Childhood-onset Lupus Nephritis Research Articles

PM2.5 constituents associated with mortality and kidney failure in childhood-onset lupus nephritis: A 19-year cohort study

BackgroundChildhood-onset lupus nephritis (cLN) is a severe form of systemic lupus erythematosus (SLE) with high morbidity and mortality. The impact of long-term exposure to fine particulate matter (PM2.5) on adverse outcomes in cLN remains unclear. MethodsWe combined a 19-years cLN cohort from seven provinces in China with high-resolution PM2.5 dataset from 2001 to 2020, investigating the association between long-term exposure to PM2.5 and its constituents (sulfate, nitrate, organic matter, black carbon, ammonium) with the risk of death and kidney failure, analyzed with multiple variables Cox models. We also evaluated the association between 3-year average PM2.5 exposure before study entry and baseline SLE disease activity index (SLEDAI) scores using linear regression models. ResultsEach 10 μg/m3 increase in annual average PM2.5 exposure was associated with an increased risk of death and kidney failure (HR = 1.58, 95 % CI: 1.24–2.02). Black carbon showed the strongest association (HR = 2.14, 95 % CI: 1.47–3.12). Higher 3-year average exposures to PM2.5 and its constituents were significantly associated with higher baseline SLEDAI scores. ConclusionsThese findings highlight the significant role of environmental pollutants in cLN progression and emphasize the need for strategies to mitigate exposure to harmful PM2.5 constituents, particularly in vulnerable pediatric populations.

#896 Long-term renal outcome in childhood-onset lupus nephritis

Abstract Background and Aims Lupus nephritis (LN) is a common and severe complication of childhood-onset SLE. Little is known about the long-term renal outcome of childhood-onset LN. We investigated predictive factors of end-stage kidney disease (ESKD) and chronic kidney disease (CKD) in a paediatric cohort of patients with LN. Method This is a retrospective multicentre study including patients with childhood-onset (<18 years) biopsy-proven LN. Clinical features were analysed at disease onset, time of kidney biopsy, 12 and 24 months after biopsy, and last follow-up. We investigated the prognostic significance of clinical, laboratory and histologic characteristics on the incidence of ESKD and CKD stage 3-5. Results We included 73 patients with a median age of 14 years (IQR 11.5-17) . At the time of kidney biopsy, most subjects displayed an aggressive disease: 2 (3%) children required haemodialysis, 27 (38%) had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. The overall median eGFR was 70 mL/min/1.73 m2 (IQR 43-96) . Moreover, the median proteinuria was 4 g/24 h (IQR 1.35-7.41) , with 41 (59%) children displaying a nephrotic range proteinuria (i.e., >3 g/24 h) . The median follow-up was 13.3 years (IQR 4.7-25.4) . A total of 10 patients (13.7%) reached ESKD, the majority of whom (12%) within 10 years from kidney biopsy; during the subsequent follow-up the incidence of ESKD stabilised (Fig. 1). At last follow-up, around 50% of patients displayed an eGFR <90 mL/min/1.73 m2. A younger age at LN onset, a lower eGFR and central nervous system involvement at the time of kidney biopsy were identified as predictors of ESKD by a univariable Cox regression model (Table 1). The same features were significantly associated with the occurrence of CKD stage 3-5 at last follow-up at a univariable logistic regression analysis. Conclusion LN often presents with severe kidney function impairment and aggressive systemic involvement in children. In our cohort, whose follow-up was among the longest reported in the literature, 12% of patients reached ESKD within 10 years from kidney biopsy. Significant predictors of poor kidney outcome in the long term were a younger age at LN onset, a lower eGFR and the presence of neurological manifestations at the time of kidney biopsy.

Prognostic Value of the 2019 EULAR/American College of Rheumatology Systemic Lupus Erythematosus Classification Criteria to Renal Response One Year After Treatment in a Cohort With Childhood-Onset Lupus Nephritis.

In 2019, the EULAR/American College of Rheumatology developed classification criteria for systemic lupus erythematosus (SLE). A positive correlation between summary score at diagnosis and SLE disease activity at five years has been noted in adult patients with lupus, but little is known among the pediatric population. We evaluated the prognostic value of higher summary scores and number of extrarenal domains at diagnosis (low/moderate number [1-5] vs high number [6-9]) to renal outcomes after one year of treatment in pediatric patients with lupus nephritis (LN). This retrospective, single-center cohort study included 74 pediatric patients with LN. Published pediatric renal response definitions were used for our outcome measure (no, partial, and complete response). Descriptive statistics were reported, and an ordinal logistic regression estimated adjusted odds ratios (ORs) for renal response including 95% confidence intervals (CIs). Patients with high extrarenal domains had OR 1.47 (95% CI 0.55-2.91) of having a complete renal response compared to patients with low/moderate domains. Patients with a summary score <30 had OR 1.31 (95% CI 0.50-3.44) of having a complete renal response relative to a summary score ≥30, though a larger proportion of patients with a summary score of ≥30 had no renal response after one year of treatment. More extrarenal domains at diagnosis did not have a statistically significant impact on renal response at one year, nor did a higher summary score. However, a larger portion of patients with a summary score <30 achieved complete renal response compared to patients with a score ≥30.

Managing Lupus Nephritis in Children and Adolescents.

Lupus nephritis is an important manifestation of systemic lupus erythematosus, which leads to chronic kidney disease, kidney failure, and can result in mortality. About 35%-60% of children with systemic lupus erythematosus develop kidney involvement. Over the past few decades, the outcome of patients with lupus nephritis has improved significantly with advances in immunosuppressive therapies and clinical management. Nonetheless, there is a paucity of high-level evidence to guide the management of childhood-onset lupus nephritis, because of the relatively small number of patients at each centre and also because children and adolescents are often excluded from clinical trials. Children and adults differ in more ways than just size, and there are remarkable differences between childhood- and adult-onset lupus nephritis in terms of disease severity, treatment efficacy, tolerance to medications and most importantly, psychosocial perspective. In this article, we review the 'art and science' of managing childhood-onset lupus nephritis, which has evolved in recent years, and highlight special considerations in this specific patient population.

Long-term outcomes and associated prognostic risk factors of childhood-onset lupus nephritis.

This study investigated the clinical characteristics and kidney outcomes of childhood-onset lupus nephritis (LN), and risk factors associated with prognosis. We enrolled 216 patients with histologically diagnosed LN during childhood. The Korean Society of Pediatric Nephrology organized a retrospective cohort study of childhood-onset LN in 13 major pediatric nephrology centers in South Korea. The mean age at kidney biopsy was 13.2 ± 3.22 years. The main forms of presentation were nephrotic syndrome and/or hematuria in 152 patients (70.4%), and the most common histological finding was World Health Organization (WHO) class IV in 138 patients (63.9%), followed by WHO class III in 34 patients (15.7%). In the outcome analysis, the mean follow-up period of the patients was 7.8 ± 5.11 years. At last follow-up, 32 patients (14.8%) developed advanced chronic kidney disease (CKD). Male sex and failure to achieve remission at 12 months of treatment were significant risk factors for developing advanced CKD (hazard ratio of 2.57 and 2.29, respectively). Our study demonstrated the clinical characteristics and long-term outcomes of patients with childhood-onset LN. Male sex and failure to achieve remission in the first year of treatment were predictive of advanced CKD. Therefore, prompt awareness and close monitoring of these high-risk patients are needed, which may further improve the prognosis of children with LN.

Renal relapse in children and adolescents with childhood-onset lupus nephritis: a 20-year study.

There is little data on renal relapse in childhood-onset LN (cLN). We investigate the incidence, predictive factors and outcomes related to renal relapse. We conducted a retrospective cohort study of all cLN diagnosed at ≤18 years between 2001-2021 to investigate the incidence and outcomes related to renal relapse. Ninety-five Chinese cLN patients (91% proliferative LN) were included. Induction immunosuppression was prednisolone and CYC [n = 36 (38%)] or MMF [n = 33 (35%)]. Maintenance immunosuppression was prednisolone and MMF [n = 53 (54%)] or AZA [n = 29 (31%)]. The rates of complete remission/partial remission (CR/PR) at 12 months were 78.9%/7.4%. Seventy renal relapses occurred in 39 patients over a follow-up of 10.2 years (s.d. 5.9) (0.07 episode/patient-year). Relapse-free survival was 94.7, 86.0, 80.1, 71.2, 68.3, 50.3 and 44.5% at 1, 2, 3, 4, 5, 10 and 20 years, respectively. Multivariate analysis showed that LN diagnosis <13.1 years [adjusted hazard ratio (HRadj) 2.59 995% CI 1.27, 5.29), P = 0.01], AZA maintenance [HRadj 2.20 (95% CI 1.01, 4.79), P = 0.05], PR [HRadj 3.9 (95% CI 1.03, 9.19), P = 0.01] and non-remission [HRadj 3.08 (95% CI 1.35, 11.3), P = 0.04] at 12 months were predictive of renal relapse. Renal relapse was significantly associated with advanced chronic kidney disease (stages 3-5) and end-stage kidney disease (17.9% vs 1.8%, P < 0.01). Furthermore, patients with renal relapse showed an increased incidence of infections (30.8% vs 10.7%, P = 0.02), osteopenia (38.5% vs 17.9%, P = 0.04) and hypertension (30.8% vs 7.1%, P < 0.01). Renal relapse is common among cLN, especially among young patients, and is associated with an increased incidence of morbidity and mortality. Attaining CR and the use of MMF appear to decrease the incidence of renal relapse.

Long-term outcomes with rituximab as add-on therapy in severe childhood-onset lupus nephritis.

Long-term data pertaining to rituximab as add-on therapy in childhood-onset lupus nephritis (cLN) is scarce. A retrospective cohort study was conducted on all patients with proliferative cLN, diagnosed ≤ 18years and between 2005 and 2021, who received rituximab for LN episodes that were life/organ threatening and/or treatment resistant to standard immunosuppression. Fourteen patients with cLN (female, n = 10) were included, with median follow-up period of 6.9years. LN episodes (class III, n = 1; class IV, n = 11; class IV + V, n = 2) requiring rituximab occurred at 15.6years (IQR 12.8-17.3), urine protein:creatinine ratio was 8.2mg/mg (IQR 3.4-10.1) and eGFR was 28mL/min/1.73 m2 (IQR 24-69) prior to rituximab treatment. Ten and four patients received rituximab at 1500mg/m2 and 750mg/m2, which were given at 46.5days (IQR 19-69) after commencement of standard therapies. Treatment with rituximab resulted in improvements in proteinuria (ps < 0.001), eGFR (ps < 0.01) and serological parameters, including haemoglobin levels, complement 3 levels and anti-dsDNA antibodies, compared with baseline. Rates of complete/partial remission at 6-, 12- and 24-month post-rituximab were 28.6/42.8%, 64.2/21.4% and 69.2/15.3%. All three patients who required acute kidney replacement therapy became dialysis-free after rituximab. Relapse rate following rituximab was 0.11 episodes/patient-year. There was no lethal complication or severe infusion reaction. Hypogammaglobulinaemia was the most frequent complication (45%) but was mostly asymptomatic. Neutropenia and infections were observed in 20% and 25% of treatments. Upon last follow-up, three (21%) and two (14%) patients developed chronic kidney disease (stage 2, n = 2; stage 4; n = 1) and kidney failure, respectively. Add-on rituximab is an effective and safe rescue therapy for cLN patients with life-/organ-threatening manifestations or treatment-resistance. A higher resolution version of the Graphical abstract is available as Supplementary information.

Elevated serum levels of human epididymis protein 4 in adult patients with proliferative lupus nephritis.

This study aimed to access whether serum human epididymis protein 4 (HE4) level could identify lupus nephritis (LN) pathological classes in adults and children. The serum HE4 levels of 190 healthy subjects and 182 patients with systemic lupus erythematosus (SLE) (61 adult-onset LN [aLN], 39 childhood-onset LN [cLN], and 82 SLE without LN) were determined using Architect HE4 kits and an Abbott ARCHITECT i2000SR Immunoassay Analyzer. Serum HE4 level was significantly higher in the aLN patients (median, 85.5 pmol/L) than in the patients with cLN (44 pmol/L, P < 0.001) or SLE without LN (37 pmol/L, P < 0.001), or the healthy controls (30 pmol/L, P < 0.001). Multivariate analysis showed that serum HE4 level was independently associated with aLN. Stratified by LN class, serum HE4 level was significantly higher in the patients with proliferative LN (PLN) than in those with non-PLN, and this difference was found only in aLN (median, 98.3 versus 49.3 pmol/L, P = 0.021) but not in cLN. Stratified by activity (A) and chronicity (C) indices, the aLN patients with class IV (A/C) possessed significantly higher serum HE4 levels than those with class IV (A) (median, 195.5 versus 60.8 pmol/L, P = 0.006), and this difference was not seen in the class III aLN or cLN patients. Serum HE4 level is elevated in patients with class IV (A/C) aLN. The role of HE4 in the pathogenesis of chronic lesions of class IV aLN needs further investigation.

Identification of biomarkers that predict renal flare in childhood-onset lupus nephritis with mycophenolate acid.

Children-onset lupus nephritis (cLN) occurs>50% of patients with systemic lupus erythematosus. Mycophenolic acid (MPA) is the first-line agent for the induction and maintenance treatment of LN. This study was to explore the predictors of renal flare in cLN. Data from 90 patients were included in population pharmacokinetic (PK) models to predict MPA exposure. Cox regression models and restricted cubic spline were performed in 61 patients to identify the risk factors for renal flare, baseline clinical characteristics and MPA exposures as potential covariates. PK best fitted a two-compartment model of first-order absorption and linear elimination, with delayed absorption. Clearance increased with weight and immunoglobulin G (IgG), but decreased with albumin and serum creatinine. During follow-up of 1040 (658-1359) days, 18 patients experienced a renal flare, after a median time of 932.5 (663.5-1316) days. Each 1-mg·h/L increase of MPA-AUC was associated with a 6% decreased risk of an event (HR=0.94; 95% CI: 0.90-0.98), while IgG significantly increased this risk (HR=1.17; 95% CI: 1.08-1.26). ROC analysis showed that MPA-AUC0-12h<35mg·h/L and IgG>17.6g/L had a good prediction of renal flare. Of restricted cubic spline, the risk of renal flares decreased with higher MPA exposure but reached a plateau when AUC0-12h>55mg·h/L, while substantially increases when IgG is>18.2g/L. Monitoring MPA exposure together with IgG could be very useful during clinical practice to identify patients with a potential high risk of renal flare. This early risk assessment would allow for the treat-to-target and tailored medicine.

Long-Term Outcomes of Children and Adolescents With Biopsy-Proven Childhood-Onset Lupus Nephritis

Long-term data pertaining to childhood-onset lupus nephritis (cLN) remain extremely scarce. We conducted a retrospective cohort study of biopsy-proven cLN with onset age <18 years diagnosed from 2001 to 2020 to ascertain the long-term patient and kidney survival rates, and the incidence of advanced chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR]<60 ml/min per 1.73 m2). A total of 92 subjects (78 female; age 13.7 ± 3.3 years; all Chinese) were included, with follow-up duration of 10.3 years (interquartile range, 5.8-15.9). Of these, 83 children (90%) had proliferative lupus nephritis (LN) (Class III/IV ± V). Mycophenolate was used for induction in 36%, whereas 34% received cyclophosphamide (CYC); 55% received mycophenolate as maintenance immunosuppression. The rates of complete remission (CR) and partial remission (PR) at 6 months and 12 months, respectively, were 65% and 20% and 78% and 8%. Two patients died (mortality rate 2.1/1000 patient-years), with a standardized mortality ratio of 22.3. Three patients (3.2%) developed end-stage kidney disease (ESKD), and advanced CKD occurred in 5 patients (5.4%). Survival rates without advanced CKD, ESKD, or death were 96.7%, 94.2%, 92.7%, 83.2% and 83.2% at 1 year, 5 years, 10 years, 15 years, and 20 years, respectively. Multivariate analysis revealed that severe kidney failure necessitating dialysis at presentation (adjusted hazard ratio 37.7, 95% confidence interval [CI] 4.0-355.6, P= 0.002), nonresponse (NR) after 12 months of treatment (adjusted hazard ratio 11.2, 95% CI 2.3-54.9, P= 0.003), and multiple nephritis flares (adjusted hazard ratio 2.6, 95% CI 1.1-6.2, P= 0.03) were predictive of advanced CKD, ESKD, or death. Other adverse outcomes included infections (2.9 episodes/100 patient-years), osteopenia (32%), hypertension (17%), short stature (14%), and avascular necrosis (7%). The long-term outcomes of cLN appeared to have improved in the present era with effective immunosuppression, cautious drug tapering, and assurance of medication adherence. There is still an unacceptably high prevalence of adverse outcomes.

The long-term outcome of New Zealand Maori and Pacific Island children diagnosed with childhood onset lupus nephritis.

To determine the long-term outcome of Maori and Pacific Island children diagnosed with childhood onset lupus nephritis. A chart review was conducted of children diagnosed with biopsy proven lupus nephritis seen by the Starship Hospital and Kidz First paediatric rheumatology and/or Starship renal services between January 1992 and January 2018. Baseline and follow-up kidney histology, adherence and response to therapy including partial or full renal remission, refractory disease, end-stage kidney disease (ESKD) and mortality were determined. In a New Zealand cohort of 42 with childhood onset lupus nephritis, Maori and Pacific Island children were significantly more likely to develop class 4 lupus nephritis (RR (95% CI), 11.3 (3.84-49.9), p < 0.0001), demonstrate medication nonadherence (RR (95% CI) 12.4 (3.48-85.7), p < 0.0001) and experience end stage kidney disease (RR (95% CI) 15.7 (2.97-389.3), p = 0.0003) and mortality (RR (95% CI) 11.1 (1.91-280.1), p = 0.005) compared to non-Maori and Pacific Island children. In addition, Maori children with childhood onset lupus nephritis developed chronic histological changes significantly more rapidly than Pacific or Asian children (p = 0.038). Lupus nephritis is more common among Maori and Pacific Island children in New Zealand associated with a significant incidence of end stage kidney disease and mortality, with some Maori children developing rapid histologic disease progression.

Urinary CD163 is a marker of active kidney disease in childhood-onset lupus nephritis.

The objective of this study was to evaluate the utility of urine CD163 for detecting disease activity in childhood-onset SLE (cSLE) patients. Sixty consecutive pediatric patients fulfilling four or more ACR criteria for SLE and 20 healthy controls were recruited for testing of urinary CD163 using ELISA. SLE disease activity was assessed using the SLEDAI-2K. Urine CD163 was significantly higher in patients with active LN than inactive SLE patients and healthy controls, with receiver operating characteristics area under the curve values ranging from 0.93 to 0.96. LN was ascertained by kidney biopsy. Levels of CD163 significantly correlated with the SLEDAI, renal SLEDAI, urinary protein excretion and C3 complement levels. Urine CD163 was also associated with high renal pathology activity index and chronicity index, correlating strongly with interstitial inflammation and interstitial fibrosis based on the examination of concurrent kidney biopsies. Urine CD163 emerges as a promising marker for identifying cSLE patients with active kidney disease. Longitudinal studies are warranted to validate the clinical utility of urine CD163 in tracking kidney disease activity in children with lupus.

Hydroxychloroquine blood levels predicts flare in childhood-onset lupus nephritis.

Low hydroxychloroquine (HCQ) blood levels are predictors of flare in adult lupus. Childhood-onset systemic lupus erythematosus (cSLE) has high morbidity with renal involvement in up to 80% of cases. The aim of this study is to determine the HCQ cut-off levels which predicts flare in childhood-onset lupus nephritis (LN). Sixty LN patients on HCQ use for at least 6-months were prospectively evaluated at baseline (BL) and about 6-months later for cSLE flare and HCQ blood levels (ng/mL) measured by liquid chromatography-tandem mass spectrometry. There were 19 patients (32%) with flare, during the study with median SLEDAI increase of 4 (0-8). Median (IQR) BL HCQ levels of the flare group were lower compared to stable patients [557.5 (68.6-980.3) vs. 1061.9 (534.8-1590.0ng/mL); p=0.012]. ROC curve analysis demonstrated that HCQ levels≤1075ng/mL were associated with a 5.08 (95%CI 1.28-20.13; p=0.021) times increased risk of flare. Six-month HCQ levels revealed that most patients 24/54 (44%) had persistently low levels (≤1075) during follow-up. Among those, 11/24 (46%) had flare. Multiple logistic regression analysis including prednisone use, baseline SLEDAI-2K, adherence based on pharmacy refill and BL HCQ blood levels as possible predictors of flare revealed that only HCQ blood level was independently associated with flare (OR 0.999, 95%CI 0.998-1.0, p=0.013). We demonstrated that HCQ blood cut-off level under 1075ng/mL predicts flare in childhood-onset LN patients under prescribed HCQ dose of 4.0-5.5mg/kg/day. We further observed that most of these patients have compliance issues reinforcing the need for a close surveillance particularly in those with levels below the defined cut-off.

Європейські доказові рекомендації по діагностиці та лікуванню люпус-нефриту у дітей: ініціатива SHARE

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Treatment effectiveness and long-term prognosis of childhood-onset lupus nephritis

Objectives: To analyze the clinical characteristics, treatment effectiveness and long-term prognosis of childhood-onset lupus nephritis (LN), and to explore the risk factors for progression to end-stage renal disease (ESRD). Methods: In this retrospective study, the clinical data including general conditions, clinical manifestations, laboratory examinations, treatment, following up (till December 31st, 2020) and prognosis of 343 children with LN who were treated and followed up in the First Affiliated Hospital of Sun Yat-sen University from January 1, 2003 to December 31, 2019 were analyzed. Complete remission rates were compared between different pathological types according to renal biopsies and flare rates were compared between complete remission group and partial remission group according to the treatment effectiveness after 6 months of induction treatment. To investigate the risk factors of ESRD, the prognosis of flare and non-flare cases, and of cases with normal and elevated serum creatinine levels at baseline, was compared. Chi-squared tests were used for comparison between groups, and cumulative survival rate and renal survival rates were calculated by Kaplan-Meier survival analysis. Risk factors for ESRD were analyzed by COX regression model. Results: Among the 343 children, 68 were males (19.8%) and 275 were females (80.2%) with a median age of 13.0 (11.0, 16.0) years. Regarding the renal symptoms, 305 (88.9%) children had proteinuria and 245 (71.4%) had hematuria; while for extra-renal manifestations, 273 (79.6%) had anemia, 183 (53.4%) had rashes and 165 (48.1%) had fever. A total of 212 (61.8%) children had severely active SLE at initial presentation. After 6 months of induction treatment, the complete remission rate was 63.8% (219/343) and the partial remission rate was 27.1% (93/343). The complete remission rate was significantly higher in type Ⅰ and type Ⅱ LN compared to type Ⅳ LN (10/12 vs. 82/135 (60.7%), χ²=3.936, P=0.047). One hundred and ten children who achieved remission, including complete remission and partial remission, experienced renal flare with a flare rate of 35.3% and a mean time to flare was (43.2±28.4) months. There was no significant difference in flare rates between complete and partial remission group (36.1% (79/219) vs. 33.3% (31/93), χ²=3.394, P=0.065). The follow-up time of all the children was 60.4 (32.3, 100.9) months. During the follow-up period, 15 children died and the cumulative survival rates at 3, 5 and 10 years were 97.2%, 96.4% and 93.3%, respectively; 14 children progressed to ESRD and the cumulative renal survival rates at 3, 5, and 10 years were 99.2%, 97.1%, and 93.4%, respectively. COX multivariate analysis demonstrated that elevated serum creatinine at baseline, nephritic flare and nephrotic flare were independent risk factors for progression of ESRD (hazard ratio (HR)=3.575, 21.550 and 8.590, 95%CI 1.127-11.341, 2.394-194.027 and 1.042-70.823, P=0.031, 0.006, and 0.046, respectively). Conclusions: Children with LN are characterized by high SLE disease activity and multi-system involvement at onset. After 6 months of induction treatment, most of LN children could achieve clinical remission but some would experience renal flare. Nephritic flare, nephrotic flare and elevated serum creatinine at onset are independent risk factors for the progression of ESRD in children with LN.

Comprehensive Analysis of Clinical Trials Registration for Lupus Nephritis Therapy on ClinicalTrials.gov.

Objective: Clinical trials are the most effective method for evaluating therapeutic strategies. The purpose of this study was to comprehensively assess the characteristics of trials on lupus nephritis (LN) and provide a reference for LN treatment and research.Methods: Registered therapeutic trials on drug interventions for LN were obtained from ClinicalTrials.gov up to December 3, 2020. The general characteristics, methodological characteristics, detailed characteristics, investigated drugs, eligibility criteria, and outcome measures of these trials were analyzed.Results: A total of 126 eligible trials were evaluated, and these trials mainly investigated the initial treatment of adult proliferative LN. Half of the trials enrolled <50 participants, and 70.7% of the trials lasted for 6–24 months. In total, 95.2% of trials adopted an interventional study design. Of intervention trials, 56.6% were in phase 2 or phase 3, 76.7% were randomized, 77.5% employed a parallel assignment, and 41.7% were masked. The eligibility criteria and outcome measures of the included trials varied and involved a variety of indicators. Chemical agents and biologics are the most widely studied immunotherapies, of which mycophenolate mofetil, tacrolimus, and rituximab are the most studied. In addition, some trials studied cell transplantation treatment.Conclusions: The majority of clinical trials for LN therapy registered on ClinicalTrials.gov investigated the initial treatment of adult proliferative LN, and most of these trials were randomized, parallel assigned, and insufficiently masked interventional trials with small scale, short duration, various eligibility criteria, and outcome measures. We hope that more large-scale, long-term multicenter, and high-quality RCT trials with standardized inclusion criteria/exclusion criteria and treatment effect evaluation systems will be conducted and that more energy and funding will be put into exploring biological products and stem cell therapies. In addition, trials for membranous LN, childhood-onset LN, and maintenance phase LN are needed to establish optimal treatment strategies.

Glomerular Expression of Some Profibrotic Factors in Progressive Childhood Lupus Nephritis.

Lupus nephritis (LN) is a major cause of mortality and morbidity in both adult and pediatric patients. However, studies regarding pathogenesis and predictors of renal outcomes in childhood LN are limited. Transforming growth factor-β1 (TGF-β1) and Connective tissue growth factor (CTGF) have an important role in proliferative and fibrotic changes in many renal diseases. We aim to evaluate the role of such two profibrotic factors in the progression of childhood onset LN and to detect if their glomerular expression could represent an early predictor of future deterioration of renal function. 34 children with new onset of LN were included. Glomerular expressions of TGF-β1 and CTGF were evaluated by immunohistochemical analysis in the renal tissue of such patients and in control tissue. GFR was estimated at time of renal biopsy at the onset of LN and after 2 years of follow-up. Rate of GFR change (ΔGFR) was calculated and used as indicative of degree of renal disease progression. Glomerular TGF-β1 and CTGF expressions in children with LN were significantly higher than in control tissue (LN 15.41 ± 9.84 and 15.56 ± 10.51 vs. 2.15 ± 1.45 and 1.35 ± 1.07 in control respectively, with p < 0.001 in both). In addition, the glomerular expressions of TGF-β1 and CTGF were significantly higher in patients with further decline in GFR (20.68 ± 7.73 and 21.05 ± 8.75) versus (5.75 ± 4.37 and 5.50 ± 3.78) in those without change in GFR with (p = 0.000 for both of them). Patients with LN have increased glomerular expressions of TGF-β1 and CTGF, which were higher in those with further decline in GFR. These profibrotic factors are suspected to be involved in pathogenesis of LN and could be evaluated as a target for therapeutic intervention to stop progression of LN. In addition, their glomerular expression could be used as an early predictor of progression of LN, to justify early aggressive therapy in those with suspected rapid progression.

Mycophenolic acid area under the concentration-time curve is associated with therapeutic response in childhood-onset lupus nephritis.

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is widely used in lupus nephritis treatment. Therapeutic drug monitoring of adults suggests that area under the concentration-time curve (AUC) of MPA (MPA-AUC) is associated with clinical outcomes, but childhood data are scarce. Retrospective study of 27 children with biopsy-proven lupus nephritis treated with MMF between 2008 and 2016. In 25 children, MPA-AUC was performed within 6months after kidney biopsy and MMF initiation. Treatment response at 6months was defined as normal or improved GFR by 25% compared with baseline, 50% reduction of proteinuria to < 0.5g/day or 50mg/mmol, and no hematuria. A total of 62 MPA-AUC were analyzed in 27 patients. Overall median was 44mgh/L (interquartile range [IQR] 33-54). Individual dose adaptation was required in 32 cases (52%) to achieve target AUC of 30-60mgh/L. At 6months, 14/25 patients were defined as responders (56%, median MPA-AUC 49mgh/L (40-59)) and 11/25 as non-responders (44%, 29mgh/L (24-38)). Patients with MPA-AUC levels > 45, 30-45, and < 30mgh/L had 6-month response rates of 89% (8/9), 60% (6/10), and 0% (0/6), respectively. In a logistic regression model adjusted for age, sex, lupus nephritis classification, and time since MMF initiation, an MPA-AUC > 45mgh/L was significantly associated with therapeutic response (OR 3.6, 95% CI 2.4-9.5, p= 0.03). Therapeutic drug monitoring leading to individualized dosing may improve efficacy of MMF. MPA-AUC > 45mgh/L is associated with better response rate and may be considered as a target value in pediatric lupus nephritis.

Outcomes of Mycophenolate Mofetil vs. Intravenous Cyclophosphamide in Induction Therapy of Childhood-Onset Lupus Nephritis

Background: Intravenous cyclophosphamide (IVCY) concomitant with corticosteroids demonstrated better outcomes in therapy of proliferative lupus nephritis albeit adverse effects may occur. Mycophenolate mofetil (MMF) is a newer oral medication for treating lupus nephritis. Objective: To compare renal outcomes between IVCY and MMF in conjunction with corticosteroid for induction therapy of proliferative lupus nephritis. Materials and Methods: The authors reviewed the medical records from four university hospitals of children who received prednisolone with either MMF or IVCY for induction therapy of proliferative lupus nephritis between 2005 and 2014 in the present retrospective cohort study. Results: Twenty-eight and 85 patients were included in the MMF and IVCY group, respectively. The respective mean age at MMF and IVCY initiation was 12.36±2.87 and 11.84±3.04 years. Renal remission was not significantly different between the groups (p=0.690). Non-nephrotic range proteinuria (adjusted OR 2.93, 95% CI 1.23 to 6.94, p=0.015), and high initial GFR (adjusted OR 2.93, 95% CI 1.14 to 7.56, p=0.026) were significantly associated with achieving renal remission. Both infectious (82.1%) and non-infectious complications (96.9%) were more common in the IVCY group. Neither death nor end-stage renal disease (ESRD) occurred during the induction therapy. Conclusion: There was no significant difference in renal remission whether children received MMF or IVCY for induction therapy of lupus nephritis; however, adverse events occurred less frequently in the MMF group. Keywords: Children, Lupus nephritis, Systemic lupus erythematosus, Mycophenolate, Cyclophosphamide, Induction

Approach to Classification and Management of Childhood-Onset Lupus Nephritis

(1) To discuss the relevance of the 2018 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification system for nephritis in childhood-onset systemic lupus erythematosus (SLE). (2) To highlight current practices not addressed in the 2013 Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plan (CTP) for pediatric lupus nephritis (LN). In addition to class of glomerular involvement, multiple features on kidney biopsy can be assessed for prognosis and therapeutic decision-making. There is pediatric evidence and expertise for optimization of LN classification. Yet, treatment is based primarily on whether nephritis is proliferative or membranous. Moreover, alternative strategies for induction therapy are more commonly prescribed for children. There is a need for pediatric data to evaluate/validate LN classification systems. Updates are needed to CTPs for LN induction therapy. Pediatric nephrologists should be enrolling LN patients into existing prospective registries to build the evidence base for treatment decisions.