Pulmo-Cardio-Renal Continuum in Chronic Lung Diseases: A 3-Year Prospective Cohort Study

Background/Objectives: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) and chronic obstructive pulmonary disease (COPD) are linked to multi-organ vulnerability involving the lungs, heart, and kidneys. This study aimed to compare the annual changes in pulmonary, cardiac, and renal parameters in patients with SSc-ILD and COPD across three consecutive years, using both individual biomarkers and integrated composite profiles. Methods: This observational longitudinal study included repeated assessments in 2023, 2024, and 2025. Functional, laboratory, and imaging parameters were collected: 6-min walk test (6MWT), SpO₂ (pre-/post-exercise), spirometry/CT lung volumes, gas exchange (pO₂/pCO₂/lactate), echocardiography [left ventricular ejection fraction (LVEF), estimated systolic pulmonary artery pressure (sPAP)], cardiac biomarkers (NT-proBNP, MR-proANP, hsTnT), renal markers [eGFR, creatinine, albuminuria, albumin-to-creatinine ratio (ACR)], heart rate variability (HRV), and renal CT densitometry. All markers were standardized (z-scores, higher values = worse). Subprofiles were generated and aggregated into three integrated profiles (cardiac, renal, pulmonary). Within-group dynamics were analyzed using the Wilcoxon signed-rank test (year-to-year deltas), between-group comparisons with the Mann-Whitney U test, effect sizes via Cliff's delta, and multiple testing correction with the Benjamini-Hochberg false discovery rate (FDR). Results: Exercise tolerance declined in both groups: by 2025, 6MWT distance decreased by -10 m in SSc-ILD (p = 0.006; q = 0.010) and -20 m in COPD (p = 0.002; q = 0.004); post-exercise SpO₂ fell in both cohorts (both p < 0.001; q < 0.001). MR-proANP remained consistently higher in SSc-ILD across all years (p ≤ 0.005; q ≤ 0.028). sPAP increased in both groups, reaching higher values in COPD by 2025 (p = 0.007; q = 0.033). NT-proBNP and hsTnT increased over time, while eGFR declined, and ACR rose in both cohorts (both p < 0.001; q < 0.001). HRV (HF/total power) decreased by 2025. Composite profiles showed: in 2023, the cardiac profile was worse in SSc-ILD (δ ≈ 0.27; p = 0.011; q = 0.048), but differences diminished by 2025; the renal profile was initially worse in SSc-ILD but later shifted unfavorably in COPD; the pulmonary profile showed no consistent between-group differences. Conclusions: Over three years, patients with SSc-ILD and COPD exhibited concordant deterioration in pulmonary, cardiac, and renal function. Distinct leading markers emerged: desaturation during exercise and neurohormonal activation (MR-proANP) in SSc-ILD, versus reduced 6MWT and higher sPAP in COPD. These findings support the need for integrated monitoring of the cardio-pulmo-renal continuum. Limitations include the observational design, multiple comparisons, and absence of advanced repeated-measures modeling.