Efficacy of mizoribine followed by low-dose prednisone in patients with idiopathic membranous nephropathy and nephrotic-range proteinuria

Abstract

Background: Idiopathic membranous nephropathy (IMN) patients with persistent high-grade proteinuria are at the highest risk for developing end-stage renal failure. We previously reported the effects of treatment with mizoribine followed by low-dose prednisone treatment in 4 IMN patients. The purpose of the present study was to further assess the effects of this combined treatment in a larger study group. Method: Thirteen patients with IMN and nephrotic-range proteinuria received combined treatment. Mizoribine was initiated at a dose of 150?mg/day, and 2–3 months later, 20?mg/day prednisone was added to the mizoribine regimen. The dosage of prednisone and/or mizoribine was tapered according to the urinary protein-to-creatinine ratio (P/C). We evaluated patient responses for up to 12 months after the initiation of combination therapy. Results: Before treatment, patient urinary P/C ranged from 3.7 to 15.9?g/g. Although these values did not decrease during mizoribine monotherapy, all patients showed dramatic P/C decreases over the course of combination therapy. At 3, 6, and 12 months after combination therapy, 15%, 31%, and 62% of patients attained complete remission, respectively, and all patients were in partial or complete remission 6 months after combination therapy. No notable side effects were observed. Conclusion: The addition of prednisone after mizoribine monotherapy can be beneficial for all IMN patients with nephrotic-range proteinuria syndrome. The risks associated with immunotherapy can be decreased by initially prescribing mizoribine alone, which might act as a base for establishing therapy, followed by low-dose prednisone treatment.     

Immunosuppressive Treatment of Primary Cadaveric Renal Transplant Patients Receiving Kidneys from Non-Heart Beating Donors

Abstract: Since November 1982, 276 primary cadaveric kidney transplants have been performed using kidneys from non-heart beating donors. Between November 1982 and December 1986, 49 transplant patients were treated with cyclosporine and steroid immunosuppressive therapy (CSA regimen). Twenty-seven patients were treated with low dose cyclosporine (initial dosage, 4 mg/kg/day), steroid therapy, and a 21-day course of 500 mg/day anti-lymphocyte globulin (ALG 1 regimen) between January 1987 and December 1987. Seventy-nine patients were treated with low dose cyclosporine (initial dosage, 6 mg/ kg/day), steroid therapy, and a 14-day course of 1,000 mg/day antilymphocyte globulin (ALG 2 regimen) between January 1988 and June 1990, and 85 patients were treated with low dose cyclosporine (initial dosage, 6 mg/ kg/day), steroid therapy, and a 14-day course of 1,000 mg/day antilymphocyte globulin followed by 2 mg/kg/day mizoribine (ALG 3 regimen) between July 1990 and May 1995. Ten patients, who showed hypersensitivity to antilymphocyte globulin therapy, were treated with low dose cyclosporine, steroid therapy, and mizoribine. Finally, 26 patients were treated with FK506 and steroid therapy (FK.506 regimen) between June 1990 and February 1992. Graft survival was 78% at 1 year, 69% at 3 years, 63% at 5 years, and 51% at 10 years in the CSA regimen group and 67% at 1 year, 52% at 3 years, and 48% at 5 years in the ALG 1 regimen group. It was 85% at 1 year, 70% at 3 years, and 62% at 5 years in the ALG 2 regimen group and 87% at 1 year and 67% at 3 years in the ALG 3 regimen group. In the FK506 regimen group, graft survival was 92% at 1 year and 80% at 3–5 years. Never-functioning grafts were observed in 3 CSA patients (6%), I ALG 1 patient (4%), 3 ALG 2 patients (4%), 3 ALG 3 patients (4%), and I FK506 patient (4%). These results indicate that low dose cyclosporine (initial dosage, 6 mg/kg/day), steroid therapy, and a 14 day course of antilymphocyte globulin therapy is beneficial for cadaveric renal transplant patients receiving kidneys from non-heart beating donors; FK506 and steroid therapy might be more effective than cyclosporine based immunosuppressive therapies even in such patients.     

Efficacy of single dose of oral mizoribine pulse therapy two times per week for frequently relapsing nephrotic syndrome

We assessed the efficacy of a single dose of oral mizoribine (MZB) pulse therapy two times per week for children with frequently relapsing nephrotic syndrome (FRNS). Eleven children with FRNS in remission were treated with oral MZB pulse therapy (daily dose 6 mg/kg; maximum total dose 300 mg). We compared their clinical manifestations before and after oral MZB pulse therapy and examined the changes in serum MZB concentration in each patient on the days when MZB was administered. Eight patients had no subsequent relapses (responders), and prednisolone could be discontinued. Although 2 of the other 3 patients (nonresponders) had one relapse and the remaining patient had two relapses, both the dosages of prednisolone and frequency of relapse after oral MZB pulse therapy were significantly lower than before oral MZB pulse therapy. The peak blood concentration and AUC0-4 of MZB in the responders were higher than in the nonresponders. None of patients had severe adverse effects, such as uricacidemia, leukopenia, liver dysfunction or alopecia. Oral mizoribine pulse therapy consisting of a single dose two days a week may be effective and safe in some FRNS patients.     

Immunotherapy in IgA nephropathy

Summary: The purpose of this presentation was to review the recent results of immunotherapy (i.e. corticosteroids, cyclosporine A and mizoribine), in patients with IgA nephropathy. We summarized the effects of corticosteroid therapy in patients with advanced stage of IgA nephropathy in our division. These patients were divided into steroid or non-steroid (anti-platelet and/or anti-coagulation drug) therapy group. The clinical findings, 6 years after renal biopsy, were observed in this study. Mean levels of urinary protein excretion in the steroid therapy group (11 patients; 3.42 g/day) were higher than those in the non-steroid therapy group (nine patients; 1.64 g/day) at the time of renal biopsy. The mean levels of creatinine clearance (CCr) in the steroid or non-steroid therapy group were 61.2 and 78.6 mL/min, respectively. Efficacy of steroid or non-steroid therapy was similar in patients with the advanced stage of IgA nephropathy, and it appeared that the steroid therapy was not effective for patients in the advanced stage of this disease. Cyclosporine A is a fungal peptide with immunoregulatory properties inhibiting activation of both T and B cells. Recently, a new immunosuppressive agent, mizoribine has been developed in Japan. Mizoribine has a suppressive effect on antibody formation via the direct inhibition of B cell function. Koshikawa et al. reported the effect of this drug in 158 patients with steroid-resistant nephrotic syndrome in multi-center studies in Japan. Mizoribine was administered orally at 150 mg/day for 24 weeks. Efficacy of treatment with mizoribine was marked compared with that with placebo in patients with IgA nephropathy and membranous nephropathy. At present, the authors are determining the clinicopathological effects of mizoribine in ddY mice, a spontaneous animal model of IgA nephropathy.     

Effect of oral mizoribine pulse therapy for frequently relapsing steroid-dependent nephrotic syndrome

AIM: To evaluate the efficacy of oral mizoribine (MZB) pulse therapy given twice a week for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS). SUBJECTS: 16 patients with FR-SDNS with a median age of 11.6 years (range 5.1 a 17.8 years) were enrolled in the study. This study was a Phase II trial. METHODS: The dose of MZB was adjusted to achieve a peak blood level of about 3 microg/ml (10.0-19.7 mg/kg/d, maximum total dose 750 mg) in two divided doses given 2 days a week before a meal. The therapeutic benefits of MZB pulse therapy were assessed based on a comparison of the incidence of relapse (times/year) and the required daily dosage of prednisolone (PSL) before and after therapy. RESULTS: The incidence of relapse after therapy was significantly lower than that before therapy (2.4 A+/- 1.6 vs. 3.4 A+/- 1.1 times/year, p < 0.05), and the required daily dosage of PSL after therapy was lower than that before therapy (0.39 A+/- 0.26 vs. 0.47 A+/- 0.24 mg/kg/d; not significant). During the follow-up period, discontinuation of PSL was possible in 6 of 12 patients who showed a decreased rate of relapse after therapy. The age at entry into the study and the peak blood concentration of MZB of these patients were significantly higher than in four patients who did not show a decreased rate of relapse (12.3 A+/- 4.3 vs. 7.9 A+/- 2.6 years, p < 0.05; 3.00 A+/- 0.93 vs. 1.97 A+/- 0.36 microg/ml, p < 0.005, respectively). No adverse effects were observed in any patients. CONCLUSION: Our results show that MZB pulse therapy is effective in decreasing the frequency of relapse and reducing the required PSL dosage in older pediatric patients with FR-SDNS.     

Efficacy of prednisolone and mizoribine therapy for diffuse IgA nephropathy

OBJECTIVE: There have been only a few studies concerning oral prednisolone and mizoribine therapy for diffuse IgA nephritis (IgAN). We evaluated the efficacy of prednisolone and mizoribine therapy for diffuse IgAN. METHODS: We enrolled 34 patients who had been diagnosed as having diffuse IgAN with severe proteinuria during the period from 1992 to 1999. Following diagnostic renal biopsy, the patients were treated with prednisolone, mizoribine, warfarin and dilazep dihydrochloride. The clinical features, laboratory data and pathological findings between pre- and post-therapy were investigated. RESULTS: The mean urinary protein excretion after 6 months of treatment had decreased significantly compared to pre-therapy. The incidence of hematuria in post-therapy was lower than that of pre-therapy. The grading index decreased significantly from 4.8 +/- 2.1 at the first biopsy to 2.3 +/- 1.7 at the second biopsy (p < 0.001) and the staging index decreased significantly from 4.1 +/- 1.9 at the first biopsy to 2.7 +/- 2.4 at the second biopsy (p < 0.05). Macrophage infiltration and alpha-smooth muscle actin-positive cells in the glomerulus and interstitial region decreased significantly in post-therapy compared with pre-therapy. At the most recent follow-up, none of the 34 patients had renal insufficiency. CONCLUSIONS: Our study suggested that prednisolone and mizoribine therapy is effective for those patients with the risk of progression of IgAN.     

A case of acute renal failure with marked hyperuricemia developing during mizoribine administration

A 50-year-old man diagnosed as having AGA(Churg-Strauss syndrome) was administered steroid. After treatment with mizoribine, hyperuricemia and acute renal failure occurred as side effects of this drug. Accordingly we started dialysis treatment, terminated mizoribine treatment, and administered allopurinol dosage. Hemodialysis was necessary every day for 11 days and his renal function recovered after one month. In 67Ga scintigraphy, accumulation of 67Ga was seen in the kidney.     

Oral mizoribine pulse therapy for patients with steroid-resistant and frequently relapsing steroid-dependent nephrotic syndrome.

BACKGROUND: We investigated the efficacy of oral mizoribine pulse therapy (mizoribine-pulse) for cyclosporin (CyA)-dependent, steroid-resistant nephrotic syndrome (SRNS) and frequently relapsing, steroid-dependent nephrotic syndrome (FR-SDNS). METHODS: One child with CyA-dependent SRNS and eight children with CyA-dependent FR-SDNS were treated with mizoribine-pulse (daily dose: 10 mg/kg; maximum total dose 500 mg). We compared clinical manifestations before and after mizoribine-pulse, and studied the changes in serum mizoribine concentration in each patient on days when mizoribine was administered. RESULTS: Four patients had no subsequent relapses (responders). Two of the four responders discontinued prednisolone and CyA, the other two discontinued CyA. Although each of the five other patients (non-responders) experienced single subsequent relapses, the dosages of prednisolone and CyA after mizoribine-pulse were decreased significantly compared with before mizoribine-pulse. The peak blood concentration of mizoribine in the responders was higher than in the non-responders (3.6+/-0.9 vs 1.8+/-0.4 microg/ml). CONCLUSIONS: Mizoribine-pulse may be effective for some patients with CyA-dependent SRNS and FR-SDNS.     

Conversion from mycophenolate mofetil to mizoribine for patients with positive polyomavirus type BK in urine

It is known that administration of mycophenolate mofetile (MMF) is associated with BK virus (BKV) nephropathy in renal transplant recipients. To determine any inhibitory effect of mizoribine for BKV, seven patients with positive BKV in their urine who took MMF as immunosuppressive therapy were evaluated after MMF was changed to mizoribine. Baseline BKV DNA in urine, which ranged from 2.2 x 10(2) to 5.5 x 10(6) copies per milliliter, decreased in all cases (mean = 1.9 x 10(-1) times; median 2.8 x 10(-3) times). Four cases turned negative within 6 months and one within 12 months. No acute rejection or deterioration of graft function occurred during the administration of mizoribine. An inhibitory effect of mizoribine on BKV was suggested.     

Amelioration of steroids and cyclosporine-resistant nephrotic syndrome by pravastatin

We report the case of a girl with steroids and cyclosporine (CsA) resistant focal segmental glomerulosclerosis (FSGS) whose proteinuria and hypoproteinaemia were dramatically resolved by pravastatin. She had been in a nephrotic condition for 6 years. Prednisolone, pulse methylprednisolone therapy, low-density lipoprotein (LDL) apheresis, CsA, cyclophosphamide and mizoribine (MZR) had proved to be ineffective. She was started on pravastatin for her hyperlipidaemia 6 and a half years from onset, in addition to the baseline therapy, which included CsA; remission of the nephrotic syndrome was unexpectedly attained after 10 months of treatment. The baseline therapy has not been changed since the inclusion of pravastatin. This case suggests that, in patients with hyperlipidaemia, the response to CsA could be restored by lowering cholesterol levels with statins. The decrease of cholesterol levels might have improved the pharmacokinetics of CsA in this patient. Furthermore, the anti-inflammatory and immuno-modulatory effects, recently attributed to statins, may also have been involved in the improvement experienced by our patient. There were no conflicts of interest in the writing of this article.     

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

Cyclosporin A (CsA) is an effective treatment for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS), but its use can be complicated by renal toxicity and a high incidence of relapses after withdrawal. We report 9 adolescent patients with childhood-onset FR-SDNS who had been treated with long-term CsA that resulted in moderate-to-severe CsA nephropathy (CsAN). They were treated with high-dose (mean: 10.1 mg/kg per day) mizoribine (MZR) in an attempt to allow weaning of CsA and/or steroid therapy, and reduce the frequency of relapses. Seven out of 9 patients were weaned off CsA by 1-year follow-up, although in the remaining 2 patients, MZR did not show any beneficial effects. Overall, this high-dose MZR therapy results in significant steroid sparing and reduction in relapse rates in our patients. Our experience shows that high-dose MZR therapy in patients with FR-SDNS who are also CsA-dependent appears to be effective in reducing CsA exposure as well as in decreasing the frequency of relapses.     

The first year results of mizoribine/tacrolimus-based multitarget treatment for consecutive patients with lupus nephritis

Background

Despite the high efficacy of mycophenolate mofetil (MMF)/tacrolimus-based multitarget treatment, risks of infections are a matter of concern. In the present study, we clarified the potential of multitarget therapy using mizoribine opposed to MMF.

Methods

A total of 36 patients with biopsy-proven lupus nephritis were treated with mizoribine, tacrolimus, and glucocorticoids and then retrospectively evaluated. To determine the efficacy, proteinuria remission (≤?0.2 g/day), complete remission (Liu et al. in Ann Intern Med 162:18–26, 2015) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) remission rates, and the prednisolone dose at months 6 and 12 were evaluated. The associations between serum mizoribine/tacrolimus levels and clinical parameters were investigated. To assess safety, adverse events were inspected.

Results

All patients could continue the original treatment regimen without withdrawal or exacerbations through month 12. At month 6, the proteinuria remission, complete remission, SLEDAI remission rates, and prednisolone dose were 69, 53, 36%, and 12.1 mg/day, respectively, whereas the values at 12 months were 92, 67, 50%, and 8.8 mg/day, respectively. The treatment was efficacious for every histologic type of nephritis and non-renal manifestations of SLE. Excluding one patient who was hospitalized due to upper respiratory tract infection, serious infections, including pneumonia and cytomegalovirus disease, were not observed. Higher trough tacrolimus levels were associated with normalization of complement, whereas higher peak mizoribine levels with prevention of cytomegalovirus viremia.

Conclusions

Our results suggest that multitarget therapy using mizoribine opposed to MMF is highly safe and effective through 12 months. The therapy may enable faster dose reduction of concomitant glucocorticoids.

     

Population Pharmacokinetic Analysis of Mizoribine in Chinese Renal Transplant Recipients

Background

We calculated the population pharmacokinetics of mizoribine in adult Chinese patients and compared the parameters with those of Japanese patients to determine whether there are any ethnic differences in blood concentration transition between these 2 populations.

Oral mizoribine pulse therapy for steroid-dependent focal segmental glomerulosclerosis

A 24-year-old woman with focal segmental glomerulosclerosis was referred to our hospital for treatment of nephrotic syndrome. Though she experienced partial remission following treatment with prednisone and cyclosporine, she had a relapse of nephrotic syndrome when her prednisone was tapered off to 30 mg/day. The prednisone could not be tapered to less than 30 mg/day due to repeated relapses. After introduction of oral mizoribine (MZR) pulse therapy, the patient's prednisone was tapered to 15 mg/day and she had no signs of relapse for more than 1 year. This case suggests that oral MZR pulse therapy is a good therapeutic option for patients with steroid-dependent nephrotic syndrome.     

Whole-body artificial controlled hyperthermia and hyperglycemia in the combined treatment of metastatic kidney cancer

The attempt of treatment for metastatic renal cancer has not been a success as all the methods known failed to produce any significant effect on the development of metastases. So the search for the means which could potentiate the antitumor activity of the drugs or radiation therapy is still a problem. Various physicochemical methods, including hyperthermia and hyperglycemia, have been used as modifiers of tumor cell responses. When properly employed, hyperthermia and hyperglycemia can produce an antitumor effect. However, their ability to selectively potentiate radiation or chemotherapy is more valuable. A total of 25 patients with renal cell carcinoma and multiple metastases have undergone a comprehensive treatment: radiation therapy for metastases at the total dosage of 60 Gr after removal of the primary tumor. The session of hyperthermia and hyperglycemia was performed in the course of the radiation therapy. During the session chemotherapeutic agents were administered in a half-course dosage. The second part of the radiation therapy was continued after the session. The treatment course included 5 sessions and lasted 12 months. An immediate stabilization of the health status was recorded in all the patients. Some of them had the total or partial regression of metastases. Yet since the follow-up time was not long the authors could make no conclusions.     

A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome

BACKGROUND: The use of corticosteroids or cytotoxic/immunosuppressive agents such as cyclophosphamide, chlorambucil, and cyclosporine for the treatment of frequently relapsing nephrotic syndrome (FRNS) is limited because of their adverse effects. This study was conducted to evaluate the efficacy and safety of mizoribine, a relatively new immunosuppressive drug developed in Japan, in children with FRNS. METHODS: A double-blind, placebo-controlled, multicenter trial was carried out in children, from 2 to 19 years old, with FRNS. At relapse, patients were treated with prednisolone. According to a dynamic allocation, mizoribine or a placebo was concurrently administered to each patient. Prednisolone was gradually tapered and discontinued within 12 weeks. The test drug was maintained for 48 weeks. The primary end point was the relapse rate (the total number of relapses/the total treatment days for all patients). Analyses were performed according to the intention-to-treat principle. RESULTS: The primary analysis was conducted on 99 mizoribine- and 98 placebo-treated patients. The relapse rate was lower in the mizoribine group than in the placebo group (0.0055 vs. 0.0067; ratio 0.81, 95% CI, 0.61 to 1.05, P = 0.12). The hazard ratio of the cumulative remission rate between the two groups was 0.79 (95% CI, 0. 57 to 1.08). In the subgroups consisting of patients 10 years old or younger, the relapse rate ratio between the mizoribine subgroup (54 patients) and the placebo subgroup (57 patients) was 0.66 (95% CI, 0. 44 to 0.94, P = 0.017). The hazard ratio of the cumulative remission rate between the two subgroups was 0.56 (95% CI, 0.37 to 0.85, P = 0. 007). Hyperuricemia was the most common adverse event with mizoribine (16%), but was transient. CONCLUSIONS: Compared with the placebo, mizoribine significantly decreased the relapse rate and prolonged the remission period in the subgroup consisting of patients 10 years old or younger. This drug may be useful in young children with FRNS who generally relapse more frequently than older children.     

Mizoribine, tacrolimus, and corticosteroid combination therapy successfully induces remission in patients with lupus nephritis

Background

Conventional cyclophosphamide-based treatment regimens for lupus nephritis (LN) are still not considered to be optimal. The aim of this study was to evaluate the efficacy and safety of mizoribine, tacrolimus, and corticosteroid combination therapy for LN.

Methods

We retrospectively evaluated a combination treatment of mizoribine and tacrolimus with corticosteroids as induction therapy in eight newly diagnosed systemic lupus erythematosus (SLE) patients with biopsy-proven LN.

Results

All patients were women, and their mean [standard deviation (SD)] age was 48.5 (20) years. All patients (100?%) had positive anti-double-stranded DNA (anti-dsDNA) antibody titers, and four (50.0?%) were nephrotic. Mean (SD) serum creatinine and daily proteinuria levels were 0.72 (0.4) mg/dl (range 0.33–1.55?mg/dl) and 4.56 (2.8) g (range 0.77–8.2?g), respectively. By month 2, significant improvements in the anti-dsDNA antibody titers, levels of proteinuria, serum albumin, and C3, and SLE disease activity index score were observed. By month 6, seven patients (87.5?%) were in complete remission, with normalized levels of both proteinuria and serum creatinine.

Conclusions

This pilot study suggests that mizoribine and tacrolimus treatment with corticosteroids is well tolerated and may prove to be an optimal alternative remission-inducing regimen for LN.     

Experiences of high-dose mizoribine as antimetabolite immunosuppressants for kidney transplantation

We have used low doses of mizoribine (MZ) or mycophenolate mofetil (MMF) as induction and maintenance immunosuppressants, but since 2009 have employed a high dose of MZ. We reviewed the efficacy and side effects of MZ compared with MMF. It is difficult to compare graft survivals between these periods because of different patient demographics, though the high dose of MZ cohort showed no significant difference from MMF. High doses of MZ serum to prevent acute rejection episodes as the induction and maintenance therapy. MZ controlled with blood concentrations showed less side effects, suggesting that high MZ doses could be safely used for an induction and maintenance antimetabolite.     

Effect of conversion from cyclosporine A to mizoribine on transplant arteriosclerosis in rat aortic allograft models

Recent studies suggested that conversion from cyclosporine A (CsA) to antimetabolic agents protects allograft vasculopathy. However, the mechanism of this beneficial effect by the conversion therapy is not fully understood. In the present study, we investigated the effects of conversion from CsA to antimetabolic agent mizoribine (MZR) on the formation of transplant arteriosclerosis in rat aortic allografts. Conversion from CsA to MZR significantly prevented intimal hyperplasia and perivascular inflammatory cell infiltration at 28 days after aortic transplantation. These findings suggest that conversion therapy from CsA to antimetabolic agents might have therapeutic potential in transplant patients with chronic vascular rejection.     

Effective treatment of a refractory case of systemic lupus erythematosus with low-dose tacrolimus

It has been reported that aggressive immunosuppressive treatment is effective for controlling the disease activity of refractory systemic lupus erythematosus (SLE). However, little information on a regimen including tacrolimus (TL) for the treatment of refractory SLE has been available. We report a successful low dose TL treatment of a 25-year-old male patient with refractory SLE. He developed SLE with proliferative lupus nephritis(WHO class IVb) at the age of 11 years. During the past 4 years, despite aggressive immunosuppressive treatment consisting of methylprednisolone pulse therapy, mizoribine pulse therapy, cyclosporine A and intravenous cyclophosphamide pulse therapy, frequent flares associated with presumptive hypercytokinemia i.e., increased levels in the serum C-reactive protein, ferritin and soluble IL-2 receptor, occurred. Hence, administration of low-dose TL at 3 mg per day, was initiated. The blood levels of TL at approximately 12 hours post-dosing were maintained at between 3 and 5 ng/mL. Within 3 weeks following TL administration, the serum levels of C3, C4 and CH50 began to increase rapidly, and the prednisolone dose could be successfully tapered. No adverse effects of TL were observed. We suggest that TL may be the treatment of choice for selected patients with refractory SLE.