Causal Relationship Between Kidney Function and Cancer Risk: A Mendelian Randomization Study.

Rationale & objective: Patients treated with kidney replacement therapy experience a 1.5- to 2-fold increased risk of cancer and cancer mortality compared with the general population. Whether this excess risk extends to people with earlier stage chronic kidney disease and whether reduced kidney function is causally related to cancer is unclear.

Study design: Two-sample Mendelian randomization (MR).

Setting & participants: Genome-wide association study (GWAS) summary statistics for estimated glomerular filtration rate (eGFR) (n=567,460) and urinary albumin-creatine ratio (UACR) (n=127,865) from the CKDGen consortium and cancer outcomes from the UK Biobank (n = 407,329).

Exposure: eGFR and UACR.

Outcome: Overall cancer incidence, cancer-related mortality and site-specific colorectal, lung, and urinary tract cancer incidence.

Analytical approach: Univariable and multivariable MR conducted for all outcomes.

Results: The mean eGFR and median UACR were 91.4mL/min/1.73m² and 9.32mg/g, respectively, in the CKDGen, and 90.4mL/min/1.73m² and 9.29mg/g, respectively, in the UK Biobank. There were 98,093 cases of cancer, 15,850 cases of cancer-related death, 6,664 colorectal, 3584 lung, and 3,271 urinary tract cancer cases, respectively. The genetic instruments for eGFR and UACR comprised 34 and 38 variants, respectively. Genetically predicted kidney function (eGFR and UACR) was not associated with overall cancer risk or cancer death. The association between genetically predicted eGFR and UACR and overall cancer incidence had an odds ratio of 0.88 ([95% CI, 0.40-1.97], P=0.8) and 0.90 ([95% CI, 0.78-1.04], P=0.2) respectively, using the inverse-variance weighted method. An adjusted generalized additive model for eGFR and cancer demonstrated evidence of nonlinearity. However, there was no evidence of a causal association between eGFR and cancer in a stratified MR.

Limitations: To avoid overlapping samples a smaller GWAS for UACR was used, which reduced the strength of the instrument and may introduce population stratification.

Conclusions: Our study did not show a causal association between kidney function, overall cancer incidence, and cancer-related death.

Plain-language summary: Does reduced kidney function cause cancer? Patients with chronic kidney disease have been shown to have an increased risk of cancer and cancer-related death. However, it is not clear whether kidney disease is causally related to cancer or the association is due to other factors such as immune suppression and inflammation or a result of distortion of the analyses from unidentified variables (confounding). We used large, published genetic studies as well a database including 407,329 people in the United Kingdom in a series of Mendelian randomization analysis. Mendelian randomization uses the random assignment of genetic variants at birth to investigate causal relationships without confounding from measured and unmeasured confounders. We found that there is no evidence of a causal relationship between reduced kidney function and cancer.