Renal and patient survival in lupus nephritis : the impact of conventional and novel immunosuppressive treatments

Abstract

Lupus nephritis (LN)is an important clinical manifestation of systemic lupus erythematosus (SLE)and contributes significantly to patient morbidity and mortality. In the era of effective immunosuppressive treatments, the clinical outcomes of LN patients have substantially improved, and the10-year patient and renal survival rates were98.2% and 98.0% respectively. With prolonged patient survival, infection (50.0%), cardiovascular disease (20.8%) and malignancy(12.5%)but not uncontrolled disease, have emerged as the leading causes of death in LN patients. The strongest predictor of mortalityin LN patients, however, was endstage renal disease (ESRD)as indicated by a high standardized mortality ratio of 26.1which doubled that of cardiovascular disease and history of malignancy. Despite the improved patient outcomes, conventional treatment such as cyclosphosphamide (CTX) was associated with significant toxicities and suboptimal long-term renal prognosis and hence alternative immunosuppressive agents with anti-fibrotic properties such as mycophenolate mofetil (MMF) and proliferation signal inhibitors (PSI)warrants further investigation. In Chinese patients with proliferative LN, corticosteroids and MMF as initial therapy conferred favorable long-term outcomes, with 10-year patient and renal survival of91% and 86% respectively. This regimen, when used as continuous induction-maintenance treatment, is Efficacious and well-tolerated, and the continuation of MMF treatment for at least 24 months was associated with significantly lower risk of relapse when compared to treatment for shorter duration. As the severity of tubulointerstitial fibrosis can be attenuated by growth factors with anti-fibrotic properties such as bone morphogenetic protein 7 (BMP7), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), studies were conducted in NZB/W F1 mice to investigate the impact of treatment on intra-renal expression of growth factors pertinent to fibrosis. Methylprednisolone (MP) combined with either MMF or CTX have resulted in increased BMP7 and reduced HGF and VEGF in the renal parenchyma, reduced fibrosis, and improved clinical parameters, compared with MP alone. The data also suggested that the increase in BMP7, a potentially anti-fibrotic cytokine, was observed earlier in the mice treated with MMF compared with those treated with CTX. Our preliminary clinical experience also suggested that PSI combined with corticosteroids may serve as an efficacious and well-tolerated immunosuppressive regimen in human LN, especially in patients with MMF intolerance or history of malignancy. These observations have important implications on the choice of therapy for the treatment of proliferative LN. As for membranous LN, our pilot results suggested that corticosteroids combined with either MMF or tacrolimus can be effective treatment options for patients with significant proteinuria, while each regimen exhibits distinct efficacy and tolerability profiles. In conclusion, the results from the studies included in this thesis show the magnitude of benefit conferred by novel immunosuppressive treatment regimens for LN on renal and patient survival, and on the associated intra-renal mechanisms pertaining to fibrosis.