1 00:00:02,240 --> 00:00:05,040 Welcome to KD GO Conversations in Nephrology. 2 00:00:05,240 --> 00:00:09,920 This episode titled Burden and Pathophysiology of a Pol One 3 00:00:09,920 --> 00:00:15,560 Kidney Disease is provided by KD Go and supported by Vertex. 4 00:00:15,840 --> 00:00:18,000 Here's your host, Doctor Kirk Campbell. 5 00:00:19,200 --> 00:00:22,800 Hello and welcome to KD Go Conversations in Nephrology. 6 00:00:23,360 --> 00:00:26,200 I'm Doctor Kirk Campbell, Chief of the Reno Division at the 7 00:00:26,200 --> 00:00:29,480 University of Pennsylvania. Joining me to discuss the burden 8 00:00:29,480 --> 00:00:32,880 on pathophysiology of April 1 kidney disease is Doctor Bessie 9 00:00:32,880 --> 00:00:35,120 Young. Doctor Young is vice Dean and 10 00:00:35,120 --> 00:00:38,560 medical director for the Office of Healthcare Equity at the 11 00:00:38,560 --> 00:00:42,040 University of Washington, where she also serves as professor of 12 00:00:42,040 --> 00:00:43,960 medicine in the Division of Nephrology. 13 00:00:44,200 --> 00:00:46,960 Her clinical and research interests include genetic 14 00:00:46,960 --> 00:00:51,200 testing and April one health outcomes in home dialysis and 15 00:00:51,200 --> 00:00:53,360 health inequities in kidney disease. 16 00:00:53,920 --> 00:00:55,920 Doctor Young, welcome to the podcast. 17 00:00:56,200 --> 00:00:58,640 Thank you, Doctor Campbell. It's a pleasure to be here. 18 00:00:58,880 --> 00:01:01,320 Thank you so much. So let's begin our discussion 19 00:01:01,640 --> 00:01:04,319 around April one. Since it's a relatively new 20 00:01:04,319 --> 00:01:07,640 genetic finding, can you discuss the history of the discovery of 21 00:01:07,680 --> 00:01:10,080 April 1? Provide some background on how 22 00:01:10,080 --> 00:01:12,600 quickly the findings have been translated into clinical 23 00:01:12,600 --> 00:01:14,480 knowledge? Thank you for that question. 24 00:01:14,480 --> 00:01:18,440 So the April 1 gene story is really one of discovery. 25 00:01:18,840 --> 00:01:22,720 For years, researchers have been searching for a gene associated 26 00:01:22,720 --> 00:01:26,000 with kidney disease and African American individuals or black 27 00:01:26,000 --> 00:01:29,800 individuals or specifically people with recent African 28 00:01:29,800 --> 00:01:32,640 ancestry. And we know that the rates of 29 00:01:32,640 --> 00:01:35,600 end stage kidney disease are significantly higher and those 30 00:01:35,600 --> 00:01:37,880 who are black compared to those who are white. 31 00:01:37,880 --> 00:01:41,160 And black individuals usually develop kidney failure 10 years 32 00:01:41,160 --> 00:01:44,920 earlier than white individuals. So there was a real search for 33 00:01:44,920 --> 00:01:48,320 something that was related to, like a genetic finding that was 34 00:01:48,320 --> 00:01:51,720 related to kidney disease. So there was a potential hit 35 00:01:51,840 --> 00:01:57,680 that was found with MHY 9 in 2008, and people started to look 36 00:01:57,680 --> 00:02:00,400 at that. But then in 2010, Doctor 37 00:02:00,400 --> 00:02:04,320 Genovese and Martin Pollock discovered an association of 38 00:02:04,320 --> 00:02:08,360 tripanalytic April 1 variants with kidney disease and African 39 00:02:08,360 --> 00:02:12,080 American individuals, which was published in 2010 in Science. 40 00:02:12,640 --> 00:02:16,680 And the same year Doctor Sewer and discovered the same April 1 41 00:02:16,680 --> 00:02:19,200 genetic variants were associated with greater rates of kidney 42 00:02:19,200 --> 00:02:22,480 disease than those with recent African ancestry. 43 00:02:22,960 --> 00:02:27,200 So these variants are named G1 and G2, and that has to do with 44 00:02:27,200 --> 00:02:30,120 their amino acid substitutions and deletions. 45 00:02:30,440 --> 00:02:34,280 G1 has two amino acid substitutions and G2 has two 46 00:02:34,280 --> 00:02:38,240 amino acid base pair deletions and these variants are 47 00:02:38,320 --> 00:02:42,480 protective from African sleeping sickness from Trypanosoma. 48 00:02:42,480 --> 00:02:44,400 Bruce I. I would say that this 49 00:02:44,400 --> 00:02:48,280 information has been relatively rapidly translated into clinical 50 00:02:48,280 --> 00:02:51,040 medicine. April 01 genetic testing is 51 00:02:51,080 --> 00:02:54,280 currently available and there are recent clinical trials that 52 00:02:54,280 --> 00:02:56,840 have been initiated with biologics that interfere with 53 00:02:56,840 --> 00:03:00,040 April 01 and definitely long term studies that are still 54 00:03:00,040 --> 00:03:02,520 recruiting for applicants with April 01. 55 00:03:02,720 --> 00:03:05,880 Thank you so much for that very detailed, concise history. 56 00:03:05,880 --> 00:03:09,520 Regarding April 1, can you tell us a little bit more about April 57 00:03:09,520 --> 00:03:12,240 one kidney disease? What exactly is it then? 58 00:03:12,240 --> 00:03:15,880 What's the prevalence, epidemiology, manifestations and 59 00:03:15,880 --> 00:03:17,600 different phenotypes that one could see? 60 00:03:18,080 --> 00:03:21,360 Sure. So we know from epidemiologic 61 00:03:21,360 --> 00:03:25,160 data that there are approximately 30% of African 62 00:03:25,160 --> 00:03:30,520 American individuals who have G1 or G2 or both G1 and G2. 63 00:03:30,600 --> 00:03:34,880 And we also know that about 13% of those with recent African 64 00:03:34,880 --> 00:03:39,720 ancestry in the US have both G1 and G2, which are termed high 65 00:03:39,720 --> 00:03:43,480 risk April 1 variance. So this is roughly about 5 66 00:03:43,480 --> 00:03:47,040 million people in the US who have the high risk April 1 67 00:03:47,040 --> 00:03:50,240 variance. It is thought that these April 1 68 00:03:50,240 --> 00:03:53,960 variants are passed down as autosomal recessive as a genetic 69 00:03:53,960 --> 00:03:56,600 trait. And we also know from recent 70 00:03:56,600 --> 00:04:00,680 data that the prevalence of April 1 high risk variance is 71 00:04:00,680 --> 00:04:02,640 probably greatest in West Africa. 72 00:04:02,640 --> 00:04:05,360 There was a recent paper in the New England Journal of Medicine 73 00:04:05,360 --> 00:04:09,720 that showed that the individuals from West Africa have really 74 00:04:09,720 --> 00:04:14,360 high rates of G1 and G2, and it varies by tribe and country. 75 00:04:14,920 --> 00:04:18,079 We also know that those with high risk variants have the 76 00:04:18,079 --> 00:04:21,120 greatest risk of developing end stage kidney disease are going 77 00:04:21,120 --> 00:04:24,960 on to dialysis, while those who have either one of the variants 78 00:04:24,960 --> 00:04:29,160 T1 or G2 have an increased risk of developing chronic kidney 79 00:04:29,160 --> 00:04:32,960 disease or albuminuria. And we also know that there's 80 00:04:32,960 --> 00:04:36,040 been a lot of progress in regards to April one kidney 81 00:04:36,040 --> 00:04:38,520 disease. So now April one kidney disease 82 00:04:38,520 --> 00:04:42,960 is termed April 1 mediated kidney disease or AMKD. 83 00:04:43,000 --> 00:04:46,400 You'll see that in some of the literature, there's also an ICD 84 00:04:46,440 --> 00:04:51,680 TEN approval and the 2025 ICD 10 update, so that there are now 85 00:04:51,680 --> 00:04:55,880 diagnosis codes for April 1. But as you know, in a conference 86 00:04:55,920 --> 00:04:59,800 in Ghana with patients, researchers and others, the term 87 00:04:59,800 --> 00:05:03,040 April 01 kidney disease was also chosen to represent kidney 88 00:05:03,040 --> 00:05:06,600 disease and those with April 01. So there are a lot of names out 89 00:05:06,600 --> 00:05:09,240 there for April 01 mediated kidney disease. 90 00:05:09,240 --> 00:05:12,640 And I think it just depends on, you know, where you're coming 91 00:05:12,640 --> 00:05:14,640 from in terms of what name you use. 92 00:05:14,640 --> 00:05:18,720 But AMKD is showing up in the literature more and more. 93 00:05:18,720 --> 00:05:23,040 April one kidney disease was initially associated with FSGS 94 00:05:23,040 --> 00:05:25,480 or focal segmental glomerulosclerosis. 95 00:05:25,880 --> 00:05:28,800 It was also shown to be increased in those with HIV 96 00:05:28,800 --> 00:05:31,040 nephropathy and hypertensive kidney disease. 97 00:05:31,040 --> 00:05:35,240 So originally there were case control studies that showed that 98 00:05:35,240 --> 00:05:39,440 there is a 7 to 10 fold greater risk of FSGS, end stage kidney 99 00:05:39,440 --> 00:05:42,160 disease and those with A41 positivity. 100 00:05:42,560 --> 00:05:46,000 It was also shown in those early case studies that HIV 101 00:05:46,000 --> 00:05:51,400 nephropathy had like a odds ratio of 28% to 29% increased 102 00:05:51,400 --> 00:05:55,200 risk of HIV nephropathy and end stage kidney disease. 103 00:05:55,680 --> 00:05:59,560 So with larger population based cohort studies, that risk 104 00:05:59,560 --> 00:06:03,000 decreased to about twofold. But there's still an increased 105 00:06:03,000 --> 00:06:06,600 risk of Apollo 1 kidney disease with end stage kidney disease 106 00:06:06,600 --> 00:06:10,640 and kidney disease progression. And then pathologically, I'd say 107 00:06:10,840 --> 00:06:14,920 the spectrum of kidney disease associated with 01 is probably 108 00:06:14,920 --> 00:06:19,600 bad of the collapsing variant of FSGS and it's known to affect 109 00:06:19,600 --> 00:06:22,640 podocytes. It can cause tubular injury and 110 00:06:22,640 --> 00:06:26,040 interstitial fibrosis and global sclerosis if it's diagnosed 111 00:06:26,080 --> 00:06:28,400 later on. If you're just tuning in, you're 112 00:06:28,400 --> 00:06:30,920 listening to the K Diego podcast on the burden and 113 00:06:30,920 --> 00:06:33,320 pathophysiology of April 1 kidney disease. 114 00:06:33,600 --> 00:06:36,160 I'm Doctor Kirk Campbell and I'm speaking with Doctor Bessie 115 00:06:36,160 --> 00:06:37,960 Young. Doctor Young, thank you for that 116 00:06:37,960 --> 00:06:39,880 description of April 1 kidney disease. 117 00:06:40,560 --> 00:06:43,280 Can you describe what we know about the disease mechanisms 118 00:06:43,280 --> 00:06:45,000 based on the current pathophysiology? 119 00:06:45,000 --> 00:06:47,480 Are there any protected variants, for example we should 120 00:06:47,480 --> 00:06:48,600 be aware of? Yeah. 121 00:06:48,600 --> 00:06:52,400 Thanks, Kurt for that question. So the disease mechanism of the 122 00:06:52,400 --> 00:06:55,920 April 1 genes are complex and I think people are still trying to 123 00:06:55,920 --> 00:06:59,680 figure out the exact mechanism. But what the research data has 124 00:06:59,680 --> 00:07:03,200 shown and points towards is there is injury of the POTUCite. 125 00:07:03,640 --> 00:07:07,840 So April 1 can basically form a pore or an ion channel in the 126 00:07:07,840 --> 00:07:11,320 podocyte which leads to an increase in chloride or other 127 00:07:11,320 --> 00:07:14,800 ion flux and causes osmolysis of the podocyte. 128 00:07:15,040 --> 00:07:17,720 And this is a similar mechanism to that found in the 129 00:07:17,720 --> 00:07:20,960 tripanosomes, which basically leads to their death and those 130 00:07:20,960 --> 00:07:26,320 who have April 1 variance. So this osmolysis leads to put 131 00:07:26,320 --> 00:07:29,720 aside effacement and detachment, which can then result in 132 00:07:29,720 --> 00:07:32,920 increased inflammation and probably leads to what we see 133 00:07:32,920 --> 00:07:36,000 when people actually have biopsies and we see inflammation 134 00:07:36,000 --> 00:07:39,960 or we see FSGS. April One has also been shown to 135 00:07:39,960 --> 00:07:43,280 cause misfolding of the endoplasmic reticulums and it 136 00:07:43,280 --> 00:07:45,400 could compromise mitochondrial function. 137 00:07:45,400 --> 00:07:49,040 So it has a wide variety of functions and I don't think we 138 00:07:49,040 --> 00:07:52,240 know all the mechanisms of disease of April 1. 139 00:07:53,000 --> 00:07:56,520 April 1's also found in lung, it's found, I think in liver, 140 00:07:56,520 --> 00:07:59,760 it's found in vessels. So there may be some additional 141 00:07:59,760 --> 00:08:02,000 function that we're not aware of. 142 00:08:02,400 --> 00:08:05,160 It's also thought that environmental stressors such as 143 00:08:05,160 --> 00:08:09,360 inflammation or high interferon states may really exacerbate 144 00:08:09,360 --> 00:08:11,560 April one disease and lead to progression. 145 00:08:11,840 --> 00:08:14,720 And some of the drivers that have been found include things 146 00:08:14,720 --> 00:08:17,720 like viral infection. So the research really points 147 00:08:17,720 --> 00:08:21,680 towards HIV sort of being a driver of April 1 kidney 148 00:08:21,680 --> 00:08:24,720 disease. We know from the COVID pandemic 149 00:08:24,720 --> 00:08:27,960 that COVID and those who had COVID and developed kidney 150 00:08:27,960 --> 00:08:30,800 disease, they had faster progression and they had acute 151 00:08:30,800 --> 00:08:33,760 kidney injury that was associated with April 1. 152 00:08:34,159 --> 00:08:38,039 There's ischemia reperfusion as a driver and there's an 153 00:08:38,039 --> 00:08:41,520 increased risk of progression in individuals who have sickle cell 154 00:08:41,520 --> 00:08:43,600 disease. We know that there's kidney 155 00:08:43,600 --> 00:08:46,880 allograft rejection that might be a driver associated with 156 00:08:46,880 --> 00:08:49,960 April One disease. And then in lupus, we know that 157 00:08:49,960 --> 00:08:54,520 autoimmune diseases can lead to worse disease with April 1. 158 00:08:54,680 --> 00:08:58,120 And then you asked about a protectant variant in April 1. 159 00:08:58,120 --> 00:09:02,840 So there is a study from Doctor Adriana Hung at Vanderbilt who 160 00:09:02,840 --> 00:09:06,160 used data from the Million Veteran Program, the Vanderbilt 161 00:09:06,160 --> 00:09:10,360 Biobank and the NIH, All of us study to look to see if there 162 00:09:10,360 --> 00:09:15,280 were any protective variants and they found one called PN264K. 163 00:09:15,280 --> 00:09:17,960 And I'll assume that they'll probably change the name of 164 00:09:17,960 --> 00:09:20,600 that. But this variant was shown to 165 00:09:20,600 --> 00:09:26,160 basically block the poor forming function of APOL one and the ion 166 00:09:26,160 --> 00:09:30,080 channel conduction and reduce the toxicity of APOL one. 167 00:09:30,400 --> 00:09:34,120 It kind of plugs the hole of the poor, if you will, and decreases 168 00:09:34,120 --> 00:09:36,640 the pathology associated with the ponocyte. 169 00:09:36,720 --> 00:09:41,640 So there are people who have this variant, but the one study 170 00:09:41,640 --> 00:09:44,520 that I think led to the discovery of this variant showed 171 00:09:44,520 --> 00:09:47,240 that if a person has this variant, they actually are 172 00:09:47,240 --> 00:09:49,880 susceptible to African sleeping sickness. 173 00:09:50,080 --> 00:09:52,640 Story certainly is getting more complex and interesting. 174 00:09:52,880 --> 00:09:55,560 Can you describe what studies are out there that might provide 175 00:09:55,560 --> 00:09:58,320 additional information to our listeners regarding April One 176 00:09:58,320 --> 00:09:59,720 kidney disease? Sure. 177 00:09:59,720 --> 00:10:03,120 There are additional studies that will provide information 178 00:10:03,120 --> 00:10:05,960 about April 1 gene and the development of that first kidney 179 00:10:05,960 --> 00:10:08,760 outcomes. And 1 of this is called Apollo 180 00:10:09,040 --> 00:10:13,000 or the April 1 Long Term Kidney Transplantation Outcomes Network 181 00:10:13,080 --> 00:10:15,080 study. And this is a study that will 182 00:10:15,080 --> 00:10:18,480 look at the long term effects of April one on kidney donors 183 00:10:18,600 --> 00:10:21,880 prospectively to determine who progresses and if there's an 184 00:10:21,880 --> 00:10:25,480 increased risk of donation of kidney failure in people who 185 00:10:25,480 --> 00:10:28,720 donate a kidney. There are also many studies that 186 00:10:28,720 --> 00:10:32,440 are looking at new medications that are coming out and I think 187 00:10:32,480 --> 00:10:35,040 we'll have another podcast on these. 188 00:10:35,040 --> 00:10:38,080 There are studies that are looking at April one small 189 00:10:38,080 --> 00:10:42,320 molecule inhibitors, anti censolago nucleotide inhibitors 190 00:10:42,320 --> 00:10:45,480 and the Jack stat inhibitors that are currently in clinical 191 00:10:45,480 --> 00:10:48,200 trials. And I also just wanted to point 192 00:10:48,200 --> 00:10:51,240 towards there is one recent paper that is more of a 193 00:10:51,560 --> 00:10:55,920 epidemiologic paper that really shows the high risk of April one 194 00:10:55,920 --> 00:10:59,520 in Africa that was recently published that just showed the 195 00:10:59,560 --> 00:11:01,920 very high rates in Western Africa. 196 00:11:01,920 --> 00:11:05,720 So I think there are more trials out there, more research out 197 00:11:05,720 --> 00:11:08,640 there that's being done. And so the story is not 198 00:11:08,640 --> 00:11:12,280 completely known in terms terms of treatment, in terms of the 199 00:11:12,400 --> 00:11:16,440 mechanisms and probably there's more that needs to be known in 200 00:11:16,440 --> 00:11:18,360 terms of the epidemiology as well. 201 00:11:18,600 --> 00:11:19,840 Yeah. Thanks for sharing those 202 00:11:19,840 --> 00:11:21,680 resources. So, before we close Doctor 203 00:11:21,680 --> 00:11:23,880 Young, are there any final messages you'd like to leave 204 00:11:23,880 --> 00:11:25,520 with our listeners? Sure. 205 00:11:25,520 --> 00:11:28,480 I would just like to say that the April 1 gene and knowledge 206 00:11:28,480 --> 00:11:31,760 regarding pathophysiology and treatment are a major step 207 00:11:31,760 --> 00:11:34,960 forward for modern medicine and research in stage. 208 00:11:34,960 --> 00:11:39,280 Kidney disease is a deep disease that as you know effects African 209 00:11:39,280 --> 00:11:42,720 Americans and other individuals who have recent African 210 00:11:42,760 --> 00:11:45,760 ancestry. And we've been waiting for 211 00:11:45,760 --> 00:11:49,440 something that really shows that it's not just lifestyle, but 212 00:11:49,440 --> 00:11:53,040 there's really something intrinsic about either a gene or 213 00:11:53,040 --> 00:11:55,920 something that is associated with end stage kidney disease. 214 00:11:55,920 --> 00:11:59,240 And this, I think has really changed the way that we look at 215 00:11:59,240 --> 00:12:01,840 kidney disease. This is a disease where you can 216 00:12:01,840 --> 00:12:04,120 truly say that research changes lives. 217 00:12:04,520 --> 00:12:07,520 I would say that the speed at which treatment was developed is 218 00:12:07,600 --> 00:12:11,800 relatively swift, 15 years, but it still lags behind many other 219 00:12:11,800 --> 00:12:15,360 diseases, you know, such as COVID, where a vaccine was 220 00:12:15,360 --> 00:12:19,560 developed in 6 to 12 months. And so I'm hoping that the 221 00:12:19,760 --> 00:12:23,080 treatment for April 1 kidney disease will advance very 222 00:12:23,080 --> 00:12:26,840 quickly and that there will be more clinical trials to prevent 223 00:12:27,080 --> 00:12:30,200 thousands of people from having to go on dialysis in the future. 224 00:12:30,480 --> 00:12:32,600 There's certainly a lot of progress with more work to be 225 00:12:32,600 --> 00:12:35,880 done to lead to direct patient benefit, but thank you so much. 226 00:12:35,880 --> 00:12:38,760 Again, Doctor Young, I'd like to thank you for joining me. 227 00:12:38,760 --> 00:12:40,360 It's great having you on the podcast. 228 00:12:40,680 --> 00:12:42,840 Doctor Campbell, thank you again for inviting me. 229 00:12:43,000 --> 00:12:45,360 This series will help our listeners understand April One 230 00:12:45,360 --> 00:12:48,360 Kidney Disease a bit better and I really look forward to the 231 00:12:48,360 --> 00:12:51,440 other sessions. I'm Doctor Kurt Campbell. 232 00:12:51,440 --> 00:12:54,440 To access this and other episodes in our series, visit 233 00:12:54,440 --> 00:12:57,960 kedego.org podcast. Thanks for listening.