Clinicopathological differences in the activation pattern of the complement system between pediatric and adult lupus nephritis: a single centered retrospective study in Korea

Min Ji Park; Man Hoon Han; Mee-seon Kim; Yong-Jin Kim; Sang Jin Lee; Dongsub Kim; Hee Sun Baek; Min Hyun Cho

doi:10.3339/ckd.25.001

Child Kidney Dis > Volume 29(1); 2025 > Article

Park, Han, Kim, Kim, Lee, Kim, Baek, and Cho: Clinicopathological differences in the activation pattern of the complement system between pediatric and adult lupus nephritis: a single centered retrospective study in Korea

Original Article

Child Kidney Dis 2025;29(1):24-31.

Published online: February 11, 2025

DOI: https://doi.org/10.3339/ckd.25.001

Clinicopathological differences in the activation pattern of the complement system between pediatric and adult lupus nephritis: a single centered retrospective study in Korea

Min Ji Park^1,^*

, Man Hoon Han^2,^*

, Mee-seon Kim²

, Yong-Jin Kim²

, Sang Jin Lee³

, Dongsub Kim¹

, Hee Sun Baek⁴

, Min Hyun Cho¹

¹Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

²Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

³Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

⁴Department of Pediatrics, Yeungnam University College of Medicine, Daegu, Republic of Korea

Correspondence to Min Hyun Cho Department of Pediatrics, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 130 Dongdeok-ro, Jung-gu, Daegu 41944, Republic of Korea E-mail: chomh@knu.ac.kr

^*Min Ji Park and Man Hoon Han contributed equally to this study as co-first authors.

Received November 18, 2024 Revised December 30, 2024 Accepted January 10, 2025

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

Abstract

Purpose

Lupus nephritis (LN) can be caused by the complement activation. This study aimed to investigate the differences and clinical implications of the activation pattern of the complement system for pediatric and adult LN patients.

Methods

We retrospectively reviewed the medical records of 40 patients (14 pediatric and 26 adult patients) diagnosed with LN through kidney biopsy.

Results

The mean ages at diagnosis of pediatric and adult patients were 11.7±2.92 and 37.3±13.5 years, respectively. At the first LN diagnosis, compared with adult patients, pediatric patients had a higher estimated glomerular filtration rate and milder proteinuria; however, there was no statistical significance. The age-adjusted mean serum complement 3 value was significantly lower in the pediatric group (33.0±11.3 mg/dL) than in the adult group (50.8±25.2 mg/dL) (P<0.01). Based on the findings of kidney biopsy, no significant differences were observed in the severity of pathologic classification and the positive rate of complements between adults and children. However, the chronicity index score of adult patients was significantly higher than that of pediatric patients and in the case of complement 4d, despite a similar positive rate, the intensity was significantly stronger for adults (2.35±0.83 vs. 1.54±0.52, P=0.04).

Conclusions

The activation pattern of the complement system in LN differs clinicopathologically between pediatric and adult patients and these differences might play an important role in the age-dependent prognosis of LN.

Key words: Adult; Child; Complement activation; Lupus nephritis

Introduction

Lupus nephritis (LN) is one of the major clinical manifestations that determine the prognosis of patients with systemic lupus erythematosus (SLE). Despite advances in LN treatment, LN still plays a major role in the high morbidity and mortality of patients with SLE [1-3]. In general, in contrast to 20%–40% of adults with SLE, 60%–80% of children and adolescents with SLE have abnormal urine test results regardless of kidney impairment, and kidney disorders develop in 90% of patients within 2 years of the onset of the primary disease [1,2,4,5]. In addition, compared with LN onset in adults, LN onset in children and adolescents has shown a more severe disease course [6-9].

LN can be caused by the activation of the complement system, specifically the classical pathway [10-14]. Recently, studies have analyzed the activation of alternative and lectin pathways in LN [15-18]. Therefore, this study aimed to investigate the clinical implications of the activation pattern of the complement system in LN and the differences in the activation pattern of the complement system between pediatric and adult patients with LN.

Methods

Study population

We retrospectively reviewed the medical records of 40 patients (14 children and 26 adults) diagnosed with LN through kidney biopsy at Kyungpook National University Hospital between January 2011 and December 2019. SLE was diagnosed based on the clinical and immunological results of the patients according to the 1997 American College of Rheumatology criteria and the 2019 European League Against Rheumatism/American College of Rheumatology classification [19]. Initial chief complaints at the time of SLE diagnosis, including fever of unknown origin (FUO), arthralgia, skin rash, abnormal urinalysis, edema, and dyspnea, were recorded. Laboratory findings including serum creatinine, estimated glomerular filtration rate (eGFR), complement 3 (C3), complement 4 (C4), antinuclear antibody, anti-double-stranded DNA antibody, total protein, albumin, and urine chemicals (spot urine creatinine, protein, and calcium) were analyzed in this study. The eGFR was calculated using the modified Schwartz formula for pediatric patients and the Modification of Diet in Renal Disease formula for adult patients [20,21]. After the follow-up period, the final prognosis was determined based on the laboratory test results from the last hospital visit. Patients with an eGFR below 90 mL/min/1.73 m² were classified as having chronic kidney disease (CKD), and the incidence of dialysis or mortality was also determined. Kidney biopsy was performed for patients with SLE and proteinuria (≥500 mg/day on 24-hour urine collection or spot urine protein-to-creatinine ratio [UPCR] ≥0.5 g/g).

Pathological evaluation of the activation of the complement system

The activation of the complement system was evaluated by immunofluorescence staining for C3 (a component of the alternative pathway) and C1q (a component of the classical pathway) and immunohistochemical staining for C4d (a component of the classic and lectin pathway) in the glomeruli of kidney tissue. For C4d staining, a formalin-fixed, paraffin-embedded kidney tissue sample was sliced into 2 µm sections and stained with an anti-C4d rabbit monoclonal primary antibody (Clone SP91; Cell Marque) using the BenchMark ULTRA Immunohistochemical Stainer (Ventana Medical System) following the manufacturer’s protocol. The staining intensity for C4d, C1q, and C3 was scored as 0, 1, 2, or 3 (0, absence of complement staining; 1, weak staining; 2, moderate staining; 3, strong staining) (Fig. 1). Two pathologists (MK and YJK) evaluated the histopathological features of all specimens, and a score of 1 or more was defined as positive. The histopathological classification of patients with LN was based on the International Society of Nephrology and Renal Pathology Society (ISN/RPS) 2003 classification system [22].

Treatment regimen

All pediatric patients with pathological findings corresponding to class III or IV received corticosteroid and mycophenolate mofetil (MMF) combination therapy according to published recommendations [23-26]. On the contrary, among adult patients in class III or IV, 46.7% of them received corticosteroid and MMF combination therapy, 40% of them received corticosteroid and cyclophosphamide combination therapy, and 13.3% of them received a triple immunosuppressive regimen including corticosteroids, MMF, and calcineurin inhibitors.

Statistical analysis

Continuous variables were evaluated using the Student t-test and the chi-square test. A P-value of <0.05 was considered statistically significant. All statistical analyses were conducted using R software version 3.4.3 (R Foundation for Statistical Computing).

Results

The study enrolled 40 patients (14 pediatric and 26 adult patients), and the proportion of female patients was significantly higher in both the pediatric and adult groups. At the time of the first diagnosis of LN, the mean eGFR and UPCR of the 40 patients were 98.2±40.2 mL/min/1.73 m² and 3.56±3.10 g/g, respectively. Following kidney biopsy, more than half of all patients (60%) were diagnosed with LN class III or IV according to the 2003 ISN/RPS classification. The mean ages at diagnosis of pediatric and adult patients were 11.7±2.92 and 37.3±13.5 years, respectively. At the first hospital visit, the chief complaints were FUO and skin rash in the pediatric group, whereas they were joint pain and abnormal urinalysis in the adult group. At the first LN diagnosis, compared with adult patients, pediatric patients had a higher eGFR and milder proteinuria; however, there was no statistical significance. The age-adjusted mean C3 value was significantly lower in the pediatric group (33.0±11.3 mg/dL) than in the adult group (50.8±25.2 mg/dL) (P<0.01). Although the serum C4 value also tended to be lower in the pediatric group, this difference was not statistically significant. Except for age and C3 level, the baseline clinical characteristics of pediatric and adult patients were comparable. Pathologic classification showed no difference in the proportions of LN class III and IV between the two groups. However, no pediatric patients were diagnosed with class V LN, and the chronicity index score of adult patients was significantly higher than that of pediatric patients (Table 1). The mean follow-up period after the initial diagnosis was 7.65 years (4.58 years in the pediatric group and 9.31 years in the adult group). During the follow-up period, two of 26 adult patients died, and two patients progressed to end-stage kidney disease. The other 12 patients progressed to CKD. On the other hand, none of the 14 pediatric patients progressed to CKD or died.

Based on the kidney biopsy results of all subjects, the positive rate of C3 and C1q was 82.5% (33 of 40 patients), whereas that of C4d was 90.0% (36 of 40 patients). The relationship between staining intensity and the clinical symptoms of LN was examined for each complement, which showed that the intensity of C1q was significantly stronger in the younger age group (33.9±17.6 years [score 0–1] vs. 20.6±11.8 years [score 2–3], P=0.01), and the UPCR was significantly higher in patients with a stronger intensity of C4d (2.23±2.07 [score 0–1] vs. 4.55±3.41 [score 2–3], P=0.03). There were no significant differences in the remaining data, including eGFR, level of serum C3/C4, and scores of activity index and chronicity index on biopsy (Table 2).

We further compared differences in the complement activity between adults and children. No significant differences were observed in the positive rate of complements between adults and children. However, in the case of C4d, despite a similar positive rate, the intensity was significantly stronger for adults (2.35±0.83 vs. 1.54±0.52, P=0.04) (Table 3, Fig. 2).

Discussion

In this study, we investigated the clinical implications of the activation pattern of the complement system in LN and the differences in the activation pattern of the complement system between pediatric and adult patients with LN. The level of serum C3 was significantly lower at the time of diagnosis in pediatric LN patients than in adult LN patients. The level of serum C4 also appeared to be lower; however, the result was not statistically significant. In more than 80% of all patients, complement system activation was pathologically confirmed, and significant differences in some clinical findings were confirmed according to the staining intensity of complements. The UPCR was significantly higher in the intensity 2–3 of C4d compared to the intensity 0–1 of C4d, indicating a distinct association between stronger C4d staining intensity and increased UPCR. The difference in the staining intensity of C4d was also observed when comparing between children and adults. There was no difference in the positive rate of C4d between both groups; however, the staining intensity was significantly higher for adults.

It is well known that the activation of the complement system, particularly the activation of the classical pathway, plays an important role in the pathogenesis of LN [10-14]. Apart from the classical pathway, the activation of the alternative pathway has been reported as another important factor in determining the long-term prognosis of LN [15,16]. Song et al. [27] analyzed the complement components and clinicopathological features of 222 patients with active biopsy-proven LN, suggesting that the activation of an alternative complement pathway might play a more important role in LN pathogenesis and that factor Bb may be a useful marker for evaluating kidney disease activity and outcomes. In addition, Kim et al. [16] found that the alternative pathway group was older, had a poorer response to 1-year immunosuppressive treatment, and had a significantly higher progression rate of kidney disease when compared with the classical pathway group with or without alternative pathway activation. In this study, serological analysis confirmed that the serum C3 concentration of pediatric LN patients was significantly lower than that of adult patients, which may suggest the relative overactivation of the alternative pathway. However, since this difference could not be confirmed in the histological comparative analysis in this study, it differs from the previous studies mentioned above. Therefore, the clinical implications of the results should be clarified in a long-term prognostic analysis in the future.

In addition to well-known complement system pathways such as the classical and alternative pathways, the lectin pathway has recently been reported as a biological marker of LN progression [17,18,28]. C4d generated by the activation of C4 in the classical and lectin pathways may be considered a potential marker as it has been reported to be related to the disease activity of LN, which maintains covalent bonds with the tissue, including basement membranes and endothelial surfaces [29]. Martin et al. [30] demonstrated that plasma C4d may be a valuable marker for use in monitoring patients with SLE, particularly for LN. They also showed that C4d levels can predict impending LN flares and may be useful for determining treatment. In this study, 90.0% of all LN patients showed C4d positivity on kidney biopsy, and the UPCR was significantly higher in the group with a stronger staining intensity of C4d. Therefore, C4d may be a meaningful biological marker that can predict LN prognosis, as indicated in previous studies.

According to the literature, SLE is associated with a higher incidence of LN in children than in adults, and its prognosis has been reported to be poor [1,2,4,5]. In a multiethnic U.S. cohort study, there were higher rates of kidney damage and end-stage kidney disease in adolescent-onset SLE than in adult-onset SLE [7]. Similarly, Brunner et al. [31] and Sato et al. [8] reported more active disease at the time of diagnosis and during follow-up among patients with childhood-onset SLE compared with patients with adult-onset SLE. In addition, Tucker et al. [6] compared 165 patients with adult-onset SLE with 39 with childhood-onset SLE and reported that pediatric patients had severe clinical symptoms such as hematological manifestations at disease onset, and low serum C3 was more common among patients with childhood-onset SLE.

A noteworthy finding in this study was the difference in the staining intensity of C4d between adult and pediatric LN patients. Various studies have demonstrated that the activation of the lectin pathway, expressed as C4d, is an important biological marker that determines the prognosis of LN [15,17,18]. However, few studies have investigated the difference in the level of C4d between adult and pediatric LN patients. In this study, C3 and C1q, representing other complement pathways, did not show significant differences between the two groups in terms of their positive rate and staining intensity. In the case of C4d, although there was no difference in the positive rate, a significant difference in the staining intensity between the adult and pediatric LN groups was observed. In previous studies, it has been reported that C4d is a biological marker indicating a poor prognosis of LN, and the clinical prognosis of pediatric LN is poorer compared with that of adult LN. Recently, Wang et al. [32] reported that kidney C4d may be a potential biomarker of the activity and severity of LN in pediatric patients. Therefore, we expected C4d to be more strongly expressed in the pediatric LN group in this study; however, a contrasting result was obtained. The C4d staining intensity of adult LN patients was significantly stronger than that of pediatric LN patients. As this study was a cross-sectional study with a small number of enrolled patients, it was difficult to establish the clinical significance of the significantly weak staining intensity of C4d in the pediatric LN group compared with the adult LN group. Nevertheless, there are limited studies with etiological evidence of the clinical course of LN in children and adults; thus, differences in the activation pattern of the complement system, particularly the staining intensity of C4d observed in this study, could provide clues to elucidate age-related differences in the prognosis of LN.

This study has some limitations. First, it was difficult to compare the clinical outcomes and exact prognoses of LN between children and adults because of the difference in the follow-up period between the groups. In particular, the follow-up period of pediatric patients was less than 5 years; thus, the worse prognosis of pediatric LN reported in previous studies could not be directly confirmed. Second, the difference in treatment regimens between pediatric and adult patients with the same class of pathological findings, particularly the more frequent use of stronger immunosuppressive therapies in adults, may have influenced the observed differences in outcomes between the two groups. Third, the pathological confirmation method for C4d was different from that for the other two complements. As mentioned in the materials and methods section, C3 and C1q were evaluated by immunofluorescence staining; however, C4d was evaluated by immunohistochemical staining; thus, there may be measurement bias. Nevertheless, we assumed that age-related differences in the clinical course and prognosis of LN might be attributed to differences in the complement activation pattern and analyzed the relationship between the complement activation pattern and prognosis.

In conclusion, the activation pattern of the complement system in LN differs clinicopathologically between pediatric and adult patients and these differences might play an important role in the age-dependent prognosis of LN. In the future, clarifying the relationship between the activation pattern of the complement system and clinical outcomes in larger cohort studies with long-term follow-up is necessary.

Notes

Ethical statements

This study was conducted following the principles of the Declaration of Helsinki. It was reviewed and approved by the Institutional Review Board of Kyungpook National University Hospital (IRB No. 2023-03-001). The need for informed consent was waived owing to the retrospective design of the study.

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization: MHC

Data curation: MJP, MHH, HSB

Formal analysis: MK, YJK, SJL, DK

Investigation: MHC, MJP, MHH

Methodology: MHC, MJP, MHH

Project administration: MHC

Visualization: MJP, MHH

Writing-original draft: MJP, MHH

Writing–review & editing: MHC, MJP, MHH

All authors read and approved the final manuscript.

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Fig. 1.

Representative biopsies showing the detection of C3 and C1q by immunofluorescence staining (magnification, ×400) and C4d by immunohistochemistry staining (magnification, ×400). Kidney biopsy staining results for C4d, C1q, and C3 were scored as 0, 1, 2, or 3 (0, absence of complement staining; 1, weak staining; 2, moderate staining; 3, strong staining). The histopathological features of all specimens were evaluated by two pathologists. C3, complement 3; C4d, complement 4d; C1q, complement 1q.

Fig. 2.

Comparison of intensity of C4d staining between pediatric and adult patients with severe LN (ISN/RPS class IV). Periodic acid-Schiff (PAS) and immunohistochemical (IHC) stain for C4d in a biopsied kidney tissue of a 14-year-old girl with LN class IV (A), an 11-year-old girl with LN class IV (B), and PAS and IHC stain for C4d in biopsied kidney tissues of two adult patients with LN class IV (C, D). The intensity of IHC stain for C4d in adult patients with LN class IV is significantly stronger than that in pediatric patients with LN class IV (magnification, ×400). C4d, complement 4d; LN, lupus nephritis; ISN/RPS, International Society of Nephrology and Renal Pathology Society.

Table 1.

Baseline characteristics of overall patients and comparison between pediatric and adult patients with lupus nephritis at the time of diagnosis

Clinical data	Total (n=40)	Children (n=14)	Adults (n=26)	P-value
Sex (female:male)	34:6	12:2	22:4	0.93
Age (yr)		11.7±2.92	37.3±13.5
Chief complaint				0.24
FUO	12 (30.0)	7 (50.0)	5 (19.2)
Arthralgia	8 (20.0)	1 (7.14)	7 (26.9)
Skin rash	6 (15.0)	3 (21.4)	3 (11.5)
Abnormal UA	7 (17.5)	2 (14.3)	5 (19.2)
Edema	6 (15.0)	1 (7.14)	5 (19.2)
Dyspnea	1 (2.50)	0	1 (3.85)
eGFR (mL/min/1.73 m²)	98.2±40.2	112.2±50.1	86.3±42.9	0.09
Serum protein (g/dL)	6.52±1.38	6.42±1.50	6.57±1.35	0.75
Serum albumin (g/dL)	3.06±0.79	3.09±0.91	3.03±0.73	0.83
Spot UPCR (g/g)	3.56±3.10	3.00±2.37	3.85±3.44	0.36
C3 (mg/dL)	45.5±23.2	33.0±11.3	50.8±25.2	<0.01
C4 (mg/dL)	7.74±7.22	5.14±4.83	9.14±7.96	0.06
Positive rate of anti-dsDNA (%)	75.0	78.6	73.1	0.70
Pathologic grade (ISN/RPS)				0.08
Class I	5 (12.5)	3 (21.4)	2 (7.69)
Class II	4 (10.0)	3 (21.4)	1 (3.84)
Class III	11 (27.5)	1 (7.14)	10 (38.5)
Class IV	13 (32.5)	7 (50.0)	6 (23.1)
Class V	7 (17.5)	0	7 (26.9)
Pathological findings
Activity index	5.15±3.81	4.64±3.58	5.42±3.96	0.54
Chronicity index	1.05±1.72	0.14±0.36	1.54±1.96	<0.01
Mean follow-up time (yr)	7.65	4.58	9.31
Prognosis
CKD	12 (30.0)	0	12 (46.3)
Dialysis	2 (5.00)	0	2 (7.69)
Death	2 (5.00)	0	2 (7.69)

Values are presented as mean±standard deviation or number (%).

FUO, fever of unknown origin; UA, urinalysis; eGFR, estimated glomerular filtration rate; UPCR, urine protein-to-creatinine ratio; C3, complement 3; C4, complement 4; anti-dsDNA, anti-double-strand DNA; ISN/RPS, International Society of Nephrology and Renal Pathology Society; CKD, chronic kidney disease.

Table 2.

Comparison of clinical and laboratory findings according to the staining intensity of each complement

Variable	Staining intensity of C3^a)			Staining intensity of C4d			Staining intensity of C1q
Variable	0–1	2–3	P-value	0–1	2–3	P-value	0–1	2–3	P-value
Age (yr)	30.3±16.7	26.6±16.9	0.50	27.9±16.5	28.6±16.8	0.90	33.9±17.6	20.6±11.8	0.01
UPCR (g/g)	3.48±3.03	3.75±3.27	0.80	2.23±2.07	4.55±3.41	0.03	3.93±3.22	3.25±3.07	0.54
eGFR (mL/min/1.73 m²)	111.7±48.9	89.5±45.5	0.17	107.0±46.5	92.3±49.5	0.38	108.0±50.4	89.8±43.6	0.27
C3 (mg/dL)	49.3±23.9	39.7±22.0	0.20	46.7±28.0	44.1±28.3	0.99	48.9±25.1	38.5±19.4	0.17
C4 (mg/dL)	8.17±7.30	7.32±7.50	0.72	5.68±6.08	8.98±7.67	0.16	8.56±7.45	6.59±7.18	0.41
Positive rate of anti-dsDNA (%)	65.0	85.0	0.14	80.0	72.0	0.57	69.6	82.4	0.36
Activity index	4.80±4.43	5.63±3.17	0.50	6.20±3.68	4.52±3.81	0.18	5.26±4.38	5.13±3.03	0.92
Chronic index	1.00±1.62	1.16±1.89	0.78	1.47±1.88	0.80±1.61	0.24	1.43±1.97	0.56±1.21	0.12

Value are presented as mean±standard deviation.

C3, complement 3; C4d, complement 4d; C1q, complement 1q; UPCR, urine protein-to-creatinine ratio; eGFR, estimated glomerular filtration rate; C4, complement 4; anti-dsDNA, anti-double-stranded DNA.

^a)The staining intensity for C4d, C1q, and C3 was scored as 0, 1, 2, or 3 (0, absence of complement staining; 1, weak staining; 2, moderate staining; 3, strong staining) by two pathologists.

Table 3.

Comparison of the positive rate of complement staining and intensity of biopsy specimens positive for complement staining between all pediatric and adult patients

Staining^a)		Pediatric (n=14)	Adult (n=26)	P-value
C3 staining	Positive rate (%)	92.9	76.9	0.21
C3 staining	Intensity	1.92±0.86	2.35±0.81	0.16
C4d staining	Positive rate (%)	92.9	88.5	0.66
C4d staining	Intensity	1.54±0.52	2.35±0.83	0.04
C1q staining	Positive rate (%)	85.7	80.8	0.69
C1q staining	Intensity	2.00±0.74	2.05±0.86	0.87

Values are presented as the mean±standard deviation.

C3, complement 3; C4d, complement 4d; C1q, complement 1q.

^a)The staining intensity for C4d, C1q, and C3 was scored as 0, 1, 2, or 3 (0, absence of complement staining; 1, weak staining; 2, moderate staining; 3, strong staining) by two pathologists, and a score of 1 or more was defined as positive.