Maintenance therapy with mycophenolate mofetil after rituximab in pediatric patients with steroid-dependent nephrotic syndrome

Rituximab (RTX) has a significant steroid-sparing effect in children with steroid-dependent nephrotic syndrome (SDNS). However, patients are likely to relapse with the recovery of CD20+ cells. We conducted a small prospective cohort study with a historical control to evaluate the effect of RTX infusion followed by mycophenolate mofetil (MMF) as a maintenance therapy. Nine patients with SDNS who stopped their steroid treatment but were treated with MMF after RTX infusion were prospectively observed (group A). Seven patients with SDNS who discontinued steroid and immunosuppressive agents after RTX administration served as a control (group B). During the first year after the administration of RTX, six patients in group A and one patient in group B did not suffer a relapse (p < 0.05). The number of patients who relapsed during the 1 year preceding RTX treatment did not differ between the two groups [4.1 (A) vs. 5.7 (B)], but it was significantly lower in the MMF-treated group 1 year after the RTX treatment [0.4 (A) vs. 2.3 (B), p < 0.005]. The daily amount of prednisolone after the RTX treatment was lower in group A than in group B (0.11 vs. 0.46 mg/kg/day, respectively; p < 0.05). Three patients in group A and five patients in group B relapsed to SDNS and needed additional RTX treatment(s) within 1 year (odds ratio 5.0). Based on these results, we conclude that maintenance therapy with MMF after RTX is a good clinical option.     

Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy

A 16-year-old patient with steroid-dependent nephrotic syndrome with more than 35 relapses developed severe relapsing idiopathic thrombocytopenic purpura (ITP). At the age of 2 years, nephrotic syndrome was diagnosed and successfully treated with a standard prednisone regimen. Frequent relapses occurred. Treatment with oral cyclophosphamide followed by cyclosporine was successful, but several attempts to withdraw steroids failed and the patient suffered from multiple relapses. At the age of 12 years, renal biopsy revealed focal segmental glomerulosclerosis and cyclosporine toxicity. A second course of oral cyclophosphamide was unsuccessful and tacrolimus resulted in the development of diabetes mellitus, which was reversed after discontinuation of the drug. At the age of 15 years the patient, still being steroid dependent, developed ITP. Neither steroids nor intravenous immunoglobulins induced permanent remission. Only weekly immunoglobulin infusions could temporarily restore the platelet count. To treat ITP in this desperate situation we decided to deplete B-cells with the monoclonal anti-CD20 antibody rituximab. Intravenous infusions of rituximab (375 mg/m²) were given once weekly for 4 consecutive weeks without adverse events. Four weeks after the first rituximab dosage, the thrombocyte count increased to normal values. There has been no subsequent relapse of either thrombocytopenia or nephrotic syndrome (on cyclosporine, without steroids) to date. We conclude that B-cell depletion with rituximab might have altered the course of steroid-dependent nephrotic syndrome in our patient.     

Pharmacokinetics of rituximab in a pediatric patient with therapy-resistant nephrotic syndrome

Background

Rituximab (RTX) has recently been introduced as a second-line therapy for nephrotic syndrome in children. Studies show that RTX given during the nephrotic state may be less effective than treatment during a non-nephrotic state, possibly due to loss of RTX in the urine.

Case-Diagnosis/Treatment

We describe a 10-year-old boy with steroid-resistant nephrotic syndrome (SRNS) treated with RTX during a phase of active non-selective proteinuria. The serum half-life of RTX in this patient was less than 1 day compared to 20 days in patients without protein losses. Urinary clearance was at least 25 %, compared to approximately 0 % in control patients. However, RTX loss in the urine, as well as in pleural effusion and ascites, only partly explains the rapid drop in the serum RTX concentration of this patient.

Conclusions

Serum half-life of RTX can be extremely short, partly due to excessive urinary losses in therapy-resistant nephrotic syndrome with non-selective proteinuria, as seen in our patient. These findings may help to explain the poor results of RTX treatment in patients with active proteinuria.

     

Tacrolimus therapy in pediatric patients with treatment-resistant nephrotic syndrome

This is a retrospective analysis of 16 children started on tacrolimus with various types of treatment-resistant nephrotic syndrome. There are 13 patients with focal glomerulosclerosis, 1 minimal change disease, and 2 IgA nephropathy with nephrosis. The mean age of the children was 11.4 years (range 3.5–18.1 years) with a mean age at diagnosis of 5.6 years (range 1.6–13.3 years). All patients initially received prednisone 2 mg/kg per day. Other therapies for 15 of 16 included cyclosporine (n=15), chlorambucil (n=5), mycophenolate mofetil (n=5), levamisole (n=3), i.v. methylprednisolone (n=3), and cyclophosphamide (n=2). The major indication for the initiation of tacrolimus included treatment resistance/dependence (n=15) and intolerable side effects from other therapies (n=1). The average time from the diagnosis to initiation of tacrolimus was 5.3 years (range 0.3–13.3 years, median 6 years). The initial dosage of tacrolimus utilized was 0.1 mg/kg per day divided into two doses. The mean follow-up period was 6.5 months (range 2.5–18 months). Thirteen patients (81%) went into a complete remission within an average of 2 months (range 0.5–5.5 months), with 3 patients relapsing while on treatment. Three patients did not respond. Of these, 2 had partial remissions (13%) and 1 failed to respond. Adverse events included anemia (n=1), seizure (n=1), worsening or new-onset hypertension (n=5), and sepsis (n=1). All patients remain on tacrolimus. Tacrolimus is an effective, well-tolerated medication for treatment-resistant forms of nephrotic syndrome in children, with a complete remission rate of 81% and a partial remission rate of 13% (totaling 94%).     

利妥昔单抗在难治性肾病综合征中的应用现状

原发性肾病综合征(idiopathic nephrotic syndrome, INS)是儿童及成人常见的肾小球疾病,糖皮质激素是INS治疗的基础用药。对于原发性难治性肾病综合征(idiopathic refractory nephrotic syndrome, IRNS)患者,多数需在糖皮质激素基础上联用其他免疫抑制剂或细胞毒类药物。近年来逐渐有学者利用利妥昔单抗(RTX)治疗IRNS并取得较好疗效,本文主要就IRNS的发病机制及RTX在不同病理类型中的应用情况做一综述。     

Variability among pediatric nephrologists in the initial therapy of nephrotic syndrome

The objective of this study was to describe the practices of North American pediatric nephrologists in treating new-onset steroid-sensitive nephrotic syndrome and impressions regarding the effect of therapy duration on the risk of relapse. A questionnaire was mailed to 130 pediatric nephrologists in the United States and Canada. One hundred and five (81%) replied. Of the respondents, 39% believed a longer steroid regimen results in more-sustained remissions; 19% did not; 18% believed perhaps, but not enough to risk the increased side-effects of the longer steroid regimen; and 24% did not know. Half of the respondents prescribed an 8-week regimen and 21% prescribed a 12-week regimen; however, in 70% of both regimens, respondents appended an additional taper. The remaining respondents either tapered at urinary remission (14%) or used another regimen (15%). Physicians using the 12-week regimen expected 44% of patients to be relapse free at 1 year, compared with 31% of patients of respondents using other regimens (P=0.005). Over the previous 5 years, 38% of respondents changed their approach; of these, 70% lengthened the treatment course. Physician perceptions and strategies did not vary according to years of clinical experience. In conclusion, there is significant variability in practice and perceptions among pediatric nephrologists; however, most have extended therapy beyond the traditional 8-week course. Received: 27 July 1999 / Revised: 22 November 1999 / Accepted: 23 November 1999     

Venous thromboembolism in pediatric nephrotic syndrome

Childhood nephrotic syndrome (NS) is one of the most common pediatric kidney diseases, with an incidence of 2–7 per 100,000. Venous thromboembolism (VTE) is associated with significant morbidity and mortality, and occurs in ～3 % of children with NS, though incidence approaches 25 % in high-risk groups. VTE etiology is multifactorial, with disease-associated coagulopathy thought to be a significant contributor. Other risks include age, disease severity, and treatment-related hazards, such as the presence of central venous catheters. Non-pharmacologic preventive measures such as ambulation and compression stockings are recommended for patients with identified VTE risks. Central venous catheters should be avoided whenever possible. Symptoms of VTE include venous catheter dysfunction, unilateral extremity symptoms, respiratory compromise, flank pain, and gross hematuria. When VTE is suspected, confirmatory imaging studies should be obtained, followed by appropriate laboratory evaluation and treatment. Therapeutic goals include limiting thrombus growth, extension, and embolization by early institution of anticoagulant therapy. Anticoagulation is recommended for a minimum of 3 months, but should be continued until NS remission is achieved. Further studies are necessary to identify VTE-risk biomarkers and optimal therapeutic regimens. Observational cohort studies are needed to identify VTE-risk groups who may benefit from thromboprophylaxis and to define disease-specific treatment algorithms.     

Long-term follow-up after cyclophosphamide therapy in steroid-dependent nephrotic syndrome

Cyclophosphamide (CP) has been used for over 40 years in patients with steroid-sensitive nephrotic syndrome (SSNS) presenting frequent relapses or steroid dependence (SD). We evaluated retrospectively and tried to identify parameters possibly associated with a prolonged and sustained remission (PSR+) ≥5 years in 108 children with steroid-dependent nephrotic syndrome (SDNS) treated with oral CP. Patients had a follow-up time ≥5 years and were divided into two groups according to achievement of PSR (+ and –). Gender, histological injury, cumulative doses of CP, age of onset of illness, and start of treatment and prednisone dose on the occasion of relapse were analyzed. The overall cumulative sustained remission for 5 and 10 years was 25 and 21.6%, respectively. The only factor that influenced a PSR was the degree of SD: the group PSR+ relapsed at prednisone dose of 0.96 ± 0.51 mg/kg vs. 1.29 ± 0.59 mg/kg in group PSR– (p = 0.01). Also, patients who relapsed in the presence of prednisone doses ≤1.4 mg/kg showed a cumulative sustained remission of 43, 35, and 32.7% at 2, 5, and 10 years, respectively, versus 22.5, 12.5, and 5% in those with prednisone >1.4 mg/kg (p = 0.001). Our findings suggest that patients with SDNS who relapse on prednisone dose >1.4 mg/kg are especially prone to an unfavorable response to CP use.     

Single infusion of rituximab for persistent steroid-dependent minimal-change nephrotic syndrome after long-term cyclosporine

Rituximab (RTX) has been successfully used as a rescue therapy in children with steroid-dependent nephrotic syndrome (SDNS). However, little is known regarding maintenance therapy after a successful response to RTX in such patients. The efficacy and safety of a single RTX infusion (375 mg/m²) were assessed in ten patients who had persistent SDNS associated with minimal-change disease (MCD) despite the long-term use of cyclosporine (CsA). The mean follow-up after RTX infusion was 17 months. Applying RTX resulted in a significant reduction in the mean prednisolone (PSL) dose from 0.39 ±0.18 to 0.15 ± 0.14 mg/kg per day. The mean 12-month relapse rates significantly decreased from 4.1 ± 1.7 to 0.6 ± 0.6. All but one patient who had continued CsA as maintenance therapy after a single RTX infusion were able to withdraw from PSL without any relapses during the study period, whereas the remaining five patients who discontinued CsA experienced relapses after CD19 cells re-emerged, leading to the reintroduction of CsA or an additional RTX infusion. Infusion reactions occurred in five of ten patients. These data indicate that a single RTX infusion may improve response to CsA in patients with persistent SDNS due to the phenomenon of secondary resistance to CsA.     

原发性肾病综合征确诊后未即时实施常规激素治疗的130例患儿分析

目的 分析小儿原发性肾病综合征(primary nephrotic syndrome,PNS)在临床上确诊后未即时实施常规糖皮质激素治疗的现象,探讨不同原因以及转归.方法 收集浙江大学医学院附属儿童医院肾内科2005年1月1日至2014年12月31日收治的初次发病的PNS、确诊后未即时使用常规糖皮质激素治疗的患儿的临床资料,进行回顾性分析并随访.结果 研究期间共收治初次发病PNS患儿1 431例,男1 061例,女370例,其中130例未即时进行常规糖皮质激素治疗,占9.1%.130例未即时进行常规糖皮质激素治疗患儿中,75例患儿初发后经对症处理自行缓解;23例直接用促肾上腺皮质激素(ACTH)治疗;1例直接用霉酚酸酯(MMF)治疗;31例拒绝用糖皮质激素或免疫抑制剂治疗.自行缓解的75例中,经5~10年随访有16例持续缓解,39例复发后采用糖皮质激素治疗,6例复发后采用ACTH治疗,失访14例.初治方案为ACTH的29例患儿中持续缓解7例.拒绝用糖皮质激素或免疫抑制剂治疗31例中,死亡1例.单独应用MMF控制不佳.结论 儿童PNS初次发病时,有小部分患儿呈现自行缓解现象,但大多数随后即复发,需要常规糖皮质激素治疗;一般常规糖皮质激素治疗不需要延长等待时间,除非患儿已经发生自行缓解.部分患儿家属不接受糖皮质激素治疗,需要加强沟通.在肾病发病伊始即行ACTH治疗患儿中有长期缓解者,可以进一步观察和研究,以了解ACTH作为初始方案的有效性和安全性.     

Cyclophosphamide and rituximab in frequently relapsing/steroid-dependent nephrotic syndrome

Background

Steroid-sensitive nephrotic syndrome is the most common form of nephrotic syndrome in childhood, defined by the response to treatment with glucocorticoids with consequent remission. While most children eventually experience spontaneous resolution of the disease, some have a difficult course with frequent relapses or steroid dependence nephrotic syndrome (FRSDNS). The consequent steroid toxicity often prompts administration of other immunosuppressive drugs, traditionally cyclophosphamide. Recently, rituximab has been reported as effective in this disorder, but long-term experience is lacking.

Methods

Retrospective note review of all children with FRSDNS treated with a first course of cyclophosphamide and/or rituximab in our center between December 2006 and April 2015. We reviewed time to first relapse after treatment, co-medications, and side effects.

Results

A total of 102 children were treated with cyclophosphamide (79) and/or rituximab (42). Of these, 34 received cyclophosphamide prior to rituximab. Median time to first relapse was 7 months after cyclophosphamide and 14 months after rituximab. Documented side effects of cyclophosphamide included neutropenia, hair loss, and hemorrhagic cystitis (1). Rituximab was associated with an allergic reaction at infusion in two patients.

Conclusions

Rituximab was used in children with the most difficult to treat FRSDNS, yet was associated with longer remission time and less side effects than cyclophosphamide. A randomized controlled trial is needed to directly compare these drugs.

     

Atypical Pneumocystis jiroveci pneumonia with multiple nodular granulomas after rituximab for refractory nephrotic syndrome

Background

Rituximab, an anti-CD20 antibody that targets B cells, is a promising agent against steroid-dependent and steroid-resistant nephrotic syndrome in children.

Case-Diagnosis/Treatment

We report a 3-year-old boy who presented with atypical Pneumocystis jiroveci pneumonia (PCP) following administration of rituximab for refractory nephrotic syndrome. He had received cyclosporine and daily prednisolone for over 1?year. Following rituximab therapy, a hazy shadow was observed on his chest X-ray. Chest-computed tomography revealed multiple nodular lesions in bilateral lungs, although his clinical symptoms were subtle. PCR analysis demonstrated the presence of Pneumocystis DNA in his bronchoalveolar lavage. Lung wedge resection of the nodular lesion exhibited granulomas containing a few cysts of P. jiroveci that primarily consisted of T cells and histiocytes and lacked B cells. A deficiency of B cells following rituximab treatment suggests a dramatic effect on the immune response and, therefore, could result in granulomatous PCP. Nodular granulomatous lesions of PCP comprise an emerging concept previously reported in adults with hematological disease, bone marrow transplant, or treatment with rituximab. We report the first pediatric case of nodular PCP. Granulomatous PCP can be life-threatening. Moreover, bronchoalveolar lavage often fails to demonstrate the presence of P. jiroveci DNA. Wedge biopsy is warranted for definitive diagnosis. Our patient fully recovered with sulfamethoxazole/trimethoprim treatment because of early detection.

Conclusions

The indication of rituximab for refractory nephrotic syndrome has increased recently. Therefore, recognition of the risk of atypical PCP is important. Our findings suggest that PCP prophylaxis should be considered following rituximab therapy.     

Short-term efficacy of rituximab versus tacrolimus in steroid-dependent nephrotic syndrome

Although therapy with intravenous (IV) rituximab and tacrolimus reduces the relapse rate in steroid-dependent nephrotic syndrome (SDNS), studies on comparative efficacy are lacking. We retrospectively reviewed the records of patients with difficult-to-treat SDNS who had previously received levamisole, cyclophosphamide and/or mycophenolate mofetil, then treated with either rituximab or tacrolimus and followed for 12 months. Between January 2009 and April 2010, ten patients received two to three doses of IV rituximab (375 mg/m²/week) and 13 received tacrolimus (0.1–0.2 mg/kg/day) for 12 months; none had previously received either agent. Patients received tapering doses of alternate-day prednisolone; other immunosuppressive agents were discontinued. The mean age of the patients at treatment initiation with rituximab and tacrolimus was 12.2 ± 2.3 and 12.3 ± 3.0 years, respectively. The respective pre-treatment relapse rates (3.1 ± 1.1 and 3.5 ± 1.6 relapses per year) and cumulative prednisolone dose (137.2 ± 69.4 and 140.5 ± 59.0 mg/kg/year) were similar. Therapy resulted in a decline in relapse rate in both groups (P < 0.001). The number of relapses in the rituximab and tacrolimus groups was similar at 6 months (0.3 ± 0.5 vs. 0.3 ± 0.6 episodes, respectively), 12 months (0.8 ± 1.0 vs. 0.9 ± 1.1 episodes) and last follow-up (1.2 ± 1.0 vs. 1.5 ± 1.3 episodes). There were no differences in relapse-free survival at 6, 12 and 18 months. Therapy resulted in a significant decline in the cumulative prednisolone dose (67.2% in the rituximab group and 43.6% in the tacrolimus group) and a reduced body mass index. These findings suggest that in our patients with difficult-to-treat SDNS, treatment with two to three doses of rituximab was as effective as 12 months of therapy with tacrolimus in terms of steroid sparing and reduction in the relapse rate.