An early diagnosis of kidney stones (ages <40) was signiﬁcantly associated with an increased overall renal cell carcinoma risk versus a later kidney stone diagnosis (ages ≥40), according to a Dutch research team.
Case-cohort analysis in almost 5,000 patients from the Netherlands Cohort Study (NLCS) who were followed for 2 decades showed that the overall risk of renal cell carcinoma (RCC) was doubled in those with an early history of kidney stones compared with those without an early history (hazard ratio 2.10). Similarly, the risk of upper tract urothelial carcinoma (UTUC) was 1.7 higher in those with an early history of kidney stones compared with those without (HR 1.66), reported Jeroen A. A. van de Pol, PhD, of Maastricht University in the Netherlands, and colleagues.
Kidney stones were also associated with an increased risk of papillary RCC (pRCC, HR 3.081), but not clear-cell RCC (ccRCC. HR 1.14), they wrote in the British Journal of Cancer.
While these results support findings from previously published studies, this may be the first prospective study to show heterogeneity of associations between pRCC and ccRCC, the authors said. But they emphasized that more research is needed, noting that the number of eligible cases for these analyses was limited.
“In light of the findings of this study, more research is needed to unravel the mechanisms behind the relation[ship] of kidney stones and RCC and UTUC,” they wrote.
They also said that better understanding about the relationship between kidney stones and pRCC; the impact on cell metabolism and cancer development of kidney stone composition, stone laterality, and exposure to stone-forming solutes; and “the sex-specific differences in RCC and UTUC risk as a result of kidney stones” is needed.
Raising Awareness — But No More
In general, kidney stones are more common in men than in women, the researchers pointed out. Risk increases with age and can be reduced by increasing intake of fluids, fruits, and vegetables, as well as by reducing salt intake. Although an earlier study reported an increased RCC risk associated with kidney stones in males, but not females, the current study found no sex-based differences in risk, they said.
Van de Pol told MedPage Today that he hopes these findings will raise clinicians’ awareness about the implications of a history of kidney stones on future cancer risk, and lead to lifestyle recommendations that could lower this risk.
David L. Graham, MD, of the Levine Cancer Institute in Charlotte, North Carolina, agreed that the study is the first to report an association between kidney stones and pRCC. But he also said the study is limited because “correlation is not the same as cause.”
Graham, who was not involved in the study, emphasized that the study poses “some interesting questions, but nothing more” and advised against any changes to clinical practice based on its findings.
“This simply illustrates the difficulties with these sorts of trials,” he told MedPage Today. “As much as we try, it is very difficult, in a correlation study, to know and account for all the confounding factors that may be present. We are noting an increased number of genetic mutations that can be associated with renal cell carcinomas in general, and certain mutations are specifically associated with papillary renal cell carcinoma. The paper does not have the ability to look at these genetic risks.”
The researchers used data from participants in the NLCS, a nationwide cohort study on diet and cancer that was initiated in the Netherlands in 1986 and included 58,279 men and 62,573 women, ages 55 to 69.
At baseline, 120,852 participants completed a self-administered questionnaire on diet, medical conditions, and other risk factors for cancer. After 20.3 years of cancer follow-up, van de Pol and colleagues conducted their case-cohort analysis in 4,352 subcohort members, 544 RCC cases and 140 UTUC cases.
The researchers pointed out that because detailed information had been collected prior to diagnosis on risk factors associated with kidney stones, RCC and UTUC, they were able to adjust for multiple confounders.
A total 8.4% of the subcohort had a history of kidney stones. No analyses were performed for ureter cancer in female participants because of the absence of exposed cases, they said.
In general, patient characteristics at baseline were similar across the study population. However, there were proportionately fewer current smokers among the men with kidney stones compared with those without kidney stones. There was also an increased fruit and vegetable intake in both men and women with kidney stones versus those without.
Assessment of tumor histology, carried out by two pathologists, did not find a difference in risk for developing pRCC between participants with pRCC type 1 and pRCC type 2 based on a history of kidney stones.
While the biological mechanisms potentially linking kidney stone formation to subsequent kidney cancer are not known, it is “presumed” that renal calculi create chronic localized irritation in the kidney and ureter, the researchers said. A study showing that most renal pelvis and ureter cancers occurred on the same side that kidney stones formed appears to support this theory.
“An earlier kidney stones diagnosis could provide a longer time period for kidney stones to induce chronic irritation to the local environment or for potentially harmful solutes in the urine to have a carcinogenic effect,” van de Pol and colleagues suggested. “Therefore, the found associations could indicate that the lifestyle of kidney stone formers may already play a role in the development of cancer during the early stages of life.”
Study limitations included the fact that information on kidney stones retrieved from the self-administered questionnaire at baseline may not have included data on any subsequent kidney stone formation that occurred later on. They also acknowledged that there was no information on kidney stone composition, frequency, or laterality. “This information could provide additional insight on the mechanisms behind the found association in future studies,” they said.
Van de Pol and co-authors disclosed no relevant relationships with industry.