Cosmic kidney disease in spaceflight and terrestrial nephrology: Mechanisms and translation

Astronauts experience nephrolithiasis at incidence rate ratios two- to seven-fold higher than pre-flight estimates, a disparity historically attributed to microgravity-induced bone demineralization. The 2024 Cosmic Kidney Disease study reframed this paradigm by demonstrating a primary renal tubulopathy with direct relevance to terrestrial nephrology. This review synthesises mechanistic and clinical data on spaceflight-induced renal dysfunction and maps the identified mechanisms to terrestrial scenarios, including immobilization-related stone disease, radiation nephropathy, enteric hyperoxaluria, and heat-dehydration syndromes affecting Middle East and North Africa/Gulf Cooperation Council populations. Six databases (PubMed/MEDLINE, Embase, Cochrane Library, NASA Technical Reports Server, ClinicalTrials.gov, and the Space Omics and Medical Atlas) were searched from inception to March 2026; after deduplication and screening, 101 records met the inclusion criteria. Evidence appraisal used SANRA quality items, GRADE certainty assessment, and AGREE II principles. Spaceflight produces dephosphorylation of NKCC2 (SLC12A1) in the thick ascending limb, generating a primary hypercalciuric tubulopathy that resembles type-I Bartter syndrome. NCC (SLC12A3) dephosphorylation creates an unresolved paradox with implications for thiazide use, while distal convoluted tubule expansion appears within 28 days in rodent models. Simulated GCR produces structural and functional injury with TGF-β dysregulation and little recovery within tested observation windows in mice. Hindlimb-unweighting models add intrarenal artery remodelling, Rho-kinase-mediated vasoconstriction, and impaired NO -eNOS vasodilation as a fourth mechanistic axis alongside tubular, radiation, and microbiome injury. Microbiome shifts correlate with hyperoxaluria. Computational modelling supports fluid intake near 3.2 L/day to normalise calcium-oxalate supersaturation, although thiazide therapy requires prospective evaluation. Renoprotective countermeasures against GCR damage are relevant to both deep-space missions and abdominopelvic radiotherapy. Cosmic kidney disease is therefore best understood as a primary multi-mechanism tubulopathy rather than a passive consequence of bone loss, with each mechanism mapping to a clinical scenario already encountered in nephrology.