Kidney function and cancer risk: An analysis using creatinine and cystatin C in a cohort study

Abstract

Background: We examined whether an increased risk of cancer incidence and death is associated with kidney function and albuminuria and whether the risk is more readily identified when kidney function is estimated using cystatin C.

Methods: Participants were from UK Biobank (recruitment spanning 2007-2010), excluding those with a prior diagnosis of cancer. Estimated glomerular filtration rate (ml/min/1.73m²) was calculated using creatinine (eGFRcr), cystatin C (eGFRcys) and creatinine-cystatin C (eGFRcr-cys). Cox proportional hazards models tested associations between eGFR, urinary albumin:creatinine ratio (uACR) and cancer incidence and death.

Findings: In 431,263 participants over median follow-up of 11.3 (IQR 10.6-12.0) years, there were 41,745 incident cancers and 11,764 cancer deaths. eGFRcys was most strongly associated with cancer incidence and death (HR 1.04 (95% CI 1.03-1.04) and 1.06 (1.05-1.07) per 10 ml/min/1.73m² decline, respectively). eGFRcr was not associated with either outcome (incidence: HR 1.00 (1.00-1.01); death: HR 0.99 (0.98-1.01) per 10 ml/min/1.73m² decline). Relative to eGFRcys>90 or uACR<3 mg/mmol, eGFRcys60-89 (HR 1.04 (95% CI 1.02-1.07)), eGFRcys<60 (HR 1.19 (1.14-1.24)) and uACR≥3 mg/mmol (HR 1.09 (1.06-1.12)) were associated with higher risk of incident cancer. eGFRcys60-89 (HR 1.15 (1.10-1.21)); eGFRcys<60 (HR 1.48 (1.38-1.59)) and uACR≥3 mg/mmol (HR 1.17 (1.11-1.24)) were associated with cancer death.

Interpretation: Excess risk of cancer incidence and cancer death is more readily captured in early chronic kidney disease by eGFRcys than by current measures. The association between kidney function, uACR and cancer death in particular is concerning and warrants further scrutiny.

Funding: Chief Scientist Office; ANID Becas Chile; Medical Research Council; British Medical Association; British Heart Foundation.

Keywords: CKD; cancer; cystatin C; eGFR; epidemiology; kidney function.

Fig. 1

Adjusted penalised splines of risk of cancer incidence and cancer death across the spectrum of eGFRcr, eGFRcys, eGFRcr-cys and uACR. Penalised splines of hazard ratios (95% confidence intervals) of each outcome were plotted for all eGFR measures and for uACR, after adjustment for known risk factors for cancer development: age, sex, smoking and alcohol history, BMI, ethnicity, deprivation index, C-reactive protein, uACR (for all eGFR splines), eGFRcys (for uACR splines only), systolic and diastolic blood pressure, total and LDL cholesterol, use of antihypertensive medication, use of cholesterol-lowering medication, baseline diabetes, hypertension and cardiovascular disease. eGFR 90 ml/min/1.73m² was considered the reference value for all outcomes. P nonlinear: likelihood-ratio test for addition of eGFR as a continuous variable to adjusted Cox proportional hazards model adjusted for other variables as above. P Overall: likelihood-ratio test for addition of eGFR as a spline term to Cox proportional hazards model adjusted for other variables as above.

Fig. 2

Forest plots for cancer incidence by cancer subtype according to eGFR and uACR categories. Results are presented as the hazard ratio and 95% confidence intervals (adjusted for age, sex, smoking and alcohol history, BMI, ethnicity, deprivation index, C-reactive protein, uACR (for eGFR categories), eGFRcys (for uACR categories), systolic and diastolic blood pressure, total and LDL cholesterol, use of antihypertensive medication, use of cholesterol-lowering medication, baseline diabetes, hypertension and cardiovascular disease). Results are stratified by eGFRcr, eGFRcys and eGFRcr-cys categories and compared to reference group with eGFR >90 ml/min/1.73m². For uACR category, uACR >= 3 mg/mmol is presented compared to the reference group with uACR <3 mg/mmol, after adjustment for eGFRcys and other variables as above.

Fig. 3

Forest plots for cancer death by cancer subtype according to eGFR and uACR categories. Results are presented as the hazard ratio and 95% confidence intervals (adjusted for age, sex, smoking and alcohol history, BMI, ethnicity, deprivation index, C-reactive protein, uACR (for eGFR categories), eGFRcys (for uACR category), systolic and diastolic blood pressure, total and LDL cholesterol, use of antihypertensive medication, use of cholesterol-lowering medication, baseline diabetes, hypertension and cardiovascular disease). Results are stratified by eGFRcr, eGFRcys and eGFRcr-cys categories and compared to reference group with eGFR >90 ml/min/1.73m². For uACR category, uACR >= 3 mg/mmol is presented compared to the reference group with uACR <3 mg/mmol, after adjustment for eGFRcys and other variables as above.