Long-term low-dose cyclosporin A in steroid dependent nephrotic syndrome of childhood

Therapy of steroid-dependent idiopathic nephrotic syndrome is often unsatisfactory. Since 1986 we have treated nine children (six male and three female), aged 3–16 years, with cyclosporin A (CsA) during 2.0–5.2 (median 3.1) years. All had minimal change disease on renal biopsy and had previously received cyclophosphamide. Mean daily dosage of CsA was 4.1 mg/kg (range 2.7–5.8) and mean whole blood trough level was 220ng/ml (range 141–271). The relapse rate decreased from 3.4/patient year before CsA to 0.55 on CsA. Discontinuation of CsA or reduction below 2 mg/kg daily was always followed by a relapse. The overall relapse rate, including the period with very low-dose CsA, was 0.95/patient year. Four patients required additional low-dose alternate-day prednisone. Repeat renal biopsy showed minimal change disease in eight patients and focal segmental glomerulosclerosis in one; CsA-toxicity was mild in two and moderate in one. The latter was the only patient with slightly reduced glomerular filtration rate. Two boys with delayed puberty spontaneously matured and reached expected final height. We conclude that long-term low-dose CsA is very effective and steroid-sparing. Its use is justified in selected patients, particularly in those with numerous relapses and in male patients before and during puberty, as long as renal function and CsA-toxicity are carefully monitored.     

Involvement of CD5+CD19+Cell in steroid‐dependent nephrotic syndrome treated with B‐cell targeting therapy

We showed in this study the longitudinal changes of the B‐cell counts in patients with steroid‐dependent nephrotic syndrome (SDNS) treated with cyclophosphamide (CPM) and mycophenolate mofetil (MMF). In our case with SDNS, this combined therapy not only decreased B‐cell counts but also increased CD5⁺CD19⁺ (CD5⁺B)/ CD5^‐CD19⁺ (CD5‐B) cell ratio. Recurrence was not observed when an elevated CD5⁺B/CD5‐B cell ratio was maintained even after the B cells increased. Therefore, this ratio might be more important than the whole B‐cell counts. The changes of this ratio could be a good predictor of the clinical course of the patients treated with B‐cell targeting therapy.     

Childhood idiopathic nephrotic syndrome in Turkey

BACKGROUND: It has been reported that there are racial and regional differences in peak incidence age, histopathological features and response to steroid therapy in childhood idiopathic nephrotic syndrome. METHODS: One hundred and thirty-eight patients with a diagnosis of idiopathic nephrotic syndrome, followed up in 1994-2000, were assessed retrospectively. The aim of this study was to assess the patients' response pattern to steroid therapy, to determine whether the duration of the initial steroid therapy alters the steroid response pattern of the disease and to assess renal biopsy results. RESULTS: One hundred and fourteen patients who initially received only steroid therapy and were followed up regularly were classified according to response pattern. Of the 114 patients, 30 children had an initial response, 25 children had infrequent relapse, 19 had frequent relapse, 25 had steroid dependence and 15 children had steroid resistance. The 99 patients with steroid responsive nephrotic syndrome were divided into two groups with respect to duration of the initial steroid therapy. There was no statistically significant difference between standard and short therapy groups with respect to the steroid response patterns. Percutaneous renal biopsy was performed in 43 of the 138 patients. Mesengioproliferative glomerulonephritis was the most common histopathological lesion, followed by membranoproliferative glomerulonephritis. The proportions of membranous glomerulonephritis, focal segmental glomerulosclerosis and minimal change nephrotic syndrome were low in our group. CONCLUSIONS: Our study group is similar to one reported from Saudi Arabia with respect to the steroid response pattern and to Saudi Arabian and Nigerian reports with respect to the histopathology. Although it has been reported that short initial steroid therapy was followed by a higher rate of relapses, there was no statistically significant difference between standard and short therapy groups with respect to the relapse rate in our study group.     

霉酚酸酯与环磷酰胺治疗肾病综合征型紫癜性肾炎疗效比较

目的 比较霉酚酸酯（MMF）与环磷酰胺（CTX）静脉冲击治疗以肾病综合征为临床表现的紫癜性肾炎（HSPN）的疗效。方法 将37例临床表现为肾病综合征的HSPN患儿分为两组：一组用激素联合MMF治疗,另一组行激素联合CTX冲击治疗。结果 治疗6、9和12个月临床完全缓解率MMF组与CTX组分别为36．8％和27．8％、63．2％和44．4％、68.4％和44．4％（P〉0．05）;临床部分缓解率MMF组与CTX组分别为36．8％和38．9％、31．6％和44．4％、26-3％和33．3％（P〉0．05）;总缓解率（完全＋部分缓解）MMF组与CTX组分别为73．7％和66．7％、94．7％和88．9％、94．7％和77．8％（P〉0．05）,两组在临床缓解率上差异无统计学意义。治疗6、12个月时尿蛋白缓解率MMF组高于CTX组,分别为73．7％与33-3％（P〈0．05）、和84．2．与50．O％（P〈0．05）。治疗6个月时血尿缓解率MMF组高于clx组,为47．4％与16．7％（P〈0．05）,12个月时两组血尿缓解率相近（73．7％与66．7％,P〉o．05）。MMF组出现不良反应4例,轻度胃肠道反应2例和呼吸道感染2例;CTX组不良反应7例,表现为严重胃肠道反应3例,支气管肺炎、白细胞下降、肝功能损害、脱发各1例。结论 与CTX结合小剂量激素治疗相比较,MMF结合小剂量激素治疗以肾病综合征为临床表现的HSPN有相近的临床缓解率,而在缓解蛋白尿和血尿方面,MMF较CTX更为有效。MMF不良反应亦明显少于CTX。     

Persistent hypercholesterolaemia in frequently relapsing steroid-responsive nephrotic syndrome

Objective: To investigate long-term changes of serum cholesterol levels in children with frequently relapsing steroid-responsive nephrotic syndrome (NS).
Methodology: Serum cholesterol values just before and during or immediately after 'relapse' were reviewed and the incidence of hypercholesterolaemia (≥200 mg/dL) was determined in eight patients (M:F, 6:2).
Results: The patients with frequently relapsing NS usually showed hypercholesterolaemia (mean incidence, 81%) just before 'relapse' during clinical remission, as well as in relapse (mean incidence, 96%). A high incidence of steroid therapy was also found in each case (mean, 89%) just before relapse.
Conclusions: Our results demonstrate that children with frequently relapsing NS have prolonged periods of hypercholesterolaemia, even during clinical remission. It is suggested that serum lipid profiles be monitored carefully in such patients.     

Treatment of steroid sensitive nephrotic syndrome

Childhood idiopathic nephrotic syndrome (NS) is a chronic glomerular disorder, and if untreated, is associated with increased risk of life-threatening infections, thromboembolism, lipid abnormalities, and malnutrition. The aim of the management of NS in children is to induce and maintain complete remission with resolution of proteinuria and edema without encountering serious adverse effects of therapy. Over 90% of cases in children are due to minimal change disease (MCD) and a majority of them will respond to corticosteroid therapy. Steroid sensitive NS is considered to be a relatively benign condition; progression to end stage renal failure is extremely rare and over 80% achieve spontaneous remission in later childhood. The early disease is characterized by a relapsing course, placing the child at risk of acute complications. The occurrence of frequent relapses necessitates clear therapeutic strategies in order to maintain sustained remission and minimize steroid toxicity. Numerous therapeutic regimens have been proposed utilizing steroid sparing agents such as alkylating agents, principally, cyclophosphamide and chlorambucil, calcineurin inhibitors namely cyclosporin A and immunomodulatory drug levamisole with variable success and associated side-effects. It is therefore important that the benefits and risks of these agents are weighed before considering their use in the treatment of patients with NS.     

Steroid response pattern in Indian children with nephrotic syndrome

Gulati S, Kher V, Sharma RK, Gupta A. Steroid response pattern in Indian children with nephrotic syndrome. Acta Pædiatr 1994;83:530–3. Stockholm. ISSN 08033–5253
The steroid response pattern to standard prednisolone therapy is of immense diagnostic, therapeutic and prognostic value for the treating physician in managing children with nephrotic syndrome. None of the studies from our country has analysed the clinical, biochemical and histopathological profile in different steroid response categories. To address this problem we conducted a study comprising 127 children with nephrotic syndrome referred to our Institute. They were treated with oral prednisolone according to the APN protocol. Based on the subsequent response these children were classified into different steroid response categories on follow-up. Of the 116 children with follow-up of more than six months, infrequent relapsers constituted the majority (37.9%). The frequency of other steroid response categories was as follows: frequent relapsers (21.6%), steroid-dependent (18.1%), initial non-responders (17.3%) and subsequent non-responders (5.1%). The factors predicting a poor response to standard prednisolone therapy in our study were age of onset more than eight years, male sex, hypertension, microscopic haematuria and presence of non-minimal change nephrotic syndrome lesions on histopathology     

Plasma and urinary platelet activating factor concentrations and leukotriene releasing activity of leukocytes in steroid sensitive nephrotic syndrome of childhood

Platelet activating factor (PAF) is synthesized and secreted by glomerular mesangial and endothelial cells. It increases glomerular basement membrane permeability and induces proteinuria. Leukotrienes (LT) are mediators released by either leukocytes or glomerular cells under the PAF effect. The possible role of PAF in steroid sensitive nephrotic syndrome (SSNS) of childhood was studied in 8 children with SSNS in the acute stage, 5 children in remission and 8 healthy controls. The PAF concentrations in urine and plasma were determined. Leukocytes were stimulated in vitro and the LT release in response to stimulation was determined. The urinary and plasma concentrations of PAF were significantly higher in the acute phase than in remission and in control patients. Children with SSNS were found to have peripheral leukocytes with increased LT releasing activity in vitro. These results are in accordance with clinical and experimental observations indicating that PAF originates in the kidney and plays a role in normal kidney physiology. Urinary PAF concentrations may be related to proteinuria because they were strongly correlated in the present study. Elevated plasma PAF concentrations in the acute stage of SSNS could result from either its secretion from the circulating leukocytes or decreased acetyl hidrolase activity needed for its hydrolysis in plasma. The increased LT release in vitro suggests that these cells might have been activated by PAF secreted from glomeruli. It is proposed that PAF and different LT in systemic and glomerular circulation are important mediators in childhood SSNS.     

Free carnitine levels in children with steroid–sensitive nephrotic syndrome

BACKGROUND: Carnitine transports long-chain fatty acids across the inner mitochondrial membrane. Carnitine metabolism is disturbed in some renal diseases, such as chronic renal failure. Previous studies have shown that children had normal serum free carnitine (FC) and total carnitine levels in idiopathic nephrotic syndrome, IgA nephropathy, non-IgA nephropathy and focal segmental glomerulosclerosis. The aim of the present study was to determine FC concentrations in plasma and urine during acute and remission periods of steroid-sensitive nephrotic syndrome (SSNS) and its association with hyperlipidemia. METHODS: Plasma and urinary FC concentrations were assayed in 15 children with SSNS in acute and in 16 children in remission period. Six of them were followed-up longitudinally in both periods. RESULTS: Plasma FC concentrations were significantly higher in the acute period of the disease than in the remission period and of the controls. The patients had lower FC levels in the remission period as compared to the controls. Urinary FC concentration was decreased in acute disease period when compared to the remission period and the controls. The FC concentrations in plasma and urine did not correlate with each other. Plasma FC exhibited significant positive correlation with low-density lipoprotein cholesterol, total cholesterol and trygliceride, but negative correlation with high-density lipoprotein cholesterol. CONCLUSIONS: The present study showed disturbed FC concentration in SSNS. Increased plasma and decreased urinary FC levels in acute disease might be associated with its altered renal handling or some extrarenal factors such as hyperlipidemia.     

Increased frequency of steroid non-responsive nephrotic syndrome in Iranian children

During an eight year period, 66 Iranian children with nephrotic syndrome without renal failure were studied for their response to prednisone therapy. Twentysix (39·3%) of these were early steroid non-responsive. Of 40 responders, 70 per cent responded within the first 2 wk, 22·5 per cent within the second 2 wk, and 3 children during the next 4 wk of therapy. Two patients (3·03%) were steroid late non-responders.     

Multiple drug-resistant gene 1 in children with steroid-sensitive nephrotic syndrome

Background: A full dose of corticosteroid is required to induce complete remission (CR) in steroid‐sensitive nephrotic syndrome (SSNS), unless it is possible to taper and discontinue along with the course after CR. But the mechanism of this change in steroid sensitivity remains unknown. P‐glycoprotein (PGP) can eliminate given corticosteroids from cytoplasm, which results in corticosteroid resistance. Therefore, drug delivery was analyzed using real‐time polymerase chain reaction (PCR) of multiple drug‐resistant gene 1 (MDR1; encoding PGP) mRNA expression. Methods: Fourteen patients with SSNS (male/female: 14/0; age: 1–23 years; mean 10.4 years) were enrolled in the study. MDR1 mRNA gene expression of peripheral blood nucleated cells (PBNC), before and after CR (19 sets of blood samples), was quantified using real‐time PCR. Results: The MDR1 mRNA levels before CR were variable in each patient, but there was an apparent decrease in the MDR1 gene expression of PBNC after CR (P < 0.003). Conclusion: PGP may play a role in the tapering of corticosteroids after CR in SSNS.     

Anti-oxidant vitamins and steroid responsive nephrotic syndrome in Indian children

OBJECTIVE: In recent years, it has been proposed that nephrotic syndrome is a consequence of an imbalance between oxidant and anti-oxidant activity. In the present study, the levels of micronutrient anti-oxidant vitamins (vitamin E, vitamin C, carotene and riboflavin) in Indian children with steroid responsive nephrotic syndrome were investigated. Their levels were measured during the acute proteinuric phase of the disease, as well as during clinical recovery (remission), in order to understand the possible role of nutritionally modifiable anti-oxidants in the aetiopathogenesis of the disease. METHODS: The study was a hospital based, prospective cohort study. Serum and erythrocyte vitamin E, leucocyte vitamin C, serum carotene, erythrocyte riboflavin activity and serum malonyldialdehyde (MDA) levels were measured in 30 consecutive cases of children with nephrotic syndrome (International Study of Kidney Diseases in Children (ISKDC) criteria) during the proteinuric phase of the disease and at 4 weeks after remission was induced by steroid therapy. The same biochemical parameters were measured in healthy siblings (controls) of the 30 patients. RESULTS: Mean vitamin E (serum and erythrocyte), vitamin C and carotene were significantly lower during the proteinuric phase of the disease, and there was decreased erythrocyte riboflavin activity. There was significant elevation in the serum level of MDA during this phase. In addition, all these parameters tended to improve during remission, although complete normalization did not occur. CONCLUSION: These vitamins were active in performing their anti-oxidant function, as indicated by significant depression in their levels during the acute (proteinuric) phase, followed by partial recovery during remission. It may be concluded that steroid responsive nephrotic syndrome in children is associated with oxidative stress.     

长春新碱对激素依赖型肾病综合征的治疗

目的：目前对于激素依赖型肾病综合征的治疗仍较困难,我们回顾性地评价了长春新碱对用过环磷酰胺治疗后而仍有复发的激素依赖型肾病综合征患儿的治疗效果。方法：14例口服过一个疗程以上环磷酰胺而仍有复发的激素依赖型肾病综合征患儿接受了长春新碱治疗。长春新碱的用法为每周静脉注射1次,连用4周,然后每月1次,连用4月,每次剂量为1~1.5 mg/m2。结果：13例完成了长春新碱的整个疗程。正处于肾病复发期的8例患儿,6例(75%)完全缓解,蛋白尿在用长春新碱治疗2~3剂后消失。在疗程结束后对处于肾病缓解状态的12例患儿随访,发现4例(33.3%)未再复发,持续保持缓解9~40月(中位数为13.5月);半年内的肾病复发次数由治疗前的1.67次降至0.67次(P<0.05);8例再复发者,7例再次注射长春新碱(1 mg/m2)1~2剂后蛋白尿均消失。除用1.5 mg/m2剂量时腹痛较显著外患儿未出现其他明显副作用。结论：长春新碱能诱导激素依赖型肾病综合征复发患儿的完全缓解,还有可能降低复发频率。对于再复发患儿,少数几次长春新碱的使用可能优于口服一个疗程的泼尼松龙或环孢素。[中国当代儿科杂志,2005,7(6):495-498]     

儿童激素耐药型与激素敏感型肾病综合征尿蛋白组学的初步研究

目的：筛选和鉴定激素耐药型（SRNS）与激素敏感型原发性肾病综合征（SSNS）尿液中差异表达的蛋白质,寻找可能与肾病综合征激素耐药和激素敏感相关的蛋白质。方法：SSNS治疗前后病例、SRNS、正常对照各5例,提取尿液全蛋白,采用双向凝胶电泳建立全蛋白凝胶图谱;银染后用Image Master 2D V3.01软件分析差异表达蛋白质点,利用MALDI-TOF-MS分析获得肽质量指纹图谱,通过Mascot软件进入NCBI数据库,鉴定出差异表达蛋白质。结果：SRNS组与SSNS治疗前组尿液2-DE凝胶比较有差异蛋白质点66个,其中仅出现于SRNS组24个、SSNS治疗前组27个;SSNS治疗后组与正常对照组尿液2-DE凝胶比较有差异蛋白质点75个,其中仅出现于SSNS治疗后组11个。对18个差异蛋白质点进行分析,鉴定出α1-抗胰蛋白酶、转铁蛋白、带异类电荷糖蛋白复合体等9类差异表达的蛋白质。结论：成功鉴定了SRNS和SSNS的尿液中存在9类差异表达的蛋白质,部分蛋白可能是SRNS或SSNS的标志物。［中国当代儿科杂志,2009,11（5）：341-345］     

Bone mineral content and collagen metabolites in children receiving steroid treatment for nephrotic syndrome

Bone mineral density (BMD) and content (BMC) were measured in nine children treated with corticosteroids for nephrotic syndrome and in age-matched controls, using dual-energy X-ray absorptiometry (DEXA). The urinary excretion of cross-linked N-telopeptide (NTx) released from collagen type I as a specific marker of bone resorption was also measured. There were no significant differences in body size, BMD results or NTx urinary concentrations between patients and controls, nor could any significant differences be found when the six patients given a cumulative corticosteroid dose of >15 g were analysed separately. The lack of significant differences could be due to the small number of patients included in the study. But when the measured BMD and BMC were analysed according to methods that corrected for body size and puberty stage, values well within the normal range were found in patients as well as in controls. There was, however, a significant, negative correlation between the urinary excretion of NTx and the cumulative dose of corticosteroids. CONCLUSION: Despite treatment for long periods with high, cumulative doses of corticosteroids, the skeletons of the patients had a normal mineral content, which is encouraging for all those in need of steroids for nephrotic syndrome. A negative correlation between urinary collagen degradation products and the cumulative steroid dose might point to a reduced growth velocity in patients on high doses of steroids earlier than an effect on bone mineralization.     

Major histocompatibility complex antigens and immune mechanisms in steroid-responsive nephrotic syndrome

Although the pathogenesis of steroid-responsive nephrotic syndrome (SRNS) is obscure, involvement of an immune mechanism is often suggested. Further evidence of an immune basis for this disorder is an increased frequency of specific major histocompatibility complex (MHC) antigens. In the first part of this study, the phenotypic frequency of HLA-A, -B, -C, -DR antigens were investigated in 30 children with SRNS and in 630 controls. In the second part, total T (CD3⁺ cells) and B lymphocytes (CD19⁺ cells) and the lymphocyte subsets (CD4⁺, CD8⁺ cells and their ratio) were studied in the same patients and in 30 healthy children. The investigations of all the patients were performed during the acute stage and 14 of 30 during remission stage. Human leukocyte antigens (HLA) were determined by standard microlymphocytotoxicity assay and lymphocytes were analyzed by flow cytometry. Human leukocyte antigens A3, DR4, DR7 and the haplotype HLA-A2/B12 showed the strongest association with SRNS. In the studies for cellular immune disorder, CD3⁺ and CD8⁺ cells were found to be decreased significantly in the acute stage before beginning steroid therapy. No significant difference in lymphocyte subsets was observed in the remission stage without steroid or immunosuppressive therapy.     

Rituximab for childhood refractory nephrotic syndrome

Several therapies including immunosuppressive agents have been shown to be effective and safe for frequently relapsing nephrotic syndrome/steroid‐dependent nephrotic syndrome (FRNS/SDNS) and steroid‐resistant nephrotic syndrome in children. It is evident, however, that a substantial number of children are still refractory to treatment despite these therapies. Rituximab is a chimeric monoclonal antibody, which inhibits CD20‐mediated B‐cell proliferation and differentiation. It was first introduced for the treatment of B‐cell non‐Hodgkin's lymphoma and was subsequently administered to patients with autoimmune diseases, such as rheumatoid arthritis, lupus erythematosus, or immunocomplex glomerulonephritis. Recently, a number of case reports and non‐controlled clinical trials have suggested that rituximab may be effective for children with refractory nephrotic syndrome. Controlled prospective trials, however, are required to establish the value of rituximab in refractory nephrotic syndrome. The purpose of the present study was therefore to evaluate the efficacy and safety of rituximab in childhood‐onset refractory nephrotic syndrome. The Research Group of Childhood‐onset Refractory Nephrotic Syndrome (RCRNS) conducted a randomized, double‐blind, placebo‐controlled, multi‐center clinical trial (RCRNS‐01) and an open‐label, multi‐center, pharmacokinetic clinical trial (RCRNS‐02). These two trials were investigator‐initiated, registration‐directed clinical trials designed to apply Ministry of Health, Labour and Welfare approval for the use of rituximab for childhood‐onset refractory FRNS/SDNS in Japan. RCRNS‐01 could be the first study to clarify whether rituximab is effective and safe for childhood‐onset refractory FRNS/SDNS.