Injury and progressive loss of peritubular capillaries in the development of chronic allograft nephropathy.

BACKGROUND

Chronic allograft nephropathy (CAN) remains the most important cause of late renal graft loss. However, the mechanism for graft dysfunction and the process of the development of CAN are not well understood. This study examined the role of microvascular injury in the development of CAN.

METHODS

We studied renal biopsies obtained from grafts with CAN (N= 79) and pretransplant control kidneys (N= 20). Microvascular injury was examined morphologically, and was correlated with interstitial fibrosis, glomerular sclerosis, graft function, and the severity of CAN. The humoral and cellular immunity involved in CAN were examined by C4d, CD3, and TIA-1 staining.

RESULTS

In all the cases of CAN, microvascular injury was evident with or without CD3-positive T cells, TIA-1-positive cytotoxic cells, and/or C4d+ complement deposition. Irrespective of chronic rejection (N= 14), C4d+ chronic humoral rejection (N= 6), or other CAN, the development process of CAN was characterized by injury and progressive loss of identifiable peritubular capillaries (PTCs) accompanied with the development of interstitial fibrosis. Injured PTCs were characterized morphologically by the process of angioregression with the presence of apoptotic cells, lamination of the basement membrane, and loss of PTCs. The low number of PTCs correlated significantly with the severity of CAN (r=-0.74, P < 0.001), the development of interstitial fibrosis (r=-0.75, P < 0.001), graft dysfunction (r=-0.69, P < 0.001), and also correlated weakly with proteinuria (r=-0.45, P < 0.05). In the glomeruli, capillary loss significantly correlated with the degree of glomerular sclerosis (r=-0.66, P < 0.001) and proteinuria (r=-0.65, P < 0.001), but did not correlate with the severity of CAN (r=-0.24, P > 0.05) or graft dysfunction (r=-0.32, P > 0.05).

CONCLUSION

CAN was characterized by progressive injury to the renal microvasculature and the development of renal scarring. In particular, injury, angioregression and progressive loss of the PTC network strongly contributed to the development of interstitial fibrosis and graft dysfunction in CAN, and might play a crucial role in the development of CAN.