Glomerular Disease Clinical Case Review

In this video, Craig Gordon, MD, nephrologist at Tufts Medical Center and associate professor of medicine at Tufts University School of Medicine, discusses management strategies and treatment options in this case of lupus nephritis:

Editor’s note: The following is an automatically generated transcript of the above video.

"So we're going to turn now to the questions of management and really what should our approach be to management. And I want to call attention to the listeners to the quite recent publication of an update to the KDIGO clinical practice guidelines on the management of lupus nephritis. And I think we should all be aware of this. So as many people listening may know, KDIGO has produced a number of very, very successful clinical practice guidelines, and the glomerular disease in particular in 2021 has been very well received. There was recognition that there likely would be required updates to this guideline, chapter by chapter, based on new information being published. And one of the first updated chapters was the chapter on lupus nephritis. So I'm going to turn to some of the guideline statements made related to induction, initial treatment of lupus nephritis, and use that as a guide to how decisions were made regarding the patient described earlier.

So first, when we turn to induction therapy, when we're looking at Class III or IV lupus nephritis, which is active, and I'll show you what the schematic of an algorithm in a moment, the recommendation was that people with active Class III or IV lupus nephritis, whether they have or do not have a membranous, i.e. Class V, component, that these individuals should be treated initially with glucocorticoids plus any one of the following four approaches. The first two are the more time-honored approaches of using mycophenolic or related agents. Or low-dose IV cyclophosphamide. This is in contrast to the earlier NIH regimen, which was higher in dose, so this is following the Euro-Lupus regimen. There are some subcategories where you might prefer one or the other of these, and I'll come back to that in a few slides. But the major additions to the update to the lupus nephritis guideline were discussions about when we should consider belimumab, which is an anti-BLyS or BAFF, two terms that are used somewhat synonymously, an agent, which is used for lupus treatment irrespective of lupus nephritis. But given recent data in lupus nephritis, this is a potential add-on therapy either to mycophenolate or to the low-dose IV cyclophosphamide.

And the fourth and final possibility currently is either the mycophenolate in combination with a calcineurin inhibitor. This takes into account the recent data on voclosporin (Lupkynis, Aurinia) as well as earlier data tacrolimus and other CNIs. But the thought is that CNIs should really not be used in patients with severely impaired kidney function. This is referring to those with a GFR less than 45. So just schematically, this is represented here. Again, this is borrowed from the KDIGO guidelines. So individuals with class III or IV, with or without V, who have active disease. So that puts us in this lighter green pathway. This sort of aqua color represents people with chronic condition but not active disease. Patients should be treated with glucocorticoids and any of these four options. And there's no preference in KDIGO for these options, which are either the mycophenolate, the cyclophosphamide, the three-drug therapy, including belimumab (Benlysta, GlaxoSmithKline), mycophenolate, and prednisone, or three drugs including a calcineurin inhibitor, mycophenolate, and prednisone, with consideration of either voclosporin or some of the earlier CNIs. All of these regimens, all four of them should be given with glucocorticoids. I'll talk a little bit later about the tapering schedules.

So KDIGO was very helpful here in this update to help us think about situations where we might prefer one agent over others. So IV cyclophosphamide is something we would consider in those who we thought might not adhere well to an oral regimen so we can observe and make sure they're attending their infusions. Mycophenolate might be preferred for people who were concerned about infertility, perhaps those with a moderate to high previous cyclophosphamide exposure. And relevant to our patient that therapy initially with an immunosuppressive agent, including a CNI, and again, with no preference of which CNI, may be preferred in those, first, with relatively preserved kidney function, you don't want to use this in people with GFR less than 45, and in particular in the group with nephrotic-range proteinuria where you think there might be extensive podocyte injury, which might be ameliorated by the CNI. And then finally, I do want to mention belimumab, which is suggested in people who either have had or are at risk of repeated flares of lupus nephritis or at high risk of progression to kidney failure, perhaps because of already preexisting reduced GFR. And I'll show you in the next slide a nice table from the executive summary of the guideline that really emphasizes these points.

So you could see here in the first column is voclosporin and the second is belimumab. Again, voclosporin you want to be cautious in patients with low GFR. Belimumab can potentially be used in people with more significant declines in GFR. And there's some early evidence that actually it may slow the rate of decline of GFR in part from lowering the incidences of lupus nephritis flares. Voclosporin, similar to the above, shouldn't be used in those with lots of scarring on the biopsy, and may be a preferentially chosen agent in patients with severe proteinuria and significant podocyte injury. Whereas belimumab might be more effective in those with subnephrotic proteinuria. Belimumab probably has a better effect in reducing flares of both systemic lupus itself as well as lupus nephritis. And in contrast, voclosporin is not currently known to have such an effect. There's some subtleties here about ... There's no data, really, existing on the combination of cyclophosphamide and voclosporin. This is why earlier you could see in the previous slide we referred to voclosporin being used in combination with an antimetabolite, whereas belimumab, there's more evidence with MMF, but some with cyclophosphamide. Belimumab likely is favored in those who have extrarenal manifestations of lupus because there's years and years of high-quality data showing that this works really well to alleviate those. There's not much in the way of evidence for calcineurin inhibitors including voclosporin. And then we have to monitor the GFR carefully with voclosporin and monitor in both groups for potential risk of adverse events. Although in the studies they really didn't see much in the way of increases in these despite the additional immunosuppression.

And finally, there's not much evidence on either of these two groups of agents in those who were pregnant or considering pregnancy. Just before I get to some discussion of what happened in the case, I do want to point out that KDIGO recommends, actually quite more abrupt than we're used to, tapering glucocorticoids. You can see there's both a high, moderate, and reduced-dose approach, but either way, by the time you've hit up to four to six months into therapy and cross all of these, we should be at minimal dosing or no dosing of corticosteroids. And then finally, before we return to our patient, I want to mention some of the definitions of response, because this will be helpful in finding out what happened to our patient. So a complete response is defined as a reduction in proteinuria down to 0.5 grams per gram with stable or perhaps improvement in kidney function. And this generally is seen six to 12 months after starting therapy, but could take longer.

In a lot of the clinical trials, the primary outcome was primary efficacy renal response defined as a PCR reduction to 0.7 grams per gram with an eGFR no worse than 20% below the pre-lupus nephritis flare value or greater than 60. A partial response, to compare it with the complete response, was defined as a reduction in proteinuria by at least 50% and to below three grams per gram with, again, stabilization of the kidney function, if not improvement. And this, again, within six to 12 months of starting therapy. And no response is not achieving any of these and requires adjustment of therapy. So it's a little premature to use any of these terms on our patient, but let's come back to our case."