End-stage renal disease (ESRD), the final stage of chronic kidney disease (CKD), is a significant global health concern. While diabetes and hypertension are leading causes, a substantial portion of ESRD cases remain unexplained, particularly in agricultural regions. Recent research has suggested a potential link between nitrate in drinking water and ESRD. Inorganic nitrate, a common groundwater contaminant from fertilizers and waste, has been implicated in ESRD hotspots in several regions. Besides contaminated water, dietary sources, especially processed meats, are significant contributors to nitrate and nitrite exposure. Nitrite, through nitrosation, can form carcinogenic N-nitroso compounds (NOCs), which have been linked to renal cell carcinoma and other cancers. Animal studies show NOCs' association with oxidative stress and kidney damage. This Agricultural Health Study (AHS) aimed to investigate the association between water nitrate and dietary nitrate/nitrite intake with ESRD incidence, considering modifying effects of vitamin C and heme iron, known to influence endogenous nitrosation.

The literature review highlighted the global burden of ESRD and the lack of complete understanding of its etiology beyond traditional risk factors. Studies have linked high nitrate concentrations in groundwater to unexplained ESRD clusters, particularly in agricultural areas. Dietary nitrate and nitrite intake, primarily from processed meats and vegetables, are also relevant exposure pathways. The carcinogenic potential of N-nitroso compounds (NOCs) formed from nitrite has been extensively studied in relation to various cancers, including renal cell carcinoma. However, limited research has directly explored the relationship between nitrate/nitrite intake and ESRD risk. Prior studies have shown mixed results regarding the association between water nitrate and kidney cancer, with some indicating a link only at high exposure levels and long-term exposure durations. Similarly, the impact of dietary nitrate on CKD/ESRD is largely unexplored. Existing literature underscores the need for a comprehensive study to investigate this association, taking into account the potential modifying effects of dietary factors influencing endogenous nitrosation.

The study used data from the Agricultural Health Study (AHS), a prospective cohort of 89,655 licensed pesticide applicators and their spouses in Iowa and North Carolina. The analysis focused on 84,739 private pesticide applicators and their spouses. Water nitrate exposure was estimated using historical data for public water supplies and random forest models for private wells, incorporating factors like well depth, land use, and nitrogen inputs. Dietary nitrate and nitrite intake was assessed using the National Cancer Institute (NCI) Diet History Questionnaire (DHQ) completed by 30,177 participants during follow-up (1999–2003). Incident ESRD cases through 2018 were ascertained via linkage with the U.S. Renal Data System (USRDS). Cox proportional hazards models were used to assess associations between exposure tertiles and ESRD risk, adjusting for age, sex, education, state of residence, smoking status, and total caloric intake (for dietary analyses). Subgroup analyses were conducted to explore effect measure modification (EMM) by vitamin C and heme iron intake and by sex and state. Sensitivity analyses were performed to address potential confounders such as pre-enrollment diabetes, BMI, pesticide exposure, and year of enrollment. Alternative exposure categorizations and cumulative exposure assessments were also explored.

The study found no association between water nitrate exposure and ESRD risk. However, dietary nitrate/nitrite intake from processed meats showed a significant positive association with ESRD incidence. The hazard ratios (HRs) for the highest tertile of processed meat nitrate and nitrite were 2.05 (95% CI: 1.37, 3.05) and 2.22 (95% CI: 1.47, 3.34), respectively. Total dietary nitrite intake also showed a modest increase in ESRD risk (HR=1.36, 95% CI: 0.83, 2.21). Stratified analyses revealed stronger associations between dietary nitrite and ESRD in subgroups with below-median vitamin C intake (HR=2.26, 95% CI: 1.05, 4.86) or above-median heme iron intake (HR=1.73, 95% CI: 0.89, 3.39). No significant interactions were found between nitrate/nitrite and vitamin C or heme iron. Subgroup analyses by sex and state did not reveal significant heterogeneity in the associations.

The study's findings suggest a potential link between dietary nitrate and nitrite, particularly from processed meats, and ESRD risk. The stronger associations observed in subgroups with low vitamin C or high heme iron intake are consistent with the role of these factors in endogenous nitrosation, the process by which nitrite is converted to carcinogenic NOCs. Processed meats contain nitrosation precursors and enhancers, while plant-based sources often include nitrosation inhibitors. The lack of association with water nitrate might be due to several factors including the relatively low average nitrate levels in the study population compared to some areas with high ESRD incidence and the potential for other confounding environmental exposures impacting kidney health. The study underscores the importance of considering dietary patterns and individual susceptibility when assessing the risk of ESRD.

This study provides preliminary evidence suggesting a potential association between dietary nitrite, especially from processed meats, and increased ESRD risk, particularly among individuals with low vitamin C or high heme iron intake. The lack of association with water nitrate highlights the need for further research focusing on dietary factors and their interaction with endogenous nitrosation pathways. Future studies should examine CKD as an outcome to better understand the disease progression and explore a broader range of environmental and dietary factors influencing ESRD risk in diverse populations.

The study's limitations include potential selection bias due to missing data, limited racial/ethnic diversity restricting generalizability, and uncertainty in exposure estimates, especially for private well users. The use of self-reported data on dietary intake and pre-existing conditions introduces the potential for misclassification and residual confounding. Additionally, the study examined incident ESRD rather than CKD, potentially missing early-stage disease cases. The focus on an agricultural cohort might limit the generalizability of findings to non-agricultural populations.