The Histologic Classification of Lupus Nephritis
In this video, James Matera, DO, discusses work-up over several years in a 25-year-old woman with lupus nephritis, including treatment approach considerations and the varying histologic classifications of lupus nephritis. This is part two of a two-part series.
Additional Resources:
- Kidney Disease: Improving Global Outcomes (KDIGO) Lupus Nephritis Work Group. KDIGO 2024 Clinical Practice Guideline for the management of LUPUS NEPHRITIS. Kidney Int. 2024;105(1S):S1-S69. doi:https://doi.org/10.1016/j.kint.2023.09.002
Watch part one of this two-part series here.
TRANSCRIPTION:
James Matera, DO: Good afternoon everyone. This is Dr James Matera. I am a nephrologist and the Chief Medical Officer at Centra State Medical Center, an affiliate of Atlantic Health System here in Freehold, New Jersey. And today I'm going to talk to you about an interesting case of lupus nephritis that I've followed for a number of years. This case we'll review is about a 25-year-old Caucasian female. She has a known family history of lupus, and in fact, her mother had lupus starting at an early age, which led to severe lupus nephritis and kidney failure. Her mom has had to undergo two renal transplants over the course of years, and she's now 52 years of age. Our particular patient, however, started to develop symptoms of joint pain back when she was only 18 years of age. And at that time, she presented to the hospital up in New Brunswick.
She required temporary hemodialysis because she had acute kidney injury where serum creatinine when she got in was 7.2. She had hyperkalemia of 6.2 metabolic acidosis and a urinalysis that showed over 4g of protein. Her complement levels of ANA were very low. Her ANA and anti-double-stranded DNA were very high. So, a new diagnosis of lupus was made in conjunction with renal failure. After a day or so of dialysis, it was decided that we would perform a kidney biopsy, and at this time, it revealed class 4 lupus nephritis, very similar to what we had in our first case presentation. The patient was able to come off dialysis at that time and was treated with a combination of high-dose corticosteroids and also started with mycophenolate mofetil and hydroxychloroquine. She then developed type 2 diabetes over time, requiring an insulin pump, and because the steroids that she was on affected the diabetes, she ended up needing the care of an endocrinologist and continuous glucose monitoring.
When she stabilized on that regimen, after we had done the kidney biopsy through the last few years, she did very well. Her renal function improved all the way down to a creatinine 1.0, and her protein levels in her urine, which were over 4g, were hovering at about 500mg per day. And she continued to do well, although other symptoms of her lupus, particularly polyarthralgia, she had some mild-to-moderate cognitive impairment, which affected her profession, which was a registered nurse. And she started to develop significant rashes and intermittent seizures. So, on my last visit with her, she still had fairly stable renal function, creatinine was 1.0, and her urine protein was down just about normal. She continued to have a positive ANA, low complement levels, and an anti-double-stranded DNA of 38, which is elevated.
I chose then, in 2022, to do a repeat renal biopsy, which showed a different class of lupus, namely class 3 and class 5. So, I want to take you through, very briefly, what some of the classes mean. Class 1 lupus nephritis is minimal mesangial proliferation. It's rare, it may be the earliest and mildest form, and generally, doesn't require any treatment. I usually don't see those cases. Class 2 would be a more mesangial proliferative. This also has a good prognosis and specific therapy doesn't necessarily have to be undertaken if renal function is stable. Classes 3 and 4, sometimes we loop them together because those are more proliferative. Class 3 is focal proliferative. Class 4 is diffuse proliferative. And with that, it really depends on the biopsy, and what percentage of glomeruli you see that are effective. If it's over 50%, it's diffuse, and those can be the most prominent and difficult to manage. If you remember back to 2016, that's what our patient had.
Class 5 is membranous nephropathy, which also we know as a primary renal disease, so about 10 to 20% of patients can have membranous nephropathy. There is a new class 6, or relatively new, which is advanced sclerosis. And every time we hear the word sclerosing, we get concerned. Those generally are not very treatable. So it's very important to know the class. When we're treating this, we must also take into account the patient demographics and social determinants of health. Here's a 25-year-old woman who is expecting to maybe have children down the road. These are all considerations. So, we know that in these cases we have to have immune-modulating treatment, especially when we have class 3 or 4, and that's what we did in 2016. And there are lots of algorithms available to look at these approaches, including the 2024 KDIGO guidelines, which we referred to in the first video. And don't ever forget about lifestyle modifications, such as diet. And we'll talk a little bit about that.
When we look at, again, therapy, MMF vs cyclophosphamide, or mycophenolate vs cyclophosphamide, when we looked at these studies all the way back to the 2000's–2009 or so–when this was looked at, a lupus management study at that time showed that there was equal efficacy of both mycophenolate and cyclophosphamide. And that was really the study that said, so MMF is non-inferior to cyclophosphamide, but yet has fewer adverse effects. And for me, that really led to a transition over to MMF. Corticosteroids, as we said, alone are not recommended.
And at some point they should be tapered to the lowest possible dose to try to maintain what's going on. If we look at what we're looking at now in 2009, the European Alliance or EULAR also looked at guidelines for lowering the target doses of prednisone because, again, of all the adverse effects. So, instead of what traditionally we would go at 0.5mg/k to 1mg/k, they looked at 0.3mg/k to 0.5mg/k per day. And what they then tried to do was get them down to the lowest dose by the end of about 120 days or 4 months. And again, there's no real set way. You have to see what their response is to that. So that was a good study for us too. So, while we use these agents as primary medications, there are quite a few other agents that are being evaluated or have been evaluated that could be of use.
We made mention of the monoclonal antibody, belimumab. And again, when we look at some of those studies, there also seems to be a benefit to this, which could be steroid-sparing in some, and there's actually a subQ dose out there now that would eliminate the use for intravenous. Currently, we've been giving intravenous doses of belimumab where we go 400mgs per day and then 200 milligrams once a week thereafter and follow their targets. They've been used for as long as two years after therapy. So, that's something to consider. We talked a little bit about voclosporin in the last video. And again, this acts kind of like a calcineurin inhibitor and could be also of good use. In a study that was done using that, we looked at 357 patients who were either to receive voclosporin at a dose of 23.7 BID or placebo. All these patients also got MMF, so remember, voclosporin is an adjunct to what you're already doing, and low-dose prednisone, which was then tapered. What they found was they had a really good outcome in that their response to the voclosporin was higher than those without voclosporin. So, it did lead to a higher evidence of hypertension. So we have to remember our old-fashioned therapy of using ACE inhibitors and ARBs in these patients, as well. Once the patient attains a remission, what do we do then? In the past, either maintaining MMF or moving to another agent, azathioprine or Imuran, has often been the longstanding way that we try to maintain these patients. So again, if we look at that, we have a lot of options for that as well.
And again, I want to taper these over time. At some point we have to make a decision, are we going to commit the patient to long-term medications? And remember, MMF could have some effects if the patient wants to get pregnant, so that may alter your way of, uh, doing things as well.
It is so imperative to maintain other supportive measures as well. Don't ever forget those. And those include hypertension management. These patients have to be on RAs agents, again an issue with pregnancy, but these patients have to be on those, whether it's ACEs or ARBs. I think those would work well to try to control the blood pressure. Protein restriction and sodium restriction in their diet are essential. You want to manage their lipids as well, and you want to continue shared-decision making. You and your patient are a partner in this journey because this is a lifetime journey for these patients.
Let's go back to our patient, the 25-year-old who had a totally different approach than she did in 2016. She was treated initially with a combination of prednisone, mycophenolate, and hydroxychloroquine. Unfortunately, she couldn't tolerate the mycophenolate. She had significant GI effects, and we went down to a lower dose, and that started to cause a little bit of flare. Her proteinuria went up, and she also had significant chronic leukopenia with white counts as low as 1.8. So mycophenolate wasn't a good choice for us. Um, also she was susceptible to infections and continued to get a lot of urinary tract infections and skin infections. At that point, she didn't want to be on prednisone any longer, so we had tapered off her prednisone. But what we did is we added Belimumab to her therapy. Currently, she's maintained on Belimumab and hydroxychloroquine through her rheumatologist because the latter, the hydroxychloroquine, seems to hold off her other lupus flares and symptoms at this time.
So currently she's on belimumab, 200mg/weekly. She's been on this dose for about 8 months now and continues to enjoy proteinuria that is in the normal range, a serum creatinine that's down to 0.9. And with her insulin pump and not being on corticosteroids, she has less requirement for basal insulin. Her hemoglobin A1C at last check was 6.9%. During our last visit the patient started to bring up the possibility of pregnancy, which is another reason why being off MMF is a good indication. These patients are at high risk for flares. So again, this has to be shared decision-making. We have to go over all the potential things that may happen. But with a 25-year-old female, it's important to understand that these things have to come into consideration when you're making your choices. So my take-home point for this is we have a lot of things available to us to treat lupus nephritis.
Our primary goal, especially in someone who's presenting with significant lupus nephritis, is to limit the immune effects and lower the inflammatory effects to try to preserve renal function. This is a lifetime disease. Even if you go into remission, there could be a potential for a flare. Pregnancy has been known to increase flares. Some these are conversations you have to have. You have to know the adverse effects of the medications, and how you're going to supplement your individual patient's requirements to those and pay attention to all the things that are important–routine follow-up management, age-appropriate cancer screening, treatment of blood pressure, and dietary modifications are also important. We've all heard lupus called the great impersonator, and it's very important for us to sit down and understand our patients. There are studies with newer agents that are coming out. I think we'll continue to enjoy the possibility of being able to positively impact our patients with lupus, and I hope that this gave you an idea into how we can manage that. So, once again, thank you for your attention, and have a great afternoon.