Abstract
INTRODUCTION: Current markers of chronic kidney disease (CKD) primarily reflect kidney glomerular health and do not include markers of kidney tubule health. METHODS: We used a case-cohort design with 1246 adults randomly sampled from the general population-based Trøndelag health study (HUNT)-3 study (Norway, 2006-2008) and 445 cases experiencing major adverse kidney events (MAKE; progressive CKD [n = 341], rapid estimated glomerular filtration rate [eGFR] decline [n = 232], kidney replacement therapy [KRT, n = 10], or kidney death [n = 9]) during 13 years of follow-up. Associations of proximal tubule reabsorption markers in the urine (alpha-1-microglobulin [A1M], beta-2-microglobulin [B2M], and cystatin C [CysC]) with MAKE were evaluated using weighted logistic regression analyses. RESULTS: At baseline, mean age was 53 years (SD: 15), eGFR was 92 ml/min per 1.73 m(2) (SD: 22), and median urine albumin-creatinine-ratio was 1.3 mg/mmol (interquartile range [IQR]: 1.0-1.8). The prevalence of diabetes, cardiovascular disease (CVD), and treated hypertension was 5%, 9%, and 23%, respectively. Independent of eGFR, albuminuria, and CKD risk factors, each 1-SD higher urine A1M and B2M were associated with greater odds of MAKE (odds ratio [OR]: 1.45, 95% confidence interval [CI]: 1.17-1.81 and OR: 1.23, 95% CI: 1.05-1.44, respectively). No significant association was observed for urine CysC (OR: 0.94, 95% CI: 0.74-1.19). There was significant interaction between A1M and eGFR (P = 0.03), and 2-way sensitivity analysis displayed that levels of urine A1M particularly influenced the MAKE risk in those with eGFR of 45 to 75 ml/min per 1.73 m(2) at baseline. CONCLUSION: The proximal tubule reabsorption markers, urine A1M and B2M, were associated with MAKE beyond eGFR, albuminuria, and CKD risk factors. Assessing tubule health may improve CKD staging and risk stratification.