Abstract
Objectives: To observe the induction efficacy of mycophenolate mofetil and cyclophosphamide under different complete remission (CR) criteria in children with proliferative lupus nephritis, and to further explore the factors influencing the judgment of remission. Methods: From 2003 to 2019, children who diagnosed proliferative lupus nephritis underwent induction therapy of MMF or CYC in three hospitals were consecutively collected. Based on this population, we compared CR rates between two groups under six CR criteria selected from related recommendations and clinical trials. Then degrees and impact factors of disagreement among CR rates evaluated by selected criteria would be analyzed by Kappa test and multivariable logistic-regression models. Results: A total of 161 children were included in this study, 27 patients received induction therapy of mycophenolate mofetil (MMF) and 134 patients recieved cyclophosphamide (CYC). Under different CR criteria, CR rates in MMF group fluctuated between 18.5%-74.1% and that in CYC group ranged from 16.4%-73.9%. Moreover, comparison between the two drugs in induction treatment under different criteria showed an opposite trend in efficacy. The results of six criteria were inconsistent, with pair-to-pair Kappa values ranging from 0.118 to 0.858. The most important factors leading to disagreement in judgment were urinary protein and urinary red blood cells. Conclusions: The definition of complete response, especially the factors of the urinary protein and urinary red blood cells, significantly impacts the clinical judgment of children with lupus nephritis.
Keywords: Pediatric lupus nephritis, outcome measures, complete response, immunosuppressant
Introduction
As a heterogeneous autoimmune disease with multiple organs involvement, the severity and morbidity of systemic lupus erythematosus (SLE) vary among different races and ages [1]. The incidence of lupus nephritis (LN) is 67%-82% in children, which is significantly higher than that in adults [2,3]. About 15% of pediatric LN (pLN) patients die between 22 and 27 years of age due to disease damage or treatment complications, it is also significantly higher than adults [4]. Therefore, it’s vital to pay more attention to the diagnosis and treatment of pLN.
Whether complete response or remission (CR) is achieved after initial induction treatment is decisive to evaluate the prognosis [5,6] and guide subsequent maintenance treatment [7-11], especially for the proliferative LN, the most common pathological type with the worst prognosis [2,12]. With the absence of randomized controlled trials (RCT) on pediatric LN in the past 20 years [13], guidelines for pediatric LN were mainly based on evidences from RCTs in adult or retrospectivestudies of children [7,9]. Adult LN guidelines recommended Mycophenolate Mofetil (MMF) and Cyclophosphamide (CYC) as both the first line induction therapy [8,10,11]. However, different pediatric guidelines held different opinions on the use of MMF and CYC [7,9], since that LN in children differs greatly from adults, such as a higher disease activity score, a greater demanding for moderate-to-high dose corticosteroids and a higher incidence of adverse events [2,3]. Furthermore, responses to MMF and CYC are diverse in patients with LN in different races [14], and there is no study aiming at Asian children with proliferative LN up to now. Also, studies [15-17] have shown that CYC has severer and higher rates of adverse events than MMF, primarily gonadal suppression, bone marrow suppression and severe infection, which could cause great harms to children in a long term. Therefore, it is crucial to balance clinical efficacy and potential harms properly between CYC and MMF in the induction treatments for LN specifically in children.
An important obstacle to this clarity is that current definition of CR standard is still not uniform, and different studies and guidelines set various definitions. Among RCTs of adult proliferative LN [15-17], the reported CR rates ranged from 8.6% to 81.0% for MMF and 5.8% to 76.0% for CYC according to different criteria. Different definitions of CR make it more challenging to explore the efficacy of MMF and CYC in pediatric LN. Up till now, there are only three small-sample studies [18-20] have reported the effectiveness of MMF compared with CYC in proliferative pediatric LN, and the observed CR rates also varied markedly with different definitions of CR.
The purpose of this study was to observe the efficacy of MMF and CYC under different CR definitions based on a retrospective multicenter cohort in Asian children with LN, and to explore the impact factors accounting for the disagreement between the CR standards in efficacy evaluation and to provide evidence for the establishment of an unified and comparable CR standard for future prospective clinical studies of pediatric LN.
Materials and methods
Data collection
This study retrospectively included LN children in the First Affiliated Hospital of Sun Yat-sen University, Guangzhou Women and the 900th Hospital of The Joint Logistic Support Force of The Chinese People’s Liberation Army from January 1, 2003, to July 31, 2019. Inclusion criteria included all of the following: 1) Diagnosis of SLE according to the American College of Rheumatology (ACR) criteria in 1997 [21]. 2) Aged ≤18 years old. 3) Kidney biopsy with a histologic diagnosis of LN (International Society of Nephrology/Renal Pathology Society 2003 classification of lupus nephritis [22]) class III or class IV, alone or in combination with class V. 4) 24 hours urine protein >500 mg at initial assessment. Patients with an estimated glomerular filtration rate (eGFR) lower than 30 mL/min/1.73 m2 or accepting pulse methylprednisolone therapy within two weeks or treated regularly with MMF, CYC or other immunosuppressive agents within six months in other hospitals were excluded.
The study flow chart is shown in Figure 1. Clinical and laboratory data including age, gender, duration of disease, clinical manifestations, weight and height, urinalysis, serum levels of complement 3 and 4, serum creatinine (Scr), albumin (ALB), hemoglobin and treatment regimens were collected. This study was approved by the ethics committee of hospitals and the license number of ethics approval was [2019]248, and informed consent was waived.
Figure 1.
Patient disposition.
Treatment protocols
MMF group: Children were treated with oral MMF combined with oral corticosteroids. The initial dose of prednisone was 2 mg/kg/d with a daily maximum of 60 mg, followed by gradual reduction. And the prescription of MMF was 20-30 mg/kg/d with a daily maximum of 2 g, or initial dose was 1 g/d and gradually increased to 2 g/d, both divided into twice a day and administered for six months.
CYC group: Children were treated with intravenous CYC combined with oral corticosteroids. The therapeutic regimens of corticosteroids were the same as MMF group. And the dose of CYC was 8-12 mg/kg/d, once every 2 weeks for 2 days in a row, totally for 6-8 times, or 0.5-1 g/m2, once a month and 6 times in total.
Screening for CR
Firstly, we adopted two definitions of complete response from Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations in 2012 [11] and Chinese Pediatric Society of Chinese Medical Association pediatric lupus nephritis guidelines in 2016 [7]. And then we searched for published LN clinical trials from 1999 to 2019 on PubMed with the search strategy of lupus nephritis treatment [Journal] Filters: Clinical Trial. We included all trials published on journals with an impact factor above 5.0, and those with consistent definitions with guidelines or previous studies were excluded (Supplementary Figure 1).
Finally, four clinical trials including Chan et al. [16], Ginzler et al. [17], Deng et al. [23], and ALMS (the Aspreva Lupus Management Study) trial [15] were included in this study, as well as the CR criteria of the EULAR/ERA-EDTA and the Chinese pLN guidelines (see Table 1 for the specific definition of CR). In general, these criteria set by four selected trials and guidelines involved four factors, namely urinary protein, renal function, urinary sediment and Serum Albumin (ALB). All criteria defined a threshold for urinary protein quantification, with the minimum of 0.15 g/d as defined by the Chinese pLN guidelines, and the maximum of 0.5 g/d as defined by the EULAR/ERA-EDTA and the ALMS. As for renal function, Ginzler, ALMS and Deng assessed Serum Creatinine (Scr), while those two guidelines used eGFR. All criteria but the EULAR/ERA-EDTA included urinary sediment. However, the Chinese pLN guidelines and Deng merely defined the threshold value of urinary red blood cells (uRBCs), and only Chan’s criteria included ALB.
Table 1.
Definitions of complete remission in lupus nephritis trials or recommendations
| Source of criteria | Factors | |||
|---|---|---|---|---|
|
| ||||
| Urine protein | Renal function | Urinalysis | ALB | |
| EULAR/ERA-EDTA* | <0.5 g/d | Within 10% of normal eGFR | - | - |
| 2016-CLN* | <0.15 g/d | Normal eGFR | uRBCs <5/HP | |
| Chan | <0.3 g/d | Both Scr and eGFR that were 15% or less above the base-line values | Normal | Normal |
| Ginzler | Within 10% of normal values | Within 10% of normal values of Scr | Within 10% of normal values | - |
| ALMS | ≤0.5 g/d | Normal Scr | Normal | - |
| Deng | <0.3 g/d | Within 20% of baseline values of Scr | uRBCs <10/HP | - |
2016-CLN: the guideline for children released by pediatric group, Chinese Medical Association in 2016. EULAR/ERA-EDTA: the recommendation of Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association in 2012.
When comparing the differences of CR rate in MMF and CYC groups using CR criteria from the four trials, patients enrolled for this analysis would also meet the inclusion criteria of the corresponding trial (Supplementary Tables 1 and 2). When comparing the consistency between two different CR criteria, we analyzed based on the all patients included.
Statistical analysis
Stata/MP 14.0 (StataCorp LP, College Station, TX) was conducted for analysis. The quantitative data conforming to the normal distribution was expressed by means ± standard deviation, and the contrast between groups was evaluated by t test. As for the quantitative data not fitting the normal distribution, it was represented by median (M) and quartile spacing, and Mann-Whitney U test was applied for comparing. Similarly, the rate (%) and Fisher’s exact tests were employed for qualitative data. The agreement means that patients were judged as CR or No remission (NR) under different criteria, expressed as percent concordance and the strength was determined using Kappa scores which are considered to be near perfect, substantial, moderate, fair, poor or null when they are 1-0.8, 0.8-0.6, 0.6-0.4, 0.4-0.2, 0.2-0 or ≤0, respectively. And then we set up multivariable logistic-regression models to excavate the relative contribution of various factors to agreement or disagreement between different standards. Tests with p-values of <0.05 were considered statistically significant.
Results
Patients
This study included 161 children with LN, whose baseline data was shown in Table 2. There were 27 patients in the MMF group, including 9 males (33.3%) and 18 females (66.7%), with an average age of 12.6±3.9 years. And in the 134 patients of the CYC group, males accounted for 21.6% (29/134), while the proportion of females was 78.4% (105/134), with an average age of 10.9±3.1 years. Although the age, ALB and serum C3 of the MMF group were higher than those of the CYC group (P<0.05), there was no significant difference in the duration of SLE, duration of LN, Scr, eGFR, 24-hour urinary protein quantification or urinary red blood cells between MMF and CYC groups at baseline (P>0.05). The main pathological types of the MMF and CYC groups were class IV making up 63.0% and 76.9%, respectively.
Table 2.
Characteristics of patients at the beginning of induction therapy
| Characteristic | MMF (n=27) | CYC (n=134) | Total (n=161) | P |
|---|---|---|---|---|
| Age (year) | 12.6±3.9 | 10.9±3.1 | 11.2±3.3 | 0.014 |
| Sex (male/female) | 9/18 | 29/105 | 38/123 | 0.217 |
| Duration of SLE (mo) | 1.5 (0.6, 4.0) | 1.1 (0.6, 2.1) | 1.1 (0.6, 2.6) | 0.249 |
| Duration of LN (mo) | 0.9 (0.5, 3.4) | 0.7 (0.4, 1.3) | 0.7 (0.4, 1.6) | 0.132 |
| Urine protein (g/24 h) | 1.9 (1.0, 3.9) | 2.5 (1.5, 4.2) | 2.4 (1.4, 4.0) | 0.306 |
| Scr (μmol/L) | 72.0 (52.0, 96.0) | 74.0 (52.0, 107.0) | 73.0 (52.0, 106.0) | 0.955 |
| eGFR (ml/min/1.73 m2) | 110.9 (75.6, 151.1) | 97.0 (68.7, 137.9) | 100.6 (69.5, 141.0) | 0.349 |
| ALB (g/L) | 27.8±7.8 | 24.9±5.9 | 25.4±6.3 | 0.030 |
| Serum C3 (g/L) | 0.4 (0.3, 0.5) | 0.3 (0.2, 0.4) | 0.3 (0.2, 0.4) | 0.022 |
| uRBCS* (n, %) | 0.728 | |||
| - | 3 (11.1) | 7 (5.2) | 10 (6.2) | |
| ± | 1 (3.7) | 10 (7.5) | 11 (6.8) | |
| + | 4 (14.8) | 27 (20.1) | 31 (19.3) | |
| ++ | 6 (22.2) | 36 (26.9) | 42 (26.1) | |
| +++ | 7 (25.9) | 24 (17.9) | 31 (19.3) | |
| ++++ | 6 (22.2) | 30 (22.4) | 36 (22.4) | |
| Range of GFR (ml/min/1.73 m2, n, %) | 0.507 | |||
| ≥90 | 17 (63.0) | 77 (57.5) | 94 (58.4) | |
| ≥60 to <90 | 8 (29.6) | 34 (25.4) | 42 (26.1) | |
| ≥30 to <60 | 2 (7.4) | 23 (17.2) | 25 (15.5) | |
| Renal biopsy class (n, %) | 0.064 | |||
| III | 8 (29.6) | 14 (10.4) | 22 (13.7) | |
| IV | 17 (63.0) | 103 (76.9) | 120 (74.5) | |
| III+V | 0 (0.0) | 3 (2.2) | 3 (1.9) | |
| IV+V | 2 (7.4) | 14 (10.4) | 16 (9.9) |
The number of red blood cells per high-power field corresponding to urinary red blood cell grades: -, 0/HP; ±, 1-5/HP; +, 6-50/HP; ++, 51-100/HP; +++, 101-300/HP; ++++, 301-full field/HP.
Complete response rates
In this study, six CR criteria were used to evaluate the efficacy of MMF and CYC groups in the corresponding population cluster at 6-month (see Table 3). The CR rates of MMF group were superior to that of CYC group under the evaluation of CR criteria in the EULAR/ERA-EDTA, Chinese pLN guidelines, Chan and ALMS; and under the CR criteria of Ginzler and Deng, the CR rates of CYC group were superior to that of MMF group (P>0.05). CR rates evaluated by different CR standards varied greatly between groups. For the evaluation of MMF groups, the lowest CR rate was 18.5% as assessed in the Chinese pLN guidelines, and the highest was 74.1% as assessed in the EULAR/ERA-EDTA. Similarly, the lowest CR rate in the CYC group was 11.2% as assessed by Chan, and the highest was 73.9% as assessed by the EULAR/ERA-EDTA. And the results obtained from the all patients were similar to those from specific patients’ clusters (Supplementary Table 3).
Table 3.
CR rates at 6 months in MMF group and CYC group on the basis of the corresponding study population
| Source of criteria (n, %) | MMF | CYC | P |
|---|---|---|---|
| EULAR/ERA-EDTA | 20/27 (74.1) | 99/134 (73.9) | 1.000 |
| 2016-CLN | 5/27 (18.5) | 22/134 (16.4) | 0.781 |
| Chan | 3/14 (21.4) | 11/ 98 (11.2) | 0.379 |
| Ginzler | 5/20 (25.0) | 38/146 (26.0) | 1.000 |
| ALMS | 5/19 (26.3) | 29/146 (19.9) | 0.548 |
| Deng | 5/17 (29.4) | 34/ 88 (38.6) | 0.588 |
Baseline data for patients with or without CR under different CR criteria are shown in Supplementary Table 4. eGFR and serum ALB of baseline were higher, and urine protein was lower in CR patients than NR under all CR criteria (P<0.05).
Agreement of different criteria
Supplementary Table 5 showed that the CR rates of all patients under different criteria. The highest CR rate is 73.9%, and the lowest is 15.0%. As showed in Table 4, the consistency of different CR standards varied greatly. The CR criteria of Chinese pLN guidelines, Chan, Ginzler and ALMS showed high consistency in the assessment (Kappa: 0.723-0.858), while the EULAR/ERA-EDTA guidelines had a low degree of compliance with other CR criteria (Kappa: 0.118-0.427). Moreover, the criteria of Deng showed moderate consistency with other standards (Kappa: 0.378-0.587).
Table 4.
Kappa Consistency test of pairwise CR criteria
| Kappa | EULAR/ERA-EDTA | 2016-CLN | Chan | Ginzler | ALMS | Deng |
|---|---|---|---|---|---|---|
| Deng | 0.427 | 0.415 | 0.378 | 0.587 | 0.394 | |
| ALMS | 0.167 | 0.796 | 0.809 | 0.750 | ||
| Ginzler | 0.203 | 0.735 | 0.723 | 0.203 | ||
| Chan | 0.118 | 0.858 | ||||
| 2016-CLN | 0.133 | |||||
| EULAR/ERA-EDTA |
Impact factors of disagreement
In the multivariable logistic-regression analysis, the main factors leading to the inconsistencies between the EULAR/ERA-EDTA or Deng and other standards were urinary protein (OR 2016-CLN vs. EULAR/ERA-EDTA =141.49, OR Deng vs. EULAR/ERA-EDTA =156.33, OR Chan vs. EULAR/ERA-EDTA =11.93, OR Ginzler vs. EULAR/ERA-EDTA =125.95, P<0.01; OR 2016-CLN vs. Deng =18.94, OR Ginzler vs. Deng =7.34, P<0.05) and urinary red blood cells (OR 2016-CLN vs. EULAR/ERA-EDTA =21.07, OR Deng vs. EULAR/ERA-EDTA =37.77, OR Chan vs. EULAR/ERA-EDTA =7.48, OR Ginzler vs. EULAR/ERA-EDTA =25.04, OR ALMS vs. EULAR/ERA-EDTA =25.54, P<0.001; OR 2016-CLN vs. Deng =32.18, OR Chan vs. Deng =15.29, OR Ginzler vs. Deng =35.27, OR ALMS vs. Deng =11.82, P<0.001) (Figure 2; Supplementary Table 6). There was no significant correlation between the disagreement of evaluation and differences in the definitions of leukocytes of urinary sediment (P>0.05). Analysis of the EULAR/ERA-EDTA or Deng compared to other CR criteria showed that differences in renal-function definitions did not increase the risk of inconsistencies (OR EULAR/ERA-EDTA vs. Ginzler <1, OR Deng vs. 2016-CLN <1, P<0.05; Others, P>0.05). And according to the comparison between Chan and EULAR/ERA-EDTA or Deng, serum albumin also did not increase the risk of disagreement (OR EULAR/ERA-EDTA vs. Chan <1, P<0.05; P Deng vs. Chan >0.05).
Figure 2.
Multivariable logistic-regression models compared with EULAR/ERA-EDTA (A) or Deng trial (B).
Discussion
According to our Asian multicenter retrospective pLN cohort study, the CR rates range from 18.5% to 74.1% for MMF and 16.4% to 73.9% for CYC under different standards. Also, consistency on response between any two CR criteria varied widely. Further multivariable logistic regression analysis revealed that the disagreement of responses evaluated by six different CR criteria was mainly caused by two factors, urine protein and urine red blood cells.
CR is widely used in clinical trials, guidelines, and clinical practice as a composite indicator to evaluate the outcome and efficacy in treatments of LN, but its definition has not yet uniformed. A total of 161 patients with proliferative LN were included in this study, which is the largest study to evaluate the efficacy of MMF and CYC in induction therapy of proliferative pLN. On the basis of our study population, we comprehensively compared the six most representative CR standards. Notably, we excluded studies that only used spot UPCR for urinary protein excretion assessment because it was confirmed that spot UPCR could not effectively predict 24-hour UPCR when urine protein beyond the range of 0.5-3.0 g/24 h, the range where most of the patients with LN flares would fall [24]. The 6-month complete response rates of total population in this study varied significantly according to six criteria, ranging from 15.0% as assessed by Chan criteria to 73.9% by the EULAR/ERA-EDTA criteria, which was similar to the adult study [25]. In addition, the CR rates of different treatment groups also fluctuated greatly, among which the rates of MMF group ranged from 18.5% to 74.1%, while the rates of CYC group ranged from 11.2% to 73.9%. Moreover, comparison between the two drugs in induction treatment under different CR standards showed an opposite trend in efficacy.
Based on multiple clinical trials, guidelines [8,10,11] for adult LN have recommended both MMF and CYC as the first-line induction treatment. However, a well-accepted recommendation was not reached in pLN guidelines [7,9]. A retrospective study [20] with 13 LN children reported a CR rate of 66% in MMF group and 0% in CYC group (P>0.05). The other two [18,19], also limited by small sample sizes, reported that the efficacy of MMF was similar to CYC, which is consistent with our findings. These retrospective studies have small sample sizes and low-evidence quality hence large RCTs for children are of great importance. Compared with adults, lack of evidence from children RCTs would require more careful consideration before initiatiation of trials. Although long-term renal survival and mortality rates remain to be the golden standard for evaluating the treatment efficacy of LN, CR is the most commonly selected surrogate end point in LN clinical trials [26] due to its clinical features of relapsing and long-course. A suitable surrogate endpoint should be clearly defined in order to effectively reflect the patient’s disease courses [27-29]. The six CR standards included in this study evaluated four aspects: urinary protein, renal function, urinary sediment and serum albumin, among which urinary protein was included in all standards, with a threshold value ranges from 0.15 g/d to 0.5 g/d. Renal function was assessed by serum creatinine or in combination with eGFR. Urinary sediment including urine red blood cells and urine white blood cells should be normal according to Chan, Ginzler and ALMS criteria, while the 2016-CLN guidelines and Deng only defined the cut-off value of urinary RBCs. Urinary albumin was only included in Chan’s criteria. Among these factors, differences in the cut-off values of urinary protein and urinary red blood cell significantly influenced the results of CR evaluation in different criteria. Although the indexes or cut-off values of renal function, serum albumin and urinary leukocyte were obviously different, they did not significantly relate to the differences in rates of complete remission. On the other hand, Chan, Ginzler, ALMS and 2016-CLN guidelines criteria have a high consistency in the assessment of remission. Although setting different cut-off values of other factors, these studies selected the same cut-off value for urinary-red blood cell. Which further indicated that the urinary RBCs may be the most important factor affecting the evaluation of remission. Previous research [30] has reported that 24-hour urinary protein is the best independent predictor of long-term prognosis among all kinds of commonly used renal parameters, such as serum creatinine and urinary RBCs. The prognosis-predictive capacity of urinary protein combined with urinary RBCs would reduce compared to that of urinary protein alone. Qualified surrogate endpoints should reflect patients’ ultimate clinical benefits. Therefore, defining the threshold for urinary protein, the most important prognostic indicator, in a uniform and clear way is crucial in developing CR standards for pLN randomized controlled trials. Since the addition of urinary RBCs reduces the ability to predict prognosis, and different threshold values of urinary red blood cells lead to disagreement of remission rates between different criteria, this factor should be carefully included.
Limitations of this study include the relatively small sample size of MMF group, with only 27 cases. Secondly, the follow-up time of this study was short and was insufficient to evaluate long-term renal survival rate and mortality rate. Hence in the comparison between the efficacy of MMF and CYC, only complete remission was taken into account without a long-term efficacy.
In summary, different CR criteria will impact the efficacy of MMF and CYC in pediatric proliferative lupus nephritis induction therapy. CR rates with different definitions in comparison of MMF and CYC fluctuated markedly and even an opposite trend of efficacy was observed. The urine protein and urine red blood cells significantly related to the differences in rates of complete remission. However, urinary red blood cells could not increase the ability to predict long-term prognosis, therefore it is not recommended to include this parameter in CR evaluation. This study also provides the basis for establishing uniform and comparable complete remission criteria for prospective clinical studies of pediatric lupus nephritis.
Acknowledgements
This work was supported by two projects of National Natural Scientific Foundation of China (NSFC No. 81800605, NSFC No. 81970611) and a Guangdong Basic and Applied Basic Research Foundation (2019A1515011546).
Disclosure of conflict of interest
None.
Supporting Information
References
- 1.Almaani S, Meara A, Rovin BH. Update on lupus nephritis. Clin J Am Soc Nephrol. 2017;12:825–835. doi: 10.2215/CJN.05780616. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Brunner HI, Gladman DD, Ibañez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum. 2008;58:556–562. doi: 10.1002/art.23204. [DOI] [PubMed] [Google Scholar]
- 3.Malattia C, Martini A. Paediatric-onset systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2013;27:351–362. doi: 10.1016/j.berh.2013.07.007. [DOI] [PubMed] [Google Scholar]
- 4.Hersh AO, Trupin L, Yazdany J, Panopalis P, Julian L, Katz P, Criswell LA, Yelin E. Childhood-onset disease as a predictor of mortality in an adult cohort of patients with systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2010;62:1152–1159. doi: 10.1002/acr.20179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Chen YE, Korbet SM, Katz RS, Schwartz MM, Lewis EJ Collaborative Study Group. Value of a complete or partial remission in severe lupus nephritis. Clin J Am Soc Nephrol. 2008;3:46–53. doi: 10.2215/CJN.03280807. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Illei GG, Takada K, Parkin D, Austin HA, Crane M, Yarboro CH, Vaughan EM, Kuroiwa T, Danning CL, Pando J, Steinberg AD, Gourley MF, Klippel JH, Balow JE, Boumpas DT. Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies. Arthritis Rheum. 2002;46:995–1002. doi: 10.1002/art.10142. [DOI] [PubMed] [Google Scholar]
- 7.Society of Pediatrics, Chinese Medical Association. Evidence-based guidelines for the diagnosis and treatment of lupus nephritis (2016) Chin J Pediatr. 2016;2:88–94. doi: 10.3760/cma.j.issn.0578-1310.2018.02.003. [DOI] [PubMed] [Google Scholar]
- 8.KDIGO. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int. 2012:S139–S274. [Google Scholar]
- 9.Groot N, de Graeff N, Marks SD, Brogan P, Avcin T, Bader-Meunier B, Dolezalova P, Feldman BM, Kone-Paut I, Lahdenne P, McCann L, Özen S, Pilkington CA, Ravelli A, Royen-Kerkhof AV, Uziel Y, Vastert BJ, Wulffraat NM, Beresford MW, Kamphuis S. European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative. Ann Rheum Dis. 2017;76:1965–1973. doi: 10.1136/annrheumdis-2017-211898. [DOI] [PubMed] [Google Scholar]
- 10.Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, Karpouzas GA, Merrill JT, Wallace DJ, Yazdany J, Ramsey-Goldman R, Singh K, Khalighi M, Choi SI, Gogia M, Kafaja S, Kamgar M, Lau C, Martin WJ, Parikh S, Peng J, Rastogi A, Chen W, Grossman JM American College of Rheumatology. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012;64:797–808. doi: 10.1002/acr.21664. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, Boletis J, Cervera R, Dörner T, Doria A, Ferrario F, Floege J, Houssiau FA, Ioannidis JP, Isenberg DA, Kallenberg CG, Lightstone L, Marks SD, Martini A, Moroni G, Neumann I, Praga M, Schneider M, Starra A, Tesar V, Vasconcelos C, van Vollenhoven RF, Zakharova H, Haubitz M, Gordon C, Jayne D, Boumpas DT European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis. 2012;71:1771–1782. doi: 10.1136/annrheumdis-2012-201940. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1971-2015: a systematic review and bayesian meta-analysis. Arthritis Rheumatol. 2016;68:1432–41. doi: 10.1002/art.39594. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Tunnicliffe DJ, Palmer SC. Immunosuppressive treatment for proliferative lupus nephritis: summary of a cochrane review. Am J Kidney Dis. 2018;72:756–757. doi: 10.1053/j.ajkd.2018.07.008. [DOI] [PubMed] [Google Scholar]
- 14.Isenberg D, Appel GB, Contreras G, Dooley MA, Ginzler EM, Jayne D, Sánchez-Guerrero J, Wofsy D, Yu X, Solomons N. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology (Oxford) 2010;49:128–140. doi: 10.1093/rheumatology/kep346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sanchez-Guerrero J, Solomons N, Wofsy D. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20:1103–1112. doi: 10.1681/ASN.2008101028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, Lau CS, Wong AK, Tong MK, Chan KW, Lai KN. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med. 2000;343:1156–1162. doi: 10.1056/NEJM200010193431604. [DOI] [PubMed] [Google Scholar]
- 17.Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, Petri M, Gilkeson GS, Wallace DJ, Weisman MH, Appel GB. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353:2219–2228. doi: 10.1056/NEJMoa043731. [DOI] [PubMed] [Google Scholar]
- 18.Smith E, Al-Abadi E, Armon K, Bailey K, Ciurtin C, Davidson J, Gardner-Medwin J, Haslam K, Hawley D, Leahy A, Leone V, McErlane F, Mewar D, Modgil G, Moots R, Pilkington C, Ramanan A, Rangaraj S, Riley P, Sridhar A, Wilkinson N, Beresford MW, Hedrich CM. Outcomes following mycophenolate mofetil versus cyclophosphamide induction treatment for proliferative juvenile-onset lupus nephritis. Lupus. 2019;28:613–620. doi: 10.1177/0961203319836712. [DOI] [PubMed] [Google Scholar]
- 19.Cooper JC, Rouster-Stevens K, Wright TB, Hsu JJ, Klein-Gitelman MS, Ardoin SP, Schanberg LE, Brunner HI, Eberhard BA, Wagner-Weiner L, Mehta J, Haines K, McCurdy DK, Phillips TA, Huang Z, von Scheven E. Pilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis. Pediatr Rheumatol Online J. 2018;16:65. doi: 10.1186/s12969-018-0279-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Lau KK, Ault BH, Jones DP, Butani L. Induction therapy for pediatric focal proliferative lupus nephritis: cyclophosphamide versus mycophenolate mofetil. J Pediatr Health Care. 2008;22:282–288. doi: 10.1016/j.pedhc.2007.07.006. [DOI] [PubMed] [Google Scholar]
- 21.Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725. doi: 10.1002/art.1780400928. [DOI] [PubMed] [Google Scholar]
- 22.Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M International Society of Nephrology Working Group on the Classification of Lupus Nephritis; Renal Pathology Society Working Group on the Classification of Lupus Nephritis. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65:521–30. doi: 10.1111/j.1523-1755.2004.00443.x. [DOI] [PubMed] [Google Scholar]
- 23.Deng D, Zhang P, Guo Y, Lim TO. A randomised double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis. Ann Rheum Dis. 2017;76:1436–1439. doi: 10.1136/annrheumdis-2017-211073. [DOI] [PubMed] [Google Scholar]
- 24.Birmingham DJ, Rovin BH, Shidham G, Nagaraja HN, Zou X, Bissell M, Yu CY, Hebert LA. Spot urine protein/creatinine ratios are unreliable estimates of 24 h proteinuria in most systemic lupus erythematosus nephritis flares. Kidney Int. 2007;72:865–870. doi: 10.1038/sj.ki.5002421. [DOI] [PubMed] [Google Scholar]
- 25.Wofsy D, Hillson JL, Diamond B. Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions. Arthritis Rheum. 2012;64:3660–3665. doi: 10.1002/art.34624. [DOI] [PubMed] [Google Scholar]
- 26.Tunnicliffe DJ, Palmer SC, Henderson L, Masson P, Craig JC, Tong A, Singh-Grewal D, Flanc RS, Roberts MA, Webster AC, Strippoli GF. Immunosuppressive treatment for proliferative lupus nephritis. Cochrane Database Syst Rev. 2019;1:CD012732. doi: 10.1002/14651858.CD002922.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Levey AS, Inker LA, Matsushita K, Greene T, Willis K, Lewis E, de Zeeuw D, Cheung AK, Coresh J. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis. 2014;64:821–835. doi: 10.1053/j.ajkd.2014.07.030. [DOI] [PubMed] [Google Scholar]
- 28.Cox GF. The art and science of choosing efficacy endpoints for rare disease clinical trials. Am J Med Genet A. 2018;176:759–772. doi: 10.1002/ajmg.a.38629. [DOI] [PubMed] [Google Scholar]
- 29.Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012;31:2973–2984. doi: 10.1002/sim.5403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Dall’Era M, Cisternas MG, Smilek DE, Straub L, Houssiau FA, Cervera R, Rovin BH, Mackay M. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the euro-lupus nephritis cohort. Arthritis Rheumatol. 2015;67:1305–1313. doi: 10.1002/art.39026. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.