High-dose mizoribine therapy for childhood-onset frequently relapsing steroid-dependent nephrotic syndrome with cyclosporin nephrotoxicity

Ohtomo, Yoshiyuki; Fujinaga, Shuichiro; Takada, Moriatsu; Murakami, Hitohiko; Akashi, Shunji; Shimizu, Toshiaki; Kaneko, Kazunari; Yamashiro, Yuichiro

doi:10.1007/s00467-005-2025-3

Cited by 37 publications

(31 citation statements)

References 21 publications

(27 reference statements)

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“…24 On the other hand, we have successful experience with high dose mizoribine (mean 10.1 mg/kg/day) for children with steroid dependent who are also CsA dependent. 25 This therapy reduced CsA exposure and relapse rates. Furthermore, the multivariate analysis also revealed that an age younger than 5 years at the start of CsA treatment was another independent risk factor for CsAN.…”

Section: Discussionmentioning

confidence: 99%

Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome

Fujinaga

Kaneko²,

Muto³

et al. 2006

Archives of Disease in Childhood

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Background: Cyclosporine A (CsA) has been widely used in children with steroid dependent and steroid resistant nephrotic syndrome (NS) because of its efficacy in relieving these patients from systemic side effects of steroids. However, its long term use is controversial, since chronic CsA induced nephropathy (CsAN) may develop in a considerable number of patients. Aims and Methods: In order to clarify the risk factors for the development of CsAN, the clinical characteristics of children with steroid dependent or steroid resistant NS taking CsA (target blood trough levels 50-150 ng/ml) for more than six months, managed at a single centre, were retrospectively analysed. Results: Thirteen of 30 children (24 boys and 6 girls) taking CsA (mean duration 43 months, range 6-144) had CsAN defined as the presence of CsA associated arteriopathy with or without striped tubulointerstitial lesions. The multivariate analysis revealed that CsA treatment for more than 36 months and an age younger than 5 years at the start of CsA treatment were independent risk factors for the development of CsAN. The univariate analysis also showed that patients with CsAN had more frequent relapses during CsA treatment than those without CsAN. Conclusion: An alternative treatment should be seriously considered after a 36 month administration of CsA in order to prevent CsAN. Data also suggest that CsA treatment in children younger than 5 years should be avoided if possible.

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Section: Discussionmentioning

confidence: 99%

Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome

Fujinaga

Kaneko²,

Muto³

et al. 2006

Archives of Disease in Childhood

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“…Moreover, the effects of mizoribine on the intracellular energy balance and nephrin biogenesis were observed at clinically attainable concentrations. [51][52][53] A better understanding of the pathomechanism of NS and the mechanisms by which antiproteinuric agents lead to remission in NS may allow development of new therapies.…”

Section: Discussionmentioning

confidence: 99%

Mizoribine Corrects Defective Nephrin Biogenesis by Restoring Intracellular Energy Balance

Nakajo

Khoshnoodi

Takenaka

et al. 2007

Journal of the American Society of Nephrology

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Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5Ј-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.

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“…Preliminary data from a series of pediatric (1)(2)(3)(4)(5)(6)(7)(8) and adult (9 -11) studies suggest that mycophenolate mofetil (MMF) may represent a less toxic alternative for patients with FRNS. Other recent studies have reported that mizoribine (12)(13)(14)(15)(16)(17) or levamisole (18) also may be options to consider in such patients.…”

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confidence: 99%

Mycophenolate Mofetil in Children with Frequently Relapsing Nephrotic Syndrome

Hogg¹,

Fitzgibbons²,

Bruick³

et al. 2006

Clinical Journal of the American Society of Nephrology

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Children with frequently relapsing nephrotic syndrome (FRNS) often develop adverse effects from prednisone. Attempts to induce long-term remission in such patients have had varying levels of success. In this multicenter, prospective, open-label study, 14 centers enrolled 33 patients with FRNS, all of whom were in remission at the time of entry. Six of the patients were steroid dependent. The patients received mycophenolate mofetil (MMF) 600 mg/m 2 twice daily (maximum 1 g twice daily) for 6 mo. A tapering dosage of alternate-day prednisone was given to each patient during the first 16 wk of MMF therapy. Patients were monitored for relapses of NS during and after MMF therapy. Treatment failure was defined as a relapse of NS. The patients had the following features at study entry: Age 6.8 ؎ 2.7 yr (range 2 to 15 yr); 56% male, 44% female; and 50% white; 25% black, and 25% other. Estimated GFR at entry was 138 ؎ 42 ml/min per 1.73 m 2 . Twenty-four (75%) of 32 patients stayed in remission throughout the 6 mo of MMF therapy. The relapse rate in these patients improved from one episode every 2 mo before MMF to one every 14.7 mo after MMF. Eight patients stayed in remission during the post-MMF period, for periods of 18 to 30 mo, whereas 16 relapsed after stopping MMF. Eight (25%) of 32 patients relapsed while taking MMF. It is concluded that MMF is effective for maintaining remission in patients who have FRNS and receive treatment for at least 6 mo and is associated with a low incidence of adverse events.

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High-dose mizoribine therapy for childhood-onset frequently relapsing steroid-dependent nephrotic syndrome with cyclosporin nephrotoxicity

Cited by 37 publications

References 21 publications

Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome

Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome

Mizoribine Corrects Defective Nephrin Biogenesis by Restoring Intracellular Energy Balance

Mycophenolate Mofetil in Children with Frequently Relapsing Nephrotic Syndrome

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