1 00:00:02,120 --> 00:00:05,080 Welcome to KD GO Conversations in Nephrology. 2 00:00:05,480 --> 00:00:09,480 This episode in our complement mediated kidney disease series 3 00:00:09,560 --> 00:00:16,160 titled Diagnosis and Management of C3G is provided by KD GO and 4 00:00:16,160 --> 00:00:20,720 supported by Apellus and Sobi. Here's your host, Doctor Carla 5 00:00:20,720 --> 00:00:23,680 Nester. Hello and welcome to KD Go 6 00:00:23,680 --> 00:00:27,520 Conversations in Nephrology. I'm Doctor Carla Nester, 7 00:00:28,120 --> 00:00:31,120 Professor of Internal Medicine and Pediatrics, Stead Family 8 00:00:31,120 --> 00:00:34,840 Children's Hospital, University of Iowa, and joining me to 9 00:00:34,840 --> 00:00:38,560 discuss diagnosis and management of C3G is Doctor David 10 00:00:38,560 --> 00:00:41,520 Kavanaugh. Dr. Kavanaugh is Professor of 11 00:00:41,520 --> 00:00:45,160 Complement Therapeutics at the National Renal Complement 12 00:00:45,160 --> 00:00:49,440 Therapeutic Center, Newcastle, England, and his clinical and 13 00:00:49,440 --> 00:00:53,480 research interests include complement mediated renal and 14 00:00:53,520 --> 00:00:57,200 retinal diseases. Doctor Kavanaugh, welcome to the 15 00:00:57,200 --> 00:00:59,200 podcast. Thanks very much, Carla. 16 00:00:59,400 --> 00:01:02,440 It's a pleasure to be here. Always great to discuss 17 00:01:02,440 --> 00:01:04,319 complement mediated renal disease. 18 00:01:04,599 --> 00:01:08,920 Let's begin our discussion with how do patients present and 19 00:01:08,920 --> 00:01:12,880 particularly how do you make the diagnosis of C3G or immune 20 00:01:12,920 --> 00:01:17,120 complex in PGN. C3 glomerulopathy is an ultra 21 00:01:17,120 --> 00:01:20,560 rare kidney disease. We estimate that there will be 22 00:01:20,560 --> 00:01:24,560 about 10,000 patients in the United States with C3G. 23 00:01:25,600 --> 00:01:30,680 The clinical presentation of C3G can be buried from asymptomatic 24 00:01:30,680 --> 00:01:34,200 presentations on routine screening with hematuria or 25 00:01:34,200 --> 00:01:37,880 proteuria on debt stick, nephrotic syndrome, or acute 26 00:01:37,880 --> 00:01:41,520 kidney failure. Serum complement C3 levels are 27 00:01:41,520 --> 00:01:44,680 low in the majority of cases and this is one of the first 28 00:01:44,680 --> 00:01:48,920 indications that C3G should form part of the differential 29 00:01:48,920 --> 00:01:53,280 diagnosis. The diagnosis of C3G however, is 30 00:01:53,280 --> 00:01:57,120 made on renal biopsy and it's based on the presence of 31 00:01:57,120 --> 00:02:00,600 dominant C3D position on immunofluorescence. 32 00:02:01,680 --> 00:02:06,840 Sub classification of C3G into dense deposit disease and C3 33 00:02:06,840 --> 00:02:11,200 glomerulonephritis is then based on the appearances on electron 34 00:02:11,200 --> 00:02:14,440 microscopy. There is substantial overlap 35 00:02:14,440 --> 00:02:17,920 between immune complex MPGN and C3G. 36 00:02:18,720 --> 00:02:22,040 When we see the biopsy feature then we need to establish what 37 00:02:22,040 --> 00:02:26,040 may be driving disease and to exclude any secondary causes. 38 00:02:26,800 --> 00:02:31,960 C3 dominant glomerulonephritis is not necessarily C3G. 39 00:02:32,480 --> 00:02:35,560 So that's an excellent point that C3 dominant 40 00:02:35,560 --> 00:02:38,800 glomerulonephritis is not necessarily C3G. 41 00:02:39,280 --> 00:02:42,440 So then the follow up question becomes to your mind, is there 42 00:02:42,440 --> 00:02:45,840 anything on the biopsy that helps you rule out those 43 00:02:45,840 --> 00:02:49,160 confounders? C3 may accumulate an areas of 44 00:02:49,160 --> 00:02:52,840 glomerular or tubular interstitial scarring and due to 45 00:02:52,840 --> 00:02:57,000 prior inflammation or ischemia. I do see this very commonly. 46 00:02:57,320 --> 00:03:00,680 It tends to be focal and it's limited to areas of scarring. 47 00:03:01,320 --> 00:03:04,720 The intensity of C3 staining tends to be a bit more modest 48 00:03:05,160 --> 00:03:09,800 and moderate at most and the EM may show non specific deposits 49 00:03:09,800 --> 00:03:13,480 are scoring. However, when we get a boxy with 50 00:03:13,480 --> 00:03:18,120 AC-3 dominant picture, we should undertake a diagnostic work up. 51 00:03:18,520 --> 00:03:22,320 So what do you consider is the bare minimum diagnostic work up 52 00:03:22,320 --> 00:03:25,280 and why? When we get a renal bopsy that 53 00:03:25,280 --> 00:03:29,040 shows AC 3 dominant glomerulonephritis, it may point 54 00:03:29,160 --> 00:03:33,040 to AC 3G either due to a quadrant inherited complement 55 00:03:33,040 --> 00:03:36,480 defects. There are a few caveats however. 56 00:03:37,040 --> 00:03:40,680 This may depend on where in the course of the illness you 57 00:03:40,680 --> 00:03:44,000 bought. See for instance, 30% of post 58 00:03:44,000 --> 00:03:47,760 infectious glomerulonephritis will be C3 dominant and sub 59 00:03:47,760 --> 00:03:51,360 epithelial humps are not passing pneumonic for post infectious 60 00:03:51,360 --> 00:03:54,760 glomerulonephritis. So I'll ask for the history of 61 00:03:54,760 --> 00:04:00,800 pharyngitis or impetigo. I'll measure ASO titers if it's 62 00:04:00,800 --> 00:04:02,920 a post infectious glomerulonephritis. 63 00:04:03,600 --> 00:04:07,120 The hematuria, proteinuria and low complement levels we 64 00:04:07,120 --> 00:04:10,520 normally see initially will resolve within about 3 months. 65 00:04:11,000 --> 00:04:14,640 I will look for a paraprotein mediated disease. 66 00:04:15,120 --> 00:04:18,839 The renal biopsy may give us a clue to a monoclonal gammopathy 67 00:04:18,839 --> 00:04:21,839 driven disease. We may see Kappa or Lambda 68 00:04:21,839 --> 00:04:24,960 restriction on immunohistice chemistry and it's really 69 00:04:24,960 --> 00:04:29,720 important that this is done. Pronase digestion may reveal 70 00:04:29,720 --> 00:04:33,440 hidden aminoglobulin or light chains deposited that would 71 00:04:33,480 --> 00:04:38,840 otherwise not be seen and C4D Studying of the biopsy may also 72 00:04:38,840 --> 00:04:42,640 help to suggest a para protein mediate disease. 73 00:04:42,880 --> 00:04:46,440 Clearly we need to do serum and urine protein electrophoresis 74 00:04:46,680 --> 00:04:49,080 and serum free light chains are important too. 75 00:04:49,920 --> 00:04:53,480 This is a disorder that's more common as you age. 76 00:04:53,640 --> 00:04:58,440 About 1.6% of people over 50 will have a monoclonal gemopathy 77 00:04:58,640 --> 00:05:02,320 and this rises to about 6 1/2% in those over 80. 78 00:05:03,200 --> 00:05:06,920 It must be remembered, however, that rarely younger patients 79 00:05:06,920 --> 00:05:09,320 with lymphomas can present like this. 80 00:05:10,000 --> 00:05:13,160 We must also rule out secondary infectious causes such as 81 00:05:13,160 --> 00:05:17,560 hepatitis, B&C, and other chronic infections such as 82 00:05:17,560 --> 00:05:21,520 endocarditis. Depending on the travel history, 83 00:05:21,520 --> 00:05:24,120 we should also look for tropical diseases such as 84 00:05:24,120 --> 00:05:27,840 schistosomiasis. We should also try to exclude 85 00:05:27,840 --> 00:05:32,280 autoimmune diseases such as SLE, rheumatoid arthritis, and 86 00:05:32,280 --> 00:05:36,200 cryoglopial anemia. More specialist complement tests 87 00:05:36,200 --> 00:05:38,600 may be available in some centers. 88 00:05:39,160 --> 00:05:42,080 Nephritic factors and auto antibodies to complement 89 00:05:42,080 --> 00:05:47,280 proteins are frequently found in C3G and provide reassurance as 90 00:05:47,280 --> 00:05:51,280 to the diagnosis. Likewise, genetic analysis may 91 00:05:51,280 --> 00:05:55,480 be performed and in rare cases an underlying mutation and 92 00:05:55,480 --> 00:06:00,360 factory HRC three may be found. An array of complement tests are 93 00:06:00,360 --> 00:06:05,400 available that assess the state of complement activation in C3. 94 00:06:05,800 --> 00:06:09,400 However, although these may speak of the underlying 95 00:06:09,400 --> 00:06:14,160 pathogenesis, they do not confirm a diagnosis of C3G or, 96 00:06:14,160 --> 00:06:18,720 as yet, gait treatment. It is likely, however, that as 97 00:06:18,720 --> 00:06:22,040 Complement Therapeutics enter the real world, we'll work out 98 00:06:22,040 --> 00:06:24,800 how to use these tests to guide treatment. 99 00:06:25,440 --> 00:06:27,400 Thank you. That's actually a very nice list 100 00:06:27,400 --> 00:06:29,840 of ways we can rule out some of these confounders. 101 00:06:29,840 --> 00:06:33,000 And I also like the way you portray the finding of auto 102 00:06:33,040 --> 00:06:36,280 antibodies, for instance, as quote UN quote reassurance of 103 00:06:36,280 --> 00:06:39,440 the diagnosis. I think with that in mind, I'll 104 00:06:39,440 --> 00:06:42,640 take that one step further and just ask you, is testing for 105 00:06:42,640 --> 00:06:46,560 these auto antibodies required for the diagnosis of C3G or 106 00:06:46,560 --> 00:06:52,040 immune complex MPGN? No, the diagnosis of C3G, an 107 00:06:52,040 --> 00:06:55,480 immune complex MPGN, is a bumpy diagnosis. 108 00:06:55,920 --> 00:06:59,360 These are really just additional tests that may allow you to 109 00:06:59,360 --> 00:07:04,400 confirm that this is driven by complement over activation. 110 00:07:04,800 --> 00:07:08,400 If you're just tuning in, you're listening to the KD Go podcast 111 00:07:08,400 --> 00:07:11,000 on diagnosis and management of C3G. 112 00:07:11,320 --> 00:07:14,240 I'm Carla Nester, and I'm speaking with Doctor David 113 00:07:14,240 --> 00:07:16,480 Kavanaugh. So let's jump to our next 114 00:07:16,480 --> 00:07:19,040 question. How do you treat your newly 115 00:07:19,040 --> 00:07:23,320 diagnosed C3G patient? As with most proteinuric renal 116 00:07:23,320 --> 00:07:27,400 diseases, I start with nonspecific approaches such as 117 00:07:27,400 --> 00:07:31,040 optimization of blood pressure and proteinuria control with 118 00:07:31,040 --> 00:07:35,440 renal angiosystem inhibition and SGL 2 inhibitors. 119 00:07:36,160 --> 00:07:38,600 I'll give lipid loading agents when required. 120 00:07:39,120 --> 00:07:43,040 In patients with more than half a gram of proteinuria, worsening 121 00:07:43,040 --> 00:07:45,920 renal function or severe inflammation in the renal 122 00:07:45,920 --> 00:07:50,800 biopsy, I will try non specific immunosuppression in the form of 123 00:07:50,800 --> 00:07:54,480 steroids and MMF. I would say the evidence for 124 00:07:54,480 --> 00:07:58,520 this is all retrospective, but until now it's the only 125 00:07:58,520 --> 00:08:01,880 treatment I had. And Despite that most patients 126 00:08:01,880 --> 00:08:04,040 progress to end stage kidney failure. 127 00:08:04,640 --> 00:08:08,680 We know that C3G is a disorder of the alternative pathway of 128 00:08:08,680 --> 00:08:12,080 complement and therefore eclusumab acts too far 129 00:08:12,080 --> 00:08:15,520 downstream to effectively treat C3G. 130 00:08:16,640 --> 00:08:21,200 The new alternative pathway targeted agents at Tacapan and 131 00:08:21,200 --> 00:08:26,240 Pigsetic Plan are a pivotal moment for patients with C3G as 132 00:08:26,240 --> 00:08:29,960 we can now effectively target the site of complement over 133 00:08:29,960 --> 00:08:33,520 activation. This is a really exciting time 134 00:08:33,520 --> 00:08:37,960 for patients with C3G. I agree 100%, But before we get 135 00:08:37,960 --> 00:08:41,039 to the new therapeutics, I'm sure as glomerular disease 136 00:08:41,039 --> 00:08:45,120 doctors, we've both had some successes with mycophenolate and 137 00:08:45,120 --> 00:08:49,200 steroids with other diseases. Would you like to take a stab at 138 00:08:49,200 --> 00:08:51,880 why this approach may be effective, or for that matter 139 00:08:51,880 --> 00:08:53,960 not effective in this particular setting? 140 00:08:54,120 --> 00:08:56,360 Yeah, that's a very interesting point, Carla. 141 00:08:56,560 --> 00:09:00,560 I mean, we have all treated some patients with steroids and MMS 142 00:09:01,040 --> 00:09:04,440 and seen good response. Now I suppose all the evidence 143 00:09:04,440 --> 00:09:07,640 is retrospective, so we don't know if people would have got 144 00:09:07,640 --> 00:09:11,080 better anyway. And indeed, I've seen some 145 00:09:11,080 --> 00:09:13,520 patients just get better without any treatment. 146 00:09:13,720 --> 00:09:16,880 So the evidence for this is all retrospective. 147 00:09:16,880 --> 00:09:21,040 However, as I said, most patients in MMS and steroid will 148 00:09:21,040 --> 00:09:24,080 progress to end stage whatever we do now. 149 00:09:24,400 --> 00:09:27,880 I think that's because we might see an initial response to 150 00:09:27,880 --> 00:09:31,400 steroids and that's just treating the nonspecific 151 00:09:31,400 --> 00:09:33,600 inflammation we see in the kidney. 152 00:09:34,080 --> 00:09:38,840 However, we do not get rid of the underlying driver of disease 153 00:09:38,840 --> 00:09:43,200 at complement activation, C3 depositing in the kidney and 154 00:09:43,200 --> 00:09:46,080 that ultimately leads to end stage renal failure. 155 00:09:46,680 --> 00:09:51,720 And although we might feel MMS may be targeting auto antibodies 156 00:09:51,720 --> 00:09:56,960 as it may do in other diseases, we've had really poor success in 157 00:09:56,960 --> 00:10:01,080 eliminating nephritic factors. Whatever we do, we have not 158 00:10:01,080 --> 00:10:03,720 really been able to get rid of these nephritic factors. 159 00:10:03,960 --> 00:10:08,080 And I believe you don't require terribly much C3 NAV to cause 160 00:10:08,080 --> 00:10:10,240 disease. That all makes sense to me. 161 00:10:10,240 --> 00:10:12,000 Thank you. Now let's move forward. 162 00:10:12,000 --> 00:10:15,160 So when the new therapeutic options are available to you, 163 00:10:15,880 --> 00:10:18,680 how do you plan to use them moving forward? 164 00:10:19,200 --> 00:10:23,240 Clearly we all await the updated K Daigo guidance on treatment, 165 00:10:23,560 --> 00:10:27,640 but as a personal view, I will start ACE inhibitors and SGL 2 166 00:10:27,640 --> 00:10:31,720 inhibitors as I would in any proteinuric renal disease. 167 00:10:32,720 --> 00:10:36,560 I view alternative pathway inhibition as first line 168 00:10:36,560 --> 00:10:39,480 therapy. I will not start MMS and 169 00:10:39,480 --> 00:10:42,080 steroids first and see if there's a response. 170 00:10:42,640 --> 00:10:47,080 We exquisitely know the pathogenesis of C3G and these 171 00:10:47,080 --> 00:10:51,240 alternative pathway agents target this Tachopan and 172 00:10:51,240 --> 00:10:54,520 Pigsetica plant have been shown to be effective and gold 173 00:10:54,520 --> 00:10:57,720 standard randomized placebo-controlled trials. 174 00:10:58,440 --> 00:11:01,360 That has never been a randomized controlled trial of MMF and 175 00:11:01,360 --> 00:11:06,640 steroids in C3G and these agents come with marked side effects. 176 00:11:07,400 --> 00:11:11,640 Despite their use, most patients progressed to end stage renal 177 00:11:11,640 --> 00:11:15,480 failure anyway. Thus, I would not want to see a 178 00:11:15,480 --> 00:11:20,560 gatekeeper role for MMF and steroids part accessing the 179 00:11:20,600 --> 00:11:24,240 evidence based treatment, pixetical plan and Tachopan. 180 00:11:24,760 --> 00:11:28,040 Many questions remain about alternative pathway agents 181 00:11:28,040 --> 00:11:31,720 optimal use, such as how long we need to continue and what 182 00:11:31,720 --> 00:11:35,600 constitutes successful treatments, and whether we need 183 00:11:35,600 --> 00:11:38,720 to swap between agents if we're not seeing successful treatment. 184 00:11:39,360 --> 00:11:42,320 I think, however, many of these questions will only be answered 185 00:11:42,320 --> 00:11:44,600 when we use these agents in the real world. 186 00:11:45,640 --> 00:11:47,680 I think that those are all excellent points. 187 00:11:47,920 --> 00:11:51,200 So I'm going to push back a little bit and ask you maybe a 188 00:11:51,200 --> 00:11:55,560 harder question. What if your ACE inhibitor plus 189 00:11:55,560 --> 00:12:00,640 your SGLT 2 inhibitor takes a patient, let's say from 1.9 190 00:12:00,640 --> 00:12:05,240 grams of urine protein down to 0.7g of urine protein? 191 00:12:05,800 --> 00:12:08,280 Are you still going to consider one of the new therapies? 192 00:12:08,480 --> 00:12:12,360 Yes, not all reduction in proteinuria is the same. 193 00:12:13,120 --> 00:12:17,160 ACE inhibitors, SGL 2 inhibitors will have a known specific 194 00:12:17,160 --> 00:12:21,440 effect on proteinuria, however they're not going to prevent 195 00:12:21,440 --> 00:12:24,840 that ongoing complement activation damaging the kidney. 196 00:12:25,360 --> 00:12:28,320 It's really the alternative pathway agents that hit the 197 00:12:28,320 --> 00:12:31,200 disease at the source. Well, I think that's pretty 198 00:12:31,200 --> 00:12:33,440 straightforward. Thank you very much for that. 199 00:12:33,440 --> 00:12:36,520 So now let's jump over to transplantation. 200 00:12:36,520 --> 00:12:39,680 Are there issues about transplantation that you would 201 00:12:39,680 --> 00:12:42,840 like to chat about? One of the most desperately 202 00:12:42,840 --> 00:12:46,720 disappointing features of this disease for our patients was an 203 00:12:47,080 --> 00:12:51,800 up to 80% of cases the disease relapsed after transplantation. 204 00:12:52,360 --> 00:12:54,600 Our patients had seen their native kidney function 205 00:12:54,600 --> 00:12:58,560 deteriorate to the point where they needed dialysis, and then 206 00:12:58,560 --> 00:13:01,040 they were fortunate enough to get a transplant. 207 00:13:02,000 --> 00:13:04,960 But frequently we had to tell them that the disease had come 208 00:13:04,960 --> 00:13:08,160 back and there was little we could do to stop this. 209 00:13:09,360 --> 00:13:13,760 Both at TACPAN and phase two trials and Picksetica plan and 210 00:13:13,760 --> 00:13:16,440 phase two and three trials have been used in transplant 211 00:13:16,440 --> 00:13:20,120 recurrence with good result. That does not appear to be a 212 00:13:20,120 --> 00:13:23,920 safety signal when used in combination with transplant 213 00:13:23,920 --> 00:13:27,600 immunosuppression. The infectious risks of 214 00:13:27,600 --> 00:13:31,240 complement blockade is well known but can be mitigated with 215 00:13:31,280 --> 00:13:35,360 antibiotic prophylaxis, vaccination, and patient 216 00:13:35,360 --> 00:13:37,800 awareness. That's been my experience also, 217 00:13:37,800 --> 00:13:40,120 that the prognosis post transplant can be just as 218 00:13:40,120 --> 00:13:42,320 daunting as it was in the native kidney. 219 00:13:42,720 --> 00:13:46,120 Can I ask you, just for our audience more than anything, 220 00:13:46,160 --> 00:13:49,560 what constitutes recurrence in that transplant for you? 221 00:13:49,640 --> 00:13:53,000 Well, that does seem like an easy question, but actually it's 222 00:13:53,000 --> 00:13:56,800 not quite as straightforward. You could say I need to see 223 00:13:57,160 --> 00:14:00,800 evidence of proteinuria worsening renal function or 224 00:14:00,800 --> 00:14:04,320 should we do a renal biopsy? But if we do a renal biopsy, is 225 00:14:04,320 --> 00:14:09,480 C3D position enough or do I also need to see a 226 00:14:09,480 --> 00:14:13,280 glomerulonephritis? My feeling is that we know the 227 00:14:13,280 --> 00:14:17,600 pathogenesis of disease and I don't want to wait until there's 228 00:14:17,680 --> 00:14:20,040 marked proteinurian worsening renal function. 229 00:14:20,320 --> 00:14:24,120 If I do a kidney biopsy and I'm seeing pathological recurrence 230 00:14:24,120 --> 00:14:27,240 with a glomerulonephritis, I'm going to want to treat. 231 00:14:27,600 --> 00:14:32,240 Now that is a reactive treatment and there is one other 232 00:14:32,240 --> 00:14:36,720 complement mediated condition, atypical HUS that also recurs 233 00:14:36,720 --> 00:14:41,760 post transplant, but in that we give eclizumab prophylactically 234 00:14:41,760 --> 00:14:45,440 to prevent disease. Now that's a very acute 235 00:14:45,440 --> 00:14:50,360 presentation and these patients with atypical HUS can lose their 236 00:14:50,360 --> 00:14:54,880 kidneys very quickly. In C3G it tends to be far 237 00:14:54,880 --> 00:14:57,960 slower. So we will have time to react 238 00:14:58,400 --> 00:15:02,760 and do a biopsy. I don't, however, rule out 239 00:15:02,880 --> 00:15:09,080 giving prophylactic tacpan or pixetical plan in certain cases 240 00:15:09,440 --> 00:15:12,520 where there might be a high risk of recurrence. 241 00:15:12,800 --> 00:15:16,560 But as yet, we'll need to see how this pans out in the real 242 00:15:16,560 --> 00:15:19,280 world. Again, all excellent points I 243 00:15:19,280 --> 00:15:23,120 think you're making and thank you for a wonderful discussion 244 00:15:23,120 --> 00:15:26,800 about the C3 GI. Want to thank my guest, Doctor 245 00:15:26,800 --> 00:15:30,400 David Kavanaugh for joining me. Doctor Kavanaugh, it was great 246 00:15:30,400 --> 00:15:33,720 having you on the podcast. It's always a pleasure. 247 00:15:34,280 --> 00:15:38,360 I'm Doctor Carla Nester, To access this and other episodes 248 00:15:38,360 --> 00:15:43,200 in our series, visit kdgo.org/podcast. 249 00:15:43,720 --> 00:15:44,680 Thanks for listening.