A single simultaneous injection of two monoclonal antibodies causes novel progressive renal lesions with characteristic proteinuria kinetics

Abstract

　　In the clinical setting, we have encountered cases of renal lesions, although once resolved, that progress gradually to end-stage renal disease after an extended latent period. However, appropriate model explaining renal lesions with such an insidious progression is limited. It has been reported that prior minor podocyte injury without proteinuria could exacerbate mesangial alterations and cause irreversible mesangial proliferative glomerulonephritis with persistent proteinuria. To better understand the possible protective relationship of podocytes and mesangial cells against chronic disease progression, we examined the effect of concomitant damage to both cells using anti-Thy-1 monoclonal antibody (mAb) 1-22-3 and anti-nephrin mAb 5-1-6. When injected separately, the mAbs induced reversible renal lesions with transient proteinuria, whereas simultaneous injection evoked immediate massive proteinuria that steadily decreased to low levels until 3 months. The most remarkable feature of this model was that the proteinuria then began to gradually rise until 9 months, at which time electron microscopy revealed effacement of foot processes and accumulation of collagen fibrils in the tubulointerstitium and immunofluorescence showed deposition of collagen type I in glomeruli.

　　When the proteinuria commenced increasing at 3 months, mesangial proliferation was already evident in light microscopy and collagen deposition was present in glomeruli according to immunofluorescence. These results suggested that simultaneous insult to podocytes and mesangial cells caused novel progressive renal lesions with the characteristic proteinuria kinetics of chronic glomerulonephritis and indicated the possibility of a coordinated protective cellular role. There have been no other models of a single injection causing such progressive renal lesions to date. This novel system may shed light on the mechanism and treatment of gradually deteriorating renal lesions.