Preventing Relapses in Childhood Nephrotic Syndrome

The majority of children with steroid sensitive idiopathic nephrotic syndrome (SSNS) will eventually attain complete remission. Treatment balances side effects of different immunosuppressants whilst we await disease resolution. Rituximab decreases the risk of relapses in children with frequently relapsing nephrotic syndrome (FRNS) or steroid dependant nephrotic syndrome (SDNS) who still have difficult to control disease on other steroid-sparing agents.(1Iijima K. Sako M. Nozu K. Mori R. Tuchida N. Kamei K. et al.Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial.Lancet. 2014; 384: 1273-1281Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 2Ravani P. Rossi R. Bonanni A. Quinn R.R. Sica F. Bodria M. et al.Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial.J Am Soc Nephrol. 2015; 26: 2259-2266Crossref PubMed Scopus (140) Google Scholar, 3Chan EY-h Webb H. Yu E. Ghiggeri G.M. Kemper M.J. Ma AL-t et al.Both the rituximab dose and maintenance immunosuppression in steroid-dependent/frequently-relapsing nephrotic syndrome have important effects on outcomes.Kidney Int. 2020; 97: 393-401Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar) More recently, rituximab has been trialled with good effect as a first-line steroid-sparing agent in children with FRNS/SDNS.(4Basu B. Sander A. Roy B. Preussler S. Barua S. Mahapatra T.K.S. et al.Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome: A Randomized Clinical Trial.JAMA Pediatr. 2018; 172: 757-764Crossref PubMed Scopus (82) Google Scholar, 5Kari J.A. Alhasan K.A. Albanna A.S. Safdar O.Y. Shalaby M.A. Böckenhauer D. et al.Rituximab versus cyclophosphamide as first steroid-sparing agent in childhood frequently relapsing and steroid-dependent nephrotic syndrome.Pediatr Nephrol. 2020; 35: 1445-1453Crossref PubMed Scopus (11) Google Scholar, 6Ravani P. Lugani F. Drovandi S. Caridi G. Angeletti A. Ghiggeri G.M. Rituximab vs Low-Dose Mycophenolate Mofetil in Recurrence of Steroid-Dependent Nephrotic Syndrome in Children and Young Adults: A Randomized Clinical Trial.JAMA Pediatr. 2021; 175: 631-632Crossref PubMed Scopus (20) Google Scholar). In this issue, Liu et al ask if using rituximab in conjunction with prednisone for the presenting episode of SSNS can decrease the risk of developing FRNS/SDNS.(7Liu J, Deng F, Wang X, Liu C, Zhang R et al. Early Rituximab as an Add-On Therapy in Children with the Initial Episode of Nephrotic Syndrome, KI Reports. in press.Google Scholar) They undertook a single-arm, open label, prospective study in China of a single 375mg/m2 dose of rituximab after remission of the initial presentation. Forty-four children were enrolled, median age 4 years, 77% male and all had B cell depletion after the single dose of rituximab. One child was lost to follow up. At 12 months 32/43 (74%) remained in remission and 5/43 (12%) had FRNS/SDNS. At 24 months 27/43 (63%) remained relapse free with rates of FRNS/SDNS not reported. Significant neutropenia occurred in 9% of children and infusion-related reactions in 3%. Relapse rates for Liu et al were markedly better than other much larger trials and cohort studies, but marked heterogeneity between studies makes it difficult to compare outcomes. Over the last 50 years, various prednisone courses induced slightly different short-term remission rates, however by 2 years most children had relapsed.(8Tarshish P. Tobin J.N. Bernstein J. Edelmann C.M.J. Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children.J Am Soc Nephrol. 1997; 8: 769-776Crossref PubMed Google Scholar, 9Trautmann A. Boyer O. Hodson E. Bagga A. Gipson D.S. Samuel S. et al.IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome.Pediatr Nephrol. 2023; 38: 877-919Crossref PubMed Scopus (39) Google Scholar) In 3200 children, the relapse free rate at around 2 years was 26%, compared to 63% for Liu et al. (Figure 1) ( See supplemental references S1, S2, S3, S4, S5) In 2600 children, the rate of SDNS/FRNS by 12 months post presentation was 43% compared to 12% for Liu et al.(S3, S5, S4, S7, S8, S9) The relapse rates in the study by Liu et al are also superior to other trials of rituximab in children previously only treated with prednisone. (Table 1). The largest study randomized Indian children with SDNS and no prior steroid-sparing agent to receive either rituximab or tacrolimus.(4, S10) The rituximab group had a 90% sustained remission rate by 12 months, which dramatically dropped to 0% by 24 months, compared to 63% remission rate at 24 months in the study by Liu et al.(S10) A large retrospective study of children who had varying steroid sparing agents prior to rituximab found one-year remission rates ranged from 20-50% in children with severe disease (2-3 immunosuppressive drugs prior to rituximab) and 60-90% in children with milder disease.(S11) Comparisons between studies are difficult. The aforementioned studies all capture different populations, with different severity of disease, at different times in the disease course and at differing risks of future relapse. The work by Liu et al involves an unselected cohort at first presentation of disease and hence at much lower risk of relapse. Ethnic differences and the inherent uncertainty in small sample sizes may also account for the differing relapse rates. In addition, the Liu study involves no randomised control arm of standard care for comparison.Table 1Relapse rates in children treated with rituximab with no prior steroid sparing agentStudyPopulation1 year relapse (%)2 year relapseRituximab doseLiu et al(7Liu J, Deng F, Wang X, Liu C, Zhang R et al. Early Rituximab as an Add-On Therapy in Children with the Initial Episode of Nephrotic Syndrome, KI Reports. in press.Google Scholar)First presentation11/4326%16/4337%1 x 375 mg/m2Basu 2018, Basu 2023(4, S10)SDNS6/5910%59/59100%2-4 x 375 mg/m2Kari 2020(5)FRNS or SDNS3/1916%-2 x 375 mg/m2Ravani 2021(6)SDNS2/1513%-1 x 375 mg/m2Legend: Note that some children in Ravani et al had previously had other steroid sparing agents > 6 months before recruitment Open table in a new tab Legend: Note that some children in Ravani et al had previously had other steroid sparing agents > 6 months before recruitment In contrast, an intriguing explanation for the apparent dramatic decrease in the risk of relapse could be that rituximab, when given at disease onset, may change the natural course of the disease. The physiopathology of SSNS is still unclear, but recent studies suggest a role for anti-nephrin antibodies that cause disruption of the glomerular filtration barrier.(S12) Hypothetically, early rituximab therapy could prevent the formation of long-lived plasma cells that cause relapsing disease. To date, no disease-modifying drugs have been identified in SSNS. However, trials testing rituximab in SSNS suggest that a limited number of patients do not relapse after rituximab therapy, which could indicate permanent effects of RTX on the immune system. Limited other data exists for rituximab use at first presentation of nephrotic syndrome, because of concerns about the risk-benefit profile. Three Chinese children treated with 4 doses of rituximab attained remission within 2 weeks and were relapse free at 4 months.(S13) In adults, case reports of 24 Chinese and Italian adults with first presentation of minimal change disease revealed most gained remission after rituximab.(S14, S15, S16) Reluctance to perform these studies stems from concerns of over-treating patients with mild disease using a drug with rare but significant side effects. Rare, but potentially serious adverse events include rituximab-associated lung injury, anaphylactic reactions, fulminant myocarditis, hepatitis B virus reactivation, severe colitis, and possibly, multifocal leukoencephalopathy.(S17) In addition, post-rituximab hypogammaglobulinemia is of concern, occurring in 14-58% of children.(S18) In a French multicenter study including 107 children with SDNS, 43% of patients experienced at least one episode of hypogammaglobulinemia that persisted for more than 1 year in 12% of cases.(S19) Similar rates were reported in an Italian study including 27 patients with SDNS, four of whom developed severe persisting hypogammaglobulinemia requiring long-term periodic immunoglobulin substitution.(S20) Importantly, younger children were at higher risk of developing hypogammaglobulinemia in both studies, which corresponds to the age of patients that present with a first episode of SSNS, such as those that were included in the study by Liu et al. Should we envision treating all children with rituximab at disease onset? Firstly, the authors should continue monitoring their cohort to inform the scientific community on the outcome of their patients in the long term. If a significant proportion of patients remain in remission after 4-5 years, the risk/benefit ratio of treating children with rituximab at disease onset would favor testing this more aggressive approach. Any future studies should include a randomised control group treated with standard prednisone-based protocols, in order to compare benefits and side effects of therapy. Given 50% of children are likely to have no to infrequent relapses, rituximab administration in the initial presentation poses risks without benefits to around half of children. Potential factors associated with developing FRNS/SDNS include younger age at first presentation, longer time until remission and shorter time to first relapse.(S6, S8, S19, S21, S22, S23) Any potential future trials could target these subgroups to further maximise risk-benefit balances. Download .pdf (.05 MB) Help with pdf files Early Rituximab as an Add-On Therapy in Children With the Initial Episode of Nephrotic SyndromeKidney International ReportsPreviewThe approximately 70% 12-month relapse in children experiencing the initial episode of steroid-sensitive nephrotic syndrome (SSNS) is a significant concern, with over 50% developing frequent relapses or steroid-dependent nephrotic syndrome (FRNS/SDNS). There is a lack of strategies to reduce relapse after the onset. Whether early administration of rituximab, which effectively reduces relapses in FRNS/SDNS, may be a solution has not been evaluated. Full-Text PDF Open Access