Change in Albuminuria and Risk of Renal and Cardiovascular Outcomes: Natural Variation Should Be Taken into Account

Introduction: Changes in urinary albumin-to-creatinine ratio (UACR) may affect the risk of advanced chronic kidney disease (CKD). How much the association changes after taking account for natural variation in UACR and the length of time taken to observe changes in UACR is unknown. Methods: English Clinical Practice Research Datalink records (2000−2015) with linkage to secondary care and death certification were used to identify prospective cohorts with at least 2 measures of UACR within 1, 2, and 3 years. Adjusted Cox regression assessed the separate relevance of the baseline UACR and the UACR change to the risk of developing stages 4 to 5 CKD and end-stage renal disease (ESRD). Associations were compared before and after accounting for the effects of the natural variation in UACR (i.e., regression to the mean). Results: A total of 212,810 individuals had baseline UACR measurements; 22% had a UACR ≥3.4 mg/mmol, and 3% had UACR ≥33.9 mg/mmol. During a median 4-year follow-up, 5976 developed stage 4 to 5 CKD, and 1076 developed ESRD. There were strong associations between baseline UACR and stage 4 to 5 CKD or ESRD risk, which doubled in strength after accounting for regression to the mean. Over 3 years, the hazard ratios (95% confidence intervals) for stage 4 to 5 CKD, relative to stable UACR, were 0.62 (0.50−0.77) for at least a halving of UACR and 2.68 (2.29−3.14) for at least a doubling of UACR. Associations were weaker for shorter exposure windows (and for cardiovascular disease or death), but strengthened after allowing for regression to the mean. Conclusion: Baseline values and subsequent medium-term increases in albuminuria are both associated with substantially increased risk of developing advanced CKD. Standard analyses, not allowing for natural variation in UACR, may underestimate these associations. Keywords: albuminuria, biomarkers, chronic, kidney failure, renal insufficienc