Temporal dynamics of glomerular and microvascular remodeling in high-altitude renal injury: a structure-function analysis in rats.

INTRODUCTION: The temporal dynamics of renal acclimatization during the sub-acute transition to high altitude remain poorly defined. Specifically, the relationship between structural integrity and functional adaptation under sustained hypobaric hypoxia is unclear. This study aims to characterize the time-dependent trajectories of renal remodeling and identify the critical biological window for potential intervention.

METHODS: Male Sprague-Dawley (SD) rats were randomized to a normobaric normoxia control group or a simulated hypobaric hypoxia group (5,000 m, PO2: 11.3 kPa) for 3, 7, 14, and 28 days (n=6/group). Renal filtration function was assessed via serum creatinine (CRE) and cystatin C (CysC), while tubular injury and systemic inflammation were evaluated using neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18). Structural alterations were quantified through hematoxylin and eosin (H&E) and Periodic Acid-Schiff (PAS) staining, with peritubular capillary (PTC) density assessed via immunohistochemistry. The temporal associations and exploratory biomarker discrimination were analyzed using restricted cubic spline (RCS) regression, Spearman correlation, and receiver operating characteristic (ROC) analyses.

RESULTS: Despite stable gross kidney weight and length throughout the exposure, histological analysis revealed progressive microscopic injury. PTC density exhibited a continuous, time-dependent decline that was significantly inversely correlated with tubular injury scores and medullary congestion. Notably, glomerular morphometry exhibited a distinct biphasic response: an initial significant reduction in glomerular diameter at Day 3, followed by subsequent enlargement peaking at Day 14. Temporally, serum biomarkers showed heterogeneous and exploratory trajectories, whereas histological injury remained more persistent. CysC and CRE showed overall temporal variation, but Tukey-adjusted post hoc comparisons did not identify significant pairwise differences between individual time points. In the exploratory Day 3 ROC analysis, CRE showed no meaningful early discriminatory ability (AUC = 0.486, 95% CI: 0.124-0.848), whereas KIM-1 showed the highest AUC among the examined circulating biomarkers (AUC = 0.861, 95% CI: 0.641-1.000). However, DeLong pairwise comparisons did not remain statistically significant after Tukey correction, and these ROC findings should be interpreted as hypothesis-generating.

CONCLUSION: Hypobaric hypoxia induces a distinct state of structure-function uncoupling, characterized by persistent microvascular rarefaction that antedates measurable systemic functional decline. The first week of exposure represents a biologically active phase of vascular remodeling and tubular stress. These findings suggest that relying solely on functional markers may underestimate the severity of sub-clinical renal injury in hypoxic environments, highlighting the potential value of integrating structural biomarkers for more accurate risk stratification.