Edgar Lerma, MD

Despite being the most common primary glomerulonephritis worldwide, 

 and end-stage kidney disease. Despite advances in understanding its pathophysiology, treatment options have historically been limited to supportive care, including renin-angiotensin system inhibitors, blood pressure control, and corticosteroids for high-risk patients.

Recently, a growing understanding of the immunopathogenesis of IgAN has led to the emergence of novel therapeutic strategies, including the inhibition of A proliferation-inducing ligand (APRIL), a key driver of IgA production. By reducing pathogenic IgA1 production at its source, APRIL inhibition has the potential to alter the course of the disease. Accordingly, several anti-APRIL drug candidates, including sibeprenlimab, atacicept, telitacicept, and zigakibart, are in clinical development for IgAN.

For more on APRIL inhibition and the current IgAN treatment landscape, the editorial team of 

 spoke with Edgar Lerma, MD, a clinical associate professor of medicine in the section of nephrology at the University of Illinois at Chicago.

: Can you provide an overview of the current treatment landscape for IgA nephropathy and what unmet needs exist for patients?

: One of the things that's interesting [about IgAN] is that this is considered a rare kidney disease, but it is the most common primary glomerulonephritis worldwide. In fact, there's an annual global incidence of 2.5 cases per 100,000 persons.

The disease manifests in several ways. Patients can present with asymptomatic hematuria, which means blood in the urine, or proteinuria, and that is protein in the urine, or they can present with advanced stages of kidney disease.

If you think about it, any patient who is diagnosed with what is called a rare kidney disease, it's a little bit disconcerting, right? So there's uncertainty about it, and this obviously impacts the patient's physical, mental, and emotional health. A lot of patients become anxious, and this can affect their daily activities, as well as even their daily work lives.

One of the things that's important about IgA nephropathy is that when patients are diagnosed, usually they are between 20 and 40 years of age. That's a very young population, right? So if these patients are 20 to 40 years of age, if you think about them and you think they eventually progress to kidney failure or what we call end-stage kidney disease, that means requirement of dialysis or kidney transplantation, this happens in their lifetimes.

So if they get to that point of reaching kidney failure, it's really a lifestyle change. They have to adjust to this new condition in their lives and it affects not only their personal lives, but also the lives of their families and their relatives.

: What challenges exist for developing effective pharmacologic therapies for IgA nephropathy?

: Let me put this in perspective. For many years, for many decades, whenever we diagnosed a patient with IgA nephropathy, and by the way, the only way to diagnose a patient with IgAN is through a kidney biopsy. Whenever a patient is diagnosed with IgAN, we explain to them that this is how the disease happens, this is what to expect, and so on and so forth.

For many years, the only thing we had to offer patients was treatment and medications to manage their symptoms and maybe slow down the progression of the kidney disease.

For blood pressure control, we use certain antihypertensive agents called renin-angiotensin system blockers. And of course, along with that, it's lifestyle – dietary salt restriction, aerobic exercise on most days, weight loss if necessary, cessation of smoking, so on and so forth.

And then the only other treatment that we offer is, whenever they don't respond to the ones I mentioned earlier, the next step would be to consider immunosuppressive therapies.However, the therapies that we had available back then had significant side effects and long-term toxicity.

So when you mention novel agents, over the past few years, we have had a deluge of novel therapeutic agents for IgAN. We now have a better understanding of the pathophysiology of how it can develop, and by understanding this mechanism, several phase 2 and phase 3 clinical trials have been published and have influenced the way we manage the disease. There are now different options for treatment that target the different pathophysiologic steps that lead to eventual kidney failure.

: There has recently been an increased focus on targeting APRIL. Can you tell me a little bit about that?

: So when we say APRIL, it stands for A proliferation-inducing ligand. This is actually a cytokine in the tumor necrosis factor family, and APRIL is integral to the development and progression of IgAN.

When we say cytokine, it is a substance secreted by certain cells of the immune system, and these cytokines have an effect on the other cells.

APRIL actually promotes the survival and the class switch, switching up B cells to produce IgA, particularly what we call the pathogenic galactose deficient IgA1. The abbreviation is Gd-IgA1, which actually forms immune complexes in the kidneys.

So these complexes are deposited in the glomeruli, which later on triggers inflammation, and as you trigger this inflammation, it leads to kidney damage. One way of thinking about this is you think of APRIL as a toggle within the immune system. So if you think of an electrical grid, APRIL powers specific circuits, and when you activate it, you turn it on, it helps promote the production of these pathogenic Gd-IgA1 and immune complexes formation and this leads to kidney damage and injury.

If you target APRIL, you turn it off, it is like pushing the toggle, turning it off and then this reduces the production of those harmful molecules that I mentioned. If you reduce the production of those molecules, then you prevent that damage and the injury that follows.

So, targeting APRIL represents a potential therapeutic strategy that disrupts this pathogenic sequence. If you inhibit APRIL, you can decrease the production of those harmful molecules, those Gd-IgA1, and eventual immune complex formation deposition into the kidneys, which eventually leads to end-stage kidney disease and the need for dialysis or transplantation.

: There are some promising agents in clinical development progressing through phase 2 and phase 3 trials. Is there anything that you think holds the most therapeutic potential for improving IgAN care?

: Right now we are actually looking at the guidelines for sort of directing how these agents will be used in the future, so it's exciting for us as nephrologists because now we have so many options. Before, we only had symptom management and blood pressure control.

For more information about IgAN and the role of APRIL, there's actually a website, 

, that has a lot of new insights and news about IgAN.

Editors’ note: Lerma has relevant disclosures with Travere Therapeutics, Akebia/Otsuka, Astra Zeneca, Bayer, Glaxo Smith Kline, Otsuka, Vifor, and Bayer.

Mathur M, Chan TM, Oh KH, et al. A PRoliferation-Inducing Ligand (APRIL) in the Pathogenesis of Immunoglobulin A Nephropathy: A Review of the Evidence. 

Articles

IgA nephropathy (IgAN) is a prevalent primary glomerulonephritis and a significant cause of chronic and end-stage kidney disease. Traditional treatments have been limited to supportive care, but recent insights into IgAN's immunopathogenesis have led to novel therapies targeting APRIL, a cytokine involved in IgA production. Inhibiting APRIL could alter disease progression by reducing pathogenic IgA1 production. Several anti-APRIL drugs, such as sibeprenlimab and atacicept, are in clinical trials, offering hope for improved management of IgAN and addressing unmet therapeutic needs.

Lerma discusses the current treatment landscape for IgA nephropathy and what role APRIL inhibition may play in treating IgAN.

The Therapeutic Potential of APRIL Inhibition in IgAN, with Edgar Lerma, MD

Exploring the Cardiovascular Benefits, Potential of Finerenone

Management of chronic kidney disease among patients with type 2 diabetes has undergone significant change in the last decade. Once handcuffed by a lack of safe and efficacious options, changing standards of care coming as the result of pharmacotherapeutic advancement have ushered in a new era of management for this patient population.

This change has been spearheaded by 2 particular classes—a familiar face in the form of SGLT2 inhibitors and the novel nonsteroidal mineralocorticoid receptor antagonist (nsMRA) finerenone (Kerendia), which received approval in July 2021 for reducing the risk of sustained eGFR decline, kidney failure, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease associated with type 2 diabetes.

Finerenone first captivated the attention of nephrologists, endocrinologists, and other providers managing patients with type 2 diabetes with the release of data from the FIDELIO-DKD and FIGARO-DKD trials. The number of specialists captivated by the agent and its potential benefit grew with the release of data surrounding the cardiovascular benefits among patients with heart failure observed within the FINEARTS-HF trial at the European Society of Cardiology Congress 2024.

In this segment, which is part 5 of a 5-part series, discussants Edgar Lerma, MD, a nephrologist, and Anuradha Lala-Trindade, MD, a cardiologist, dive into the cardiovascular benefits highlighted in the FINEARTS-HF trial with finerenone, specifically its impact on heart failure with preserved ejection fraction (HFpEF). Lala-Trindade elaborates on the historical challenges of treating HFpEF, noting that earlier trials with steroidal MRAs like spironolactone showed mixed results. However, finerenone demonstrated a significant reduction in cardiovascular death and heart failure hospitalizations, marking a substantial advancement for both heart and kidney health in HFpEF patients.

They discuss the paradigm shift in treatment approaches—favoring simultaneous, low-dose initiation of all four heart failure “pillars” rather than sequential dosing. Lala-Trindade points to finerenone’s unique, manageable side-effect profile, particularly its lower risk of hyperkalemia, as promising for broader applicability. They conclude with a look at the practical questions surrounding accessibility and cost, noting the need for more data on the value finerenone may add compared to traditional MRAs.

 a clinical professor of Medicine in the Section of Nephrology at the University of Illinois at Chicago and a nephrologist with Associates In Nephrology based in Chicago.

 the director of Heart Failure Research, program director of the Advanced Heart Failure and Transplant Fellowship, and associate professor of Medicine at The Mount Sinai Fuster Heart Hospital & Department of Population Health Science and Policy.

Relevant disclosures for Lerma include Akebia, Astra Zeneca, Bayer, Boehringer Ingelheim, Glaxo Smith Kline, Otsuka, Travere, Vifor, and Fresenius. Relevant disclosures for Lala-Trindade include Merck, AstraZeneca, Cytokinetics, and Novartis.

Campbell P. Finerenone (Kerendia) approved for chronic kidney disease associated with type 2 diabetes. HCP Live. July 9, 2021. Accessed October 23, 2024. https://www.hcplive.com/view/finerenone-kerendia-approved-chronic-kidney-disease-associated-with-type-2-diabetes.

Campbell P. FDA updates Finerenone label to reflect Cardiovascular Outcomes Data. HCP Live. September 8, 2022. Accessed October 23, 2024. https://www.hcplive.com/view/fda-updates-finerenone-label-to-reflect-cardiovascular-outcomes-data.

Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. 

. Published online September 1, 2024. doi:10.1056/NEJMoa2407107

Videos

In the final part of this 5-part series, Lala-Trindade discusses the findings of the FINEARTS-HF trial and how it might inform use of finerenone. 

Applying guideline directed management in CKD care

In this segment, which is part 4 of a 5-part series, discussants Edgar Lerma, MD, a nephrologist, and Anuradha Lala-Trindade, MD, a cardiologist, explore the substantial impact recent guideline updates have had on chronic kidney disease treatment strategies. Lerma details how clinicians increasingly employ an integrated approach, utilizing ACE inhibitors or ARBs, SGLT2 inhibitors, and finerenone as part of a multi-step, pillar-based strategy to slow chronic kidney disease progression. He notes that traditional protocols involve sequentially adding each treatment every 3 to 6 months, but recent discussions in publications, like one in 

, propose accelerated options. These accelerated approaches may be more appropriate for high-risk patients, where clinicians can implement all therapies simultaneously to swiftly mitigate cardiovascular and renal complications.

Lerma also addresses the ongoing concern around hyperkalemia, especially when using mineralocorticoid receptor antagonists, which remains a potential side effect. He shares his anticipation for the FIND-CKD study, which may extend finerenone’s applications beyond diabetic chronic kidney disease, allowing more chronic kidney disease patients to benefit from its reno-protective effects.

In part 4 of this 5-part series, discussants explore the influence of recent guidelines on changing standards of CKD care.

Applying Recent Guidelines, 4-Pillared Approach to CKD Care

Addressing cardiovascular risk in CKD care

In this segment, which is part 3 of a 5-part series, discussants Edgar Lerma, MD, a nephrologist, and Anuradha Lala-Trindade, MD, a cardiologist, delve into the updated clinical guidelines for managing chronic kidney disease (CKD), especially among patients with type 2 diabetes and elevated cardiovascular risk. Lerma emphasizes the KDIGO guidelines, which now endorse finerenone as an effective treatment option following results from the FIDELIO and FIGARO studies. 

He outlines the modern 4-pillar approach to managing diabetic kidney disease, which includes Metformin, ACE inhibitors or ARBs, SGLT2 inhibitors, and finerenone. Each drug offers unique cardio-renal benefits, working through different mechanisms to slow chronic kidney disease progression and reduce complications. Lerma also stresses the essential role of primary care providers as first responders in identifying at-risk patients, fostering early intervention with this comprehensive, multi-disciplinary approach.

Chronic kidney disease management in type 2 diabetes has evolved significantly due to pharmacotherapeutic advancements, particularly with SGLT2 inhibitors and the novel nsMRA finerenone. Finerenone, approved in 2021, has shown efficacy in reducing risks associated with kidney and cardiovascular complications. The FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF trials have highlighted its benefits. Updated KDIGO guidelines now recommend a 4-pillar approach, including Metformin, ACE inhibitors or ARBs, SGLT2 inhibitors, and finerenone, emphasizing the role of primary care providers in early intervention.

In part 3 of this 5-part series, Lerma discusses recent updates in the management of chronic kidney disease in people with type 2 diabetes. 