Unscripted - Understanding IgA Nephropathy and the New 2025 KDIGO Guidelines

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Welcome to Unscripted - The AMCP podcast, a look inside managed care pharmacy. Listen in as experts explore the challenges, innovations and opportunities shaping health care for millions of patients. Welcome to this episode of Unscripted - the AMCP podcast. I'm your host, Fred Goldstein. In this episode, we will present to continuing pharmacy Education Program on the recent 2025 CDD guidelines updates for IGA nephropathy. 

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All medications mentioned in this episode are for educational purposes only. This activity is supported by an independent medical education grant from Collegiate Pass 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. 

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Participants should be able to discuss the latest advancements in IGA nephropathy management as updated in the 2025 KDD guidelines. It is now my pleasure to introduce our faculty for today's program. Doctor Kartik Caro, nephrologist at Geisinger Health System. Welcome, Doctor Kalra. Hey. Thank you Fred. Thank you for having me. It's a pleasure to be here and discuss this timely and important topic. 

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Fantastic. Why don't we just dive right into it and give a little bit of background on IGA nephropathy? Why? Jennifer. Property 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 IGA one. They form immune complexes. 

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These immune complexes deposit in the glomerular, 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 the prevalence of the disease varies in US versus Europe versus the, Asian belt, just because of the aggressiveness to do biopsy. 

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So one of the biggest challenges that we are facing, in clinical practice today, today is the delay in diagnosis. So, Doctor Coller, could you discuss how we're diagnosing again for apathy in 2025? And what's the prognostication. Oh, that's a great question, Fred. Unfortunately, we do not have any, noninvasive biomarkers. The only biomarkers that we have right now is, following proteinuria, which is the protein leak in the urine. 

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The proteins reactant ratio, the, the rate of EGFR decline. We can only diagnose, IDR 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 and shift in thinking about this disease. We need to, aggressively biopsy these patients to, to make a diagnosis at an early stage so we can, get these patients with the right, immunological management or disease modification to help modify the course of the disease in the long run. 

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Once we have the biopsy results, the biopsy results tell us whether a patient has more of a fibrosis or an inflammatory or a mixture of inflammation and fibrosis. This together with patients age, blood pressure, where the patient is under blockers, immunosuppression, helps us. We can put all of this in an IGA prognostication tool, which helps us prognosticate a patient and helps us tell the patient whether what is the risk of, patients decline. 

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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, 20 to 30 years old. It presents like microscopic hematuria. It can present to something called a cin pharyngitis, hematuria, which is after an upper respiratory infection. You suddenly have blood in the urine. 

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Most common presentation is microscopic material, 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. 

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The 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 the patient's quality of life, but also shortens the life expectancy by, a decade, almost. Wow. So I believe the last guidelines came out in 2021. 

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Where are we with the latest 2025 guidelines? Well, this actually brings us to the exciting part. Now we have the 2025 CDA guideline update. It was much needed at this time. This just, released last month in September. And, 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 IgG nephropathy. 

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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. 

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So it's more it's taking away from the regular watch and weight therapy to, 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. 

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Absolutely. These guidelines are stating that patients with Igen, who are at risk of progressive kidney loss if their protein leak is greater than 0.5g 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, in parallel, reduce the consequences of existing IGA induced nephron loss. 

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So 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, it grease the wheels for all the newer therapies in IgG 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. 

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But radar data challenged this old dogma whereby, even with patients with lower degree of protein, urea, even with less than half a gram or less than even one gram, are progressing towards kidney disease in their lifetime. So, this was pretty shocking. And, the other parameter that we are using is to reduce the rate of GFR decline or to flatten the curve. 

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We are trying to slow the rate of a 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, it's it's a really, really powerful study, and we need to focus our decisions. 

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We need to change the course, in, in in the way we are thinking. We really need to change the approach from a more, reactive strategy to a more proactive strategy by simultaneously managing the immune mediated galactose deficit, igg1 production halting and nephron loss through the CKD mechanisms. So it really is about combination therapy to try to slow this progression. 

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It's absolutely a lot about combination therapy. It's about tailoring the more personalized more combination approach targeting multiple pathways because we have better mechanistic insights into this disease at this point. So we know, that there are, multiple hits that are, 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. 

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When you're thinking about these combination therapies in slowing the progression, how does that outlook look now as you start to look forward on the patients over the term of their life or these, combination therapies or in general, disease modifying, I put them in two buckets disease modification and foundational therapies. Both are actually helping in proteinuria reduction in their own mechanistic ways. 

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But we need to understand the proteinuria reduction. But disease modification is different from proteinuria reduction with the hemodynamic effects of foundational therapies. So we need to 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. 

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But the, guidelines and what they are suggesting is that there's a strong clinical evidence that these therapies are actually, slowing down the progression of this disease by acting on multiple heads and eventually, preventing, kidney failure in the, in the lifetime of a patient, because we are extrapolating this data to ten, 20, 30 years. Excellent. 

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So how should payers and others look at this? The payers should, look at this. Is that, we are clearly moving from a linear, one size fits all approach treatment. It is no longer supportive care followed by steroids of supportive care and steroids. This the guidelines now incorporate a broader range of therapeutic options. We have, disease modifying therapy like infection or RPO. 

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We have endothelium receptor antagonist likes percent. We have the CRT two inhibitors and we have the underlying Raas blockers. So we need to, we are moving away from traditional corticosteroids like prednisone and methylprednisolone. We need to be more cautious and more selective. In our approach, while still I feel that there are tools. Steroids are a tool in the clinical armamentarium. 

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They are no longer a default second line therapy or first line therapy for patients with persistent proteinuria. We need to kind of think about prioritizing steroid sparing therapies, which are disease modifying, because the side effects of steroids based on the prior trials, like testing do like, stop. I again, outweigh the benefits that they have, in clinical care, side effects being infections, diabetes, weight gain, bone density losses, increasing health care, leading to increased healthcare utilization costs. 

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Well, fantastic. Thank you, Doctor Kalra. Thank you so much, Fred. And thank you for listening. This episode of unscripted, the AMCP podcast. To claim credit for today's podcast, you can go to AMC Learn forward slash code and enter the code P is in Paul, X is an x ray. L is in line, R is in radio. It is an alpha m as in mic that's p l r am. 

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