Progressive kidney fibrosis is associated with peritubular capillary (PTC) loss in both native and transplant kidneys, but molecular mechanisms underlying PTC rarefaction are unknown. We hypothesized that PTC rarefaction in deteriorating transplant kidneys is related with low pro-angiogenic microenvironment. We studied PTC density and intragraft expression of 31 angiogenesis-related genes by microarrays in 100 kidney posttransplant biopsies for clinical indications from 83 recipients (42% presenting with chronic renal dysfunction; median time post-transplant: 15-months, median follow-up time: 32 months), and compared to 40 normal implantation biopsies. We labeled PTCs with CD31 immunostaining and quantified using two methods: 1. PTC number per unit-area (0.25 mm²); 2. PTC-to-tubule ratio. A class comparison analysis showed that expression of 27 of 31 angiogenesis-related genes was significantly different in posttransplant biopsies versus controls (corrected p<0.05). Several potent proangiogenic molecules were dowregulated in posttransplant biopsies including VEGF-A, VEGF-A receptors 1 and 2, co-receptor neuropilin 1, fibroblast growth factor 1 and its receptors, platelet derived growth factor alpha and beta. In contrast, anti-angiogenic endostatin was upregulated in posttransplant biopsies. Decreased VEGFA in posttransplant biopsies was correlated with low eGFR at time of biopsy, more proteinuria, and donor specific antibody (p<0.05). Demographic factors, use of renin-angiotensin system inhibitors in the peribiopsy period, and time posttransplantation were not related with VEGFA levels in biopsy tissues. Interestingly, decreased VEGFA in posttransplant biopsies was correlated with more interstitial fibrosis and tubular atrophy, PTC rarefaction, and graft inflammation (i-,t-,g-,ptc-scores) (p<0.001). In a multivariate model, decreased VEGFA was a strong and independent predictor of death-censored graft failure (HR=0.20, p=0.007) after adjusting for multiple clinico-pathological and molecular prognostic factors.

These data suggest that decreased VEGF-A signaling may be a driving mechanism for kidney transplant fibrosis and failure.

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