Treatment Of Steroid-dependent Nephrotic Syndrome Research Articles

What is The Best Choice in Steroid-Dependent Nephrotic Syndrome: Mycophenolate Mofetil Plus Dexamethasone or Cyclosporine A.

The use of mycophenolatemofetil (MMF) in the treatment of steroid-dependent nephrotic syndrome (SDNS) is beneficial in decreasing the relapse rate and/or steroid dose. The effectiveness and long-term results of MMF/dexamethasone (DEX) in the treatment of SDNS are not well known. In this study, we aimed to determine the efficiency, safety, and long-term results of MMF/DEX in patients with SDNS in comparison with cyclosporine A (CsA) in a retrospective single-center trial. Between January 2009 and December 2015, 54 SDNS patients were treated with either MMF/DEX (n = 29) or CsA (n = 25). Relapse rates, relapse-free time, cumulative exposure to corticosteroids, proteinuria, and estimated glomerular filtration rate (eGFR) were retrospectively evaluated at 0, 3, 6, 12, 24, and 36 months after the initiation of treatment. The mean cumulative exposure to corticosteroids for the MMF/DEX and CsA groups was 72.40 ± 71.85 mg/kg/year and 122.31 ± 74.35 mg/kg/year, respectively. There was a significant decrease in the cumulative exposure to corticosteroids in the MMF/DEX group (Z = 3.869; P <0.001). While the mean annual relapse for the MMF/DEX group was 1.07 ± 0.25, it was 1.70 ± 1.01 in the CsA group, and this difference was statistically significant (Z = 1.968; P = 0.049). Relapse-free time for the 1st, 2nd, and 3rd years compared between the MMF/DEX and CsA groups was 9.57 ± 2.58 versus 6.38 ± 2.43, 10.27 ± 1.98 versus 8.28 ± 2.28, and 9.67 ± 2.06 versus 6.52 ± 3.04, respectively. The difference was significantly higher in favor of MMF/DEX (between-subject effects F = 48.352; P<0.001). Both eGFR and proteinuria significantly changed over time. However, there was no significant difference between the groups until the later time points of the follow-up. The difference became evident only at the 2nd-and 3rd-year measurements. MMF/DEX seems superior to CsA in preventing relapses and reducing cumulative exposure to cortico-steroids. Thus, it may be considered a treatment option in children with SDNS.

Efficacy and safety of intravenous immunoglobulin with rituximab versus rituximab alone in childhood-onset steroid-dependent and frequently relapsing nephrotic syndrome: protocol for a multicentre randomised controlled trial

IntroductionGuidelines for the treatment of steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS) are lacking. Given the substantial impact of SDNS/FRNS on quality of life, strategies aiming to...

Rituximab for very low dose steroid-dependent nephrotic syndrome in children: a randomized controlled study.

Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, randomized controlled trial was designed to test whether the monoclonal antibody rituximab is non-inferior to steroids in maintaining remission in juvenile forms of SDNS and how long remission may last (EudraCT:2008-004486-26). We enrolled 30 children 4-15years who had developed SDNS 6-12months before and were maintained in remission with low prednisone doses (0.1-0.4mg/Kg/day). Participants were randomized following a non-inferiority design to continue prednisone alone (n 15, controls) or to add a single intravenous infusion of rituximab (375mg/m2, n 15 intervention). Prednisone was tapered in both arms after 1month. Children assigned to the control arm were allowed to receive rituximab to treat disease relapse. Proteinuria increased at 3months in the prednisone group (from 0.14 to 1.5g/day) (p < 0.001) and remained unchanged in the rituximab group (0.14g/day). Fourteen children in the control arm relapsed within 6months. Thirteen children assigned to rituximab (87%) were still in remission at 1year and 8 (53%) at 4years. Responses were similar in children of the control group who received rituximab to treat disease relapse. We did not record significant adverse events. Rituximab was non-inferior to steroids for the treatment of juvenile SDNS. One in two children remains in remission at 4years following a single infusion of rituximab, without significant adverse events. Further studies are needed to clarify the superiority of rituximab over low-dose corticosteroid as a treatment of SDNS.

Mycophenolic Acid Pharmacokinetics and Relapse in Children with Steroid-Dependent Idiopathic Nephrotic Syndrome.

Therapeutic drug monitoring of mycophenolic acid can improve clinical outcome in organ transplantation and lupus, but data are scarce in idiopathic nephrotic syndrome. The aim of our study was to investigate whether mycophenolic acid pharmacokinetics are associated with disease control in children receiving mycophenolate mofetil for the treatment of steroid-dependent nephrotic syndrome. This was a retrospective multicenter study including 95 children with steroid-dependent nephrotic syndrome treated with mycophenolate mofetil with or without steroids. Area under the concentration-time curve of mycophenolic acid was determined in all children on the basis of sampling times at 20, 60, and 180 minutes postdose, using Bayesian estimation. The association between a threshold value of the area under the concentration-time curve of mycophenolic acid and the relapse rate was assessed using a negative binomial model. In total, 140 areas under the concentration-time curve of mycophenolic acid were analyzed. The findings indicate individual dose adaptation in 53 patients (38%) to achieve an area under the concentration-time curve target of 30-60 mg·h/L. In a multivariable negative binomial model including sex, age at disease onset, time to start of mycophenolate mofetil, previous immunomodulatory treatment, and concomitant prednisone dose, a level of area under the concentration-time curve of mycophenolic acid >45 mg·h/L was significantly associated with a lower relapse rate (rate ratio, 0.65; 95% confidence interval, 0.46 to 0.89; P=0.01). Therapeutic drug monitoring leading to individualized dosing may improve the efficacy of mycophenolate mofetil in steroid-dependent nephrotic syndrome. Additional prospective studies are warranted to determine the optimal target for area under the concentration-time curve of mycophenolic acid in this population.

DI-099 Effectiveness and safety study in children with steroid-dependent nephrotic syndrome treated with levamisole

BackgroundLevamisole has been shown to have a steroid-sparing effect in children with steroid-sensitive nephrotic syndrome, but also could produce adverse drug reactions such as reversible neutropenia.PurposeTo determine the effectiveness and...

Population pharmacokinetics and Bayesian estimator of mycophenolic acid in children with idiopathic nephrotic syndrome

To develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration-time curve over 12 h (AUC(0-12)). The pharmacokinetic model of MMF was described from 23 patients aged 7.4 +/- 3.9 years (range 2.9-14.9) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag-time and first-order absorption and elimination was developed. The final model was validated using visual predictive check. Bayesian estimator was validated using circular permutation method. The population pharmacokinetic parameters were apparent oral clearance 9.7 l h(-1), apparent central volume of distribution 22.3 l, apparent peripheral volume of distribution 250 l, inter-compartment clearance 18.8 l h(-1), absorption rate constant 5.16 h(-1), lag time 0.215 h. The covariate analysis identified body weight and serum albumin as individual factors influencing the apparent oral clearance. Accurate Bayesian estimation of AUC(0-12) was obtained using the combination of three MPA concentrations measured just before (T(0)), 1 and 4 h (T(1) and T(4)) after drug intake with a small error of 0.298 microg h(-1) ml(-1) between estimated and reference AUC(0-12). The population pharmacokinetic model of MPA was developed in children with INS. A three-point (T(0), T(1) and T(4)h) Bayesian estimator of AUC(0-12) was developed and might be used to investigate the relation between MPA pharmacokinetic and pharmacodynamics in children with INS and determine if there is any indication to monitor MPA exposure in order to improve patient outcome based on individual AUC-controlled MMF dosing.

Progress in immunosuppressive agents in the treatment of steroid-dependent nephrotic syndrome in children

激素依赖型肾病综合征(steroid_dependent nephrotic syndrome,SDNS)在儿童原发性肾病中所占比例较高,但目前尚无公认统一的治疗方案.近几年发现越来越多的免疫抑制剂对治疗SDNS有效,如利妥昔单抗、吗替麦考酚酯等,这些药物虽给SDNS的治疗带来了曙光,但若使用不当,将产生严重的不良反应.因此了解该病的临床治疗进展,选择合理的联合治疗方案对SDNS的治疗及预后至关重要。

Is tacrolimus for childhood steroid-dependent nephrotic syndrome better than ciclosporin A?

The dosage and 3 months duration of glucocorticoidtreatment in steroid-sensitive childhood idiopathicnephrotic syndrome, mainly associated with thehistological picture of minimal change glomerulopa-thy, is based on the evidence of randomized clinicaltrials with clear-cut end points [1–3]. Duration of up to7 months of the therapy may even be more effective inachieving sustained remission. A further well-designedand adequately powered randomized controlled trial is,however, required. To avoid steroid toxicity, there isconvincing evidence for the use of oral cyclopho-sphamide in patients with frequent relapses [4]. Theevidence, however, is less stable for the treatment ofsteroid-dependent nephrotic syndrome (SDNS), i.e.recurrence of nephrotic syndrome within 2 weeks ofcessation of steroid treatment [5,6]. One of the majorconcerns with regard to the use of alkylating agentssuch as cyclophosphamide or chlorambucil in childrenand adolescents is gonadotoxicity [7]. Therefore,ciclosporin A (CSA) has been advocated when toxiceffects of prednisone and cyclophosphamide areexpected. CSA results in a remission rate of 85% inchildren with SDNS, bearing, however, the risk ofcalcineurin inhibitor-induced nephrotoxicity [8].Thus, alternative immunosuppressive drugs such asmycophenolate mofetil [9,10], rituximab [11] andsirolimus [12] are currently under investigation.Levamisol has been found to be of benefit in SDNSand has limited toxicity [13]. Data on the use of thecalcineurin inhibitor tacrolimus (TAC) are scarce.

Impact of the cyclosporine-ketoconazole interaction in children with steroid-dependent idiopathic nephrotic syndrome

Children with steroid-dependent nephrotic syndrome experience serious side effects from steroid therapy. Cyclosporine A (CsA), which is an effective agent in the treatment of steroid-dependent nephrotic syndrome, is expensive and, consequently, often unaffordable in developing countries. Many studies have documented the benefit of ketoconazole administration in transplant adults treated with CsA. We have conducted a retrospective study with the objective of addressing cost-savings, safety, and the efficacy of the co-administration of ketoconazole and CsA to children with steroid-dependent nephrotic syndrome. This study included 102 nephrotic patients who were steroid-dependent and who received cyclosporine therapy. The commonest pathologic lesions were focal segmental glomerulosclerosis (64 patients) and minimal change disease (36 patients). Among the patients participating in the study, 78 received daily ketoconazole therapy (ketoconazole group) in the form of a 50-mg dose accompanied by an initial one-third decrease in the CsA dose, while 24 received CsA alone (non- ketoconazole group). All of the patients were children (below 18 years), and the male-to-female ratio was 3:1. The mean duration of treatment was 22.9 months. The characteristics of both groups were comparable. Co-administration of ketoconazole significantly reduced mean doses of CsA by 48% with a net cost savings of 38%. It also resulted in a significant improvement in the CsA response and a more successful steroid withdrawal as well as a decrease in the frequency of renal impairment. Liver function tests remained normal in both groups up to and including the final follow-up (mean of 33.6 months). The co-administration of ketoconazole to CsA in children with idiopathic steroid-dependent nephrotic syndrome safely results in a significant reduction in CsA cost, which causes great concern in developing countries. It may also improve CsA response.

Management of the Difficult Nephrotic Patient

Most children with nephrotic syndrome do well, usually with multiple relapses and remissions. Some children require high doses of oral steroids to sustain a remission and develop significant steroid toxicity. These patients frequently can be managed with oral alkylating agents or with cyclosporine. A few nephrotic children to not respond to oral prednisone. The most common biopsy finding in steroid-resistant patients is focal segmental glomerulosclerosis. Many patients with this condition progress to chronic renal failure. Evidence suggests that the outcome is improved with either cyclosporine or with a protocol using pulse intravenous methylprednisolone and oral alkylating agents.