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 effect depends upon natural variation and the time period for the change 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 two measures of UACR within 1, 2 and 3 years. Adjusted Cox regression assessed the separate relevance of baseline UACR and UACR change to the risk of developing CKD stage 4-5 and end-stage renal disease (ESRD). Associations were compared before and after accounting for the effects of natural regression to the mean (RtM). Results: 212,810 individuals had baseline UACR measurements; 22% had a UACR ≥3.4, and 3% had UACR ≥33.9, mg/mmol. During a median 4.0 years follow-up, 5976 developed CKD stage 4-5 and 1076 developed ESRD. There were strong associations between baseline UACR and CKD stage 4-5 or ESRD risk, which doubled in strength after accounting for RtM. Over 3 years, the hazard ratios, HRs (95%CIs) for CKD stage 4-5, 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. Associations were weaker for shorter exposure windows (and for cardiovascular disease or death), but strengthened after allowing for RtM. Conclusion: Baseline values and medium term increases in albuminuria are both associated with substantially increased risk of developing advanced CKD. Standard analyses, not allowing for RtM, may underestimate these associations.