| Abstract|| |
Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder. Renal involvement usually develops in the first few years of illness and should be detected early by periodic urine analysis and quantitation of proteinuria. The aim of our work was to evaluate the biological marker [anti-complement 1q antibodies (anti-C1q Ab)] in lupus nephritis (LN) patients and its correlation to SLE disease activity. Sixty-five subjects were divided into four groups; Group I: SLE patients with LN (proteinuria >0.5 g/day), Group II: SLE patients without LN (all of them had a lupus flares rather than nephritis; active nonrenal), Group III: SLE patients without any activity (inactive disease), and Group IV: Control group. All subjects underwent urine analysis, complete blood picture, liver function tests, kidney function tests, albumin/ creatinine ratio, antinuclear antibody, anti-double stranded DNA (anti-dsDNA) antibody, C3, C4, and anti-C1q Ab. All patients in the first group underwent renal biopsy and pathological diagnosis showed: Class II in two patients, Class III and IV in nine patients, and Class V in four patients. Anti-C1q Ab were found in the serum of SLE patients and not in the control group and showed an association with active lupus with much higher concentration in active renal group, specifically those with severe renal histological lesions (proliferative form). There was significant statistical positive correlation between anti-C1q Ab with anti-dsDNA and SLE disease activity index in both active groups. There was statistically significant negative correlation between anti-C1q Ab with C3 and C4 in both active groups. Anti-C1q Ab could be used as useful marker for active lupus, especially with nephritis.
|How to cite this article:|
Emad G, Al-Barshomy SM. Anti-C1q antibodies in lupus nephritis and their correlation with the disease activity. Saudi J Kidney Dis Transpl 2020;31:342-52
|How to cite this URL:|
Emad G, Al-Barshomy SM. Anti-C1q antibodies in lupus nephritis and their correlation with the disease activity. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Jul 13];31:342-52. Available from: http://www.sjkdt.org/text.asp?2020/31/2/342/284008
| Introduction|| |
Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder with a wide range of clinical features, which predominantly affects women. Diagnosis is based on clinical features and laboratory investigations. The first few years of illness carry the risk of renal involvement and can be detected early by periodic urine analysis, proteinuria quanti- tation, and estimation of the glomerular filtration rate (GFR).
Complement 1q (C1q) is the first component of the classical pathway of complement activation and its main function is to clear immune complexes from tissues and self-antigens generated during apoptosis. Antibodies to C1q antibodies (anti-C1q Ab) directed against the collagen-like region of q sub-unit of C1 are thought to be able to contribute to renal involvement in SLE.
Antibodies directed to Clq (anti-Clq) were reported in the serum of patients with SLE, with a prevalence ranging from 34% to 47%, and in patients with hypocomplementemic urti- carial vasculitis syndrome with a prevalence of 100%.
| Aim|| |
Our study aimed to evaluate the biological marker (anti-C1q Ab) in lupus nephritis (LN) patients and its correlation to SLE disease activity.
| Patients and Methods|| |
This study was conducted on 65 subjects, both females and males; their ages ranged from 18 to 45 years. Forty-five patients diagnosed to have SLE and fulfilled at least four of 11 American College of Rheumatology (ACR) revised criteria for SLE. These participants were divided into four groups:
- Group I: SLE patients with LN (active renal).
This group comprised 15 SLE patients (14 females and one male with percentage of 93.3% and 6.6%, respectively) who were admitted to the nephrology unit due to lupus flares; all had clinical nephritis: proteinuria >0.5 g/day and some patients had elevated serum creatinine (SCr) level (>1.1 mg/dL in female and >1.2 mg/dL in males)
All the patients in this group had a renal biopsy at time of blood sampling and were proved to have LN. Renal histologies were classified according to the International Society of Nephrology/Renal Pathology Society criteria The renal disease was:
- Class II in two patients (non- proliferative LN) (13.3%)
- Class III and IV in nine patients (proliferative LN) (60%)
- Class V in four patients (membranous LN) (26.7%).
All the patients were sampled before having immunosuppressants in their course of treatment
- Group II: SLE patients without LN (active nonrenal):
This group comprised 15 SLE patients (13 females and 2 males with percentage of 86.7% and 13.3%, respectively) were admitted to the rheumatology unit due to lupus flares with arthritis, proteinuria <0.5 g/day, no hematuria, or urinary casts sediment and all of them had a normal kidney function (SCr <1.1 mg/dL in females or <1.2 mg/dL in males) with estimated glomerular filtration rate (eGFR) >90 mL/ min/1.73 m2
All the patients were sampled before having immunosuppressants in their course of treatment
- Group III: SLE patients without any activity (nonactive disease):
This group comprised 15 SLE patients (13 females and 2 males with percentage of 86.7% and 13.3%, respectively) were sampled during their routine visit in the rheumatology and internal medicine clinics, All of them have nonactive disease with SLE Disease Activity Index (SLEDAI) <8
- Group IV: Control group:
Twenty healthy individuals (17 females and 3 males with percentage of 85% and 15%, respectively) were chosen with their age-matching previous groups ranging 1845 years. None had any immunological disease or other medical disorders.
Excluded in the study were:
- Patients who have other autoimmune disease or did not meet four of revised ACR criteria for SLE
- Patients who developed end-stage renal disease and had received renal replacement therapy
- Patients receiving recent or ongoing
immune suppressant for the treatment of disease flare before sampling 4. Patients aged <18 years and nonavailability of written consent. Written informed consent was obtained from the patients to participate in the study. Approval for performing the study was obtained from Internal Medicine and Clinical Pathology Departments, Zagazig University Hospitals, after taking Institutional Review Board approval. All subjects in the study subjected to:
- History (full-detailed medical history)
- Clinical examination
Clinical examination was done to exclude any hidden medical problems, especially undiscovered diabetes mellitus, chronic liver diseases or other causes of glomerulonephritis, detection of any of the following: malar flush, photosensitivity, alopecia, oral ulcers, arthritis, Raynaud’s phenomenon, pleurisy or pleural effusion, pericarditis or pericardial effusion, convulsions or cerebral accidents.
The activity of SLE was measured using the SLEDAI, scores >8 indicate active disease, and activity variations >12 points mean severe activity with maximum score of 105
- Laboratory investigations
- Complete blood count
- Urine analysis and albumin/Cr ratio in urine for detection of proteinuria
- Kidney function test (blood urea and SCr)
- Liver function test [alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum albumin and total plasma protein].
- Erythrocyte sedimentation rate (ESR)
- Antinuclear antibody (ANA)
- Anti-double stranded DNA (anti- dsDNA)
- Antineutrophil cytoplasmic antibodies and anticardiolipin antibody
- C3, C4
- Anti-Clq Ab: Measurement was made using the ELISA kit (manufactured by Orgentic Diagnostica Gmbh/Mainz - Germany). The lower detection for anti-Clq was determined at 0.5 U/mL; the levels are considered elevated if >40 U/mL
- Calculation of eGFR using Modification of diet in renal disease equation GFR (mL/min/1.73 m2) = 175 x (SCr) -1.154 x (Age)-0.203 x (0.742 if female).6 4. Renal biopsy.
After obtaining written informed consent, patients in Group I underwent ultrasound- guided renal biopsy taken by a specialized radiologist and the World Health Organization classification of LN was used to define the histological lesions.
| Statistical Analysis|| |
Statistical analysis was performed using the IBM SPSS Statistics software version 21.0 (IBM Corp., Armonk, NY, USA). Data were summarized as mean, standard deviation, and percentage. Nonparametric (Mann-Whitney U) test was used for analysis of quantitative data, as data were not symmetrically distributed. The Chi-square test was used for analysis of qualitative data, while the Kruskal- Wallis H test was done for analysis of more than two variables.
| Results|| |
There was no statistical significant difference between all groups with regard to age or sex distribution. Systolic blood pressure (SBP) and temperature were significantly higher in active renal SLE group than the other groups; further, hemoglobin (Hb) and platelet level showed high statistical significant difference among all groups [Table 1].
Serum total protein and albumin were significantly lower in active renal SLE group compared to the other three groups.
Kidney function tests
There was high statistical significant difference among all groups with regard to SCr,
eGFR and Alb/Cr ratio in the urine. SCr and SLEDAI were significantly higher in active renal SLE group compared to other groups.
There was high statistical significant difference among all groups with regard to all immunological tests (ANA, anti-dsDNA, C3, C4 and anti-C1q Ab). C3 and C4 were significantly lower in SLE groups compared to the control group. There was a statistical significant positive correlation between anti-C1q Ab and anti- dsDNA and SLEDAI in active nonrenal SLE.
There was a statistical significant difference among LN biopsy classes regarding SBP, Hb, and SCr and there was high statistical significant difference regarding plasma protein, serum albumin, eGFR, Alb/Cr ratio, ESR, and anti-C1q Ab.
There was no statistical significant correlation between anti-C1q Ab and other variables in nonactive SLE.
| Discussion|| |
SLE is a chronic autoimmune disease of unknown etiology which is characterized by production of various autoantibodies against self-antigens (autoantigens). SLE can affect multiple systems and major organs, among which LN is a common major organ manifestation and a main cause of morbidity and mortality of the disease. Anti-C1q Ab directed against the collagen-like region of q sub- unit of C1 is thought to be able to contribute to renal involvement in SLE.
Anti-C1q autoantibodies have been proposed as useful markers in SLE since their occurrence correlates with renal involvement and possibly with nephritic activity.
In the present study, as shown in [Table 1], there was no statistical significant difference between all groups of the study and the control group regarding age or sex distribution, and this excludes the effect of age and sex in interpretation of this biomarker.
Regarding SBP, it was higher in active renal SLE than other groups. This result was supported by Hanly et al, who found that hypertension was more frequent in patients with nephritis. Further, Al Alfy et al reported significant difference between active renal and inactive disease regarding SBP and diastolic blood pressure, being higher in active renal SLE patients.
The pathogenesis of hypertension in SLE is not fully understood; a combination of traditional (age, sex, obesity, ethnicity) and disease- related factors (immune system dysfunction, inflammation, renal involvement, drug side effects) may contribute to hypertension in SLE patients.,
The body temperature was higher in active lupus groups (renal and nonrenal) and this goes in harmony with Inoue et al, who reported that SLE activity was the most common cause of fever in lupus patients. In addition, Zhou and Yang concluded in their study that the causes of fever in hospitalized patients with SLE are complicated and are primarily due to infection and SLE activity.
Regarding Hb level, there was significant statistical difference between active SLE groups (renal and nonrenal) and nonactive SLE (being lower in active groups) and no statistical significant difference was seen between active renal and active nonrenal SLE groups.
There was no statistical significant differences in liver function tests (ALT and AST and total serum bilirubin) between groups, but there was high statistical significant difference between groups regarding total plasma protein and serum albumin (being lower in active renal SLE group) and this goes in harmony with Sui et al.
In our study, the SCr was significantly higher while the eGFR was lower in active renal SLE compared to other all groups. This was reported by Al Alfy et al as well, who got the same results.
Regarding proteinuria measured by Alb/Cr ratio in urine, there was high statistical significant difference between active renal SLE and all other groups, being higher in the active renal SLE group, and this is in accordance with Medina-Rosas et al, Al Alfy et al, and Chi et al. Nephrotic syndrome (NS) is a common sign of LN. NS is particularly characteristic of proliferative LN (Class III, Class IV) or membranous LN (Class V).
Regarding the SLEDAI index, there was high statistical significant difference between active SLE (renal and nonrenal) and nonactive SLE, being higher in the active groups, but there was no statistically significant difference between active renal and active nonrenal SLE groups These results are consistent with Oelzner et al, Meyer et al, and Al Alfy et al.
Regarding ANA and anti-dsDNA, there was statistical significant difference between control group and both active SLE groups (renal and non-renal) being higher in active groups. In addition, there was high statistical significant difference between active renal SLE and all other groups, being higher in active renal SLE. These results are consistent with Hewala et al and Chi et al.
In our work, C3 and C4 showed high statistical significant difference between control group and all SLE groups, being lower in SLE groups, and these results are consistent with Li et al. At the same time, Chi et al concluded that serum concentrations of complements C3 and C4 were lower in patients with active SLE and LN relative to those with respective inactive SLE and non-LN groups P <0.05 for LN versus non-LN).
Regarding anti-C1q Ab, there was high statistical significant difference between active renal SLE and all other groups of the study (being higher in active renal SLE). There was statistical significant difference between control group and both active SLE groups (renal and nonrenal), being higher in active groups, but no statistical significant difference was seen between control group and non-active SLE group. Finally, there was statistical significant difference between active nonrenal SLE group and nonactive SLE group regarding Anti-C1q, which was higher in active nonrenal SLE. These results are consistent with Chi et al, Smykal-Jankowiak et al, and Orbai et al.
Comparison between all biopsy classes of active renal SLE group is shown in [Table 2]. There was statistical significant difference between biopsy classes regarding SBP, Hb, and SCr, and there was high statistical significant difference regarding total protein, serum albumin, eGFR, Alb/Cr ratio, ESR, and C1q Ab, in harmony with Mavragani et al, and Moroni et al.
|Table 2: Comparison between all biopsy classes of active renal systemic lupus erythematosus group.|
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Regarding anti-C1q Ab, there was statistical significant difference between proliferative LN (Class III and IV) from nonproliferative (Class II) and membranous LN (Class V) (being higher in proliferative LN). There was no statistical significant difference between classes of proliferative LN (Class III and IV). There was no statistical significant difference between Class II and Class V.
In concordance with these findings, Moroni et al, who found that anti-C1q Ab had significant higher prevalence and higher titers in proliferative than in nonproliferative forms of LN. Further, Fang et al investigated the clinical and pathological association of anti- C1q in LN and found a higher prevalence of the autoantibody in Class IV than in the other histological classes.
Instead, other cohort studies did not show differences in the prevalence of anti-C1q antibodies between proliferative and non- proliferative LN. This discrepancy could be due to the fact that in these studies, the diagnosis of renal activity was made on clinical grounds and not confirmed by renal biopsy.
As shown in [Table 3], the correlation between anti-C1q antibodies and the other parameters, especially parameters of activity, showed strong positive correlation in active renal SLE group and moderate positive correlation in active nonrenal group.
|Table 3: Correlation coefficient between anticomplement 1q antibody and each parameter in the three systemic lupus erythematosus groups.|
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Interestingly, no significant correlation was found with SCr, eGFR, and proteinuria in harmony with the findings of Marto et al, Chi et al, Smykal-Jankowiak et al, Zhang et al, and Julkunen et al.
The validity of anti-C1q antibodies in diagnosis of LN activity was assessed, and we found out that anti-C1q antibody had the highest specificity and sensitivity in diagnosing LN activity in comparison to C3, C4, ANA and SLEDAI, but share the same specificity and sensitivity with anti-dsDNA (sensitivity: 93.3% and specificity: 98.0%) [Table 4].
| Conclusion|| |
Anti-C1q antibodies were found to be elevated in SLE patients and can be used as useful marker for lupus activity, especially with nephritis.
Conflict of interest: None declared.
| References|| |
D’Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet 2007;369:587-96
Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241-50
Walport MJ. Complement. First of two parts. N Engl J Med 2001;344:1058-66
Jaekell HP, Trabandt A, Grobe N, Werle E. Anti-dsDNA antibody subtypes and anti-C1q antibodies: Toward a more reliable diagnosis and monitoring of systemic lupus erythe- matosus and lupus nephritis. Ann NY Acad Sci 2005;1050:193-200
Marto N, Bertolaccini ML, Calabuig E, Hughes GR, Khamashta MA. Anti-C1q antibodies in nephritis: Correlation between titres and renal disease activity and positive predictive value in systemic lupus erythe- matosus. Ann Rheum Dis 2005;64:444-8
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12
Cozzani E, Drosera M, Gasparini G, Parodi A. Serology of lupus erythematosus: Correlation between immunopathological features and clinical aspects. Autoimmune Dis 2014;2014: 321359
Yap DY, Lai KN. Pathogenesis of renal disease in systemic lupus erythematosus-the role of autoantibodies and lymphocytes subset abnormalities. Int J Mol Sci 2015;16:7917-31
Jaekell HP, Trabandt A, Grobe N, Werle E. Anti-dsDNA antibody subtypes and anti-C1q antibodies: Toward a more reliable diagnosis and monitoring of systemic lupus erythematosus and lupus nephritis. Lupus 2006;15: 335-45
Sinico RA, Radice A, Ikehata M, et al. Anti- C1q autoantibodies in lupus nephritis: Prevalence and clinical significance. Ann N Y Acad Sci 2005;1050:193-200
Hanly JG, O’Keeffe AG, Su L, et al. The frequency and outcome of lupus nephritis: Results from an international inception cohort study. Rheumatology (Oxford) 2016;55:252- 62. ' '
AL Alfy MN, AL Hakim MS, Abd Elmouttaleb AT, Bayomy EM, Abonar AA, Abood MA. Study of interleukin-12 cytokine and anti-C1q antibodies in lupus nephritis patients. Int J Internal Med 2014;3:13-26
Ryan MJ. The pathophysiology of hypertension in systemic lupus erythematosus. Am J Physiol Regul Integr Comp Physiol 2009;296:R1258- 67
Sabio JM, Mediavilla JD, Fernandez-Torres C, Aliaga L, Jimenez-Alonso J. Risk factors related to hypertension in a Spanish systemic lupus erythematosus cohort. Lupus 2001;10: 451-2
Chaiamnuay S, Bertoli AM, Roseman JM, et al. African-American and Hispanic ethnicities, renal involvement and obesity predispose to hypertension in systemic lupus erythematosus: Results from LUMINA, a multiethnic cohort (LUMINAXLV). Ann Rheum Dis 2007;66: 618-22
Inoue T, Takeda T, Koda S, et al. Differential diagnosis of fever in systemic lupus erythematosus using discriminant analysis. Rheumatol Int 1986;6:69-77
Zhou WJ, Yang CD. The causes and clinical significance of fever in systemic lupus erythematosus: A retrospective study of 487 hospitalised patients. Lupus 2009;18:807-12
Ines L, Duarte C, Silva RS, Teixeira AS, Fonseca FP, da Silva JA. Identification of clinical predictors of flare in systemic lupus erythematosus patients: A 24-month prospective cohort study. Rheumatology (Oxford) 2014;53:85-9
Sui M, Jia X, Yu C, Guo X, Liu X, Ji Y, et al. Relationship between hypoalbuminemia, hyperlipidemia and renal severity in patients with lupus nephritis: A prospective study. Cent Eur J Immunol 2014;39:243-52
Medina-Rosas J, Yap KS, Anderson M, Su J, Touma Z. Utility of urinary protein-creatinine ratio and protein content in a 24-hour urine collection in systemic lupus erythematosus: A systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2016;68:1310-9
Chi S, Yu Y, Shi J, Zet al. Antibodies against C1q are a valuable serological marker for identification of systemic lupus erythematosus patients with active lupus nephritis. Dis Markers 2015;2015:450351
Hu W, Chen Y, Wang S, et al. Clinical- morphological features and outcomes of lupus podocytopathy. Clin J Am Soc Nephrol 2016; 11:585-92
Oelzner P, Deliyska B, Funfstuck R, Hein G, Herrmann D, Stein G. Anti-C1q antibodies and antiendothelial cell antibodies in systemic lupus erythematosus - relationship with disease activity and renal involvement. Clin Rheumatol 2003;22:271-8
Meyer OC, Nicaise-Roland P, Cadoudal N, Grootenboer-Mignot S, Palazzo E, Hayem G, et al. Anti-C1q antibodies antedate patent active glomerulonephritis in patients with systemic lupus erythematosus. Arthritis Res Ther 2009;11:R87
El Hewala A, Nageeb GS, El-Shahawy EE, et al. Anti-C1q and anti-dsDNA antibodies in systemic lupus erythematosus: Relationship with disease activity and renal involvement in Sharkia governorate, Egypt. Egypt Rheumatol 2011;33:203-8
Li H, Lin S, Yang S, Chen L, Zheng X. Diagnostic value of serum complement C3 and C4 levels in Chinese patients with systemic lupus erythematosus. Clin Rheumatol 2015;34: 471-7
Smykal-Jankowiak K, Niemir ZI, Polcyn- Adamczak M. Do circulating antibodies against C1q reflect the activity of lupus nephritis? Pol Arch Med Wewn 2011;121:287- 95
Orbai AM, Truedsson L, Sturfelt G, Nived O, Fang H, Alarcon GS, et al. Anti-C1q antibodies in systemic lupus erythematosus. Lupus 2015;24:42-9
Mavragani CP, Fragoulis GE, Somarakis G, Drosos A, Tzioufas AG, Moutsopoulos HM. Clinical and laboratory predictors of distinct histopathogical features of lupus nephritis. Medicine (Baltimore) 2015;94:e829
Moroni G, Quaglini S, Radice A, et al. The value of a panel of autoantibodies for predicting the activity of lupus nephritis at time of renal biopsy. J Immunol Res 2015; 2015:106904
Fang QY, Yu F, Tan Y, et al. Anti-C1q antibodies and IgG subclass distribution in sera from Chinese patients with lupus nephritis. Nephrol Dial Transplant 2009;24:172-8
Kumar A, Gupta R, Varghese T, Pande RM, Singal VK, Garg OP. Anti-C1q antibody as a marker of disease activity in systemic lupus erythematosus. Indian J Med Res 1999; 110:190-3
Matrat A, Veysseyre-Balter C, Trolliet P, et al. Simultaneous detection of anti-C1q and anti- double stranded DNA autoantibodies in lupus nephritis: Predictive value for renal flares. Lupus 2011;20:28-34
Zhang CQ, Ren L, Gao F, Mu FY, You YQ, Liu YH. Anti-C1q antibodies are associated with systemic lupus erythematosus disease activity and lupus nephritis in northeast of China. Clin Rheumatol 2011;30:967-73.
Julkunen H, Ekblom-Kullberg S, Miettinen A. Nonrenal and renal activity of systemic lupus erythematosus: A comparison of two anti-C1q and five anti-dsDNA assays and complement C3 and C4. Rheumatol Int 201.
Said M Al-Barshomy
Department of Internal Medicine and Nephrology, Zagazig University, Zagazig
[Table 1], [Table 2], [Table 3], [Table 4]