1 00:00:02,080 --> 00:00:05,000 Welcome to KD GO Conversations in Nephrology. 2 00:00:05,320 --> 00:00:09,760 This episode titled Treatment Revolution in IGA Nephropathy is 3 00:00:09,760 --> 00:00:13,440 provided by KD Go and supported by Trevir. 4 00:00:13,880 --> 00:00:16,160 Here's your host, Doctor Donna Rizik. 5 00:00:17,520 --> 00:00:21,280 Hello and welcome to KD Go Conversations in Nephrology. 6 00:00:21,760 --> 00:00:25,480 I am Doctor Dana Raziq, I am a professor of medicine in the 7 00:00:25,480 --> 00:00:28,040 Division of Nephrology at the University of Alabama at 8 00:00:28,040 --> 00:00:31,400 Birmingham, where I also serve as the Associate Dean for 9 00:00:31,400 --> 00:00:33,800 Clinical Trials Research for the School of Medicine. 10 00:00:34,520 --> 00:00:37,960 Joining me to discuss the latest updates in IJN treatment is 11 00:00:37,960 --> 00:00:41,440 Doctor Shika Wadhwani. Dr. Wadhwani is an associate 12 00:00:41,440 --> 00:00:44,200 professor of medicine at the University of Texas Medical 13 00:00:44,200 --> 00:00:47,560 Branch, and her clinical and research interests center around 14 00:00:47,560 --> 00:00:50,720 glomerular diseases. Dr. Wadhwani, welcome to the 15 00:00:50,720 --> 00:00:53,720 podcast. Thank you, so happy to be here. 16 00:00:54,160 --> 00:00:57,040 It's a pleasure having you. So today we're going to discuss 17 00:00:57,120 --> 00:01:00,240 the treatment revolution that we're witnessing in IGA 18 00:01:00,240 --> 00:01:04,280 nephropathy and understanding how the IGA nephropathy 19 00:01:04,280 --> 00:01:08,040 pathophysiology contributed to this revolution. 20 00:01:08,240 --> 00:01:12,520 So let me start by asking you, how has the IGA and treatment 21 00:01:12,520 --> 00:01:17,840 paradigm changed since the KD GO 2021 guidelines were published? 22 00:01:18,480 --> 00:01:20,640 Yeah. So it's kind of incredible. 23 00:01:20,640 --> 00:01:23,920 You know, so much has changed in just four years. 24 00:01:23,920 --> 00:01:28,280 And I think prior to this, not much movement had happened in 25 00:01:28,280 --> 00:01:30,520 this field. And now we're at a place where 26 00:01:30,760 --> 00:01:33,960 there's really been like a seismic shift in the treatment 27 00:01:33,960 --> 00:01:37,200 paradigm really based on our improved understanding of the 28 00:01:37,200 --> 00:01:41,480 disease, the risks associated with the disease, and as we're 29 00:01:41,480 --> 00:01:44,520 all excited about new available treatment options. 30 00:01:44,880 --> 00:01:48,800 So, you know, for decades the focus has really been on the 31 00:01:48,800 --> 00:01:52,480 effects of the disease, which we really collectively called 32 00:01:52,480 --> 00:01:55,560 supportive care. And we would only resort to 33 00:01:55,560 --> 00:01:59,200 immunosuppressive therapies such as corticosteroids in those 34 00:01:59,200 --> 00:02:02,560 patients who did not have a proteinuric response to those 35 00:02:02,560 --> 00:02:06,880 supportive measures and remained at what we called high risk. 36 00:02:07,160 --> 00:02:09,680 In the past, we thought that threshold was greater than a 37 00:02:09,680 --> 00:02:14,160 gram per day of proteinuria, But as you know, the 2021 KD GO 38 00:02:14,160 --> 00:02:16,960 guidelines were an update to the 2012 guidelines. 39 00:02:17,600 --> 00:02:22,280 And so much has changed in this field since 2021 that there has 40 00:02:22,280 --> 00:02:27,560 been a need for a major update, given the trial successes, which 41 00:02:27,760 --> 00:02:32,280 really led to the availability of therapies that now target not 42 00:02:32,280 --> 00:02:36,560 only the consequences of nephron laws, but also the drivers of 43 00:02:36,560 --> 00:02:38,840 the disease. Yeah, absolutely. 44 00:02:38,840 --> 00:02:41,640 Then it sounds like these updates may start coming more 45 00:02:41,640 --> 00:02:47,520 frequently, which is wonderful. So how did understanding the 46 00:02:47,600 --> 00:02:50,720 pathophysiology of IGA nephropathy contribute to this 47 00:02:51,000 --> 00:02:54,600 therapeutic revolution? You know, I think that's a 48 00:02:54,600 --> 00:02:58,840 really important piece of this. And really I think better 49 00:02:58,840 --> 00:03:03,560 understanding the disease pathogenesis reframed how we 50 00:03:03,560 --> 00:03:09,520 think about our therapies and moved us from kind of a generic 51 00:03:09,640 --> 00:03:14,600 way of treating everyone the same to really being able to 52 00:03:14,760 --> 00:03:20,800 target specific hits in the four hit hypothesis of IGA 53 00:03:20,800 --> 00:03:24,040 nephropathy, which we're all becoming much more familiar 54 00:03:24,040 --> 00:03:26,040 with. So when we think about a 55 00:03:26,040 --> 00:03:29,400 genetically susceptible individual, it's really felt 56 00:03:29,400 --> 00:03:32,080 that IGA nephropathy is initiated by increased 57 00:03:32,080 --> 00:03:37,000 production of pathogenic Galactus deficient IGA one in 58 00:03:37,000 --> 00:03:40,640 response to some sort of environmental or infectious 59 00:03:40,640 --> 00:03:44,040 trigger. And we collectively named that 60 00:03:44,040 --> 00:03:49,960 hit one and then that antigenic GD IGA one is then recognized by 61 00:03:50,040 --> 00:03:55,440 anti GD IGA one auto antibodies and that piece of it is called 62 00:03:55,440 --> 00:03:59,040 HIT 2. And then the GD IG1 and the auto 63 00:03:59,040 --> 00:04:02,760 antibodies combined to form immune complexes, which we call 64 00:04:02,760 --> 00:04:06,080 HIT 3. And those immune complexes go 65 00:04:06,080 --> 00:04:10,160 and deposit specifically in the mesangium of the glomerulus, 66 00:04:10,400 --> 00:04:13,920 which is that fourth hit. And that's when we get the 67 00:04:13,920 --> 00:04:17,000 glomerular inflammation complement activation and 68 00:04:17,000 --> 00:04:21,399 subsequent damage to our glomerular capillaries, which 69 00:04:21,399 --> 00:04:24,680 leads to the hematuria and proteinuria that we can detect 70 00:04:24,680 --> 00:04:29,480 in clinic and you know sets off our protocol for evaluating that 71 00:04:29,480 --> 00:04:31,640 patient, getting a kidney biopsy, et cetera. 72 00:04:32,080 --> 00:04:36,960 So I think now that we are able to think about this disease from 73 00:04:36,960 --> 00:04:41,920 this sort of four hit hypothesis, we are able to then 74 00:04:41,920 --> 00:04:46,480 say, you know what, we we don't just need to address one part of 75 00:04:46,480 --> 00:04:50,440 this hypothesis. We can really look at targeting 76 00:04:50,440 --> 00:04:53,920 specific hits. We can look to maybe combining 77 00:04:53,920 --> 00:04:58,240 therapies and trying to target multiple hits so that we can 78 00:04:58,240 --> 00:05:01,320 hopefully have greater success. And I think that's what we're 79 00:05:01,320 --> 00:05:03,160 seeing with the recent clinical trials. 80 00:05:03,720 --> 00:05:06,600 That sounds great. So if you're just tuning in, 81 00:05:06,600 --> 00:05:10,040 you're listening to the KD GO podcast on treatment revolution 82 00:05:10,040 --> 00:05:13,320 in IGA nephropathy. I am Doctor Danner Zuk, and I'm 83 00:05:13,320 --> 00:05:15,480 speaking with Doctor Shika Advani. 84 00:05:16,160 --> 00:05:19,000 So Shika, with the larger armamentarium of available 85 00:05:19,000 --> 00:05:22,880 therapies that you just alluded to, what are some of the factors 86 00:05:22,960 --> 00:05:26,160 to consider when selecting specific agents? 87 00:05:26,800 --> 00:05:29,840 Yeah, this is a great question and it's one that many of us in 88 00:05:29,840 --> 00:05:32,200 this space are really fielding regularly. 89 00:05:32,400 --> 00:05:35,640 I think that just like with any other condition, we have to 90 00:05:35,640 --> 00:05:39,800 weigh risks versus benefits and actively engage our patients in 91 00:05:39,800 --> 00:05:42,280 these decisions. So I think that's the number one 92 00:05:42,280 --> 00:05:45,040 thing. So there's no one-size-fits-all 93 00:05:45,040 --> 00:05:49,160 therapy plan, especially when it comes to treating a disease with 94 00:05:49,160 --> 00:05:52,640 not only heterogeneity in terms of the presentation of the 95 00:05:52,640 --> 00:05:56,720 disease, but also in terms of disease course and prognosis. 96 00:05:57,280 --> 00:06:00,880 So we now have the luxury of having observational registry 97 00:06:00,880 --> 00:06:04,840 data from multiple large international cohorts, which all 98 00:06:04,840 --> 00:06:08,240 point to the fact that again, patients have a very high 99 00:06:08,240 --> 00:06:12,000 lifetime risk of kidney failure even at proteinuria levels that 100 00:06:12,000 --> 00:06:15,240 were traditionally thought to be safe or low enough. 101 00:06:15,440 --> 00:06:20,240 And we know from these studies as well as our recent randomized 102 00:06:20,240 --> 00:06:23,600 control clinical trials that patients who were treated with 103 00:06:23,640 --> 00:06:27,720 Ras inhibition alone actually have significant GFR decline 104 00:06:27,720 --> 00:06:30,720 even just in nine months, which is at the time of interim 105 00:06:30,720 --> 00:06:33,680 analysis for phase three trials currently. 106 00:06:34,080 --> 00:06:39,360 So we've learned that in order to truly avoid kidney failure in 107 00:06:39,360 --> 00:06:43,480 the lifetime of our patients, our patients need to be able to 108 00:06:43,480 --> 00:06:47,600 reduce the rate of kidney function loss to around 1ML per 109 00:06:47,600 --> 00:06:52,120 minute per year GFR, which is essentially that of the normal 110 00:06:52,120 --> 00:06:57,000 population after the age of 40. So to me, anyone who presents 111 00:06:57,000 --> 00:07:03,800 with proteinuria over 0.5g per gram needs a kidney biopsy to 112 00:07:03,800 --> 00:07:07,360 first of all definitively diagnose hygiene nephropathy and 113 00:07:07,360 --> 00:07:11,360 then initiate treatment. So I think the paradigm is 114 00:07:11,360 --> 00:07:15,520 really shifting to thinking about simultaneously addressing 115 00:07:15,520 --> 00:07:19,240 consequences of nephron loss and drivers of disease 116 00:07:19,240 --> 00:07:22,720 simultaneously. And so that means that we're 117 00:07:22,880 --> 00:07:25,760 sort of automatically considering a multi targeted 118 00:07:25,760 --> 00:07:29,360 therapy regimen. And just like with other 119 00:07:29,360 --> 00:07:32,040 autoimmune diseases we treat, I think we're really shifting our 120 00:07:32,040 --> 00:07:34,600 concept of what is standard of care. 121 00:07:34,960 --> 00:07:39,000 So when I think about this and I think there's a lot more that we 122 00:07:39,000 --> 00:07:42,600 need to learn about the new therapies and real world 123 00:07:42,600 --> 00:07:45,840 evidence is of course going to be extremely helpful in addition 124 00:07:45,840 --> 00:07:48,960 to the trial data. But patients who have a very 125 00:07:48,960 --> 00:07:53,280 high degree of proteinuria have declining GFR, or some people 126 00:07:53,280 --> 00:07:56,760 may think about, you know, an inflammatory phenotype on a 127 00:07:56,760 --> 00:08:00,120 kidney biopsy. Those may be patients that are 128 00:08:00,120 --> 00:08:03,200 more likely to be prescribed immunomodulatory therapies. 129 00:08:03,760 --> 00:08:08,120 But in many ways, this is really a reactive rather than a 130 00:08:08,120 --> 00:08:11,840 proactive approach. And some people would argue that 131 00:08:12,360 --> 00:08:14,840 all IGA nephropathy patients should be offered 132 00:08:15,080 --> 00:08:19,080 immunomodulatory therapy to really prevent disease 133 00:08:19,080 --> 00:08:23,760 progression and not just sort of cover up the problem that we've 134 00:08:23,760 --> 00:08:27,280 already discovered. So the choice between therapies 135 00:08:27,280 --> 00:08:30,800 that target the earlier hits and Igan pathogenesis is 136 00:08:30,800 --> 00:08:33,280 challenging. And part of that is because the 137 00:08:33,280 --> 00:08:37,240 patients enrolled in the recent trials are pretty similar and 138 00:08:37,240 --> 00:08:41,000 also because the published analysis we have thus far has 139 00:08:41,000 --> 00:08:44,039 not shown that certain and subgroups seem to respond, while 140 00:08:44,039 --> 00:08:46,560 others do not. It's also important to note that 141 00:08:46,560 --> 00:08:50,040 patients in the recent trials were not enrolled at the time of 142 00:08:50,040 --> 00:08:52,800 biopsy. So it's really difficult to make 143 00:08:52,800 --> 00:08:56,800 any suggestions based on kidney biopsy findings in particular. 144 00:08:57,160 --> 00:09:01,960 And that's something that comes down to conversations between 145 00:09:01,960 --> 00:09:03,360 the nephrologist and the patient. 146 00:09:03,760 --> 00:09:07,120 But I really think that ultimately the decision of what 147 00:09:07,120 --> 00:09:11,080 therapies to start with will come down to what's accessible 148 00:09:11,200 --> 00:09:14,160 in that particular country, province, and whether the 149 00:09:14,160 --> 00:09:17,200 patient has any particular preferences regarding the mode 150 00:09:17,200 --> 00:09:20,160 of delivery, potential side effects, etc. 151 00:09:20,520 --> 00:09:21,920 Right. So it goes back to the 152 00:09:22,080 --> 00:09:26,440 conversation, the one-on-one that you have with your patient 153 00:09:26,440 --> 00:09:29,880 when you see him or her in clinic, no question about that. 154 00:09:29,960 --> 00:09:33,400 So what are the roles of the traditional therapies, the non 155 00:09:33,400 --> 00:09:38,800 pharmaceutical lifestyle, non systemic steroids therapies in 156 00:09:38,800 --> 00:09:42,680 the context of these new agents? So we've relied so far on 157 00:09:42,840 --> 00:09:45,760 lifestyle modification, last inhibition as you mentioned and 158 00:09:45,760 --> 00:09:48,240 then systemic steroids when needed. 159 00:09:48,560 --> 00:09:50,520 What? What are the role of these 160 00:09:50,520 --> 00:09:52,680 traditional therapies in this new world? 161 00:09:53,280 --> 00:09:56,120 Yeah. So, you know, I think when we 162 00:09:56,480 --> 00:09:59,760 have better and we know better, we should do better. 163 00:10:00,080 --> 00:10:04,240 So we of course always need to educate our patients on blood 164 00:10:04,240 --> 00:10:07,680 pressure control, you know, focusing on a healthy low sodium 165 00:10:07,680 --> 00:10:11,600 diet, weight loss as applicable. But I don't think we should be 166 00:10:11,600 --> 00:10:16,120 complacent and I think we need to instead be willing to gain 167 00:10:16,120 --> 00:10:20,720 experience with new therapies and someone who really focuses 168 00:10:20,720 --> 00:10:25,240 their career on clinical trials. In my new role at my job, I also 169 00:10:25,440 --> 00:10:28,120 want to put a plug in for continuing to enroll patients in 170 00:10:28,120 --> 00:10:31,240 clinical trials so we can hopefully have even more 171 00:10:31,240 --> 00:10:33,680 treatments available for our patients in the future. 172 00:10:34,120 --> 00:10:37,720 So I'm not saying there's no role for traditional therapies, 173 00:10:37,960 --> 00:10:40,840 but I think that we owe it to the many, many participants in 174 00:10:40,840 --> 00:10:44,040 clinical trials who got us to where we are today to really 175 00:10:44,040 --> 00:10:47,760 utilize the new drugs we have so desperately been hoping we could 176 00:10:47,960 --> 00:10:49,600 offer our patients. Finally. 177 00:10:50,040 --> 00:10:54,960 So as you know, there was not a head to head trial comparing TRF 178 00:10:54,960 --> 00:10:57,520 budesonide to systemic corticosteroids. 179 00:10:57,640 --> 00:11:01,240 But depending on, you know, where you are and whether the 180 00:11:01,240 --> 00:11:04,920 former is approved and accessible and affordable in 181 00:11:04,920 --> 00:11:07,600 that particular country or province, I do think that 182 00:11:07,600 --> 00:11:12,320 nephrologists may prefer the TRF budesonide due to perceived 183 00:11:12,680 --> 00:11:17,840 superior side effect profile and perhaps also beneficial local 184 00:11:17,840 --> 00:11:21,400 inflammatory effects. So I think there's definitely a 185 00:11:21,400 --> 00:11:24,800 movement in that direction, especially because we know all 186 00:11:24,800 --> 00:11:27,080 the terrible side effects that come with systemic 187 00:11:27,080 --> 00:11:30,320 corticosteroids. On the other hand, we also now 188 00:11:30,320 --> 00:11:33,240 have a, you know, a dual endothelial angiotensin receptor 189 00:11:33,240 --> 00:11:36,320 blocker which is sparsentin and that was studied against an 190 00:11:36,440 --> 00:11:41,560 active comparator urbisartan. And there was a clear benefit on 191 00:11:41,560 --> 00:11:46,120 proteinuran EGFR with this sparsentin, which probably makes 192 00:11:46,120 --> 00:11:50,240 it, you know, a better choice in patients who have access to and 193 00:11:50,240 --> 00:11:55,400 can tolerate this new drug given it was compared directly to 194 00:11:55,440 --> 00:11:59,440 maximum dose Ras inhibition. And then we of course we have 195 00:11:59,440 --> 00:12:03,160 SGLT 2 inhibitors. We have two large scale trials 196 00:12:03,320 --> 00:12:05,880 that included a significant number of IGA nephropathy 197 00:12:05,880 --> 00:12:10,720 patients and they saw similar benefit over placebo in those 198 00:12:10,720 --> 00:12:13,440 patients with IGA nephropathy just like they did in the rest 199 00:12:13,440 --> 00:12:16,080 of the cohort. So in patients who have IGA 200 00:12:16,080 --> 00:12:20,600 nephropathy and decreased GFR at presentation, I do think that 201 00:12:20,600 --> 00:12:23,600 most of us would agree that there is definitely a role for 202 00:12:23,600 --> 00:12:28,000 SGLT 2 and inhibitor therapy. And then the story doesn't stop 203 00:12:28,000 --> 00:12:30,280 there. So we now have complement 204 00:12:30,280 --> 00:12:35,760 inhibitors, anti April or April bath therapies and plasma cell 205 00:12:35,760 --> 00:12:39,320 therapies that are all in phase three clinical trials. 206 00:12:39,640 --> 00:12:43,120 So we will definitely be keeping our KD GO friends very busy 207 00:12:43,120 --> 00:12:46,520 updating the guidelines in the upcoming years because I think 208 00:12:46,520 --> 00:12:49,280 there's a lot more to come. Yeah, absolutely. 209 00:12:49,280 --> 00:12:52,520 And these are, you know, living, breathing documents that need to 210 00:12:52,520 --> 00:12:55,400 be updated as new data is generated. 211 00:12:56,000 --> 00:12:59,440 So before we close Shika, are there any final messages you'd 212 00:12:59,440 --> 00:13:00,920 like to leave with our listeners? 213 00:13:01,400 --> 00:13:04,440 Yeah, thanks. So I think, you know, as many of 214 00:13:04,440 --> 00:13:08,120 us say these days, we're truly in the midst of a revolution in 215 00:13:08,240 --> 00:13:10,200 Igan. And this is really due to 216 00:13:10,200 --> 00:13:14,360 decades of global research by groups like your own and as well 217 00:13:14,360 --> 00:13:18,640 the landmark success in the Kidney Health Initiative, which 218 00:13:18,840 --> 00:13:21,520 established endpoints for clinical trials in IGA and 219 00:13:21,520 --> 00:13:24,920 nephropathy. So there are, in my opinion, far 220 00:13:24,920 --> 00:13:27,360 too many people with this disease ending up needing 221 00:13:27,360 --> 00:13:31,040 dialysis or a kidney transplant. And we have to remember that 222 00:13:31,040 --> 00:13:34,000 these patients are typically diagnosed in their 20s and 40s, 223 00:13:34,000 --> 00:13:37,600 which is very, very young. So in my mind, you know, my 224 00:13:37,600 --> 00:13:41,400 message is let's seize the moment, let's shorten the time 225 00:13:41,400 --> 00:13:43,680 to diagnosis. And then once we have a 226 00:13:43,680 --> 00:13:48,160 diagnosis, we really need to change our mindset to start with 227 00:13:48,440 --> 00:13:51,920 a multi targeted approach to this disease and eliminate any 228 00:13:51,920 --> 00:13:54,040 sort of therapeutic inertia we may have. 229 00:13:54,560 --> 00:13:58,360 And then above all, I think we need to continue to ensure we're 230 00:13:58,360 --> 00:14:01,600 engaging our patients in these discussions by educating them 231 00:14:01,600 --> 00:14:03,640 and really understanding their goals of care. 232 00:14:03,960 --> 00:14:07,440 Thank you so much, Doctor Shika Wadwani, thank you for joining 233 00:14:07,440 --> 00:14:09,080 me. It was great having you on the 234 00:14:09,080 --> 00:14:11,320 podcast. Thank you so much, Donna. 235 00:14:11,320 --> 00:14:15,800 It was lovely to be here. I am Doctor Donna Rizuk and to 236 00:14:15,800 --> 00:14:19,120 access this and other episodes in our series, please visit 237 00:14:19,120 --> 00:14:23,560 kdgo.org/podcast. Thank you so much for listening 238 00:14:23,640 --> 00:14:25,280 and until we meet next time.