Predictors of Stone Recurrence in the NOSTONE Trial: Post Hoc Analysis

Background: In the NOSTONE trial, hydrochlorothiazide (HCTZ) did not reduce stone recurrence and lowered urine calcium less than expected. Here we conduct a post-hoc analysis to examine the effect of HCTZ and additional risk factors affecting urine solute excretion and recurrence rates. Methods: In this post-hoc analysis, we aimed at (i) investigating the effect of baseline urine sodium (an established proxy of intake), calcium and relative supersaturation ratios (RSRs) CaOx and CaP on stone recurrence (symptomatic, radiologic or combined recurrence), and ii) exploring the relationship between change in urine sodium, calcium and RSRs on recurrence. The effect of each predictor was tested separately on each stone outcome considering either the value measured at baseline or collected during follow-up (time-varying). The eventuality of an influence of the treatment group on the relationship between the outcomes was investigated by testing the interaction effect between the predictor and the treatment group. Results: No significant association was observed between any baseline predictor and symptomatic recurrence. Radiologic recurrence was significantly associated with baseline urinary sodium (OR = 1.36, p = 0.025), RSR CaP (OR = 5.57, p < 0.001) but not RSR CaOx. For the composite outcome, only baseline RSR CaP predicted the risk of recurrence (HR = 2.27, p = 0.004). None of these effects differed significantly between treatment groups. In the time-varying analysis, RSR CaP but not urine sodium or urine calcium were significantly associated with symptomatic recurrence (HR = 2.21, 95% CI: 1.29–3.79, p = 0.004). No time-varying predictor was significantly associated with the composite outcome. Urinary sodium had a positive, treatment-dependent effect on the change in urine calcium with a stronger effect observed in the placebo vs HCTZ groups (interaction p = 0.007). Conclusion: Our analysis reveals baseline RSR CaP as a strong predictor of radiologic stone recurrence. The effect of dietary sodium on urine calcium was attenuated in patients receiving HCTZ compared to patients receiving placebo. Furthermore, both composite and radiologic stone recurrence appear to be independent of dietary sodium intake.