Mycophenolate mofetil in steroid/cyclosporine-dependent/resistant nephrotic syndrome

Attempts to minimize the effects of prolonged steroid use in steroid-dependent nephrotic syndrome (SDNS) and the need to overcome steroid resistance (SRNS) justifies immunosuppressant therapy. We report our experience in a cohort of patients with SD/SRNS during the administration of mycophenolate mofetil (MMF) in a prospective protocol initiated in January 2001. Twenty-six children with idiopathic nephrotic syndrome were included (21 steroid dependent and 5 steroid resistant), whose response did not change after sequential treatment with cyclophosphamide (CPM) and cyclosporine (CsA). Histopathologic patterns were: 11 minimal change disease (MCD), 1 diffuse mesangial proliferation (DMP), 13 focal segmental glomerulosclerosis (FSGS) and membranous 1 glomerulonephritis (MGN). The median age of onset of NS was 2.8 years (range 1.2–12.5), and treatment with MMF was performed at a median age of 11.4 years (range 5–17) with an initial dose of 600 mg/m²/12 h, adjusted to maintain levels of mycophenolic acid (MPA) at 2.5–5 mcg/ml. The planned duration of study to assess treatment efficacy was 6 months. The mean MMF dose required was 624 (SD=136) mg/m²/12 h (range 415–970), which maintained mean C₀-MPA levels of 2.9 (SD=1.17) mcg/ml (range 1.2–5.9 mcg/ml). In the five patients with SRNS, only one achieved complete remission. In the patients with SDNS, steroid sparing was achieved in 15 and 9 remained in remission on MMF monotherapy. Withdrawal of MMF resulted in immediate relapse in 47%. In our study, MMF was a useful immunosuppressant due to its fewer undesirable effects and similar efficacy to other drugs used. It appears effective for the maintenance of remission in SDNS patients, with a response similar to that of CsA.     

Mycophenolate mofetil in children with multidrug-resistant nephrotic syndrome

AIM: The aim of the present study is to report our clinical experiences with MMF in problematic children with chronic glomerulonephritis resistant to corticosteroids and/or other immunosuppressive drugs. PATIENTS AND METHODS: Ten patients with chronic glomerulonephritis resistant to treatment with corticosteroids and other immunosuppressive drugs were treated with mycophenolate mofetil (MMF). Causes of chronic glomerulonephritis were mesangial proliferative glomerulonephritis (4), membranoproliferative glomerulonephritis (3), chronic sclerosing glomerulonephritis (1), focal segmental glomerulosclerosis (1), diffuse endo- and extracapillary proliferative glomerulonephritis (1). MMF 15 mg/kg was used in combination with low-dose corticosteroids and angiotensin-converting enzyme inhibitors. RESULTS: During 24 weeks of MMF therapy, no significant changes were detected in mean serum creatinine, albumin and proteinuria. Severe leukopenia was seen in 1 patient. Additional adverse effects, including nausea and diarrhea, were observed in another patient when the dosage was increased to 20 mg/kg per day. During MMF treatment proteinuria decreased slightly without remission in 6 of 10 patients. CONCLUSION: Further data and clinical trials are needed to evaluate the possible role of MMF in the treatment of chronic glomerulonephritis of similar etiologies in pediatric patients.     

Mycophenolate mofetil therapy for children with steroid-resistant nephrotic syndrome

Treating children with steroid-resistant nephrotic syndrome (SRNS) has been a clinical challenge for pediatricians. We recruited 24 children (18 boys and six girls) with steroid-resistant idiopathic nephrotic syndrome (SRINS) who were <2 years. All patients were administered prednisone 2 mg/kg per day prior to mycophenolate mofetil (MMF). By the end of the eighth week, MMF was initiated at 25–30 mg/kg daily for 6??12 months. Prednisone dose was reduced stepwise. Biochemical assays were performed every 2 months. Complete remission was achieved in 15 patients, partial remission in six, and no response to MMF was noted in three. With MMF treatment, the levels of urinary protein and serum cholesterol decreased and that of serum albumin increased in a time-dependant manner. We demonstrated the MMF could reduce proteinuria in SRINS children <2 years. Our study suggests that MMF therapy might be an effective strategy for treating SRINS in children <2 years.     

Mycophenolate mofetil in steroid-dependent idiopathic nephrotic syndrome

Background

Prospective studies have established the mycophenolate mofetil (MMF) efficiency in childhood idiopathic nephrotic syndrome (INS) but reports on the long-term outcome are lacking. Moreover, the search for factors influencing its efficiency would be useful to define its place among the other treatments.

Methods

We performed a monocentric retrospective study including 96 children with steroid-dependent INS followed for 4.7 years (median) (IQ 3–6) after the onset of MMF treatment. The characteristics of responder patients (n?=?74), as defined by a 50 % decrease of relapse rate and/or a 60 % decrease of steroid dose, and of non-responder patients (n?=?22) were compared by univariate analysis and multivariate logistic regression.

Results

Withdrawal of prednisone was achieved in 48/96 patients after a median duration of 18.1 months (IQ 7.8–30.0) of MMF. Only 26/48 patients did not relapse under MMF alone. After MMF was stopped in these patients, only six remained in remission without any treatment at last follow-up. Responders had a shorter time to remission at the first flare (9.5 vs. 15 days, p?=?0.02), a shorter disease duration prior to the onset of MMF (22.2 vs. 94.5 months, p?=?0.001), and were younger at the MMF initiation (6.7 vs. 10.1 years, p?=?0.02) than non-responder patients. The age of MMF initiation was an independent factor associated with efficiency (OR?=?0.80, 95 % CI [0.69, 0.93], p?<?0.01).

Conclusions

MMF is more efficient in young patients treated early in the disease course. Nevertheless, MMF has no remnant effect while nearly all patients relapsed after withdrawal of the drug.

     

Mycophenolate mofetil versus cyclosporine for remission maintenance in nephrotic syndrome

We performed a multi-centre randomized controlled trial to compare the efficacy of mycophenolate mofetil (MMF) to that of cyclosporine A (CsA) in treating children with frequently relapsing nephrotic syndrome and biopsy-proven minimal change disease. Of the 31 randomized initially selected patients, seven were excluded. The remaining 24 children received either MMF 1200 mg/m² per day (n = 12) or CsA 4–5 mg/kg per day (n = 12) during a 12-month period. Of the 12 patients in the MMF group, two discontinued the study medication. Evaluation of the changes from the baseline glomerular filtration rate showed an overall significant difference in favour of MMF over the treatment period (p = 0.03). Seven of the 12 patients in the MMF group and 11 of the 12 patients in the CsA group remained in complete remission during the entire study period. Relapse rate in the MMF group was 0.83/year compared to 0.08/year in the CsA group (p = 0.08). None of the patients reported diarrhea. Pharmacokinetic profiles of mycophenolic acid were performed in seven patients. The patient with the lowest area under the curve had three relapses within 6 months. In children with frequently relapsing minimal change nephrotic syndrome, MMF has a favourable side effect profile compared to CsA; however, there is a tendency towards a higher relapse risk in patients treated with MMF.     

Mycophenolate mofetil in the treatment of resistant idiopathic nephrotic syndrome.

BACKGROUND: A small proportion of patients with initially steroid-sensitive nephrotic syndrome relapse frequently, despite treatment with cyclophosphamide and/or cyclosporin. We investigated the efficacy of mycophenolate mofetil (MMF) in this group. METHODS: Seven patients with nephrotic syndrome due to minimal change nephropathy (MCN) or classical focal segmental glomerulosclerosis (FSGS) who had suffered multiple relapses over many years despite treatment with several different agents were commenced on MMF 1 g twice daily, together with a reducing dose of corticosteroids. RESULTS: Six patients went into complete remission and the seventh into partial remission. At 1 year, five remained in complete remission. The median (range) serum albumin concentration rose from 19 g/l (16-42 g/l) pre-MMF to 42 g/l (25-45 g/l) after 12 months (P=0.023), and the median (range) dose of prednisolone fell from 40 mg/day (30-60 mg/day) to 7.5 mg/day (0-40 mg/day) at 12 months (P=0.0008). CONCLUSION: MMF appears to be of benefit in the treatment of multiply relapsing nephrotic syndrome caused by MCN or FSGS. Controlled trials are required to establish the role of MMF in these disorders.     

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial

Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming's procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200 mg/m(2)/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3 months, 25% at 6 months]. Twenty-four children (median age 6.0 years, 2.8-14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6 months (estimated probability 17.6%, 95% credibility interval: 5.4-35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6 months, median (Q1-Q3) prednisone maintenance dose decreased from 25 (10-44) to 9 (7.5-11.2) mg/m(2) e.o.d (p < 0.001) and cumulative dose from 459 (382-689) to 264 (196-306) mg/m(2)/month (p < 0.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide.     

Mycophenolate mofetil restores renal function and spares steroids during idiopathic nephrotic syndrome in children. A cohort study

Renal function evolution during idiopathic nephrotic syndrome depends on treatment toxicity. Cyclosporin is effective as a steroid-sparing agent but patients are dependant on this drug, which can lead to renal toxicity. Mycophenolate mofetil, a widely used drug in organ transplantation, has short-term beneficial effects in glomerular diseases, including idiopathic nephrotic syndrome. Little is known about mycophenolate mofetil in children and long-term evolution. We analysed a cohort of 12 children with steroid-dependant nephrotic syndrome due to minimal change disease in remission with cyclosporine therapy. They were switched to mycophenolate mofetil, when renal toxicity was diagnosed. We evaluated the number of relapses, tolerance of this new treatment, renal function and body mass index under mycophenolate. After a follow-up of 31.25 months, mycophenolate mofetil alone was effective in preventing relapses in eight patients, without side effects. Renal function significantly improved and the final body mass index decreased. Three patients relapsed on discontinuation of mycophenolate mofetil. The results suggest that mycophenolate mofetil is effective and safe in preventing relapses in steroid-dependant nephrotic syndrome. Furthermore, switching from cyclosporine to mycophenolate mofetil restores renal function. Therefore, mycophenolate mofetil might be considered as an alternative to cyclosporine, to preserve renal function and spare steroids during idiopathic nephrotic syndrome in children.     

Cyclosporine and steroid therapy in children with steroid-resistant nephrotic syndrome

We conducted a prospective, multicenter trial to evaluate the efficacy and safety of a 12-month course of cyclosporine in children with steroid-resistant nephrotic syndrome (SRNS). Thirty-five patients were enrolled, of whom 28 had minimal change or diffuse mesangial proliferation (MC/DMP), and seven had focal segmental glomerulosclerosis (FSGS). All patients received cyclosporine and prednisolone; patients with FSGS additionally received methylprednisolone pulse therapy (MPT). The dose of cyclosporine was adjusted to maintain a trough level of 120–150 ng/ml during the initial 3 months of treatment, followed by 80–100 ng/ml during months 4–12. The primary end point was the remission rate at month 12. Remission was achieved in 23 of 28 (82.1%) patients in the MC/DMP group and in six of the seven (85.7%) patients in the FSGS group. Follow-up renal biopsies were performed in 26 patients (nine at month 12, 17 at month 24), and cyclosporine-related nephrotoxicity was detected in one (3.8%). Major adverse events comprised severe bacterial infections (two patients) and posterior reversible encephalopathy syndrome (one patient). In conclusion, a high remission rate was achieved in our patient cohort using a combined cyclosporine/prednisolone treatment regimen in children with SRNS who had MC/DMP and a combined cyclosporine/prednisolone plus MPT regimen in children who had FSGS.     

儿童原发性激素依赖型肾病的临床病理分析

儿童原发性激素依赖型肾病(SDNS)是指患儿对激素治疗敏感,用药后缓解,但激素减量或停药后1个月内复发,恢复用药或再次用药仍然有效,并重复2次以上的原发性肾病.目前SDNS的发病率较高,为提高对SDNS的认识,本研究回顾性分析我院85例原发性SDNS患儿的临床与病理特点.     

Subclinical non-autoimmune hypothyroidism in children with steroid resistant nephrotic syndrome

Background

Thyroid status has not been studied well in children with steroid resistant nephrotic syndrome (SRNS).

Methods

In this cross sectional study we recruited 20 children aged 1–16 years with SRNS and similar number of controls. Serum levels of FT3, FT4 and TSH were measured in all the subjects. Overt hypothyroidism was defined as low FT4 (normal values: 0.7–2.0 ng/mL) and elevated serum TSH above reference values (0.45–4.5 mIU/L). Subclinical hypothyroidism (SH) was defined as an elevation in serum TSH with a normal serum FT4 concentration. The primary outcome measure was serum levels of FT3, FT4 and TSH in children with SRNS.

Results

Thirty per cent of the children (n = 6) with SRNS had non-autoimmune subclinical hypothyroidism (2 children each with grade I, II and III). Children with SRNS had a median TSH value [3.9 mIU/L (0.5–13)] within normal range, but levels were high as compared to controls. Out of 6 children with SH, 3 were in partial remission, 3 were in complete remission. The TSH levels normalized on thyroxine supplementation in grades II and III subclinical hypothyroidism.

Conclusion

Subclinical non-autoimmune hypothyroidism is present in a significant proportion of children with SRNS despite partial or complete remission. Thyroid profile should be evaluated routinely in this subset of patients.     

Risk factors for steroid dependency in children with idiopathic nephrotic syndrome

Minimal change disease, the most common cause of idiopathic nephrotic syndrome (INS) in children, has a high relapse rate, with approximately half of patients developing steroid dependency. This study was aimed at determining the predictive risk factors for the development of steroid dependency in children diagnosed with INS. A retrospective study of 123 children with steroid-responsive INS, followed for at least 6 months between December 1974 and December 1999, was conducted. The following parameters were studied as predictors of steroid dependency: age at onset, gender, race, microscopic hematuria at onset, atopy, concomitant upper respiratory tract infections (URTI) during relapses, and days to remission with initial steroid therapy. Of the 91 children who fulfilled the inclusion criteria, 61.5% became steroid dependent. Both univariate and logistic regression analyses revealed that initial remission time of 9 or more days (P=0.02, OR=3.0, 95% CI=1.2–7.9) and concomitant URTI during relapses (P=0.01, OR=3.4, 95% CI=1.3–8.8) were significant predictors of steroid dependency. By identifying those children with predictive factors of steroid dependency, the clinician will be better able to plan the long-term management of these patients and reduce the morbidity seen with the frequent relapses and steroid treatment, in a disease that is otherwise associated with a favorable prognosis. Received: 4 October 2000 / Revised: 27 August 2001 / Accepted: 28 August 2001     

Use of tacrolimus in steroid- and cyclophosphamide-resistant minimal change nephrotic syndrome

The authors report a case of adult-onset minimal change nephrotic syndrome (MCNS) that was resistant to steroid and cyclophosphamide therapy. Introduction of cyclosporin induced an usual cutaneous reaction of severe flushing attacks. Tacrolimus successfully alleviated both the nephrotic syndrome and the cutaneous side effect associated with cyclosporin use. The antiproteinuric mechanisms of tacrolimus and its potential in treating refractory MCNS and other forms of primary glomerulonephritides are discussed.     

Nitrogen mustard therapy in children with frequent-relapsing nephrotic syndrome and steroid toxicity

Nitrogen mustard (HN-2) is an alkylating agent known to be effective in inducing and prolonging remissions of nephrotic syndrome in children. The fact that the drug is administered intravenously eliminates the problem of compliance, and the fact that the treatment needs to be given only for a few days may lower the incidence of side-effects observed with other cytotoxic agents. We administered HN-2 to 12 children with the steroid-sensitive frequent-relapsing form of nephrotic syndrome, who had evidence of steroid toxicity. Life table analysis reveals a 46% sustained remission rate after 27 mo of follow-up. Complications of HN-2 treatment included only mild thrombophlebitis (2 patients) and mild local paresthesia (1 patient).