Lupus Nephritis (Extract)
Treatment of proliferative LN includes induction therapy and maintenance therapy. Below is an extract from ‘Lupus Nephritis’, in Kidney Protection: A Practical Guide to Preserving Renal Function in Acute and Chronic Disease (eds. Vijay Lapsia, Bernard Jaar, and A. Ahsan Ejaz), 2019.
The goal of induction therapy is to rapidly halt the acute inflammatory process in the kidney and to disrupt the autoimmune pathways to achieve remission, reduce renal disease progression, and prevent relapses.
Induction therapy for diffuse or moderate to severe focal proliferative LN consists of potent immunosuppressive therapy. The induction regimen should include glucocorticoids with either cyclophosphamide or MMF.
The induction therapy is typically administered for 3 to 6 months. During this time, close monitoring is required, and if signs of disease progression such as worsening of creatinine and/or proteinuria are observed, then the immunosuppressive agents can be switched (cyclophosphamide to MMF, or vice versa).
Glucocorticoids should not be used as monotherapy for proliferative LN. Long-term renal outcomes are better when glucocorticoids are combined with an immunomodulatory agent.The initial oral prednisone dose used is 1 mg/kg/day (maximum 80 mg/day). In severe proliferative disease, intravenous (IV) methylprednisolone 500 to 1,000 mg for 1 to 3 days is administered before switching to oral prednisone. The prednisone is tapered over several weeks to a maintenance dose of 5 to 10 mg/day.
Cyclophosphamide may be administered as a high-dose regimen (National Institutes of Health [NIH] protocol) or as a low-dose regimen (Euro-lupus protocol). The NIH regimen includes IV cyclophosphamide 0.5 to 1 gram/m2 monthly for 6 to 7 months. The Euro-lupus regimen consists of IV cyclophosphamide 500 mg every 2 weeks for a total of 6 doses. It is important to note that the cumulative dose of cyclophosphamide in the Euro-lupus regimen is 3 grams, which is at least 50% lower than the NIH regimen. It is equally important to note that the Euro-lupus regimen has been found to be equivalent to the NIH regimen for remission induction and preservation of renal function at 5 and 10 years and has fewer side effects. The Euro-lupus regimen was originally studied in a predominantly white cohort with mild to moderate LN; however, more recently the short-term efficacy of this regimen was verified in a more diverse cohort of patients with LN.
Oral cyclophosphamide can also be used as induction therapy at 1 to 1.5 mg/kg/day (maximum 150 mg/day) for 2 to 4 months. This regimen of oral cyclophosphamide provides a cumulative dose of cyclophosphamide that is similar to the NIH regimen.
The use of cyclophosphamide is associated with significant adverse effects including leucopenia, gonadal failure, malignancies, infections, and hemorrhagic cystitis.
MMF has been found to be equivalent to cyclophosphamide as induction therapy for LN.22 Recently some concerns have been raised regarding the long-term renal outcomes with MMF being equivalent to cyclophosphamide, as the risk of developing ESRD from LN has risen slightly since the introduction of MMF as induction therapy. However, as of now, MMF along with cyclophosphamide remains an agent of choice for LN induction therapy.
MMF dose used for induction therapy is 2 to 3 g/day for 6 months.22 To assure better tolerability, MMF is started at a dose of 0.5 g twice daily in week 1, 1 g twice daily in week 2, with a target of 1.5 g 2× daily or 1 gram 3× daily thereafter. The adverse event rate with MMF has been found to be similar to that of cyclophosphamide; however, the types of adverse events with these agents are different. MMF has a lower incidence of ovarian failure and alopecia.
Even though the treatment guidelines for proliferative LN recommend that either cyclophosphamide or MMF can be used as induction therapy, one agent may preferable to the other in certain clinical situations:
- MMF is associated with a better response rate in black and Hispanic patients.
- Asian patients are more likely to be intolerant of higher doses of MMF but have similar response rates even at a lower dose.
- MMF may be preferable in women of childbearing age due to the risk of ovarian failure associated with cyclophosphamide.
- Cyclophosphamide (NIH) protocol is recommended for severe and/or crescentic proliferative LN.
Following the induction therapy, patients are switched to a maintenance therapy. The goal of maintenance therapy is to sustain clinical and histological remission achieved by induction therapy and to prevent renal relapses.
The maintenance therapy for LN is essential, as studies have shown that up to 50% patients may suffer from a relapse after completion of induction therapy. MMF has emerged as the agent of choice for maintenance therapy. It has been shown to be more effective than azathioprine and less toxic than cyclophosphamide. MMF dose during the maintenance therapy is 1 to 2 g/day, and it is used in conjunction with low dose prednisone 5 to 10 mg/day.
If a patient is unable to tolerate MMF, then azathioprine (2 mg/kg/day) along with low dose prednisone can be used. Azathioprine is also the agent of choice in women who are in remission and planning to become pregnant. MMF is contraindicated in pregnancy.
The duration of maintenance therapy is not well defined but can last for several months to years depending on disease severity, presence of clinical and histological remission, and the risk of relapse.
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