Ultrastructural analysis of the Fisher to Lewis rat model of chronic allograft nephropathy

Abstract

Summary Chronic allograft nephropathy (CAN) is the leading cause of graft loss following kidney transplantation. One factor contributing to CAN is chronic alloimmune injury. However, the involvement of alloantigen‐dependent and ‐independent factors in CAN is unclear. The pathomechanism of CAN has been extensively studied by utilizing the Fischer‐to‐Lewis (F344‐to‐LEW) rat model. Transplant capillaropathy (circumferential multiplication of the peritubular capillary basement membrane) and transplant glomerulopathy (reduplication of the glomerular basement membrane) have recently been validated clinicopathologically as ultrastructural indicators of chronic alloimmune injury. To investigate the presence of these markers, F344‐to‐LEW kidneys were examined by electron and light microscopy 32, 40 and 52 weeks after implantation. F344 rats with or without 30‐min ischemia of the left kidney following right nephrectomy served as controls. All transplanted rats displayed marked proteinuria. On electron microscopy, transplant capillaropathy, transplant glomerulopathy, and T‐cell cytotoxicity (indicator of ongoing cellular rejection) were absent. On light microscopy, the arteries were devoid of intimal fibrosis. Focal‐segmental glomerulopathy resembling hyperfiltration injury was encountered, with mild interstitial infiltration, fibrosis, and tubular atrophy. The proteinuria and kidney pathology were more severe in transplanted than in ischemic or uninephrectomized rats. Because chronic‐active rejection could not be detected between weeks 32 and 52, we propose that the alloantigen‐dependent initial graft injury subsides, but induces the late events: glomerular hyperfiltration, proteinuria, and glomerulosclerosis. Accordingly, the model – in the late phase – is suitable to investigate alloantigen‐independent factors of CAN and lacks markers of alloantigen‐dependent processes.

Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis-Resistant Rat Strain

“…Glomerulosclerosis was assessed according to a modified [11,27] scoring system (scores 0–4) of El Nahas et al [28] at x400 absolute magnification using an Olympus CX21 microscope (Olympus Optical Co. Ltd., Japan). Score 0: normal glomerulus.…”

Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling

“…It is not fully understood how the responses of the alloantigen-dependent Th1 subset are related to the development of CAN, but evidence from one study suggests that alloantigen-stimulated immune response (cellular rejection) initiates early graft injury, which then leads to the late events of CAN, such as glomerular hyperfiltration, proteinuria, and glomerulosclerosis (14). It has been documented that specific inhibition of MEK-ERK1/2 signaling by PD-98059 or U-0126 reduces T cell proliferation/activation in response to T cell receptor antigen stimulation (56) and suppresses Th1 differentiation and Th1 alloimmune responses to cardiac allograft (22,56,57).…”

“…It has been generally accepted that CAN is a principal cause of late graft function loss after the 1st yr of renal transplantation, and its progress depends on alloantigen-dependent immune responses and TGF␤ (14,21,28). Following up our above data showing that CI-1040 suppressed the immune responses to the alloantigen, as well as TGF␤1 production in the kidney cells, we tested whether pharmacological interference of MEK1-ERK1/2 signaling with CI-1040 protected renal allograft from the development of CAN in a mouse model, in which renal allografts exhibit reduced renal function and many of the histological features of CAN seen in chronic rejection of human kidney allografts by 6 wk after transplantation (31).…”

Renal N ε-Carboxymethyllysine Deposition After Kidney Transplantation

“…The Fisher-to-Lewis rat renal transplantation model is an accepted and a frequently-used model for chronic allograft injury, resulting in mild dysfunction when compared with the human situation (24,25). In this model, tubular CML deposition was apparent at 12 weeks after transplantation, thus preceding the development of proteinuria (26).…”