10 Common Mistakes in the Management of Lupus Nephritis
10 Common Mistakes in the Management of Lupus Nephritis
Membranous lupus nephritis (MLN) accounts for approximately 10%-20% of cases of lupus nephritis. Although the risk of decrease in kidney function is not as great as that with the endocapillary proliferative variants, up to 20% of patients with MLN require dialysis or kidney transplantation within 10 years of diagnosis. Kidney survival is only 50% in patients with MLN at 20 years, but a recent study demonstrated kidney survival > 80% at 15 years. Furthermore, there is a sizable incidence of thromboembolic events in patients with MLN. Thrombotic events are associated with antiphospholipid antibodies and nephrotic syndrome.
High-dose alternate-day corticosteroid has been used widely as the first-line agent. However, this treatment regimen was derived from studies of idiopathic membranous nephropathy and there is little evidence that it works. Still, that does not mean that daily corticosteroid therapy is not effective. A small (42-patient) randomized controlled trial compared adjunctive immunosuppressive drugs with prednisone alone. Adjunctive regimens included either cyclosporine for 11 months or alternate-month IV cyclophosphamide for 6 doses; the control group received alternate-day prednisone alone. The study showed that regimens containing cyclosporine or IV cyclophosphamide were each more effective than alternate-day prednisone alone in inducing remission of proteinuria in patients with MLN. At 1 year, the cumulative probability of remission of proteinuria was 27% with prednisone (4 of 15 patients), 60% with IV cyclophosphamide (9 of 15 patients), and 83% with cyclosporine (10 of 12 patients). Eight of the 10 patients who did not respond to prednisone or cyclosporine or who experienced a relapse after cyclosporine therapy was stopped subsequently achieved remission when treated with IV cyclophosphamide.
It is well known that the antiproteinuric effect of calcineurin inhibitors tends to dissipate when the calcineurin-inhibitor treatment is stopped. In the aforementioned study, the agents were given for 11 months. Therefore, it is not surprising that there were relapses at the 1-year mark in the group receiving cyclosporine. Furthermore, although it is widely recognized that corticosteroids alone were not effective in this study, the steroid regimen was alternate day. We have observed many patients with membranous lupus enter remission on daily modest (0.5-mg/kg) doses of corticosteroid, obviating the need for more toxic therapy.
A recent pooled analysis of 2 large, multicenter, randomized, controlled trials in pure class V MLN compared MMF versus IV cyclophosphamide for 24 weeks as induction therapy. Both groups received high-dose daily prednisone. Patients in both groups showed significant improvement in urinary protein excretion and stabilization of serum creatinine levels. Based on this finding, it was concluded that MMF was as effective as IV cyclophosphamide to induce remission in patients with class V MLN. However, it is conceivable that the remissions were obtained because of the sizable dose of corticosteroid, negating an effect of a second agent. The authors concluded that one second agent was as effective as the other, but it may be the case that the corticosteroid regimen was solely responsible for the remission. However, meta-analysis of 24 studies of class V lupus nephritis and nephrotic-range proteinuria showed that the addition of an immunosuppressive agent to prednisone resulted in a significantly higher complete or partial response rate than prednisone alone. However, there was no statistically significant difference in response rates among azathioprine, MMF, cyclophosphamide, or cyclosporine.
Class I and II lupus nephritis have minor abnormalities and excellent kidney outcomes and should not by themselves be an indication for immunosuppressive treatment. Similarly, "burnt-out" class IV lupus nephritis should be managed as in any patient with CKD, focusing on blood pressure control and other measures to delay progression.
5. Not Scaling the Intensity of Immunosuppression to the Different Classes of Lupus Nephritis, Especially Class V Membranous Lupus
Membranous lupus nephritis (MLN) accounts for approximately 10%-20% of cases of lupus nephritis. Although the risk of decrease in kidney function is not as great as that with the endocapillary proliferative variants, up to 20% of patients with MLN require dialysis or kidney transplantation within 10 years of diagnosis. Kidney survival is only 50% in patients with MLN at 20 years, but a recent study demonstrated kidney survival > 80% at 15 years. Furthermore, there is a sizable incidence of thromboembolic events in patients with MLN. Thrombotic events are associated with antiphospholipid antibodies and nephrotic syndrome.
High-dose alternate-day corticosteroid has been used widely as the first-line agent. However, this treatment regimen was derived from studies of idiopathic membranous nephropathy and there is little evidence that it works. Still, that does not mean that daily corticosteroid therapy is not effective. A small (42-patient) randomized controlled trial compared adjunctive immunosuppressive drugs with prednisone alone. Adjunctive regimens included either cyclosporine for 11 months or alternate-month IV cyclophosphamide for 6 doses; the control group received alternate-day prednisone alone. The study showed that regimens containing cyclosporine or IV cyclophosphamide were each more effective than alternate-day prednisone alone in inducing remission of proteinuria in patients with MLN. At 1 year, the cumulative probability of remission of proteinuria was 27% with prednisone (4 of 15 patients), 60% with IV cyclophosphamide (9 of 15 patients), and 83% with cyclosporine (10 of 12 patients). Eight of the 10 patients who did not respond to prednisone or cyclosporine or who experienced a relapse after cyclosporine therapy was stopped subsequently achieved remission when treated with IV cyclophosphamide.
It is well known that the antiproteinuric effect of calcineurin inhibitors tends to dissipate when the calcineurin-inhibitor treatment is stopped. In the aforementioned study, the agents were given for 11 months. Therefore, it is not surprising that there were relapses at the 1-year mark in the group receiving cyclosporine. Furthermore, although it is widely recognized that corticosteroids alone were not effective in this study, the steroid regimen was alternate day. We have observed many patients with membranous lupus enter remission on daily modest (0.5-mg/kg) doses of corticosteroid, obviating the need for more toxic therapy.
A recent pooled analysis of 2 large, multicenter, randomized, controlled trials in pure class V MLN compared MMF versus IV cyclophosphamide for 24 weeks as induction therapy. Both groups received high-dose daily prednisone. Patients in both groups showed significant improvement in urinary protein excretion and stabilization of serum creatinine levels. Based on this finding, it was concluded that MMF was as effective as IV cyclophosphamide to induce remission in patients with class V MLN. However, it is conceivable that the remissions were obtained because of the sizable dose of corticosteroid, negating an effect of a second agent. The authors concluded that one second agent was as effective as the other, but it may be the case that the corticosteroid regimen was solely responsible for the remission. However, meta-analysis of 24 studies of class V lupus nephritis and nephrotic-range proteinuria showed that the addition of an immunosuppressive agent to prednisone resulted in a significantly higher complete or partial response rate than prednisone alone. However, there was no statistically significant difference in response rates among azathioprine, MMF, cyclophosphamide, or cyclosporine.
Class I and II lupus nephritis have minor abnormalities and excellent kidney outcomes and should not by themselves be an indication for immunosuppressive treatment. Similarly, "burnt-out" class IV lupus nephritis should be managed as in any patient with CKD, focusing on blood pressure control and other measures to delay progression.