Beyond ALMS: Is MMF Better Than Cyclophosphamide in Severe Kidney Disease?

Many lupus trials do not include patients with advanced kidney injury. The Aspreva Lupus Management Trial (ALMS) trial was the largest trial to date in lupus nephritis treatment. A recent article in the American Journal of Kidney Diseases explores a sub-group of patients with poor kidney function in the ALMS trial. Dr. Michael Walsh (MW), corresponding author from McMaster University, discusses this important trial with Dr. Kenar Jhaveri (eAJKD), eAJKD Blog Editor.

eAJKD: What question remained unanswered from the ALMS trial that prompted your study?

MW: The ALMS trial randomized 370 patients from 80 countries to induction phase with either mychophenolate mofetil (MMF) at a maximum dose of 3 g per day or the NIH regimen of intravenous cyclophosphamide. One of the questions that hadn’t been directly answered by prior studies was whether MMF induction was suitable for patients with low levels of kidney function. Hence, we studied this cohort of patients from the ALMS trial in a post-hoc analysis. Our results suggest no difference in the primary outcome of response in patients with low estimated GFR treated with MMF or cyclophosphamide.  However, MMF may result in a quicker recovery of kidney function than cyclophosphamide in these patients.

eAJKD: What do you think the comfort level of nephrologists is when using MMF for severe lupus nephritis?

MW: As nephrologists, we’re often very comfortable with monthly intravenous cyclophosphamide since we can assure adherence and predict the adverse events. Many nephrologists feel that MMF may not be as effective as cyclophosphamide in severe lupus nephritis. As we choose therapy, we need to be more mindful of our biases with these agents.

eAJKD: Is there any data on the mychophenolic acid in lupus nephritis?

MW: There was one study that looked at whether steroid tapering with mychophenolic acid could be achieved as readily in lupus nephritis, but little head-to-head data comparing it to MMF.  We did a small trial of mychophenolic acid versus MMF in autoimmune diseases (unpublished) in which outcomes were similar in most autoimmune diseases.

eAJKD: Post-hoc analyses that were not pre-specified in the main trial can only be hypothesis generating. How might we use these findings?

MW: This is a post-hoc analysis on a small sub-group with an uncommon disease where it’s already difficult to do clinical trials.  Trials with a large number of patients comparing sicker lupus nephritis patients are less likely to happen in the near future. Hence, studies like this one are actually very useful.

Do we expect MMF to have a different response in patients who are very ill? In our study, we tried to select sensitive measures where there might be a difference.  We chose change in estimated GFR over the course of the 6 months, and found no evidence that MMF was inferior to cyclophosphamide during that time. Both drugs performed poorly, with small proportions (20%) of responders as defined in the original study in both groups.

eAJKD: What did we learn about the role of kidney biopsies from the ALMS trial?

MW: Pathologic information in lupus is fascinating, and an area where we really need more research to understand its best use. Repeating biopsies after induction therapy presents an opportunity to tailor therapy for patients with poor kidney function in whom we cannot explain the persistent hematuria and proteinuria.  The biopsy may be able to distinguish sub-clinical disease versus scar.

eAJKD: What is your take home message regarding trials in lupus nephritis?

MW: As nephrologists and rheumatologists, we need to do a lot more work in advancing therapy for patients with lupus nephritis, particularly in patients with severe kidney disease who are at risk of developing end-stage renal disease or being left with severe chronic kidney disease at the end of their therapy.

To view the article abstract or full-text (subscription required), please visit

Leave a Reply

%d bloggers like this: