Stuart L. Goldstein, MD Recent Improvements in End-Stage ......being indelicate to Drs. Hill, Brewer, Kohaut, Sanjad, and Alexander, I think I’m the third generation of pediatric

Stuart L. Goldstein, MD Recent Improvements in End-Stage Renal Disease Outcome

PEDIATRIC RENAL DISEASE: SELECTED TOPICS Baylor College of Medicine Houston, Texas Page 1 of 38

Slide 1

I’d like to say it’s really a thrill to actually be able to speak here. And without being indelicate to Drs. Hill, Brewer, Kohaut, Sanjad, and Alexander, I think I’m the third generation of pediatric nephrologists. The work that we are doing at Texas Children’s and around the country among people my vintage, could not be done without all the groundbreaking work that started with Dr. Hill and is continuing to be done by all the colleagues who spoke here.



Slide 2

Introduction

• ESRD Demographics• Texas Children’s Hospital

– Renal Dialysis Unit Statistics• Hemodialysis Adequacy• Fluid Removal Techniques• Access Monitoring• Outcome Measurement

My job is to talk about recent improvements in end stage renal disease outcome. Dr. Alexander did a great job talking about peritoneal dialysis in infants. I’m going to talk a little bit about the demographics of ESRD and who is getting what with respect to their treatment for end stage renal disease. And look a little bit at our own unit, and how we’ve decided to attack some of these problems in children receiving dialysis. I’m going to talk about two different technological advances that really have made hemodialysis much better for children. Much more easily tolerated. It has improved children’s morbidity on hemodialysis. Then look at some things that we need to think about with respect to outcome.



Slide 3

Renal Failure in the United States

• Prevalence– Total ESRD population: 307,719

• HD: 197K PD: 23K Transplant 88K

– Pediatric ESRD population: 5,304 (1.8%)• HD 939, PD: 663, Transplant: 3,702• 66 per million

• Incidence– Total ESRD: 287 per million– Pediatric ESRD: 11-14 per million

United States Renal Data System (USRDS) 1998

As has been stated, pediatric ESRD is a very small part of the pie. There are 310,000 or so patients or people in the United States who have ESRD. 197,000 of them are on hemodialysis; 23,000 are on peritoneal dialysis; and 88,000 of them have a kidney transplant. But if you look, right now there are only 5,300 children with end stage renal disease in the United States. It is 1.8% of the population. And I think we’re doing a very good job, and we’re doing what Dr. Alexander has told us to do. We’re transplanting the vast majority of them. But there are still a thousand kids or so who are receiving hemodialysis, and about 700 who are receiving peritoneal dialysis. The prevalence is 66 per million population. And for total ESRD, the incidence is 287 per million, and the pediatric ESRD incidence has been very stable at 11 - 14 per million. So even in a big city like Houston, we don’t see that many patients. This is a very specialized area of pediatric care.



Slide 4

Pediatric ESRD in the United States

0

1000

2000

3000

4000

5000

6000

7000

8000

Incidence # (1996-98) Prevalence # (1996-98)

0 to 45 to 910 to 1415 to 19


This graph shows you the breakdown by ages to look at the pediatric population. If we look at the incidence, you can see that it’s fairly well distributed except when you get to the adolescent ages of 15 - 19. Most of the ESRD we’re seeing is in the younger age group in our population. So once again we have to think about growth, nutrition, development, really impact children’s lives here so that when they become young adults they can have a more fulfilling and satisfying life. Of course the prevalence goes up with age because all of these patients are now growing and surviving because of all of the technological advances that my predecessors have discussed and have been involved in. Now these patients are actually living to adolescence and through adolescence to young adulthood.



Slide 5

Pediatric ESRD in the United States:Modality

0

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70

Transplant Hemo PD

All patients0-19 years%


And this just shows you again that we’re actually really doing a pretty good job of getting children to transplant, whereas for adults, only about 28% of the adult end stage renal disease population is currently transplanted. And then, based on various different issues, the rest, for children, are almost evenly split between hemo and PD.



Slide 6

Texas Children’s Hospital Renal Dialysis UnitYear 2000 Admission Statistics

0102030405060708090

100

Accessmalfunction

Fluid Overload AccessInfection

GI Other

Days

Well, now that the children are living, we wanted to actually start to improve their lives. We wanted to make their hemodialysis experience and treatment better and decrease their morbidity. So at Texas Children’s Hospital we have a very large hemodialysis unit. We looked to see, why were kids admitted to the hospital at Texas Children who were receiving dialysis? Well, in order to provide dialysis, you need to have a well-functioning access. And so there were 65 days where patients were admitted for an access malfunction. There were 80 days where patients were admitted for fluid overload. Access infection was also very prevalent. There were a lot of GI issues, mostly pancreatitis. And then a various or miscellaneous group.



Slide 7

Pediatric ESRD Clinical OutcomeAlgorithm

Clearance (Kt/V)Nutrition (nPCR)

OPTIMIZE

PREVENT

+

Access malfunctionUF associated morbidity

Infections

GrowthExercise

HospitalizationMortality

Self-esteemSchool attendanceSoc/Adaptive skillsSelf-reliance

IMPROVE

So when we started to look at a clinical outcome algorithm to try to see how we could improve upon patient care, we decided initially to look at these issues. And this is just another depiction of what Drs. Kohaut and Alexander have discussed with you with respect to children with chronic renal failure. We really want to optimize their clearance and their nutrition, and these are very specialized kinetic modeling equations that I won’t go into today. But hopefully if you improve or optimize their dialysis, you’ll decrease their infections, you’ll promote growth and exercise. But what we want to focus on in today’s talk is the prevention of these issues: Access malfunction and fluid overload. Ultrafiltration means fluid overload in the dialysis world. So, for the patients who are being admitted with fluid overload, we wanted to try to figure out how to prevent that. And we thought that if we could do that, we could decrease their hospitalizations and mortality, and then by optimizing all of this, we could get on to what’s really important, which is to improve the child’s self esteem, their school attendance, their social adaptive skills, their self-reliance, and their transition into adulthood.



Slide 8

Pediatric Dialysis: Terminology

• Ultrafiltration - fluid removal• Dialysis - solute clearance• Access - catheter, fistula, graft• Adequacy - amount of solute clearance• Outcome - ???????

And just a couple bits of terminology that we need to discuss. Ultrafiltration refers to fluid removal. Dialysis actually refers to solute clearance. And I’m not going to be talking very much about dialysis today. Access, when we’re talking about hemodialysis, there are three choices. You can have a catheter, which goes into a vein; a fistula, which is a native connection between an artery and a vein that’s performed by a surgeon; or a graft which is a Gore-Tex tube that’s actually placed connecting a patient’s artery and a vein. And through any of these devices, blood is taken from the patient, goes to the filter, the blood’s cleaned, fluid is removed, and the clean blood is returned back to the patient. When we talk about adequacy, we’re talking about amount of solute clearance. And I think our paradigm has really changed now because we can technically do these procedures. Outcome for us, now, doesn’t just mean hospitalization and death. And we’re really trying to learn how we can impact and even measure true outcome in children.



Slide 9

New Therapies In Chronic Pediatric Hemodialysis: Ultrafiltration

• Extravascular fluid replaces fluid from the intravascular space removed by ultrafiltration– Overly rapid fluid removal can lead to relative

intravascular volume depletion and symptoms

• Patient symptomatology from ultrafiltration may preclude attainment of target weight leading to:– chronic volume overload– hypertension– inadequate dialysis– left ventricular hypertrophy

So let’s talk about ultrafiltration a little bit. This was what we were first looking at impacting. When you take fluid from a patient on dialysis, all you have access to is their vascular space. So when you take that fluid off by ultrafiltration, extravascular fluid replaces the fluid from the blood vessel space that’s removed by ultrafiltration. If you do that too quickly, that’s going to lead to relative intravascular volume depletion and symptoms. Remember, we’re trying to take off all the fluid that a patient’s accumulated in 48 hours between a treatment, in the three hour to four treatment. We have to get two, three, four, sometimes five liters off of our larger adolescent patients. If you try to take that off too quickly, they’ll become hypotensive. They’ll cramp. They could become nauseated. They can vomit and feel pretty terrible. And that’s something you like to prevent. The second part of that that’s important is that if we make the patients too symptomatic, if they’re feeling horrible, then we’ll slow down their ultrafiltration. And if the symptomatology prevents us from actually getting them to their target dry weight, if we can’t attain that, that’ll lead to other problems. Chronic fluid overload. Hypertension. Inadequate dialysis. And left ventricular hypertrophy. So we have to optimize the treatment by minimizing their symptoms so that we can get them to a dry weight, removing all the fluid that’s been accumulated between treatments.



Slide 10


ICF ECF IV HD UF

This depicts this graphically. As you see, this is a hemodialyzer, and this just has access to the patient’s intravascular space. And we have to arrive at a delicate balance between ultrafiltration here and extracellular fluid to intravascular fluid movement as depicted on this graph.



Slide 11

Non-Invasive Monitoring of Hematocrit (NIVM)Principles

• Red cell volume constant during dialysis• Changes in hematocrit inversely

proportional to intravascular volume • In-line optical methods

– show real time association between fluctuating hematocrit (HCT) and intravascular volume

– are continuous during hemodialysis treatment

Well, about four or five years ago, somebody had the bright idea that we could actually monitor how much fluid we were taking out of the intravascular space in real time. What they took advantage of was the fact that during a dialysis treatment, your red cell volume remains constant. All we’re taking off is plasma water during the dialysis treatment. We’re not taking off any red blood cells. So during the hemodialysis treatment, the patient’s hematocrit actually rises. Your hematocrit is the proportion of your intravascular volume that is taken up by red blood cells. So changes in hematocrit are inversely proportional to intravascular volume. As you squeeze down the patient’s volume, their hematocrit will rise. These people invented a method, using an inline optical method which showed a real time association between fluctuating hematocrit and intravascular volume. And it was continuous. It is just a sensor that’s placed on the hemodialysis circuit that constantly measures the hematocrit.



Slide 12

NIVM: The CritLine™ Instrument

• Disposable blood chamber luerlocked between the arterial line and the dialyzer

• Optical sensor clipped to the blood chamber continuously monitors HCT

• Changes in HCT and blood volume continuously displayed both graphically and numerically on LCD screen

• Hard copy download option

So as the volume goes down, the patient’s hematocrit rises. The optical sensor is clipped to the blood chamber and continuously monitors the hematocrit, and the changes in hematocrit, and therefore the changes in the patient’s blood volume, are continuously displayed.



Slide 13


ICF ECF IV HD UF

NIVM Hct

And this is shown here in this graphic. Here’s – this is called noninvasive monitoring of hematocrit. And we just put it inline right here. And we can see what the patient’s change in hematocrit is during the treatment.



Slide 14

Non-Invasive Monitoring of Hematocrit (NIVM): Stable Treatment

HCT

BV∆

O2 sat

40%

35%

30%

+5%0-5%-10%-15%-20%

70%

1hr 2 hr 3 hr

And that’s shown on this hard copy slide. This is from an actual patient treatment. You can see here, this is the blood volume change, which is inversely proportional to the hematocrit change at one hour, two hours, and three hours. I don’t know if Dr. Stein is back here. Don’t pay attention to this O2 sat. It’s 70%, and he’d want to intubate this patient. But this is from a catheter, so this is a venous saturation. But you can see that a patient starts with zero blood volume change and slowly goes at one hour to -5%, -10%, -15%, and our nursing staff can easily monitor the patient’s blood volume change during the treatment.



Slide 15

Non-Invasive Monitoring of Hematocrit (NIVM): Unstable Treatment

HCT

BV∆

O2 sat

42%38%34%32%

+5%0-5%-10%-15%

70%

1hr 2hr 3hr

Well, why is that advantageous? Well, this is what happens during an unstable treatment. See how rapid this rise in hematocrit is, and how – so that the inverse is – this is a very rapid change in blood volume. At two hours, this patient felt very sick. Actually got some saline to make him feel better. The patient’s hematocrit then abruptly dropped and the blood volume changed, increased. So by using this continuous method of blood volume change measurement, the nursing staff is able to alter the patient’s ultrafiltration rate, prevent symptoms before they occur, and eventually get all of the fluid that needs to be removed during the treatment.



Slide 16

NIVM: Case Study #3

• Hypotension anticipated with NIVM/frequent BP

• Ultrafiltration slowed until vascular refilling seen on monitor

• Non-treatment related hysteria recognized

• Subsequent treatments more manageable

HCT

BV∆

This is a case study. And this was a very difficult patient. This patient was five years old. And so she was often very emotional during treatments, and it was very difficult to know, since she couldn’t really verbalize her symptoms, it was very difficult to know if she was really having true symptoms from cramping, or from headaches, or if she was just irritable or agitated. You can see, whoever did this treatment did an incredibly good job. You can see here, filtration was fast, and then they backed off on the ultrafiltration, let the patient refill, and went ahead and did a very good job getting this patient’s complete ultrafiltration. So the hypotension never occurred. It was anticipated with an NIVM and frequent blood pressure monitoring. Ultrafiltration was slow during the vascular refilling. Non-treatment related hysteria was recognized. And the subsequent treatments were more manageable. Why? Because our patients’ parents sit by the bedside when the children are being dialyzed. They can read the CritLine monitor now. They know that if they don’t see a deep, steep slope, that what we just need to do is comfort the child and not stop their fluid removal. And it’s been the best device to help cooperation between the nursing staff and our families.



Slide 17

Non-Invasive Monitoring of Hematocrit (NIVM): Pediatric Study

• NIVM (Crit-Line, In-Line Diagnostics, Salt Lake City, Utah) during hemodialysis has been routinely performed in Texas Children’s Hospital Renal Dialysis Unit, Houston, Texas, since February, 1998

Jain, Smith, Brewer, Goldstein: Ped Neph (2001) 16(1):15-8

One of our fellows, Dr. Jain, one of the nurses, Laurie Smith, Dr. Brewer, and I actually looked to see if we had any improvement in our patient’s symptomatology. And what this graph shows you, if we look at an event – an event is a patient’s symptom that caused the nurses to do something, stop ultrafiltration, give back saline – and we looked to see in the patients before we had these monitors – we looked at 200 treatments between them – we looked to see what the event rates were before we had these monitors, and after we had these monitors. You can see for all patients there was a tendency towards a reduction in events. But really interestingly, when we looked at our smaller patients, the ones who are most vulnerable, who can’t verbalize their symptoms, under 35 kilos, we had a very significant reduction in their event rate. And the rest of their treatments, we looked at their second events. How many of them had more than one hypotensive or symptomatic event? We had a very significant reduction. So the treatments were much smoother in this group of patients.



Slide 18

Non-Invasive Monitoring of Hematocrit (NIVM): Pediatric Study

NoNIVM

Group 1

NIVM

Group 2

p

(chi-square)

Total event/Total Rx: all pt 61/200 45/200 0.07

Total event/Rx pt



Slide 19

Arteriovenous Fistula/Grafts:Monitoring for Stenosis

• Venous stenosis predisposes to inadequate dialysis, access thrombosis/malfunction

• Prospective monitoring options– Doppler flow, MRI– Ultrasound dilution– Dynamic/static venous pressure monitoring– Venography

Okay. So I think that we were able to demonstrate that we’re able to get patients’ fluid off easier with less symptomatology. And we’re actually able to get them to their dry weight. Remember the other thing that was leading to a lot of hospitalization in our unit was problems with their vascular access. And the main problem with vascular access, when we’re thinking about one of those grafts, is that you connect a high-pressure arterial system to a low pressure venous system. And that causes stenosis. The constant pounding of the arterial side causes stenosis at the anastomosis. And I’ll show you that in a minute. If you have stenosis, if there is area that is narrowing, that’s going to predispose to inadequate dialysis, access clotting, and malfunction. There are lots of ways that you can look for stenosis, but I don’t think we are going to routinely send patients for MRI or for Doppler flow. There is a method called ultrasound dilution, which I’ll talk about. And there are some other invasive procedures, like venography, which we used to do routinely and some pressure measurements, which actually don’t apply for children.



Slide 20

Venous Outflow Stenosis

Description: Venous outflow 95% focal stenosis of forearm loop graft (intimal hyperplasia) at anastomosis

This is what a stenosis looks like. This is a loop graft. So you can see here in a patient’s elbow. And here you can see – this is where the graft goes. It actually goes out here. This is where the blood returns. You can see how it becomes very sharp right there. This is going to be an area where there is venostasis and thrombosis.



Slide 21

Arteriovenous Fistula/Grafts:Ultrasound Dilution Monitoring

• Non-invasive bedside test• 20 cc saline injection during dialysis• Flow readings reported in 1 minute• Predictive of AVG venous stenosis in adults

So there’s a new method that can actually look to see if a patient has venous stenosis that’s noninvasive. And what we actually do is look at the flow of blood through that graft. It’s a noninvasive bedside test. One of our nurses in the dialysis unit does it while the patient’s receiving treatment. It’s a 20 cc saline injection. The flow readings are reported in one minute. And it’s been predictive of graft stenosis in adults.



Slide 22

Access Flow Measurement (Blood Lines are Reversed)

Krivitski, NM, Kid Int 48: 244-250, 1995

And this is one of my favorite slides, and it comes from the company that actually makes the machine. Here you can see – this is the patient’s access. Here’s their venous line. And their arterial line. And here are the sensors. So, let’s start the slide. You can see, here is the blood flow that goes through in the patient’s normal access. The nurse injects some saline. That goes through here. We follow the arrows, and you see most of the blood – and the big arrows go back to the patient. But that tiny little arrow is the one that goes back into the arterial line. If there is a stenosis here, that arrow is going to become bigger. There’s going to be more flow there that is returned because there will be more saline that goes through there, and that’s what’s detected. The saline’s detected by that sensor. So the computer then interprets it and is able to figure out what the patient’s blood flow is.



Slide 23

Arteriovenous Fistula/Grafts:Pediatric UD Monitoring Study

• 10 patients (4 pt < 35 kg)• 28 flow (QVA) measurements (ml/minute)• Raw QVA data corrected for body surface

area (corrQVA; ml/min/1.73m2)• 7 patients with venograms

Goldstein, Allsteadt: Kidney Int. 2001 59(6):2357-60

And so we looked at this technique in children. If our patients were small, we did 28 measurements, and we corrected for the patients’ body surface size. And then we looked to see who actually had stenosis by venograms. Just like that picture I showed you with the graft, we looked, we compared what patients’ flows were by that method, comparing it to stenosis on the venogram.



Slide 24

Arteriovenous Fistula/Grafts:Pediatric UD Monitoring Study

0

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corrQVA

AllOpenStenotic

ml/min/1.73m2

Goldstein, Allsteadt: Kidney Int. 2001 59(6):2357-60

P=0.04

And here you can see that for all patients we had a flow of about 1,200. For the patients that didn’t have stenosis, we had a flow of 1,200. But the patients who were stenotic by venogram had an average flow of about 400.



Slide 25

Patient Hospitalization Days Statistics:2001 vs 2000

0102030405060708090

Fluid Overload Clotted Access

20002001

Days

Well, those machines are nice and sexy, and they’re fun, but did it actually make a difference? Well, yes, it has in our unit. If you compare our 2001 hospitalization statistics to 2000 – I think it’s remarkable, and a testament to our nursing staff, that we did not have a single patient admitted to Texas Children’s in the year 2001 for fluid overload and hypertension. And it’s because of the proper use of that machine. And we had about a 70% decrease in our access thrombosis rate. That’s better for the patient. They’re not going to surgery to have the access declotted. They don’t not have to be hospitalized. Things work much better for them.



Slide 26

Pediatric ESRD Clinical OutcomeAlgorithm

Clearance (Kt/V)Nutrition (nPCR)

OPTIMIZE

PREVENT

+

Access malfunctionUF associated morbidity

Infections

GrowthExercise

HospitalizationMortality

Self-esteemSchool attendanceSoc/Adaptive skillsSelf-reliance

IMPROVE

So I think that we’ve shown here, at least in the short term, that we’ve been able to prevent access malfunction and ultrafiltration-associated morbidity and decreased hospitalizations, hopefully mortality down the road. Well, what I didn’t show you on that slide is the number one reason that patients were admitted to Texas Children’s from our unit, and that’s for malnutrition. And so now even 20 years later we’re coming back to what Dr. Kohaut and Dr. Brewer have been teaching us, that nutrition is the key for children with end stage renal disease. And that is a very vexing problem for us, which I’m not going to go into anymore.



Slide 27

Sarnak/Levey: Cardiovascular Mortality in the General Population & Dialysis Patients

0.001

0.010

0.100

1.000

10.000

100.000

25-34 35-44 45-54 55-64 65-74 75-84 85+Age (years)

An

nu

al

mo

r

GP male GP FemaleGP Black GP WhiteDialysis Male Dialysis FemaleDialysis Black Dialysis White

MJ Sarnak and AS Levey, Epidemiology of Cardiac Disease in Dialysis Patients, Semin Dialysis, 12(2), 1999

This is also a very vexing problem. If you go to any nephrology conference around the world now, this slide always comes up. These patients are living, the children are living with end stage renal disease now. But if what this graph shows you, it’s that the cardiovascular mortality rate for patients with end stage renal disease, at 25 years of age, it’s exactly the same. There are all end stage renal disease patients. This is their mortality. It’s exactly the same as an 80-year-old without renal disease. So these children are living to young adulthood, but they’re dying of heart disease. And that’s something we have to worry about.



Slide 28

Cardiovascular Mortality in Adult ESRDCauses

• Coronary artery calcifications– Electron-beam CT scans– Not seen in children

• Malnutrition– Albumin levels < 3.0 g/dl– Albumin may be poor indicator of nutrition

status in children• Inflammation

– ESR, CRP levels

What’s the cause of this cardiovascular mortality? Well, it’s clear that coronary artery calcifications play a big role, although these have not been seen in one study that looked at them in children. Malnutrition, again, we keep coming back to that. In adults it has been shown to be associated with cardiovascular calcifications. However, albumin may be a poor indicator of nutrition status in children, and we’re looking at other ways of measuring nutrition status for children. Inflammation is clearly very important in contributing to a host of problems in children, but especially cardiovascular compromise.



Slide 29

Pro-inflammatory Cytokines in ESRD

• Increased levels of many cytokines– dialysis-membrane induced

• bio-compatible membranes

– decreased renal clearance• levels improve after renal transplantation

• Prolonged inflammation may lead to– advanced glycosylation end-products (amyloidosis)– extra-skeletal calcification

There are increased levels of many cytokines. The dialysis membrane itself induces the cytokine response. Although there are more biocompatible membranes, but nothing is like your own artery and vein wall. There’s decreased renal clearance of many cytokines and middle molecules like beta 2 microglobulin, which predispose to amyloidosis and which dialysis does a very poor job of taking care of. There’s prolonged inflammation, which may lead to amyloidosis and extraskeletal calcifications. That’s why we still think, even though we’re doing a better job with dialysis, transplantation reverses many of these problems or at least prevents you from developing more calcification. So transplant is still the best therapy.



Slide 30

Health Related Quality of Life (HRQOL)in ESRD

• No pediatric ESRD specific HRQOL assessment– General assessment tools do not distinguish between

treatment modality– ESRD-related factors that impact HRQOL

• significant dietary and fluid restriction• cycle of dialysis and transplantation• parents deliver life-saving therapy• medication side effects• social isolation (attachment to machines)

• Exercise assessment– minimal pediatric data

And we haven’t really even talked about quality of life. There’s no single pediatric health-related quality of life assessment tool. There is one for adults called the SF-36. There are lots of generalized health questionnaires for children who have a variety of different disorders, or chronic diseases, or are just generally healthy. There is nothing for children with dialysis. And ESRD-related factors are –you know, we all think we take care of the sickest patients – but there are some things for children that are really unique. There are some restrictions and hurdles that they have to overcome. There is significant dietary and fluid restriction. They have a chronic cycle – as Dr. Alexander said, this is a terminal illness – a chronic cycle of dialysis and transplantation. You are never cured of your end stage renal disease. You may be cured of your cancer, if you’re a child. You may get under good diabetic control. But you’re never cured of your end stage renal disease. This is the only therapy that I know of, especially when you’re talking about peritoneal dialysis, as Dr. Alexander showed you, where the parents are responsible every night for delivering lifesaving therapy. If they do it wrong, the patient can get an infection. If they do it wrong, the patient can get under-dialyzed. There is no other disease where I know of that we put parents in such a primary role of taking care of children. That creates huge family stress, and many of our – very few of our families are actually intact. There are medication side effects. And of course social isolation because our patients are attached to machines for a good part of their life. We’ve begun to look at the influence of exercise, and there’s a look of work going into looking at exercise in adults and children with ESRD.



Slide 31

Renal Transplantation Medicine1980’s and 1990’s

• Steroids– non-specific– growth retardation, body habitus changes– bone disease

• Cyclosporine, Tacrolimus (FK506)– calcineurin inhibitors– IL-2 production inhibitors– nephrotoxic

I want to turn a little bit at the end to talking about renal transplantation. Dr. Alexander discussed this a little bit. The medicines that were available in the eighties and nineties were steroids, which are still the mainstay of treatment. They’re nonspecific. They cause growth retardation and body habitus changes and bone disease. The great advent in the 1980s was cyclosporin, and in the 1990s it is tacrolimus. These are calcineurin inhibitors. They inhibit the production of IL-2. But in some kind of a cruel twist of fate, they are actually nephrotoxic. And that was discovered in heart transplant patients, actually, who received cyclosporin. They were found all of a sudden to develop renal failure from their chronic cyclosporin toxicity.



Slide 32

Renal Transplantation Medicine1980’s and Early 1990’s

• Azathioprine– white blood cell inhibitor– CMV, EBV infections– skin cancer

• ATGAM, ALG, OKT3– induction/rescue agents– allergic reactions (non-human sources)

In the 1980s and early nineties, also azathioprine, or as you know it as Imuran, was available. It’s a white blood cell inhibitor, but there’s a high incidence of CMV and EBV infections, and if you’re on it for long enough, you will get skin cancer. Other non-human antibodies, Atgam, ALGOKT3, were used to specifically or generally target the immune system. They are used during induction, when patients got transplants immediately, or to rescue patients from rejection. However there’s a high incidence of allergic reactions because they generally come from non-human sources.



Slide 33

Renal Transplantation MedicineLate 1990’s and Beyond

• Mycophenolate Mofetil (MMF, Cellcept™)– white cell inhibitor– less CMV/EBV?

• Humanized murine monoclonal antibodies for induction (Zenapax™, Simulect™)– Reduce acute rejection rates to 10%– No allergic reaction

• Sirolimus (Rapamune™)– serine-threonine kinase inhibitor, mTOR– decreased cytokine responses– decreased need for calcineurin inhibitors

There’s been a great advance in renal transplantation with respect to medicine, to medications, and I’ll just scratch the surface here, in the last five years. Cellcept, mycophenolate mofetil, is a white cell inhibitor much like Imuran. There seems to be less CMV and EBV disease associated with it. Probably the greatest impact in the last three years are humanized murine monoclonal antibodies for induction, Zenapax and Simulect. So instead of giving these very toxic monoclonal antibodies, we now have these humanized murine monoclonal antibodies, and it’s reduced the acute rejection rate in renal transplants in adults. And it seems to be in children, from 40% in the first year down to 10% in the first year. And there’s no allergic reaction. Sirolimus is another compound which works a different place on the cascade from cyclosporin and tacrolimus. It results in decreased cytokine response. And the thought is that it will be less nephrotoxic. But whenever we say something is less nephrotoxic, and we look at the data ten years later, we find ourselves to be fooled.



Slide 34

• NAPRTCS database• 5958 patients

A Decade of Pediatric Renal Transplant Outcome Improvement

People have mentioned the NAPRTCS database, the North American Pediatric Renal Transplant Cooperative Study. Drs. Kohaut and Alexander are prime investigators. And looking at about 6,000 patients, I’m just going to show you a little bit different take on what Dr. Alexander showed you.



Slide 35

A Decade of Pediatric Renal Transplant Outcome Improvement

46

48

50

52

54

56

58

60

62

1987 1997

Acute LRD rejectionreversal

%

If we looked at this as a decade of pediatric renal transplant outcome improvement, if we look at the ability to reverse acute rejection, it was about 52% in 1987. We are about up to 62% in 1997. So that’s a very significant improvement in our ability to reverse rejection.



Slide 36

Pediatric Renal Transplant Long-Term Outcome

0102030405060708090

100

1-year 3-year 5-year

LRDCD

%

If we look at long-term outcome, with living related donors, so from a father, grandfather, mothers, older sister or brother, and a cadaveric transplant, you can see that one year survivals were pretty close, if you look at all of the data. And then at three years the cadaverics seem to do a little more poorly. And at five years the cadaverics are doing significantly more poorly. This is all the data from 1987 to 1997.



Slide 37

A Decade of Pediatric Cadaveric Renal Transplant Outcome Improvement

0102030405060708090

100

1987/88 1998/99

1-Year graft survival

But if you look at more recent data, and we look at the cadaveric renal transplant survival, in 1987 the one year graft survival was 80%. And now it’s about 92%. Equivalent to that of LRD. So I think that we are doing a much better job, and cadaveric kidneys are lasting much longer because of our improved immunosuppression regimens.



Slide 38

Pediatric Renal TransplantationThe Future

• Steroid-sparing protocols• More targeted immunosuppression• Xenotransplantation• Tolerance

What’s the future for transplantation? People are using steroid-sparing protocols. That’s one of the prime reasons, especially for our adolescents who stop taking their medications and lose their transplant because they have body habitus changes on steroids. More targeting immunosuppression using other monoclonal antibodies. There is the specter or the possibility of xenotransplantation from other species into humans. And then the induction of tolerance. We don’t know why, yet – and there’s a lot of research looking into this – some patients seem to tolerate their kidney on very low doses of immunosuppression; and it’s possible if you stop their immunosuppression they wouldn’t reject at all. And we need to understand why are those patients tolerant to the allograft, and what can we do for our future patients to actually induce tolerance, so that you can put people like me, who are primarily dialysis physicians, out of business.

Thank you very much.

Documents

Stuart L. Goldstein, MD Recent Improvements in End-Stage ......being indelicate to Drs. Hill, Brewer, Kohaut, Sanjad, and Alexander, I think I’m the third generation of pediatric