5 Penyakit Ginjal Pada Anak

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good morning everybody for those of you
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who don't know me I'm Claudia smarm one
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of the cardiologists here and the
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medical director of the ventricular
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assist device program on behalf of the
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Department of Medicine and the division
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of Cardiology we would like to express
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our gratitude to Professor Sampson
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for supporting this visiting
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professorship and we are honored and
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delighted to be able to have dr. Keith
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Aronson from University of Michigan as
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this year's Samsun visiting professor
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dr. Aronson is an international leader
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in the field of advanced heart failure
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mechanical support and heart
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transplantation and he spend the
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principal investigator on a vast number
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of really pivotal types of clinical
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trials that have moved our field forward
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and he's the heart trumpet professor of
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medicine at University of Michigan and
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the medical director of the advanced
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heart failure program there and in
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addition to all of his PubMed searchable
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accomplishments and and his really
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prolific career he's also been a friend
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and mentor to many many people in our
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field so it's my distinct honor to
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introduce professor Aronson
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wanted me to move away from that I thank
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you for that very generous introduction
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and thank you all for inviting me here
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I'm I'm honored to be here particularly
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honored to be here for this
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professorship I had mentioned a couple
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people that I read about dr. Sampson at
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your life a few days ago and to say
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humbled isn't can't begin to express it
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I know I won't recount your
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accomplishment because I know everybody
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here's well aware of them but honestly I
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can't help but being choked up thinking
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about what you've lived through and and
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it's truly inspirational
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lilius so I do have a couple of
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questions getting when I came to the
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other day skies were grey and two things
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I couldn't figure out one was why all
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the ends were upside down that was
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really good and the other is how is that
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there's I must have walked past a few
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hundred u-dub students and nobody was
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carrying an umbrella I was walking
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around I looked like you know I might
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have just had a big B for tourists on my
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head so do you make a Gortex here what
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does how does that work alright I don't
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have any conference of interests to
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disclose I will be talking about an
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experimental device so I wanted to
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emphasize that I don't have any
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financial interest intellectual interest
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but no financial interest in the device
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at all
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at all
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at all
so cardio renal syndrome is defined as a
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pathophysiologic disorder the heart
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kidneys whereby acute or chronic
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dysfunction of one leads to acute or
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chronic dysfunction of the other it's
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been divided into into five types we are
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going to focus on type really type 1
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type 2 is chronic abnormalities in
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cardiac function causing progressive and
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potentially permanent CKD and certainly
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many of the patients we talk about will
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have underlying type to chronic cardian
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syndrome
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one is acute worsening of cardiac
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function leading to acute kidney injury
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and in fact about sixty percent of
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people who have type one acute cardio
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real syndrome have underlying chronic
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kidney disease at the time that they
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develop acute worsening heart failure
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acute worsen kidney failure in in the
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context of acute decompensated heart
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failure so CKD is president about a
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third of patients with chronic heart
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failure and is associated with increased
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mortality in both half ref and half half
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this is a study of looking at quartiles
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of GFR in patients this is a secondary
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analysis of prime to a study of a drug I
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Poppa mean which didn't work in heart
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failure but what you see there is that
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as GFR drops the likelihood of dying
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goes up whoops wrong way and this is
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looking at mortality risk as a function
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of both New York art Association class
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in GFR and you see that increasing risk
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of dying as the New York art Association
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class goes opera gets Heartfilia gets
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worse as well as an increased risk as
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the GFR drops with to an even greater
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extent and you see that these are are
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interact with each other so it's been a
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number of meta analyses looking at at
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this worsening renal function which is
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variously defined which we'll get to in
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a bit occurs in about a fifth to two
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fifths of patients hospitalized for
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heart failure associated with increased
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mortality and I mentioned that sixty
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percent of those have CKD Demi has done
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two meta-analyses there's actually a
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little bit better better graphics for
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the first one so I'll talk about that
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mainly this is of eight studies
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evaluating worsening renal function and
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all cause mortality in heart failure
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samples you see a whole lot of patients
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with plum follow-up both inpatients and
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outpatients and here Lee characterized
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worsening
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worsening
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worsening
function as as class one two or three or
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mild moderate or severe and you see the
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categories they are point 2 to point 3
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or a 5 to 10 percent decrease in GFR 0.3
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to 0.5 of creatinine or 11 to 15 or
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greater than 0.5 this the studies used
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only look at one cutoff use point three
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but you do have to look at how its
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defined in the literature to understand
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what they're saying so this is looking
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at people with moderate worsening renal
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function again that's point three two
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point five 11 and 15 mil per minute or 1
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point 7 3 meters squared and you see a a
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point estimate for for the relative risk
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of 1.48 for class 3 point 5 are greater
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than 0.5 a very large increase of over 3
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fold increase in in mortality and the
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the increased risk that's associated
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with worsening renal function is not
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just in the short term right so here you
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see a best fit curve looking at hospital
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mortality one month mortality six months
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and and greater than six months and
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while the risk does decline over time
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it's still it's still persistent and I
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think as we all know that risk is a
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function of of what the baseline certain
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creatinine is so as certain creatinine
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goes up the risk correspondingly goes on
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so this is updated in 2014 now with with
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over a million subjects in these studies
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and again very similar findings are all
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cause mortality odds ratio 2.3 worse
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than renal function the same prevalence
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really as I as I mentioned before so
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what's the relationship of Hiba dynamics
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to worsening renal function the QT
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compensated heart failure and this this
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00:08:08,080 --> 00:08:08,090
329
00:08:08,090 --> 00:08:10,780
is painful frankly for for the most of
330
00:08:10,780 --> 00:08:10,790
331
00:08:10,790 --> 00:08:12,340
us who work in
332
00:08:12,340 --> 00:08:12,350
us who work in
333
00:08:12,350 --> 00:08:13,630
us who work in
in end-stage heart failure because
334
00:08:13,630 --> 00:08:13,640
335
00:08:13,640 --> 00:08:15,850
there's a whole lot of stuff we do that
336
00:08:15,850 --> 00:08:15,860
337
00:08:15,860 --> 00:08:19,120
there's incredibly scant evidence as any
338
00:08:19,120 --> 00:08:19,130
339
00:08:19,130 --> 00:08:21,670
benefit now the truth is we all have
340
00:08:21,670 --> 00:08:21,680
341
00:08:21,680 --> 00:08:25,260
anecdotes and you know individual
342
00:08:25,260 --> 00:08:25,270
343
00:08:25,270 --> 00:08:27,160
patients that we've taken care of that
344
00:08:27,160 --> 00:08:27,170
345
00:08:27,170 --> 00:08:28,570
we're absolutely convinced it's made a
346
00:08:28,570 --> 00:08:28,580
347
00:08:28,580 --> 00:08:29,890
difference I'm still convinced that
348
00:08:29,890 --> 00:08:29,900
349
00:08:29,900 --> 00:08:32,260
there are people who we've put on
350
00:08:32,260 --> 00:08:32,270
351
00:08:32,270 --> 00:08:34,440
temporary mechanical circulatory sorry
352
00:08:34,440 --> 00:08:34,450
353
00:08:34,450 --> 00:08:36,610
temporary mechanical circulatory support
354
00:08:36,610 --> 00:08:36,620
355
00:08:36,620 --> 00:08:39,040
of one kind or another that we've helped
356
00:08:39,040 --> 00:08:39,050
357
00:08:39,050 --> 00:08:41,860
and you'll despite what I'm about to say
358
00:08:41,860 --> 00:08:41,870
359
00:08:41,870 --> 00:08:43,240
yeah you all convince me otherwise
360
00:08:43,240 --> 00:08:43,250
361
00:08:43,250 --> 00:08:45,460
but if you but if you look at the
362
00:08:45,460 --> 00:08:45,470
363
00:08:45,470 --> 00:08:48,310
studies it is extremely difficult to
364
00:08:48,310 --> 00:08:48,320
365
00:08:48,320 --> 00:08:51,220
show that so this is 145 consecutive
366
00:08:51,220 --> 00:08:51,230
367
00:08:51,230 --> 00:08:52,990
patients with Hef breath at the
368
00:08:52,990 --> 00:08:53,000
369
00:08:53,000 --> 00:08:54,490
Cleveland Clinic who works who were
370
00:08:54,490 --> 00:08:54,500
371
00:08:54,500 --> 00:08:56,710
admitted to their ICU with a QT
372
00:08:56,710 --> 00:08:56,720
373
00:08:56,720 --> 00:08:59,440
compensated heart failure which pressure
374
00:08:59,440 --> 00:08:59,450
375
00:08:59,450 --> 00:09:01,120
greater than 18 are right atrial
376
00:09:01,120 --> 00:09:01,130
377
00:09:01,130 --> 00:09:02,820
pressure greater than 8 index lessons
378
00:09:02,820 --> 00:09:02,830
379
00:09:02,830 --> 00:09:05,860
2.4 looked at the impact of baseline
380
00:09:05,860 --> 00:09:05,870
381
00:09:05,870 --> 00:09:09,970
hemodynamics on the on the occurrence of
382
00:09:09,970 --> 00:09:09,980
383
00:09:09,980 --> 00:09:13,210
worsening renal function here defined as
384
00:09:13,210 --> 00:09:13,220
385
00:09:13,220 --> 00:09:17,350
rise of cretin of 0.3 or greater so you
386
00:09:17,350 --> 00:09:17,360
387
00:09:17,360 --> 00:09:19,230
know about 2/5 developed it and about
388
00:09:19,230 --> 00:09:19,240
389
00:09:19,240 --> 00:09:23,410
3/5 did not so this is looking at
390
00:09:23,410 --> 00:09:23,420
391
00:09:23,420 --> 00:09:25,750
quartiles of serum blood pressure and
392
00:09:25,750 --> 00:09:25,760
393
00:09:25,760 --> 00:09:28,450
what you can see is below each quartile
394
00:09:28,450 --> 00:09:28,460
395
00:09:28,460 --> 00:09:30,430
of blood pressure it's telling you in
396
00:09:30,430 --> 00:09:30,440
397
00:09:30,440 --> 00:09:31,390
the same is going to be on the graphs
398
00:09:31,390 --> 00:09:31,400
399
00:09:31,400 --> 00:09:34,030
that once I show you next the next three
400
00:09:34,030 --> 00:09:34,040
401
00:09:34,040 --> 00:09:35,290
it shows you what the baseline
402
00:09:35,290 --> 00:09:35,300
403
00:09:35,300 --> 00:09:39,360
creatinine was in those patients so
404
00:09:39,360 --> 00:09:39,370
405
00:09:39,370 --> 00:09:41,980
admission SBP was not associated with
406
00:09:41,980 --> 00:09:41,990
407
00:09:41,990 --> 00:09:43,330
course the adrenal function you know one
408
00:09:43,330 --> 00:09:43,340
409
00:09:43,340 --> 00:09:45,730
of the thoughts for for worsening real
410
00:09:45,730 --> 00:09:45,740
411
00:09:45,740 --> 00:09:47,590
function is the renal perfusion gradient
412
00:09:47,590 --> 00:09:47,600
413
00:09:47,600 --> 00:09:50,620
and if you think of the input function
414
00:09:50,620 --> 00:09:50,630
415
00:09:50,630 --> 00:09:53,650
as a function of systemic blood pressure
416
00:09:53,650 --> 00:09:53,660
417
00:09:53,660 --> 00:09:56,050
and the resistance on the other side
418
00:09:56,050 --> 00:09:56,060
419
00:09:56,060 --> 00:09:58,690
being central venous pressure or such a
420
00:09:58,690 --> 00:09:58,700
421
00:09:58,700 --> 00:10:01,510
fetus pressure as a surrogate then one
422
00:10:01,510 --> 00:10:01,520
423
00:10:01,520 --> 00:10:02,950
might think that is a pressure slower
424
00:10:02,950 --> 00:10:02,960
425
00:10:02,960 --> 00:10:04,720
you'd have work more worse in renal
426
00:10:04,720 --> 00:10:04,730
427
00:10:04,730 --> 00:10:10,270
function not so admission blood pressure
428
00:10:10,270 --> 00:10:10,280
429
00:10:10,280 --> 00:10:12,160
was not associated with worsening mental
430
00:10:12,160 --> 00:10:12,170
431
00:10:12,170 --> 00:10:13,900
function can you see the creatinine who
432
00:10:13,900 --> 00:10:13,910
433
00:10:13,910 --> 00:10:17,950
are roughly the same she went across now
434
00:10:17,950 --> 00:10:17,960
435
00:10:17,960 --> 00:10:21,190
admission cardiac index was associated
436
00:10:21,190 --> 00:10:21,200
437
00:10:21,200 --> 00:10:23,620
with worsening real function but before
438
00:10:23,620 --> 00:10:23,630
439
00:10:23,630 --> 00:10:25,540
you get too excited about that and maybe
440
00:10:25,540 --> 00:10:25,550
441
00:10:25,550 --> 00:10:27,460
prints a little bit small it's the
442
00:10:27,460 --> 00:10:27,470
443
00:10:27,470 --> 00:10:29,740
higher cardiac index in this study that
444
00:10:29,740 --> 00:10:29,750
445
00:10:29,750 --> 00:10:31,000
was associated with worsening renal
446
00:10:31,000 --> 00:10:31,010
447
00:10:31,010 --> 00:10:33,760
function not lower cardiac index now you
448
00:10:33,760 --> 00:10:33,770
449
00:10:33,770 --> 00:10:35,230
now it's important to note though that
450
00:10:35,230 --> 00:10:35,240
451
00:10:35,240 --> 00:10:37,360
of these hundred forty-five patients if
452
00:10:37,360 --> 00:10:37,370
453
00:10:37,370 --> 00:10:40,180
you came in with a QT compensated heart
454
00:10:40,180 --> 00:10:40,190
455
00:10:40,190 --> 00:10:42,040
failure when the cardiac index with two
456
00:10:42,040 --> 00:10:42,050
457
00:10:42,050 --> 00:10:46,020
points of you know greater than 2.6 then
458
00:10:46,020 --> 00:10:46,030
459
00:10:46,030 --> 00:10:48,970
your your creatinine was actually at
460
00:10:48,970 --> 00:10:48,980
461
00:10:48,980 --> 00:10:50,830
baseline quite a bit higher right so
462
00:10:50,830 --> 00:10:50,840
463
00:10:50,840 --> 00:10:51,790
part of the issue here is that the
464
00:10:51,790 --> 00:10:51,800
465
00:10:51,800 --> 00:10:55,240
patients were not getting or not getting
466
00:10:55,240 --> 00:10:55,250
467
00:10:55,250 --> 00:10:58,120
effectively diary stories I'm
468
00:10:58,120 --> 00:10:58,130
469
00:10:58,130 --> 00:11:01,090
hypothesizing a resistance to trying to
470
00:11:01,090 --> 00:11:01,100
471
00:11:01,100 --> 00:11:02,590
diaries them or maybe an inability to
472
00:11:02,590 --> 00:11:02,600
473
00:11:02,600 --> 00:11:06,000
because of underlying kidney dysfunction
474
00:11:06,000 --> 00:11:06,010
475
00:11:06,010 --> 00:11:08,350
admission CVP however was strongly
476
00:11:08,350 --> 00:11:08,360
477
00:11:08,360 --> 00:11:11,370
associated with worsening renal function
478
00:11:11,370 --> 00:11:11,380
479
00:11:11,380 --> 00:11:14,080
and you see that here so CVP lesson
480
00:11:14,080 --> 00:11:14,090
481
00:11:14,090 --> 00:11:17,290
eight lowest quartile with you know less
482
00:11:17,290 --> 00:11:17,300
483
00:11:17,300 --> 00:11:19,810
than 10% of people developing or some
484
00:11:19,810 --> 00:11:19,820
485
00:11:19,820 --> 00:11:21,820
renal function whereas if your CVP was
486
00:11:21,820 --> 00:11:21,830
487
00:11:21,830 --> 00:11:23,980
over twenty four it was about close to
488
00:11:23,980 --> 00:11:23,990
489
00:11:23,990 --> 00:11:26,890
eighty percent now the secondary
490
00:11:26,890 --> 00:11:26,900
491
00:11:26,900 --> 00:11:28,690
analysis of the escaped trial that also
492
00:11:28,690 --> 00:11:28,700
493
00:11:28,700 --> 00:11:30,250
shed some light on this escape was a
494
00:11:30,250 --> 00:11:30,260
495
00:11:30,260 --> 00:11:32,110
randomized clinical trial and IH funded
496
00:11:32,110 --> 00:11:32,120
497
00:11:32,120 --> 00:11:33,610
that was looking to see whether P a
498
00:11:33,610 --> 00:11:33,620
499
00:11:33,620 --> 00:11:38,290
catheter guided therapy would lead to a
500
00:11:38,290 --> 00:11:38,300
501
00:11:38,300 --> 00:11:40,930
reduction in days alive out of the
502
00:11:40,930 --> 00:11:40,940
503
00:11:40,940 --> 00:11:44,770
hospital and that failed so the primary
504
00:11:44,770 --> 00:11:44,780
505
00:11:44,780 --> 00:11:48,730
hypothesis was was not shown to be true
506
00:11:48,730 --> 00:11:48,740
507
00:11:48,740 --> 00:11:51,100
now there was an improvement of cardiac
508
00:11:51,100 --> 00:11:51,110
509
00:11:51,110 --> 00:11:52,810
index in the PA Catherine we don't know
510
00:11:52,810 --> 00:11:52,820
511
00:11:52,820 --> 00:11:53,950
whether there was an improvement in the
512
00:11:53,950 --> 00:11:53,960
513
00:11:53,960 --> 00:11:55,480
non-key a catheter arms and we're
514
00:11:55,480 --> 00:11:55,490
515
00:11:55,490 --> 00:11:57,370
measuring it there was in the PA
516
00:11:57,370 --> 00:11:57,380
517
00:11:57,380 --> 00:11:59,080
catheter arm that was pretty substantial
518
00:11:59,080 --> 00:11:59,090
519
00:11:59,090 --> 00:12:01,480
you know about 30% that was not
520
00:12:01,480 --> 00:12:01,490
521
00:12:01,490 --> 00:12:02,950
associated with an improvement in renal
522
00:12:02,950 --> 00:12:02,960
523
00:12:02,960 --> 00:12:06,850
function and there's multiple lines of
524
00:12:06,850 --> 00:12:06,860
525
00:12:06,860 --> 00:12:08,170
evidence from this that he became he's
526
00:12:08,170 --> 00:12:08,180
527
00:12:08,180 --> 00:12:09,910
volume and volume status are not the
528
00:12:09,910 --> 00:12:09,920
529
00:12:09,920 --> 00:12:12,070
sole or major driver renal function in
530
00:12:12,070 --> 00:12:12,080
531
00:12:12,080 --> 00:12:13,840
acute decompensated heart failure so
532
00:12:13,840 --> 00:12:13,850
533
00:12:13,850 --> 00:12:16,000
baseline real function in this secondary
534
00:12:16,000 --> 00:12:16,010
535
00:12:16,010 --> 00:12:18,460
analysis was not associated with any of
536
00:12:18,460 --> 00:12:18,470
537
00:12:18,470 --> 00:12:20,380
these hemodynamic parameters listed and
538
00:12:20,380 --> 00:12:20,390
539
00:12:20,390 --> 00:12:21,880
worsening real function was not
540
00:12:21,880 --> 00:12:21,890
541
00:12:21,890 --> 00:12:23,920
associated with change in these
542
00:12:23,920 --> 00:12:23,930
543
00:12:23,930 --> 00:12:27,550
parameters and led by interventions that
544
00:12:27,550 --> 00:12:27,560
545
00:12:27,560 --> 00:12:30,670
are designed to to deal with them so I
546
00:12:30,670 --> 00:12:30,680
547
00:12:30,680 --> 00:12:32,140
said the one thing that was clear is
548
00:12:32,140 --> 00:12:32,150
549
00:12:32,150 --> 00:12:35,830
that baseline CVP is associated in most
550
00:12:35,830 --> 00:12:35,840
551
00:12:35,840 --> 00:12:39,400
studies with with
552
00:12:39,400 --> 00:12:39,410
studies with with
553
00:12:39,410 --> 00:12:41,199
studies with with
some we're seeing Emil function although
554
00:12:41,199 --> 00:12:41,209
555
00:12:41,209 --> 00:12:45,129
I not in in escape so in the DOS trial
556
00:12:45,129 --> 00:12:45,139
557
00:12:45,139 --> 00:12:47,319
they looked at again because the heart
558
00:12:47,319 --> 00:12:47,329
559
00:12:47,329 --> 00:12:48,879
failure Network and IH funded they
560
00:12:48,879 --> 00:12:48,889
561
00:12:48,889 --> 00:12:50,680
looked at high versus low dose diuretic
562
00:12:50,680 --> 00:12:50,690
563
00:12:50,690 --> 00:12:53,319
and there was in fact more fluid and
564
00:12:53,319 --> 00:12:53,329
565
00:12:53,329 --> 00:12:55,269
weight loss with high dose diuretic but
566
00:12:55,269 --> 00:12:55,279
567
00:12:55,279 --> 00:12:56,530
there was actually more worsening renal
568
00:12:56,530 --> 00:12:56,540
569
00:12:56,540 --> 00:12:58,329
function when you took off more fluid
570
00:12:58,329 --> 00:12:58,339
571
00:12:58,339 --> 00:13:02,410
what about ultra ultra filtration so no
572
00:13:02,410 --> 00:13:02,420
573
00:13:02,420 --> 00:13:05,590
improvement in renal function with ultra
574
00:13:05,590 --> 00:13:05,600
575
00:13:05,600 --> 00:13:08,829
filtration versus loop diuretics in AD
576
00:13:08,829 --> 00:13:08,839
577
00:13:08,839 --> 00:13:11,230
HF in the unload trial or rapid CHF
578
00:13:11,230 --> 00:13:11,240
579
00:13:11,240 --> 00:13:13,660
trial to a large size studies that
580
00:13:13,660 --> 00:13:13,670
581
00:13:13,670 --> 00:13:17,379
looked at ultra filtration and inker s
582
00:13:17,379 --> 00:13:17,389
583
00:13:17,389 --> 00:13:20,379
was a study of ultra filtration I'm
584
00:13:20,379 --> 00:13:20,389
585
00:13:20,389 --> 00:13:23,319
having a hard time with that one in
586
00:13:23,319 --> 00:13:23,329
587
00:13:23,329 --> 00:13:24,939
which patients had both acute
588
00:13:24,939 --> 00:13:24,949
589
00:13:24,949 --> 00:13:27,040
decompensated heart failure and we're
590
00:13:27,040 --> 00:13:27,050
591
00:13:27,050 --> 00:13:28,360
sitting real function at the time they
592
00:13:28,360 --> 00:13:28,370
593
00:13:28,370 --> 00:13:30,280
were entered into the into the study and
594
00:13:30,280 --> 00:13:30,290
595
00:13:30,290 --> 00:13:32,319
there was in fact further worsening of
596
00:13:32,319 --> 00:13:32,329
597
00:13:32,329 --> 00:13:35,019
renal function during hospitalization in
598
00:13:35,019 --> 00:13:35,029
599
00:13:35,029 --> 00:13:37,689
30 days after discharge in the patients
600
00:13:37,689 --> 00:13:37,699
601
00:13:37,699 --> 00:13:42,069
who received ultra ultra filtration so
602
00:13:42,069 --> 00:13:42,079
603
00:13:42,079 --> 00:13:43,900
that didn't work what about drug therapy
604
00:13:43,900 --> 00:13:43,910
605
00:13:43,910 --> 00:13:47,370
to protect renal function in AD HF so
606
00:13:47,370 --> 00:13:47,380
607
00:13:47,380 --> 00:13:50,559
Laughlin which is a adenosine one
608
00:13:50,559 --> 00:13:50,569
609
00:13:50,569 --> 00:13:52,059
receptor antagonist failed to preserve
610
00:13:52,059 --> 00:13:52,069
611
00:13:52,069 --> 00:13:53,620
renal function in this setting in the
612
00:13:53,620 --> 00:13:53,630
613
00:13:53,630 --> 00:13:57,819
protec trial the so tied at low dose and
614
00:13:57,819 --> 00:13:57,829
615
00:13:57,829 --> 00:14:01,179
in dopamine at low dose renal dose no
616
00:14:01,179 --> 00:14:01,189
617
00:14:01,189 --> 00:14:04,600
legal benefit in patients with a VHF and
618
00:14:04,600 --> 00:14:04,610
619
00:14:04,610 --> 00:14:07,840
renal dysfunction in rows a HF until
620
00:14:07,840 --> 00:14:07,850
621
00:14:07,850 --> 00:14:11,439
that ten the fight despite greater fluid
622
00:14:11,439 --> 00:14:11,449
623
00:14:11,449 --> 00:14:14,889
loss and greater weight loss in the
624
00:14:14,889 --> 00:14:14,899
625
00:14:14,899 --> 00:14:16,809
evidence study was actually associated
626
00:14:16,809 --> 00:14:16,819
627
00:14:16,819 --> 00:14:17,980
with a greater increase in serum
628
00:14:17,980 --> 00:14:17,990
629
00:14:17,990 --> 00:14:23,309
creatinine so none of that stuff working
630
00:14:23,309 --> 00:14:23,319
631
00:14:23,319 --> 00:14:28,840
so this is a cartoon looking at things
632
00:14:28,840 --> 00:14:28,850
633
00:14:28,850 --> 00:14:32,049
associated with heart dysfunction or
634
00:14:32,049 --> 00:14:32,059
635
00:14:32,059 --> 00:14:35,139
things that we do to people who have
636
00:14:35,139 --> 00:14:35,149
637
00:14:35,149 --> 00:14:36,939
heart dysfunction and how that might
638
00:14:36,939 --> 00:14:36,949
639
00:14:36,949 --> 00:14:41,230
impact on on kidney injury and a little
640
00:14:41,230 --> 00:14:41,240
641
00:14:41,240 --> 00:14:42,549
bit of stuff going on the other
642
00:14:42,549 --> 00:14:42,559
643
00:14:42,559 --> 00:14:46,240
direction as well and I won't go through
644
00:14:46,240 --> 00:14:46,250
645
00:14:46,250 --> 00:14:47,439
all because it's all stuff everybody
646
00:14:47,439 --> 00:14:47,449
647
00:14:47,449 --> 00:14:49,360
knows but I guess well go back to say is
648
00:14:49,360 --> 00:14:49,370
649
00:14:49,370 --> 00:14:51,009
that this stuff doesn't seem to make a
650
00:14:51,009 --> 00:14:51,019
651
00:14:51,019 --> 00:14:52,990
whole lot of difference
652
00:14:52,990 --> 00:14:53,000
653
00:14:53,000 --> 00:14:55,630
we do know I should mention just you
654
00:14:55,630 --> 00:14:55,640
655
00:14:55,640 --> 00:14:56,920
know for the sake of completeness that
656
00:14:56,920 --> 00:14:56,930
657
00:14:56,930 --> 00:14:58,630
what I haven't shown you here is a bunch
658
00:14:58,630 --> 00:14:58,640
659
00:14:58,640 --> 00:15:02,650
of analyses showing that increased real
660
00:15:02,650 --> 00:15:02,660
661
00:15:02,660 --> 00:15:05,590
dysfunction in the course of initiation
662
00:15:05,590 --> 00:15:05,600
663
00:15:05,600 --> 00:15:09,040
of ACE inhibitors is not in clinical
664
00:15:09,040 --> 00:15:09,050
665
00:15:09,050 --> 00:15:10,720
trials or in the observational analyses
666
00:15:10,720 --> 00:15:10,730
667
00:15:10,730 --> 00:15:12,900
associated with an increase in mortality
668
00:15:12,900 --> 00:15:12,910
669
00:15:12,910 --> 00:15:17,319
so you know how much do you tolerate you
670
00:15:17,319 --> 00:15:17,329
671
00:15:17,329 --> 00:15:19,269
know nobody knows the magic formula for
672
00:15:19,269 --> 00:15:19,279
673
00:15:19,279 --> 00:15:22,269
that but certainly nobody should leave
674
00:15:22,269 --> 00:15:22,279
675
00:15:22,279 --> 00:15:24,310
here and don't think anybody would have
676
00:15:24,310 --> 00:15:24,320
677
00:15:24,320 --> 00:15:26,050
but nobody should leave you're thinking
678
00:15:26,050 --> 00:15:26,060
679
00:15:26,060 --> 00:15:27,460
that we don't want to try and give a sh
680
00:15:27,460 --> 00:15:27,470
681
00:15:27,470 --> 00:15:32,199
inhibitors or some other we'll talk you
682
00:15:32,199 --> 00:15:32,209
683
00:15:32,209 --> 00:15:34,860
know it's a Cuba trial they'll sort mean
684
00:15:34,860 --> 00:15:34,870
685
00:15:34,870 --> 00:15:37,900
or no our two patients with heart
686
00:15:37,900 --> 00:15:37,910
687
00:15:37,910 --> 00:15:41,250
failure without a good reason
688
00:15:41,250 --> 00:15:41,260
689
00:15:41,260 --> 00:15:43,870
so now I'm here we've got a cartoon part
690
00:15:43,870 --> 00:15:43,880
691
00:15:43,880 --> 00:15:45,579
partly cartoon talking about immune
692
00:15:45,579 --> 00:15:45,589
693
00:15:45,589 --> 00:15:49,329
mediated damage and how that immune
694
00:15:49,329 --> 00:15:49,339
695
00:15:49,339 --> 00:15:51,790
mediated damage leading to endothelial
696
00:15:51,790 --> 00:15:51,800
697
00:15:51,800 --> 00:15:54,250
dysfunction could negatively interact
698
00:15:54,250 --> 00:15:54,260
699
00:15:54,260 --> 00:15:57,540
both on the kidney and on the heart
700
00:15:57,540 --> 00:15:57,550
701
00:15:57,550 --> 00:16:01,780
through monocyte activation and caspase
702
00:16:01,780 --> 00:16:01,790
703
00:16:01,790 --> 00:16:04,000
activation so we could talk a little bit
704
00:16:04,000 --> 00:16:04,010
705
00:16:04,010 --> 00:16:06,550
more about that as we go forward so
706
00:16:06,550 --> 00:16:06,560
707
00:16:06,560 --> 00:16:07,960
inflammation in heart failure so both
708
00:16:07,960 --> 00:16:07,970
709
00:16:07,970 --> 00:16:10,569
half wrath and half path are associated
710
00:16:10,569 --> 00:16:10,579
711
00:16:10,579 --> 00:16:15,000
with increased inflammation in 1990
712
00:16:15,000 --> 00:16:15,010
713
00:16:15,010 --> 00:16:19,269
milton Packer was smart enough to to
714
00:16:19,269 --> 00:16:19,279
715
00:16:19,279 --> 00:16:22,120
meet Beth Levine one of the residents at
716
00:16:22,120 --> 00:16:22,130
717
00:16:22,130 --> 00:16:26,710
Mount Sinai and and she had a lab and
718
00:16:26,710 --> 00:16:26,720
719
00:16:26,720 --> 00:16:28,329
you could measure TNF and she measured
720
00:16:28,329 --> 00:16:28,339
721
00:16:28,339 --> 00:16:29,860
TNF and found that it was increased in
722
00:16:29,860 --> 00:16:29,870
723
00:16:29,870 --> 00:16:33,190
people with Hef ref and and the smarter
724
00:16:33,190 --> 00:16:33,200
725
00:16:33,200 --> 00:16:37,329
thing he did was then marry her and and
726
00:16:37,329 --> 00:16:37,339
727
00:16:37,339 --> 00:16:40,210
then in and and here we are now in 2016
728
00:16:40,210 --> 00:16:40,220
729
00:16:40,220 --> 00:16:42,189
and there are a host of pro-inflammatory
730
00:16:42,189 --> 00:16:42,199
731
00:16:42,199 --> 00:16:44,680
cytokines that are have been identified
732
00:16:44,680 --> 00:16:44,690
733
00:16:44,690 --> 00:16:46,240
as markedly elevated
734
00:16:46,240 --> 00:16:46,250
735
00:16:46,250 --> 00:16:48,490
in patients with heart failure and
736
00:16:48,490 --> 00:16:48,500
737
00:16:48,500 --> 00:16:50,439
plenty of work showing that elevations
738
00:16:50,439 --> 00:16:50,449
739
00:16:50,449 --> 00:16:52,210
that these are associated with worse
740
00:16:52,210 --> 00:16:52,220
741
00:16:52,220 --> 00:16:54,329
outcomes and patients with heart failure
742
00:16:54,329 --> 00:16:54,339
743
00:16:54,339 --> 00:16:56,860
so the cytokine hypothesis was just put
744
00:16:56,860 --> 00:16:56,870
745
00:16:56,870 --> 00:17:02,230
forward by man is that heart failure
746
00:17:02,230 --> 00:17:02,240
747
00:17:02,240 --> 00:17:03,730
progresses at least in part as a result
748
00:17:03,730 --> 00:17:03,740
749
00:17:03,740 --> 00:17:06,100
of the the effects
750
00:17:06,100 --> 00:17:06,110
of the the effects
751
00:17:06,110 --> 00:17:08,679
of the the effects
that are exerted by the innate immune
752
00:17:08,679 --> 00:17:08,689
753
00:17:08,689 --> 00:17:10,900
system endogenous cytokine cascades on
754
00:17:10,900 --> 00:17:10,910
755
00:17:10,910 --> 00:17:12,370
the heart and on the peripheral
756
00:17:12,370 --> 00:17:12,380
757
00:17:12,380 --> 00:17:14,949
circulation and as I mentioned
758
00:17:14,949 --> 00:17:14,959
759
00:17:14,959 --> 00:17:16,929
elevations of these biomarkers are
760
00:17:16,929 --> 00:17:16,939
761
00:17:16,939 --> 00:17:22,179
associated with worse outcomes I further
762
00:17:22,179 --> 00:17:22,189
763
00:17:22,189 --> 00:17:25,150
propose that the the purpose of the
764
00:17:25,150 --> 00:17:25,160
765
00:17:25,160 --> 00:17:26,650
immune response is to resolve tissue
766
00:17:26,650 --> 00:17:26,660
767
00:17:26,660 --> 00:17:30,520
injury restore long-term function but
768
00:17:30,520 --> 00:17:30,530
769
00:17:30,530 --> 00:17:32,380
that ik Roenick inflammatory state of
770
00:17:32,380 --> 00:17:32,390
771
00:17:32,390 --> 00:17:35,380
Para information exists in patients with
772
00:17:35,380 --> 00:17:35,390
773
00:17:35,390 --> 00:17:38,260
heart failure and that there's a graded
774
00:17:38,260 --> 00:17:38,270
775
00:17:38,270 --> 00:17:40,930
response that may restore tissue
776
00:17:40,930 --> 00:17:40,940
777
00:17:40,940 --> 00:17:43,480
homeostasis and maybe that's what we're
778
00:17:43,480 --> 00:17:43,490
779
00:17:43,490 --> 00:17:45,070
seeing in patients who have Micro Titus
780
00:17:45,070 --> 00:17:45,080
781
00:17:45,080 --> 00:17:48,039
who resolved but that also may result in
782
00:17:48,039 --> 00:17:48,049
783
00:17:48,049 --> 00:17:51,430
further disease progression so notice I
784
00:17:51,430 --> 00:17:51,440
785
00:17:51,440 --> 00:17:53,770
exclude play a central role in heart
786
00:17:53,770 --> 00:17:53,780
787
00:17:53,780 --> 00:17:58,000
failure from inflammation there are
788
00:17:58,000 --> 00:17:58,010
789
00:17:58,010 --> 00:18:00,130
three subsets of monocytes that are
790
00:18:00,130 --> 00:18:00,140
791
00:18:00,140 --> 00:18:01,659
based on expression of cell surface
792
00:18:01,659 --> 00:18:01,669
793
00:18:01,669 --> 00:18:06,700
markers CD 14 and CD 16 the classical
794
00:18:06,700 --> 00:18:06,710
795
00:18:06,710 --> 00:18:08,620
the the majority subset is the classical
796
00:18:08,620 --> 00:18:08,630
797
00:18:08,630 --> 00:18:11,140
subset that expresses high levels of CD
798
00:18:11,140 --> 00:18:11,150
799
00:18:11,150 --> 00:18:15,730
14 but no CD 16 the intermediate subsets
800
00:18:15,730 --> 00:18:15,740
801
00:18:15,740 --> 00:18:18,250
which is also pro-inflammatory and also
802
00:18:18,250 --> 00:18:18,260
803
00:18:18,260 --> 00:18:21,010
as expressed as high level CD 14 I have
804
00:18:21,010 --> 00:18:21,020
805
00:18:21,020 --> 00:18:23,080
some CD 16 and the non classical that
806
00:18:23,080 --> 00:18:23,090
807
00:18:23,090 --> 00:18:25,360
does not as low levels of CD 14 but a
808
00:18:25,360 --> 00:18:25,370
809
00:18:25,370 --> 00:18:29,650
lot of CD 16 so as I mentioned the
810
00:18:29,650 --> 00:18:29,660
811
00:18:29,660 --> 00:18:32,080
classical and intermediate are are
812
00:18:32,080 --> 00:18:32,090
813
00:18:32,090 --> 00:18:34,419
pro-inflammatory the non classical is
814
00:18:34,419 --> 00:18:34,429
815
00:18:34,429 --> 00:18:36,690
anti-inflammatory and has reparative
816
00:18:36,690 --> 00:18:36,700
817
00:18:36,700 --> 00:18:42,610
functions and chronic heart failure
818
00:18:42,610 --> 00:18:42,620
819
00:18:42,620 --> 00:18:44,890
chronic kidney disease diabetes of all
820
00:18:44,890 --> 00:18:44,900
821
00:18:44,900 --> 00:18:45,970
been shown have an increase in
822
00:18:45,970 --> 00:18:45,980
823
00:18:45,980 --> 00:18:47,860
pro-inflammatory monocytes compared to
824
00:18:47,860 --> 00:18:47,870
825
00:18:47,870 --> 00:18:51,520
normal controls and these this increase
826
00:18:51,520 --> 00:18:51,530
827
00:18:51,530 --> 00:18:53,470
in inflammatory monocytes is associated
828
00:18:53,470 --> 00:18:53,480
829
00:18:53,480 --> 00:18:55,690
both with worse clinical outcome and
830
00:18:55,690 --> 00:18:55,700
831
00:18:55,700 --> 00:18:56,680
progressive development of
832
00:18:56,680 --> 00:18:56,690
833
00:18:56,690 --> 00:19:02,770
atherosclerosis monocytes migrate into
834
00:19:02,770 --> 00:19:02,780
835
00:19:02,780 --> 00:19:07,270
target organs and differentiate into
836
00:19:07,270 --> 00:19:07,280
837
00:19:07,280 --> 00:19:10,150
both inflammatory and anti-inflammatory
838
00:19:10,150 --> 00:19:10,160
839
00:19:10,160 --> 00:19:14,740
macrophages m1 m2 that stimulates a
840
00:19:14,740 --> 00:19:14,750
841
00:19:14,750 --> 00:19:18,909
trigger the adaptive immunity responses
842
00:19:18,909 --> 00:19:18,919
843
00:19:18,919 --> 00:19:19,970
th 1 and th
844
00:19:19,970 --> 00:19:19,980
th 1 and th
845
00:19:19,980 --> 00:19:24,890
th 1 and th
- now invalid cardiomyopathies there's
846
00:19:24,890 --> 00:19:24,900
847
00:19:24,900 --> 00:19:26,480
evidence this and ischemic as well but
848
00:19:26,480 --> 00:19:26,490
849
00:19:26,490 --> 00:19:29,120
more in dilated cardiomyopathy or at
850
00:19:29,120 --> 00:19:29,130
851
00:19:29,130 --> 00:19:31,820
more evidence all types of infiltrated
852
00:19:31,820 --> 00:19:31,830
853
00:19:31,830 --> 00:19:35,840
all types of infiltrating cells TB cells
854
00:19:35,840 --> 00:19:35,850
855
00:19:35,850 --> 00:19:38,500
granulocytes macrophages are increased
856
00:19:38,500 --> 00:19:38,510
857
00:19:38,510 --> 00:19:41,570
but only t-cells that especially
858
00:19:41,570 --> 00:19:41,580
859
00:19:41,580 --> 00:19:43,480
macrophages are preferentially increased
860
00:19:43,480 --> 00:19:43,490
861
00:19:43,490 --> 00:19:47,510
and activated macrophages contributed
862
00:19:47,510 --> 00:19:47,520
863
00:19:47,520 --> 00:19:49,010
contractile dysfunction in heart failure
864
00:19:49,010 --> 00:19:49,020
865
00:19:49,020 --> 00:19:50,690
and there's evidence that this actually
866
00:19:50,690 --> 00:19:50,700
867
00:19:50,700 --> 00:19:53,440
occurs through direct physical contact
868
00:19:53,440 --> 00:19:53,450
869
00:19:53,450 --> 00:19:57,560
with macrophages in Maya sites at least
870
00:19:57,560 --> 00:19:57,570
871
00:19:57,570 --> 00:20:03,049
in part dependent on increased Ines so
872
00:20:03,049 --> 00:20:03,059
873
00:20:03,059 --> 00:20:04,820
what about a strategy of
874
00:20:04,820 --> 00:20:04,830
875
00:20:04,830 --> 00:20:07,100
anti-inflammatory therapy in heart
876
00:20:07,100 --> 00:20:07,110
877
00:20:07,110 --> 00:20:09,740
failure and at least to date we don't
878
00:20:09,740 --> 00:20:09,750
879
00:20:09,750 --> 00:20:10,700
have any evidence that that actually
880
00:20:10,700 --> 00:20:10,710
881
00:20:10,710 --> 00:20:16,490
works so you know documented a series of
882
00:20:16,490 --> 00:20:16,500
883
00:20:16,500 --> 00:20:18,799
studies actually the guy who runs our EP
884
00:20:18,799 --> 00:20:18,809
885
00:20:18,809 --> 00:20:21,770
program a kind of well actually did a
886
00:20:21,770 --> 00:20:21,780
887
00:20:21,780 --> 00:20:24,380
bunch of those studies before he got
888
00:20:24,380 --> 00:20:24,390
889
00:20:24,390 --> 00:20:25,400
misdirected and became an
890
00:20:25,400 --> 00:20:25,410
891
00:20:25,410 --> 00:20:29,510
electrophysiologist and showed that if
892
00:20:29,510 --> 00:20:29,520
893
00:20:29,520 --> 00:20:32,960
you give TNF to two dogs with two dogs
894
00:20:32,960 --> 00:20:32,970
895
00:20:32,970 --> 00:20:34,850
you can recapitulate the heart failure
896
00:20:34,850 --> 00:20:34,860
897
00:20:34,860 --> 00:20:38,510
syndrome so studies with antennae and
898
00:20:38,510 --> 00:20:38,520
899
00:20:38,520 --> 00:20:42,820
ten recept Renaissance and recover
900
00:20:42,820 --> 00:20:42,830
901
00:20:42,830 --> 00:20:44,780
didn't show a benefit you see here
902
00:20:44,780 --> 00:20:44,790
903
00:20:44,790 --> 00:20:46,549
transfer increased mortality at a higher
904
00:20:46,549 --> 00:20:46,559
905
00:20:46,559 --> 00:20:48,950
dose no change at a lower dose with
906
00:20:48,950 --> 00:20:48,960
907
00:20:48,960 --> 00:20:53,210
recover no mortality changed at a tither
908
00:20:53,210 --> 00:20:53,220
909
00:20:53,220 --> 00:20:56,330
dose versus placebo both no studies were
910
00:20:56,330 --> 00:20:56,340
911
00:20:56,340 --> 00:20:58,130
or stopped prematurely for lack of
912
00:20:58,130 --> 00:20:58,140
913
00:20:58,140 --> 00:21:00,350
benefit renewal was a combined analysis
914
00:21:00,350 --> 00:21:00,360
915
00:21:00,360 --> 00:21:02,600
to look at mortality in fact showed no
916
00:21:02,600 --> 00:21:02,610
917
00:21:02,610 --> 00:21:04,510
benefit on death and hospitalization
918
00:21:04,510 --> 00:21:04,520
919
00:21:04,520 --> 00:21:06,830
infliximab and the attached study a
920
00:21:06,830 --> 00:21:06,840
921
00:21:06,840 --> 00:21:09,770
smaller study showed a strong trend it's
922
00:21:09,770 --> 00:21:09,780
923
00:21:09,780 --> 00:21:11,360
actually actually clinical worsening
924
00:21:11,360 --> 00:21:11,370
925
00:21:11,370 --> 00:21:13,340
clinical worsening at the at a higher
926
00:21:13,340 --> 00:21:13,350
927
00:21:13,350 --> 00:21:15,470
dose there's a couple doses studied and
928
00:21:15,470 --> 00:21:15,480
929
00:21:15,480 --> 00:21:17,390
that was due to an increase in deaths
930
00:21:17,390 --> 00:21:17,400
931
00:21:17,400 --> 00:21:18,830
and heart failure hospitalizations so
932
00:21:18,830 --> 00:21:18,840
933
00:21:18,840 --> 00:21:21,140
that study stopped and then there's a
934
00:21:21,140 --> 00:21:21,150
935
00:21:21,150 --> 00:21:24,049
study called a claim that Guillermo
936
00:21:24,049 --> 00:21:24,059
937
00:21:24,059 --> 00:21:27,140
Torre a my own ran that was kind of
938
00:21:27,140 --> 00:21:27,150
939
00:21:27,150 --> 00:21:29,810
novel II and not entirely clear what
940
00:21:29,810 --> 00:21:29,820
941
00:21:29,820 --> 00:21:31,789
they were doing they took some took
942
00:21:31,789 --> 00:21:31,799
943
00:21:31,799 --> 00:21:32,470
peripheral blood
944
00:21:32,470 --> 00:21:32,480
peripheral blood
945
00:21:32,480 --> 00:21:35,200
peripheral blood
and passed it through a verbal black box
946
00:21:35,200 --> 00:21:35,210
947
00:21:35,210 --> 00:21:39,850
it's Kevin for me and exposed it to see
948
00:21:39,850 --> 00:21:39,860
949
00:21:39,860 --> 00:21:45,150
really exposed it to to oxidative stress
950
00:21:45,150 --> 00:21:45,160
951
00:21:45,160 --> 00:21:51,789
and it did not work probably and that
952
00:21:51,789 --> 00:21:51,799
953
00:21:51,799 --> 00:21:56,230
one so therapeutic for a dhf with cardi
954
00:21:56,230 --> 00:21:56,240
955
00:21:56,240 --> 00:21:58,930
rito syndrome so many drugs that are
956
00:21:58,930 --> 00:21:58,940
957
00:21:58,940 --> 00:22:01,659
sometimes seemingly effective in
958
00:22:01,659 --> 00:22:01,669
959
00:22:01,669 --> 00:22:02,770
individual patients
960
00:22:02,770 --> 00:22:02,780
individual patients
961
00:22:02,780 --> 00:22:04,650
individual patients
all of which fail in clinical studies
962
00:22:04,650 --> 00:22:04,660
963
00:22:04,660 --> 00:22:08,620
same could be said for devices time to
964
00:22:08,620 --> 00:22:08,630
965
00:22:08,630 --> 00:22:10,750
try something new so that lets me segue
966
00:22:10,750 --> 00:22:10,760
967
00:22:10,760 --> 00:22:12,730
into this something new stuff
968
00:22:12,730 --> 00:22:12,740
969
00:22:12,740 --> 00:22:17,200
so this is our selective site or
970
00:22:17,200 --> 00:22:17,210
971
00:22:17,210 --> 00:22:19,060
ferritic device and what does that look
972
00:22:19,060 --> 00:22:19,070
973
00:22:19,070 --> 00:22:23,289
like it's a dialysis cartridge right so
974
00:22:23,289 --> 00:22:23,299
975
00:22:23,299 --> 00:22:26,440
so this is a self processing therapeutic
976
00:22:26,440 --> 00:22:26,450
977
00:22:26,450 --> 00:22:27,970
device which modulates neutrophil
978
00:22:27,970 --> 00:22:27,980
979
00:22:27,980 --> 00:22:29,680
monocyte kinetics in a low lionized
980
00:22:29,680 --> 00:22:29,690
981
00:22:29,690 --> 00:22:31,510
calcium environment achieved through
982
00:22:31,510 --> 00:22:31,520
983
00:22:31,520 --> 00:22:33,430
regional citrate and a coagulation right
984
00:22:33,430 --> 00:22:33,440
985
00:22:33,440 --> 00:22:35,740
so we give citrate when you when you do
986
00:22:35,740 --> 00:22:35,750
987
00:22:35,750 --> 00:22:37,390
dialysis you know you give heparin but
988
00:22:37,390 --> 00:22:37,400
989
00:22:37,400 --> 00:22:38,860
then the patient's anticoagulated it
990
00:22:38,860 --> 00:22:38,870
991
00:22:38,870 --> 00:22:40,090
systemic lease you give to citrate
992
00:22:40,090 --> 00:22:40,100
993
00:22:40,100 --> 00:22:41,770
because it binds calcium makes the
994
00:22:41,770 --> 00:22:41,780
995
00:22:41,780 --> 00:22:43,750
environment hypocalcemic clotting
996
00:22:43,750 --> 00:22:43,760
997
00:22:43,760 --> 00:22:46,930
factors depend on calcium to do their
998
00:22:46,930 --> 00:22:46,940
999
00:22:46,940 --> 00:22:48,430
things so if you get rid of the calcium
1000
00:22:48,430 --> 00:22:48,440
1001
00:22:48,440 --> 00:22:50,409
you don't clot off your filter hopefully
1002
00:22:50,409 --> 00:22:50,419
1003
00:22:50,419 --> 00:22:51,669
and then you give the calcium back at
1004
00:22:51,669 --> 00:22:51,679
1005
00:22:51,679 --> 00:22:53,470
the end and you're not systemic lana
1006
00:22:53,470 --> 00:22:53,480
1007
00:22:53,480 --> 00:22:58,120
coagulated so this is the setup that was
1008
00:22:58,120 --> 00:22:58,130
1009
00:22:58,130 --> 00:23:00,010
used in a number of experiments where it
1010
00:23:00,010 --> 00:23:00,020
1011
00:23:00,020 --> 00:23:05,789
was actually done in along with
1012
00:23:05,789 --> 00:23:05,799
1013
00:23:05,799 --> 00:23:07,919
continuous renal replacement therapy
1014
00:23:07,919 --> 00:23:07,929
1015
00:23:07,929 --> 00:23:10,060
when i'll be discussing with you is
1016
00:23:10,060 --> 00:23:10,070
1017
00:23:10,070 --> 00:23:11,470
doing it without we don't replacement
1018
00:23:11,470 --> 00:23:11,480
1019
00:23:11,480 --> 00:23:12,940
therapy but what you see here is that
1020
00:23:12,940 --> 00:23:12,950
1021
00:23:12,950 --> 00:23:16,000
blood flow and this set up at the top
1022
00:23:16,000 --> 00:23:16,010
1023
00:23:16,010 --> 00:23:19,180
here is directed to the outside of these
1024
00:23:19,180 --> 00:23:19,190
1025
00:23:19,190 --> 00:23:21,100
of the hollow fiber membranes in the
1026
00:23:21,100 --> 00:23:21,110
1027
00:23:21,110 --> 00:23:23,080
inner and the filter so it's sort of the
1028
00:23:23,080 --> 00:23:23,090
1029
00:23:23,090 --> 00:23:24,490
opposite of what's happening in standard
1030
00:23:24,490 --> 00:23:24,500
1031
00:23:24,500 --> 00:23:28,150
dialysis so the blood is passing through
1032
00:23:28,150 --> 00:23:28,160
1033
00:23:28,160 --> 00:23:30,190
with low shear forces and it's your
1034
00:23:30,190 --> 00:23:30,200
1035
00:23:30,200 --> 00:23:31,600
forces that are similar to what we see
1036
00:23:31,600 --> 00:23:31,610
1037
00:23:31,610 --> 00:23:39,549
in the capillary interface and i think i
1038
00:23:39,549 --> 00:23:39,559
1039
00:23:39,559 --> 00:23:41,110
talked about it well we just say it now
1040
00:23:41,110 --> 00:23:41,120
1041
00:23:41,120 --> 00:23:43,810
I don't know if I made it clear in the
1042
00:23:43,810 --> 00:23:43,820
1043
00:23:43,820 --> 00:23:44,350
slides
1044
00:23:44,350 --> 00:23:44,360
slides
1045
00:23:44,360 --> 00:23:45,880
slides
what's happening is that in this you
1046
00:23:45,880 --> 00:23:45,890
1047
00:23:45,890 --> 00:23:46,180
know
1048
00:23:46,180 --> 00:23:46,190
know
1049
00:23:46,190 --> 00:23:48,670
know
hypocalcemic environment where the where
1050
00:23:48,670 --> 00:23:48,680
1051
00:23:48,680 --> 00:23:51,550
the ionized calcium levels between 0.25
1052
00:23:51,550 --> 00:23:51,560
1053
00:23:51,560 --> 00:23:56,410
and point for monocytes and and
1054
00:23:56,410 --> 00:23:56,420
1055
00:23:56,420 --> 00:24:00,730
neutrophils and not cells the adaptive
1056
00:24:00,730 --> 00:24:00,740
1057
00:24:00,740 --> 00:24:03,670
immune system but if you have the innate
1058
00:24:03,670 --> 00:24:03,680
1059
00:24:03,680 --> 00:24:06,550
immune system it's already activated
1060
00:24:06,550 --> 00:24:06,560
1061
00:24:06,560 --> 00:24:08,380
ones that have up regulated their
1062
00:24:08,380 --> 00:24:08,390
1063
00:24:08,390 --> 00:24:11,320
integrant enough to actually bind to
1064
00:24:11,320 --> 00:24:11,330
1065
00:24:11,330 --> 00:24:16,090
these fibers so so the thought is the
1066
00:24:16,090 --> 00:24:16,100
1067
00:24:16,100 --> 00:24:17,320
operating principle here is that you've
1068
00:24:17,320 --> 00:24:17,330
1069
00:24:17,330 --> 00:24:19,030
got to get calcium levels low enough for
1070
00:24:19,030 --> 00:24:19,040
1071
00:24:19,040 --> 00:24:19,840
this to happen
1072
00:24:19,840 --> 00:24:19,850
this to happen
1073
00:24:19,850 --> 00:24:24,100
this to happen
and this in fact not just binds these
1074
00:24:24,100 --> 00:24:24,110
1075
00:24:24,110 --> 00:24:27,340
activated it fills and monocytes but in
1076
00:24:27,340 --> 00:24:27,350
1077
00:24:27,350 --> 00:24:30,790
fact D active they deactivated to the to
1078
00:24:30,790 --> 00:24:30,800
1079
00:24:30,800 --> 00:24:33,160
the membrane and then are released after
1080
00:24:33,160 --> 00:24:33,170
1081
00:24:33,170 --> 00:24:35,740
a few hours back into the central
1082
00:24:35,740 --> 00:24:35,750
1083
00:24:35,750 --> 00:24:40,510
circulation in an active state with some
1084
00:24:40,510 --> 00:24:40,520
1085
00:24:40,520 --> 00:24:43,330
revved up apatow --ss of those of those
1086
00:24:43,330 --> 00:24:43,340
1087
00:24:43,340 --> 00:24:46,870
cells so there's evidence that that
1088
00:24:46,870 --> 00:24:46,880
1089
00:24:46,880 --> 00:24:49,660
these monocytes actually shift from the
1090
00:24:49,660 --> 00:24:49,670
1091
00:24:49,670 --> 00:24:55,270
from the classical and from the - from
1092
00:24:55,270 --> 00:24:55,280
1093
00:24:55,280 --> 00:25:00,400
the to inflammatory subtypes to the
1094
00:25:00,400 --> 00:25:00,410
1095
00:25:00,410 --> 00:25:02,490
anti-inflammatory non classical subtype
1096
00:25:02,490 --> 00:25:02,500
1097
00:25:02,500 --> 00:25:06,340
and there's also evidence that tissue
1098
00:25:06,340 --> 00:25:06,350
1099
00:25:06,350 --> 00:25:09,100
macrophages are reduced when one does
1100
00:25:09,100 --> 00:25:09,110
1101
00:25:09,110 --> 00:25:12,250
that that's been shown in CKD patients
1102
00:25:12,250 --> 00:25:12,260
1103
00:25:12,260 --> 00:25:15,610
14 patients that henry ford with CKD who
1104
00:25:15,610 --> 00:25:15,620
1105
00:25:15,620 --> 00:25:20,320
were on this for six hours and it's also
1106
00:25:20,320 --> 00:25:20,330
1107
00:25:20,330 --> 00:25:23,920
been shown in a dog model that i'm going
1108
00:25:23,920 --> 00:25:23,930
1109
00:25:23,930 --> 00:25:28,480
to show you in a little bit so this is
1110
00:25:28,480 --> 00:25:28,490
1111
00:25:28,490 --> 00:25:31,030
showing leukocyte adherence to the
1112
00:25:31,030 --> 00:25:31,040
1113
00:25:31,040 --> 00:25:33,340
selective SATA faradic device membrane
1114
00:25:33,340 --> 00:25:33,350
1115
00:25:33,350 --> 00:25:37,780
in panel a here we're seeing whoops
1116
00:25:37,780 --> 00:25:37,790
1117
00:25:37,790 --> 00:25:41,950
there we go cells around each fiber and
1118
00:25:41,950 --> 00:25:41,960
1119
00:25:41,960 --> 00:25:44,410
panel B and C we're seeing higher higher
1120
00:25:44,410 --> 00:25:44,420
1121
00:25:44,420 --> 00:25:49,630
powered photos showing them found again
1122
00:25:49,630 --> 00:25:49,640
1123
00:25:49,640 --> 00:25:53,590
and in indeed while this is a little too
1124
00:25:53,590 --> 00:25:53,600
1125
00:25:53,600 --> 00:25:56,460
small I think for unclear for you to see
1126
00:25:56,460 --> 00:25:56,470
1127
00:25:56,470 --> 00:25:59,620
it's pretty clear to see we
1128
00:25:59,620 --> 00:25:59,630
1129
00:25:59,630 --> 00:26:01,060
the neutrophils there at least for me
1130
00:26:01,060 --> 00:26:01,070
1131
00:26:01,070 --> 00:26:06,280
when I see not a better slide and this
1132
00:26:06,280 --> 00:26:06,290
1133
00:26:06,290 --> 00:26:07,900
kind of goes through I think oh good
1134
00:26:07,900 --> 00:26:07,910
1135
00:26:07,910 --> 00:26:11,260
actually visible what's happening so you
1136
00:26:11,260 --> 00:26:11,270
1137
00:26:11,270 --> 00:26:12,790
have the blood flowing outside in
1138
00:26:12,790 --> 00:26:12,800
1139
00:26:12,800 --> 00:26:15,600
between the fibers and a low shear rate
1140
00:26:15,600 --> 00:26:15,610
1141
00:26:15,610 --> 00:26:18,970
here's the red cells whoops go back up
1142
00:26:18,970 --> 00:26:18,980
1143
00:26:18,980 --> 00:26:26,580
here's the activated lymphocytes with
1144
00:26:26,580 --> 00:26:26,590
1145
00:26:26,590 --> 00:26:29,260
the activated I said lymphocytes
1146
00:26:29,260 --> 00:26:29,270
1147
00:26:29,270 --> 00:26:30,760
activated leukocytes monocytes and
1148
00:26:30,760 --> 00:26:30,770
1149
00:26:30,770 --> 00:26:33,850
neutrophils binding to the to the
1150
00:26:33,850 --> 00:26:33,860
1151
00:26:33,860 --> 00:26:39,550
membrane here they are deactivating in
1152
00:26:39,550 --> 00:26:39,560
1153
00:26:39,560 --> 00:26:42,160
this low ionization environment and then
1154
00:26:42,160 --> 00:26:42,170
1155
00:26:42,170 --> 00:26:45,400
they're being released and this
1156
00:26:45,400 --> 00:26:45,410
1157
00:26:45,410 --> 00:26:47,740
increased have a peptide a great down
1158
00:26:47,740 --> 00:26:47,750
1159
00:26:47,750 --> 00:26:53,020
regulates activation so there are a host
1160
00:26:53,020 --> 00:26:53,030
1161
00:26:53,030 --> 00:26:54,940
of preclinical studies showing striking
1162
00:26:54,940 --> 00:26:54,950
1163
00:26:54,950 --> 00:27:00,130
at efficacy in big models of hemorrhagic
1164
00:27:00,130 --> 00:27:00,140
1165
00:27:00,140 --> 00:27:03,010
astral infarction acute lung injury and
1166
00:27:03,010 --> 00:27:03,020
1167
00:27:03,020 --> 00:27:04,540
septic shock I don't have time to go
1168
00:27:04,540 --> 00:27:04,550
1169
00:27:04,550 --> 00:27:05,650
through all those I'll go through a
1170
00:27:05,650 --> 00:27:05,660
1171
00:27:05,660 --> 00:27:07,690
little bit and this was published in
1172
00:27:07,690 --> 00:27:07,700
1173
00:27:07,700 --> 00:27:14,640
plus one so what not too shabby
1174
00:27:14,640 --> 00:27:14,650
1175
00:27:14,650 --> 00:27:19,060
so this is a these are brain sections of
1176
00:27:19,060 --> 00:27:19,070
1177
00:27:19,070 --> 00:27:22,510
a hemorrhagic stroke model in which
1178
00:27:22,510 --> 00:27:22,520
1179
00:27:22,520 --> 00:27:25,120
thrombin is injected you see the sites
1180
00:27:25,120 --> 00:27:25,130
1181
00:27:25,130 --> 00:27:27,250
of thrombin injection here and when I
1182
00:27:27,250 --> 00:27:27,260
1183
00:27:27,260 --> 00:27:29,530
direct your attention to so these are
1184
00:27:29,530 --> 00:27:29,540
1185
00:27:29,540 --> 00:27:31,710
animals that are treated with the sed
1186
00:27:31,710 --> 00:27:31,720
1187
00:27:31,720 --> 00:27:34,750
this is an animal this is an animal this
1188
00:27:34,750 --> 00:27:34,760
1189
00:27:34,760 --> 00:27:36,490
is an animal that was not and what you
1190
00:27:36,490 --> 00:27:36,500
1191
00:27:36,500 --> 00:27:38,110
see here is see the the clear
1192
00:27:38,110 --> 00:27:38,120
1193
00:27:38,120 --> 00:27:40,840
differentiation of white versus gray
1194
00:27:40,840 --> 00:27:40,850
1195
00:27:40,850 --> 00:27:42,520
matter here and all the way along in
1196
00:27:42,520 --> 00:27:42,530
1197
00:27:42,530 --> 00:27:45,310
this graphic and here it's is gone
1198
00:27:45,310 --> 00:27:45,320
1199
00:27:45,320 --> 00:27:48,070
because of the surrounding a demon and
1200
00:27:48,070 --> 00:27:48,080
1201
00:27:48,080 --> 00:27:52,660
fortune and this is looking at that
1202
00:27:52,660 --> 00:27:52,670
1203
00:27:52,670 --> 00:27:57,220
brain tissue and what you see here is
1204
00:27:57,220 --> 00:27:57,230
1205
00:27:57,230 --> 00:28:01,150
the is the activated neutrophils here in
1206
00:28:01,150 --> 00:28:01,160
1207
00:28:01,160 --> 00:28:03,700
and pink and a relative dearth of them
1208
00:28:03,700 --> 00:28:03,710
1209
00:28:03,710 --> 00:28:10,460
here with sed therapy
1210
00:28:10,460 --> 00:28:10,470
1211
00:28:10,470 --> 00:28:12,930
so that all it's been done this is with
1212
00:28:12,930 --> 00:28:12,940
1213
00:28:12,940 --> 00:28:15,150
pigs there's actually people so I'm
1214
00:28:15,150 --> 00:28:15,160
1215
00:28:15,160 --> 00:28:16,140
going to talk to you about a randomized
1216
00:28:16,140 --> 00:28:16,150
1217
00:28:16,150 --> 00:28:17,940
clinical trial and there were some
1218
00:28:17,940 --> 00:28:17,950
1219
00:28:17,950 --> 00:28:20,250
smaller randomized clinical trials first
1220
00:28:20,250 --> 00:28:20,260
1221
00:28:20,260 --> 00:28:21,990
this is a larger one
1222
00:28:21,990 --> 00:28:22,000
1223
00:28:22,000 --> 00:28:24,360
comparing CRT and actually you had the
1224
00:28:24,360 --> 00:28:24,370
1225
00:28:24,370 --> 00:28:26,520
option of doing any flavor of CRT you
1226
00:28:26,520 --> 00:28:26,530
1227
00:28:26,530 --> 00:28:32,130
wanted to CRT plus the s CD in ICU
1228
00:28:32,130 --> 00:28:32,140
1229
00:28:32,140 --> 00:28:34,260
patients with acute kidney injury and at
1230
00:28:34,260 --> 00:28:34,270
1231
00:28:34,270 --> 00:28:36,810
least one non failing organ so a sofa
1232
00:28:36,810 --> 00:28:36,820
1233
00:28:36,820 --> 00:28:39,560
score of two or greater or proven or
1234
00:28:39,560 --> 00:28:39,570
1235
00:28:39,570 --> 00:28:41,700
suspected sepsis so that's how you got
1236
00:28:41,700 --> 00:28:41,710
1237
00:28:41,710 --> 00:28:43,680
into the study the primary outcome was
1238
00:28:43,680 --> 00:28:43,690
1239
00:28:43,690 --> 00:28:45,600
sixty-day all cause mortality the second
1240
00:28:45,600 --> 00:28:45,610
1241
00:28:45,610 --> 00:28:47,370
secondary outcomes are a number but the
1242
00:28:47,370 --> 00:28:47,380
1243
00:28:47,380 --> 00:28:49,860
two major ones were sixty-day we don't
1244
00:28:49,860 --> 00:28:49,870
1245
00:28:49,870 --> 00:28:51,570
replace you know replacement therapy
1246
00:28:51,570 --> 00:28:51,580
1247
00:28:51,580 --> 00:28:56,400
dependency or 28-day mortality so you
1248
00:28:56,400 --> 00:28:56,410
1249
00:28:56,410 --> 00:28:59,400
see the control therapy is you're
1250
00:28:59,400 --> 00:28:59,410
1251
00:28:59,410 --> 00:29:05,600
getting CRT alone with again citrate
1252
00:29:05,600 --> 00:29:05,610
1253
00:29:05,610 --> 00:29:07,919
anticoagulation going in and calcium
1254
00:29:07,919 --> 00:29:07,929
1255
00:29:07,929 --> 00:29:11,549
you know administration going out or
1256
00:29:11,549 --> 00:29:11,559
1257
00:29:11,559 --> 00:29:14,490
you're getting all that but you also
1258
00:29:14,490 --> 00:29:14,500
1259
00:29:14,500 --> 00:29:16,140
have the sed in line and you're not
1260
00:29:16,140 --> 00:29:16,150
1261
00:29:16,150 --> 00:29:17,790
getting the calcium back until after you
1262
00:29:17,790 --> 00:29:17,800
1263
00:29:17,800 --> 00:29:24,840
get the ESD so the plant sample size for
1264
00:29:24,840 --> 00:29:24,850
1265
00:29:24,850 --> 00:29:27,810
the study was 344 patients with 1:1
1266
00:29:27,810 --> 00:29:27,820
1267
00:29:27,820 --> 00:29:30,150
randomization and it was terminated by
1268
00:29:30,150 --> 00:29:30,160
1269
00:29:30,160 --> 00:29:33,810
the sponsor side of Farex which is the
1270
00:29:33,810 --> 00:29:33,820
1271
00:29:33,820 --> 00:29:36,450
you know you haven't spin off that I
1272
00:29:36,450 --> 00:29:36,460
1273
00:29:36,460 --> 00:29:37,940
should mention David Humes
1274
00:29:37,940 --> 00:29:37,950
1275
00:29:37,950 --> 00:29:43,020
who was the head of the medicine VA when
1276
00:29:43,020 --> 00:29:43,030
1277
00:29:43,030 --> 00:29:46,260
I was an intern and then head of
1278
00:29:46,260 --> 00:29:46,270
1279
00:29:46,270 --> 00:29:49,020
department of medicine at the old
1280
00:29:49,020 --> 00:29:49,030
1281
00:29:49,030 --> 00:29:52,590
apartment at U of M when he hired me a
1282
00:29:52,590 --> 00:29:52,600
1283
00:29:52,600 --> 00:29:54,740
wonderful guy great basketball player
1284
00:29:54,740 --> 00:29:54,750
1285
00:29:54,750 --> 00:30:00,600
and so this is his company so they
1286
00:30:00,600 --> 00:30:00,610
1287
00:30:00,610 --> 00:30:01,830
stopped it after a hundred thirty-four
1288
00:30:01,830 --> 00:30:01,840
1289
00:30:01,840 --> 00:30:03,740
patients and why did they stop it well
1290
00:30:03,740 --> 00:30:03,750
1291
00:30:03,750 --> 00:30:06,060
some of you may remember that there was
1292
00:30:06,060 --> 00:30:06,070
1293
00:30:06,070 --> 00:30:08,310
a nationwide shortage of intravenous
1294
00:30:08,310 --> 00:30:08,320
1295
00:30:08,320 --> 00:30:11,100
calcium this is one of these crazy
1296
00:30:11,100 --> 00:30:11,110
1297
00:30:11,110 --> 00:30:12,720
things that we have going on now where
1298
00:30:12,720 --> 00:30:12,730
1299
00:30:12,730 --> 00:30:14,930
things that you know are not
1300
00:30:14,930 --> 00:30:14,940
1301
00:30:14,940 --> 00:30:18,510
particularly hard to make but also
1302
00:30:18,510 --> 00:30:18,520
1303
00:30:18,520 --> 00:30:20,669
unfortunately not particularly
1304
00:30:20,669 --> 00:30:20,679
1305
00:30:20,679 --> 00:30:23,549
offensive where the profit margin is low
1306
00:30:23,549 --> 00:30:23,559
1307
00:30:23,559 --> 00:30:27,440
there are often just single source
1308
00:30:27,440 --> 00:30:27,450
1309
00:30:27,450 --> 00:30:29,909
companies one company that does it and
1310
00:30:29,909 --> 00:30:29,919
1311
00:30:29,919 --> 00:30:31,680
if they're having problems with
1312
00:30:31,680 --> 00:30:31,690
1313
00:30:31,690 --> 00:30:34,139
manufacturing practices or there's just
1314
00:30:34,139 --> 00:30:34,149
1315
00:30:34,149 --> 00:30:36,690
not enough profit in there we don't have
1316
00:30:36,690 --> 00:30:36,700
1317
00:30:36,700 --> 00:30:38,340
them so there wasn't there was a
1318
00:30:38,340 --> 00:30:38,350
1319
00:30:38,350 --> 00:30:40,529
profound shortage nationwide and if
1320
00:30:40,529 --> 00:30:40,539
1321
00:30:40,539 --> 00:30:41,820
there's any apologists out here they all
1322
00:30:41,820 --> 00:30:41,830
1323
00:30:41,830 --> 00:30:44,460
know about this so what happened was the
1324
00:30:44,460 --> 00:30:44,470
1325
00:30:44,470 --> 00:30:46,710
investigators were limiting the citrate
1326
00:30:46,710 --> 00:30:46,720
1327
00:30:46,720 --> 00:30:49,680
infusion rates and that's fine if you're
1328
00:30:49,680 --> 00:30:49,690
1329
00:30:49,690 --> 00:30:52,109
okay with clotting off your your
1330
00:30:52,109 --> 00:30:52,119
1331
00:30:52,119 --> 00:30:54,149
dialysis cartridge more frequently I
1332
00:30:54,149 --> 00:30:54,159
1333
00:30:54,159 --> 00:30:56,639
want to swap out a bunch and you know
1334
00:30:56,639 --> 00:30:56,649
1335
00:30:56,649 --> 00:30:58,019
you can check how much clearance you get
1336
00:30:58,019 --> 00:30:58,029
1337
00:30:58,029 --> 00:31:01,950
and and you know the cost you more money
1338
00:31:01,950 --> 00:31:01,960
1339
00:31:01,960 --> 00:31:02,850
because you're going to use more than
1340
00:31:02,850 --> 00:31:02,860
1341
00:31:02,860 --> 00:31:04,739
Alice's cartridges but you can probably
1342
00:31:04,739 --> 00:31:04,749
1343
00:31:04,749 --> 00:31:06,749
effectively take care of patients with
1344
00:31:06,749 --> 00:31:06,759
1345
00:31:06,759 --> 00:31:09,629
respect to just doing CRT but the whole
1346
00:31:09,629 --> 00:31:09,639
1347
00:31:09,639 --> 00:31:11,430
premise behind how this thing works is
1348
00:31:11,430 --> 00:31:11,440
1349
00:31:11,440 --> 00:31:13,169
that you've got to have low ionized
1350
00:31:13,169 --> 00:31:13,179
1351
00:31:13,179 --> 00:31:14,399
calcium or it's not going to work at all
1352
00:31:14,399 --> 00:31:14,409
1353
00:31:14,409 --> 00:31:15,960
and they plenty of work they've done to
1354
00:31:15,960 --> 00:31:15,970
1355
00:31:15,970 --> 00:31:18,690
show that so as it turned out I asked
1356
00:31:18,690 --> 00:31:18,700
1357
00:31:18,700 --> 00:31:21,419
calcium levels within the circuit tended
1358
00:31:21,419 --> 00:31:21,429
1359
00:31:21,429 --> 00:31:23,639
to be higher than the target of 0.3 to
1360
00:31:23,639 --> 00:31:23,649
1361
00:31:23,649 --> 00:31:26,639
0.5 so in fact of the hundred and
1362
00:31:26,639 --> 00:31:26,649
1363
00:31:26,649 --> 00:31:29,039
thirty-four patients who had been put in
1364
00:31:29,039 --> 00:31:29,049
1365
00:31:29,049 --> 00:31:31,980
a study only 50 spent 90% or more of
1366
00:31:31,980 --> 00:31:31,990
1367
00:31:31,990 --> 00:31:33,779
their time with ionized calcium of less
1368
00:31:33,779 --> 00:31:33,789
1369
00:31:33,789 --> 00:31:36,779
than or equal to 0.4 so the primary
1370
00:31:36,779 --> 00:31:36,789
1371
00:31:36,789 --> 00:31:38,489
analysis of course just you know gotta
1372
00:31:38,489 --> 00:31:38,499
1373
00:31:38,499 --> 00:31:41,279
follow the principles of clinical trials
1374
00:31:41,279 --> 00:31:41,289
1375
00:31:41,289 --> 00:31:42,869
so the intention-to-treat analysis where
1376
00:31:42,869 --> 00:31:42,879
1377
00:31:42,879 --> 00:31:44,009
you analyze things according to
1378
00:31:44,009 --> 00:31:44,019
1379
00:31:44,019 --> 00:31:46,470
randomization didn't show it anything
1380
00:31:46,470 --> 00:31:46,480
1381
00:31:46,480 --> 00:31:49,289
absolutely nothing but a pull protocol
1382
00:31:49,289 --> 00:31:49,299
1383
00:31:49,299 --> 00:31:50,879
analysis was performed on the 50
1384
00:31:50,879 --> 00:31:50,889
1385
00:31:50,889 --> 00:31:52,950
patients who actually got the ionized
1386
00:31:52,950 --> 00:31:52,960
1387
00:31:52,960 --> 00:31:55,019
calcium down where this thing would have
1388
00:31:55,019 --> 00:31:55,029
1389
00:31:55,029 --> 00:31:57,029
a chance to work and here's what
1390
00:31:57,029 --> 00:31:57,039
1391
00:31:57,039 --> 00:32:00,330
happened so here we have 60 day
1392
00:32:00,330 --> 00:32:00,340
1393
00:32:00,340 --> 00:32:07,799
mortality so 11 and 27 people who the
1394
00:32:07,799 --> 00:32:07,809
1395
00:32:07,809 --> 00:32:09,570
control patients of 41 percent of them
1396
00:32:09,570 --> 00:32:09,580
1397
00:32:09,580 --> 00:32:12,570
died when only three of 19 or 16 percent
1398
00:32:12,570 --> 00:32:12,580
1399
00:32:12,580 --> 00:32:15,930
died with the sed douse the dependency
1400
00:32:15,930 --> 00:32:15,940
1401
00:32:15,940 --> 00:32:20,690
went from 27% to zero and a composite
1402
00:32:20,690 --> 00:32:20,700
1403
00:32:20,700 --> 00:32:26,039
went for 56% to 16% this is a mortality
1404
00:32:26,039 --> 00:32:26,049
1405
00:32:26,049 --> 00:32:28,440
wall obviously profound was not
1406
00:32:28,440 --> 00:32:28,450
1407
00:32:28,450 --> 00:32:30,799
statistically significant point oh seven
1408
00:32:30,799 --> 00:32:30,809
1409
00:32:30,809 --> 00:32:33,060
mouse's dependency and the composite
1410
00:32:33,060 --> 00:32:33,070
1411
00:32:33,070 --> 00:32:33,660
were
1412
00:32:33,660 --> 00:32:33,670
were
1413
00:32:33,670 --> 00:32:38,010
were
statistically significant in the post
1414
00:32:38,010 --> 00:32:38,020
1415
00:32:38,020 --> 00:32:39,690
hoc analysis there was absolutely no
1416
00:32:39,690 --> 00:32:39,700
1417
00:32:39,700 --> 00:32:41,970
mortality difference for controls who
1418
00:32:41,970 --> 00:32:41,980
1419
00:32:41,980 --> 00:32:43,590
had an ionized calcium of less than four
1420
00:32:43,590 --> 00:32:43,600
1421
00:32:43,600 --> 00:32:44,850
versus is greater than four us they just
1422
00:32:44,850 --> 00:32:44,860
1423
00:32:44,860 --> 00:32:46,650
lowering your calcium to 0.4 without
1424
00:32:46,650 --> 00:32:46,660
1425
00:32:46,660 --> 00:32:49,340
this device it's not is not the cure for
1426
00:32:49,340 --> 00:32:49,350
1427
00:32:49,350 --> 00:32:52,610
recording reals for acute kidney injury
1428
00:32:52,610 --> 00:32:52,620
1429
00:32:52,620 --> 00:32:55,440
I think there's a clear afrika C for
1430
00:32:55,440 --> 00:32:55,450
1431
00:32:55,450 --> 00:32:58,830
signal in the sed trading patients who
1432
00:32:58,830 --> 00:32:58,840
1433
00:32:58,840 --> 00:33:00,750
actually were able to follow the
1434
00:33:00,750 --> 00:33:00,760
1435
00:33:00,760 --> 00:33:05,220
protocol or the dr. kovala protocol so
1436
00:33:05,220 --> 00:33:05,230
1437
00:33:05,230 --> 00:33:07,020
that you know that you're not going to
1438
00:33:07,020 --> 00:33:07,030
1439
00:33:07,030 --> 00:33:09,150
be able to go out and order this right
1440
00:33:09,150 --> 00:33:09,160
1441
00:33:09,160 --> 00:33:12,840
now there is actually davis company
1442
00:33:12,840 --> 00:33:12,850
1443
00:33:12,850 --> 00:33:14,430
raised 40 million dollars and there is
1444
00:33:14,430 --> 00:33:14,440
1445
00:33:14,440 --> 00:33:16,770
an ongoing study of acute kidney injury
1446
00:33:16,770 --> 00:33:16,780
1447
00:33:16,780 --> 00:33:19,050
basically this study in the pediatric
1448
00:33:19,050 --> 00:33:19,060
1449
00:33:19,060 --> 00:33:23,160
population and why in pediatrics because
1450
00:33:23,160 --> 00:33:23,170
1451
00:33:23,170 --> 00:33:27,660
of the orphan status you can cost less
1452
00:33:27,660 --> 00:33:27,670
1453
00:33:27,670 --> 00:33:30,300
money to get that through but this will
1454
00:33:30,300 --> 00:33:30,310
1455
00:33:30,310 --> 00:33:32,840
be next
1456
00:33:32,840 --> 00:33:32,850
1457
00:33:32,850 --> 00:33:38,250
okay now luckily about hearts so this is
1458
00:33:38,250 --> 00:33:38,260
1459
00:33:38,260 --> 00:33:40,620
studying at reperfusion injury in a dog
1460
00:33:40,620 --> 00:33:40,630
1461
00:33:40,630 --> 00:33:43,500
model where the circumflex artery is
1462
00:33:43,500 --> 00:33:43,510
1463
00:33:43,510 --> 00:33:45,990
occluded with a balloon approximately
1464
00:33:45,990 --> 00:33:46,000
1465
00:33:46,000 --> 00:33:48,570
included the occlusion was maintained
1466
00:33:48,570 --> 00:33:48,580
1467
00:33:48,580 --> 00:33:50,400
for three hours and then reperfusion
1468
00:33:50,400 --> 00:33:50,410
1469
00:33:50,410 --> 00:33:53,700
occurs treatment with the SED is
1470
00:33:53,700 --> 00:33:53,710
1471
00:33:53,710 --> 00:33:55,260
initiated 30 minutes prior to
1472
00:33:55,260 --> 00:33:55,270
1473
00:33:55,270 --> 00:33:58,050
reperfusion and maintained for two and a
1474
00:33:58,050 --> 00:33:58,060
1475
00:33:58,060 --> 00:34:02,580
half hours and this is just showing you
1476
00:34:02,580 --> 00:34:02,590
1477
00:34:02,590 --> 00:34:06,630
what controls control looks like and you
1478
00:34:06,630 --> 00:34:06,640
1479
00:34:06,640 --> 00:34:08,610
see the area of infarction there and
1480
00:34:08,610 --> 00:34:08,620
1481
00:34:08,620 --> 00:34:09,690
it's producible
1482
00:34:09,690 --> 00:34:09,700
it's producible
1483
00:34:09,700 --> 00:34:14,909
it's producible
and this is showing you an sed sed
1484
00:34:14,909 --> 00:34:14,919
1485
00:34:14,919 --> 00:34:18,030
treated animal versus an honesty treated
1486
00:34:18,030 --> 00:34:18,040
1487
00:34:18,040 --> 00:34:22,409
animal with over a third or two-thirds
1488
00:34:22,409 --> 00:34:22,419
1489
00:34:22,419 --> 00:34:26,190
reduction in the size of the infarct and
1490
00:34:26,190 --> 00:34:26,200
1491
00:34:26,200 --> 00:34:31,100
this is looking at troponin elevations
1492
00:34:31,100 --> 00:34:31,110
1493
00:34:31,110 --> 00:34:33,240
in this model and you see greater
1494
00:34:33,240 --> 00:34:33,250
1495
00:34:33,250 --> 00:34:35,100
troponin elevations in the untreated
1496
00:34:35,100 --> 00:34:35,110
1497
00:34:35,110 --> 00:34:38,450
animals
1498
00:34:38,450 --> 00:34:38,460
1499
00:34:38,460 --> 00:34:42,120
those of you who work in heart failure
1500
00:34:42,120 --> 00:34:42,130
1501
00:34:42,130 --> 00:34:45,150
are probably familiar with tony Saba's
1502
00:34:45,150 --> 00:34:45,160
1503
00:34:45,160 --> 00:34:50,360
model Henry Ford this is a model of
1504
00:34:50,360 --> 00:34:50,370
1505
00:34:50,370 --> 00:34:53,910
repeated micro embolization that results
1506
00:34:53,910 --> 00:34:53,920
1507
00:34:53,920 --> 00:34:56,940
in a reproducible drop an ef-2 25 to 30
1508
00:34:56,940 --> 00:34:56,950
1509
00:34:56,950 --> 00:35:00,660
percent and this model has been very
1510
00:35:00,660 --> 00:35:00,670
1511
00:35:00,670 --> 00:35:04,530
very widely studied Tony is the is the
1512
00:35:04,530 --> 00:35:04,540
1513
00:35:04,540 --> 00:35:08,490
go-to guy for drug companies and device
1514
00:35:08,490 --> 00:35:08,500
1515
00:35:08,500 --> 00:35:11,550
companies because results in this model
1516
00:35:11,550 --> 00:35:11,560
1517
00:35:11,560 --> 00:35:14,220
have largely with various you know
1518
00:35:14,220 --> 00:35:14,230
1519
00:35:14,230 --> 00:35:15,900
therapeutic agents have largely
1520
00:35:15,900 --> 00:35:15,910
1521
00:35:15,910 --> 00:35:19,070
recapitulated what we've seen happen in
1522
00:35:19,070 --> 00:35:19,080
1523
00:35:19,080 --> 00:35:26,640
human clinical trials so this cartoon is
1524
00:35:26,640 --> 00:35:26,650
1525
00:35:26,650 --> 00:35:27,990
essentially showing that we did the same
1526
00:35:27,990 --> 00:35:28,000
1527
00:35:28,000 --> 00:35:31,620
stuff as we've been talking about they
1528
00:35:31,620 --> 00:35:31,630
1529
00:35:31,630 --> 00:35:34,170
did the same stuff with a dog that had
1530
00:35:34,170 --> 00:35:34,180
1531
00:35:34,180 --> 00:35:37,560
been rendered to have cardiomyopathy
1532
00:35:37,560 --> 00:35:37,570
1533
00:35:37,570 --> 00:35:41,700
through this micro embolization and this
1534
00:35:41,700 --> 00:35:41,710
1535
00:35:41,710 --> 00:35:45,750
is looking at from acute changes an
1536
00:35:45,750 --> 00:35:45,760
1537
00:35:45,760 --> 00:35:52,170
ejection fraction in in 20 animals 10
1538
00:35:52,170 --> 00:35:52,180
1539
00:35:52,180 --> 00:35:58,140
each and you see here a rise in a
1540
00:35:58,140 --> 00:35:58,150
1541
00:35:58,150 --> 00:36:01,080
dramatic rise in ejection fraction over
1542
00:36:01,080 --> 00:36:01,090
1543
00:36:01,090 --> 00:36:04,380
the course of four hours with a
1544
00:36:04,380 --> 00:36:04,390
1545
00:36:04,390 --> 00:36:06,330
beginning fall during the two hours of
1546
00:36:06,330 --> 00:36:06,340
1547
00:36:06,340 --> 00:36:12,330
washout here is here a preliminary data
1548
00:36:12,330 --> 00:36:12,340
1549
00:36:12,340 --> 00:36:14,960
this is just three animals per group
1550
00:36:14,960 --> 00:36:14,970
1551
00:36:14,970 --> 00:36:17,370
where we're looking now at longer-term
1552
00:36:17,370 --> 00:36:17,380
1553
00:36:17,380 --> 00:36:20,880
effects this was done as and actually
1554
00:36:20,880 --> 00:36:20,890
1555
00:36:20,890 --> 00:36:22,800
all these therapies have been done it's
1556
00:36:22,800 --> 00:36:22,810
1557
00:36:22,810 --> 00:36:26,520
six hours on most the real most of the
1558
00:36:26,520 --> 00:36:26,530
1559
00:36:26,530 --> 00:36:27,600
studies have been done is every other
1560
00:36:27,600 --> 00:36:27,610
1561
00:36:27,610 --> 00:36:30,270
day a treatment which is how this was
1562
00:36:30,270 --> 00:36:30,280
1563
00:36:30,280 --> 00:36:33,270
done so it's so six hours on day one
1564
00:36:33,270 --> 00:36:33,280
1565
00:36:33,280 --> 00:36:35,250
nothing day two six hours on day three
1566
00:36:35,250 --> 00:36:35,260
1567
00:36:35,260 --> 00:36:37,130
and day five
1568
00:36:37,130 --> 00:36:37,140
and day five
1569
00:36:37,140 --> 00:36:43,410
and day five
yellow is control blue is is the sed and
1570
00:36:43,410 --> 00:36:43,420
1571
00:36:43,420 --> 00:36:46,710
this is changing EF and you see a rise
1572
00:36:46,710 --> 00:36:46,720
1573
00:36:46,720 --> 00:36:50,070
here about six points in EF
1574
00:36:50,070 --> 00:36:50,080
1575
00:36:50,080 --> 00:36:52,950
going down to four and five and here you
1576
00:36:52,950 --> 00:36:52,960
1577
00:36:52,960 --> 00:36:54,270
see really nothing happening in the
1578
00:36:54,270 --> 00:36:54,280
1579
00:36:54,280 --> 00:36:56,099
control animals this is out two days
1580
00:36:56,099 --> 00:36:56,109
1581
00:36:56,109 --> 00:36:59,430
seven days 14 days and 28 days and again
1582
00:36:59,430 --> 00:36:59,440
1583
00:36:59,440 --> 00:37:05,339
therapies at gay the first day well day
1584
00:37:05,339 --> 00:37:05,349
1585
00:37:05,349 --> 00:37:08,370
one day three day five and whether you
1586
00:37:08,370 --> 00:37:08,380
1587
00:37:08,380 --> 00:37:09,990
surgical nut numbering of days or
1588
00:37:09,990 --> 00:37:10,000
1589
00:37:10,000 --> 00:37:13,829
medical memory or days I guess and this
1590
00:37:13,829 --> 00:37:13,839
1591
00:37:13,839 --> 00:37:15,920
is this is now looking at cardiac output
1592
00:37:15,920 --> 00:37:15,930
1593
00:37:15,930 --> 00:37:21,750
and same time whoops go back same
1594
00:37:21,750 --> 00:37:21,760
1595
00:37:21,760 --> 00:37:26,520
measurement times and credit index going
1596
00:37:26,520 --> 00:37:26,530
1597
00:37:26,530 --> 00:37:31,099
from this is actually index not output
1598
00:37:31,099 --> 00:37:31,109
1599
00:37:31,109 --> 00:37:37,109
going up day two was still sustained
1600
00:37:37,109 --> 00:37:37,119
1601
00:37:37,119 --> 00:37:40,220
effect at least out to about two weeks
1602
00:37:40,220 --> 00:37:40,230
1603
00:37:40,230 --> 00:37:43,910
and those animals treated with the sed
1604
00:37:43,910 --> 00:37:43,920
1605
00:37:43,920 --> 00:37:46,680
and nothing in control and there was no
1606
00:37:46,680 --> 00:37:46,690
1607
00:37:46,690 --> 00:37:48,390
difference in systemic vascular
1608
00:37:48,390 --> 00:37:48,400
1609
00:37:48,400 --> 00:37:49,620
resistance or heart rate between the
1610
00:37:49,620 --> 00:37:49,630
1611
00:37:49,630 --> 00:37:53,400
groups so I'm gonna give you a case an
1612
00:37:53,400 --> 00:37:53,410
1613
00:37:53,410 --> 00:37:56,910
attic throat case so a 45 year old man
1614
00:37:56,910 --> 00:37:56,920
1615
00:37:56,920 --> 00:37:59,099
with long-standing systolic heart
1616
00:37:59,099 --> 00:37:59,109
1617
00:37:59,109 --> 00:38:01,260
failure presented to the VA hospital in
1618
00:38:01,260 --> 00:38:01,270
1619
00:38:01,270 --> 00:38:03,750
June 2012 with an 18 pound weight gain
1620
00:38:03,750 --> 00:38:03,760
1621
00:38:03,760 --> 00:38:06,630
over the course of two weeks history of
1622
00:38:06,630 --> 00:38:06,640
1623
00:38:06,640 --> 00:38:08,400
diabetes sleep apnea chronic kidney
1624
00:38:08,400 --> 00:38:08,410
1625
00:38:08,410 --> 00:38:12,000
disease a fibbin hi-c deed increasing
1626
00:38:12,000 --> 00:38:12,010
1627
00:38:12,010 --> 00:38:14,070
shortness of breath such that he was
1628
00:38:14,070 --> 00:38:14,080
1629
00:38:14,080 --> 00:38:16,740
unable to walk ten yards and increasing
1630
00:38:16,740 --> 00:38:16,750
1631
00:38:16,750 --> 00:38:19,020
Lorre extremity edema
1632
00:38:19,020 --> 00:38:19,030
1633
00:38:19,030 --> 00:38:25,010
he was flogged the way we usually do and
1634
00:38:25,010 --> 00:38:25,020
1635
00:38:25,020 --> 00:38:29,339
he gets transferred to the University
1636
00:38:29,339 --> 00:38:29,349
1637
00:38:29,349 --> 00:38:33,630
Hospital where we continued to not
1638
00:38:33,630 --> 00:38:33,640
1639
00:38:33,640 --> 00:38:37,920
relent and his bu and creatinine rose to
1640
00:38:37,920 --> 00:38:37,930
1641
00:38:37,930 --> 00:38:41,070
64 and 3.38 from a baseline creatinine
1642
00:38:41,070 --> 00:38:41,080
1643
00:38:41,080 --> 00:38:45,660
1.5 te was done showing that says that
1644
00:38:45,660 --> 00:38:45,670
1645
00:38:45,670 --> 00:38:48,079
should be a right heart cath showing her
1646
00:38:48,079 --> 00:38:48,089
1647
00:38:48,089 --> 00:38:50,670
soccer wedge pressure 13 H at one point
1648
00:38:50,670 --> 00:38:50,680
1649
00:38:50,680 --> 00:38:57,630
for this was David slide she just you
1650
00:38:57,630 --> 00:38:57,640
1651
00:38:57,640 --> 00:38:59,130
know you can't trust a nephrologist to
1652
00:38:59,130 --> 00:38:59,140
1653
00:38:59,140 --> 00:39:00,120
know
1654
00:39:00,120 --> 00:39:00,130
know
1655
00:39:00,130 --> 00:39:06,570
know
what if like hard cat does and those
1656
00:39:06,570 --> 00:39:06,580
1657
00:39:06,580 --> 00:39:08,370
those allows a human dynamics were on
1658
00:39:08,370 --> 00:39:08,380
1659
00:39:08,380 --> 00:39:09,960
mill around is EF is terrible
1660
00:39:09,960 --> 00:39:09,970
1661
00:39:09,970 --> 00:39:14,880
he's begun a CVH with the sed four days
1662
00:39:14,880 --> 00:39:14,890
1663
00:39:14,890 --> 00:39:18,300
later and he's treated for four and a
1664
00:39:18,300 --> 00:39:18,310
1665
00:39:18,310 --> 00:39:25,710
quarter days with the sed so now he
1666
00:39:25,710 --> 00:39:25,720
1667
00:39:25,720 --> 00:39:27,810
remember he's dating CVH also so there's
1668
00:39:27,810 --> 00:39:27,820
1669
00:39:27,820 --> 00:39:29,310
two sort of striking things here so
1670
00:39:29,310 --> 00:39:29,320
1671
00:39:29,320 --> 00:39:31,170
first of all note that he's only getting
1672
00:39:31,170 --> 00:39:31,180
1673
00:39:31,180 --> 00:39:36,120
treated this far okay so so day five is
1674
00:39:36,120 --> 00:39:36,130
1675
00:39:36,130 --> 00:39:41,580
only a quarter of a day actually I take
1676
00:39:41,580 --> 00:39:41,590
1677
00:39:41,590 --> 00:39:41,940
that back
1678
00:39:41,940 --> 00:39:41,950
that back
1679
00:39:41,950 --> 00:39:45,060
that back
day four is only a quarter uh yeah well
1680
00:39:45,060 --> 00:39:45,070
1681
00:39:45,070 --> 00:39:46,470
think of it this way yeah a five is a
1682
00:39:46,470 --> 00:39:46,480
1683
00:39:46,480 --> 00:39:48,540
quarter of a day um here an output is
1684
00:39:48,540 --> 00:39:48,550
1685
00:39:48,550 --> 00:39:50,790
increasing right so here's your an
1686
00:39:50,790 --> 00:39:50,800
1687
00:39:50,800 --> 00:39:53,070
output despite the fact that he's
1688
00:39:53,070 --> 00:39:53,080
1689
00:39:53,080 --> 00:39:55,410
getting CVH and who makes more urine
1690
00:39:55,410 --> 00:39:55,420
1691
00:39:55,420 --> 00:40:00,210
when they're on CV age um and then the
1692
00:40:00,210 --> 00:40:00,220
1693
00:40:00,220 --> 00:40:02,910
sed is stopped and now he's going into
1694
00:40:02,910 --> 00:40:02,920
1695
00:40:02,920 --> 00:40:05,640
positive fluid balance so interesting
1696
00:40:05,640 --> 00:40:05,650
1697
00:40:05,650 --> 00:40:11,220
lis this is not just resulting in
1698
00:40:11,220 --> 00:40:11,230
1699
00:40:11,230 --> 00:40:14,400
changes in kidney function but actually
1700
00:40:14,400 --> 00:40:14,410
1701
00:40:14,410 --> 00:40:16,050
changes in filtration as well and
1702
00:40:16,050 --> 00:40:16,060
1703
00:40:16,060 --> 00:40:19,230
there's a I I wanted to show you a video
1704
00:40:19,230 --> 00:40:19,240
1705
00:40:19,240 --> 00:40:21,780
but I think I didn't bring the I didn't
1706
00:40:21,780 --> 00:40:21,790
1707
00:40:21,790 --> 00:40:23,220
link the files right so I took it out of
1708
00:40:23,220 --> 00:40:23,230
1709
00:40:23,230 --> 00:40:25,320
the slides this morning but there's a
1710
00:40:25,320 --> 00:40:25,330
1711
00:40:25,330 --> 00:40:32,910
nice nice video showing a small animal
1712
00:40:32,910 --> 00:40:32,920
1713
00:40:32,920 --> 00:40:36,210
showing sludging within the vasculature
1714
00:40:36,210 --> 00:40:36,220
1715
00:40:36,220 --> 00:40:39,030
and resolution of sledging using this
1716
00:40:39,030 --> 00:40:39,040
1717
00:40:39,040 --> 00:40:43,860
device so what is clinical support for
1718
00:40:43,860 --> 00:40:43,870
1719
00:40:43,870 --> 00:40:45,570
value in esc d in type one cardio real
1720
00:40:45,570 --> 00:40:45,580
1721
00:40:45,580 --> 00:40:48,060
syndrome I'm just to summarize so sed
1722
00:40:48,060 --> 00:40:48,070
1723
00:40:48,070 --> 00:40:49,620
reduces death in the need for perman
1724
00:40:49,620 --> 00:40:49,630
1725
00:40:49,630 --> 00:40:51,600
dialysis and people that you Kitty
1726
00:40:51,600 --> 00:40:51,610
1727
00:40:51,610 --> 00:40:52,800
injury in the setting a multi-system
1728
00:40:52,800 --> 00:40:52,810
1729
00:40:52,810 --> 00:40:56,610
organ failure and or presume sepsis
1730
00:40:56,610 --> 00:40:56,620
1731
00:40:56,620 --> 00:40:58,500
among those actually receiving the
1732
00:40:58,500 --> 00:40:58,510
1733
00:40:58,510 --> 00:41:03,180
therapy right big caveat STD acutely
1734
00:41:03,180 --> 00:41:03,190
1735
00:41:03,190 --> 00:41:05,520
improves cardiac function in canine
1736
00:41:05,520 --> 00:41:05,530
1737
00:41:05,530 --> 00:41:07,920
heart failure model or the effect
1738
00:41:07,920 --> 00:41:07,930
1739
00:41:07,930 --> 00:41:11,840
sustained for at least two weeks and
1740
00:41:11,840 --> 00:41:11,850
1741
00:41:11,850 --> 00:41:14,299
theta that I not
1742
00:41:14,299 --> 00:41:14,309
theta that I not
1743
00:41:14,309 --> 00:41:20,849
theta that I not
in in CKD patients that I leave it to
1744
00:41:20,849 --> 00:41:20,859
1745
00:41:20,859 --> 00:41:24,209
earlier showing reductions in in aisle
1746
00:41:24,209 --> 00:41:24,219
1747
00:41:24,219 --> 00:41:28,650
six sustained up to two weeks and and a
1748
00:41:28,650 --> 00:41:28,660
1749
00:41:28,660 --> 00:41:29,849
piece aisle six is associated with
1750
00:41:29,849 --> 00:41:29,859
1751
00:41:29,859 --> 00:41:33,870
decreased survival in CKD so we're
1752
00:41:33,870 --> 00:41:33,880
1753
00:41:33,880 --> 00:41:36,239
proposing an early feasibility study to
1754
00:41:36,239 --> 00:41:36,249
1755
00:41:36,249 --> 00:41:38,729
evaluate this therapy as treatment for
1756
00:41:38,729 --> 00:41:38,739
1757
00:41:38,739 --> 00:41:40,319
crs and subjects with end-stage heart
1758
00:41:40,319 --> 00:41:40,329
1759
00:41:40,329 --> 00:41:42,479
failure otherwise candidates for an L
1760
00:41:42,479 --> 00:41:42,489
1761
00:41:42,489 --> 00:41:44,670
had but are precluded by kidney
1762
00:41:44,670 --> 00:41:44,680
1763
00:41:44,680 --> 00:41:47,249
dysfunction so the idea was we're trying
1764
00:41:47,249 --> 00:41:47,259
1765
00:41:47,259 --> 00:41:48,359
to come up you know where would be a
1766
00:41:48,359 --> 00:41:48,369
1767
00:41:48,369 --> 00:41:50,009
place that we could study this and you
1768
00:41:50,009 --> 00:41:50,019
1769
00:41:50,019 --> 00:41:54,089
know elevators are just they're a
1770
00:41:54,089 --> 00:41:54,099
1771
00:41:54,099 --> 00:41:56,189
wonderful therapy for people who are
1772
00:41:56,189 --> 00:41:56,199
1773
00:41:56,199 --> 00:41:58,829
sick enough to need one you know don't
1774
00:41:58,829 --> 00:41:58,839
1775
00:41:58,839 --> 00:42:02,969
sign me up unless I need one but but
1776
00:42:02,969 --> 00:42:02,979
1777
00:42:02,979 --> 00:42:06,539
what they are are absolutely spectacular
1778
00:42:06,539 --> 00:42:06,549
1779
00:42:06,549 --> 00:42:08,670
for is it as an experimental platform
1780
00:42:08,670 --> 00:42:08,680
1781
00:42:08,680 --> 00:42:11,729
right because we can we we can get
1782
00:42:11,729 --> 00:42:11,739
1783
00:42:11,739 --> 00:42:13,319
tissue from the people when we put the
1784
00:42:13,319 --> 00:42:13,329
1785
00:42:13,329 --> 00:42:17,699
ovett in we get the apical core that we
1786
00:42:17,699 --> 00:42:17,709
1787
00:42:17,709 --> 00:42:20,669
can study sometimes you can biopsy
1788
00:42:20,669 --> 00:42:20,679
1789
00:42:20,679 --> 00:42:22,499
people before that usually the next
1790
00:42:22,499 --> 00:42:22,509
1791
00:42:22,509 --> 00:42:24,089
tissue you're getting is is sort of
1792
00:42:24,089 --> 00:42:24,099
1793
00:42:24,099 --> 00:42:25,769
after the LVAD if someone gets it goes
1794
00:42:25,769 --> 00:42:25,779
1795
00:42:25,779 --> 00:42:28,349
on if you transplanted sometimes you get
1796
00:42:28,349 --> 00:42:28,359
1797
00:42:28,359 --> 00:42:32,099
it for other reasons too yeah but so
1798
00:42:32,099 --> 00:42:32,109
1799
00:42:32,109 --> 00:42:33,859
it's it's a marvelous way for us to
1800
00:42:33,859 --> 00:42:33,869
1801
00:42:33,869 --> 00:42:35,999
really to do studies that would
1802
00:42:35,999 --> 00:42:36,009
1803
00:42:36,009 --> 00:42:37,769
otherwise not be able to be done here
1804
00:42:37,769 --> 00:42:37,779
1805
00:42:37,779 --> 00:42:40,130
the issue is that these are folks who
1806
00:42:40,130 --> 00:42:40,140
1807
00:42:40,140 --> 00:42:43,349
their trajectory in the absence of us
1808
00:42:43,349 --> 00:42:43,359
1809
00:42:43,359 --> 00:42:45,989
being able to VAD them is it's pretty
1810
00:42:45,989 --> 00:42:45,999
1811
00:42:45,999 --> 00:42:47,969
awful alright so I will tell you that
1812
00:42:47,969 --> 00:42:47,979
1813
00:42:47,979 --> 00:42:50,339
you know we are going to our IRB with
1814
00:42:50,339 --> 00:42:50,349
1815
00:42:50,349 --> 00:42:52,109
this now but I think I think we're gonna
1816
00:42:52,109 --> 00:42:52,119
1817
00:42:52,119 --> 00:42:55,410
have a pretty easy time because the
1818
00:42:55,410 --> 00:42:55,420
1819
00:42:55,420 --> 00:42:56,910
upside potential of being able to get
1820
00:42:56,910 --> 00:42:56,920
1821
00:42:56,920 --> 00:42:58,949
badges in this circumstance is high and
1822
00:42:58,949 --> 00:42:58,959
1823
00:42:58,959 --> 00:43:01,890
the risk is very very low because there
1824
00:43:01,890 --> 00:43:01,900
1825
00:43:01,900 --> 00:43:03,329
have been millions of people whose blood
1826
00:43:03,329 --> 00:43:03,339
1827
00:43:03,339 --> 00:43:05,459
has gone through a hemodialysis
1828
00:43:05,459 --> 00:43:05,469
1829
00:43:05,469 --> 00:43:09,089
cartridge and again where these people
1830
00:43:09,089 --> 00:43:09,099
1831
00:43:09,099 --> 00:43:10,469
are going in the absence is pretty clear
1832
00:43:10,469 --> 00:43:10,479
1833
00:43:10,479 --> 00:43:11,969
and then the other thing of course is
1834
00:43:11,969 --> 00:43:11,979
1835
00:43:11,979 --> 00:43:13,679
what we're really at this point just
1836
00:43:13,679 --> 00:43:13,689
1837
00:43:13,689 --> 00:43:15,329
looking for a short-term effect you know
1838
00:43:15,329 --> 00:43:15,339
1839
00:43:15,339 --> 00:43:18,289
the immune system is pretty complex and
1840
00:43:18,289 --> 00:43:18,299
1841
00:43:18,299 --> 00:43:22,349
as is as is the human body it's sort of
1842
00:43:22,349 --> 00:43:22,359
1843
00:43:22,359 --> 00:43:23,719
amazing that you can do things and they
1844
00:43:23,719 --> 00:43:23,729
1845
00:43:23,729 --> 00:43:26,939
work sometimes and something as blunt as
1846
00:43:26,939 --> 00:43:26,949
1847
00:43:26,949 --> 00:43:30,610
this
1848
00:43:30,610 --> 00:43:30,620
1849
00:43:30,620 --> 00:43:32,870
seeing long-term the long-term studies
1850
00:43:32,870 --> 00:43:32,880
1851
00:43:32,880 --> 00:43:36,830
are obviously arrays many more issues so
1852
00:43:36,830 --> 00:43:36,840
1853
00:43:36,840 --> 00:43:39,050
this is a proposing a Phase two single
1854
00:43:39,050 --> 00:43:39,060
1855
00:43:39,060 --> 00:43:41,030
arm open-label uncontrolled before and
1856
00:43:41,030 --> 00:43:41,040
1857
00:43:41,040 --> 00:43:44,930
after study in ten patients the
1858
00:43:44,930 --> 00:43:44,940
1859
00:43:44,940 --> 00:43:46,040
inclusion criteria will be a primary
1860
00:43:46,040 --> 00:43:46,050
1861
00:43:46,050 --> 00:43:48,620
hospitalization for a dhf potential all
1862
00:43:48,620 --> 00:43:48,630
1863
00:43:48,630 --> 00:43:52,520
that candidate and the four sub-bullets
1864
00:43:52,520 --> 00:43:52,530
1865
00:43:52,530 --> 00:43:54,290
there are all the indications for
1866
00:43:54,290 --> 00:43:54,300
1867
00:43:54,300 --> 00:44:01,150
destination therapy in the United States
1868
00:44:01,150 --> 00:44:01,160
1869
00:44:01,160 --> 00:44:04,580
with worsening renal function defined as
1870
00:44:04,580 --> 00:44:04,590
1871
00:44:04,590 --> 00:44:07,250
arising sim creatinine a point five or
1872
00:44:07,250 --> 00:44:07,260
1873
00:44:07,260 --> 00:44:11,000
greater from baseline and a baseline
1874
00:44:11,000 --> 00:44:11,010
1875
00:44:11,010 --> 00:44:13,190
EGFR a 40 or greater with a thought that
1876
00:44:13,190 --> 00:44:13,200
1877
00:44:13,200 --> 00:44:15,980
you know we want people who are are more
1878
00:44:15,980 --> 00:44:15,990
1879
00:44:15,990 --> 00:44:18,290
likely to be salvageable
1880
00:44:18,290 --> 00:44:18,300
1881
00:44:18,300 --> 00:44:19,640
Kirti real syndrome is most likely
1882
00:44:19,640 --> 00:44:19,650
1883
00:44:19,650 --> 00:44:21,410
explanation for their problem other
1884
00:44:21,410 --> 00:44:21,420
1885
00:44:21,420 --> 00:44:23,390
acute kidney injury excluded by an
1886
00:44:23,390 --> 00:44:23,400
1887
00:44:23,400 --> 00:44:26,300
independent or ologist a P Catherine
1888
00:44:26,300 --> 00:44:26,310
1889
00:44:26,310 --> 00:44:29,990
place measurements and evidence of
1890
00:44:29,990 --> 00:44:30,000
1891
00:44:30,000 --> 00:44:32,870
volume overload there and then the
1892
00:44:32,870 --> 00:44:32,880
1893
00:44:32,880 --> 00:44:37,310
exclusion criteria is include exclusion
1894
00:44:37,310 --> 00:44:37,320
1895
00:44:37,320 --> 00:44:40,310
criteria for getting bad therapy things
1896
00:44:40,310 --> 00:44:40,320
1897
00:44:40,320 --> 00:44:43,520
that might put you really it's all about
1898
00:44:43,520 --> 00:44:43,530
1899
00:44:43,530 --> 00:44:46,940
bad therapy with with the exception
1900
00:44:46,940 --> 00:44:46,950
1901
00:44:46,950 --> 00:44:50,360
being the foot to the end you know we
1902
00:44:50,360 --> 00:44:50,370
1903
00:44:50,370 --> 00:44:51,560
don't want people who are already
1904
00:44:51,560 --> 00:44:51,570
1905
00:44:51,570 --> 00:44:56,000
perhaps too tough and not to crack so
1906
00:44:56,000 --> 00:44:56,010
1907
00:44:56,010 --> 00:44:58,850
the intervention is this device in fact
1908
00:44:58,850 --> 00:44:58,860
1909
00:44:58,860 --> 00:45:00,050
we're just going to use an off-the-shelf
1910
00:45:00,050 --> 00:45:00,060
1911
00:45:00,060 --> 00:45:01,100
fda-approved
1912
00:45:01,100 --> 00:45:01,110
fda-approved
1913
00:45:01,110 --> 00:45:05,900
fda-approved
a filter subjects when we placed on it
1914
00:45:05,900 --> 00:45:05,910
1915
00:45:05,910 --> 00:45:08,000
for six hours of daily therapy for three
1916
00:45:08,000 --> 00:45:08,010
1917
00:45:08,010 --> 00:45:09,770
consecutive days or actually an affront
1918
00:45:09,770 --> 00:45:09,780
1919
00:45:09,780 --> 00:45:11,660
we're going to load a little bit more in
1920
00:45:11,660 --> 00:45:11,670
1921
00:45:11,670 --> 00:45:13,880
terms of the therapy given how sick
1922
00:45:13,880 --> 00:45:13,890
1923
00:45:13,890 --> 00:45:16,700
these folks are and then if subjects
1924
00:45:16,700 --> 00:45:16,710
1925
00:45:16,710 --> 00:45:18,140
have had a favorable response we can
1926
00:45:18,140 --> 00:45:18,150
1927
00:45:18,150 --> 00:45:20,810
continue it for number of more days in
1928
00:45:20,810 --> 00:45:20,820
1929
00:45:20,820 --> 00:45:22,910
part that's to get more data in part
1930
00:45:22,910 --> 00:45:22,920
1931
00:45:22,920 --> 00:45:24,530
it's because the logistics of actually
1932
00:45:24,530 --> 00:45:24,540
1933
00:45:24,540 --> 00:45:27,040
getting insurance approval for a bad and
1934
00:45:27,040 --> 00:45:27,050
1935
00:45:27,050 --> 00:45:30,920
our time the rest I'm sure we're not
1936
00:45:30,920 --> 00:45:30,930
1937
00:45:30,930 --> 00:45:35,360
unique in that and obviously if the
1938
00:45:35,360 --> 00:45:35,370
1939
00:45:35,370 --> 00:45:37,430
patient is not a bad candidate we would
1940
00:45:37,430 --> 00:45:37,440
1941
00:45:37,440 --> 00:45:39,920
stop or if there was a problem
1942
00:45:39,920 --> 00:45:39,930
1943
00:45:39,930 --> 00:45:41,509
and we're going to look at a variety of
1944
00:45:41,509 --> 00:45:41,519
1945
00:45:41,519 --> 00:45:44,239
laboratory outcomes as well as clinical
1946
00:45:44,239 --> 00:45:44,249
1947
00:45:44,249 --> 00:45:47,599
outcomes so we'll be looking at your an
1948
00:45:47,599 --> 00:45:47,609
1949
00:45:47,609 --> 00:45:50,210
output filling pressures sodium output
1950
00:45:50,210 --> 00:45:50,220
1951
00:45:50,220 --> 00:45:53,259
changes in in inflammatory biomarkers
1952
00:45:53,259 --> 00:45:53,269
1953
00:45:53,269 --> 00:45:56,660
changes in circulating with the site I'm
1954
00:45:56,660 --> 00:45:56,670
1955
00:45:56,670 --> 00:46:03,470
sorry leukocyte phenotypes we are hoping
1956
00:46:03,470 --> 00:46:03,480
1957
00:46:03,480 --> 00:46:05,660
that we are successful in some patients
1958
00:46:05,660 --> 00:46:05,670
1959
00:46:05,670 --> 00:46:07,339
in which case we'll have that apical
1960
00:46:07,339 --> 00:46:07,349
1961
00:46:07,349 --> 00:46:09,819
core and we can look at macrophage
1962
00:46:09,819 --> 00:46:09,829
1963
00:46:09,829 --> 00:46:14,920
density as well as here macrophage
1964
00:46:14,920 --> 00:46:14,930
1965
00:46:14,930 --> 00:46:18,890
subtype and we would be looking at you
1966
00:46:18,890 --> 00:46:18,900
1967
00:46:18,900 --> 00:46:20,480
know the apices of people who get the
1968
00:46:20,480 --> 00:46:20,490
1969
00:46:20,490 --> 00:46:21,680
device I'm gonna want to get an LVAD
1970
00:46:21,680 --> 00:46:21,690
1971
00:46:21,690 --> 00:46:25,009
people who just our standard Elva had
1972
00:46:25,009 --> 00:46:25,019
1973
00:46:25,019 --> 00:46:26,450
patients who weren't in the study at all
1974
00:46:26,450 --> 00:46:26,460
1975
00:46:26,460 --> 00:46:28,940
and then if by some miracle some of the
1976
00:46:28,940 --> 00:46:28,950
1977
00:46:28,950 --> 00:46:30,680
other folks get better we'd be we don't
1978
00:46:30,680 --> 00:46:30,690
1979
00:46:30,690 --> 00:46:32,329
get the sed we're in the study the
1980
00:46:32,329 --> 00:46:32,339
1981
00:46:32,339 --> 00:46:41,829
control we'll also be looking at people
1982
00:46:41,829 --> 00:46:41,839
1983
00:46:41,839 --> 00:46:44,180
to look at people percentage of people
1984
00:46:44,180 --> 00:46:44,190
1985
00:46:44,190 --> 00:46:46,130
who have successful outcomes with
1986
00:46:46,130 --> 00:46:46,140
1987
00:46:46,140 --> 00:46:47,450
respect to creatinine and filling
1988
00:46:47,450 --> 00:46:47,460
1989
00:46:47,460 --> 00:46:50,329
pressure and getting a pad and we'll
1990
00:46:50,329 --> 00:46:50,339
1991
00:46:50,339 --> 00:46:52,039
look at sustained effects after they get
1992
00:46:52,039 --> 00:46:52,049
1993
00:46:52,049 --> 00:46:54,559
of that as well and then for safety
1994
00:46:54,559 --> 00:46:54,569
1995
00:46:54,569 --> 00:46:56,690
we'll look at obviously further rises in
1996
00:46:56,690 --> 00:46:56,700
1997
00:46:56,700 --> 00:46:59,920
creatinine hypotension and MI and death
1998
00:46:59,920 --> 00:46:59,930
1999
00:46:59,930 --> 00:47:02,690
so in conclusion chronic heart failure
2000
00:47:02,690 --> 00:47:02,700
2001
00:47:02,700 --> 00:47:06,890
CKD a ki type 1 type 2 cardi renal
2002
00:47:06,890 --> 00:47:06,900
2003
00:47:06,900 --> 00:47:09,680
syndrome or inflammatory States the
2004
00:47:09,680 --> 00:47:09,690
2005
00:47:09,690 --> 00:47:11,870
president options for cardio renal
2006
00:47:11,870 --> 00:47:11,880
2007
00:47:11,880 --> 00:47:18,109
syndrome are largely ineffective so in
2008
00:47:18,109 --> 00:47:18,119
2009
00:47:18,119 --> 00:47:21,140
this group of patients who are at high
2010
00:47:21,140 --> 00:47:21,150
2011
00:47:21,150 --> 00:47:23,660
risk for not doing very well if we
2012
00:47:23,660 --> 00:47:23,670
2013
00:47:23,670 --> 00:47:25,130
continue to do the things that we do
2014
00:47:25,130 --> 00:47:25,140
2015
00:47:25,140 --> 00:47:27,769
we're going to look to see whether this
2016
00:47:27,769 --> 00:47:27,779
2017
00:47:27,779 --> 00:47:31,029
novel therapy that deactivates activated
2018
00:47:31,029 --> 00:47:31,039
2019
00:47:31,039 --> 00:47:33,079
neutrophils and monocytes frankly the
2020
00:47:33,079 --> 00:47:33,089
2021
00:47:33,089 --> 00:47:34,609
thing we think is playing a role here is
2022
00:47:34,609 --> 00:47:34,619
2023
00:47:34,619 --> 00:47:36,249
not the neutrophils but the monocytes
2024
00:47:36,249 --> 00:47:36,259
2025
00:47:36,259 --> 00:47:38,900
and reduce this issue map macrophages
2026
00:47:38,900 --> 00:47:38,910
2027
00:47:38,910 --> 00:47:40,970
will allow us to successfully bridge
2028
00:47:40,970 --> 00:47:40,980
2029
00:47:40,980 --> 00:47:43,759
these folks to pan therapy and perhaps
2030
00:47:43,759 --> 00:47:43,769
2031
00:47:43,769 --> 00:47:45,510
gain
2032
00:47:45,510 --> 00:47:45,520
gain
2033
00:47:45,520 --> 00:47:47,820
gain
allow us to gain some important insights
2034
00:47:47,820 --> 00:47:47,830
2035
00:47:47,830 --> 00:47:51,930
into the pathophysiology of cardio renal
2036
00:47:51,930 --> 00:47:51,940
2037
00:47:51,940 --> 00:47:55,829
central so thank you for or being so
2038
00:47:55,829 --> 00:47:55,839
2039
00:47:55,839 --> 00:47:58,920
kind to listen to me

5 Penyakit Ginjal Pada Anak

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5 Penyakit Ginjal Pada Anak

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1

00:00:00,800 --> 00:00:04,220

good morning everybody for those of you

wanted me to move away from that I thank

one is acute worsening of cardiac

so now I'm here we've got a cartoon part

milton Packer was smart enough to to

so this is a these are brain sections of

so that all it's been done this is with

okay now luckily about hearts so this is

seeing long-term the long-term studies

with worsening renal function defined as

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