|Year : 2016 | Volume
| Issue : 2 | Page : 305-311
|Prognostic significance of C1q deposition in serial biopsies for predicating the long-term outcome in patients with proliferative lupus nephritis
Abdulkareem Alsuwaida1, Sufia Husain2, Mohammed Al Ghonaim1, Noura Aloudah1, Anhar Ullah1, Hala Kfoury2
1 Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
2 Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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|Date of Web Publication||11-Mar-2016|
| Abstract|| |
Lupus nephritis (LN) is characterized by a highly variable clinical course. It has been reported that histopathologic lesions are risk factors for the progression of LN. The aim of this study is to investigate the relationship among the co-deposition of C1q, clinicopathological features, and renal outcomes in patients with LN. The clinical and histological parameters were studied in patients with International Society of Nephrology/Renal Pathology Society Class III or IV LN, who underwent two kidney biopsies. The patients were divided into two groups based on the glomerular C1q deposits: C1q-positive and C1q-negative. The impact of C1q status and longterm renal outcome on the doubling of serum creatinine and the rate of remission in the two groups were further investigated. Fifty-three patients had pure proliferative nephritis and 37.7% of these had a co-deposition of C1q. Doubling of serum creatinine was observed in 25% of patients with C1q-positive and 24.2% of patients with C1q-negative deposits. There was no difference between the two groups in terms of achieving complete or partial remission. The renal survival in the two groups was similar (P = 0.75). Upon repeat biopsy, the persistence of C1qpositivity was associated with a poor outcome (P = 0.007). C1q deposition in the glomerulus in the baseline biopsy was not associated with a poor renal outcome or severe pathologic features in patients with proliferative LN. However, the persistence of C1q positivity in repeat kidney biopsy is associated with a poor renal outcome.
|How to cite this article:|
Alsuwaida A, Husain S, Al Ghonaim M, Aloudah N, Ullah A, Kfoury H. Prognostic significance of C1q deposition in serial biopsies for predicating the long-term outcome in patients with proliferative lupus nephritis. Saudi J Kidney Dis Transpl 2016;27:305-11
|How to cite this URL:|
Alsuwaida A, Husain S, Al Ghonaim M, Aloudah N, Ullah A, Kfoury H. Prognostic significance of C1q deposition in serial biopsies for predicating the long-term outcome in patients with proliferative lupus nephritis. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Oct 31];27:305-11. Available from: https://www.sjkdt.org/text.asp?2016/27/2/305/178547
| Introduction|| |
Lupus nephritis (LN) is a common complica tion of systemic lupus erythematosus (SLE). Its pathogenesis involves different pathways, one of which has been proposed to be related to defects in the clearance of apoptotic cells from the body, thereby initiating an immune response. The complement system in this particular classical pathway is involved in the clearance of apoptotic cells. C1q is the first component of the classical pathway of complement activation, and its main function is to clear the immune complexes and self-antigens from the tissues during apoptosis. ,,, Recently, it has been suggested that the presence of antiC1q is strongly associated with the development of LN. ,,, Similarly, there is a growing body of evidence, indicating that anti-C1q auto-antibodies may help in distinguishing a renal from a nonrenal relapse.
However, because C1Q deposits are not essential for the definitive diagnosis of LN, little attention has been paid to their clinical significance. Therefore, we conducted this historical cohort study to assess whether mesangial C1q co-deposition status has an impact on response to therapy or on the prediction of long-term outcomes in serial biopsies among patients with diffuse proliferative LN.
| Patients and Methods|| |
The primary study was initiated to investigate the utility of repeat biopsy in assessing the response of patients with LN.  Patients were eligible for this sub-study if they were diagnosed with SLE, as defined by the American College of Rheumatology and had biopsyproven International Society of Nephrology/ Renal Pathology Society (ISN/RPS) Class III or IV LN.  We advised all patients with LN to undergo a second renal biopsy to assess the activity of the disease during the maintenance phase, 12-18 months from the initiation of induction. Renal biopsies and clinical data were collected from the years 1996 to 2012. Ethical approval was obtained from the Institutional Review Board of the King Saud University, Riyadh, Saudi Arabia. All patients provided informed consent upon participation.
The clinical and biochemical parameters were collected annually and from baseline biopsies. Renal biopsy specimens were reexamined by light, immunofluorescence, and electron microscopy and were then categorized according to the ISN/RPS by two renal pathologists who were unaware of the patients' clinical data or sequence of kidney biopsies.  The activity and chronicity indices were determined according to the scoring system of Pollak et al, and as modified by Austin, et al. , The study patients were divided into two groups, according to the presence of C1q deposits: the C1q-positive group, with both LN and C1q deposits (n = 20) and the C1qnegative group, with LN and no C1q deposits (n = 33).
We examined the probability of doubling of the initial serum creatinine at final follow-up in patients with positive immunofluorescent C1q in the baseline biopsy and compared the significance of converting into histological negative C1q staining or the persistence of the positive stain. Complete remission was defined as a serum creatinine level of ≤1.4 mg/ dL and proteinuria of ≤0.33 g/day at the time of the second biopsy. Partial remission was defined as a ≤25% increase in baseline creatinine and a ≥50% reduction in baseline proteinuria to ≤1.5 g/day (but >0.33 g/day). 
All patients with Class III to IV LN initially received induction therapy consisting of a maximum of six monthly boluses of intravenous cyclophosphamide (0.5-1.0 g per square meter body-surface area (BSA) to induce a nadir leukocyte count that was no lower than 2000 cells/mm 3 and corticosteroids. After induction, the patients were either given 0.5-1.0 g of intravenous cyclophosphamide per square meter BSA every three months or 1-3 mg of oral azathioprine per kilogram body weight daily. Since the introduction of mycophenolate mofetil in 2004, this drug has been used for both induction and maintenance phases of therapy, in addition to the above protocol. All therapeutic options were left to the discretion of the physician and patient, and the study was conducted in accordance with the Declaration of Helsinki. The study was approved by the King Khalid University Hospital Ethics Committee (E12811).
| Results|| |
The study included a total of 53 adults with proliferative LN ISN/RPS Class III or IV. The mean age (standard deviation) of the subjects included in the analysis was 25.8 (9.4) years. Male subjects constituted 15.1% (n = 8) of the study group. Other baseline characteristics are outlined in [Table 1].
C1q deposition status and its association with the clinical and pathological features
Two groups were identified according to their C1q deposits at the time of baseline renal biopsy, as shown in [Table 2]. The degree of proteinuria, hematuria, and serum creatinine was not different between the two groups. Regarding renal pathology, there were more patients with ISN/RPS Class III in the C1qnegative group than in the C1q-positive group; however, Class IV cases were equally distributed in the two groups [Table 3]. Activity and chronicity indices in the base line biopsy were not different between the two groups.
|Table 2: Comparison of baseline characteristics, therapy, and remission status between patients with C1qpositive and C1q-negative lupus nephritis.|
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|Table 3: Histological characteristics of kidney biopsy in C1q-positive and negative patients.|
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Considering light microscopy, there were no differences in fibrinoid necrosis, cellular, fibro-cellular crescents, or interstitial inflammation between the C1q-positive and C1qnegative groups. [Table 3] shows the immunofluorescence microscopy findings from the initial biopsy. A "full house" pattern with deposits of IgG, IgM, and IgA was found in 75% of the patients in the C1q-positive group and in 55% of the patients in the C1q-negative group.
Associations between C1q deposition and renal outcomes
The management protocols for the two groups were not different [Table 2]. Cyclophosphamide was used in 65% of the C1q-positive and 64% of the C1q-negative group (P = 0.81). Similarly, there was no difference in the cumulative dosage of cyclophosphamide between the two groups. Furthermore, there were no differences in the number of patients who received mycophenolate mofetil for induction [Table 2]. On the basis of the C1q staining status (C1q positive vs. negative), a complete remission was observed in 40% versus 48.5% of patients, a partial remission was observed in 30% versus 18.2% of patients, and there was no response in 30% versus 33% of patients, respectively (P values of 0.1, 0.9, and 0.2, respectively).
Furthermore, the renal outcomes in the form of doubling of the serum creatinine were not significantly different between the two groups. The doubling [Figure 1] was 25% in patients in the C1q-positive group compared with 24.2% in the C1q-negative group (P = 0.95) after a median follow-up of 8.7 years (interquartile range; 6-10.1 years). As calculated by the Kaplan-Meier method, there was no difference in the renal survival in the C1q-positive and C1q-negative groups [Figure 2]; P = 0.745). Finally, among patients with C1q positivity in the first biopsy [Figure 3], the renal survival was significantly worse in patients who still had C1q positivity in the second biopsy, compared with those who had no C1q in the second biopsy (P = 0.007).
|Figure 1: Renal survival in patients with proliferative lupus nephritis based on C1q status. The risk of doubling of serum creatinine showed no prognostic significance of C1q at baseline biopsy (P = 0.75; log rank test).|
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|Figure 2: Prevalence of complete, partial, or no remission of lupus nephritis stratified by C1q deposition status.|
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|Figure 3: Renal survival in patients with C1q-positive diffuse proliferative lupus nephritis. Survival analysis (absence of doubling serum creatinine) based on the C1q status in the second biopsy, which demonstrated a significantly worse prognosis among those with persistent C1q positivity (P = 0.007; log rank test).|
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| Discussion|| |
Activation of the complement system is one of the key participants in the injuries related to LN. Understanding the role of complement activation in glomerular injury may help in the development of new therapeutic approaches for the management of LN. Similarly, further research is needed to explore the utility of C1q as a diagnostic or prognostic parameter in these patients. Tan et al have reported that the presence of anti-C1q auto-antibodies is associated with intense glomerular deposits of C1q, both of which have been associated with the disease activity of SLE and LN.  However, a significant proportion of patients with proliferative LN do not have C1q deposits in the kidney. In our study, the frequency of positive C1q deposits in patients with proliferative LN is 37.7%, consistent with the prevalence reported by other investigators. , On the other hand, the reported prevalence of positive serum antiC1q antibodies in patients with active LN is high, 74-97.2%, ,, which is significantly higher than the rate of C1q deposits in the kidney. This discrepancy could be related to the rate of C1q clearance from renal tissue; however, this claim needs to be investigated further.
In the present study, we demonstrated that the C1q deposition status had no impact on proteinuria, initial serum creatinine, or hematuria. This has also been reported by other studies.  Earlier studies have suggested that the development or recurrence of nephritis was associated with rising titers of anti-C1q , and that these were more specific for active renal involvement than for anti-dsDNA. However, other investigators have reported no significant difference in anti-C1q prevalence between patients with SLE with or without active nephritis (32% vs. 53%, P = 0.06) or between active and inactive nephritis (74% v 53%, P = 0.06). , Katsumata et al also reported no relation between the activity of lupus and C1q antibodies in the serum.  We have also observed that C1q deposition was not associated with a greater histological activity of LN. The activity index was not different among patients with C1Q positivity or negativity. The endocapillary hypercellularity, cellular crescents, fibrinoid necrosis, sub-endothelial hyaline deposits, interstitial inflammation, and leukocyte infiltration were not different between the two groups. This suggests that these lesions are mediated by diverse mechanisms and not limited to direct complement activation. Still, the pathogenesis of these lesions requires further exploration.
Several prognostic factors such as elevated serum creatinine, anemia, hypertension, proliferative LN, and renal flare up have been demonstrated as being significantly associated with poor clinical outcomes in previous studies. , We investigated whether C1q deposits can predict the long-term outcomes of LN, and found that the C1q deposits did not impact the response to various treatment protocols or the probability of achieving remission. Similarly, the rate of serum creatinine doubling was similar in C1q-positive and negative groups. However, patients with persistent C1q deposits in their second kidney biopsies had worse renal outcomes than those with negative second biopsies. This finding may indicate that the persistence of active inflammatory processes leads to a worse renal outcome.
C1q renal deposits are not associated with worse clinical parameters or active histological inflammatory markers in LN. The persistence of C1q deposits in repeat biopsies, however, was associated with poor renal outcome. These findings should be validated in other cohorts. This study has several limitations, including its retrospective nature, relatively small sample size, and use of C1q immunofluorescence without an anti-C1q antibody titer correlation.
Conflict of interest: None declared.
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Department of Medicine, King Saud University, P.O. Box 2925 Riyadh 11321
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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