case-control studies showed an inverse association between vitamin C intake and the risk of RCC, however, this significant inverse relationship was not found in the 3 prospective cohort studies. Although a higher level of statistical evidence was detected in the cohort studies than that in the case-control studies, we noted that these 3 prospective cohort studies with a small case sample size, and none had a case sample size of more than 300. In addition, the association was not differed by population distribution, the inverse association between vitamin C intake and risk of RCC was found both in North-Americans and Europeans. The subgroup analyses added additional evidence for the association between vitamin C intake and a risk of risk of RCC.
It has been hypothesized that the risk of RCC may be associated with compromised hemodynamics or metabolic disturbances as they relate to factors induced by hypoxia (hypoxia-inducible factors) and von Hippel-Lindau proteins and the presence of oxidative stress. As an antioxidant, the role of vitamin C intake has been focused on maintaining health and reducing the risk of noncommunicable diseases such as cancer. In 1990 s, lots of evidence showed that abundant consumption of fruits and vegetables including wealth vitamin C have been associated with a decreased risk of several chronic diseases including cardiovascular diseases 26 and cancer 27 . In 1994, Okamoto et al. revealed that increased lipid peroxidation occurred in primary RCC as compared to surrounding cancer free tissues 28 . Byproducts of lipid per-oxidation have been shown to react with renal DNA to form adducts 29,30 , misrepair of the damage to DNA induced by these adducts can lead to mutations in proto-oncogenes and/or tumor suppressor genes, a critical step in the process of changing a normal cell to a malignant phenotype 31 .
Some limitations of our present study should be considered. First, the present findings were mainly based on case-control studies, although adjusted for adjusted for a wide range of potential confounders, the recall bias and selection bias were inevitable. Additionally, there were a small case sample size in the 3 prospective cohort studies, and they were based on elderly populations. Second, most of our included studies contained both male and female, however, two studies 2,8 respectively included just only male or female. Female estrogen could inhibit renal cell carcinoma cell progression through estrogen receptor-β activation 32 . Due to the hormonal factors the two included studies my change the results of our study, so more adjusted for male or female respectively studies were needed. Third, our included studies were most based on European population, with different population distribution the race, lifestyle, dietary habit would be different, the relationship between vitamin C intake and RCC risk may be different, hence more global polycentric studies association between vitamin C intake and risk of RCC were needed. Finally, we could not completely rule out such bias because of the limited number of studies, although there was no evidence of publication bias.

Conclusions
Our present meta-analysis provides evidence that vitamin C intake is associated with a reduced risk of RCC. But our conclusion was just based on ten including studies, so more high-quality of case-control studies or cohort studies which report the association between vitamin C intake and risk of RCC are needed.