SP0101 Current standard treatment for lupus nephritis

Abstract

Glomerulonephritis is a major cause for morbidity in systemic lupus erythematosus (SLE). In this disease, immune complex formation/deposition in the kidney results in intraglomerular inflammation with recruitment of leukocytes, and activation and proliferation of resident renal cells. Intense injury may destroy resident renal cells by necrosis or apoptosis resulting in fibrinoid necrosis. When injury is less intense, endocapillary cells respond by proliferating and production of extracellular matrix (proliferative lesions). Determination of disease severity: Renal biopsy, examination of the urine sediment and measurement of C3 levels (and to a lesser degree of anti-DNA titers) are essential for the management of lupus nephritis. Treatment depends on the severity of the disease. Accordingly disease severity is determined by the presence or absence of high-risk factors. These include demographic (male gender, black race), clinical (failure to acheive response or marked delay in response, multiple relapses, pregnancy), laboratory (impaired renal function, severe anaemia with hematocrit less than 26%) and histologic features (mixed membranous and proliferative or proliferative nephritis; cellular crescents and/or fibrinoid necrosis; and moderate to high degrees of interstitial fibrosis and/or tubular atrophy). Treatment: Patients with mild proliferative disease without risk factors are usually treated with corticosteroids alone or in combination with azathioprine. If the disease does not remit within 3–4 months, cytotoxic drugs such as cyclophoshamide or newer agents such as mycophenolate may be tried. For patients with moderate to severe proliferative nephritis, controlled trials have shown that pulse cyclophosphamide is the treatment of choice. Long-term follow-up of patients participating in these controlled trials suggest that combining pulse cyclophoshamide with pulse methylprednisolone increases efficacy but not toxicity. In general cytotoxic therapy continues 1 year beyond remission as shorter courses of cyclophosphamide have an increased risk for flares. Induction of response with cyclophosphamide followed by maintenance with agents such as azathioprine or cyclosporine is under investigation. For lupus membranous nephritis steroids, pulse cyclophospamide therapy or cyclosporine may be used. Relapse rates are high when cyclosporine is discontinued. In addition to immunosuppressive therapy, aggressive management of co-morbid conditions (hypertension, dyslipidemia, osteoporosis) is of paramount importance. Response rates and flares: Rates of clinical response and flares vary in different studies according to type of nephritis, treatment regimen, duration of therapy, and definition of clinical response and flare used. Flares pose a significant problem because of the risk for renal function deterioration due to cumulative damage as well as cumulative toxicities due to additional immunosuppressive therapy. Patients with nephritic flares (defined as increase in plasma creatinine level and reappearance of active nephritic urinary sediment), are more likely to progress to end-stage renal disease in spite of additional immunosuppressive therapy. Side effects: Pulse cyclophosphamide is associated with an increased risk for herpes zoster infections on the short-term and with sustained amenorrhea or azoospermia on the long-term. Gonadotropin-releasing hormone agonist (GnRH-a) may prevent accelerated recruitment and depletion of ovarian follicles (via suppression of the gonadotrophin production in the pituitary gland) and therefore protect against premature ovarian failure. In a small case series, testosterone was found to be effective in preserving fertility in patients with nephrotic syndrome treated with a short course of cyclophosphamide. New approaches: A recent controlled study reported that mycophenolate mofetil is equally effective to a regimen of oral cyclophosphamide and azathioprine used sequentially in patients with proliferative lupus nephritis However, in this study follow up was short, patients had relatively mild disease and patients with high- risk factors were not included. A controlled study comparing mycophenolate mofetil to pulse cyclophosphamide is in progress. Other investigations explore the therapeutic potential of high-dose, immunoablative cyclophosphamide therapy alone or in combination with autologous stem cell transplantation, low-dose cyclophosphamide in combination with nucleoside analogues, or biologic response modifiers. High- dose cyclophosphamide or combinations of low-doses with fludarabine may result in profound bone marrow and immune suppression. Combinations of cyclophosphamide with biologic response modifiers have shown encouraging results in preclinical animal studies and may provide a major breakthrough in the treatment of severe lupus, similar to the introduction of cytotoxic agents a few decades ago.