Rituximab for troublesome cases of childhood nephrotic syndrome

Nephrotic syndrome (NS) is the most common glomerular disease of childhood. Steroid-dependent and steroid-resistant nephrotic syndrome present challenges in their pharmaceutical management; patients may need several immunosuppressive medication for optimum control, each of which medication has its own safety profile. Rituximab (RTX) is a monoclonal antibody that targets B cells and has been used successfully for management of lymphoma and rheumatoid arthritis. Recent clinical studies showed that rituximab may be an efficacious and safe alternative for the treatment of complicated nephrotic syndrome. In this review article, we aim to review the efficacy and safety of RTX therapy in nephrotic syndrome. We reviewed the literature pertaining to this topic by searching for relevant studies on PubMed and Medline using specific keywords. The initial search yielded 452 articles. These articles were then examined to ensure their relevance to the topic of research. We focused on multicenter randomized controlled trials with relatively large numbers of patients. A total of 29 articles were finally identified and will be summarized in this review. The majority of clinical studies of RTX in complicated pediatric NS showed that rituximab is effective in approximately 80% of patients with steroid-dependent NS, as it decreases the number of relapses and steroid dosage. However, RTX is less effective at achieving remission in steroid-resistant NS. RTX use was generally safe, and most side effects were transient and infusion-related. More randomized, double-blinded clinical studies are needed to assess the role of RTX in children with nephrotic syndrome.     

Long‐term effect of rituximab in maintaining remission of recurrent and plasmapheresis‐dependent nephrotic syndrome post‐renal transplantation – Case report

Grenda R, Jarmu?ek W, Pi?tosa B, Rubik J. Long‐term effect of rituximab in maintaining remission of recurrent and plasmapheresis‐dependent nephrotic syndrome post‐renal transplantation – Case report.
Pediatr Transplantation 2011: 15: E121–E125. © 2010 John Wiley & Sons A/S. Abstract: Early recurrence of nephrotic syndrome after renal transplantation is a common serious adverse event in children with severe primary FSGS, affecting long‐term outcome. There is no consensus in terms of uniform management in these cases. We describe the long‐term effect of four unadjusted doses of 375 mg/m² i.v. rituximab, given to a five and a half‐yr‐old, nephrectomized child with immediate recurrence of nephrotic syndrome post‐transplantation and dependency from repeated PF. Rituximab was introduced at three months post‐transplantation after performing 18 sessions of PF and development of established dependency of the disease from plasma exchange. Complete remission of proteinuria was achieved with four doses, and it was maintained during next eight months of follow‐up. Complete B CD₁₉ cell depletion was observed during four months after final dose, followed by severe depletion after eight months. No side effects of therapy were noted. Patient was free from PF, which was stopped while introducing rituximab, remaining non‐proteinuric on triple immunosuppression (CsA, MMF, Pred).     

Efficiency of Rituximab in treating children with refractory nephrotic syndrome北大核心CSCD

目的评价利妥昔单抗(RTX)在难治性肾病综合征患儿中维持缓解的有效性。方法回顾性研究。将2018年11月至2020年11月华中科技大学同济医学院附属武汉儿童医院肾内科诊断为难治性肾病综合征的22例患儿纳入研究, 予RTX治疗。外周血中CD19+B淋巴细胞≥1%总淋巴细胞者追加1剂RTX(375 mg/m2), 每例患儿使用3~4剂, 早期停用钙调神经磷酸酶抑制剂(CNI), 后续使用霉酚酸酯治疗。采用Kaplan-Meier法对RTX治疗后患儿的蛋白尿无复发率和无频复发肾病综合征或激素依赖肾病综合征发生率进行分析, 采用Wilcoxon秩和检验对使用RTX前后的复发次数进行分析。采用秩和检验对RTX治疗前后患儿的体质量指数(BMI)及身高进行比较。结果 22例患儿中, 20例患儿完成治疗方案, 1年和2年的蛋白尿无复发生存率分别为85%和40%, CNI停用后复发频率降低。所有患儿BMI及身高在使用RTX治疗前与使用RTX 1年后、2年后比较, 差异均有统计学意义(均P<0.05), 使用RTX后1、2年比较, 差异均无统计学意义(均P>0.05)。结论使用RTX在停用激素和其他免疫抑制剂情况下也可有效降低难治性肾病综合征的复发率, 同时可使患儿BMI及身高得到明显改善。RTX治疗难治性肾病综合征患儿安全有效。     

Steroid sensitive nephrotic syndrome

Nephrotic syndrome in children is a common recurrent disease. Most of the cases are due to minimal change disease with a favourable outcome. More than 90% of children with minimal change disease respond to corticosteroid therapy (steroid sensitive nephrotic syndrome). 40-60% experience frequent relapses or have steroid dependence. These children require frequent corticosteroid therapy and/or immunomodulators or treatment with immunosuppressants, and are at high risk of cumulative steroid toxicity and side effects of cytotoxic therapy. Children with frequent relapses or steroid dependence should be managed in consultation with a pediatric nephrologist. Despite relapsing course, progression of minimal change nephrotic syndrome to end stage renal disease is extremely rare.     

Steroid sensitive nephrotic syndrome

Nephrotic syndrome in children is a common recurrent disease. Most of the cases are due to minimal change disease with a favourable outcome. More than 90% of children with minimal change disease respond to corticosteroid therapy (steroid sensitive nephrotic syndrome). 40–60% experience frequent relapses or have steroid dependence. These children require frequent corticosteroid therapy andJor immunomodulators or treatment with immunosuppressants, and are at high risk of cumulative steroid toxicity and side effects of cytotoxic therapy. Children with frequent relapses or steroid dependence should be managed in consultation with a pediatric nephrologist. Despite relapsing course, progression of minimal change nephrotic syndrome to end stage renal disease is extremely rare.     

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.     

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.     

Preparing for a kidney transplant: Medical nephrectomy in children with nephrotic syndrome

Nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, and general edema. These symptoms may persist in children who reach ESRD, which is unfavorable for the patient's allograft outcome. In addition, this may hamper early diagnosis of a relapse after transplantation. Surgical bilateral nephrectomy is often considered for that reason, but medical nephrectomy may be a less invasive alternative. In this retrospective single‐center case series, we identified all children on dialysis with ESRD due to nephrotic syndrome in which a medical nephrectomy was attempted before kidney transplantation between 2013 and 2018. Outcome was measured by urine output and serum albumin levels. Eight patients with either congenital nephrotic syndrome or focal segmental glomerular sclerosis were included in the study. All patients received an ACE inhibitor as drug of first choice for medical nephrectomy, to which 5 patients responded with oligoanuria and a significant rise in serum albumin, and 3 patients responded insufficiently. In 1 of these 3 patients, diclofenac was added to the ACE inhibitor, with good result. In the other 2 patients, indomethacin was initiated without success, and surgical bilateral nephrectomy was performed. Overall, 6/8 patients had a successful medical nephrectomy and did not need surgical nephrectomy. No recurrence of nephrotic syndrome was found after kidney transplantation in all but one. Medical nephrectomy with ACE inhibitors and/or non‐steroidal anti‐inflammatory drugs is a safe and non‐invasive therapy to minimize proteinuria in children with ESRD due to nephrotic syndrome before kidney transplantation. We suggest that this strategy should be considered as therapy before proceeding with surgical nephrectomy.     

Steroid-responsive nephrotic syndrome and allergy: immunological studies.

Immunological studies were performed on 84 children with steroid-sensitive nephrotic syndrome as part of an investigation of the relationship between steroid-responsive nephrotic syndrome and allergy. Serum total IgE levels tended to be raised, particularly in children who had frequent relapses of nephrotic syndrome. Ten children had extremely high levels (greater than 1500 IU/ml) and several of them had neither a history of atopy nor any other identifiable cause. 25% of the children had at least one positive test for specific IgE antibody. IgE was not detected by immunofluorescence in renal biopsy tissue from 25 children, regardless of whether the child was in remission or relapse at the time of biopsy. Serum IgG and IgA levels were depressed particularly at the time of a relapse. Serum IgM tended to be raised and to remain so, even in children who had been in remission for more than a year. No clinically useful relationship was found between the frequency of HLA antigens and the occurrence or course of the syndrome, whether or not accompanied by atopy. Clinical and immunological features of atopy are more common in children with idiopathic nephrotic syndrome. This may be a causal or non-causal association. Pollen sensitivity is a rare cause of nephrotic syndrome; careful search for provocative agents may show other causes.     

Hepatitis B-associated nephrotic syndrome in Jamaican children

Between December 1984 and November 1996, 171 children under 12 years old presented to the University Hospital of the West Indies with nephrotic syndrome. Hepatitis B surface antigen (HBsAg) was found in ten (6%) of these children, eight of whom had membranous nephropathy (MN), and one each had mesangial proliferative glomerulonephritis (MesN) and minimal change nephrotic syndrome (MCNS). Only those children with MesN and MCNS were steroid-sensitive. The HBsAg-positive status was identified incidentally on screening. At a mean follow-up of 34 months, seven of ten children had experienced complete or partial remission and three had persistent nephrotic syndrome, although none was in renal failure. Six of the ten had biochemical hepatitis. All the children were still HBsAg-positive. Hepatitis B virus (HBV) is a factor contributory to nephrotic syndrome in Jamaican children. As diagnostic clinical markers for HBV-associated nephropathy are usually absent, all children presenting with nephrotic syndrome should be screened for HBsAg. A policy should be implemented in Jamaica for screening pregnant women and at-risk groups for HBsAg, as well as for immunising susceptible neonates, in order to reduce the incidence of HBV-associated pathology.     

Recent advances in congenital nephrotic syndrome

PURPOSE OF REVIEW: This review provides a concise update of the most recent literature related to the diagnosis and care of patients with congenital nephrotic syndrome. This topic is of particular interest in light of the rapidly growing body of literature regarding mutations of proteins such as nephrin and podocin that are expressed at or near the podocyte slit diaphragm. RECENT FINDINGS: The phenotypic variance of patients with congenital nephrotic syndrome with nephrin and podocin mutations resulting from triallelic mutations represents an important advance in our understanding of the effect of multiple genetic mutations on clinical disease expression. Clinically, the management of patients with unilateral nephrectomy, rather than the classic bilateral nephrectomy, represents an efficacious alternative management strategy and may impart better chances of graft survival by allowing later transplantation. Identification of a subset of patients with congenital nephrotic syndrome at increased risk of recurrence who also have antinephrin antibodies may enhance our understanding of recurrent disease in congenital nephrotic syndrome after transplantation. SUMMARY: Exciting recent findings in the genotypic/phenotypic correlations of patients with congenital nephrotic syndrome may not only modify our understanding of this disease but may also help to revolutionize our understanding of human genetics. Promising outcomes with unilateral nephrectomy in patients with congenital nephrotic syndrome have permitted transplantation to be delayed and may potentially decrease the risk of complications. New findings regarding recurrence of nephrotic syndrome in patients with congenital nephrotic syndrome after transplantation may lead to improved survival in future renal transplantations.     

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.     

Efficacy of rituximab therapy in children with refractory nephrotic syndrome: a prospective observational study in Shanghai

Background

Idiopathic nephrotic syndrome is the most common glomerular disease in children. This study was undertaken to observe the efficacy and side-effects of rituximab (RTX) in treating children with different types of refractory primary nephrotic syndrome.

Methods

Twelve patients with steroid dependent nephrotic syndrome (SDNS), frequently relapsing nephritic syndrome (FRNS), and steroid resistant nephrotic syndrome (SRNS) were enrolled in our study. There were obvious drug side-effects, and proteinuria remained difficult to control. RTX was administered at a dose of 375 mg/m² body surface area, once or twice weekly.

Results

The male to female ratio was 3:1, and the onset age was 1.6–8.9 years. There were 9 patients with steroid sensitive nephrotic syndrome (SDNS or FRNS), and 3 patients with SRNS. There were 7 patients with minimal change disease (MCD), 3 patients with focal segmental glomerular sclerosis (FSGS), 1 with focal proliferative glomerulonephritis, and 1 without renal biopsy. The total effective treatment rate of RTX was 91.67%, and for 77.78% of the patients, steroid dosage could be reduced. Six months before and after RTX infusion, the mean steroid dosage was significantly decreased (P=0.014) and the recurrence number was significantly reduced (P<0.001). The results were better in MCD patients than in FSGS patients (P=0.045). There was no significant difference between FRNS/SDNS and SRNS patients (P=0.175). During RTX administration, 3 patients developed skin rashes, 1 developed hypotension, and 1 developed a fever. One patient experienced a persistent decrease in serum immunoglobulin level but without serious infection.

Conclusion

RTX was effective in the treatment of refractory nephrotic syndrome, and it could significantly reduce the use of steroid and immunosuppressants.     

Hepatitis B surface antigen associated nephrotic syndrome

Hepatitis B virus (HBV) has been reported in association with the nephrotic syndrome from different parts of the world, but its role as a cause of the pathological findings of nephrotic syndrome is still controversial. We report seven nephrotic children with positive hepatitis B markers in which members of their families were also positive for the markers but without clinical, renal or hepatic involvement. Four showed haematuria at onset and three developed hypertension later in the course of the disease. Only two were responsive to steroid therapy. Renal biopsy was performed in four, of whom three showed membranous nephropathy and the other showed mesangioproliferative glomerulonephritis. Four patients developed end-stage renal disease. We conclude that in our environment HBV, when detected in children with nephrotic syndrome, should not be considered as a chance finding, but may have a definite role in its pathogenesis. Moreover, the prognosis of HBV-associated nephrotic syndrome appears poor.     

Clinical course of congenital nephrotic syndrome and Denys-Drash syndrome in Japan

BACKGROUND: The prognosis of Japanese patients with congenital nephrotic syndrome (CNS) and Denys-Drash syndrome (DDS) is not clear. METHODS: Five patients with CNS and four patients with DDS, which causes secondary CNS, were studied retrospectively. RESULTS: Seven patients were sporadic and two DDS patients were identical twins. Five CNS patients presented with edema within 3 months of birth. In four DDS patients, edema was not noted and end-stage renal disease developed between 7 months and 6 years of age. Of these five CNS patients, one patient had cerebral thrombosis and cytomegalovirus pneumonia at the onset and another patient died during dialysis. Frequent intravenous albumin administration required, growth and development during infancy were varied. Of the nine patients with CNS and DDS, seven received renal transplantation and were alive with functioning grafts at the last follow up. Catch-up growth was observed in five patients after transplantation. Five school-aged patients attended school and received adequate grades and two adults worked full-time. Of the DDS patients, dysuria due to hypospadias persisted in one patient and treatment for hypogonadism was needed in one patient. CONCLUSIONS: CNS and DDS were diagnosed early after onset and adequate treatment was started. Growth and development after renal transplantation were relatively good. Thrombotic episodes or severe infection in CNS patients was difficult to manage and complications resulting from DDS affected the quality of life.     

Single-center analysis of early recurrence of nephrotic syndrome following renal transplantation in children

Recurrence of nephrotic syndrome (NS) after transplantation (Tx) occurs in 20-50% of renal transplant recipients, with a median time to recurrence of 14 days and a 50% rate of graft loss. We performed a retrospective analysis of 22 pediatric patients with NS who received renal transplants at the Children's Hospital, Boston, between 1982 and 1999. During the first 14 days following Tx, 13 (59%) patients developed clinical recurrent nephrotic syndrome (RNS). RNS developed in 50% of living donor recipients and in 70% of cadaveric donor recipients (p= non-significant). Seven of the 13 patients with RNS were treated with plasmapheresis, while six received standard immunosuppressive induction therapy only. Two of the seven treated patients and one of the six untreated patients lost their grafts to RNS, yielding a total RNS graft loss rate of 23%. However, patients with RNS who achieved remission had significantly higher cumulative graft survival at 5 yr than did RNS patients who did not achieve remission (p< 0.001). Overall cumulative graft survival at 5 yr was not significantly different between the two groups: 67% in those with non-recurrent nephrotic syndrome (NRNS) vs. 64% in those with RNS, p= non-significant. We conclude that successful reversal of early RNS improves long-term graft survival in pediatric RNS. Multi-center studies are sorely needed to develop novel, less toxic therapies for native and recurrent NS.     

Evaluation and management of steroid-sensitive nephrotic syndrome

PURPOSE OF REVIEW: This review examines new literature published in 2006 and 2007 on steroid-sensitive nephrotic syndrome. RECENT FINDINGS: Steroid-sensitive nephrotic syndrome has long been thought to be due to lymphocyte-derived circulating factors leading to podocyte injury with subsequent proteinuria. New studies support this mechanism and implicate the T helper 2 cytokine IL-13. In addition a genetic mutation in familial nephrotic syndrome has been reported in a child, who responded to corticosteroid therapy. There are new clinical trial data supporting the efficacy of levamisole in steroid-sensitive nephrotic syndrome and preliminary trial data on mycophenolate mofetil supporting its efficacy as a steroid-sparing agent. Case reports support the use of the B cell-depleting antibody rituximab in steroid-sensitive nephrotic syndrome. Finally there is a meta-analysis of six studies suggesting an increase in the incidence of focal and segmental glomerulosclerosis in steroid-sensitive nephrotic syndrome over the last 20 years. SUMMARY: Progress has been made towards elucidating the cause of steroid-sensitive nephrotic syndrome. Data from adequately powered randomized controlled trials are still required to evaluate therapies for frequently relapsing and steroid-dependent steroid-sensitive nephrotic syndrome.     

利妥昔单抗治疗难治性激素耐药型肾病综合征的疗效和安全性

目的:探讨利妥昔单抗(RTX)治疗儿童难治性激素耐药型肾病综合征(SRNS)的疗效和安全性。方法:回顾性分析2013年9月至2018年3月东部战区总医院儿科收治并接受RTX治疗的10例难治性SRNS患儿的临床资料。结果:10例患儿发病年龄(4.47±2.75)岁,男女各5例;5例(50%)肾活检为局灶节段性肾小球肾炎,...     

Ofatumumab in post‐transplantation recurrence of focal segmental glomerulosclerosis in a child

FSGS is a potentially devastating form of nephrotic syndrome. Treatment of SRNS can be difficult, especially post‐transplantation. The current therapy of post‐transplant SRNS includes plasmapheresis, ACE‐I, CNI, and monoclonal antibodies (rituximab). Patients who are refractory to these interventions have limited therapeutic alternatives. We present a case of a patient with SRNS secondary to FSGS. He did not respond to immunosuppressive medications prior to transplant, progressed to ESRD, and was started on chronic hemodialysis. He received a DDKT which was complicated by post‐transplant FSGS recurrence. A course of plasmapheresis, rituximab, and CNI were administered with some response. Ofatumumab was then given to the patient. As a result, the patient achieved partial remission. Ofatumumab may be a safe and effective option for post‐transplant recurrence of FSGS.     

Gitelman综合征合并肾病综合征1例报告并文献复习

目的总结SLC12A3基因变异致Gitelman综合征的诊断和治疗。方法回顾分析1例Gitelman综合征合并原发性肾病综合征患儿的临床资料,系统复习Gitelman综合征合并蛋白尿文献。结果6岁男性患儿,因肾病综合征复发就诊,持续低钾血症,同时伴尿钠及尿钾排出增多,低镁血症,代谢性碱中毒,低尿钙症,肾素血管紧张素系统激活,血压无异常,无特殊用药史及家族史。全外显子测序发现患儿16号染色体1号外显子SLC12A3基因存在c.179C>T(p.T60M)纯合错义变异(NM_000339),其父母均为携带者;ACMG评分为致病性突变。患儿确诊为肾病综合征合并Gitelman综合征。结论重视Gitelman综合征蛋白尿的评估和随访,保护肾功能。