Prospective, controlled trial of cyclophosphamide therapy in children with nephrotic syndrome. Report of the International study of Kidney Disease in Children. Effects of tuna fish oil on hyperlipidemia and proteinuria in childhood nephrotic syndrome. A randomized double-blind placebo-controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children. Cyclosporin A is superior to cyclophosphamide in children with steroid-resistant nephrotic syndrome-a randomized controlled multicentre trial by the Arbeitsgemeinschaft für Pädiatrische Nephrologie. Intravenous pulse cyclophosphamide--a new regime for steroid-resistant minimal change nephrotic syndrome. Cyclosporine therapy for steroid-resistant nephrotic syndrome. A controlled study. Effect of fosinopril in children with steroid-resistant idiopathic nephrotic syndrome. Irreversible renal failure after indomethacin in steroid-resistant nephrosis. Controlled trial of azathioprine in children with nephrotic syndrome. A report for the international study of kidney disease in children. Enalapril dosage in steroid-resistant nephrotic syndrome. Cyclophosphamide does not benefit patients with focal segmental glomerulosclerosis. A report of the International Study of Kidney Disease in Children. Efficacy and safety of tacrolimus versus cyclosporine in children with steroid-resistant nephrotic syndrome: a randomized controlled trial. A randomized trial of cyclosporine in steroid-resistant idiopathic nephrotic syndrome. Efficacy of intravenous pulse cyclophosphamide treatment versus combination of intravenous dexamethasone and oral cyclophosphamide treatment in steroid-resistant nephrotic syndrome.
nan This is a randomized, double-blind, placebo-controlled, cross-over study to determine whether tuna fish oil decreased hyperlipidemia and proteinuria in children with steroid-resistant nephrotic syndrome. Five boys were supplemented with both 4 grams of tuna fish oil and placebo in a randomized order for 8 weeks of each treatment separated by 6-week washout period. The results showed no statistically significant difference in serum creatinine, triglyceride, cholesterol, urine protein and creatinine clearance between fish oil supplemented group and placebo group. Small sample size, low dosage, short duration of supplementation and wash-out period are among the important limitations in this study. Further study should be performed to identify the effects of fish oil on this entity in nephrotic syndrome. There is no generally accepted treatment for primary focal segmental glomerulosclerosis (FSGS). Steroids alone and steroids plus cyclophosphamide can be expected to induce a remission of the proteinuria in only 27% of patients. Probably the majority of FSGS patients will reach ESRD over the extended course of their disease. In addition to the work presented in this study, there have been many reports of the potential effectiveness of cyclosporine (CSA) on reducing the proteinuria of FSGS. This study was undertaken to test the efficacy and safety of a 6-month course of CSA in a double-blinded, prospectively randomized, placebo-controlled trial in children with corticosteroid-resistant FSGS. The potential inhibitory effect of hypercholesterolemia on the proteinuria-reducing actions of CSA was also assessed. Twenty-five patients with FSGS were randomized to receive either placebo or CSA for 6 months. Twelve of the 12 patients that received CSA experienced a diminution of their proteinuria as opposed to only two of the 12 placebo-treated patients. Proteinuria was significantly reduced from 151.7 +/- 162.4 mg/kg per 24 h at Week 0 to 36.9 +/- 42.3 at the end of the study in the group that received CSA (P < 0.05). There was no significant change in the proteinuria of the patients in the placebo group. A significant correlation between the percentage change of proteinuria over the 6 months of the study and the prestudy serum cholesterol levels (r = 0.79, P < 0.05) was seen in the CSA group. A partial correlation analysis controlling for the effects of serum cholesterol uncovered a significant relationship between average CSA level and proteinuria change (r = -0.76, P < 0.05). The fractional decline in GFR over the course of the study was not significantly different between the CSA and placebo-treated groups. In conclusion, CSA reduces proteinuria, increases serum albumin levels, and can be expected, therefore, to reduce the symptoms of nephrotic syndrome. Hypercholesterolemia antagonizes this effect of CSA. First line immunosuppressive treatment in steroid-resistant nephrotic syndrome in children is still open to discussion. We conducted a controlled multicentre randomized open label trial to test the efficacy and safety of cyclosporin A (CSA) versus cyclophosphamide pulses (CPH) in the initial therapy of children with newly diagnosed primary steroid-resistant nephrotic syndrome and histologically proven minimal change disease, focal segmental glomerulosclerosis or mesangial hypercellularity. Patients in the CSA group (n = 15) were initially treated with 150 mg/m(2) CSA orally to achieve trough levels of 120-180 ng/ml, while patients in the CPH group (n = 17) received CPH pulses (500 mg/m(2) per month intravenous). All patients were on alternate prednisone therapy. Patients with proteinuria >40 mg/m(2) per hour at 12 weeks of therapy were allocated to a non-responder protocol with high-dose CSA therapy or methylprednisolone pulses. At week 12, nine of the 15 (60%) CSA patients showed at least partial remission, evidences by a reduction of proteinuria <40 mg/h per m(2). In contrast, three of the 17 (17%) CPH patients responded (p < 0.05, intention-to-treat). Given these results, the study was stopped, in accordance with the protocol. After 24 weeks, complete remission was reached by two of the 15 (13%) CSA and one of the 17 (5%) CPH patients (p = n.s.). Partial remission was achieved by seven of the 15 (46%) CSA and two of the 15 (11%) CPH patients (p <0.05). Five patients in the CSA group and 14 patients in the CPH group were withdrawn from the study, most of them during the non-responder protocol. The number of adverse events was comparable between both groups. We conclude that CSA is more effective than CPH in inducing at least partial remission in steroid-resistant nephrotic syndrome in children. The treatment of steroid-resistant minimal change nephrotic syndrome (MCNS) continues to pose a therapeutic challenge. We conducted a randomised prospective controlled trial to evaluate the efficacy of i.v. cyclophosphamide compared with oral cyclophosphamide in 13 children with biopsy-proven steroid-resistant MCNS. All 7 patients receiving i.v. cyclophosphamide achieved remission; this was sustained in 4 patients, while 3 relapsed. However, even these 3 patients subsequently became steroid sensitive. Of the 6 patients who received oral cyclophosphamide, 2 dropped out, 1 responded and 3 children continued to remain steroid resistant. The children who received IV cyclophosphamide had more sustained remissions, longer periods without proteinuria and fewer significant side effects; this was achieved at a lower cumulative dose. We have conducted a controlled trial on the efficacy of cyclosporine in eight patients with steroid-resistant nephrotic syndrome (four with idiopathic minimal lesion nephrotic syndrome and four with focal segmental glomerulosclerosis). Patients were randomly allocated to a cyclosporine (5 mg/kg/d) or a control group. After eight weeks of therapy and one month without cyclosporine therapy, patients in the control group were given cyclosporine for eight weeks and those in the cyclosporine group became controls. Before the initiation of treatment, there was no difference between the groups with regard to proteinuria and serum albumin levels. Proteinuria remained unchanged in the cyclosporine group, while there was a significant increase in proteinuria in the control group. There were no significant changes in serum albumin levels in either group during the trial. This study does not support the use of cyclosporine at the dose of 5 mg/kg/d in patients with steroid-resistant minimal lesion nephrotic syndrome or focal segmental glomerulosclerosis. We aimed to test if fosinopril reduces urinary protein excretion and alleviates renal tubular damage in normotensive children with steroid-resistant idiopathic nephrotic syndrome (SRINS). We also aimed to evaluate whether there are changes in steady-state blood pressure and serum concentrations of serum angiotensin-converting enzyme (ACE) and plasma renin activity or angiotensin II (AT-II) in children under this treatment. Forty-five normotensive patients with SRINS were randomly divided into two groups. Group I was treated with fosinopril and prednisone for 12 weeks, while group II was treated with prednisone alone for the same duration. The values of 24-h urinary protein excretion were 1.25+/-0.64 vs 2.52+/-0.56 g/24 h (P<0.05), 1.16+/-0.45 vs 2.42+/-0.24 g/24 h (P<0.05), and 1.10+/-0.41 vs 2.05+/-0.46 g/24 h (P<0.05) in group I and group II patients, respectively, at 4, 8, and 12 weeks. Patients in group I showed lower serum concentrations of urinary retinol-binding protein and beta(2)-microglobulin (P<0.01) at the end of the study, but the patients' blood pressure and components of the renin-angiotensin system (RAS) had no change during treatment. The result suggested that fosinopril significantly reduced proteinuria and alleviated renal tubular damage, but did not influence blood pressure and components of systemic RAS in normotensive children with SRINS. nan nan We have examined, in a randomized crossover trial, the antiproteinuric effect of treatment with low- (0.2 mg/kg daily) and high-dose (0.6 mg/kg daily) enalapril in 25 consecutive patients with steroid-resistant nephrotic syndrome (SRNS). Patients in group A ( n=11) received enalapril at low doses for 8 weeks, followed by 2 weeks of washout and then at high doses for 8 weeks. Those in group B ( n=14) initially received enalapril at high and then low doses. Patients continued to receive treatment with tapering doses of prednisolone; none received concomitant therapy with daily oral or intravenous steroids, alkylating agents, cyclosporine, non-steroidal anti-inflammatory drugs, and other antihypertensive medications. The urine albumin-to-creatinine (Ua/Uc) ratio and the percentage reduction were determined for each phase of therapy. Baseline clinical, biochemical, and histological features were comparable in the two groups. In the first phase, treatment with low-dose enalapril (group A) resulted in median 34.8% Ua/Uc reduction compared with 62.9% with high doses (group B) ( P<0.01). High-dose enalapril was associated with a significant reduction in Ua/Uc ratio in both groups. The combined median Ua/Uc (95% confidence interval) reduction in the low-dose phase was 33% (-10.3% to 72.4%) and in the high-dose 52% (15.4%-70.4%) ( P<0.05). The median Ua/Uc ratio at the end of 20 weeks was 1.1 and 1.8 in groups A and B, respectively ( P>0.05). Systolic and diastolic blood pressure reductions were similar in both groups. No period or carry-over effect was found. Prolonged treatment with enalapril thus resulted in a dose-related reduction in nephrotic-range proteinuria. Titration of the dose of enalapril may be a useful strategy for achieving substantial reduction of proteinuria in children with SRNS. Sixty children, with biopsy diagnosed focal segmental glomerulosclerosis (FSGS) and with unremitting nephrotic syndrome despite intensive therapy with adrenocortical steroids, were randomly allocated into a clinical trial comparing prednisone, 40 mg/m2 on alternate days for a period of 12 months (control group), with the same prednisone regimen plus a 90-day course of daily cyclophosphamide, 2.5 mg/kg in a single morning dose (experimental group). One-quarter of the children in each group had complete resolution of proteinuria. The proportions of children with increased, unchanged, and decreased proteinuria by the end of the study were the same in the two groups. Treatment failure was defined as an increase in serum creatinine of 30% or more or greater than 0.4 mg/dl, or onset of renal failure. Treatment failure occurred in 36% of the control group and 57% of the experimental group (P > 0.1). Five patients died during the trial, 3 in the experimental group and 2 in the control group. A Kaplan-Meier survival analysis revealed no significant differences between the two groups. Cyclophosphamide therapy for children with steroid-resistant FSGS is not recommended. To examine whether tacrolimus is more effective and safe than cyclosporine (CsA) in inducing remission in patients with steroid-resistant nephrotic syndrome (SRNS).
                Randomized controlled trial, nonblind, parallel group.
                Tertiary-care hospital; 41 consecutive patients with idiopathic SRNS, estimated glomerular filtration rate greater than 60 mL/min/1.73 m(2), and histological characteristics showing minimal change disease, focal segmental glomerulosclerosis, or mesangioproliferative glomerulonephritis were randomly assigned to treatment with tacrolimus (n = 21) or CsA (n = 20).
                Tacrolimus (0.1 to 0.2 mg/kg/d) or CsA (5 to 6 mg/kg/d) for 1 year; cotreatment with alternate-day prednisolone and enalapril.
                Patients achieving complete remission (urinary protein-creatinine ratio < 0.2 g/g and serum albumin > or = 2.5 g/dL) or partial remission (urinary protein-creatinine ratio, 0.2 to 2 g/g, and serum albumin > or =2.5 g/dL) at 6 and 12 months; time to remission; proportion with relapses; side effects.
                No patient was lost to follow-up. After 6 months of therapy, remission occurred in 18 (85.7%) and 16 patients (80%) treated with tacrolimus and CsA, respectively (relative risk [RR], 1.07; 95% confidence interval [CI], 0.81 to 1.41). Rates of remission at 12 months were also similar (RR, 1.14; 95% CI, 0.84 to 1.55). The proportion of patients who experienced relapse was significantly greater in those receiving CsA compared with tacrolimus (RR, 4.5; 95% CI, 1.1 to 18.2; P = 0.01). The decrease in blood cholesterol levels was greater with tacrolimus compared with CsA (difference in mean values, 45.1 mg/dL; 95% CI, 19.1 to 71.2). Persistent nephrotoxicity necessitating stoppage of medicine was seen in 4.7% and 10% patients, respectively. Cosmetic side effects (hypertrichosis and gum hypertrophy) were significantly more frequent in CsA-treated patients (P < 0.001).
                Single-center study, small sample size, and short duration of follow-up.
                Tacrolimus or CsA in combination with low-dose steroids show similar efficacy in inducing remission in patients with SRNS. Therapy with tacrolimus is a promising alternative to CsA in view of the lower risk of relapses and lack of cosmetic side effects. To compare the efficacy (induction of remission) and safety of cyclosporine (CsA) with those of supportive therapy in patients with steroid-resistant idiopathic nephrotic syndrome (INS), we organized an open, prospective, randomized, multicentric, controlled study for parallel groups, stratified for adults and children. Forty-five patients with steroid-resistant INS were randomly assigned to supportive therapy or CsA (5 mg/kg/day for adults, 6 mg/kg/day for children) for six months, then tapered off by 25% every two months until complete discontinuation. Four patients were lost to follow-up. During the first year 13/22 CsA-treated patients versus three of 19 controls attained remission of the nephrotic syndrome (P < 0.001). A symptom score was assessed at time 0 and at six months. The mean score significantly decreased in the CsA group (P < 0.001), but remained unchanged in the controls. At month 6 the mean urinary protein excretion, the mean serum proteins and plasma cholesterol had significantly improved in the CsA group but were not changed in the controls. There were no significant differences in serum creatinine and creatinine clearance between treatments (interaction time* treatments, P = 0.089 and P = 0.935, respectively) at month 6 versus basal. The CsA-related side-effects were mild; no significant difference in blood pressure between the two groups was seen at any time. This study shows that CsA can bring about remission in some 60% of patients with steroid-resistant INS. In patients with normal renal function and without severe hypertension, CsA at the therapeutic scheme adopted did not produce severe renal or extrarenal toxicity. We compared, in a randomized controlled trial, the efficacy of a regimen based on intravenous (i.v.) cyclophosphamide therapy with a combination of i.v. dexamethasone and oral cyclophosphamide therapy in inducing remission in patients with steroid-resistant nephrotic syndrome (SRNS). During April 2001 to December 2003, 52 consecutive patients with idiopathic SRNS, normal renal function and renal histology findings showing minimal change disease, focal segmental glomerulosclerosis or mesangioproliferative glomerulonephritis were enrolled into the study. Patients in group I received i.v. injection of cyclophosphamide once a month for 6 months and prednisolone on alternate days. Those in group II received i.v. treatment with dexamethasone (initially on alternate days, later fortnightly and monthly; total 14 doses), oral cyclophosphamide therapy (for 3 months) and prednisolone on alternate days. Data from 49 patients (26 in group I, 23 in group II) were analyzed; their clinical and biochemical features were similar at inclusion. Following treatment, complete remission was seen in 53.8% and 47.8% patients in groups I and II, respectively (P = 0.6). Long-term follow up showed favorable outcome in 14 (53.8%) patients in group I, and 9 (39.1%) in group II. Chief adverse effects, including cushingoid features and serious infections, were similar in both groups. Patients receiving i.v. dexamethasone therapy commonly showed hypertension and hypokalemia, while vomiting and reversible alopecia occurred in those receiving i.v. treatment with cyclophosphamide. In patients with SRNS, the efficacy of treatment intravenously with cyclophosphamide and orally with prednisolone was similar to the combination of dexamethasone intravenously, orally administered cyclophosphamide and prednisolone.