Proximal tubule reabsorptive dysfunction and risk of cardiovascular death among community-living adults: The HUNT-3 cohort

Aims Proximal tubule dysfunction in the kidney is associated with cardiovascular disease (CVD) in populations with prevalent chronic kidney disease (CKD). We sought to evaluate the nature of this association in the general population. Methods We conducted a case-cohort study within the North Trøndelag Health Study (HUNT-3). We randomly sampled 1,246 participants and all cases of cardiovascular death. Alpha-1 microglobulin (A1M) and beta-2 microglobulin (B2M) were measured in urine to assess proximal tubule reabsorptive dysfunction. Cardiovascular death was assessed using the Norwegian Cause of Death registry. We estimated the association of each biomarker with cardiovascular death after adjustment for baseline characteristics, including eGFR and albuminuria. Results Mean participant age was 51 years, 55% were female. Median UACR was 1.3 (IQR 1.0-1.8) mg/mmol and mean eGFR was 98 (SD 17) ml/min/1.73 m2. Cardiovascular death occurred in 166 participants over a median follow-up of 13 years. The weighted incidence among those with low-normal, mid-normal, high-normal, and elevated A1M was 0.8 (0.6-1.1), 1.5 (1.0-2.0), 2.0 (1.3-2.6), and 4.5 (2.6-6.4) percent, respectively. After adjustment for baseline characteristics, 1-SD higher urine A1M (HR 1.33, 95% CI 1.12-1.58) and urine B2M (HR 1.28, 95% CI 1.10-1.48) were each associated with higher risk of cardiovascular death. We did not observe interaction across subgroups based on age, sex, albuminuria or prevalent CVD. Conclusion In a population-based cohort of adults, proximal tubule reabsorptive dysfunction, as indicated by elevated levels of urinary A1M and B2M, was associated with higher risk of cardiovascular death independent of eGFR and albuminuria.