#NephMadness 2022: Lupus Nephritis – Progress, Far from Perfection

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Swapnil Hiremath @hswapnil

Swapnil Hiremath is an Associate Professor at the University of Ottawa and an Associate Scientist at the Ottawa Hospital Research Institute. His primary clinical and research interests are in improving care of individuals living with high blood pressure, CKD, and those receiving hemodialysis. He is co-founder of the online nephrology journal club, #NephJC.

Competitors for the Lupus Region

Belimumab vs Voclosporin

Family Planning in LN vs Pregnancy in LN

“Some days I can’t balance it all. I just have to lay in bed” – Toni Braxton

Lupus is one of the nastiest diseases out there. It has a wide variety of presentations. One can achieve remission only to have a flare up happen soon, or maybe many years later. And it has very serious consequences, soo we need very serious drugs to tackle it. The old C (cyclophosphamide) has been the mainstay for lupus nephritis for a long time, with mycophenolate, azathioprine, and calcineurin inhibitors providing more options. Vitamin R (rituximab) hasn’t impressed hugely, partly due to study design aspects of the LUNAR trial. Most of these options do have side effects that often fit the adage of the cure being worse than the disease. We need options. Safer, effective options. 

This is where the top of the bracket comes in for the Lupus region: pairing off belimumab vs voclosporin.

Belimumab (li- refers to immune directed, mu- means it is a humanized mab meaning monoclonal antibody; see here for more on terminology) is in one corner, having been available for lupus to rheumatologists for a while, and now to us after the BLISS-LN trial results. It binds to the soluble B lymphocyte stimulator (BLys, also known as B-cell activating factor or BAFF) and puts B cells in a state of bliss, ameliorating their stimulation/activity.


Voclosporin is very similar to cyclosporine, with a small change in the structure giving it many seemingly magical properties importantly including reliable pharmacokinetics (thus obviating the need for drug monitoring, its unique selling point over tacrolimus and cyclosporine). In the AURORA-1 trial, voclosporin (in addition to mycophenolate and prednisone) was compared to placebo, and found to be beneficial. So everything is nice and sunny right? We needed options, and now we have two new approved and effective agents!

Not so fast. 

If we look closely at BLISS-LN and AURORA, we can see that in both trials, the outcomes were driven by proteinuria reduction. Indeed, these trials were done early in the course of disease – and we don’t have the requisite 5-year or longer follow-up that would be needed for kidney failure outcomes. But do we know how strong the relation is between proteinuria and kidney failure in lupus? After a lot of deliberation, the FDA has accepted albuminuria reduction as a valid surrogate for new drug approval, provided subsequent hard outcome trials are done. But if we look at the underlying studies, when albuminuria reduction is driven by immunosuppression, the relationship is not that straightforward.

Treatment effect on change in albuminuria at 6 months and on the clinical endpoint in the overall population and subgroups
Data points are the estimated treatment effect and horizontal lines the 95% CIs. Data for all studies are in the appendix . Treatment effect on albuminuria is expressed as the geometric mean ratio of ACR; to convert geometric mean ratio to percentage decrease in ACR: (1–geometric mean ratio) × –100. Treatment effect on the clinical endpoint is expressed as an HR. The composite clinical endpoint was end-stage kidney disease, doubling of serum creatine concentration, or eGFR of less than 15 mL/min per 1·73 m2. ACR was log transformed in each analysis. Other chronic kidney disease refers to causes of chronic kidney disease other than glomerular disease or diabetes, or that the cause was not specified. ACR=albumin to creatinine ratio. eGFR=estimated glomerular filtration rate. HR=hazard ratio. RAAS=renin–angiotensin–aldosterone system. Figure 2 from Heerspink et al, Diabetes Endocrinol, © Elsevier Ltd. Reproduced with permission.

In most of the examples in this meta-analysis from Heerspink et al, the reduction in albuminuria aligns nicely with the clinical endpoint benefit. With immunosuppression, the benefit in endpoints seems more than what albuminuria reduction can explain (and note, as an aside, that intensive BP-lowering reduces albuminuria without clinical benefit). 

Also, in lupus, there can be residual proteinuria from scarring which may not reflect active disease. Nevertheless, one might argue, albuminuria reduction is a good signal, right? True, but at what cost? Belimumab costs $35,000 a year and comes in monthly infusions. Voclosporin comes in at $92,000 a year and comes in with a heavy daily pill burden. Do we think some measly albuminuria reduction is worth all that? Why not use good old calcineurin inhibitors like cyclosporine and tacrolimus instead if one is looking for alternatives to good old C and R without bankrupting our healthcare systems? More importantly, we may indeed have truly more effective options, such as obinutuzumab – for which the promising NOBILITY results have led to the ongoing REGENCY trial. For the sake of NephMadness, if we had to make a choice, the ‘cheaper’ drug which makes your B cells blissful seems a slightly better choice. Though it shouldn’t go too far, as we shall see next. 

Lupus is somewhat unique in having an oversize sex preponderance – mostly affecting young women. Young women who may want to have children. On the other hand, nothing causes more sleepless nights for most of us than caring for a patient with lupus nephritis who is pregnant. So many things can go wrong, and they often do. Lupus can and will flare up during pregnancy. The maternal kidneys will get inflamed and sometimes fail. Other medical badness follows, with higher rates of diabetes, infections, thrombosis, thrombocytopenia, and bleeding during pregnancy. Obstetrical and fetal outcomes are not good, due to lupus, and due to the drugs you give to keep the disease in check. Is it pre-eclampsia or a lupus nephritis flare? Easy to exclude by doing a kidney biopsy, right? Wrong – remember you are looking after a pregnant woman, and a biopsy is technically challenging. Nothing about lupus in pregnancy is easy.

Which makes the need for family planning so important in this setting. Unintended pregnancy is not uncommon and it is really important to discuss conception plans right from the diagnosis. Contraception is tricky as certain hormonal options may increase risk of lupus flares, or thrombosis. Drugs used in lupus can be teratogenic. The timing of pregnancy should be done with careful planning for this reason. At the same time, the drugs used in lupus – chiefly cyclophosphamide – can cause infertility (in both men and women). Use of GnRH agonists and cryopreservation are options to consider if accessible. The scouting report for family planning (along with the tables) is an excellent starting point for the nephrologist taking care of individuals living with lupus nephritis.

Both family planning and pregnancy are hugely important aspects in lupus nephritis. For this editorialist, the dangers of pregnancy in lupus nephritis and the crucial importance of teamwork with the obstetrics, leaning on help from someone with expertise and experience in pulling off a successful outcome gives the topic an edge. All the way to be the winner of the region over the meh progress with the newer therapeutic options we have seen so far. 

– Guest Post written by Swapnil Hiremath, AJKDBlog Contributor. Follow him @hswapnil.

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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