Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

Rituximab, a chimeric anti-CD20 monoclonal antibody originally licensed for lymphoma, is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children. The potential use of anti-CD20 monoclonal antibodies in idiopathic nephrotic syndrome has contributed to shifting the view of podocytopathies from T cell–mediated to more complex immunomediated disorders that can benefit from targeting B cells and other mediators of the early immune response. Clinical data on the use of rituximab also have implications on disease management and classification. In this review, we present results of clinical studies that support rituximab as an effective steroid-sparing agent in steroid-dependent idiopathic nephrotic syndrome. Recent randomized controlled trials suggest that potential benefits of rituximab therapy in steroid-dependent forms of idiopathic nephrotic syndrome vary depending on whether children are dependent on steroids alone or on both steroids and calcineurin inhibitors, with greater probabilities to achieve drug-free remission in the former group. Multiple-drug dependence may identify a different disease state with different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this patient population.     

AKI in Children Hospitalized with Nephrotic Syndrome

Background and objectives

Children with nephrotic syndrome can develop life-threatening complications, including infection and thrombosis. While AKI is associated with adverse outcomes in hospitalized children, little is known about the epidemiology of AKI in children with nephrotic syndrome. The main objectives of this study were to determine the incidence, epidemiology, and hospital outcomes associated with AKI in a modern cohort of children hospitalized with nephrotic syndrome.

Design, setting, participants, & measurements

Records of children with nephrotic syndrome admitted to 17 pediatric nephrology centers across North America from 2010 to 2012 were reviewed. AKI was classified using the pediatric RIFLE definition.

Results

AKI occurred in 58.6% of 336 children and 50.9% of 615 hospitalizations (27.3% in stage R, 17.2% in stage I, and 6.3% in stage F). After adjustment for race, sex, age at admission, and clinical diagnosis, infection (odds ratio, 2.24; 95% confidence interval, 1.37 to 3.65; P=0.001), nephrotoxic medication exposure (odds ratio, 1.35; 95% confidence interval, 1.11 to 1.64; P=0.002), days of nephrotoxic medication exposure (odds ratio, 1.10; 95% confidence interval, 1.05 to 1.15; P<0.001), and intensity of medication exposure (odds ratio, 1.34; 95% confidence interval, 1.09 to 1.65; P=0.01) remained significantly associated with AKI in children with nephrotic syndrome. Nephrotoxic medication exposure was common in this population, and each additional nephrotoxic medication received during a hospitalization was associated with 38% higher risk of AKI. AKI was associated with longer hospital stay after adjustment for race, sex, age at admission, clinical diagnosis, and infection (difference, 0.45 [log]days; 95% confidence interval, 0.36 to 0.53 [log]days; P<0.001).

Conclusions

AKI is common in children hospitalized with nephrotic syndrome and should be deemed the third major complication of nephrotic syndrome in children in addition to infection and venous thromboembolism. Risk factors for AKI include steroid-resistant nephrotic syndrome, infection, and nephrotoxic medication exposure. Children with AKI have longer hospital lengths of stay and increased need for intensive care unit admission.     

Cytokine Gene Polymorphisms in Chinese Children with Idiopathic Nephrotic Syndrome

Background: Cytokines play a role in the progression of idiopathic-nephrotic syndrome (INS). Objectives: To investigate the association of different cytokine genes polymorphisms with INS incidence and response to steroid therapy in Chinese children. Methods: 182 children with INS and 100 healthy controls were enrolled in this study. Blood genomic DNAs were used to analyze20 single nucleotide polymorphisms (SNPs) in 8 cytokine genes includingIL-21, IL-18, IL-6, IFN-γ, IL-4, IL-10, IL-17F, IL-17A d by multi-PCR with next-generation sequencing. Results: Among 182 children with INS, 89 (48.6%) were steroid-sensitive (SS), 73 (39.9%) were steroid-dependent (SD) and 21 (11.5%) were steroid-resistant (SR). In 20 SNPs, IL-4-rs2243283 exhibited a significantly different genotype distribution between INS and the healthy controls (CC is a risk genotype: 66.5% of INS VS 51% of the control; OR=1.91, p=0.012). Patients carrying AG genotype (rs2275913, IL-17A) had a significantly higher risk of steroid-dependent response (69.1% of SD VS 46.4% of SS; OR=2.58, p=0.014). Similarly, patients carrying A allele of IL-10-rs1800872 (39.0% of SD VS 26.7% of SS; OR=1.76, p=0.018) and C allele of IL-10-rs1800896 (12.3% of SD VS 3.9% of SS; OR=3.44, p=0.004) had a higher risk of steroid-dependent response. However, none of these 20 SNPs showed a significant difference between SS group and SR group. Conclusion: Among the 20 cytokine gene SNPs, IL-4-rs2243283 might increase the susceptibility to INS in Chinese children; rs2275913 of IL-17A, rs1180972, and rs1800896 of IL-10 show association with the steroid -response in Chinese INS children.     

Risk Factors for Cyclosporin A Nephrotoxicity in Children with Steroid-Dependant Nephrotic Syndrome

Background and objectives: Cyclosporin A (CsA) is a well-established treatment for steroid-dependent nephrotic syndrome (SDNS) that may, however, cause chronic ischemic renal lesions. The objective of the study was to assess the prevalence of CsA nephrotoxicity (CsAN) in protocol biopsies of children with SDNS.Design, settings, participants, & measurements: From 1990 through 2008, we performed 71 renal biopsies in 53 patients with SDNS. The mean CsA C2 levels were 466 ± 134 ng/ml, and the mean duration of treatment was 4.7 ± 2.0 yr before biopsy (range 2.9 to 12.7 yr).Results: CsAN was observed in 22 (31%) of 71 renal biopsies. Of these, 11 corresponded to isolated vascular or tubular lesions, and 11 corresponded to combined vascular and tubular lesions. The majority of CsAN lesions were mild (17 of 22). In no cases were lesions graded as severe. By regression analysis, CsAN was positively associated with the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and with hyperuricemia and negatively associated with minimal-change lesions. By multivariate analysis, only association with the use of ACEIs or ARBs retained significance. Stratification of the population according to CsA C2 levels showed increased risk for CsAN for C2 levels >600 ng/ml.Conclusions: Mild to moderate CsAN occurs in approximately one third of patients who have SDNS and are treated with CsA for >3 yr. Our data suggest that patients who require high dosages of CsA or treatment for hypertension, in particular when ACEIs/ARBs are used, are at higher risk for CsAN.The efficacy of cyclosporin A (CsA) in reducing the relapse rate of patients with steroid-dependent nephrotic syndrome (SDNS) and inducing remissions in a substantial number of patients with nongenetic forms of steroid-resistant nephrotic syndrome is well established (1–4). CsA has immunosuppressive effects that decrease disease activity and acts directly on podocytes to stabilize their cytoskeleton (5,6).As new treatments for SDNS become available, indications for CsA therapy need to be balanced against its adverse effects. Among these, chronic CsA nephrotoxicity (CsAN) is one of the most concerning. CsA causes vasoconstriction of afferent arterioles that is mediated by various mechanisms, including direct stimulation of smooth muscles cells, endothelial activation, and upregulation of local vasoconstrictive mediators (4).There are no reliable clinical and biologic markers for CsAN, and performing renal biopsies is the only approach to detect early signs of ischemic renal damage caused by CsA. No consensus exists on the indication of performing protocol biopsies in patients who have SDNS and are treated with CsA.Since 1990, we have performed systematic biopsies in all patients who are treated with prolonged cycles of CsA. In this work, we retrospectively analyzed these biopsies to assess the prevalence of CsAN lesions, the risk factors for the development of CsAN, and the clinical benefits of performing systematic biopsies in patients who have SDNS and are treated with CsA.     

Clinical Utility of Genetic Testing in Children and Adults with Steroid-Resistant Nephrotic Syndrome

Summary

Background and objectives

The increasing number of podocyte-expressed genes implicated in steroid-resistant nephrotic syndrome (SRNS), the phenotypic variability, and the uncharacterized relative frequency of mutations in these genes in pediatric and adult patients with SRNS complicate their routine genetic analysis. Our aim was to compile the clinical and genetic data of eight podocyte genes analyzed in 110 cases (125 patients) with SRNS (ranging from congenital to adult onset) to provide a genetic testing approach.

Design, setting, participants, & measurements

Mutation analysis was performed by sequencing the NPHS1, NPHS2, TRPC6, CD2AP, PLCE1, INF2, WT1 (exons 8 and 9), and ACTN4 (exons 1 to 10) genes.

Results

We identified causing mutations in 34% (37/110) of SRNS patients, representing 67% (16/24) familial and 25% (21/86) sporadic cases. Mutations were detected in 100% of congenital-onset, 57% of infantile-onset, 24 and 36% of early and late childhood-onset, 25% of adolescent-onset, and 14% of adult-onset patients. The most frequently mutated gene was NPHS1 in congenital onset and NPHS2 in the other groups. A partial remission was observed in 7 of 26 mutation carriers treated with immunosuppressive agents and/or angiotensin-converting enzyme inhibitors. Patients with NPHS1 mutations showed a faster progression to ESRD than patients with NPHS2 mutations. None of these mutation carriers relapsed after kidney transplantation.

Conclusions

We propose a genetic testing algorithm for SRNS based on the age at onset and the familial/sporadic status. Mutation analysis of specific podocyte-genes has a clinical value in all age groups, especially in children.     

Meta-analysis on Huaiqihuang Granule Combined with Glucocorticoid in the Treatment of Primary Nephrotic Syndrome in Children

<正>Objective To evaluate the efficacy and safety of the combination therapy of Huaiqi-huang Granule and glucocorticoid in the treatment of children with primary nephrotic syndrome (NS) by Meta-analysis. Methods All     

Characterization of Human Heterophile Antibodies Apparently Induced by Alloimmunization

Human heterophile antibodies reactive with various tissues of different species may be detected by indirect immunofluorescence. Results of screening sera obtained after rhesus immunization and before and after blood transfusion and renal transplantation suggest that such antibodies can appear following alloimmunization of group A and O individuals. Eleven positive sera selected for detailed study were found to have anti-B isohaemagglutinins together with rat erythrocyte agglutinins. Absorption studies suggested that there may be some relationship between the group B antigen and the rat antigen concerned but the precise explanation for alloimmunization remains to be determined.     

Short-Duration Prednisolone in Children with Nephrotic Syndrome Relapse: A Noninferiority Randomized Controlled Trial

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Long-Term Outcome of Biopsy-Proven,Frequently Relapsing Minimal-Change Nephrotic Syndrome in Children

Background and objectives: Frequently relapsing and steroid-dependent minimal-change nephrotic syndrome (MCNS) that originates in childhood can persist after puberty in >20% of patients. These patients require immunosuppressive treatment during several decades of their life. We examined long-term adverse effects of persistent nephrotic syndrome and immunosuppressive medications, focusing on renal function, growth, obesity, osteoporosis, hypertension, ocular complications, and fertility in adult patients with biopsy-proven childhood-onset MCNS. Molecular analysis was performed to evaluate a possible association of a complicated course of MCNS with podocyte gene mutations.Design, setting, participants, & measurements: We performed a prospective clinical examination of 15 adult patients that included serum and urine analysis; dual-energy x-ray absorptiometry; ophthalmologic examination; semen examination; and molecular analysis of NPHS1, NPHS2, CD2AP, and ACTN4 genes.Results: All patients had normal GFR. Most frequent long-term complications were hypertension (in seven of 15 patients) and osteoporosis in one third of patients. Oligozoospermia was found in one patient, reduced sperm motility in four of eight patients, and teratozoospermia in six of eight patients. Ophthalmologic examination revealed myopia in 10 of 15 patients and cataract in three of 15 patients.Conclusions: Children with MCNS that persists after puberty are at risk for complications such as osteoporosis, hypertension, cataract, and sperm abnormalities. Our study underscores a need for more effective and less toxic therapies for relapsing MCNS.Minimal-change nephrotic syndrome (MCNS) accounted for 77% of all cases of childhood nephrotic syndrome in a series of the International Study of Kidney Diseases in children (1). In general, long-term outcome of this disease is favorable, and treatment with prednisone leads to complete remission in one third of patients (1,2); however, 30% of these children develop a frequently relapsing course (FRNS) (1). In this case, patients are treated with cyclophosphamide (CP). If relapses persist afterward, then treatment with cyclosporin A (CsA) is given, which allows tapering of the steroid dosage but frequently leads to CsA dependence, necessitating long-term immunosuppressive treatment. The percentage of childhood MCNS that relapses in adulthood varied from 10 to 40% in the recent studies (2–4). There are few data about the long-term prognosis in this group of patients, especially concerning possible adverse effects of the immunosuppressive medication.Although mutations in proteins expressed by glomerular podocytes were demonstrated in up to 30% of children with steroid-resistant FSGS (5,6), it remains undetermined whether underlying genetic alterations determine the susceptibility for MCNS or predispose for a more severe course of the disease. The aim of this study was to evaluate the long-term outcome of children with biopsy-proven MCNS that persisted after puberty.     

小儿扩张型心肌病测定抗心磷脂抗体的临床意义

应用酶联免疫吸 试验对３０例扩张型心肌病患儿和４０例健康儿童进行了抗心磷脂抗体测定,包括ＡＣＡ－ＩｇＧ、ＡＣＡ－ＩｇＡ和ＡＣ－ＩｇＭ;ＤＣＭ患儿同时检查肌酸磷酸激酶心肌同功酶、心电图、多普勒超过心动图。     

肾病综合征患者尿蛋白和血白蛋白浓度与血脂异常的关系

为研究原发性肾病综合征时大量蛋白尿和低白蛋白血症与脂质代谢异常之间的关系，检测20例住院原发性肾病综合征病人24h尿蛋白排泄量、血白蛋白浓度、血总胆固醇及低密度脂蛋白浓度。结果发现，肾病综合征病人都有明显的脂质代谢异常，尿蛋白量和血总胆固醇浓度呈正相关（r=0．43，P＜0．05），和低密度脂蛋白有一定相关，但无统计学意义（r＝0．37，P＞0．05）；血白蛋白浓度和血总胆固醇及低密度脂蛋白均呈明显负相关（分别为r=-0．69，P＜0．01及r=-0．51，P＜0．01）。提示，肾病综合征时蛋白尿和低白蛋白血症与脂质代谢异常存在明显的相关关系。     

Nephrotic Syndrome Associated with Buerger's Disease

We herein report a 43-year-old woman with Buerger''s disease who presented with nephrotic syndrome, renal dysfunction, and mild hypertension. A kidney biopsy revealed focal segmental glomerulosclerosis (FSGS), but there were no findings associated with frequent secondary FSGS or a history of long-term hypertension. A small focal renal infarction was seen on ^99mTc-dimercaptosuccinic acid renal scintigraphy, suggesting that FSGS was due to renal microinfarction associated with Buerger''s disease. After the commencement of angiotensin-converting enzyme inhibitor therapy, the hypertension immediately improved, along with significant attenuation of proteinuria. Renal ischemia by vasoconstriction of the glomerular efferent arterioles in association with Buerger''s disease may result in glomerular hyperfiltration followed by FSGS.     

Comparison of Immunoblotting and ELISA for Detection of Anti-Ganglioside Antibodies in Children with Guillain-Barre Syndrome

Background: Anti-ganglioside antibody assays are widely used for diagnosis of autoimmune peripheral neuropathies. Objective: This study aimed to determine serum levels of anti-ganglioside antibodies in children with Guillain-Barre syndrome by immunoblotting technique and compare the results with those obtained by ELISA method. Method: In this investigation, 50 children with Guillain-Barre syndrome (GBS) who were admitted from July 2006 to July 2008, to Tabriz Children’s hospital in the northwest of Iran were studied. 30 children admitted for various other reasons than GBS were randomly selected as a control group. The levels of anti-ganglioside antibodies in serum were measured by ELISA and immunoblotting methods using commercial kits. Results: Anti-ganglioside antibodies (IgG) were detected in 16 (32%) GBS patients and in 1 (3.3%) control using ELISA assay. However, by employing immunoblotting technique, antibodies against seven gangliosides were found positive in 28 (56%) GBS patients and none in the control group. The sensitivities of immunoblotting and ELISA methods were 56% and 32% and their specificities were 100% and 97%, respectively (p<0.001). Conclusion: According to the clinical criteria of GBS, the specificity and sensitivity of immunoblotting was better than those of ELISA. It is important to notice that the immunoblotting method is able to measure the seven types of antibodies (GM1, GM2, GM3, GD1a, GD1b, GT1b, and GQ1b) simultaneously and it is an easy, routine method with a lower cost.     

Short-Term Effects of Rituximab in Children with Steroid- and Calcineurin-Dependent Nephrotic Syndrome: A Randomized Controlled Trial

Summary

Background and objectives

Prednisone and calcineurin inhibitors are the mainstay therapy of idiopathic nephrotic syndrome (INS) in children. However, drug dependence and toxicity associated with protracted use are common. Case series suggest that the anti-CD20 monoclonal antibody rituximab (RTX) may maintain disease remission.

Design, setting, participants, & measurements

This open-label randomized controlled trial was powered to show that a strategy based on RTX and lower doses of prednisone and calcineurin inhibitors was noninferior to standard doses of these agents in maintaining 3-month proteinuria as low as baseline or up to 1 g/d greater (noninferiority margin). Participants were stratified by the presence of toxicity to prednisone/calcineurin inhibitors and centrally assigned to add RTX (Mabthera, 375 mg/m² intravenously) to lower doses of standard agents or to continue with current therapy alone. The risk of relapse was a secondary outcome.

Results

Fifty-four children (mean age 11 ± 4 years) with INS dependent on prednisone and calcineurin inhibitors for >12 months were randomized. Three-month proteinuria was 70% lower in the RTX arm (95% confidence interval 35% to 86%) as compared with standard therapy arm (intention-to-treat); relapse rates were 18.5% (intervention) and 48.1% (standard arm) (P = 0.029). Probabilities of being drug-free at 3 months were 62.9% and 3.7%, respectively (P < 0.001); 50% of RTX cases were in stable remission without drugs after 9 months.

Conclusions

Rituximab and lower doses of prednisone and calcineurin inhibitors are noninferior to standard therapy in maintaining short-term remission in children with INS dependent on both drugs and allow their temporary withdrawal.     

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort

Background and objectives

Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome.

Design, setting, participants, & measurements

Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal.

Results

Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%–16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%–45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis.

Conclusions

The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.     

Early Markers of Tubulointerstitial Fibrosis in Children With Idiopathic Nephrotic Syndrome: Preliminary Report

Tubulointerstitial fibrosis and tubular atrophy play a crucial role in the pathogenesis of chronic kidney disease (CKD). They are also major determinants in chronic kidney disease development and progression in patients with primary renal diseases characterized by persistent or recurrent proteinuria. The purpose of the study was to assess urinary excretion of alpha-glutathione S-transferase (alpha-GST), pi-glutathione S-transferase (pi-GST), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and serum NGAL level in children with idiopathic nephrotic syndrome (INS). Patients and methods: the study group comprised of 39 children with INS and the control group consisted of 20 healthy children. A total of 23 patients were affected with steroid-dependent nephrotic syndrome (SDNS) and 16 with steroid-resistant nephrotic syndrome (SRNS). In the majority of patients, a histopathologic examination revealed minimal change disease (MCD)—25 (64%). Focal segmental glomerulosclerosis (FSGS), mesangioproliferative glomerulonephritis (MesPGN), membranoproliferative glomerulonephritis (MPGN), and membranous glomerulonephritis (MGN) were diagnosed in 4 (10.3 %), 6 (15.5%), 2 (5.1%), and 2 (5.1%) children, respectively. Urinary alpha-GST, urinary pi-GST, urinary KIM-1, and urinary and serum NGAL concentrations were measured using specific enzyme-linked immunosorbent assay. The urinary results were expressed in nanograms per milligram of creatinine (ng/mg). Results: The authors observed significantly higher levels of urinary alpha-GST/creatinine ratio (P = 0.03), urinary KIM-1/creatinine ratio (P < 0.02), serum NGAL level (P < 0.01), and urinary NGAL/creatinine ratio (P = 0.02) in children with INS compared with controls. The median values of urinary pi-GST/creatinine ratio in children with INS and controls did not differ significantly. In children with SRNS, the median values of urinary NGAL/creatinine ratio (P = 0.02) and urinary KIM-1/creatinine ratio (P = 0.02) were significantly higher compared with children with SDNS. The authors noted significant positive correlation between KIM-1/creatinine ratio and proteinuria (r = 0.56, P < 0.05). The analysis of alpha-GST/creatinine ratio, pi-GST/creatinine ratio, sNGAL, and uNGAL/creatinine ratio concerning the histopathologic examination, the duration of the disease, and number of relapses did not show any significant differences. Conclusions: 1. Both children with SDNS and those with SRNS were characterized by increased tubular injury marker levels. 2. Patients with SRNS and higher proteinuria are more susceptible to early kidney damage.     

Nephrotic Syndrome Associated with Chronic Lymphocytic Leukaemia

The simultaneous presentation of B-cell chronic lymphocytic leukaemia and nephrotic syndrome is described. The leukaemia responded to cytotoxic therapy but prednisolone was required to achieve remission of the nephrotic syndrome. The nephrotic syndrome relapsed when the leukaemia again became active and the white cell count rose above 20 × 10 9 /l, and it remitted again with treatment. The relationship between the two diseases is discussed.     

Antithrombin III and the Nephrotic Syndrome

Plasma and urinary antithrombin III (AT-III) was measured in 15 cases of nephrotic syndrome. Plasma AT-III correlated well with serum albumin, but poorly with pro-teinuria, whereas urinary AT-III correlated well to proteinuria. The plasma AT-III level had a mean similar to 25 healthy controls, but the range was significantly wider. A case with nephrotic syndrome and left renal vein thrombosis is reported. The urinary output of AT-III rose and the plasma level fell with the activity of the disease. Although AT-III and albumin have similar molecule weight, their renal clearance was found to be different. It is suggested that urinary loss of AT-III plays a role in the hypercoagulable state sometimes found in the nephrotic syndrome.