Introduction: Aging is a critical yet often overlooked factor influencing renal allograft outcomes. Experimental studies suggest that aged endothelial cells (EC) exhibit diminished production of nitric oxide (NO) and vascular endothelial growth factor (VEGF), key regulators of angiogenesis and vascular integrity. This decline is associated with a reduction in both glomerular capillaries (GC) and peritubular capillaries (PTCs), leading to chronic ischemia—a major driver of tubulointerstitial and glomerular injury in transplanted kidneys. To determine whether age-related changes in angiogenic signaling contribute to capillary rarefaction, we investigated the impact of aging on GC and PTC density in renal allografts.
Methods: This study included 150 renal transplant recipients, of whom 42 (28%) were pediatric patients. Among pediatric recipients, 25 received grafts from younger donors (<40 years, Group P1), while 18 had older donors (>40 years Group P2). Among 108 adult recipients, 50 had donors <40 years old (Group A1), and 57 had donors >40 years (Group A2).  GC and PTC density were assessed using CD31 and HLA-DR staining. VEGF and NO expression in GCs and PTCs, along with EC proliferation index (PI), were evaluated using PCNA staining. Tubular villin and PCNA expression were also examined. Follow-up biopsies were analyzed for interstitial fibrosis (IF) and glomerulosclerosis (GS) development.
Results: VEGF, NO, and PCNA expression, along with capillary density in both GCs and PTCs, were significantly higher in pediatric recipients than in adults (p<0.01). Among all groups, P1 had the highest levels, followed by P2, A1, and A2. Similarly, tubular PCNA and Villin expression were highest in pediatric recipients, with the same ranking order (p<0.01). The number of PTCs showed a strong negative correlation with PTCitis, tubular Villin expression proteinuria, IF, and graft loss (p<0.001). Conversely, it positively correlated with PTC-VEGF and PTC-NO expression (p<0.001).  Similarly, GC loss was significantly associated with GC inflammation, tubular Villin expression, proteinuria, GS, and graft loss while positively correlating with GC-VEGF and GC-NO expression (p<0.001). Overall 10-year graft survival rates were 76% in P1, 61% in P2, 50% in A1, and 32% in A2 group (p=0.004).
Conclusion: Aging markedly affects renal allograft microvascular integrity and long-term survival. Pediatric recipients with younger donors (P1) showed the highest VEGF/NO expression, capillary density, and EC proliferation, resulting in better graft outcomes. Conversely, adult recipients with older donors (A2) experienced significant MV loss, increased IF and GS, and the lowest survival rates. These results suggest that age-related declines in angiogenic signaling lead to capillary rarefaction and graft dysfunction, highlighting the need for targeted strategies to improve longevity, especially in older donor-recipient pairs.