Long-term, small dose prednisone therapy in frequently relapsing nephrotic syndrome of childhood. Effect on remission, statural growth, obesity, and infection rate

A prospective study was performed to evaluate the effect of long-term small-dose prednisone therapy in frequently relapsing nephrotic syndrome (NS); 37 patients were included, with a relapse rate 4.6/patient/year (range, 3-8) (mean age, 6.7 years; range, 2-15 years). Prednisone was started 2 mg/kg/day once remission was induced. Prednisone was progressively reduced over weeks until 10 mg/day was reached, and then the daily dose was changed to 10 mg on alternate days. On follow-up (mean, 25.4 months; range, 10-58 months), only five had subsequent relapses and their relapse rate decreased significantly to 1.2/patient/year (p less than 0.05). Forty-six episodes of infection were associated with exacerbation of NS; 41 of these excerbations remitted spontaneously without an increase in the dose of prednisone. Serial height and weight measurements revealed evidence of improved height velocity and obesity persisted in only two of 13 initially obese children.     

Cyclosporin therapy in steroid-dependent nephrotic syndrome

Abstract Five children with multiple relapsing steroid-dependent nephrotic syndrome were treated with continuous cyclosporin for periods ranging from 18 to 48 months. Renal biopsy showed mild mesangial proliferation in three of the children and minimal change in two. All children previously had been treated with cyclophosphamide. Cyclosporin was started during remission at 5 mg/kg per day. If a relapse occurred the dose was increased until a trough blood level of 100–250 ng/mL (HPLC) was achieved. In the initial 12 months of treatment, the mean number of relapses decreased from 6.4±0.54(s.d.) per annum to 1.6±1.3 per annum (P<0.01). Cyclosporin was effective in maintaining long-term remission in four of the five patients. Side effects included hypertrichosis (5) and gum hyperplasia (1). The mean creatinine clearance decreased from 126±16 to 97=22 mL/min per 1.73 m² (P = NS). A renal biopsy in all five patients after 12 months therapy showed no nephrotoxicity. A further biopsy in one patient after 4 years therapy showed interstitial fibrosis. Cyclosporin should be considered in children with steroid-dependent nephrotic syndrome who show signs of steroid toxicity and have only a short remission period after cyclophosphamide. Serial renal biopsies are recommended if prolonged therapy is used.     

Chlorambucil dosage in frequently relapsing nephrotic syndrome: a controlled clinical trial

A controlled clinical trial was performed using two dosage regimens of chlorambucil to treat children with frequently relapsing nephrotic syndrome. All children concurrently received prednisone (60 mg/m2 on alternate days). Ten children (Group I) were given chlorambucil as a stable dose (0.2 mg/kg/day) for 56 to 60 days, and 11 children (Group II) received increasing doses (0.2 to 0.63 mg/kg/day) for 42 to 77 days. Two children in each group subsequently relapsed. Follow-up averaged 28.6 and 27.2 months in Groups I and II, respectively. Three children in Group II developed infectious complications. The data indicate that a stable dosage regimen for chlorambucil is as effective as an increasing dose regimen in achieving long-term remission of frequently relapsing nephrotic syndrome.     

Daily single-dose and daily reduced-dose prednisone therapy for children with the nephrotic syndrome

Most current reference sources recommend that initial therapy for minimal lesion nephrotic syndrome consist of prednisone, 60 mg/m2 per 24 hours or 2 mg/kg per 24 hours, given in divided doses, and that this regimen be repeated for each relapse. The need for divided-dose daily-administered prednisone is predicated on anecdotal observations that single-dose daily administration is not effective. Because single-dose daily-administered and reduced-dose daily-administered prednisone has been used to treat this condition for several years, experience with these regimens in nephrotic children was analyzed. Forty-one patients were studied, including 22 treated from the onset of their disease. Of these 22, 17 (77%) responded to single-dose daily-administered prednisone (2 mg/kg); after subsequent biospy, each of the nonresponders proved to have lesions other than minimal change disease. The mean response time with single-dose daily-administered prednisone (9.6 days for treatment of the initial onset of nephrotic syndrome and 11.1 days for treatment of relapses) was comparable to that previously reported with divided-dose regimens. In 14 patients with frequent relapses, a single reduced-dose daily-administered dose of prednisone (0.2 to 1.5 mg/kg/d) successfully induced remissions in 55 of 63 relapse episodes. It is concluded that a single morning dose of prednisone effectively induces remission in children with minimal lesion nephrotic syndrome. Among selected patients with frequent relapses, additional steroid sparing may be achieved by the use of this regimen with reduced doses during treatment of relapses.     

Intermittent intravenous cyclophosphamide therapy for lupus nephritis

We carried out a preliminary study to determine whether intermittent intravenous cyclophosphamide therapy could be safely and effectively used in the treatment of childhood lupus nephritis. Sixteen children (4 to 18 years of age) with lupus nephritis were treated with cyclophosphamide monthly for 6 months and then every 3 months. Eight children were treated because of corticosteroid-unresponsive active lupus nephritis, with a fall in their creatinine clearance to less than 100 ml/min/1.75 m2, and eight children were treated because of corticosteroid-dependent nephrotic syndrome or active lupus nephritis with unacceptable corticosteroid-induced side effects. Cyclophosphamide treatment was associated with significant improvement at 1 year in mean levels of hemoglobin (11.3 +/- 0.5 to 13.1 +/- 0.3 gm/dl), C3 (52 +/- 5.9 to 108 +/- 13.7 mg/dl), and C4 (7.6 +/- 0.9 to 15.9 +/- 2.2 mg/dl) (all p less than 0.005), despite a significant reduction in mean prednisone dosage (31 +/- 5 to 14 +/- 2 mg/day; p less than 0.005). There was a decrease in 24-hour urine protein excretion from 3121 +/- 913 to 1016 +/- 364 mg/24 hours (p less than 0.05). For children whose initial creatinine clearance was less than 100 ml/min/1.75 m2, creatinine clearance also improved significantly (57.5 +/- 11 to 121 +/- 24.5 ml/min/1.75 m2; p less than 0.05). The long-term safety of intravenous cyclophosphamide therapy and its long-term efficacy in comparison with prednisone alone remain to be established. In the interim, intravenous cyclophosphamide therapy should be reserved for children with severe, unacceptable corticosteroid side effects or with corticosteroid-resistant and potentially life-threatening disease.     

Renal effects of cyclosporin A in children treated for idiopathic nephrotic syndrome

Little data have been published on tubular renal function during cyclosporin A treatment in children without transplants. We studied 12 young subjects (mean age 10 years) with steroid-responsive idiopathic nephrotic syndrome and with signs of steroid toxicity. After achieving remission with prednisone 60 mg/m², 8 children started cyclosporin A therapy (6 mg/kg/day) (group A) and 4 children were given cyclophosphamide 2.5 mg/kg/day (group B). The latter were considered as controls together with 10 other children with idiopathic nephrotic syndrome in complete remission and off therapy (group C). We monitored creatinine clearance and tubular handling of β₂-microglobulin, sodium, phosphorus and uric acid for one year. Cyclosporin A induced a decrease in creatinine clearance with a decrease in fractional excretion of β₂-microglobulin; sodium excretion was similar in the two treated groups and a transient decrease in fractional excretion of uric acid was seen only in patients receiving cyclosporin A. Both groups showed an increased renal threshold phosphate concentration. Our results suggest that in children, cyclosporin A therapy induces a decrease in glomerular filtration rate associated with increased reabsorption activity of proximal tubular cells.     

Cyclosporin A plus prednisone treatment of steroid-sensitive frequently relapsing nephrotic syndrome in children

Recently, there have been numerous reports on the use of cyclosporin A (CyA) in children with nephrotic syndrome (NS). In this prospective study, we wanted to evaluate the efficacy of CyA together with prednisone therapy in children with steroid-sensitive frequently relapsing NS. A total of 11 children (7 boys, 4 girls) with steroid-sensitive NS were included in this study. The patients ranged in age from 3.5 to 15 years (average 8.45 +/- 4.26 years). Renal biopsy showed minimal change disease in five, mesangial proliferation in four, focal glomerulosclerosis in one and membranous glomerulonephritis in one. The NS had lasted from 13 to 113 months (average 50.27 +/- 38.60 months). The number of relapses varied from three to 10 episodes with an average of 5.9 +/- 3.3 episodes. Patients received 5 mg/kg CyA daily in two divided doses for five months and prednisone for a total of eight weeks (30 mg/m2 daily for 4 weeks followed by 30 mg/m2 on alternate days for 4 weeks). After the completion of the treatment protocol, no therapy was given unless a relapse was observed. Mean follow-up period was 14.9 +/- 5.99 months with a range from six to 26 months. Before this combined treatment, there was a mean relapse rate of 0.144 +/- 0.05 relapses month with a range from 0.088 to 0.238. After discontinuation of therapy, the relapse rate dropped to a mean of 0.0179 +/- 0.031 with a range of 0 to 0.083. In conclusion, it would appear that a combination of CyA and prednisone is effective, sustaining the remission in steroid-sensitive NS. Corticosteroids in combination with CyA may be a better approach than conventional steroid treatment in such patients.     

小剂量肝素钙治疗小儿原发性肾病综合征疗效评价

目的 探讨小剂量肝素钙在小儿原发性肾病综合征中的治疗作用。方法：对82例原发性肾病综合征合并高凝状态的患儿进行前瞻性研究,所有患儿均常规服用泼尼松每日2 mg/kg (最大量<60 mg/d),其中52例患儿为肝素钙治疗组(每日50 IU/kg,静脉点滴4周),另外30例为对照组。结果：治疗组尿蛋白转阴率与对照组差异无显著性(P>0.05)。尿蛋白转阴病例中,治疗组尿蛋白转阴时间明显短于对照组［(13.08±4.75) d vs (19.33±4.48) d］(P<0.01),开始利尿时间亦明显少于对照组［(9.64±2.65) d vs (17.07±3.99) d］(P<0.01)。治疗组血纤维蛋白原恢复正常率明显高于对照组(93.3% vs 65.4%)(P<0.05)。治疗组尿FDP恢复正常率与对照组差异无显著性(P>0.05)。结论：小剂量肝素钙不能提高原发性肾病综合征患儿尿蛋白转阴率,但可缩短诱导缓解时间,增强利尿效果,且小剂量肝素钙抗凝作用明显。     

Prednisone therapy of membranoproliferative glomerulonephritis in children

Six children with biopsy-proved type 1 membranoproliferative glomerulonephritis (MPGN) improved clinically during a 2-year course of prednisone therapy. All children had nephrotic syndrome. Creatinine clearance was less than or equal to 80 ml/min/1.73 m2 in four patients. Initial prednisone dosage ranged from 20 mg every other day to 2 mg/kg/day (maximum 60 mg), with subsequent modifications based on improvement. After completion of a 2-year course of steroid therapy, a repeat kidney biopsy was performed in each child; a decrease in glomerular disease activity was noted in five of them. After a mean follow-up of almost 5 years, all children have creatinine clearance greater than 120 ml/min/1.73 m2, and only one remains nephrotic. Although the use of prednisone in children with MPGN remains controversial, we have observed a diminution in proteinuria and normalization of creatinine clearance with therapy initiated early in the disease course.     

Pattern of response to prednisone in idiopathic, minimal lesion nephrotic syndrome as a criterion in selecting patients for cyclophosphamide therapy

Twenty-three children with idiopathic, relapsing minimal lesion nephrotic syndrome were divided according to their pattern of response to prednisone: (1) steroid dependent, if the relapse occurred while the dosage of prednisone was being decreased; and (2) frequent relapser, if the relapse occurred at variable periods of time (one week to two months) after discontinuing prednisone therapy. All patients received cyclophosphamide for eight weeks in a single daily dose of 2 mg/kg, in order to prolong the length of the remission. The percentage of patients who continued in remission at the end of the first year and thereafter was greater in the frequent relapser group (P = 0.05). This study suggests that the pattern of response to prednisone may be another criterion for the selection of patients who will benefit from cyclophosphamide therapy.     

Cyclophosphamide in treatment of minimal change nephrotic syndrome

Nineteen children with the minimal change form of nephrotic syndrome were divided according to their pattern of response to prednisone: steroid-dependent and frequent relapsers. All patients received cyclophosphamide for 56 days in a single daily dose of 2.5 mg/kg (total 140 mg/kg), in order to prolong the length of remission. The percentage of patients who continued in remission at the end of the 1st, 2nd and 5th years was greater in the frequent-relapser group. This retrospective analysis confirms that the pattern of response to prednisone may be an important criterion for the selection of patients who will benefit from cyclophosphamide therapy.     

不同方案泼尼松治疗儿童原发性肾病综合征的疗效及复发危险因素分析北大核心CSCD

目的探讨足量泼尼松应用4周与6周方案治疗初发原发性肾病综合征患儿的疗效及对缓解后复发的影响。方法采用非随机对照临床研究法,前瞻性纳入2017年12月至2019年5月住院并诊断为初发原发性肾病综合征的89例患儿为研究对象,分别予泼尼松2 mg/(kg·d)(最多60 mg)应用4周(4周组)或6周(6周组)治疗。之后均改为2 mg/kg(最多60 mg)隔日应用4周,之后逐渐减停。定期随访1年。比较两组维持缓解时间、复发率等指标,并采用Cox回归分析复发的危险因素。结果泼尼松治疗后3个月内4周组复发率高于6周组(P<0.05);随访1年时,两组复发率、维持缓解时间及复发频率的比较差异无统计学意义(P>0.05)。起病年龄≥6岁及24 h尿蛋白定量升高是复发的危险因素(P<0.05)。结论足量泼尼松治疗初发原发性肾病综合征的方案由4周延至6周可减少患儿前3个月内的复发。临床上应高度关注起病年龄≥6岁和高水平尿蛋白量患儿,建议给予足量泼尼松治疗6周以降低复发风险。[中国当代儿科杂志,2022,24(8):853-857]     

Glucocorticoid receptor and vascular endothelial growth factor in nephrotic syndrome

AIM: The aim of the study was to assess plasma and urine concentrations of vascular endothelial growth factor (VEGF) in nephrotic syndrome children (NS) depending on the total dose of glucocorticoids (GC) and the percentage of lymphocytes with glucocorticoid receptor expression (CD3/GCR). METHODS: We examined 51 children (2-15 years), allocated to three groups: group I: 13 children with the first NS onset, group II: 13 children with NS relapse, group C: 25 healthy children. The NS patients were examined: (A) before treatment and (B) 4-5 weeks after prednisone administration at a dose of 60 mg/m2/24 h. Plasma and urinary VEGF levels were determined using the immunoenzymatic ELISA method. Flow cytometry was applied to assess CD3/GCR expression. RESULTS: Higher plasma and urinary VEGF concentrations were noted in NS children before treatment (A), as compared to control subjects (C). Following prednisone therapy (B), VEGF level was reduced but it was still higher than in the control group. Positive correlation was observed between VEGF and protein in the urine (group I r = 0.660, P < 0.05, group II r = 0.818, P<0.01) and a weak positive correlation between VEGF in plasma and urine (group I r = 0.531, P<0.05, group II - r = 0.581, P<0.05). CD3/GCR expression was lower in group II. In both groups, the correlation between plasma VEGF and CD3/GCR was positive (P<0.05).Conclusions: 1. Plasma and urinary VEGF levels increase during nephrotic syndrome onset. 2. Glucocorticoid treatment reduces plasma and urinary VEGF levels in NS children.     

Intermittent versus long-term tapering prednisolone for initial therapy in children with idiopathic nephrotic syndrome

Forty-six children with steroid-responsive nephrotic syndrome were randomly allocated to receive two different prednisolone regimens for initial therapy. Twenty-nine children (group 1) received an intermittent regimen (60 mg/m2/day for 4 weeks, followed by 40/mg/m2/day on 3 days a week for 4 weeks); 17 children (group 2) had a long-term regimen (60 mg/m2/day for 4 weeks, followed by the same dose on alternate days for 4 weeks and the doses tapered by 10 mg/m2, given on alternate days every 4 weeks for 5 months). There was no difference between the two groups in the regimen used to treat relapses, steroid responsiveness, number of patients with relapses, and frequency of toxic reactions to steroids. However, the number of patients with a relapse within 6 months after initial therapy and the number of those with frequent relapses or steroid dependence were significantly higher in group 1 than in group 2 (P less than 0.05 for both). The data indicate that the long-term tapering regimen appears to be both safe and preferable to the intermittent regimen for initial therapy in children with idiopathic nephrotic syndrome.     

A prospective randomly controlled clinical trial on azithromycin therapy for induction treatment of children with nephrotic syndrome

A prospective study was designed to evaluate the efficacy of azithromycin (AZM) when combined with prednisone therapy compared with prednisone therapy alone in children with primary nephrotic syndrome (PNS) undergoing induction treatment. A prospective randomly controlled clinical trial was conducted. Randomization was performed to select the research subjects who were composed of children with PNS and treated with AZM combined with prednisone (the intervention group) and with prednisone alone (the control group). A total of 211 randomly selected patients with PNS received either AZM combined with prednisone (n?=?106) or prednisone alone (n?=?105) for 6 months. At three months in the follow‐up period, 12 patients were lost to follow up (intervention group, 7; control group, 5), and 6 patients had a transient hypocomplementemia (intervention group, 4 ; control group, 2). AZM was administered at a dose of 10 mg/kg q.d (1 dose per day) for three consecutive days. The median duration before remission was 6 days in the intervention group and 9 days in the control group (p?<?0.0001). Relapse rate differed among the groups at 3 months (11.6 vs. 21.4 %, p?=?0.049). No difference in relapse rate was observed between the two groups within 4 to 6 months and at 6 months (p?=?0.168, 0.052). After 4 weeks of treatment, steroid resistance occurred in 1 out of 95 (1.05 %) patients in the intervention group and in 10 out of 98 (10.2 %) patients in the control group (p?=?0.006). After 8 weeks of treatment, no difference was found in steroid resistance between two groups (1/95 vs. 3/98, p?=?0.327). During follow-up at 6 months, no difference was exhibited by the two groups on frequent relapse rates (p?=?0.134). Conclusion: If a course of AZM is added to the glucocorticoid-induced treatment among children with PNS, then the sensitivity of prednisone increases. This increase consequently reduces duration to remission and decreases relapse. However, further studies are necessary to confirm these results.     

High dose methylprednisolone therapy in nephrotic syndrome

This study was done to determine the efficacy of oral high dose methylprednisolone (HDMP) therapy in the treatment of childhood nephrotic syndrome (NS). Fifteen patients were enrolled in the study. Patients were arbitrarily divided into two groups. Group I received prednisolone (daily 60 mg/m² for 4 weeks, 45, 30, 20, 10, 5 mg/m² on alternate days for 4 weeks) and group II received HDMP (30 mg/kg/d for 3 days, 20 mg/kg/d for 4 days, 10 mg/kg/for a week, before 9 am, orally). The patients were followed-up for a duration of 38.0±5.5 months (range 24–68 months) in group I and 42.1±5.5 months (range 16–72 months) in group II. No significant difference was obtained in the duration of remission between both groups (p>0.05), while HDMP induced early remission than prednisolone (p<0.05). The mean relapse rate was 0.8/year in group I and 0.8/year in group II (p>0.05). Although, the number of the patients were limited in the study it can be recommended that patients with NS can be treated with oral HDMP therapy as an alternative to standard oral prednisolone therapy.     

肾脏疾病合并头孢曲松相关假性胆结石患儿的临床分析

目的 探讨肾脏疾病患儿合并头孢曲松相关假性胆结石的临床特点.方法 回顾性分析3例合并头孢曲松相关假性胆结石的肾脏疾病患儿临床资料.结果 病例1,男,11岁,诊断"肾病综合征",因"胃肠炎"予头孢曲松2g/d[50 mg/(kg·d)]抗感染,3 d后发现胆囊内泥沙样沉积,伴纳差、恶心;停药16 d后胆囊结石消失.病例2,男,10岁,诊断"急性链球菌感染后肾小球肾炎、肾功能不全",因"胃肠炎"予头孢曲松1.5 g/d[30 mg/(kg·d)],疗程6 d时发现胆囊结石,伴恶心、呕吐和腹痛,Murphy's征阳性;停药18 d后胆囊结石消失.病例3,男,12岁,诊断"肾病综合征",因"胃肠炎?"给予头孢曲松2g/d[40 mg/(kg·d)]联合甲硝唑抗感染、疗程2周,感染控制,但有中上腹压痛,停药3 d后发现胆囊结石;停药2个月后复查结石回声消失.结论 上述3例患儿出现胆囊结石时头孢曲松治疗剂量较低、结石出现早、临床表现相对重,可能与肾脏疾病患儿同时存在血液浓缩、高凝状态、肾功能不全或补充钙剂等高危因素有关.     

Cyclophosphamide treatment of steroid dependent nephrotic syndrome: comparison of eight week with 12 week course. Report of Arbeitsgemeinschaft für P?diatrische Nephrologie.

In a prospective study (Cytotoxic Drug Study II), 18 children with steroid dependent nephrotic syndrome and steroid toxicity were treated with cyclophosphamide (2 mg/kg body weight/day) for 12 weeks in combination with reducing doses of prednisone (group A). This group was compared retrospectively with 18 children with steroid dependent nephrotic syndrome, studied as part of the Cytotoxic Drug Study I, and who had received cyclophosphamide for eight weeks (group B). There were no differences between the groups in age at the onset of the nephrotic syndrome, age at entry into the study, and duration of the nephrotic syndrome before entry into the study. The number of relapses during the six months before the treatment was the same in both groups. Two years after treatment 12 of 18 children treated with cyclophosphamide for 12 weeks were still in remission. By contrast, only four of of 18 children treated with cyclophosphamide for eight weeks were still in remission. The cumulative rates of sustained remissions were significantly higher (67% and 22%, respectively) in group A. All relapses were observed within 400 days of stopping cytotoxic treatment. No severe side effects of cyclophosphamide occurred up to two years after treatment had been stopped. We conclude that for children with steroid dependent nephrotic syndrome and steroid toxicity cyclophosphamide treatment should be prolonged to 12 weeks to increase the likelihood of a prolonged remission.     

他克莫司联合小剂量激素治疗儿童激素抵抗型肾病综合征21例临床分析

目的 分析评估他克莫司对治疗儿童激素抵抗型肾病综合征的疗效及其安全性.方法 采用回顾性纵向研究分析21例激素抵抗型肾病综合征患儿,他克莫司初始剂量0.10 ～0.15 mg/(kg·d),每12小时1次,定期监测血药浓度、尿常规、血常规及肝肾功能等指标.同时口服小剂量泼尼松0.20 ～0.75 rmg/( kg·d).结果 1～3个月后观察近期疗效,完全缓解者14例,部分缓解者7例,完全缓解率66.7％.16例患儿接受了肾活检,其中6例微小病变型肾病患儿中3例完全缓解,3例部分缓解;4例局灶节段性肾小球硬化患儿中2例完全缓解,2例部分缓解;5例lgM肾病及1例系膜增生性肾小球肾炎患儿均完全缓解.服药期间6例患儿出现一过性不良反应,经对症处理后均缓解.20例患儿获随访,1年内共4例复发,第2年共4例6次出现复发.结论 他克莫司对儿童激素抵抗型肾病综合征有较好的疗效,不良反应较少,大多可耐受,但服药1～2年内复发率较高,因此其长期疗效仍有待于进一步随访观察.     

High-dose steroids in childhood acute idiopathic thrombocytopenia purpura

Nine newly diagnosed, previously untreated children (mean age: 4.2 years, range: 1-9 years) with severe acute idiopathic thrombocytopenia purpura (mean platelet count: 5.8 X 10(9)/L, range: 1-12 X 10(9)/L) were treated with high-dose steroids (prednisone 4-8 mg/kg/day). Steroid dose was based on platelet count at presentation: Group I (platelets less than 5 X 10(9)/L) was started on 8 mg/kg/day; Group II (platelets 5-15 X 10(9)/L) received 6 mg/kg/day. All patients had serologic and histologic evidence of acute idiopathic thrombocytopenia purpura. On this protocol, it took a mean number of 1.9 days (1-3 days) to reach a platelet count of at least 20 X 10(9)/L and 9.2 days (3-26 days) to reach a normal platelet count. No significant toxicity was observed except for weight gain ranging from 3-10% and mild behavioral problems. Both groups were on high-dose steroids (4-8 mg/kg/day) for 7.3 +/- 2.1 days. Only one patient had a brief relapse to a platelet count of 18 X 10(9)/L while on therapy (day 14), but responded promptly to an increase in prednisone dose. Presently, all nine patients are in remission and have not required maintenance medication.