Introduction
Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE), characterized by disorders of innate and adaptive immunities, resulting in immune complex deposition in the affected kidney, eventually leading to chronic irreversible kidney damage [1–3]. Although the therapeutic management of LN has improved patient and kidney survival over the past few decades, the prognosis of LN is highly variable, and efforts have been made to identify factors predicting kidney outcomes [4–9]. Race, sex, presence or lack of specific autoantibodies, kidney function at diagnosis, certain histopathologic findings, nephritic flares, and treatment response may influence the prognosis of LN [4,6,10–14]. Among them, treatment response and histological findings of proliferative LN have been consistently reported to be related to kidney outcomes in pediatric LN patients, but the influence of other factors on prognosis remains controversial [15–20].
Furthermore, because childhood-onset LN is extremely rare, little is known about the clinical characteristics, kidney outcomes, and prognostic factors in this population. Our goals were to analyze the clinical features and course of childhood-onset LN and determine predictive factors for poor kidney prognosis.
Methods
Participants
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 cohort included patients diagnosed with LN before the age of 18 years from 2000 to 2020. This study was conducted in accordance with the 1964 Declaration of Helsinki and approved by the Institutional Review Board of Seoul National University Hospital (No. 2103-067-1203). Patients registered in the cohort were histologically diagnosed by percutaneous kidney biopsy and classified according to the World Health Organization classification [21]. Demographic data, clinical characteristics, laboratory values at the time of diagnosis, and kidney outcomes of the patients during visits were reviewed retrospectively from electronic medical records. Patients who could not be followed for at least 12 months to assess treatment response were excluded from the study.
Laboratory methods
The glomerular filtration rate (GFR) was estimated using Schwartz’s formula [22]. Complement 3 (C3) and complement 4 (C4) levels were measured using nephelometry. Anti–double-stranded DNA (anti-dsDNA) antibody was measured using qualitative fluoroenzyme immunoassay.
Definitions
Azotemia was defined as an estimated GFR (eGFR) below 90 mL/min/1.73 m2. When classifying a patient's response to treatment, complete remission (CR) was defined as stable serum creatinine and reduction of proteinuria to <0.5 g/day in at least two consecutive measurements or subsequent visits, partial remission (PR) was defined as a reduction of proteinuria to 0.5–3.0 g/day or a decrease >50% from baseline, and resistant was defined as failure to achieve PR or CR [21]. In the outcome analysis, advanced chronic kidney disease (CKD) was defined as confirmed stages 3, 4, and 5 of CKD classification [21].
Statistical analysis
Qualitative variables are described as percentages. Continuous variables are presented as means and standard deviations. The chi-square tests were used to investigate the association between qualitative variables, and the Mann-Whitney U tests were used to compare differences between two independent groups on a continuous scale. Cox proportional‐hazards regression analysis was used to detect the HRs and the independent effect of each clinical factor on the composite outcome (risk of developing advanced CKD by 10 years). In the analysis, male sex, azotemia at onset, proliferative LN, and failure to achieve remission at 12 months of treatment were considered as clinical risk factors for advanced CKD. Potential confounders were checked a priori using directed acyclic graphs (Supplementary Figure 1, available online) [23]. Statistical significance was set at p < 0.05. Statistical analysis was performed using IBM SPSS for Windows version 26.0 (IBP Corp.).
Results
Clinical characteristics of the cohort
We analyzed the records of 216 patients enrolled in this cohort. The mean age at the onset of nephropathy was 13.2 ± 3.22 years, and 59 patients (27.3%) were male. Of these, 32 patients (14.8%) were previously diagnosed with SLE. The main forms of presentation were nephrotic syndrome with or without hematuria in 152 patients (70.4%), followed by proteinuria with or without hematuria in 46 patients (21.3%). Eighteen patients (8.3%) presented with isolated hematuria. At the onset of nephropathy, 110 patients (50.9%) had normal kidney function, and 106 patients (49.1%) had azotemia. 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%), and WHO class V in 24 patients (11.1%). Laboratory tests revealed that C3 levels were lower in 194 patients (89.8%), and C4 levels were lower in 171 patients (79.2%). High anti-dsDNA levels were observed in 154 patients (71.3%). The proportion of azotemia at the onset of LN was significantly higher in male patients than in females (p = 0.03) (Table 1).
Treatment responses of the cohort
All patients received corticosteroids. Forty-six (21.3%) and 91 patients (42.1%) received mycophenolate mofetil (MMF) and cyclophosphamide (CPM), respectively, while 25 patients (11.6%) sequentially switched from CPM to MMF as induction therapy. MMF has been currently more frequently used than before (39.4% vs. 22.6%, p = 0.01) as induction therapy in patients diagnosed with LN since 2010.
Patients were classified into proliferative and nonproliferative LN based on histological findings and kidney outcomes were analyzed at 6 and 12 months after treatment. Of 172 patients with proliferative LN, 113 (65.7%) achieved CR after 6 months of induction treatment, and 135 (78.5%) achieved CR after 12 months. In addition, out of 44 patients with nonproliferative LN, 38 (86.4%) achieved CR after 6 months of induction treatment, and 36 (81.8%) maintained CR after 12 months. By comparing induction treatment in male than in females, the proportion of CR after 6 and 12 months in proliferative LN and CR after 12 months in nonproliferative LN were all higher in females than in males; although, there were no statistically significant differences (Table 2).
Kidney outcomes of the cohort
In the kidney outcome analysis, the mean follow-up period of the patients was 7.8 ± 5.11 years. At the last follow-up visit, 18 patients (8.3%) progressed to CKD stage 5, 14 patients (6.5%) progressed to CKD stages 3 and 4, while 184 patients (85.2%) remained in CKD stages 1 and 2. When comparing males and females, there was no significant difference in the follow-up period, but males had higher rates of advanced CKD than females (Table 3). Patients who progressed to advanced CKD at the last follow-up reached that status within a mean of 6.7 ± 3.63 years after diagnosis, and there was a significant difference in the follow-up period between patients with advanced and non-advanced CKD (10.9 ± 7.11 vs. 7.3 ± 4.49, p = 0.01). There were six deaths (2.8%) due to severe anemia, pancreatitis, liver failure, cerebral infarction, myocardial infarction, and cardiomyopathy caused by active and severe SLE.
We conducted a Cox proportional‐hazards regression analysis to explore the independent risk factors for developing advanced CKD by 10 years. In the adjusted model, there was an increased risk of developing advanced CKD in males (hazard ratio [HR], 2.566; 95% confidence interval [CI], 1.149–5.733; p = 0.02) and in patients who failed to achieve CR at 12 months of treatment (HR, 2.29; 95% CI, 1.06–4.94; p = 0.04) (Table 4). Development of advanced CKD was not associated with other clinical factors (azotemia at onset and proliferative LN).
Discussion
To date, this is the largest multicenter study of childhood-onset LNs in South Korea and the study comprehensively shows clinicopathological characteristics, treatment responses, kidney outcomes, and risk factors associated with the development of advanced CKD in childhood-onset LNs. We attempted to collect long-term data with a large number of patients, through a retrospective multicenter study involving 13 major pediatric nephrology centers across South Korea. For the clinical characteristics, the cohort mainly presented as nephrotic syndrome and WHO class IV being the most common form, and these have similarly been reported in previous pediatric LN studies [2,17,19]. In this study, nonproliferative LN patients showed better treatment responses than proliferative LN patients, and approximately 15% of the patients developed advanced CKD at the last follow-up. These results are comparable to recent pediatric LN cohorts where overall CR rates at 12 to 24 months ranged from 53.3% to 78.3% and rates of progression to advanced CKD at the last follow-up ranged from 8.7% to 28.8% [17–19].
The risk of kidney function deterioration in pediatric LN patients has been strongly associated with the histological findings of proliferative LN and poor treatment response [4,17–20]. In this study, failure to achieve remission in the first year was an independent risk factor for developing advanced CKD in childhood-onset LN, whereas the histological finding of proliferative LN was not associated with the development of advanced CKD. Although it is difficult to clearly explain why the results of the study differ from those of previous studies, it is possible that active and effective treatments have been implemented in proliferative LN patients as awareness of these high-risk patients increased [5,9].
In addition, male was also an independent risk factor for progression to advanced CKD in this study. Till date, there have been conflicting reports when kidney prognosis between males and females among LN and SLE patients are compared [24–27]. Moreover, data on pediatric LN are limited, and there are few data on the effect of sex on the outcome of childhood-onset LN. A recent pediatric LN cohort study from Turkey (10 males) reported results similar to those of the present study. In this study, male sex was a predictor of poor kidney outcome [15]. Data from India (13 males) and South Korea (22 males) identified male sex as a significant risk factor for predicting kidney failure in childhood LN in the multivariable analysis [17,28]. However, these results could not be confirmed in pediatric LN cohort studies that enrolled a relatively large number of patients with LN. The Italian Collaborative Study reported the results of analyzing data from 161 pediatric LN patients (39 males). They could not find any statistical significance between sex and progression to kidney failure, although male sex was associated with a higher risk of nephritic flares [18]. A retrospective cohort of 92 pediatric LNs from Hong Kong (14 males) showed no association between the development of advanced CKD and sex [19]. Although these pediatric LN cohort studies have the advantage of including a larger number of total LN patients than previous studies, they still have limitations such as the small number of male patients included or the short follow-up period. As the pathogenesis of LN is widely heterogeneous, it is possible that some regional or ethnic factors other than sex may have played a role [29–32]. Therefore, more studies on the prognostic factors of pediatric LN are needed to better identify high-risk groups and further improve kidney outcomes.
Our study expands on the results of recent pediatric LN cohort studies on the effects of male sex and treatment responses on kidney prognosis but best reflects the homogeneity of ethnic and sociodemographic characteristics of South Korea. While this study has the strength of including a large number of pediatric LN patients and providing a relatively longer follow-up period, it also has some limitations. This was a retrospective multicenter cohort study, and it is inevitable that some information would be missing. Data were unavailable on frequent nephritis flares and specific autoantibodies, a powerful predictor of prognosis in LN patients. We were also unable to analyze data on cumulative doses of immunosuppressive drugs such as steroids. Although we classified the renal histology according to the WHO classification, we did not analyze the information related to activity or chronicity. Finally, we used an intermediate measure of outcome (advanced CKD) rather than a hard point (kidney failure or death) for outcome analysis. Further studies in a prospective pediatric LN cohort collecting a large number of male patients and all possible clinical risk factors related to kidney prognosis and providing a longer follow-up period are needed.
In summary, our cohort showed that childhood-onset LN commonly presents as nephrotic syndrome, with WHO class IV being the most common form, and approximately 15% of the patients developed advanced CKD. Male sex and failure to achieve remission in the first year were independently associated with the development of advanced CKD. In order to establish appropriate treatment and follow-up plans for children with LNs, timely evaluation and close monitoring of these high-risk patients are required.
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