Purine-Metabolism Reprogramming Associated with Failed-Repair Proximal Tubule States in the AKI-to-CKD Transition

Background/Objectives: The acute kidney injury (AKI) to chronic kidney disease (CKD) transition has been associated with a failed-repair proximal tubule (FR-PT) cell state. Hyperuricemia is an established CKD risk factor, but whether FR-PT cells have a coordinated metabolic signature reproducibly detectable across mouse models and human kidney disease remains unresolved. Methods: We assembled a pre-registered meta-analysis of 16 public mouse-kidney metabolomic cohorts (383 samples; five model classes; three injury phases) through a three-path harmonization pipeline. Convergent validation drew on KPMP single-nucleus RNA-seq (78,480 proximal tubule cells), two-sample Mendelian randomization of serum urate (102 instruments) against AKI/CKD/eGFR GWAS, and cross-cohort human plasma metabolomics across 2058 CKD/DKD patients. Results: Mouse meta-analysis identified uric acid (g = +2.70) and AICAR (g = +1.50) as the only cross-class conserved metabolites, with uric acid peaking during the AKI-to-CKD transition and returning to baseline in mouse CKD due to uricase clearance. Cross-class overlap between model classes was low (mean pairwise Jaccard = 0.109, below the pre-registered 0.20 threshold), invoking the pre-registered M-S1 stop rule: model-specific metabolic responses dominate, and the conserved signal is a small two-metabolite core superimposed on these largely model-specific programs. KPMP failed-repair PT cells exhibited transcriptional patterns consistent with coordinated four-arm purine-pathway dysregulation (de novo synthesis ↑, AMPK ↑, MOCOS ↑, URAT1 ↓), with this transcriptional pattern observed in both AKI and CKD donors (Spearman ρ = +0.900). Mendelian randomization was consistent with a possible causal contribution of serum urate to AKI/CKD/eGFR risk, with colocalization evidence at GCKR (PP.H4 = 1.000). Cross-cohort human plasma profiling across 2058 patients confirmed the systemic detectability of 29 purine-pathway metabolites in uricase-deficient humans (a translational-plausibility check, not validation of cellular source). Conclusions: The integrated data support a model in which FR-PT-associated purine-pathway reprogramming may contribute to the elevated urate signal observed during AKI-to-CKD transition, with uric acid as the candidate metabolic readout. Differences in uricase activity between mice and humans may help explain why chronic-phase urate signals are attenuated in mice but persist in humans. This work nominates a candidate cell-state metabolic readout of the AKI-to-CKD transition as a hypothesis for prospective testing; it does not establish causation, and therapeutic translation would require dedicated interventional studies.