Authors' Reply: Aldosterone-to-Renin Ratio and eGFR Decline: Sensitivity to the Renin Assay Floor
Year: 2026
Type: letter
Abstract: We thank Lin et al. for their thoughtful comments1 regarding the handling of renin values below the assay reporting limit in our JASN article titled “Subclinical Primary Aldosteronism and eGFR Decline Over Time.”2 We agree that analytic decisions at the lower end of renin measurement warrant careful consideration, particularly in studies evaluating renin-independent aldosterone production. In our cohort of 976 participants, only 18 individuals (1.8%) had a direct renin concentration below the lower limit of reporting for the assay used (<1.0 ng/L [1.67 mU/L]). For these participants, values were assigned to 0.9 ng/L (1.50 mU/L) to avoid overinflation of the aldosterone-to-renin ratio (ARR). This approach has been standard practice in primary aldosteronism research for many years and reflects the nonlinear behavior of ARR as renin approaches very low values.3 In this range, small absolute differences in renin can yield large proportional changes in ARR, and analytic inflation at the assay floor may complicate interpretation of associations with clinical outcomes. Importantly, assigning values just below the reporting limit would be expected to bias effect estimates toward the null rather than exaggerate associations. Given that <2% of participants were affected by this handling, any impact on aggregate ARR distribution or the ARR–eGFR slope is necessarily small and highly unlikely to alter the direction, magnitude, strength, or clinical interpretation of the observed association. Our primary objective was to test whether renin-independent aldosteronism (conceptualized along a continuum and modeled using continuous exposures) was associated with steeper kidney function decline over time in a general population-based cohort. The robustness of the observed signal across multiple sensitivity analyses supports this inference. Finally, we note that the broader discussion regarding renin-centered versus ARR-centered screening strategies for primary aldosteronism pertains to traditional categorical diagnostic frameworks.4,5 Our analyses treated ARR and renin as continuous, nonmutually exclusive measures of renin-independent aldosterone physiology; therefore, the handling of a small number of values at the assay floor does not materially inform that debate. We appreciate the opportunity to clarify these points and believe the findings remain robust and consistent with renin-independent aldosteronism (even when below traditional biochemical thresholds for defining primary aldosteronism) contributing to steeper kidney function decline over time.
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7147655939