Lupus Nephritis Guideline Updated to Advance Care, Reflect New Therapies

New therapeutic options

With growing numbers of nephrology drugs receiving approval and many more in the pipeline, KDIGO decided to adopt a more rapid approach to updating its recommendations based on emerging evidence. The KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases, which included a chapter on lupus, was completed shortly before belimumab and voclosporin became the first two FDA-approved therapies for adults with lupus nephritis (5). In response, KDIGO released a focused update solely on lupus nephritis.

“Lupus nephritis was the obvious first choice for this living document [approach],” said Brad Rovin, MD, FASN, co-chair of KDIGO's lupus nephritis guideline work group and director of the Division of Nephrology at The Ohio State University Wexner Medical Center in Columbus.

National Kidney Foundation President-Elect Kirk Campbell, MD, FASN, called the updated lupus nephritis guideline “a welcome development.” Campbell, a professor of medicine and pharmacological sciences at the Icahn School of Medicine at Mount Sinai, New York, explained, “It is important to put approved therapies in the proper context for practicing clinicians and to better inform patients about those treatment options that might be available.”

With data from the pivotal clinical trials, Rovin and his colleagues crafted new recommendations on which patients might be appropriate candidates for the novel therapies. Rovin said that post hoc analyses that provided additional nuance are discussed in the guideline, although the evidence was not strong enough for specific recommendations. For example, he noted a nonsignificant trend toward less decline in estimated glomerular filtration rate among patients who received belimumab than among those who did not in the trial. This might suggest a potential benefit for patients already experiencing kidney impairment. Additionally, voclosporin was beneficial among patients with all levels of proteinuria, whereas belimumab had better outcomes among patients with proteinuria below 3 g/day, he noted. “We are getting closer to that idea of personalized or precision medicine,” Rovin said.

Campbell agreed about the importance of matching therapies with patient characteristics. “A patient who is at higher risk of kidney disease progression or lupus nephritis flares may benefit from more aggressive treatment regimens from the outset,” he explained. “That will ensure that they are not going to have repeated cycles of additional medications to treat flares and associated hospitalizations down the line.”

Rovin said that it is also essential to consider the drugs’ high price tags. Benlysta, the name brand of belimumab, has a list price of $1,210.63 per weekly subcutaneous injection, according to the patient assistance program of GlaxoSmithKline (GSK), the drug's manufacturer (6). Lupkynis, the name brand of voclosporin, costs $15,482 for 180 oral capsules, according to Drugs.com (7).

A cost-effectiveness analysis by the Institute for Clinical and Economic Review found that both drugs fall within the thresholds for cost-effective interventions (8). Rovin noted that the costs of poorly controlled lupus nephritis or progression to kidney failure are also substantial for both the health system and patients. However, in some cases, he noted, insurance companies will not approve the use of the drug unless a patient has failed another therapy. Alternatively, insurance companies may approve therapy use with a very high co-pay.

“We see patients from across the socioeconomic spectrum with lupus and lupus-related kidney disease, and many cannot afford the co-payments,” he said. For patients without insurance, the costs of paying the full price are even farther out of reach, he noted. “Cost is a big consideration for the patient.”

Campbell noted that there is also a public health need to ensure access to patients who would benefit. “We also need to ensure that the newly approved therapies are available and accessible to patients who need them the most,” he said.

Rovin stated that another important consideration is whether patients are struggling with adherence to their current treatment regimens. “Patients who are having problems adhering to their medications may not enjoy the fact that the full dose of voclosporin used in the clinical trial is six additional pills a day,” he said. He noted that some patients may already be taking 20 to 30 pills a day. “Belimumab can be given intravenously once a month or subcutaneously, so that might be necessary for patients having challenges with adherence.” He noted that belimumab has long been FDA approved for systemic lupus erythematosus and may also be a better choice as an add-on for patients with many systemic lupus symptoms.

Buyon said the guideline was not overly prescriptive, and she would have liked to see more specific guidance on when to select the new drugs. Overall, she said, the guideline reinforced what many clinicians caring for patients with lupus nephritis already do. “Even with these [new] drugs, we still have a long way to go,” she said.

Taking the long view

The new recommendations also highlight the importance of kidney preservation and balancing patients’ quality of life with therapeutic considerations.

The guideline recommends pulsed doses of intravenous methylprednisolone at the start of therapy to enable lower dosing later and a more rapid taper even on a standard treatment regimen. Rovin noted that adding belimumab may enable clinicians to start with a modest dose of glucocorticoids, and voclosporin may enable patients to start with a very low dose. He asserted that lower glucocorticoid doses are vital to mitigate side effects that can lower patients’ adherence, particularly at the start of therapy. “If you could start out with a lower steroid dose, and patients do not have as many side effects, and you are bolstering the immunotherapy because you have two different drugs on board,” he said, “[patients] are going to be more likely to take the regimen and not be turned off immediately.” Buyon agreed with the more conservative approach to using glucocorticoids, which she said reflected, in part, confidence in the potential of the new drugs.

Campbell noted that about half of patients with lupus will eventually develop kidney diseases, and approximately 1 in 10 patients advances to kidney failure. He said that makes controlling the symptoms of lupus to protect the kidneys and slowing the progression of kidney diseases when they occur essential. “Almost everyone after the first episode of lupus nephritis has chronic kidney disease,” Rovin said. “We have to think about how we can preserve as much kidney function as possible so they can keep their kidneys their whole life expectancy.”

Rovin noted that renin-angiotensin system inhibition is beneficial for preserving kidney function. He explained that there is evidence that belimumab may provide some kidney protection, and calcineurin inhibitors, like cyclosporine, may help protect podocyte integrity, vital to safeguarding nephrons. Campbell noted that sodium-glucose cotransporter-2 inhibitors and other therapies, like endothelin receptor antagonists, may also eventually help further customize patient care. “One could foresee in the future more options to optimize what we traditionally consider the supportive foundational regimens versus targeted disease-modifying immunosuppressive agents that we may not want to keep patients on indefinitely or may want to be more cautious about administering to the right patients,” he reflected.

Izmirly recommended that rheumatologists and nephrologists rethink their reliance on proteinuria to diagnose and monitor lupus nephritis. Earlier work from AMP shows aggressive lupus nephritis in biopsies done with protein levels between 0.5 g/g and 1 g/g (9), and AMP is working on identifying potential urinary biomarkers to diagnose and track lupus nephritis (10–12). Buyon said that she was concerned that the KDIGO guideline which considers the threshold for kidney involvement and biopsy as 0.5 g/g for the urine protein-to-creatinine ratio (UPCR) is too conservative. She noted that in the continued new AMP, which is studying early nephritis, patients with a UPCR between 0.25 g/g and 0.49 g/g often have actionable lupus nephritis. “We see people rapidly progress from 0.4 to higher levels of proteinuria,” she said. “If that is a window of opportunity, [this guideline] may be missing it.”

The guideline also highlighted the robust pipeline of new lupus nephritis drugs, which may lead to additional updates to the guideline. Rovin noted that the drugs may also enable more personalized approaches to patient care. Buyon agreed that future therapies may focus on more personalized approaches. She noted that emerging transcriptome data from AMP reveal that some patients may have more B cell activity. In contrast, others may have more T cell activation, which may help clinicians choose the best drugs for patients. She and Izmirly hope that the AMP study will help identify new drug targets, biomarkers, and other ways to enhance care.

Campbell also emphasized the importance of more research to help clinicians understand lupus nephritis’ genetic and molecular basis. He indicated a need for biomarkers that can predict patients’ response to therapy, provide even more targeted therapies, and allow clinicians to monitor their patients’ treatment responses. “We need to develop and validate biomarkers that we can use to follow the tissue response to treatment in real-time to help manage immunosuppression and identify an impending lupus nephritis flare that can help us decide if we need preemptive immunosuppression,” he said.

In the meantime, Rovin said that the approvals help create a pathway for future therapies. “We know we can get approval,” Rovin said. “That is the most exciting part. These two drugs have kicked off a flurry of investment from smart scientists to develop drugs for lupus nephritis.”