Welcome to Unscripted the AMCP podcast, a look inside managed care pharmacy. Listen in as experts explore the challenges, innovations, and opportunities shaping healthcare for millions of patients. Welcome to this episode of Unscripted, the AMCP podcast. I'm your host, Fred Goldstein. In this episode, we'll present a continuing pharmacy education program on the recent 2025 KDIGO Guidelines updates for IgA nephropathy. All medications mentioned in this episode are for educational purposes.
This activity is supported by an independent medical education grant from Calliditas Therapeutics. AMCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Instructions for claiming credit are located in the show notes. Please refer to the handout in the show notes for detailed instructions on how to claim CPE credit.
At the completion of this activity, participants should be able to discuss the latest advancements in IgA nephropathy Management as updated in the 2025 KDO guidelines. It is now my pleasure to introduce our faculty for today's program, Dr. Kartik Kalra, nephrologist at Geisinger Health System. Welcome Dr. Kalra. Thank you, Fred. Thank you for having me. It's a pleasure to be here and discuss this timely and important topic. Fantastic.
Why don't we just dive right into it and give a little bit of background on IgA nephropathy. IgA nephropathy is still classified under the Rare Disease Consortium. It's one of the most common causes of glomerular disease worldwide. It's a B-cell mediated autoimmune disorder whereby you have poorly glycosylated, galactose deficient IgA1. They form immune complexes.
These immune complexes deposit in the glomeruli, which are the kidney filtering units and trigger inflammatory cascade and cause progressive kidney damage. It is a B-cell mediated autoimmune disease. It is still under the rare disease consortium because we don't biopsy enough and, uh, the prevalence of the disease varies in, um, US versus Europe versus the. Uh, Asian belt just because of the aggressiveness to do biopsy.
So one of the biggest challenges that we are facing, uh, in clinical practice today, today is the delay in diagnosis. So, Dr. Kalra, could you discuss how we're diagnosing IgA nephropathy in 2025? And what's the prognostication? Uh, that's a great question, Fred. Unfortunately, we do not have any, uh, non-invasive biomarkers. The only biomarkers that we have right now is, uh, following proteinuria.
Which is the protein leak in the urine, the protein creatinine ratio, the, uh, the rate of EGFR decline. We can only diagnose, uh, IG nephropathy with a kidney biopsy. Since our thresholds, based on the RaDaR data have gone low with proteinuria, we need to decrease our thresholds for biopsy. Also, this calls for a change in paradigm, a change in shift in, uh, thinking about this disease. We need to, uh, aggressively biopsy these patients to diag, uh, to make a diagnosis at an early stage.
So we can target these patients with the right, uh, immunological management or disease modification to help modify the course of the disease in the long run. Uh, once we have the biopsy results, uh, the biopsy results tell us whether a patient has more of a fibrosis or, or an inflammatory or a mixture of inflammation and fibrosis. This together with patient's age, blood pressure. Uh, whether patient is on RAS blockers, uh, immunosuppression, uh, helps us.
We can put all of this in an IgA, uh, prognostication tool, uh, which helps us prognosticate a patient and helps us tell the patient whether the, what is the risk of, uh, patient's decline. So, can you talk a little about the impact of disease progression and how it goes? Absolutely. So this disease is the disease of the young, mostly seen in young twenties to 30 years old. Uh, it presents like microscopic hematuria.
It can present to something called a syn pH hematuria, which is after an upper respiratory infection, you suddenly have blooded the urine. Most common presentation is microscopic hematuria or just blood on a dipstick, which is going unnoticed for years. By the time they develop more overt symptoms like protein leak in the urine or declining kidney function, often irreversible damage has already occurred.
Unfortunately, we are diagnosing this disease much later in the course already, where 50 over 50% of the kidney loss has already occurred. Though impact of this disease progression is profound. We know that around 50% of the patients will eventually progress to end stage kidney disease requiring dialysis or a kidney transplant in their lifetime. This not only dramatically reduces a patient's quality of life, but also shortens their life expectancy by, uh, a decade almost.
Wow. So I believe the last guidelines came out in 2021. Where are we with the latest 2025 guidelines? Oh, this actually brings us to the exciting part. Now we have the 2025 KDIGO guideline update was much needed at this time. Was just, uh, released last month in September. And, uh, this, this definitely isn't a minor refresh. We are challenging the previous dogma of conservative management. It represents a fundamental shift in how we can manage IgA nephropathy.
This is driven by a plethora of clinical trial evidence over decades. The previous guidelines had recommended to enroll patients in trial, and now we are getting all the fruits. Now we are getting all the trial results. These guidelines are more a refined framework for risk stratification. They help us better predict who, which patients are at higher risk of progression and which one need aggressive therapy.
So it's, it's more, it's taking away from the regular watch and wait therapy to, uh, targeted disease modification or foundational therapy. It's, it's not tailoring to one side fits all rule, fits all rule. It's more about tailoring the right therapy for the right patient. So when you think about this, obviously there's an urgency to get this going early, correct? Absolutely.
These, these guidelines are stating that patients with IgAN, uh, who are at risk of progressive kidney loss, if their protein leak is greater than 0.5 gram per deciliter while on or off treatment. We need to start additional treatment for these patients. And it's delineating the fact that in most of the patients, we need to simultaneously prevent IgA mediated immune complex formation, which is one side of the graph.
And, uh, in parallel reduce the consequences of existing IgA induced nephron loss. So it, it wants us to manage two diseases at the same time, or which is called simultaneously the latest data by RaDaR, which basically paved the way. Uh, it greased the wheels for all the newer therapies in IgA nephropathy. It basically stated that the earlier proteinuria guidelines were anything less than a gram should be.
Okay. And we were watching and waiting for decades because we did not have newer therapies, but RaDaR data, challenging this old dogma. Whereby, uh, even with patients with lower degree of proteinuria, even with less than half a gram or less than even one gram are progressing towards kidney disease in their lifetime. So, uh, this was pretty shocking. And, uh, the other parameter that we are using is to, uh, reduce the rate of GFR decline or to flatten the curve.
We are trying to slow the rate of GFR decline to less than. One mL per minute per year. It's been seen that even patients who are at one mL per minute, less than 50 years, 40% of those patients will see dialysis in their lifetime. So, um, it's, it's a really, really powerful study and we need to focus our decisions. We need to change the course, uh, in way in, in the way we are thinking.
We really need to change the approach from a more, uh, reactive strategy to a more proactive strategy by simultaneously managing the immune mediated galactose deficient IgA1 production halting and nephron loss through the CKD mechanisms. So it really is about combination therapy to try to slow this progression. It's absolutely a lot about combination therapy. It's about tailoring the more personalized, more combination approach.
Uh, targeting multiple pathways because we have better mechanistic insights into this disease at this point. So we, we know, uh, that there are, uh, multiple hits that are, uh, leading to this disease. So it's important to target different hits at the same time and different hits, targeting different hits requires combination therapies.
When you're thinking about these combination therapies and slowing the progression, how does that outlook look now as you start to look forward on the patients over the term of their life? Oh, these, uh, combination therapies or in general, uh, disease modifying, I put them in two buckets: disease modification and foundational therapies. Both are actually helping in proteinuria reduction in their o- own mechanistic ways.
But we need to understand the proteinuria reduction with disease modification is different from proteinuria reduction with hemodynamic effects of foundational therapies. So we need to, we, we, we are still kind of awaiting more data. We still have only two years or three years worth of data. We are still wanting more data. We don't have more data on combination therapies at this point.
But the, uh, guidelines and what they're suggesting is that there's a strong clinical evidence that these therapies are actually, uh, slowing down the progression of this disease by acting on multiple hits and eventually, uh, preventing, uh, uh, kidney failure in their, in the lifetime of a patient because we are extrapolating this data to 10, 20, 30 years. Excellent. So how should payers and others look at this?
The payers should, uh, look at this, is that, uh, we are clearly moving from a linear one size fits all approach treatment. It is no longer supportive care followed by steroids or supportive care and steroids. This, the guidelines now incorporate a broader range of therapeutic options. We have, uh, disease modifying therapy like, uh, Nefecon or TARPEYO. Uh, we have endothelin receptor antagonists like sparsentan. We have the SGLT2 inhibitors, and we have the underlying RAS blockers.
So we need to, uh, we are moving away from traditional corticosteroids like prednisone and methylprednisolone. Uh, we need to be more cautious and more selective, uh, in our approach. While still I feel that they are a tool, steroids are a tool in the clinical armamentarium. Uh, they are no longer a default second line therapy or first line therapy for patients with persistent proteinuria.
Uh, we need to kind of think about prioritizing steroid sparing therapies, which are disease modifying, uh, because the side effects of steroids based on the prior trials, like testing to like, uh, uh, stop igan, uh, uh, outweigh, uh, the benefits that they have, uh, in clinical care. Uh, side effects being infections, diabetes, weight gain, bone density losses, uh, increasing healthcare, uh, leading to increase healthcare utilization costs. Well, fantastic. Thank you Dr. Kra.
Thank you so much Fred, and thank you for listening to this episode of Unscripted the AMCP podcast to claim credit for today's podcast, you can go to AMCP learn slash code and enter the code, P as in Paul, X as in x-ray, L as in lion, R as in radio. A as in alpha, M as in Mike, that's P-X-L-R-A-M. From there, you'll need to go back and complete the evaluation to claim your CE. Full instructions are available in the show notes.