Treating Membranous Nephropathy: Pieces in the Puzzle
Treating Membranous Nephropathy: Pieces in the Puzzle
The Lancet study is a randomized trial of 108 patients with biopsy-proven idiopathic membranous nephropathy. It tested the efficacy of 3 arms: prednisolone and chlorambucil, cyclosporine, or supportive therapy alone. Participating patients were recruited from the United Kingdom and had a serum creatinine level less than 3.4 mg/dL, with a 20% or greater decline in kidney function within the 2 years prior to study entry. All patients received renin/angiotensin blockade, statins, and anticoagulants as indicated.
Participants who were randomly assigned to prednisolone and chlorambucil received 1 g of methylprednisolone per day for 3 days, followed by 0.5 mg/kg of oral prednisolone per day for 28 days during months 1, 3, and 5. During months 2, 4, and 6, these patients received oral chlorambucil at 0.15 mg/kg per day. Participants randomly assigned to cyclosporine received a starting dose of 5 mg/kg per day adjusted to achieve a trough concentration of 100-200 µg/L. Participants were followed for a minimum of 3 years or until they reached the primary endpoint of a further 20% decline in kidney function.
Of the 108 randomized patients, only 2 were not included in the final analysis. One patient experienced a major deviation from the protocol and was withdrawn from the study by his physician, and 1 was discovered to not meet inclusion criteria after randomization.
At baseline, participants were in their sixth decade of life (mean ages, 58, 58, and 56 years in the prednisolone/chlorambucil, cyclosporine, and supportive therapy groups, respectively). The average proteinuria in each group was 10.1 (5.3 SD), 6.8 (4.7 SD), and 9.1 (5.3 SD) g, respectively, and mean creatinine clearance was 50 (16 SD), 49 (18 SD), and 50 (20 SD) mL/min.
The rate of a further 20% decline in kidney function was slowest in the prednisolone/chlorambucil group. Compared with the group receiving supportive care, the risk for decline in the prednisolone/chlorambucil group was significantly lower (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.24-0.78; P = .0042), which was mirrored by a greater decrease in proteinuria (-2.2 g per 24 hours; P = .014). Of note, the risk for decline in kidney function was no different between the groups receiving cyclosporine and supportive care alone (HR, 1.17; 95% CI, 0.70-1.95; P = .54). A smaller, nonsignificant mean reduction in proteinuria was seen in the group receiving cyclosporine (-0.7 g per 24 hours; P = .46). In the 3 groups overall, 11 patients reached end-stage renal disease: 1 patient in the prednisolone/chlorambucil group, 6 in the cyclosporine group, and 4 in the supportive therapy group.
With respect to safety, there were no differences in overall survival among groups. Whereas 42% of patients in the supportive care group experienced a significant adverse event (hospitalization) during follow-up, this proportion was greater in the cyclosporine (49%) and prednisolone/chlorambucil (61%) groups.
Description of the Study
The Lancet study is a randomized trial of 108 patients with biopsy-proven idiopathic membranous nephropathy. It tested the efficacy of 3 arms: prednisolone and chlorambucil, cyclosporine, or supportive therapy alone. Participating patients were recruited from the United Kingdom and had a serum creatinine level less than 3.4 mg/dL, with a 20% or greater decline in kidney function within the 2 years prior to study entry. All patients received renin/angiotensin blockade, statins, and anticoagulants as indicated.
Participants who were randomly assigned to prednisolone and chlorambucil received 1 g of methylprednisolone per day for 3 days, followed by 0.5 mg/kg of oral prednisolone per day for 28 days during months 1, 3, and 5. During months 2, 4, and 6, these patients received oral chlorambucil at 0.15 mg/kg per day. Participants randomly assigned to cyclosporine received a starting dose of 5 mg/kg per day adjusted to achieve a trough concentration of 100-200 µg/L. Participants were followed for a minimum of 3 years or until they reached the primary endpoint of a further 20% decline in kidney function.
Of the 108 randomized patients, only 2 were not included in the final analysis. One patient experienced a major deviation from the protocol and was withdrawn from the study by his physician, and 1 was discovered to not meet inclusion criteria after randomization.
At baseline, participants were in their sixth decade of life (mean ages, 58, 58, and 56 years in the prednisolone/chlorambucil, cyclosporine, and supportive therapy groups, respectively). The average proteinuria in each group was 10.1 (5.3 SD), 6.8 (4.7 SD), and 9.1 (5.3 SD) g, respectively, and mean creatinine clearance was 50 (16 SD), 49 (18 SD), and 50 (20 SD) mL/min.
The rate of a further 20% decline in kidney function was slowest in the prednisolone/chlorambucil group. Compared with the group receiving supportive care, the risk for decline in the prednisolone/chlorambucil group was significantly lower (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.24-0.78; P = .0042), which was mirrored by a greater decrease in proteinuria (-2.2 g per 24 hours; P = .014). Of note, the risk for decline in kidney function was no different between the groups receiving cyclosporine and supportive care alone (HR, 1.17; 95% CI, 0.70-1.95; P = .54). A smaller, nonsignificant mean reduction in proteinuria was seen in the group receiving cyclosporine (-0.7 g per 24 hours; P = .46). In the 3 groups overall, 11 patients reached end-stage renal disease: 1 patient in the prednisolone/chlorambucil group, 6 in the cyclosporine group, and 4 in the supportive therapy group.
With respect to safety, there were no differences in overall survival among groups. Whereas 42% of patients in the supportive care group experienced a significant adverse event (hospitalization) during follow-up, this proportion was greater in the cyclosporine (49%) and prednisolone/chlorambucil (61%) groups.
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