From Bone-Centric to Kidney-Centric: Environment-Dependent Shift of Spaceflight Renal Stone Pathways

Human deep-space missions face bone–kidney risks that cannot be extrapolated from six-month ISS data. We built a 12-state Ca-bone-urine-stone mechanistic ODE model and jointly calibrated its 11 physiological parameters on eight ISS targets by Bayesian identification (M₀ base = 19-D; M₁ extension adds a GCR–bone coupling term for parsimony testing only), then propagated the M₀ posterior to four environments (ISS, Lunar subsurface, Lunar surface, Mars). Lumbar-lower BMD loss increases with mission duration and partial-gravity unloading (ISS 180 d −4.83% → Mars 730 d −12.15%; 2³ factorial: duration 82.9%, gravity 12.5%, GCR main effect ≈ 0), whereas stone rate follows the opposite gradient (ISS 16.1 vs Mars 13.1 per 1000 person-years), reflecting weakened partial-gravity bone resorption alongside residual urinary chemistry changes. The dominant pathway thus shifts from bone-centric on the ISS to kidney-centric on Mars, where residual urinary-chemistry changes—not bone resorption—drive stone risk. The direct GCR–bone coupling term is unidentifiable at current ISS doses (ΔWAIC = +0.0076 ± 0.126 SE), so M₀ is retained as the main inference model. Bisphosphonates provide ≥84% BMD protection but leave a urinary-chemistry residual, so bisphosphonate monotherapy would underestimate Mars stone risk; potassium–magnesium–citrate combinations (RRR_RSS 51%) should therefore be added to deep-space countermeasures. A Lunar-surface 365-day mission is the earliest environment on the NASA roadmap to cross a composite RED threshold. That profile differs from the regolith-shielded 180-day case in both cumulative GCR (∼69×) and duration (2×), so a shielding-specific effect cannot be isolated here; forcing the GCR coupling terms to zero leaves all four composite tiers unchanged (0/4, Supp §S24), and the shielded 180-day profile is YELLOW rather than GREEN. Independent hold-out validation (Culliton 2025 60-day HDT-bedrest RCT, n=8 control arm of n=24 total) supports the M₀ posterior predictive distribution on the lumbar-BMD sub-scope.