# The Birth and Evolution of Medical Renal Pathology

April 25, 2022## Information

April 21, 2022

Yale Pathology Grand Rounds

Michael Kashgarian, MD, FASN

ID7753

To CiteDCA Citation Guide

- 00:00Quantum everyone for the forest.
- 00:05In person grand wrong
- 00:07of pathology department.
- 00:08After two years and then required this.
- 00:13This is a special marker lectureship for
- 00:16excellence in search of the apology and,
- 00:20very fittingly, it goes through the area.
- 00:24It's so it's pretty because Mike
- 00:29was the one who actually started
- 00:33raising funds for this lecture ship
- 00:36to honor his teacher and mentor,
- 00:39William Barry.
- 00:41Listen junior Barry McAllister was
- 00:45a graduate of the college and of the
- 00:49Johns Hopkins Medical School and the
- 00:52Department of Pathology at Johns.
- 00:55Pockets after this training he
- 00:57came back as chief of surgical
- 01:00typology for the memorial dynamic
- 01:03of the year new in the hospital.
- 01:07In that position, he said for 25 years,
- 01:11from 1953 to 1978.
- 01:15It was during that period that.
- 01:18Michael was a resident in the topology,
- 01:21rotated with him, and learned from him.
- 01:25This too was a consumer diagnostic
- 01:29apologist and educator whose teachings were
- 01:32not limited to the science of medicines,
- 01:36but they also extended to to
- 01:39the art of living.
- 01:40She was an extraordinary motor advisor,
- 01:44friend and confidant to students,
- 01:48residents, who workers and
- 01:52physicians from all disciplines.
- 01:55With that introduction from the department,
- 02:00we have a 200 gratitude.
- 02:05Owner Mike,
- 02:06as well as the listener.
- 02:12Thank you so much Mike.
- 02:20Hello, a long time colleague
- 02:23of mine. When they get short.
- 02:31OK, thank you, Manju.
- 02:33And it is a great honour.
- 02:38For me to introduce today's
- 02:42McAllister Memorial Lecture, speaker,
- 02:44Doctor Mike Fisherian Mike came to
- 02:48Yale 68 years ago to attend medical
- 02:52school after graduating from NYU.
- 02:54And he has been associated
- 02:57with the ever since,
- 02:59was just short interruption of internship
- 03:02at Barnes Hospital in Saint Louis
- 03:06and Research Fellowship in Germany.
- 03:09Might is known for being one of the
- 03:12founders of the field of renal pathology.
- 03:16And he has worked all of his professional
- 03:18life to move the field forward and
- 03:21disseminate the knowledge of renal pathology.
- 03:24But then he was giving the lifetime
- 03:27achievement award the Robert
- 03:28Heptinstall Lifetime Achievement
- 03:30award by the Renal Pathology Society.
- 03:34Moreover, Mike would say
- 03:36quintessential physician scientist.
- 03:38During residency,
- 03:39he spent a year in the Physiology department
- 03:43of Cuttington University in Germany,
- 03:46working with the renowned leaders
- 03:48of German Physiology that called
- 03:51Krama Cal Orey had called.
- 03:53Throughout his professional career as
- 03:55an academic pathologist here at Yale,
- 03:58he forged many collaborations with
- 04:00faculty and Department of Physiology,
- 04:03Cell biology and Internal Medicine,
- 04:05which led to over 350 peer
- 04:09reviewed papers in top journals.
- 04:12And these collaborations
- 04:14were very dear to him.
- 04:17I remember when I started out in
- 04:20renal pathology at Yale that very
- 04:23prominent physicians and scientists
- 04:25would walk in and ask for Mike.
- 04:28They never asked for Professor Casparian.
- 04:31They always ask this Mike here.
- 04:33Can I meet with them?
- 04:34So he had this very personal relationship
- 04:38to all these stranded collaborators?
- 04:41Umm?
- 04:42So Mike's achievements and the list of his
- 04:48achievements in the city is sold on all
- 04:50the leadership positions that he has held.
- 04:53All of the prices he has won all the
- 04:56communities that it would take another
- 04:59hour to go through all of that.
- 05:01I just want to mention that in addition to
- 05:05being an exceptional physician and scientist,
- 05:09Mike is also exceptional human being.
- 05:12This specific activities over many
- 05:14years in the Church of Christ,
- 05:17Yale,
- 05:17New Haven Symphony Orchestra,
- 05:19and in the Connecticut Fund for the
- 05:21Environment show his deep and broad interest,
- 05:24dedication in the local community,
- 05:27where he has lived over 65 years.
- 05:30I think that we are the best would
- 05:33have Michael Sharian as a leader and
- 05:35Mayor Thomas and our department,
- 05:37and especially for the
- 05:39junior faculty and trainees.
- 05:41Mikes life achievements are
- 05:44great template for their all
- 05:47professional professional life model.
- 05:50So when it's title is the birth
- 05:52and growth of renal pathology,
- 05:55today's Macalister Memorial lecturer
- 05:57please welcome micro sharing.
- 06:07Well, it's a particular,
- 06:10particularly wonderful honor,
- 06:12but also an interesting
- 06:13experience to be here in the at
- 06:17the podium instead of up there.
- 06:19And I noticed that you that
- 06:22things have improved around here.
- 06:24You all have a box ledge instead
- 06:26of having to go and get pieces
- 06:28of of of whatever is left.
- 06:30Over one of the the attractions
- 06:34of the of the.
- 06:36Grand rounds at but of pathology
- 06:38is that it brought in an enormous
- 06:40number of people because there
- 06:41were there were good lunches here.
- 06:48I'd like to make one a couple of
- 06:52comments about Barry McAllister.
- 06:54I think he was a consummate
- 06:58surgical pathologist.
- 07:00He was he was a general surgical pathologist.
- 07:03Everything he and everything that
- 07:05came to him, he would look at.
- 07:08He would be an expert in the memorial
- 07:12unit was populated primarily by.
- 07:17Community physicians and surgeons.
- 07:20And they actually really look to
- 07:24him for for help and assistance.
- 07:27Now it was this very small room
- 07:30and with the way we did frozen
- 07:33sections was kind of interesting.
- 07:36We I would take get the specimen,
- 07:39take a small piece of it,
- 07:41put it in a bottle cap with full
- 07:44formalin and put it over a Bunsen burner.
- 07:47To cook it,
- 07:48and once it was cooked then I put it.
- 07:51I froze it on a freezing microtome
- 07:54and and and and that made sections
- 07:58which we stay in primarily with H&amp;E.
- 08:02But if necessary,
- 08:03we had the opportunity to use
- 08:05some special stains as well.
- 08:07So it was.
- 08:08It was really an interesting
- 08:10way of doing things,
- 08:12but it was one where at least
- 08:15for residents who worked there,
- 08:17we there was a broad ordening experience
- 08:20on how to deal with different surgeons.
- 08:24And there was one surgeon
- 08:26that the gynecology,
- 08:27who thought that he knew it all.
- 08:30And he would come down.
- 08:32And it was, if it was a particularly
- 08:34if it was an ovarian tumor,
- 08:36he would never take a Barry
- 08:40diagnosis for granted.
- 08:41He would have to look at it
- 08:44himself and finally decide that,
- 08:45yeah, it was a bit what it,
- 08:47what,
- 08:48what Barry was saying is really what it was.
- 08:50He had been in in Boston.
- 08:52And so he thought that some
- 08:54of that Bostonian stuff had
- 08:56rubbed off of him on him.
- 09:00And I actually, you know,
- 09:03we have a student plays.
- 09:06And I actually was.
- 09:09Took his part and I sang song
- 09:13that my name is John McCain.
- 09:16John McCain.
- 09:19And and and a marvelous GYN surgeon, am I?
- 09:25And and that's sadistic
- 09:28statistic is my characteristic,
- 09:31and I'm in love with a wonderful guy.
- 09:35And and but, but he really.
- 09:38But Barry was able to handle
- 09:40any anything that came as well.
- 09:42And it was. It was.
- 09:44It was a joy to work with him as a.
- 09:48As a matter of fact,
- 09:50I started working with him in the summer
- 09:52and he would always leave at 4:00 o'clock.
- 09:55The reason he had to leave at 4:00 o'clock
- 09:57is that was he had to catch the the
- 09:59the ferry out to his island in the thimbles,
- 10:02and so I would.
- 10:03I would be I would be left taking care of
- 10:06all of these private surgeons all by myself,
- 10:09and it was quite an experience.
- 10:13Well. Uh.
- 10:16It knows surgical pathology is
- 10:21relatively new as a sort of a discipline.
- 10:24You know people were
- 10:25doing autopsies for many,
- 10:27many years,
- 10:28but none of them ever really made
- 10:31a connection with the with the.
- 10:34With the clinical experience they
- 10:36just did it mostly for anatomy and
- 10:39anatomists were the primarily dissectors,
- 10:41but surgeons would also dissect,
- 10:44but they they would not really use the
- 10:48their findings in an academic way until
- 10:51Giovanni Battista Morgani, who is?
- 10:54Who we can call the father of modern
- 10:58anatomic pathology, he wrote this book.
- 11:00They said it was a crisis mode.
- 11:02All of them that are in the in the goddess.
- 11:06In 1917. Sixty one.
- 11:10And the.
- 11:11That's translated and I'm not,
- 11:14and I will somebody else translated for me.
- 11:16I'm not good at.
- 11:18At Latin the seats and causes of
- 11:21disease are as investigated by anatomy.
- 11:25And in him,
- 11:26and in his thesis he just says the
- 11:30description of gross pathology.
- 11:32Represents the cry of suffering
- 11:35from the organs,
- 11:37so the organs sang to him and
- 11:40and and and he really and his.
- 11:42His book was really one one of
- 11:47the only theses that that had
- 11:50used anatomic pathology.
- 11:51Anatomic pathology as part
- 11:53of overall part of medicine.
- 12:00That's it.
- 12:05Nephrology in those days was
- 12:09didn't really exist unless you
- 12:12wanted to and because most of the
- 12:15diagnosis was done by **** prophets.
- 12:20And they juggled the *******
- 12:23and we have to juggling.
- 12:25The ******* would come up with a
- 12:28diagnosis and now that wasn't that
- 12:30it was not with one single profit,
- 12:34but the profits used to
- 12:37help and consultation.
- 12:39And you could see runners coming going
- 12:42across the city carrying despots from
- 12:44one place to another for diagnosis.
- 12:47Well this was this. Uh.
- 12:52This treatise here is a criticism of of
- 12:56of the process and and and and and it,
- 13:01Brian says the fraudulent use
- 13:04of uroscopy by by examining the
- 13:07patients by is by some physicians.
- 13:12He called them quacks.
- 13:14And so you're right,
- 13:18Nephrology was really that
- 13:21much well developed.
- 13:28However, Richard Bright.
- 13:32In English physician.
- 13:34Decided that he was be that the.
- 13:38The physicians were seeing
- 13:41patients with dropsy.
- 13:44And and where they had.
- 13:47Albuminuria.
- 13:50And so they were swollen.
- 13:52They had the nephrotic syndrome.
- 13:55And he decided that he should
- 13:58look at all of the patients with
- 14:00them and he came across him.
- 14:02He created a,
- 14:04a categorization of the diseases
- 14:07which were associated with dropsy.
- 14:11And they they covered into
- 14:15the inflammatory diseases.
- 14:17And and he talks about acute and
- 14:20chronic popular in Ireland on Fridays,
- 14:23lipoid,
- 14:24nephrosis acute and chronic
- 14:27pyelonephritis and nephrosclerosis
- 14:29associated with cardiac hypertrophy.
- 14:32And that and and that combination
- 14:34of of nephrosclerosis and
- 14:36hypertrophy was actually looking
- 14:38at patients with hypertension.
- 14:41Umm?
- 14:42And his categorization of of renal
- 14:46diseases lasted not because there
- 14:49was no real nobody else who even
- 14:52took on the attempt to look at the
- 14:56cause of dropsy and and and whatnot.
- 14:59So his.
- 15:03But on the other hand,
- 15:05the in the and in the 19th
- 15:09century there were several.
- 15:12Anatomists,
- 15:12who were interested in the
- 15:14kidney and one was the Alcop,
- 15:17had Henley.
- 15:19And he was the one who was
- 15:23looked at the kidney and saw
- 15:25that it was made up of tubules.
- 15:28And the tubules were the organ,
- 15:31and not the not,
- 15:33not the the overall organ,
- 15:35and he I,
- 15:37I think you probably all remember that
- 15:41that we talked about the the Henleys loop,
- 15:45which was is responsible for
- 15:48maintaining our internal environment
- 15:50and the concentration of your.
- 15:53So.
- 15:55As it turned out,
- 15:57when I had a fellowship in Germany,
- 16:00I went to Gottingen which was
- 16:02the same place that he had been
- 16:04so kind of a double honor.
- 16:09And the other person of of of
- 16:11prominence in the 19th century
- 16:13was been a glaude bell now.
- 16:15He described the the million terrier.
- 16:20He he was saying that the the the,
- 16:24the fluid that exists in
- 16:26our bodies surrounding it,
- 16:28surrounding the cells with very important,
- 16:32and it had to be kept in relatively.
- 16:37Close concentration and of ions
- 16:41and also in terms of its tonicity
- 16:46and that it had to be stable.
- 16:50And so the interstitial fluids
- 16:52had to be actively maintained
- 16:54around stable settings,
- 16:56so that and that the stability was
- 16:59a prerequisite for the development
- 17:01of a complex nervous system.
- 17:03Umm?
- 17:07Uh, so that the fluids where it
- 17:10being interested were were were of
- 17:12interest and but we're not really
- 17:15being investigated very well,
- 17:17so I'm jumping to the Yale
- 17:20University to Yale Medical School,
- 17:22the Internal medicine,
- 17:25internal Medicine department in the
- 17:28early 20th century, relatively small.
- 17:30They had maybe had four or five professors,
- 17:33and. The giant planet Peters.
- 17:40There was a case,
- 17:42and so he established chemical laboratories.
- 17:45And and he saw almost every patient
- 17:50in the in the hospital and to
- 17:53look at at at their electrolyte
- 17:57balance and and water balance.
- 18:00And he set up these laboratories and he
- 18:05became with a with a a chemist colleague.
- 18:09He wrote this book,
- 18:10the clinical Chemistry which
- 18:12established a whole.
- 18:16Science of clinical chemistry.
- 18:18So there was interest in looking at the
- 18:22body's fluids, but not the we weren't.
- 18:25They weren't really looking at how the
- 18:28body fluids were being maintained.
- 18:31Aside story about. Leaders.
- 18:36Is that during the time when?
- 18:43People were being examined for
- 18:46being communists and and whatnot.
- 18:49He was that he was attacked
- 18:52and and and his his he.
- 18:56Famously, his NIH grants were cut off.
- 19:00Uh, and he went and he. Umm?
- 19:07He challenged that in the courts.
- 19:11All the way up to the Supreme Court.
- 19:15And the Supreme Court upheld his position.
- 19:18Unfortunately,
- 19:19he never heard it because he died just
- 19:23before the Supreme Court made its.
- 19:26Decision that that and so.
- 19:31It he's his, his legal.
- 19:39History is also important.
- 19:40It's in that it's in the
- 19:42archives here at the library.
- 19:49The brides characterization
- 19:50is the renal disease,
- 19:51which remain the standard.
- 19:54Until the 20th century.
- 19:57And in the early 20th century. 2 Germans.
- 20:03Full height when far wrote a textbook.
- 20:07I'm diseases of the kidney. And.
- 20:13Are made pet plants painstakingly accurate?
- 20:18Drawings of the Histology of
- 20:20rights disease and if you look
- 20:23at at at his drawings you think
- 20:25that they were microscope.
- 20:27They were microscopically produced,
- 20:29but no, he did it by drawing.
- 20:33Umm? And there's this was
- 20:36published in the British.
- 20:40And early in 1914,
- 20:43so there was beginning interest in.
- 20:48Renal diseases and their
- 20:51effects in patients.
- 20:54It was not until the 1950s that.
- 20:59There was a lot of valuable
- 21:01to take biopsies of the
- 21:04kidney and examine them and.
- 21:09Robert Clark and Robert Merky at
- 21:12the University of Illinois decided
- 21:14that they would try and do it,
- 21:15so they actually started
- 21:17to do needle biopsies of.
- 21:22Of the kidney, and they needed
- 21:24a pathologist to look at them.
- 21:29And the chairman of Pathology
- 21:31there went to the the youngest
- 21:34pathologist in the in the.
- 21:38In the department because he didn't
- 21:40think anything would come of it.
- 21:42That was that what it was
- 21:44totally useless to do this.
- 21:47The pathologist was Conrad Pirani.
- 21:50Ohh became one of the leaders of retail
- 21:55pathology in the 20th century. Umm?
- 22:01In 19 six enough people.
- 22:03Not very many people were doing.
- 22:05If I have this other kidney,
- 22:08but it was in in in in 1961 the Ciba
- 22:13Foundation hold held a symposium in London.
- 22:18And 29 physicians and pathologists met.
- 22:23To discuss what they thought was the
- 22:26utility of doing needle biopsies of
- 22:28the kidney and what it would find out.
- 22:36It was it they came through
- 22:38some interesting conclusions.
- 22:40One is they felt that if if
- 22:41the biopsies were being done,
- 22:43they should be looked at by people
- 22:45who were expert in looking at them.
- 22:49And that.
- 22:52And that they should be done
- 22:55in an organized fashion. And.
- 23:01And they came up with some standards
- 23:04of Care now this this is a little
- 23:07bit of expansion of the standards
- 23:09of care that they came up with,
- 23:11but the standard of care.
- 23:13For the medical renal biopsy became
- 23:16serial thin section paraffin embedded.
- 23:21Umm? Slides stained with HEPS Jones
- 23:25silver triple that bottle of water.
- 23:40Thank you.
- 23:48Some immunologists were also becoming
- 23:51interested in in in the renal disease.
- 23:56And they decided that that some of the
- 23:58diseases that they were looking at,
- 24:00like commercial or Fridays,
- 24:02were immune mediated and so they
- 24:05started to look at that real biopsies
- 24:07using fluorescence techniques where
- 24:10the antibodies were directed against.
- 24:13Immunoglobulin is kind of
- 24:15complement components,
- 24:17and if there if was known of any
- 24:20specific antibodies to the antigens.
- 24:23And and, and and and so that fluorescence
- 24:29examination of the biopsies became also
- 24:31part of the of the standard of care.
- 24:38Are they some centers? Also felt that
- 24:43electron microscopy might be useful and.
- 24:50But the cell biologist felt that
- 24:53that was in there first purview,
- 24:55that that wasn't for pathologists.
- 24:58They got to be a cell biologist
- 25:01to look at and Marilyn Farquhar.
- 25:04Decided that she would look at the
- 25:07at the kidney and she did look at
- 25:10the kidney and then actually found
- 25:12the that that the effacement of
- 25:15the foot processes in patients with
- 25:18dropsy or or nephrotic syndrome. Yes.
- 25:23But that expanded very quickly to
- 25:27other electronic microscopists and.
- 25:31I'm I was in. I came back from my my.
- 25:39My fellowship in Germany in 1962
- 25:42and I was able to not only establish
- 25:46my micropuncture laboratory,
- 25:49but I went and started to do a kidney
- 25:56biopsies, but I needed a clinician.
- 25:59Because you can't do it by yourself.
- 26:03And the nephrology section who
- 26:07helped me in establishing my my my.
- 26:12My laboratory also sent me a fellowship,
- 26:17a fellow.
- 26:18His name was John Hazlett and he was he.
- 26:22He was beginning to learn how to
- 26:24do a micropuncture and we did a
- 26:27number of studies looking at at
- 26:29the maintenance of the electrical
- 26:32potential across proximal 2 views so
- 26:34that we absorption could occur but
- 26:37at the same time he ran a clinic.
- 26:39The clinic for patients with lupus.
- 26:43And so he he talked to me, and he said,
- 26:47well, maybe we should biopsy them.
- 26:49I said, OK, if you can biopsy them,
- 26:51we can look at them together and
- 26:53that any any did,
- 26:54and we we collected and biopsies
- 26:59from some 200 patients with lupus.
- 27:05Uh, we we actually.
- 27:10And engaged a British epidemiologist who
- 27:13is in the Department of Medicine at that
- 27:17time to help us in in analyzing what,
- 27:21what, what we found. And we found some
- 27:25very interesting things by this time.
- 27:28By this time I had a small
- 27:31electron microscope,
- 27:31so we were doing EM here and one
- 27:35and we found one of the interesting
- 27:38thing is that the the patients
- 27:41with the most severe disease had
- 27:45subendothelial electron dense deposits
- 27:47and they had my immunofluorescence.
- 27:51Multiple immunoglobulins and compliment.
- 27:55And so we. We were able to look
- 28:00at these patients overtime.
- 28:02And and at that time the only
- 28:04you know therapy was used.
- 28:09Azathioprine and so.
- 28:10All of these patients were
- 28:12treated in exactly the same way,
- 28:14and we could see what the outcome was.
- 28:18And we, with the aid of the epidemiologists,
- 28:22we wrote papers on on what
- 28:25was what were signs of and of
- 28:29of progression, and so on.
- 28:32And he did something really,
- 28:34really interesting.
- 28:37He selected, I think it was about
- 28:4120 nephrologists in in Canada.
- 28:44And he gave them the history of
- 28:48those patients. Without the biopsy.
- 28:53And he asked them to come.
- 28:55And and the. The agreement between
- 29:00them was not really great and there
- 29:03was a lot of questions about it.
- 29:05He then gave them the results of
- 29:08the biopsy and everything codified
- 29:10into the groups of patients that
- 29:13were existed and one and that the
- 29:15treatment actually was was useful
- 29:17in in diminishing the inflammatory
- 29:20process that was that with lupus and
- 29:23and so it became that the biopsy
- 29:27actually became a very useful tool.
- 29:30In in clinical nephrology.
- 29:34Umm? So, so the standard of care,
- 29:39and this is an expansion of that.
- 29:41Was that the medical renal biopsy
- 29:43had to be done on biopsy on serial
- 29:49thin section paraffin embedded
- 29:51slides so that they were we.
- 29:54We would have a a bunch of slides.
- 29:58At and looked at serially so we could
- 30:01see a a greater number of glomeruli
- 30:06and and variety of vessels. Umm?
- 30:10Uh, and and we we we we did as the
- 30:14immunologists were taught, told us to do.
- 30:17We look for immunoglobulins.
- 30:19And indeed we found them.
- 30:21And one other outcome of the
- 30:25treatment was that there was a
- 30:27shift from the acute inflammatory.
- 30:32Elephantitis of lupus to the membranous
- 30:35of form of lupus which was not
- 30:38which had no inflammation at all.
- 30:41But it had the deposits of
- 30:44immunoglobulin in the peripheral
- 30:47basement membrane and and and the
- 30:51patients all had an abnormal.
- 30:54Your ends with with a lot of protein in them.
- 30:58Umm?
- 31:03Now, so that a renal biopsy has with or
- 31:10with all of these different parameters.
- 31:14That you have is is not a
- 31:18simple means of diagnosis.
- 31:21You know you're a surgical pathologist.
- 31:23You look at the slide,
- 31:24you call it cancer.
- 31:25Tell the surgeon would take
- 31:26it out and that's about it.
- 31:30Here with the renal biopsy that the
- 31:33nephrologists were more interested in,
- 31:36the not only the the the disease process,
- 31:41but what what could be
- 31:44predicted about the possible.
- 31:47The possible response to therapy and
- 31:49those days it was immuno immunosuppressive
- 31:52therapy was just beginning and
- 31:55cyclophosphamide and some other
- 31:58immunosuppressants were were being used
- 32:00and so they wanted more information.
- 32:03And so it was necessary to do all three.
- 32:09Types of microscopy to come up with
- 32:12an come up with a diagnosis. Now.
- 32:18The approach for for diagnosing renal
- 32:23biopsy requires information from
- 32:25these several different sources to be
- 32:29integrated into a single interpretation.
- 32:32The sources included the clinical
- 32:34data examination by light microscopy,
- 32:38immunohistology and electron microscopy.
- 32:41Each of the sources.
- 32:44Has several individual variables in
- 32:48terms of which which immunoglobulins
- 32:50are involved with the local localization
- 32:53of the immune complex as well and and
- 32:57and they had to either be included
- 33:00or dismissed in in in order to
- 33:03make the final diagnosis.
- 33:04George boole who was a 19th century.
- 33:12Pastor, he was a he was at.
- 33:14He was a clergyman.
- 33:19And he developed. Umm?
- 33:23A A branch of algebra.
- 33:28Which which this this?
- 33:31Either that variables could
- 33:34either be included or dismissed.
- 33:38And that they were either
- 33:40positive or negative.
- 33:42And this branch of algebra,
- 33:46which the value variables or
- 33:49truths or or or or false.
- 33:52And then this expanded the range of
- 33:55applications that had to be handled
- 33:58from proportion propositions that
- 34:00only have two potential values
- 34:03to those that have many and.
- 34:06And really so that looking at the
- 34:09kidney biopsy is is is a method.
- 34:12We're all doing Boolean algebra.
- 34:17Now.
- 34:21He wasn't the only clergyman who was
- 34:25interested in looking at things in
- 34:28a different way, and Thomas Bayes.
- 34:32Uh. Decided that that his
- 34:38statistic using statistics.
- 34:40It was that one that Bayes theorem
- 34:44provides a way to revise the findings of.
- 34:50Of the findings of the biopsy,
- 34:53both light microscopy and whatnot,
- 34:55and put them into categories again.
- 35:01Again. Saying OK,
- 35:05This is the pattern that we would
- 35:08see and and then with with with
- 35:12Bayesian statistical methods.
- 35:14That's the way AI started.
- 35:18So AI actually is using Bayesian
- 35:21statistics to take a large number of
- 35:24of variables and look at the of the
- 35:27individual variables as variables
- 35:29as well as individuals as well as
- 35:33the variables of themselves and
- 35:36in the patterns there are, and.
- 35:38So what what happens is that you
- 35:41look at the light microscopy and
- 35:43you have one level of of. Of.
- 35:46Of information you add on to that a
- 35:50second level of the immunofluorescence.
- 35:54And then you add on the third
- 35:56level of immunofluorescence.
- 35:57And if you think about what I what
- 36:00AI does is it looks like it looks
- 36:03like it looks at the data and at
- 36:06one level and then looks at the
- 36:09second level and and decides whether
- 36:11or not it has a contributory way
- 36:14of looking at a final result.
- 36:19And and. AI does does this with with
- 36:25with large volumes of of of data,
- 36:29and so you really need to have the
- 36:33computer backing that to do this with.
- 36:36Umm?
- 36:36And so the data of the single
- 36:39biopsy went are analyzed further
- 36:41by using our AI and and and within
- 36:46the background of existing data.
- 36:48The predictive value of the biopsy
- 36:51in the sector in the selection of
- 36:54therapy and outcome is greatly enhanced.
- 36:56So. You know the.
- 36:59The application of AI to looking at the
- 37:04kidney biopsy has become at least somewhat.
- 37:11Of interest, there's a group in and in Paris,
- 37:15which is looking at patients with lupus
- 37:18and and looking at all the data and and
- 37:21that can be obtained by from the biopsy
- 37:24and lupus and and and predict. See.
- 37:29The. There's a group here at at Yale
- 37:35that is looking at donor donor biopsies.
- 37:39There's a, there's a problem,
- 37:41and that we don't have enough
- 37:43donors and a lot of donor kidneys
- 37:47that are dismissed without good.
- 37:50Reason and so they are.
- 37:53They're working on on and and actually
- 37:58those of you who have to do the the
- 38:00the county of the Gloria glomeruli.
- 38:02And looking at the vessels and donut
- 38:06donor biopsies should realize that they
- 38:08that there's a lot of information there.
- 38:11But you can't just look at it and say OK,
- 38:15no good because we have too many goals,
- 38:17sclerotic,
- 38:17Andreoli or the vessels show arterial.
- 38:20Sclerosis and so.
- 38:22The group here is is using
- 38:26artificial intelligence to look
- 38:29at the at at digitized images.
- 38:33Of the of the donor biopsies and coming
- 38:37up with algorithms to to separate out
- 38:41those which which is going to be useful
- 38:44and those that are not so I think.
- 38:50The the renal biopsy now is is an
- 38:54experiment in, in and of itself.
- 38:59You know, when and and and it requires a
- 39:03lot of data and it's sort of interesting
- 39:06that when I came back from Germany in
- 39:121961, nineteen 62. The number
- 39:16of biopsies that would have
- 39:17been done here at Yale was 10.
- 39:22We we now have, what is it over 10,000?
- 39:28Yeah, but without that thousand
- 39:31a year so overall for overall,
- 39:34maybe even more than 10,000.
- 39:37So we so we have the the data
- 39:43bank which is necessary to use
- 39:47artificial intelligence and and
- 39:50and and come up with new ideas.
- 39:56And the The thing is that the
- 39:58what we get from our artificial
- 40:01intelligence is what the data tells us.
- 40:04But once put, when they're when they're
- 40:06put in the context of the clinical situation.
- 40:10Well, there there are some visual
- 40:13findings that that that that can be
- 40:17linked to disease outcomes and that
- 40:19and that and can be mined to discern
- 40:23previously unknown molecular mechanisms.
- 40:26So my advice to all of you in surgical
- 40:30pathology is when you look at a slide think.
- 40:36You know when when, when desktop computers
- 40:40first came out and you at a very high
- 40:44price IBM would give you this then this
- 40:48desktop computer at $10,000 and not
- 40:50very much information on how to use it.
- 40:53But all also gave you a plaque.
- 40:56Not the Plackett said think you had
- 41:00to hang a plaque over the computer
- 41:02so that it would work. So I think.
- 41:07Umm? We're now we, we are now.
- 41:10I guess we have a a something which would
- 41:15where we can digitize our our our specimens.
- 41:20And and if we digitize.
- 41:25Do this over a period of time.
- 41:27We will get sufficient data so that
- 41:30we can can come up with new ideas.
- 41:35Ideas that we didn't without premises.
- 41:39And I think we're in a new new way,
- 41:44so my advice to the residents and especially
- 41:50residents who are in the front lines,
- 41:55is think how you can use the multi source
- 41:58data obtained from digital biopsies.
- 42:01When we begin to apply.
- 42:05So I'm happy to answer any questions.
- 42:18Yes.
- 42:20I was a young president
- 42:21here. One of the things that impressed
- 42:24upon me was said, you know, I didn't
- 42:26know. The rest is true.
- 42:29Comment on what you say.
- 42:33Well, it says that in to the
- 42:37results from immunofluorescence or
- 42:39have several variables in that are
- 42:43intrinsic in the preparation so.
- 42:49The the, the nature and strength
- 42:51of the antibodies is 1.
- 42:54The preparation and of the
- 42:58specimen is another.
- 43:00The combination of of of
- 43:03the ability to have good.
- 43:10Good samples that you can compare,
- 43:14and so when you're looking at,
- 43:16you're looking at new antibody with.
- 43:19For IgG it's a common.
- 43:23Common antibody you have to look at.
- 43:27You can't just look at 1 biopsy
- 43:30and say oh the IGT is in in the
- 43:33mesangial We haven't know that
- 43:36when you look at it normal.
- 43:38Of kidney that with that same
- 43:41antibody that it shows nothing.
- 43:44We need the controls and so it's tricky.
- 43:48You have to really know what you're doing.
- 43:52You have your selection of bio of of
- 43:56your 8 reagents is important your your.
- 43:58Yeah.
- 43:59Your validation of those
- 44:01agents is very important.
- 44:05And I think, but on the other hand,
- 44:09you know with experience and.
- 44:14Of using fluorescence and I
- 44:17know that you've done a lot,
- 44:19particularly in terms of
- 44:22quantitative fluorescence,
- 44:23it all of these things take it are
- 44:26have to be taken into consideration,
- 44:29but it was tricky enough for you to do.
- 44:36What were you ever bored?
- 44:39Bored, bored? What's that?
- 44:45No, you know that's that's the thing
- 44:49that every time you do something,
- 44:51something else pops up.
- 44:54And you never sit there and and
- 44:57try and sit on your laurels.
- 45:00You have to look at it and and say OK,
- 45:03what, what, what, what does this mean
- 45:06and and does it really mean that?
- 45:08You you really and and the.
- 45:12The fact that I was constantly
- 45:15interacting with clinicians,
- 45:17they never let it be bored or boring.
- 45:20They never let it.
- 45:22They would never let me do things
- 45:24without complete explanation.
- 45:26I would have to go over
- 45:29every slide and with them,
- 45:30and they had to learn as much
- 45:32pathology as I could teach them.
- 45:37So I think. So much for
- 45:41this historical perspective
- 45:43that I think
- 45:44you glossed over very
- 45:46modestly. Thank you, your contributions,
- 45:50but I'm just struck by a couple of things.
- 45:53That first of all,
- 45:55to share that it was also hepatologists
- 45:59and gastroenterologists who made
- 46:01ologists look at tiny liver dies and
- 46:04tiny and discovered the obtained Posa.
- 46:09Jerry Askin right here in the
- 46:12liver with Grandmaster and they
- 46:13sorted that out and sign.
- 46:15Ruben was one of the fathers of modern.
- 46:20So that's one comment, and so the
- 46:24analogy is that our pathologist
- 46:27had to be pulled along.
- 46:30And I wonder the analogy being with today,
- 46:34as you're making this comment that
- 46:36we are also being asked today to
- 46:40go along again with with digital
- 46:44and AI and machine learning.
- 46:45And so this is another in
- 46:48the right direction.
- 46:50So I have to see it instead of the treatment.
- 46:53Well, you know it always interested
- 46:56me that the two that two Protestant
- 47:00clerical clerical clerics in the 19th
- 47:05century came up with ideas about thought.
- 47:09And how thought and came out
- 47:12in terms of of giving answers.
- 47:16And I said, well, maybe look,
- 47:19maybe they're looking for a proof of God.
- 47:24They're looking at what's
- 47:25what's going on in the world,
- 47:27and they looking at the statistics
- 47:30of what they see and so.
- 47:32But the Boolean algebra and the Bayesian
- 47:36statistics are really interesting things
- 47:39that can't come come from clerics.
- 47:43Who you know you think?
- 47:46Well, the only thing they
- 47:47ever do is read the Bible.
- 47:49And read it over and over and over again.
- 47:52But you know,
- 47:53if you read it over and over and over again,
- 47:55you have a different interpretation
- 47:56of what you read from the last time.
- 47:59Yes,
- 48:00Mike, thanks for this greater lecture,
- 48:02so I don't know if we use you
- 48:05remember the first time you
- 48:07start doing the the real biopsy?
- 48:13So how do they transform the service?
- 48:18Well, the first time I had to do
- 48:21a biopsy on a kidney transplant.
- 48:24Well, I was my wife and I
- 48:26were at a cocktail party.
- 48:30Have you had a cocktail party?
- 48:33And I got a phone call saying
- 48:36that I had to come in.
- 48:38Because I had to look at
- 48:41some transplants. Now the.
- 48:45The the electrical surgeon who was
- 48:47who was also at the cocktail party
- 48:49so so we we the two of us went
- 48:53into totally unknown territory.
- 48:58And we had a we had.
- 49:02Basically what we were looking at was
- 49:05to see the viability of the tissues
- 49:08that we were getting because the our
- 49:11our patients were a group of Yale
- 49:14undergraduates who are coming back from
- 49:17chasing girls up in in in Massachusetts.
- 49:22Because that's where the girls all the
- 49:24troops were and they they ran into fog.
- 49:27Mine on I-91 and it was it terrible
- 49:33and six or eight of them were killed.
- 49:37And their parents actually were
- 49:40the ones who suggested that they
- 49:44that they that they be selected
- 49:47for transplant at the donors,
- 49:50and so that was those were the first ones,
- 49:53that that way I had to look at.
- 49:57And then The thing is that we
- 49:59hadn't got transplants here before.
- 50:02These were the first transplants.
- 50:04And it was important to know whether.
- 50:08That whether they were.
- 50:10Whether they would they would
- 50:12bear with rejection or not at all
- 50:14over the period of time that they
- 50:16were being observed clinically.
- 50:18And so again, we had to learn.
- 50:21Or I had to learn.
- 50:24And I, but again,
- 50:26I learned with the clinician.
- 50:28And and and we we came up
- 50:32with actually the 1st.
- 50:35Regret categorization of of of
- 50:38transplant rejection and it was because.
- 50:43I I if I did it alone,
- 50:46it would not have been as as important.
- 50:49The fact that the that I did it with a
- 50:53clinician at my side was was very important.
- 50:57And actually,
- 50:58when when you talked about that the klatskin,
- 51:03the first renal biopsies that were
- 51:05that were being done when I came
- 51:08back in Doctor Clasko's laboratory.
- 51:10Because he was.
- 51:11He's already experienced at
- 51:13doing liver biopsies,
- 51:15and his laboratory was experienced
- 51:17in making the thin sections and
- 51:21staining them well and limiting the
- 51:24variabilities and it it gave us.
- 51:28The opportunity to do it.
- 51:30The other thing that he did was.
- 51:33With every biopsy that he did.
- 51:36He he had,
- 51:38he created a card with punch holes in them.
- 51:43You had a card with punch holes in them,
- 51:45and each of the punch holes meant meant
- 51:48meant something about the the the.
- 51:50The laboratory findings that
- 51:52clinical findings and so on.
- 51:54So if you wanted to find out something
- 51:56would stick a needle into the into the
- 51:59bunch and then pull out the pull out
- 52:01the the group and and so that was when.
- 52:09Actually I was working with working
- 52:12with John Hazlett in the in in the.
- 52:15In these patients with lupus,
- 52:18and we essentially did the same thing,
- 52:20but I didn't.
- 52:21I didn't have punch cards,
- 52:22but but it was a matter of
- 52:25tabulating the data in such a way
- 52:28that the data was not static.
- 52:32The data was was was.
- 52:35Something which was was predictive
- 52:38and and was and and we didn't even
- 52:42know it was going to be predicted.
- 52:45And so without trying we could.
- 52:48We couldn't do anything.
- 52:50But but we try and we did.
- 52:54And and you know, that's.
- 52:56The opportunities here.
- 52:59In pathology are enormous.
- 53:02You just have to.
- 53:03You just have to decide to think for
- 53:05them and think about them and do.
- 53:11And I like doing it if the in in
- 53:13renal disease and and the fact
- 53:16that we now have over 10,000,
- 53:19maybe even more a year, years of experience.
- 53:24Well, I I produced in Atlas.
- 53:28Yes, it was actually.
- 53:30A clinician who wrote a
- 53:32big tone on nephrology.
- 53:35Came to me, I think maybe 20 years ago and
- 53:40said we need an Atlas of the pathology.
- 53:44To go along with this with this arbeitete,
- 53:49our big textbook of of of nephrology.
- 53:53And so I I got I got I.
- 53:59Wanted to do it by myself.
- 54:01I know I couldn't.
- 54:02And I didn't.
- 54:04I was unhappy about doing
- 54:06it with a with a committee.
- 54:09The committees don't get very much done.
- 54:14And so I was lucky to recruit Agnes Fogel.
- 54:20And so the two of us.
- 54:24Put everything that we knew and from
- 54:27our selections in into that book.
- 54:30And so the. The 4th edition
- 54:32just came out just came out.
- 54:42Well, thank you for listening.