Use of mizoribine as a rescue drug for steroid-resistant pediatric IgA nephropathy

Abstract

Recent clinical trials have shown a beneficial effect of mizoribine (Miz), an immunosuppressive drug, in the treatment of new-onset pediatric IgA nephropathy (IgAN). In this study, we evaluated the efficacy of Miz treatment in three children with established steroid-resistant IgAN. The patients had IgAN featuring persistent proteinuria and diffuse mesangial proliferation and had failed to respond to 2 years of treatment with prednisolone. Based upon the second biopsy results, patients were given methylprednisolone (mPSL) pulse therapy that induced a transient reduction in proteinuria, which was reversed when the mPSL dose was tapered. Miz therapy was then instigated in place of pulse mPSL. All three patients showed a substantial reduction in proteinuria and resolution of hematuria within 5 months. A follow-up biopsy in two of the patients showed a substantial reduction in the severity of glomerular lesions and a decrease in the number of activated macrophages. In conclusion, Miz therapy was found to be a safe and effective therapy in three cases of steroid-resistant pediatric IgAN. The ability of Miz to reduce the number of activated macrophages may be an important mechanism by which this drug ameliorated renal disease in these patients.

Contrasting Effects of Steroids and Mizoribine on Macrophage Activation and Glomerular Lesions in Rat Thy-1 Mesangial Proliferative Glomerulonephritis

“…Cases of steroid-resistant disease are treated with additional immunosuppressant agents. For example, mizoribine (MZR) is used as a rescue drug in steroid-resistant IgA nephropathy [10,11], but little is known of any potential effects of MZR upon macrophage activation.…”

Treatment of Pediatric-Onset Lupus Nephritis: A New Option of Less Cytotoxic Immunosuppressive Therapy

“…This may, in turn, lead to suppression of the activity of 3 1-integrin, which is known to play a role in the development of interstitial fibrosis. Indeed, in a clinical setting, it has also been reported that posttreatment renal biopsy specimen from patients with severe IgA nephropathy treated with MZR, showed marked attenuation of glomerular and interstitial lesions, and significantly reduced the number of activated macropharges, associated with the expression of 14-3-3 proteins and HSP60, which are known to be MZR-binding proteins, in the inflamed glomerular cells (Ikezumi et al, 2008). Thus, it is speculated that MZR may bind directly to inflamed glomerular cells and prevent progressive damage by suppressing activated macrophages and intrinsic renal cells.…”

“…This low clinical toxicity is an important advantage of MZR-P treatment, especially for long-term treatment of young patients. Besides its immunosuppressive effects, MZR has recently been reported to suppress the progression of histologic chronicity in selected patients with lupus nephritis and IgA nephropathy (Kawasaki et al, 2004;Tanaka et al, 2007b and c;Ikezumi et al, 2008). Moreover, MZR has been reported to attenuate tubulointerstitial fibrosis in a dosedependent manner in rat models of unilateral ureteral obstruction, non-insulin-dependent diabetes and peritoneal fibrosis via suppression of macrophage infiltration of the interstitium (Sato et al, 2001;Kikuchi et al, 2005;Takahashi et al, 2009).…”

“…1). Since the inflamed glomeruli express 14-3-3 proteins and HSP60 (Ikezumi et al, 2008), MZR may directly interact with inflamed glomerular cells, because MZR is directly excreted into the urine. Moreover, Takeuchi et al (2010) reported that MZR directly prevented podocyte injury in experimental puromycin aminonucleoside-induced nephropathy, suggesting an anti-proteinuic effect of MZR besides its immunosuppressive effects.…”

Proteinuria rebound in IgA nephropathy associated with obesity-related glomerulopathy

“…A diagnosis of IgAN with pathological features of membranoproliferative glomerulonephritis (MPGN) type I was made. Combination therapy was started as reported previously, with modifications [7][8][9]. The modified combination therapy consisted of prednisolone, mizoribine, heparin-warfarin, urokinase, dipyridamole, and candesartan cilexetil.…”