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Renal pathology and C4d deposition in kidney tissues from patients with pSS related renal impairments. pSS renal impairments (light microscopy, IHC). Tubulointerstitial C4d and peritubular capillary C4d staining were semi-quantitatively scored from 1 to 3. A1 × 200, pSS-related MN, C4d continuous staining along GBM and mild staining in mesangium(arrow). A2 × 200, pSS-related MN, C4d segmental staining along GBM. A3 × 100, pSS-related IgAN, mild mesangial staining of C4d which did not meet the criteria for G-C4d+, mesangial deposition of IgA and C3 positive. B1 × 200, TI-C4d score 1. Clinically dRTA, TIN, IF(−). B2 × 200, TI-C4d score 2. Clinically dRTA, TIN, IF(−). B3 × 200, TI-C4d score 3. Clinically RTA, TIN+mild MePGN, glomerular IF(−), interstitial C3 deposition positive by IF. C1 × 200, PTC C4d score 1(minimal staining). TIN+MePGN, IF(−). C2 × 200, PTC C4d score 2(focal staining). Early MN, with IgG(3+), IgA(2+) and C3(3+) deposition along GBM, C1q negative. C3 × 200, PTC-C4d score 3(diffuse staining). TIN
Source publication
Background:
To evaluate renal expression of C4d, a complement component in the classical/mannose binding lectin (MBL) pathway, in patients with primary Sjögren's syndrome (pSS)-associated renal impairments.
Methods:
We retrospectively reviewed the clinical and pathological data from 39 patients with pSS presenting with renal impairments. C4d was...
Contexts in source publication
Context 1
... positive control for C4d was obtained from dendritic lymphocytes in human tonsil tissues from a patient undergoing an operation for obstructive sleep apnoea hypopnea syndrome (Additional file 1: Figure S1) [26]. Renal tissues from patients with mild lesions who underwent a biopsy for microscopic haematuria were used as negative controls (Additional file 1: Figure S2). ...
Context 2
... with MN, 5 with MePGN, 2 with IgAN and 3 with MCD. Twenty-one patients were diagnosed with TIN. Specifically, 2 patients were diagnosed with acute interstitial nephritis, and the other 19 were diagnosed with chronic interstitial nephritis. All 8 patients with MN exhibited C4d deposition along the glomerular capillary and/ or in mesangium (Fig. 2A1, A2). IF staining revealed IgG deposition in 7/8 of patients with MN and C3 deposition in 2/8 of patients with MN. Only 1 patient displayed weak C1q deposition using IF staining. Sub-epithelial electrondense deposits (EDDs) and occasional mesangial EDDs were also observed in patients with MN using EM, including the patient with negative ...
Context 3
... of the patients with MN were diagnosed with stage II-III disease and exhibited different degrees of mesangial proliferation. Four cases had segmental thickening of GBM. Three out of five patients with MePGN and 1/2 patients with IgAN had mild mesangial deposition of C4d, but the staining area did not meet the criteria for glomerular C4d positive (Fig. ...
Context 4
... C4d deposition was observed in 32 patients (17/21 patients with TIN and 15/18 patients with GMN), including 16 patients with weak or spotty staining, 12 patients with patchy C4d staining, and 4 patients with diffuse C4d staining (Fig. 2B1, B2 and ...
Context 5
... C4d deposition was observed in 12 patients, including 4 patients with minimal deposition (Fig. 2C1), 4 patients with local deposition (Fig. 2C2) and 4 patients with diffuse deposition (Fig. 2C3). The PTC C4d score was positively correlated with the ANA titre (Spearman's Rho = 0.458, P = 0.003). All of 4 patients with diffuse deposition had elevation of serum IgG levels, and 3 of them had concomitant elevation of serum IgA levels and ...
Context 6
... C4d deposition was observed in 12 patients, including 4 patients with minimal deposition (Fig. 2C1), 4 patients with local deposition (Fig. 2C2) and 4 patients with diffuse deposition (Fig. 2C3). The PTC C4d score was positively correlated with the ANA titre (Spearman's Rho = 0.458, P = 0.003). All of 4 patients with diffuse deposition had elevation of serum IgG levels, and 3 of them had concomitant elevation of serum IgA levels and ANA titre at 1:1280, the serum levels of IgM ...
Context 7
... C4d deposition was observed in 12 patients, including 4 patients with minimal deposition (Fig. 2C1), 4 patients with local deposition (Fig. 2C2) and 4 patients with diffuse deposition (Fig. 2C3). The PTC C4d score was positively correlated with the ANA titre (Spearman's Rho = 0.458, P = 0.003). All of 4 patients with diffuse deposition had elevation of serum IgG levels, and 3 of them had concomitant elevation of serum IgA levels and ANA titre at 1:1280, the serum levels of IgM were within normal range for all 4 ...
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Citations
... Moreover, Xia et al. performed a retrospective study and investigated the prevalence and localization of C4d deposits in renal biopsy tissues of patients with pSS. They found that glomerular C4d deposition was observed in all patients with pSS-related membranous nephropathy (MN) and suggested a role for the mannan-binding lectin pathway of complement activation in patients with pSS-related MN [31]. Furthermore, our lymphocyte profile studies revealed that, for the first time, significant decreases in absolute numbers of CD16/CD56+ NK cells were found in HC patients, and had a positive correlation with both C3 and C4, which might enforce the concept that complement activation affects the function of NK cells [32]. ...
Objective
The aim of the present study was to assess the clinical characteristic of hypocomplementemia (HC) in primary Sjogren’s syndrome (pSS), and to address possible risk factors and the prognosis associated with HC in pSS patients.
Methods
pSS patients with HC in Hebei General Hospital from September 2016 to March 2019 were retrospectively analyzed and compared to those with normocomplementemia (NC). Logistic regression analysis was used to detect risk factors.
Results
Of the 333 patients with pSS, 84 patients (25.23%) were presented with HC at diagnosis. The presence of hyper-IgG and anti-Ro52 antibodies was significantly more common in patients with HC. In addition to systemic involvement, pSS patients with HC had more hematological, renal, and nervous system involvement, and received more immunosuppressant treatments than NC group ( p < 0.05). ESSDAI score was significantly higher in patients with HC ( p < 0.05). Multivariate logistic analysis indicated that leukopenia (OR = 2.23) and hyper-IgG (OR = 2.13) were independent risk factors for pSS with HC. In addition, profound CD16/CD56+ NK-cell lymphopenia was found in pSS-HC patients. More pSS patients developed SLE in the HC group than NC group (4.76% vs. 0.80%, p = 0.04) during the follow-up.
Conclusion
HC was not an uncommon manifestation of pSS and had an independent association with the main clinical and immunological features. Patients with pSS-HC had an increased possibility to develop SLE that required more positive treatment with glucocorticoids and immunosuppressants.
Key Points
• Hypocomplementemia had an independent association with the main clinical and immunological features in primary Sjogren’s syndrome patients.
• ESSDAI score was significantly higher in patients with hypocomplementemia.
• The pSS patients with hypocomplementemia had an increased possibility to develop SLE.
... A single study has evaluated the pattern of complement deposition in renal biopsies from 39 SjS patients with kidney involvement, describing tubulointerstitial C4d deposition in patients with tubulointerstitial nephritis and in those with membranous nephropathy. In the latter case, all patients presented a pattern of glomerular C4d deposition without concomitant C1q deposition, a finding that is suggestive of the local activation of the lectin pathway (Xia et al., 2019). MBL genotypes have been associated with a less severe presentation of SjS (Ramos-Casals et al., 2008). ...
Evidence about the relevance of the complement system, a highly conserved constituent of the innate immunity response that orchestrates the elimination of pathogens and the inflammatory processes, has been recently accumulated in many different rheumatologic conditions. In rheumatoid arthritis, complement, mainly the classical pathway, contributes to tissue damage especially in seropositive subjects, with complement activation occurring in the joint. Data about complement pathways in psoriatic arthritis are dated and poorly consistent; among patients with Sjögren syndrome, hypocomplementemia exerts a prognostic role, identifying patients at risk of extra-glandular manifestations. Hints about complement involvement in systemic sclerosis have been recently raised, following the evidence of complement deposition in affected skin and in renal samples from patients with scleroderma renal crisis. In vasculitides, complement plays a dual role: on one hand, stimulation of neutrophils with anti-neutrophil cytoplasmic antibodies (ANCA) results in the activation of the alternative pathway, on the other, C5a induces translocation of ANCA antigens, favouring the detrimental role of antibodies. Complement deposition in the kidneys identifies patients with more aggressive renal disease; patients with active disease display low serum levels of C3 and C4. Even though in dermatomyositis sC5b-9 deposits are invariably present in affected muscles, data on C3 and C4 fluctuation during disease course are scarce. C3 and C1q serum levels have been explored as potential markers of disease activity in Takayasu arteritis, whereas data in Behçet disease are limited to in vitro observations. Pregnancies in women with rheumatologic conditions are still burdened by a higher rate of pregnancy complications, thus the early identification of women at risk would be invaluable. A fine-tuning of complement activation is required from a physiological progression of pregnancy, from pre-implantation stages, through placentation to labour. Complement deregulation has been implicated in several pregnancy complications, such as recurrent abortion, eclampsia and premature birth; low complement levels have been shown to reliably identify women at risk of complications. Given its physiologic role in orchestrating pregnancy progression and its involvement as pathogenic effector in several rheumatologic conditions, complement system is an attractive candidate biomarker to stratify the obstetric risk among women with rheumatologic conditions.
... It has been reported that in addition to C4d+ in glomeruli and tubules, C4d+ in PTC also occurs in primary Sjögren's syndrome-related membranous nephropathy and IgA nephrosis. [19] Therefore, differential diagnosis of recurrent or new nephropathy with PTC C4d+ should be considered when graft pathology is used for the diagnosis of AMR. ...
Background:. The complement system plays an important role in the immune response to transplantation, and the diagnostic significance of peritubular capillary (PTC) C4d deposition (C4d+) in grafts is controversial. The study aimed to fully investigate the risk factors for PTC C4d+ and analyze its significance in biopsy pathology of kidney transplantation.
Methods:. This retrospective study included 124 cases of kidney transplant with graft biopsy and donor-specific antibody (DSA) testing from January 2017 to December 2019 in a single center. The effects of recipient pathological indicators, eplet mismatch (MM), and DSAs on PTC C4d+ were examined using univariate and multivariate logistic regression analyses.
Results:. In total, 35/124 (28%) were PTC C4d+, including 21 with antibody-mediated rejection (AMR), eight with renal tubular injury, three with T cell-mediated rejection, one with glomerular disease, and two others. Univariate analysis revealed that DSAs (P
... Especially, Zadura, et al. found that with the widespread autoantibody production, the C4BP levels decreased in parallel with the C3 and C4 levels in active patients with pSS, which suggested that disturbed complement regulation may contribute to pSS pathogenicity 19 22 . With the evidence of the complement system in vivo activation, these results suggested that complement consumption affects pSS pathophysiology. ...
We assessed the prevalence of hypocomplementemia (HC), possible risk factors, and its prognosis in patients with primary Sjögren’s syndrome (pSS). The data of 84 patients with HC admitted in Hebei General Hospital were retrospectively analyzed and compared to data of patients with normocomplementemic (NC). Logistic regression analysis was used to detect risk factors. The presence of hyper-immunoglobulin G (IgG) and anti-Ro52 was significantly higher in patients with HC. The patients with pSS with HC had higher hematologic, renal, and nervous system involvement and The European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index score (p < 0.05) and received more immunosuppressant treatments than those with NC (p < 0.05). Multivariate logistic analysis indicated that renal involvement (odds ratio [OR] = 4.09), nervous system involvement (OR = 3.82), leukopenia (OR = 2.57), and hyper-IgG (OR = 3.34) were independent risk factors for pSS with HC. Thus, HC was not an uncommon manifestation of pSS and was associated with leukocytopenia, renal and nervous system involvement, and severe disease activity. HC occurred in younger and short-term patients with pSS. Those with pSS-HC had an increased possibility to develop systemic lupus erythematosus. Such patients have distinctive clinical manifestations and worse prognosis that require extensive treatments.
... Cryoglobulinemia and immunecomplex deposition were found in glomerulonephritis (8,27). As for these two types of renal impairment in pSS, the anti-SSB antibody did not show a predominance in any one of them (8,11,28,29). The treatment of abatacept in pSS could reduce activated circulating follicular helper T cell to attenuate B cell hyperactivity, in which the titer of the anti-SSB antibody decreased as well as EULAR Sjogren's syndrome disease activity index (ESSDAI) and Clinical ESSDAI scores (30). ...
Background: Renal impairment is a critical complication in primary Sjögren's syndrome (pSS), resulting in chronic renal disease and even death. This meta-analysis was designed to find out the relevant factors of renal involvement in pSS.
Methods: PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science were systemically searched until August 30, 2019. Studies were selected according to inclusion criteria, and data was extracted by two researchers independently. The Newcastle-Ottawa Scale was applied for quality assessment. Random- and fixed-effects models were used in this meta-analysis based on the result of the heterogeneity test. Meanwhile, a sensitivity analysis was conducted to investigate the cause of heterogeneity. Publication bias was shown in the funnel plot and evaluated further by Begg's and Egger's tests.
Results: Of the 9,989 articles identified, five articles enrolling 1,867 pSS patients were included in the final analysis, 533 with and 1,334 without renal involvement. There was no statistical significance in age and gender between these two groups. According to the meta-analysis, anti-SSB antibody, and arthralgia showed a significant association with renal involvement in pSS, the overall odds ratio (OR) values of which were 1.51 (95% CI, 1.16–1.95) and 0.59 (95% CI, 0.46–0.74), respectively. On the other hand, the overall OR values of anti-SSA antibody, rheumatoid factor, dry eyes, and labial salivary gland biopsy were just 0.90 (95% CI, 0.49–1.64), 1.05 (95% CI, 0.59–1.86), 0.60 (95% CI, 0.34–1.06), and 1.38 (95% CI, 0.98–1.95), respectively.
Conclusion: The presence of anti-SSB antibody is positively associated with renal involvement in pSS, while arthralgia is inversely associated. Large-scale prospective cohort studies are needed in the future to identify further risk factors.
... In a different study, it was noted that increased tubulointerstitial complement deposition (C4d in the absence of C1q) could be observed in most patients suffering from pSS renal disease (28). Investigators hypothesized a role for the mannose binding lectin pathway of complement activation. ...
... In two studies, levels of C3 were found to be reduced more commonly in patients with renal disease than in the other group (24,25). While this is contradicted by another study, it may further support the notion that complement activation plays a role in Sjogren's nephritis (23,28). As complement pathways are multiple, it is unknown which of those is most involved and through which mechanisms. ...
Primary Sjogren's syndrome (pSS) is an autoimmune disorder in which lymphocytic infiltration leads to lacrimal and salivary glands dysfunction, which results in symptoms of dryness (xerophthalmia and xerostomia). Extraglandular features are common and may affect several organs. Renal involvement has long been known as one of the systemic complications of pSS. The most classical lesion observed in pSS is tubulointerstitial nephritis (TIN) and less frequently membranoproliferative glomerulonephritis (MPGN), which is related to cryoglobulinemia. In some cases, renal biopsy is necessary for the definitive diagnosis of kidney involvement. Patients may present with proximal renal tubular acidosis, distal renal tubular acidosis and chronic kidney disease. Response to treatment is usually favorable. However, occasionally severe and rarely lethal outcomes have been described. Recently, several case series and cross-sectional studies have been published which investigated the factors associated with renal involvement in pSS and the most accurate screening tests for early detection. The presence of xerophthalmia, anti-SSA and rheumatoid factor positivity, low C3 levels and other features have all shown either positive or inverse associations with the development of renal complications. Serum creatinine, alpha-1-microglobulin, cystatin-C have been evaluated as early detection biomarkers with variable accuracy. More advanced techniques may be necessary to confirm proximal and distal renal tubular acidosis, along with nephrogenic diabetes insipidus. The aim of the current paper is to summarize and critically examine these findings in order to provide updated guidance on serum biomarkers and further testing for kidney involvement in pSS.
Background: Increasing studies in the last decade have led to the widespread understanding that C4d, a split product of complement component 4 (C4), is a potential biomarker for systemic lupus erythematosus (SLE) and lupus nephritis (LN).
Purpose: The aim of this review is to summarize the highlights of studies investigating the use of C4d as a biomarker for diagnosing and monitoring SLE and LN patients.
Data collection: we searched PubMed/Medline and Wanfang databases using the terms “C4d and systemic lupus erythematosus”, “C4d and lupus nephritis”, and “Complement C4d”.
Results: The deposition of C4d on circulating blood cells has been shown in several clinical studies to be a potential diagnostic marker that can be used to monitor patients with SLE. In addition, C4d deposits on circulating blood cells may be a helpful diagnostic marker for LN, one of the most severe complications of SLE. Meanwhile, studies utilizing renal biopsy specimens have indicated that C4d deposition in the renal peritubular capillaries of LN patients may predict more severe LN or a worse patient prognosis. Generally, a high plasma C4d level and a high plasma C4d/C4 ratio may also be promising indicators that can be used to monitor patients with SLE and LN.
Conclusions: C4d detection may be a novel strategy for further clinical prediction and therapy.
Background
Systemic lupus erythematosus (SLE), a multisystemic autoimmune disease, is very aggressive in pediatric-onset patients as they are prone to develop lupus nephritis (LN). Although renal C4d positivity is correlated with the activity of renal disease and SLE in adult-onset LN patients, available information for pediatric-onset patients is limited.
Methods
To evaluate the potential diagnostic significance of renal C4d staining in pediatric LN patients, we retrospectively detected C4d staining by immunohistochemistry on renal biopsy specimens from 58 pediatric LN patients. The clinical and laboratory data at the time of the kidney biopsy and the renal disease activity of histological injury were analyzed according to the C4d staining status.
Results
Glomerular C4d (G-C4d)-positive staining was detected in all 58 cases of LN. Patients with a G-C4d score of 2 displayed more severe proteinuria than those with a G-C4d score of 1 (24-h urinary protein: 3.40 ± 3.55 g vs. 1.36 ± 1.24 g, P < 0.05). Peritubular capillary C4d (PTC-C4d) positivity was found in 34 of 58 LN patients (58.62%). The PTC-C4d-positive patient groups (patients with a PTC-C4d score of 1 or 2) had higher serum creatinine and blood urea nitrogen levels as well as renal pathological activity index (AI) and SLE disease activity index (SLEDAI) scores; however, they had lower serum complement C3 and C4 levels compared to PTC-C4d-negative patients ( P < 0.05). In addition, there was positive tubular basement membrane C4d (TBM-C4d) staining in 11 of 58 LN patients (18.96%), and a higher proportion of TBM-C4d-positive patients than TBM-C4d-negative patients (63.63% vs. 21.27%) had hypertension.
Conclusion
Our study revealed that G-C4d, PTC-C4d, and TMB-C4d were positively correlated with proteinuria, disease activity and severity, and hypertension, respectively, in pediatric LN patients. These data suggest that renal C4d is a potential biomarker for disease activity and severity in pediatric LN patients, providing insights into the development of novel identification and therapeutic approaches for pediatric-onset SLE with LN.
