Erythrocyte and glomerular C4d deposits as a biomarker for active lupus nephritis

Introduction

Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE) and histologically evident even in those without clinical manifestations of renal disease.

Alternative complement pathway activation in thrombotic microangiopathy associated with lupus nephritis

Clinical Rheumatology - Thrombotic microangiopathy (TMA) in systemic lupus erythematosus is a rare manifestation associated with activation of the complement system. This study aimed to compare...     

Bilateral nephrectomy for the treatment of refractory lupus nephritis with features overlapping with thrombotic microangiopathy resembling thrombotic thrombocytopenia purpura

We report a patient with a diagnosis of systemic lupus erythematosus who concurrently developed a syndrome of thrombotic microangiopathy that resembled thrombotic thrombocytopenic purpura. The patient underwent plasma exchange and immunosuppressive therapy for months before clinical improvement was finally achieved through bilateral nephrectomy. Ultimately, our patient died of disseminated aspergillosis from prolonged immunosuppression. We believe that recognition of bilateral nephrectomy as a potential treatment earlier in her course would have spared her this unfortunate demise. We hope that this review of current literature will help the reader to consider bilateral nephrectomy in patients with refractory systemic lupus erythematosus with clinical overlap of thrombotic microangiopathy resembling thrombotic thrombocytopenic purpura.     

Ⅳ型狼疮性肾炎伴血栓性微血管病变的临床特点及预后

目的:回顾性分析Ⅳ型狼疮性肾炎(LN)伴肾间质血管血栓性微血管病变(TMA)患者的临床、病理及预后。方法:33例在解放军肾脏病研究所住院、经肾活检诊断为Ⅳ型LN(参照2003年ISN/RPS分型方案)伴肾间质血管TMA病变的患者,女性27例,男性6例,平均年龄(31.8±10.9)岁,回顾性分析其临床特点(肾脏表现、肾外脏器受累、免疫学异常及病理特征)及预后特征(近期疗效、远期人、肾存活率及终末期肾衰发生的危险因素)。结果:(1)27例(81.8%)入院即表现为肾功能不全[SCr(274.0±176.8)μmol/L],其中14例(42.4%)需要肾脏替代治疗。高血压、肾病范围蛋白尿、肉眼血尿的比例分别为93.9%、57.6%和24.2%。(2)微血管病性溶血性贫血(MHA)比例为60.6%,神经系统损害、心、肺受累及浆膜腔炎的发生率分别为:18.1%、36.3%、15.1%和66.7%。(3)血清ANA、抗ds-DNA及抗心磷脂抗体阳性率分别为90.9%,75.8%和33.3%。96.9%和42.4%的患者伴有低C3及C4血症。(4)肾活检病理分型Ⅳ(G)型25例(75.8%)、Ⅳ Ⅴ型7例(21.2%)、Ⅳ(S)型1例(3.0%)。袢坏死、Fribin阳性的袢内血栓及新月体比例分别为:51.5%,69.7%和60.6%。20例(60.7%)肾间质小动脉有血栓形成。中-重度小管-间质慢性化损害者达78.8%。(5)患者中位随访时间为13月(1～101月),6例(42.9%)摆脱肾脏替代治疗,6月及12月治疗有反应率分别为38.9%和55.2%。死亡3例(感染、不明死因和多器官功能衰竭各1例),10例(38.5%)进展为终末期肾衰。患者1年、3年、5年人生存率分别为96.2%,69.2%和69.2%;肾存活率分别为:62.3%,62.3%和46.7%。结论:伴TMA的Ⅳ型LN患者肾脏损害严重,部分患者可无典型MHA表现,肾小球病理类型以Ⅳ(G)和Ⅳ Ⅴ型多见,Ⅳ(S)型少见,患者预后差。应加强LN伴TMA的早期诊断,探索有效的治疗手段。     

狼疮性肾炎患者肾小管周毛细血管C4d沉积及其意义

目的：探讨狼疮性肾炎（LN）是否存在肾小管管周毛细血管（PTC）C4d沉积以及其沉积的病理生理机制。方法：455例经肾活检证实的LN患者，用间接免疫荧光法检测肾活检冰冻切片组织C4d、C1q和C3的沉积，并与21例C4d阳性的移植肾急性排斥患者进行比较。结果：15例LN患者（3.29％）肾小管PTC C4d弥漫阳性主要为Ⅳ型狼疮，其中，Ⅱ型LN3例，Ⅳ型LN9例，Ⅲ＋Ⅳ型LN1例，Ⅳ＋Ⅴ型LN2例。本组患者抗核抗体均强阳性，73.3％的患者抗dsDNA阳性，40％的患者抗Smith抗体阳性，60％的患者抗心磷脂抗体阳性，所有患者补体C3均明显下降，80％患者补体C4下降。同时，LN PTC C4d沉积阳性的患者，绝大多数合并其他补体成分的沉积，12例（80％）患者伴有C1q共沉积，4例患者（26.7％）伴C3沉积，2例患者（13．3％）伴IgG沉积，而21例移植肾C4d阳性急性排斥患者未发现其他补体成分的共沉积。LN患者PTC C4d阳性沉积者肾组织PTC无中性粒细胞浸润。结论：部分LN患者肾组织PTC C4d沉积，其存在自身免疫功能亢进和补体经典途径的激活。与移植肾急性排斥反应伴PTC C4d阳性的沉积者不同，LN患者PTC C4d阳性的同时，合并有其他补体成分的沉积，而其PTC并无特殊的病理学改变，提示LN患者PTC C4d沉积的机制有别于抗体介导的肾移植急性排斥，它的存在可能代表了LN中一个相对独特的亚型。     

Complement split product C3d as an indicator of disease activity in systemic lupus erythematosus

Summary In order to investigate, if complement levels can be used as an indicator of clinical activity in systemic lupus erythematosus (SLE), levels of C3, C4, CH50, and C3d were measured in 79 patients, 41 with inactive, 31 with moderately active and 7 with severely active disease. Our study shows that C3d, and particularly the C3d/C3 ratio, provide sensitive markers for disease activity in SLE. Since C3d is a direct measurement of complement turnover, it reflects complement activation better than C3, C4 and CH50.     

Peritubular capillary C4d deposition in lupus nephritis different from antibody-mediated renal rejection

C4d deposition in peritubular capillaries (PTC) has been used as a marker of antibody-mediated rejection (AMR). However, PTC C4d deposition is not described in patients with lupus nephritis (LN). C4d deposition in PTC was detected in 455 patients with biopsy proven LN in the present study. Renal tissues from 21 cases of acute AMR served as controls. C4d deposition in PTC was found in 31 patients (6.81%) with LN. Patients with PTC C4d positive showed higher SLEDAI score and higher frequency of hypocomplementemia as compared to C4d negative. The prevalence of ANA, anti-dsDNA, anti-Sm and ACA were higher in C4d positive group, and most of these patients showed the diffuse proliferative glomerular lesion. In contrast with acute AMR, the staining pattern of C4d was granular deposition and the detection of C4d along PTC was accompanied by deposition of IgG and C1q or C3. Electron dense deposition on PTC was observed in most of LN patients. In conclusion, C4d deposition in PTC could be found in a small part of patients with LN. Our study suggested for the first time that C4d positive deposition were close relation with the higher disease activity of LN, and that immune complex formation might be involved in PTC C4d deposition in LN patients, Such PTC C4d deposition is distinct from that of AMR.     

A case of thrombotic microangiopathy complicated with systemic lupus erythematosus

A woman was admitted to the hospital with joint pain. She was also found to have pericardial effusion, renal dysfunction, pancytopenia, and positive antinuclear antibody; a diagnosis of systemic lupus erythematosus (SLE) was made. Although she had neither neurological symptoms nor fever, laboratory tests showed microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Therefore, we diagnosed her illness as SLE complicated by thrombotic microangiopathy (TMA). Plasmapheresis was performed in addition to immunosuppressive therapy. TMA improved rapidly and renal function improved gradually. The number of patients with SLE complicated by TMA is relatively small and the mortality rate is extremely high. A diagnosis of TMA is difficult to determine in patients with SLE because of the overlapping clinical symptoms. The data suggest that prompt induction of plasmapheresis in addition to immunosuppressive therapy is necessary in SLE patients having symptoms suspicious of TMA even before they fulfill the 5 symptoms typical of TMA.     

Refractory thrombotic thrombocytopenic purpura in a lupus nephritis patient

Thrombotic thrombocytopenic purpura is an uncommon disease and is rare in systemic lupus erythematosus. Rarely, patients do not respond to plasma exchange therapy, and treatment options are limited and often disappointing, thus it is a therapeutic challenge to clinicians. We report a patient with lupus nephritis who developed refractory thrombotic thrombocytopenic purpura and was subsequently treated with cyclosporin A. An immediate and sustained response was demonstrated, and she remained well; eventually she was able to be cyclosporin free after the acute episode. Cyclosporin A can be a safe and effective therapeutic option in patients with refractory thrombotic thrombocytopenic purpura.     

Reticulocytes bearing C4d as biomarkers of disease activity for systemic lupus erythematosus

OBJECTIVE: There is an urgent need for biomarkers with which to monitor disease activity in patients with systemic lupus erythematosus (SLE). We recently showed that abnormal levels of C4d, an activation-derived fragment of complement component C4, are deposited on the surface of erythrocytes from patients with SLE. This study focused on reticulocytes, the youngest and shortest-lived erythrocytes (lifespan 24-48 hours), with the objective of testing our hypothesis that when reticulocytes emerge from the bone marrow, they are immediately exposed to and acquire C4d at levels proportionate to the extent of complement activation at that time, thereby reflecting disease activity in SLE. METHODS: We conducted a cross-sectional study of 156 patients with SLE, 140 patients with other diseases, and 159 healthy controls. Levels of C4d on the surface of reticulocytes were examined using a 2-color flow cytometric assay. The results were analyzed for correlations with SLE disease activity. RESULTS: A wide range of increased levels of reticulocyte C4d was specifically detected in SLE patients. These levels fluctuated in SLE patients and correlated with clinical disease activity, as determined by the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus Activity Measure (SLAM). Specifically, in cross-sectional analyses, patients with reticulocyte C4d levels in the highest quartile compared with those in the lowest quartile had significantly higher SELENA-SLEDAI (P = 0.00002) and SLAM (P = 0.02) scores. Longitudinal observation demonstrated that the reticulocyte C4d levels changed in relation to the clinical course in individual patients. CONCLUSION: These findings support our hypothesis that C4d-bearing reticulocytes may serve as biomarkers of disease activity in patients with SLE.     

Complement degradation product C3d in urine: marker of lupus nephritis

OBJECTIVE: To examine whether serum and urine C3d, a degradation product of C3, correlate with renal and extrarenal lupus activity. METHODS: Serum and urinary C3d levels were measured by ELISA in 15 healthy individuals and 24 patients with systemic lupus erythematosus (SLE) (8 with inactive disease, 7 with active but nonrenal disease, 9 with active lupus nephritis). Disease activity variables like serum C3, C4, and anti-dsDNA antibodies were also measured. RESULTS: The median serum C3d levels were significantly higher (p < 0.01) in patients with active (26 arbitrary units/ml; AU/ml) and inactive SLE (27 AU/ml) compared to healthy controls (11.25 AU/ml); levels were comparable in patients with active renal and extrarenal SLE. On the other hand, urine C3d was elevated only in patients with active SLE; its level was highest in patients with active lupus nephritis (0.87 AU/ml) compared to patients with active extrarenal diseases (0.31 AU/ml; p < 0.05), to patients with inactive lupus nephritis (0.06 AU/ml; p < 0.001), or to levels in healthy individuals (0.06; p < 0.001). Urine C3d showed stronger correlation with disease activity score (SLE Disease Activity Index) than serum C3, C4, anti-dsDNA antibodies, and serum C3d. CONCLUSION: Urine C3d is a good index of active lupus, particularly lupus nephritis.     

Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus

Objective

Disease activity in systemic lupus erythematosus (SLE) is typically monitored by measuring serum C3 and C4. However, these proteins have limited utility as lupus biomarkers, because they are substrates rather than products of complement activation. The aim of this study was to evaluate the utility of measuring the erythrocyte‐bound complement activation products, erythrocyte‐bound C3d (E‐C3d) and E‐C4d, compared with that of serum C3 and C4 for monitoring disease activity in patients with SLE.

Methods

The levels of E‐C3d and E‐C4d were measured by flow cytometry in 157 patients with SLE, 290 patients with other diseases, and 256 healthy individuals. The patients with SLE were followed up longitudinally. Disease activity was measured at each visit, using the validated Systemic Lupus Activity Measure (SLAM) and the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).

Results

At baseline, patients with SLE had higher median levels of E‐C3d and E‐C4d (P < 0.0001) in addition to higher within‐patient and between‐patient variability in both E‐C3d and E‐C4d when compared with the 2 non‐SLE groups. In a longitudinal analysis of patients with SLE, E‐C3d, E‐C4d, serum C3, and anti–double‐stranded DNA (anti‐dsDNA) antibodies were each significantly associated with the SLAM and SELENA–SLEDAI. In a multivariable analysis, E‐C4d remained significantly associated with these SLE activity measures after adjusting for serum C3, C4, and anti‐dsDNA antibodies; however, E‐C3d was associated with the SLAM but not with the SELENA–SLEDAI.

Conclusion

Determining the levels of the erythrocyte‐bound complement activation products, especially E‐C4d, is an informative measure of SLE disease activity as compared with assessing serum C4 levels and should be considered for monitoring disease activity in patients with SLE.

     

Association of glomerular podocytopathy and nephrotic proteinuria in mesangial lupus nephritis

We investigated a series of patients with systemic lupus erythematosus (SLE), who had sparse subepithelial and mesangial immune deposits. Our goal was to determine structure: function correlation. We examined whether proteinuria correlated with either capillary wall immune aggregate formation or abnormal podocyte morphology. Renal biopsies from patients with sparse (two or fewer subepithelial or intramembranous electron dense deposits per glomerular capillary loop) immune deposits and podocyte effacement were studied. Patients fulfilled criteria for the diagnosis of SLE. Cases were excluded if the biopsy showed endocapillary proliferation or necrosis. Eighteen biopsies were studied, five from patients with nephrotic range proteinuria (> or =3 g/day) and 13 from patients with non-nephrotic proteinuria (<3 g/day). The five nephrotic patients had a mean foot process effacement of 48% +/- 39% (range 10-100%). Thirteen non-nephrotic patients had a mean foot process effacement of 11.7% +/- 8% (range 0-20%). The only distinguishing morphologic finding associated with nephrotic range proteinuria was diffuse foot process effacement. No correlation between subepithelial deposits and proteinuria was observed. There were no other histologic differences between the nephrotic and non-nephrotic patients. Among these patients, the nephrotic syndrome appears best correlated with podocytopathy rather than subepithelial electron dense deposits, mesangial deposits, or mesangial hypercellularity.     

Prospective assessment of C4d deposits on circulating cells and renal tissues in lupus nephritis: a pilot study

Complement activation plays a key role in the pathogenesis of lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE). We prospectively evaluated 15 LN subjects and two control groups: 13 non-SLE renal subjects (control A) and 239 SLE subjects without LN (control B). All had C4d levels on circulating erythrocytes (E-C4d), reticulocytes (R-C4d) and platelets (P-C4d) measured by flow cytometry, while C4d deposition in renal tissue was semiquantitatively assessed in LN subjects and control A using immunoperoxidase staining. Compared with control A, LN biopsies had higher glomerular-C4d scores (p?=?0.003), which were associated with more frequent granular glomerular immunofluorescence staining and electron dense deposits (p?相似文献   

Mycophenolate mofetil as treatment for lupus nephritis

Advances in immunosuppressive treatment and supportive care over the past few decades have led to improved clinical outcomes in patients with severe lupus nephritis. The management of severe proliferative lupus nephritis can be divided into an initial induction phase followed by a prolonged maintenance phase. Combined use of corticosteroid and cyclophosphamide has been the standard induction therapy, although a significant proportion of patients develop treatment‐related complications such as infection and gonadal failure. While there is general agreement on the immunosuppressive regimen for induction treatment, there is marked variation with regard to maintenance immunosuppressive regimens. The latter is consequent to a paucity of data, since a big sample size and prolonged follow‐up is required for clinical studies that investigate maintenance treatment, in view of the marked heterogeneity in patient characteristics and individual differences in the propensity for relapse. Nevertheless, there is accumulating evidence that a combination of corticosteroid and mycophenolate mofetil can be adopted as effective and well‐tolerated treatment both for induction and for long‐term maintenance in lupus nephritis. Favourable long‐term prognosis can be ensured provided that effective treatment can be instituted early, before irreversible renal parenchymal damage is established.