a United States Army Medical Department 

continuing education program,

immuno suppressive management 

with Jeremiah G.

Turcotte M.D.

Professor of surgery.

University of michigan hospital at Ann Arbor.

I think this is a 

particularly important time to be considering 

and reconsidering immune suppression 

because in fact the success 

of transplantation has plateau owed in recent 

years.

Uh And it's mainly due to the fact that we 

haven't made any breakthroughs in the area of 

transplant of immune suppression.

We start with that first slide.

So I think it's time to rethink what we've been 

doing.

Go back to the drawing board 

and if we're really going to get any 

significant improvements in the years to come,

might be helpful just to review how we got to 

where we are today.

And uh here is simply a summary of 

some historical highlights have to,

it has to do with the development of neuron as 

a clinical immune suppressive agent.

Small business started in 59 when Bob 

Schwartz and domestic in Boston 

demonstrated that six more capital 

period could produce tolerance to bovine 

serum albumin doesn't have a great deal to do 

with rejection.

But was the first demonstration that compounds of this 

type were immune suppressants.

Uh Zukovsky and 

calm.

Then tried six mp in canine kidney 

grafts and demonstrated that it 

would prolong arenal 

Allah graphs.

Um In about 

61 Roy Calm did a series of 

about 120 dogs at the Brigham 

And used a variety of compounds,

all of which were analog of six MP 

in urine being simply one of them 

did about 10 dogs in each group with 

each compound And found that he had 

a little less toxicity in 10 

dogs out bred dog population 

with what was then called Burroughs.

Welcome with a number after it.

Uh,

and on that basis selected that 

drug as a more promising analog of 

six mp to use clinically promptly 

took it to the clinic.

And that's where we've been ever since.

And the reason I would emphasize that is 

that there really hasn't been a great deal of 

a broad look and a lot of 

chemotherapeutic agents,

uh,

either experimentally or clinically.

And we've sort of arrived at using in urine on the 

basis of just a modest research experience.

And then what seemed to work out reasonably while in the clinic.

But when you look at the scientific foundation on which the 

use of this drug lies,

it's not very firm or complete.

However,

it does work.

It possibly is less toxic than six MP.

Although people will debate that and 

it is a convenient drug to use.

The drug did allow the first long term survivals 

of human non twin renal alla 

graphs,

with the occasional exception,

prior to that time,

that a few people with total body radiation 

had long term survivals of their graphs.

Next slide,

Okay,

now,

let's look at steroids,

I just might say when you look at the ad about the 

various chemo therapeutic 

immunosuppressants.

The only other one that's had very widespread clinical use of 

Cytoxan.

That is a very good drug.

It has a few more side effects.

A little difficult to manage.

What is the drug of choice and by 

certain groups anyway,

save with bone marrow grafting 

steroids I think are even a little more interesting story.

Um Rabbits are very 

sensitive to cortical steroids and way back 

in 51 billing Ham showed 

that steroids will prolong rabbit 

skin alla g.

Uh this stimulated a great deal of other work using 

various cortical steroids,

most of which was negative.

And if one studied antibody 

synthesis,

induction tolerance and so on steroids,

a secondary response versus the primary response 

steroids had very little effect.

And about this time by the time we got the 60s,

in the early 60s,

if you asked three out of four people in the 

field of immune suppression of steroids had any role,

they would say no and they've been pretty much 

almost given up.

Um Nevertheless,

a few surgeons who I didn't 

believe everything they heard and maybe haven't read all the basic 

science literature,

continued to use steroids 

and chuck zukowski again was now at 

Tucson did use very large 

doses of predniSONE alone.

These were unheard of 

uh doses at that time to use 

this larger dose on a frequent basis 

and got a modest prolongation of 

canine.

Real,

real Allah graphs.

The crucial observation was 

1963 by dr goodwin 

was a urologist uh on the 

West coast.

And he had a patient who is treating with urine 

and started to undergo a massive rejection 

and he didn't have anything else to do.

So he gave the patient large dose 

steroids and reverse the rejection.

And that was the first time that an established rejection 

episode had ever been reversed either in humans or 

animals.

And it was on the basis of that clinical observation then that we 

added steroids to the immunosuppressive regimen.

Initially they were reserved to the time that rejection took 

place.

And later on we're used prophylactically.

So then there was a 62 63 where the 

clinical trials using both of the drugs together 

began.

And that's what put renal transplantation 

on the horizon or in 

use as a clinically 

therapeutic measure.

And it's these two drugs of course that's still form the 

basis of all immune suppression in renal 

transplants.

And as a matter of fact there's been no other drug or 

combination of drugs that has ever been 

demonstrated to be more efficacious than simply using 

in urine and steroids to 

date in the clinical setting.

Next slot.

So I think from this 

experience there's a few basic lessons that we've learned 

and I think you ought to keep in mind when we're talking about other 

immunosuppressants.

First of all,

all Allah graphs even we shared HL antigens will 

reject without immune suppression.

It's been demonstrated clinically and H.

L.

A identical mlc 

unresponsive graphs at Duke,

they all reject.

And even within your in about three quarters of them 

rejecting urine alone.

Neither in your interest,

your eyes and use the loan are very effective.

It's the combination.

I'd ask you to keep that in mind when you're looking at 

various other problems 

in medicine where people are using immunosuppressants to 

treat what are supposed presumed to be 

immulogic disease is most of the clinical 

trials would use what we would 

think of as inadequate immune suppression to prevent 

rejection.

One wonders if they didn't use a combination.

And the doses that we usually use in kidney 

transplantation and for instance,

results with rheumatoid arthritis and some other 

potential immulogic diseases might be better than have been 

reported to date.

Both the graft and the host.

Quote adapt with time allowing the doses of MR 

presents to be reduced.

We'll get back to that later.

That's an old term.

I guess if you make a long story short I think 

we've been inducing partial and few cases 

complete tolerance for a long time in humans 

without recognizing it.

Using these drugs.

Uh not all rejection episodes can be prevented and 

reviews and the therapeutic index of 

available.

MR.

President says low and of course this is one of the 

major problems and we're looking for less toxic but 

at least equally potent image oppressive regiments.

Well here's the standard immunosuppressive regimen.

We used at michigan.

We've had a we've done about 

375 kidney grafts there in the past 10 

years and tried a variety 

of fancy regimens and not so fancy 

regimens.

This is what we use at the moment is a thigh preen 

three mg per kilogram for 10 days,

maximum 200 

Milligrams,

mg after 10 days if tolerated.

Maximum 100 50 predniSONE,

1.5 mg per kilo for seven days,

tapered to a milligram during the second week and 

then tapered to a quarter milligram,

kilogram by 3 to 6 months is tolerated.

We use that for both category graphs and related 

graphs.

I'll point out a few things in 

the early days of transplantation,

Almost everybody used loading doses 

of Iran say they use four or 56 mg per 

kilo for the first day or just prior to the transplant 

or they would give large doses of 

steroids in the first couple of days and then taper down to 

something in this range and 1.5 range.

There's absolutely no evidence that I can detect that that does any 

good.

And in our own hands program,

as I outlined out here has just as good results 

as some of these variations that have 

been used in the past and in some cases have been 

used today.

Another point 

referring to this adaptation or partial tolerance 

induction,

there are many patients who are on steroids alone 

after several months.

Post transplant.

In other words,

the neuron has been stopped and they 

develop uh paddock toxicity or some other 

reason,

low white count and they do 

find there are very few patients in whom 

steroids have been able to be stopped.

And there is still a question whether in urine is 

needed at all in the very late post transplant 

period.

Now,

Dr.

Marr Chiaro University of Washington he 

uses never gives more than 25 

mg of urine a day.

25 mg,

which is a homeopathic dose.

And his results seem to be as good as many people.

So one wonders if after this initial 

Week or two or a month or even three months 

if a different situation hasn't developed and perhaps you can 

get by and much less in urine,

you're less likely to get by on without 

steroids.

I keep this in mind because we don't hesitate to 

stop in urine after 3 to 6 months if we're having a 

problem and haven't really seen any 

detectable bad results from that or at 

least to lower it down to very low doses 

25 50 mg.

We our philosophy is to use as much 

in urine as people will tolerate.

But again,

we're much less hesitant.

We used to be to get it down to a rather low dose 

level in the late post transplant period if that's 

necessary.

I'm just gonna talk for a few minutes about a couple of subjects that have 

interested us were interested is 

answering these two questions.

Is there a minimum dose of steroids below what's the probability 

rejection is so great.

That is inadvisable to reduced oral steroids below this 

critical level in most patients.

In other words,

we've all been sort of flying by the seat of our pants,

we keep lowering the steroid dose and then we hope that 

rejection won't intervene.

But we wanted to look at this in a mathematical way and see if we could 

predict a dose below which we should not 

go or related question.

In individual patients,

can a minimum dose of steroids be identified 

below which rejection is likely to occur?

We did analyze our series.

We essentially looked at all our cattle Eric transplants 

who were six months post transplant and were relatively 

stable at that point.

And then followed them from that point on 

this is simply the survival curves 

uh of the patients 

studied um who fit 

our criteria that have a creatinine below 2.5 and so 

on.

And then uh and of all our patients who had 

graph functioning at six months,

which is a different group.

So this is a group we're looking at up here.

Uh If you look at this bar 

graph,

the black is uh numbers of patients 

with rejection episodes.

The white is no rejection episodes.

And this is the predniSONE dosage in milligrams per 

kilogram,

you'll see that all the way from 

zero predniSONE up 

2.7 or 0.69 mg per 

kilo,

there's a scattering of rejection episodes.

So it doesn't if you look at this,

you'd say no,

there is no you know,

there's a great individual variation in 

terms of what steroid dose 

uh will be given at the time that 

rejection occurs.

Converses,

here's uh six patients who are 

below uh 

.9 mg or 0.9 I guess it is per 

kilo have never had a rejection 

episode.

So there is not a sharp line of 

demarcation,

there's a great deal of individual variation.

However,

when you look at this in a variety of ways,

the median dose is is about a quarter milligram per 

kilo at which 

rejection occurs.

And that keeps recurring depending on how you want to 

analyze it.

That that quarter milligram per kilo is 

the important point where 

uh most half the 

rejection episodes will be under that.

So it's sort of the danger point.

Once you get to that level,

Another way of looking at trying to hold 

time relatively constant 

here,

only looking at those within the one year.

And this is a cumulative frequency curve.

And here you'll see that 

uh Those 

who are 50% of rejection episodes are 

occurring at less than about .25 or 

.3 mg per kilo.

So I think uh again we looked at this in a number of 

other ways which you don't have time to go into,

but about 50% of rejection is occurring six months or more 

transplantation take place when predniSONE is 

reduced to 0.25 or below.

So I think when you get to that range,

you better hold there if your patients tolerating it 

well or go very slow because you really are 

getting into the when you lower it much more,

you're going to have an increased incidence of rejection.

What about the individual patients?

Well here we're looking at 

zero line here or baseline is the 

predniSONE dose at which a first rejection episode 

occurred.

And then we're looking at second rejection episodes and say,

you know,

at what predniSONE dose does rejection occur 

relative to the dose that it occurred at at the first time 

around.

And you'll see that these black dots 

are almost all the 

exception of those two,

within 25% 

of the baseline dose or below it.

Now there are some people who will get 

below baseline and never do reject 

the second time or at least haven't up until at the time of this 

study.

So again,

there's a great individual variation.

But again,

I would make the point that when you get 

Near that range when you're back to within 

25% of what of the dose,

which the first rejection episode occurred.

Then you'd better go slow.

Be careful because you're getting into the 

range at which rejection is much more likely to occur 

a second time.

Let's just skip this for now.

And we tried to determine whether kidneys that 

rejected at high predniSONE doses did 

better or worse than kidneys that rejected at low 

uh predniSONE doses in the long 

run.

And we we could not tell any difference.

Let me just spend a moment on pulse therapy.

We've had a couple of publications from our institution on 

pulse therapy.

The history of pulse therapy was that it 

started at stanford 

really when Dr sam was there and he gave 

ivy methylprednisolone directly into the 

renal artery with a drip.

And initially he thought that he got superior results 

using that method of administration.

But then he did a control giving an ivy 

systemically and he found that his controls did as 

well as those that he gave an intra arterial e but he was using 

1000 mg per day 

in this study.

The basis of that then started giving at the time of 

rejection and it was used sporadically,

but not a great deal talked about until some 

publications from England and from from our 

place came out 

in recent years.

People question the 

value of pulse therapy 

and whether or not it has more or less 

side effects and so on.

I think a lot of the difference of opinion has to 

do with the mode of administration 

and what you're trying to achieve what we 

did in this uh study,

we used methylprednisolone,

30 mg per kilogram ivy in 

250 ml or 5% dextrose and 

water.

You take that much.

Practice alone and shove it in 

just inject it directly.

Uh you will have an incidence of side 

effects Uh hypertensive 

crises.

Uh and so on.

It's low but it will occur.

So if you're gonna use this dose you have to give it over 

30 minutes or an hour.

We raised our daily oral predniSONE by 

10 mg or 25%.

Whichever was greater.

We only repeated it the pulse that is every 

48 to 72 hours if renal 

function did not improve.

And the maximum number of doses we used was four doses 

gradually tapered the oral predniSONE.

Okay well the point I would like to make is the whole idea of 

giving pulse therapy 

ah was to get 

away from the chronic administration of high doses the 

daily or the B.

I.

D.

Or the T.

I.

D.

Dose.

With the thought that we 

would maintain the effectiveness as far 

as reversing rejection.

Hopefully minimize the side effects.

And that's a timing problem in terms of how 

often you give them the dose and here is 

the half life of I.

V.

Methylprednisolone is determined by gas 

chromatography and it's 

about it's either 

2.3 or 2.7 hours half light.

And here's what happens to the serum levels.

And you see that by 24 hours after an I.

V.

Dose it's down to almost undetectable 

levels.

Same dose given orally last much longer.

I don't think there's much point in giving pulses if you're going 

to give it every eight hours you're gonna give it B.

I.

D.

Because you're gonna have these curves overlapping and you're not 

gonna get down into this low dose range 

and therefore I don't think you would expect a 

reduction in side effects.

And I think some people have forgotten that they give a pulse every day and 

they give it every twice a day.

I don't think there's any evidence to determine 

what the proper dose level should be.

Is this 30 mg per kilo.

Works out to about 1800 mg in Most 

people perhaps 1000 mg is 

enough.

Perhaps 500 is enough.

There's simply no data.

Comparative data.

But I don't think that if you're giving pulses every 

eight hours you should try to compare it and say with a study 

that we did.

And our own impression is I think it's 

effective.

Um 92% of the rejection 

episodes were reversed.

Um Here's just some conclusion.

There's 2.3 plus or -17 hours is the half 

line.

There's no question that will reverse rejection.

Whether it's better than oral 

pulsing or some other treatment is simply 

undetermined.

We have the distinct clinical impression that it 

reduces side effects and there's some other 

conveniences to using it.

But 

uh I don't think there's any 

concrete evidence of that.

So we still use pulse therapy.

We think it's less side effect.

We think it's easy to use.

We don't see toxicity from the 

injection.

If we give it over 30 minutes to an hour.

But we would qualify that with saying,

we don't repeat it any more often than every 48 hours 

and give a maximum of 3-4 doses.

And I think those people who 

Have criticized pulse therapy really have no more evidence 

to base their criticism on.

Then.

Perhaps we do to say that it's better than 

giving oral doses.

But I can tell you from 

personal experience that it's much less toxic than giving 

200 mg of predniSONE orally a day for a week or 

something of that sort.

Well where are we at with immune suppression 

Essentially the results of transplantation have plateau 

the last three or four years.

I think the 10 years prior to that we've 

spent refining our management without any 

basic breakthroughs.

I think more and more people are coming to the conclusion 

that whatever we do uh 

to manipulate the immune system and to achieving this 

depression,

there's something that goes on early in the course 

that determines the long term fate of that kidney.

To conclusions from that one,

maybe we should focus on what we do in an image 

suppressant way early rather than just 

long term chronic regimens.

And secondly,

if you're having a lot of trouble with the kidney in the late post transplant 

period,

it's fate is probably pretty well determined and we don't 

persist as long as we used to in trying to 

maintain that kidney but we'll give up on it,

stop them and suppression or lower the dose 

and then do a second graf,

immuno suppressive management 

with Jeremiah G.

Turcotte,

M.

D.

Professor of surgery,

University of Michigan Hospital at ANn Arbor 

was produced through the mobile facilities of the television 

division,

Academy of Health Sciences,

United States Army,

Fort sam Houston texas.