Proximal Tubule Reabsorption and CKD Progression in the General Population

TL;DR

This study shows that markers of kidney tubule health, specifically alpha-1-microglobulin and beta-2-microglobulin in urine, are linked to chronic kidney disease progression, even when accounting for traditional markers like glomerular filtration rate.

Contribution

The study introduces proximal tubule reabsorption markers as novel indicators for predicting CKD progression in the general population.

Findings

Urine alpha-1-microglobulin and beta-2-microglobulin were independently associated with major adverse kidney events beyond traditional markers.

The association of alpha-1-microglobulin with kidney disease risk was strongest in individuals with moderate kidney function (eGFR of 45 to 75 ml/min per 1.73 m2).

Cystatin C in urine did not show a significant association with adverse kidney outcomes.

Abstract

Current markers of chronic kidney disease (CKD) primarily reflect kidney glomerular health and do not include markers of kidney tubule health.

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.

At baseline, mean age was 53 years (SD: 15), eGFR was 92 ml/min per 1.73 m2 (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 m2 at baseline.

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.

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