Lupus Nephritis: Many Unanswered Questions

Interestingly, we conducted a questionnaire study in which we asked 71 lupus experts whether they would stop steroids in a 21-year-old female with class IV nephritis who was in stable remission for 2 years, and there was an exact balance of opinion: One-third each would stop, wouldn’t stop, and didn’t know. When we looked for differences among the responders, we found that physicians in the United States and Canada had more enthusiasm for stopping steroids, while those in Europe prefer to keep them going. Also, by specialty, nephrologists were keener to stop them and rheumatologists were keener to keep going. In other words, there is no universal standard of care to answer this question.

QUESTION: What is the best measure for assessing treatment response?

Dr. Jayne: Typically, the criteria are proteinuria, urinary sediment, and renal function. The majority of patients will have normal renal function or near-normal renal function when they come to us, so the [glomerular filtration rate] is turning out not to be a useful marker for renal response. Yes, the loss of hematuria is useful and that’s part of a complete response definition, but really it’s the reduction of proteinuria that drives renal response definitions. So a reduction by 50% from baseline to subnephrotic levels (less than 3 g/day) is a partial response, and a complete response is down to less than 0.5 g/day.

Proteinuria means a lot of different things. One of the confusions in managing lupus nephritis is that proteinuria does not just reflect activity. You can switch off all of the activity in the kidney, but the proteinuria declines quite slowly. It takes a long time – up to 3 years – for the proteinuria to get as good as it’s going to get, but too many studies have short, 6-month end points. We really look at 2 years as being the induction period. Initially, proteinuria is reflecting disease activity, but subsequently reflects the recovery phase of the glomerulus. The immune complexes are being solubilized and removed. This is the remodeling phase, which lasts a long time. Then there is the fibrotic phase that contributes a relatively small amount to proteinuria.

For this reason, nephrologists would really love repeat renal biopsies. Several small studies have demonstrated that patients often have persistent disease activity even when proteinuria has gone down to relatively low levels. So even when the parameters we measure have gotten better, the activity may not be gone. A renal biopsy will tell you whether there has been a change in scarring or chronicity.

QUESTION: What’s on the horizon for the management of lupus nephritis?

Dr. Jayne: There are some new treatment directions, including tacrolimus (Prograf). This drug, which is widely used in the prevention of renal transplant rejections, also appears to have benefits for lupus nephritis. Tacrolimus has direct effects on the podocyte where it influences the cytoskeleton and the permeability of the glomerular basement membrane, as well as immunosuppressant effects, so it has a dual action in lupus nephritis, but we need more data.

The role of B-cell depletion has also been explored. Many physicians have been using rituximab (Rituxan) in their clinics for a number of years, and data from retrospective cohort studies suggest that it is effective for relapsing or refractory disease. However, the findings of double-blind, placebo-controlled trials of rituximab and another B-cell–depleting drug, ocrelizumab, when added on top of either mycophenolate mofetil or cyclophosphamide, suggested only relatively small treatment differences between the study drug and placebo. The failure of the trials may be associated with aspects of their design, such as short follow-up and small sample size.

QUESTION: Who should manage lupus nephritis?

Dr. Jayne: Should it be the nephrologist or the rheumatologist? That’s the most controversial issue of all. In reality, it should be a partnership.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Jayne reported no financial conflicts of interest.