The prevalence of renal TMA, including acute and chronic changes, in our cohort with lupus nephritis was 24.3% (36/148), which was higher than that in previous studies (0.5% to 10%) [2
]. The most possible reason might be that our diagnosis was based on the strict histopathological criteria, not just clinical evaluation, which might increase the ratio. In fact, diagnosis of TMA in SLE is sometimes difficult because these two disorders share similar clinical features, including anemia, thrombocytopenia, neurological deficits, renal involvement and fever. Therefore, the pathological criteria should be regarded as the "gold standard" in patients with SLE.
As reported in the previous studies [25
], patients with both renal TMA and lupus nephritis in our center presented with more severe renal injury features, including a higher amount of proteinuria, higher value of serum creatinine, higher scores of total AI indices, endocapillary hypercellualrity, cellular crescents, subendothelial hyaline deposits, interstitial inflammation, glomerular leukocyte infiltration, total CI indices, tubular atrophy and interstitial fibrosis in pathological evaluations, compared with the patients without TMA. Although with more intensive immunosuppressive therapy, patients with TMA had a poorer renal outcome than those without renal TMA. Renal TMA was found as an independent risk factor for renal outcome in lupus nephritis.
The pathogenesis of renal TMA in lupus nephritis remains unclear and may be multifactorial, which might be attributed to APS, TTP-HUS, malignant hypertension, pregnancy, scleroderma, drugs and so on. Thus, we further investigated the above risk factors in the 36 renal TMA patients. Interestingly, only seven patients were found with clear reasons, including two with TTP-HUS, two with APS, two with malignant hypertension and one with scleroderma. The other 29 patients only presented with pathological evidence of renal TMA.
It is suggested that immune complex-mediated complement activation via the classical pathway plays a key role in the pathogenesis of tissue injury in lupus nephritis [28
]. C4d is produced mainly through the classical complement activation cascade and can covalently bind to glomerular endothelial surfaces and basement membranes through the thiol ester site [31
]. Recently, Danielle et al.
] and Shen et al.
] found that positive C4d staining in glomeruli correlated with the development of renal microthrombi and demonstrated that activation of the complement classical pathway might be a crucial factor in the development of TMA in lupus nephritis. In our study, we also found that a high ratio (19/36) of patients had C4d deposition on vessels in patients with renal TMA. Li et al.
] recently reported that C4d deposition in peritubular capillaries was closely related with low serum C4 level and higher disease activity of lupus nephritis. It is possible that although it intend to clear the immune complexes, the activation of complement classical pathway may further cause the inflammation and injury of the endothelium. Because C4d is also involved in the lectin pathway, we cannot exclude the possibility that C4d deposition partly reflects activation of the mannose-binding lectin (MBL) pathway, which needs further investigation.
Although it has been suggested that the development of SLE, especially lupus nephritis, is closely associated with immune complex-induced complement activation via classical pathways, recent studies [34
] demonstrated that activation of the alternative complement pathway could accurately reflect disease activity and the ongoing activation paralleled with flares in patients with SLE, and the alternative pathway might play an important role in complement activation-induced self-injury and inflammatory response in SLE [35
]. Further studies suggested that patients with deficiency of complement regulators, such as complement factor H, of the alternative pathway, was susceptible to SLE [36
]. A recent study has shown that factor H deficiency accelerates the development of lupus nephritis in lupus-prone mice MRL-lpr [39
]. As mutations and single nucleotide polymorphisms (SNPs) in complement factor H have been implicated in a variety of human pathological conditions, especially atypical hemolytic uremic syndrome (aHUS), one of the reasons for TMA, we further detected concentrations of serum factor H in our patients. Interestingly, nearly half of the patients in our renal TMA group were found with decreased serum complement factor H. Complement factor H is a fluid phase complement regulator of the alternative complement pathway [40
]. It can bind to endothelial cells and protects them from being attacked by the complement system. It is suggested that dysfunction or reduced levels of serum factor H may cause endothelial cell damage which may be followed by platelet consumption, red cell damage and the final TMA [42
]. The potential reasons for lower factor H in renal TMA with lupus nephritis, including autoantibodies against factor H or factor H gene mutations, need further study.
Furthermore, we divided TMA patients into two groups based on C4d deposition in the kidney and the value of serum factor H, and found that the patients with both C4d deposition and decreased serum complement factor H presented with higher pathological AI scores and poorer renal outcome. The results supported that over-activation of both complement classic and alternative pathways might aggravate TMA injury in lupus nephritis. Previous studies also suggested that classic pathway activation can recruit the potent components to further amplify generation of C3 and C5 activation products and alternative pathway activation might hold the key to continuous tissue damage via the amplification loop in kidney situ
in lupus nephritis [43
Tissue factor is an inducer of thrombosis. Interestingly, recent studies strengthened the idea that tissue factor activation which can be induced by the activation of complement, might be important in the pathogenesis of TMA [44
We also observed that the ratio of nephrotic syndrome and the amount of proteinuria were both higher in the TMA group than that in the pure lupus nephritis group. As proteinuria might be a risk factor for thromboembolism, owing to loss of plasma antithrombin III and activation of the coagulation system [46
], further studies were needed to confirm the pathogenetic role of proteinuria in renal TMA.
Many studies, including experimental models [48
] and clinical observations [50
], have shown complement activation to be essential in TMA. So our findings hold promise for complement inhibition as a therapeutic approach in the further treatment of TMA with lupus nephritis.