WEBVTT 00:00.000 --> 00:30.000 position:50% align:top line:0% *This machine-generated transcript may have errors. If remediation or a manually-generated transcript is needed, please contact NLM Support at https://support.nlm.nih.gov.* 00:10.650 --> 00:13.080 a United States Army Medical Department 00:13.080 --> 00:15.390 continuing education program, 00:15.960 --> 00:18.240 immuno suppressive management 00:19.080 --> 00:20.300 with Jeremiah G. 00:20.300 --> 00:21.400 Turcotte M.D. 00:22.110 --> 00:23.290 Professor of surgery. 00:23.290 --> 00:25.880 University of michigan hospital at Ann Arbor. 00:27.530 --> 00:29.010 I think this is a 00:29.870 --> 00:32.810 particularly important time to be considering 00:32.810 --> 00:35.350 and reconsidering immune suppression 00:35.450 --> 00:38.430 because in fact the success 00:38.430 --> 00:41.200 of transplantation has plateau owed in recent 00:41.200 --> 00:41.850 years. 00:42.490 --> 00:45.320 Uh And it's mainly due to the fact that we 00:45.320 --> 00:48.250 haven't made any breakthroughs in the area of 00:48.260 --> 00:49.930 transplant of immune suppression. 00:50.370 --> 00:51.820 We start with that first slide. 00:53.070 --> 00:55.690 So I think it's time to rethink what we've been 00:55.690 --> 00:56.340 doing. 00:56.950 --> 00:58.730 Go back to the drawing board 00:59.310 --> 01:01.840 and if we're really going to get any 01:01.840 --> 01:04.630 significant improvements in the years to come, 01:06.760 --> 01:09.680 might be helpful just to review how we got to 01:09.680 --> 01:10.820 where we are today. 01:11.400 --> 01:14.350 And uh here is simply a summary of 01:14.350 --> 01:17.200 some historical highlights have to, 01:17.210 --> 01:20.180 it has to do with the development of neuron as 01:20.180 --> 01:22.320 a clinical immune suppressive agent. 01:24.010 --> 01:26.660 Small business started in 59 when Bob 01:26.660 --> 01:28.830 Schwartz and domestic in Boston 01:29.260 --> 01:31.760 demonstrated that six more capital 01:31.770 --> 01:34.630 period could produce tolerance to bovine 01:34.630 --> 01:37.230 serum albumin doesn't have a great deal to do 01:37.230 --> 01:38.410 with rejection. 01:38.410 --> 01:40.920 But was the first demonstration that compounds of this 01:40.920 --> 01:43.130 type were immune suppressants. 01:43.840 --> 01:45.790 Uh Zukovsky and 01:45.790 --> 01:46.870 calm. 01:46.880 --> 01:49.870 Then tried six mp in canine kidney 01:49.870 --> 01:52.170 grafts and demonstrated that it 01:52.170 --> 01:54.920 would prolong arenal 01:54.920 --> 01:55.830 Allah graphs. 01:56.710 --> 01:59.270 Um In about 01:59.270 --> 02:02.140 61 Roy Calm did a series of 02:02.140 --> 02:04.990 about 120 dogs at the Brigham 02:05.730 --> 02:08.060 And used a variety of compounds, 02:08.060 --> 02:10.600 all of which were analog of six MP 02:11.200 --> 02:13.690 in urine being simply one of them 02:13.950 --> 02:16.950 did about 10 dogs in each group with 02:16.950 --> 02:19.870 each compound And found that he had 02:19.870 --> 02:22.720 a little less toxicity in 10 02:22.720 --> 02:25.640 dogs out bred dog population 02:26.210 --> 02:28.820 with what was then called Burroughs. 02:28.820 --> 02:30.500 Welcome with a number after it. 02:30.510 --> 02:31.730 Uh, 02:31.740 --> 02:34.040 and on that basis selected that 02:34.050 --> 02:36.770 drug as a more promising analog of 02:36.770 --> 02:39.580 six mp to use clinically promptly 02:39.580 --> 02:41.170 took it to the clinic. 02:41.250 --> 02:42.850 And that's where we've been ever since. 02:42.920 --> 02:45.430 And the reason I would emphasize that is 02:45.430 --> 02:48.410 that there really hasn't been a great deal of 02:48.420 --> 02:50.870 a broad look and a lot of 02:50.880 --> 02:52.440 chemotherapeutic agents, 02:52.450 --> 02:53.680 uh, 02:55.650 --> 02:57.790 either experimentally or clinically. 02:58.890 --> 03:01.440 And we've sort of arrived at using in urine on the 03:01.440 --> 03:04.250 basis of just a modest research experience. 03:04.610 --> 03:07.180 And then what seemed to work out reasonably while in the clinic. 03:07.480 --> 03:10.370 But when you look at the scientific foundation on which the 03:10.370 --> 03:11.830 use of this drug lies, 03:11.830 --> 03:13.530 it's not very firm or complete. 03:14.410 --> 03:14.830 However, 03:14.830 --> 03:15.780 it does work. 03:16.190 --> 03:19.040 It possibly is less toxic than six MP. 03:19.040 --> 03:21.780 Although people will debate that and 03:21.790 --> 03:23.730 it is a convenient drug to use. 03:24.640 --> 03:27.540 The drug did allow the first long term survivals 03:27.550 --> 03:30.120 of human non twin renal alla 03:30.120 --> 03:30.670 graphs, 03:31.160 --> 03:32.940 with the occasional exception, 03:32.940 --> 03:33.890 prior to that time, 03:33.890 --> 03:36.040 that a few people with total body radiation 03:36.810 --> 03:39.270 had long term survivals of their graphs. 03:39.680 --> 03:40.210 Next slide, 03:41.150 --> 03:41.500 Okay, 03:41.500 --> 03:41.660 now, 03:41.660 --> 03:42.910 let's look at steroids, 03:43.430 --> 03:46.240 I just might say when you look at the ad about the 03:46.250 --> 03:49.180 various chemo therapeutic 03:49.190 --> 03:50.370 immunosuppressants. 03:50.380 --> 03:53.090 The only other one that's had very widespread clinical use of 03:53.090 --> 03:53.950 Cytoxan. 03:54.400 --> 03:55.930 That is a very good drug. 03:55.940 --> 03:57.390 It has a few more side effects. 03:57.390 --> 03:59.040 A little difficult to manage. 03:59.230 --> 04:02.080 What is the drug of choice and by 04:02.080 --> 04:03.090 certain groups anyway, 04:03.090 --> 04:04.760 save with bone marrow grafting 04:06.800 --> 04:09.730 steroids I think are even a little more interesting story. 04:10.380 --> 04:13.230 Um Rabbits are very 04:13.230 --> 04:16.200 sensitive to cortical steroids and way back 04:16.200 --> 04:18.870 in 51 billing Ham showed 04:18.870 --> 04:21.500 that steroids will prolong rabbit 04:21.500 --> 04:22.860 skin alla g. 04:23.880 --> 04:26.680 Uh this stimulated a great deal of other work using 04:26.680 --> 04:28.300 various cortical steroids, 04:28.570 --> 04:30.780 most of which was negative. 04:31.720 --> 04:34.060 And if one studied antibody 04:34.060 --> 04:34.960 synthesis, 04:34.960 --> 04:37.480 induction tolerance and so on steroids, 04:37.980 --> 04:40.750 a secondary response versus the primary response 04:41.270 --> 04:43.090 steroids had very little effect. 04:43.310 --> 04:46.150 And about this time by the time we got the 60s, 04:46.530 --> 04:47.490 in the early 60s, 04:47.490 --> 04:50.420 if you asked three out of four people in the 04:50.420 --> 04:53.020 field of immune suppression of steroids had any role, 04:53.020 --> 04:55.760 they would say no and they've been pretty much 04:55.760 --> 04:56.780 almost given up. 04:57.760 --> 05:00.110 Um Nevertheless, 05:00.110 --> 05:02.900 a few surgeons who I didn't 05:02.900 --> 05:05.780 believe everything they heard and maybe haven't read all the basic 05:05.780 --> 05:06.680 science literature, 05:06.680 --> 05:09.520 continued to use steroids 05:09.720 --> 05:12.630 and chuck zukowski again was now at 05:12.640 --> 05:15.170 Tucson did use very large 05:15.170 --> 05:16.640 doses of predniSONE alone. 05:16.640 --> 05:17.930 These were unheard of 05:18.420 --> 05:21.230 uh doses at that time to use 05:21.230 --> 05:23.720 this larger dose on a frequent basis 05:24.200 --> 05:27.170 and got a modest prolongation of 05:27.180 --> 05:28.010 canine. 05:28.010 --> 05:28.230 Real, 05:28.240 --> 05:29.430 real Allah graphs. 05:30.020 --> 05:32.780 The crucial observation was 05:32.790 --> 05:35.450 1963 by dr goodwin 05:35.460 --> 05:38.310 was a urologist uh on the 05:38.310 --> 05:39.390 West coast. 05:39.400 --> 05:42.200 And he had a patient who is treating with urine 05:42.800 --> 05:45.160 and started to undergo a massive rejection 05:45.670 --> 05:48.230 and he didn't have anything else to do. 05:48.230 --> 05:50.250 So he gave the patient large dose 05:50.610 --> 05:52.750 steroids and reverse the rejection. 05:53.540 --> 05:56.170 And that was the first time that an established rejection 05:56.170 --> 05:58.810 episode had ever been reversed either in humans or 05:58.810 --> 05:59.770 animals. 06:00.110 --> 06:03.050 And it was on the basis of that clinical observation then that we 06:03.050 --> 06:06.020 added steroids to the immunosuppressive regimen. 06:06.410 --> 06:09.230 Initially they were reserved to the time that rejection took 06:09.230 --> 06:09.770 place. 06:10.170 --> 06:13.090 And later on we're used prophylactically. 06:13.160 --> 06:16.000 So then there was a 62 63 where the 06:16.010 --> 06:18.320 clinical trials using both of the drugs together 06:18.320 --> 06:19.050 began. 06:19.490 --> 06:22.070 And that's what put renal transplantation 06:22.430 --> 06:25.050 on the horizon or in 06:25.050 --> 06:26.800 use as a clinically 06:27.050 --> 06:29.030 therapeutic measure. 06:29.200 --> 06:32.130 And it's these two drugs of course that's still form the 06:32.140 --> 06:34.680 basis of all immune suppression in renal 06:34.680 --> 06:35.350 transplants. 06:35.350 --> 06:37.770 And as a matter of fact there's been no other drug or 06:37.770 --> 06:40.440 combination of drugs that has ever been 06:40.440 --> 06:43.340 demonstrated to be more efficacious than simply using 06:43.340 --> 06:45.800 in urine and steroids to 06:45.800 --> 06:47.600 date in the clinical setting. 06:47.610 --> 06:48.330 Next slot. 06:49.140 --> 06:51.690 So I think from this 06:51.690 --> 06:54.620 experience there's a few basic lessons that we've learned 06:54.620 --> 06:57.100 and I think you ought to keep in mind when we're talking about other 06:57.470 --> 06:58.470 immunosuppressants. 07:00.000 --> 07:00.570 First of all, 07:00.570 --> 07:03.140 all Allah graphs even we shared HL antigens will 07:03.140 --> 07:04.740 reject without immune suppression. 07:04.750 --> 07:07.150 It's been demonstrated clinically and H. 07:07.150 --> 07:07.340 L. 07:07.340 --> 07:08.830 A identical mlc 07:10.120 --> 07:12.800 unresponsive graphs at Duke, 07:13.320 --> 07:14.430 they all reject. 07:14.430 --> 07:17.190 And even within your in about three quarters of them 07:17.190 --> 07:18.370 rejecting urine alone. 07:19.450 --> 07:20.500 Neither in your interest, 07:20.500 --> 07:22.370 your eyes and use the loan are very effective. 07:22.620 --> 07:23.690 It's the combination. 07:24.690 --> 07:27.080 I'd ask you to keep that in mind when you're looking at 07:27.090 --> 07:30.020 various other problems 07:30.020 --> 07:32.900 in medicine where people are using immunosuppressants to 07:32.900 --> 07:35.380 treat what are supposed presumed to be 07:35.380 --> 07:37.760 immulogic disease is most of the clinical 07:37.760 --> 07:40.330 trials would use what we would 07:40.340 --> 07:43.210 think of as inadequate immune suppression to prevent 07:43.210 --> 07:43.820 rejection. 07:44.230 --> 07:46.910 One wonders if they didn't use a combination. 07:46.910 --> 07:49.800 And the doses that we usually use in kidney 07:49.800 --> 07:51.570 transplantation and for instance, 07:52.180 --> 07:54.840 results with rheumatoid arthritis and some other 07:54.900 --> 07:57.480 potential immulogic diseases might be better than have been 07:57.480 --> 07:58.470 reported to date. 08:00.000 --> 08:01.640 Both the graft and the host. 08:01.640 --> 08:04.280 Quote adapt with time allowing the doses of MR 08:04.280 --> 08:05.370 presents to be reduced. 08:05.820 --> 08:07.200 We'll get back to that later. 08:07.920 --> 08:09.250 That's an old term. 08:10.050 --> 08:13.010 I guess if you make a long story short I think 08:13.010 --> 08:15.700 we've been inducing partial and few cases 08:15.700 --> 08:18.490 complete tolerance for a long time in humans 08:18.500 --> 08:20.020 without recognizing it. 08:20.030 --> 08:21.660 Using these drugs. 08:22.530 --> 08:24.930 Uh not all rejection episodes can be prevented and 08:24.930 --> 08:27.630 reviews and the therapeutic index of 08:27.630 --> 08:28.110 available. 08:28.110 --> 08:28.370 MR. 08:28.370 --> 08:31.160 President says low and of course this is one of the 08:31.160 --> 08:34.130 major problems and we're looking for less toxic but 08:34.140 --> 08:37.140 at least equally potent image oppressive regiments. 08:40.570 --> 08:43.260 Well here's the standard immunosuppressive regimen. 08:43.260 --> 08:44.460 We used at michigan. 08:45.510 --> 08:47.760 We've had a we've done about 08:47.770 --> 08:50.390 375 kidney grafts there in the past 10 08:50.390 --> 08:52.900 years and tried a variety 08:52.910 --> 08:55.270 of fancy regimens and not so fancy 08:55.270 --> 08:56.040 regimens. 08:56.110 --> 08:58.960 This is what we use at the moment is a thigh preen 08:58.970 --> 09:01.050 three mg per kilogram for 10 days, 09:01.050 --> 09:02.360 maximum 200 09:03.100 --> 09:04.270 Milligrams, 09:04.480 --> 09:06.690 mg after 10 days if tolerated. 09:06.990 --> 09:09.820 Maximum 100 50 predniSONE, 09:09.820 --> 09:12.570 1.5 mg per kilo for seven days, 09:12.760 --> 09:15.720 tapered to a milligram during the second week and 09:15.720 --> 09:17.430 then tapered to a quarter milligram, 09:17.440 --> 09:20.010 kilogram by 3 to 6 months is tolerated. 09:20.610 --> 09:23.250 We use that for both category graphs and related 09:23.250 --> 09:23.940 graphs. 09:24.910 --> 09:27.870 I'll point out a few things in 09:27.870 --> 09:29.500 the early days of transplantation, 09:29.500 --> 09:31.640 Almost everybody used loading doses 09:32.270 --> 09:35.100 of Iran say they use four or 56 mg per 09:35.100 --> 09:38.030 kilo for the first day or just prior to the transplant 09:38.230 --> 09:40.590 or they would give large doses of 09:40.600 --> 09:43.460 steroids in the first couple of days and then taper down to 09:43.460 --> 09:46.320 something in this range and 1.5 range. 09:46.620 --> 09:49.500 There's absolutely no evidence that I can detect that that does any 09:49.500 --> 09:50.270 good. 09:50.620 --> 09:52.620 And in our own hands program, 09:52.620 --> 09:55.460 as I outlined out here has just as good results 09:55.850 --> 09:58.750 as some of these variations that have 09:58.750 --> 10:01.090 been used in the past and in some cases have been 10:03.090 --> 10:03.910 used today. 10:05.500 --> 10:06.460 Another point 10:08.020 --> 10:10.950 referring to this adaptation or partial tolerance 10:10.950 --> 10:11.530 induction, 10:12.280 --> 10:15.020 there are many patients who are on steroids alone 10:15.030 --> 10:16.510 after several months. 10:17.480 --> 10:18.480 Post transplant. 10:19.700 --> 10:20.680 In other words, 10:20.690 --> 10:22.990 the neuron has been stopped and they 10:22.990 --> 10:25.990 develop uh paddock toxicity or some other 10:25.990 --> 10:26.570 reason, 10:26.580 --> 10:28.600 low white count and they do 10:28.600 --> 10:31.360 find there are very few patients in whom 10:31.360 --> 10:33.280 steroids have been able to be stopped. 10:33.940 --> 10:36.800 And there is still a question whether in urine is 10:36.800 --> 10:39.710 needed at all in the very late post transplant 10:39.720 --> 10:40.270 period. 10:40.910 --> 10:41.120 Now, 10:41.120 --> 10:41.490 Dr. 10:41.490 --> 10:43.990 Marr Chiaro University of Washington he 10:44.000 --> 10:46.140 uses never gives more than 25 10:46.140 --> 10:48.700 mg of urine a day. 10:48.710 --> 10:49.940 25 mg, 10:49.940 --> 10:52.580 which is a homeopathic dose. 10:53.570 --> 10:56.470 And his results seem to be as good as many people. 10:56.500 --> 10:59.020 So one wonders if after this initial 11:01.290 --> 11:04.070 Week or two or a month or even three months 11:04.450 --> 11:07.370 if a different situation hasn't developed and perhaps you can 11:07.370 --> 11:09.180 get by and much less in urine, 11:09.760 --> 11:12.460 you're less likely to get by on without 11:12.460 --> 11:13.070 steroids. 11:13.990 --> 11:16.720 I keep this in mind because we don't hesitate to 11:16.720 --> 11:19.370 stop in urine after 3 to 6 months if we're having a 11:19.380 --> 11:22.150 problem and haven't really seen any 11:22.240 --> 11:25.070 detectable bad results from that or at 11:25.070 --> 11:27.570 least to lower it down to very low doses 11:27.570 --> 11:29.130 25 50 mg. 11:29.220 --> 11:32.120 We our philosophy is to use as much 11:32.120 --> 11:34.420 in urine as people will tolerate. 11:34.430 --> 11:35.200 But again, 11:35.200 --> 11:36.640 we're much less hesitant. 11:36.640 --> 11:39.450 We used to be to get it down to a rather low dose 11:39.450 --> 11:42.380 level in the late post transplant period if that's 11:42.380 --> 11:43.140 necessary. 11:48.230 --> 11:51.110 I'm just gonna talk for a few minutes about a couple of subjects that have 11:51.110 --> 11:54.030 interested us were interested is 11:54.330 --> 11:55.680 answering these two questions. 11:55.680 --> 11:58.330 Is there a minimum dose of steroids below what's the probability 11:58.330 --> 12:00.140 rejection is so great. 12:00.150 --> 12:03.140 That is inadvisable to reduced oral steroids below this 12:03.140 --> 12:04.800 critical level in most patients. 12:05.650 --> 12:06.100 In other words, 12:06.100 --> 12:08.370 we've all been sort of flying by the seat of our pants, 12:08.370 --> 12:11.060 we keep lowering the steroid dose and then we hope that 12:11.060 --> 12:13.060 rejection won't intervene. 12:13.110 --> 12:16.100 But we wanted to look at this in a mathematical way and see if we could 12:16.100 --> 12:18.760 predict a dose below which we should not 12:18.760 --> 12:21.680 go or related question. 12:21.690 --> 12:23.140 In individual patients, 12:23.140 --> 12:25.510 can a minimum dose of steroids be identified 12:25.530 --> 12:27.690 below which rejection is likely to occur? 12:28.770 --> 12:30.730 We did analyze our series. 12:30.740 --> 12:33.670 We essentially looked at all our cattle Eric transplants 12:33.670 --> 12:36.250 who were six months post transplant and were relatively 12:36.250 --> 12:38.250 stable at that point. 12:38.380 --> 12:41.230 And then followed them from that point on 12:41.240 --> 12:43.900 this is simply the survival curves 12:43.910 --> 12:46.240 uh of the patients 12:46.240 --> 12:49.160 studied um who fit 12:49.160 --> 12:52.090 our criteria that have a creatinine below 2.5 and so 12:52.090 --> 12:52.260 on. 12:52.260 --> 12:55.150 And then uh and of all our patients who had 12:55.150 --> 12:56.630 graph functioning at six months, 12:56.730 --> 12:58.520 which is a different group. 12:58.660 --> 13:00.430 So this is a group we're looking at up here. 13:03.640 --> 13:05.870 Uh If you look at this bar 13:05.870 --> 13:07.030 graph, 13:07.230 --> 13:10.040 the black is uh numbers of patients 13:10.050 --> 13:11.540 with rejection episodes. 13:11.540 --> 13:14.320 The white is no rejection episodes. 13:14.330 --> 13:16.730 And this is the predniSONE dosage in milligrams per 13:16.740 --> 13:17.440 kilogram, 13:18.260 --> 13:20.620 you'll see that all the way from 13:20.630 --> 13:23.260 zero predniSONE up 13:23.270 --> 13:26.100 2.7 or 0.69 mg per 13:26.100 --> 13:26.770 kilo, 13:27.440 --> 13:30.130 there's a scattering of rejection episodes. 13:30.170 --> 13:32.370 So it doesn't if you look at this, 13:32.370 --> 13:33.270 you'd say no, 13:33.270 --> 13:34.620 there is no you know, 13:34.620 --> 13:37.360 there's a great individual variation in 13:37.360 --> 13:39.160 terms of what steroid dose 13:40.000 --> 13:42.930 uh will be given at the time that 13:42.930 --> 13:44.190 rejection occurs. 13:44.200 --> 13:45.150 Converses, 13:45.150 --> 13:47.420 here's uh six patients who are 13:47.420 --> 13:49.740 below uh 13:50.270 --> 13:53.050 .9 mg or 0.9 I guess it is per 13:53.050 --> 13:55.630 kilo have never had a rejection 13:55.630 --> 13:56.150 episode. 13:56.280 --> 13:58.710 So there is not a sharp line of 13:58.710 --> 13:59.470 demarcation, 13:59.470 --> 14:01.970 there's a great deal of individual variation. 14:03.860 --> 14:04.660 However, 14:04.800 --> 14:07.040 when you look at this in a variety of ways, 14:08.050 --> 14:10.970 the median dose is is about a quarter milligram per 14:10.970 --> 14:13.360 kilo at which 14:13.370 --> 14:14.800 rejection occurs. 14:14.820 --> 14:17.540 And that keeps recurring depending on how you want to 14:17.550 --> 14:18.220 analyze it. 14:18.230 --> 14:21.130 That that quarter milligram per kilo is 14:21.130 --> 14:23.490 the important point where 14:23.500 --> 14:26.450 uh most half the 14:26.450 --> 14:28.120 rejection episodes will be under that. 14:28.120 --> 14:29.600 So it's sort of the danger point. 14:29.600 --> 14:31.070 Once you get to that level, 14:32.200 --> 14:34.470 Another way of looking at trying to hold 14:34.470 --> 14:36.780 time relatively constant 14:36.780 --> 14:37.730 here, 14:37.740 --> 14:40.640 only looking at those within the one year. 14:40.650 --> 14:43.080 And this is a cumulative frequency curve. 14:43.300 --> 14:44.780 And here you'll see that 14:44.790 --> 14:47.770 uh Those 14:47.770 --> 14:50.600 who are 50% of rejection episodes are 14:50.600 --> 14:53.520 occurring at less than about .25 or 14:53.520 --> 14:55.040 .3 mg per kilo. 14:59.210 --> 15:02.200 So I think uh again we looked at this in a number of 15:02.200 --> 15:03.930 other ways which you don't have time to go into, 15:03.930 --> 15:06.840 but about 50% of rejection is occurring six months or more 15:06.840 --> 15:09.570 transplantation take place when predniSONE is 15:09.570 --> 15:12.120 reduced to 0.25 or below. 15:12.200 --> 15:14.580 So I think when you get to that range, 15:14.680 --> 15:17.460 you better hold there if your patients tolerating it 15:17.460 --> 15:20.370 well or go very slow because you really are 15:20.370 --> 15:22.320 getting into the when you lower it much more, 15:22.320 --> 15:25.250 you're going to have an increased incidence of rejection. 15:26.610 --> 15:28.400 What about the individual patients? 15:28.410 --> 15:31.120 Well here we're looking at 15:31.690 --> 15:34.160 zero line here or baseline is the 15:34.170 --> 15:36.920 predniSONE dose at which a first rejection episode 15:36.920 --> 15:37.590 occurred. 15:38.430 --> 15:41.150 And then we're looking at second rejection episodes and say, 15:41.150 --> 15:41.480 you know, 15:41.490 --> 15:44.290 at what predniSONE dose does rejection occur 15:44.830 --> 15:47.810 relative to the dose that it occurred at at the first time 15:47.810 --> 15:48.170 around. 15:49.020 --> 15:51.220 And you'll see that these black dots 15:51.230 --> 15:53.840 are almost all the 15:53.850 --> 15:55.470 exception of those two, 15:55.500 --> 15:58.260 within 25% 15:58.270 --> 16:01.050 of the baseline dose or below it. 16:01.060 --> 16:03.690 Now there are some people who will get 16:03.700 --> 16:06.620 below baseline and never do reject 16:06.620 --> 16:09.570 the second time or at least haven't up until at the time of this 16:09.570 --> 16:10.020 study. 16:10.050 --> 16:11.160 So again, 16:11.160 --> 16:13.040 there's a great individual variation. 16:13.100 --> 16:13.900 But again, 16:13.900 --> 16:16.830 I would make the point that when you get 16:17.550 --> 16:19.930 Near that range when you're back to within 16:19.930 --> 16:22.130 25% of what of the dose, 16:22.130 --> 16:24.200 which the first rejection episode occurred. 16:24.450 --> 16:26.050 Then you'd better go slow. 16:26.060 --> 16:28.260 Be careful because you're getting into the 16:29.010 --> 16:31.930 range at which rejection is much more likely to occur 16:31.940 --> 16:32.760 a second time. 16:35.030 --> 16:37.480 Let's just skip this for now. 16:37.480 --> 16:40.220 And we tried to determine whether kidneys that 16:40.220 --> 16:43.070 rejected at high predniSONE doses did 16:43.080 --> 16:45.830 better or worse than kidneys that rejected at low 16:45.840 --> 16:48.510 uh predniSONE doses in the long 16:48.510 --> 16:48.900 run. 16:48.910 --> 16:50.700 And we we could not tell any difference. 16:53.840 --> 16:55.920 Let me just spend a moment on pulse therapy. 16:55.920 --> 16:58.830 We've had a couple of publications from our institution on 16:58.840 --> 16:59.700 pulse therapy. 17:00.840 --> 17:03.440 The history of pulse therapy was that it 17:03.440 --> 17:06.270 started at stanford 17:06.270 --> 17:09.130 really when Dr sam was there and he gave 17:09.130 --> 17:12.040 ivy methylprednisolone directly into the 17:12.040 --> 17:13.260 renal artery with a drip. 17:14.000 --> 17:16.890 And initially he thought that he got superior results 17:17.290 --> 17:19.160 using that method of administration. 17:19.600 --> 17:22.210 But then he did a control giving an ivy 17:22.210 --> 17:25.140 systemically and he found that his controls did as 17:25.140 --> 17:27.880 well as those that he gave an intra arterial e but he was using 17:27.940 --> 17:30.800 1000 mg per day 17:30.810 --> 17:31.560 in this study. 17:32.050 --> 17:34.500 The basis of that then started giving at the time of 17:34.500 --> 17:36.830 rejection and it was used sporadically, 17:36.830 --> 17:38.970 but not a great deal talked about until some 17:38.970 --> 17:41.780 publications from England and from from our 17:41.780 --> 17:43.320 place came out 17:44.500 --> 17:45.470 in recent years. 17:45.470 --> 17:48.420 People question the 17:48.430 --> 17:50.620 value of pulse therapy 17:50.660 --> 17:53.620 and whether or not it has more or less 17:53.620 --> 17:55.020 side effects and so on. 17:55.030 --> 17:57.540 I think a lot of the difference of opinion has to 17:57.540 --> 18:00.000 do with the mode of administration 18:01.180 --> 18:04.110 and what you're trying to achieve what we 18:04.110 --> 18:06.000 did in this uh study, 18:06.010 --> 18:07.760 we used methylprednisolone, 18:07.760 --> 18:10.470 30 mg per kilogram ivy in 18:10.470 --> 18:13.290 250 ml or 5% dextrose and 18:13.290 --> 18:13.740 water. 18:13.840 --> 18:14.910 You take that much. 18:14.910 --> 18:17.570 Practice alone and shove it in 18:17.580 --> 18:19.080 just inject it directly. 18:19.090 --> 18:21.810 Uh you will have an incidence of side 18:21.810 --> 18:24.460 effects Uh hypertensive 18:24.460 --> 18:25.270 crises. 18:25.280 --> 18:27.000 Uh and so on. 18:27.010 --> 18:28.690 It's low but it will occur. 18:28.700 --> 18:31.690 So if you're gonna use this dose you have to give it over 18:31.700 --> 18:33.640 30 minutes or an hour. 18:33.650 --> 18:36.400 We raised our daily oral predniSONE by 18:36.400 --> 18:38.330 10 mg or 25%. 18:38.330 --> 18:39.520 Whichever was greater. 18:39.710 --> 18:42.690 We only repeated it the pulse that is every 18:42.690 --> 18:45.290 48 to 72 hours if renal 18:45.290 --> 18:46.880 function did not improve. 18:46.950 --> 18:49.630 And the maximum number of doses we used was four doses 18:50.180 --> 18:52.080 gradually tapered the oral predniSONE. 18:52.280 --> 18:55.210 Okay well the point I would like to make is the whole idea of 18:55.210 --> 18:56.810 giving pulse therapy 18:57.470 --> 19:00.200 ah was to get 19:00.200 --> 19:03.190 away from the chronic administration of high doses the 19:03.190 --> 19:04.200 daily or the B. 19:04.200 --> 19:04.300 I. 19:04.300 --> 19:04.580 D. 19:04.580 --> 19:05.130 Or the T. 19:05.130 --> 19:05.220 I. 19:05.220 --> 19:05.430 D. 19:05.430 --> 19:05.950 Dose. 19:05.990 --> 19:08.340 With the thought that we 19:08.340 --> 19:11.290 would maintain the effectiveness as far 19:11.290 --> 19:12.450 as reversing rejection. 19:12.460 --> 19:15.190 Hopefully minimize the side effects. 19:16.300 --> 19:19.040 And that's a timing problem in terms of how 19:19.050 --> 19:21.960 often you give them the dose and here is 19:21.960 --> 19:23.960 the half life of I. 19:23.960 --> 19:24.210 V. 19:24.210 --> 19:26.420 Methylprednisolone is determined by gas 19:26.420 --> 19:28.280 chromatography and it's 19:28.280 --> 19:31.160 about it's either 19:31.160 --> 19:33.500 2.3 or 2.7 hours half light. 19:33.730 --> 19:35.300 And here's what happens to the serum levels. 19:35.300 --> 19:38.130 And you see that by 24 hours after an I. 19:38.130 --> 19:38.390 V. 19:38.390 --> 19:40.780 Dose it's down to almost undetectable 19:40.780 --> 19:41.630 levels. 19:41.790 --> 19:44.360 Same dose given orally last much longer. 19:46.360 --> 19:49.330 I don't think there's much point in giving pulses if you're going 19:49.330 --> 19:51.830 to give it every eight hours you're gonna give it B. 19:51.830 --> 19:51.920 I. 19:51.920 --> 19:52.270 D. 19:53.100 --> 19:56.000 Because you're gonna have these curves overlapping and you're not 19:56.000 --> 19:58.890 gonna get down into this low dose range 19:58.900 --> 20:01.480 and therefore I don't think you would expect a 20:01.490 --> 20:02.900 reduction in side effects. 20:03.070 --> 20:06.040 And I think some people have forgotten that they give a pulse every day and 20:06.040 --> 20:07.490 they give it every twice a day. 20:08.180 --> 20:11.090 I don't think there's any evidence to determine 20:11.090 --> 20:13.050 what the proper dose level should be. 20:13.050 --> 20:15.450 Is this 30 mg per kilo. 20:15.450 --> 20:18.260 Works out to about 1800 mg in Most 20:18.270 --> 20:21.120 people perhaps 1000 mg is 20:21.120 --> 20:21.430 enough. 20:21.430 --> 20:22.670 Perhaps 500 is enough. 20:22.670 --> 20:24.010 There's simply no data. 20:24.160 --> 20:25.310 Comparative data. 20:25.980 --> 20:28.920 But I don't think that if you're giving pulses every 20:28.920 --> 20:31.590 eight hours you should try to compare it and say with a study 20:31.910 --> 20:32.930 that we did. 20:33.280 --> 20:35.660 And our own impression is I think it's 20:35.660 --> 20:36.620 effective. 20:37.220 --> 20:39.940 Um 92% of the rejection 20:39.940 --> 20:41.520 episodes were reversed. 20:44.070 --> 20:46.960 Um Here's just some conclusion. 20:46.960 --> 20:49.700 There's 2.3 plus or -17 hours is the half 20:49.700 --> 20:49.990 line. 20:50.380 --> 20:52.190 There's no question that will reverse rejection. 20:52.200 --> 20:54.590 Whether it's better than oral 20:54.590 --> 20:56.860 pulsing or some other treatment is simply 20:56.860 --> 20:57.650 undetermined. 20:58.340 --> 21:01.040 We have the distinct clinical impression that it 21:01.040 --> 21:03.060 reduces side effects and there's some other 21:03.330 --> 21:05.480 conveniences to using it. 21:05.490 --> 21:06.620 But 21:07.310 --> 21:09.830 uh I don't think there's any 21:09.900 --> 21:11.240 concrete evidence of that. 21:11.240 --> 21:13.430 So we still use pulse therapy. 21:15.300 --> 21:17.260 We think it's less side effect. 21:17.270 --> 21:19.160 We think it's easy to use. 21:19.200 --> 21:21.800 We don't see toxicity from the 21:21.800 --> 21:22.400 injection. 21:22.400 --> 21:25.320 If we give it over 30 minutes to an hour. 21:26.170 --> 21:28.500 But we would qualify that with saying, 21:28.500 --> 21:31.470 we don't repeat it any more often than every 48 hours 21:31.470 --> 21:34.300 and give a maximum of 3-4 doses. 21:35.130 --> 21:37.110 And I think those people who 21:38.410 --> 21:41.320 Have criticized pulse therapy really have no more evidence 21:41.320 --> 21:42.970 to base their criticism on. 21:42.970 --> 21:43.090 Then. 21:43.090 --> 21:45.850 Perhaps we do to say that it's better than 21:45.850 --> 21:47.280 giving oral doses. 21:47.470 --> 21:49.640 But I can tell you from 21:50.280 --> 21:53.000 personal experience that it's much less toxic than giving 21:53.000 --> 21:55.780 200 mg of predniSONE orally a day for a week or 21:55.780 --> 21:56.850 something of that sort. 21:57.940 --> 21:59.780 Well where are we at with immune suppression 22:01.500 --> 22:04.470 Essentially the results of transplantation have plateau 22:04.470 --> 22:06.110 the last three or four years. 22:06.600 --> 22:09.480 I think the 10 years prior to that we've 22:09.490 --> 22:11.830 spent refining our management without any 22:11.830 --> 22:13.880 basic breakthroughs. 22:14.620 --> 22:17.550 I think more and more people are coming to the conclusion 22:17.550 --> 22:20.530 that whatever we do uh 22:21.250 --> 22:23.960 to manipulate the immune system and to achieving this 22:23.960 --> 22:24.660 depression, 22:25.110 --> 22:27.570 there's something that goes on early in the course 22:28.010 --> 22:30.730 that determines the long term fate of that kidney. 22:31.590 --> 22:33.180 To conclusions from that one, 22:33.180 --> 22:36.070 maybe we should focus on what we do in an image 22:36.070 --> 22:38.860 suppressant way early rather than just 22:38.940 --> 22:40.930 long term chronic regimens. 22:41.490 --> 22:42.430 And secondly, 22:42.430 --> 22:45.280 if you're having a lot of trouble with the kidney in the late post transplant 22:45.290 --> 22:46.080 period, 22:46.100 --> 22:48.780 it's fate is probably pretty well determined and we don't 22:48.790 --> 22:51.700 persist as long as we used to in trying to 22:51.700 --> 22:53.820 maintain that kidney but we'll give up on it, 22:54.380 --> 22:56.820 stop them and suppression or lower the dose 22:57.210 --> 22:58.470 and then do a second graf, 22:59.850 --> 23:02.320 immuno suppressive management 23:02.660 --> 23:03.720 with Jeremiah G. 23:03.720 --> 23:04.360 Turcotte, 23:04.580 --> 23:04.860 M. 23:04.860 --> 23:05.200 D. 23:05.200 --> 23:06.560 Professor of surgery, 23:06.560 --> 23:09.390 University of Michigan Hospital at ANn Arbor 23:10.120 --> 23:12.960 was produced through the mobile facilities of the television 23:12.960 --> 23:13.570 division, 23:13.860 --> 23:15.370 Academy of Health Sciences, 23:15.370 --> 23:16.590 United States Army, 23:16.780 --> 23:18.540 Fort sam Houston texas.