The spectrum of renal thrombotic microangiopathy in lupus nephritis

Arthritis research & therapy (Impact Factor: 4.12). 01/2013; 15(1):R12. DOI: 10.1186/ar4142
Source: PubMed

ABSTRACT INTRODUCTION: Among various lupus renal vascular changes, thrombotic microangiopathy (TMA) presented with most severe clinical manifestations and high mortality. The pathogenesis of TMA in systemic lupus erythematosus (SLE) was complicated. The aim of this study was to assess clinical manifestations, laboratory characteristics, pathological features and risk factors for clinical outcomes of lupus nephritis patients co-existing with renal TMA in a large cohort in China. METHODS: Clinical and renal histopathological data of 148 patients with biopsy-proven lupus nephritis were retrospectively analyzed. Serum complement factor H, ADAMTS-13 activity, antiphospholipid antibodies and C4d deposition on renal vessels were further detected and analyzed. RESULTS: In the 148 patients with lupus nephritis, 36 patients were diagnosed as co-existing with renal TMA based on pathological diagnosis. Among the 36 TMA patients, their clinical diagnoses of renal TMA were as followings: 2 patients combining with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 2 patients combining with anti-phospholipid syndrome, 2 patients with malignant hypertension, 1 patient with scleroderma and the other 29 patients presenting with isolated renal TMA. Compared with non-renal TMA group, patients with renal TMA had significantly higher urine protein (7.09+/-4.64 vs. 4.75+/-3.13 g/24h, P=0.007) and serum creatinine (159, 86-215 vs. 81, 68-112 mumol/l, P<0.001), higher scores of total activity indices (AI) (P<0.001), endocapillary hypercellularity (P<0.001), subendothelial hyaline deposits (P=0.003), interstitial inflammation (P=0.005), glomerular leukocyte infiltration (P=0.006), total chronicity indices (CI) (P=0.033), tubular atrophy (P=0.004) and interstitial fibrosis (P=0.018). Patients with renal TMA presented with poorer renal outcome (P=0.005) compared with non-TMA group. Renal TMA (hazard ratio (HR): 2.772, 95% confidence interval: 1.009-7.617, P=0.048) was an independent risk factor for renal outcome in patients with lupus nephritis. The renal outcome was poorer for those with both C4d deposition and decreased serum complement factor H in TMA group (P=0.007). CONCLUSIONS: There were various causes of renal TMA in lupus nephritis. Complement over-activation via both classical and alternative pathways might play an important role in the pathogenesis of renal TMA in lupus nephritis.

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    ABSTRACT: Renal involvement is a severe complication in Systemic Lupus Erythematosus (SLE). Moreover, a subset of SLE patients develop the anti-phospholipid syndrome (APS), characterised by the occurrence of anti-phospholipid antibodies (aPL) in combination with macro- and microvascular thrombotic manifestations, including acute and chronic antiphospholipid associated nephropathy (APLN). Clinical presentations of lupus nephritis and APLN are similar and a renal biopsy is necessary to differ between the conditions. Our aim with this study was to investigate the occurrence of histopathological findings consistent with APLN (hAPLN) in renal biopsies from SLE patients and to investigate associations with aPL specificities, clinical manifestations, HLA-DRB1 alleles and long term renal outcome. Consecutive renal biopsies from 112 SLE patients with renal involvement were investigated and evaluated for findings of hAPLN, in all 236 renal biopsies. Data from biopsy reports and clinical information were collected. Autoantibodies against cardiolipin (aCL) and β2glykoprotein1 (β2GP1) were measured by enzyme-linked immunosorbent assay (ELISA). Lupus anticoagulant (LA) test was determined with a modified Dilute Russel Viper Venom method. HLA genotyping was performed by sequence-specific primer-polymerase chain reaction. Renal outcome was determined at study end. The prevalence of hAPLN was 14.3 % among SLE patients with renal involvement. Compared to patients with pure lupus nephritis (LN), occurrence of hAPLN was associated with intima changes (OR = 24, CI:3.0-189.8, p < 0.0001), hypertensive vascular changes (OR:7.8, CI:1.6-39.4, p = 0.01), inflammatory infiltrates (OR = 6.5, CI:1.7-25.1, p = 0.007) and tubular atrophy (OR = 13.1, CI:1.7-103.6, p = 0.002). hAPLN was associated with the presence of aCL antibodies (OR = 3.3, CI:1.0-10.8, p = 0.05) and triple aPL positivity (OR = 4.2, CI:1.3-13.7, p = 0.02). Patients with hAPLN were more hypertensive (OR = 3.8, CI:1.2-12.3, p = 0.03) and had higher levels of creatinine as compared to LN (median 116 vs 75 μmol/L, p < 0.0001). We found significantly higher frequency of HLA-DRB1*13 (OR = 5.1, CI:1.7-15.4, p = 0.03) and development of end stage renal disease (ESRD) (OR = 5.8, CI:1.7-19.7, p = 0.008) in hAPLN in comparison to LN. hAPLN is a severe and often unrecognized condition in SLE patients with renal involvement. We have demonstrated an increased risk for development of renal impairment and a genetic predisposition in hAPLN patients compared to LN patients.
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    ABSTRACT: Lupus nephritis is a common and severe manifestation of systemic lupus erythematosus, and an important cause of both acute kidney injury and end-stage renal disease. Despite its aggressive course, lupus nephritis is amenable to treatment in the majority of patients. The paradigm of immunosuppressive treatment for lupus nephritis has evolved over the past few decades from corticosteroids alone to corticosteroids combined with cyclophosphamide. Sequential treatment regimens using various agents have been formulated for induction and long-term maintenance therapy, and mycophenolate mofetil has emerged as a standard of care option for both induction and maintenance immunosuppressive treatment. The current era has witnessed the emergence of multiple novel therapeutic options, such as calcineurin inhibitors and biologic agents that target key pathogenetic mechanisms of lupus nephritis. Clinical outcomes have improved in parallel with these therapeutic advances. This Review discusses the evidence in support of current standard of care immunosuppressive treatments and emerging therapies, and describes their roles and relative merits in the management of patients with lupus nephritis.
    Nature Reviews Nephrology 11/2014; 11(1). DOI:10.1038/nrneph.2014.215 · 8.37 Impact Factor
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    ABSTRACT: Thrombotic microangiopathies (TMA) are rare but severe disorders, characterized by endothelial cell activation and thrombus formation leading to hemolytic anemia, thrombocytopenia, and organ failure. Complement over activation in combination with defects in its regulation is described in an increasing number of TMA and if primary for the disease denominated as atypical hemolytic-uremic syndrome. Although TMA predominantly affects the renal microvasculature, extra-renal manifestations are observed in 20% of patients including involvement of the central nerve system, cardiovascular system, lungs, skin, skeletal muscle, and gastrointestinal tract. Prompt diagnosis and treatment initiation are therefore crucial for the prognosis of disease acute phase and the long-term outcome. This review summarizes the available evidence on extra-renal TMA manifestations and discusses the role of acute and chronic complement activation by highlighting its complex interaction with inflammation, coagulation, and endothelial homeostasis.
    Frontiers in Pediatrics 09/2014; 2:97. DOI:10.3389/fped.2014.00097

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