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Carlton Bates, MD, chief of the Division of Pediatric Nephrology, has been caring for children with pediatric kidney disease for many years, but he often finds another organ on his mind: the bladder and the role it plays in the health of a kidney. Dr. Bates discusses his well-recognized research program in Pittsburgh focused on the genetic regulation of kidney and bladder development.
View the transcript for this podcast (PDF)
John: This podcast is for informational and educational purposes only, and is not to be
considered medical advice for any particular patient. Clinicians must rely on their own
informed clinical judgements when making recommendations for their patients.
Patients in need of medical advice should consult their personal healthcare provider.
Stephanie: From UPMC Children's Hospital Pittsburgh, welcome to That's Pediatrics. I'm Steph
Dewar, Director of The Pediatric Residency Training Program and member of the
Hospitalist Division. Happy that you're back with us today.
John: And I'm John Williams, Chief of Pediatric Infectious Diseases.
Stephanie: We're here today with Dr. Carlton Bates who is the Chief of the Division of Pediatric
Nephrology, and Vice Chair of Basic Research in the Department of Pediatrics. In
addition to caring for children with pediatric kidney disease for many years, Dr. Bates
has a well-recognized research program focused on genetic regulation of kidney and
bladder development, with nearly 20 years of continuous funding from the NIH.
Welcome Dr. Bates.
Carlton: Thank you, glad to be here.
Stephanie: Well, we're so curious to hear about what are the types of patients that you're here at
Children's taking care of.
Carlton: We have quite a wide range of children. Sometimes people might ask, "What does a
pediatric kidney doctor do?" It is somewhat a specialty of rare diseases, but some of the
more common things that we see patients we take care of, are those that have
problems with hypertension and kidney stones or crystals in the urine. Those are
probably the two major populations. And then one might ask, "Well, why would we care
for patients with hypertension?" And that's because a significant portion of children that
have hypertension have something wrong with their kidneys. Either compromised blood
flow, a scar in their kidneys. Now, unfortunately these days, an increasing cause of
hypertension is primarily related to obesity, as well as genetics. That is our most
I'd say those are the two primary conditions we see. Certainly we have many other
patients that have proteinuria, hematuria, more rare genetic types of diseases. It is an
interesting specialty. We do have quite a spectrum of patients that we see. We never
quite know when we're going to clinic exactly what we're going to see.
John: So, well get into this, Carl, when we talk about your research in a couple of minutes. But,
it sounds like from what you're saying, that there's also a lot of ways that things can go
wrong in the kidney; either in the way it forms, the way the plumbing is connected, or
the way it functions.
John: Is that these rare disease you're talking about?
Carlton: Right. It can range from, as you said, there are genetic diseases leading to malformed
kidneys. More often than not we don't understand the genetics, we know there's
something wrong with the genes, but it doesn't follow a typical Mendelian inheritance
pattern. So many of the causes, like posterior urethral valves, which is the number one
cause of structural disease leading to end-stage kidney disease. We don't even
understand what valves are. At an embryologic level you're not supposed to have them,
and somehow, these things appear. No one is even sure exactly what they are, why they
Whereas, there are other clearly defined genetic disorders. Some of that has to do with
our knowledge base increasing. For instance, there are nephrotic syndrome, inherited
forms of nephrotic syndrome, that we've known about for some time, but then there've
been others that we thought were more sporadic that we've identified, that no, in fact,
they are monogenic forms of nephrotic syndrome. Probably well over 20% of patients in
an early stage that have nephrotic syndrome have a genetic cause.
So, the mutations that you see can lead to problems with glomerular formation, tubular
formation, tubular function, overall kidney architecture that doesn't form right, vascular
problems within the kidneys. So, yes, there're quite a wide range of things that can go
Stephanie: So, most of the patients then that you see on an ongoing practice in your clinic, are
these patients who have underlying disorders of structure or function, or are these new
referrals from out in the community?
Carlton: Well, probably about a third of the patients we see in clinic are new. And the others are
patients that we continue to follow. The frequency with which we follow up patients
depends on their underlying condition. There's some that have relatively minor
conditions, like persistent microscopic hematuria that we'll see, probably, on a yearly to
every other year basis. To those that have advancing chronic kidney disease, that will
see us frequently as every other month.
So, it really varies. Most of our patients we see at about every six months or so. The
average patient with kidney stones that has hypercalciuria, we'll follow on about a six
month basis. Or patients with hypertension, every six months to a year. The rest of
them, as I say, it really varies on what their underlying disease state is, as well as how
progressive it is.
Stephanie: I'm wondering what your current research interests are and what exciting new you have
to share about that front?
Carlton: So, most of my personal research has focused on the molecular control of kidney
development. Kidney and lower-urinary tract development. And one might ask, "Why do
we care?" Well, if you look at the leading causes of chronic kidney disease, about half
are structural. And among that half its split fairly evenly into aplasia, dysplasia,
hypoplasia. Meaning that it just didn't form right. The kidney didn't form right.
The other half are plumbing problems, that something is obstructing urine flow.
Posterior urethral valves, ureteropelvic junction obstruction, UVJ obstruction. So, those
two categories make up over half of the cases of patients with chronic kidney disease
leading to end-stage kidney disease. So to make an impact on that... So, you might say,
"Well, we have treatments. We have dialysis and transplant. That's effective, right?" Not
really. There are no cures for end-stage kidney disease. If you are unfortunate enough to
be born, or to be a child... we won't even go birth, birth is worse. A child, and you
develop end-stage kidney disease, you lose. You lose, on average, 50, 5-0, 50 years of
life. 50 years of life on dialysis.
Well, we can transplant them, right? We can do a lot better. Well, you only lose 25 years
of life if you get a kidney transplant, your quality of life is much better. When you
provide dialysis for patients, you give them basically enough kidney function back with
dialysis so that they don't die, is really the truth of the matter. If your GFR is below 10
mL/min from a .73 meters squared, you're going to die. We give them enough dialysis
that we're barely above 10.
So, imagine that you're a child, you're trying to grow, thrive, learn, go to school when
you have almost the level of kidney function provided that you don't die. And it actually
speaks to one thing about our program that I'm very happy about, is we are a very
aggressive kidney transplant program. Despite the size of Pittsburgh, we are in the top
10, if not the top 5, for the number of patients that we take care of that have end-stage
kidney disease. A large portion of those come from outside of Pittsburgh. Buffalo,
Morgantown, they send all of their kidney transplants to us. In fact, we have patients
that have come from 18 states outside of Pennsylvania for kidney transplants. Including
programs that have transplant programs, but they just feel the patients are too
complicated, or too small, medically complex to transplant.
We have a very small chronic dialysis program. And I'm proud of that, because we don't
let the kids languish on dialysis. We transplant them. But even that said, transplants not
a cure either, it's better, you feel better, you now have 50% to 70% GFR. But you still
have problems, and you still die young. Unlike cancer with our 80% cure rates, we have
0% cure rates for end-stage kidney disease. That's why I think looking at... My point in
my research, what I always put in from my significant sections is these very issues, that
we have palliative care for end-stage kidney disease. If we want to make an impact we
need to figure out what goes wrong with kidney development, and what can we do to
make it go right.
As an extension of my work related to understanding the molecular control of kidney
development, and this is really in the mouse. We make lots of mouse models where we
manipulate gene expression, and we reproduce the kinds of structural kidney disease
that you see in children. Absent kidneys, duplex kidneys, hypoplastic kidneys, dysplastic
kidneys, cystic kidneys. Well, that's all well and good, but how do you take that and do
something that's translatable?
I've been working recently with a team including members of the McGowan
Regenerative Institute at Pitt on looking at, "Can you regrow a kidney in a dish?" And
there are lots of people looking at this now, but my collaborate Eric LaGasse floored me
when he showed that he could take an embryonic mouse kidney, mince it up, inject it
into a host lymph node, it reconstituted kidney tissues that were profused, that
entrapped a fluid that concentrated urea. The only fluid that concentrates that urea is
urine, he made functioning kidney tissues within a lymph node. This is stunning to me.
So we're working with him now on, "Well that's great. You take minced embryonic
kidneys, we can't really do that as a source. Can you get progenitors?" So there's a large
movement in the research community looking at induced pluripotent stem cells and
converting them, driving to a renal state. The kidney's complex though, it's not like...
Not to denigrate other organs, but a liver cell, where you take hematoblast, and you
make that at an hematocyte. Well, the kidney has, really, four different progenitor cell
types that all need to be present. The nephron progenitors that make nephron epithelial
cells, at which there are 21 different epithelial cell types, that's complicated enough. A
ureteric epithelium, which is the progenitor for the collecting system. And those two
need to be cross-talking and signaling to each other. Then around that is a renal cortical
stroma that acts as an organizer for all this to work. And then, of course, you need blood
vessels. Many which are coming within the kidney.
So, there are people out there that can make nephron progenitors grow into these blobs
that kind of have epithelial structures. But we're looking at the lymph node as a bio
reactor that has these amazing organizing properties. The lymph node can organize liver
cells, beta cells in the pancreas to make functioning tissues. If you think about it,
cancer's teaching us that. How does cancer spread through the body? Through the
lymphatic system. They've known that the lymph node's a potent bioreactor for some
We're trying to harness that capability to say, "Let's take your favorite IPS cells, make
them into nephron progenitors, make them into ureteric cells, combine them together,
put them in the lymph node." In fact, we're actually now talking to a group from Japan
that has done some really successful research doing exactly that in a dish, but they can
only go so far. These tissues that they're combining in a dish, while they kind of look like
early kidneys, they're really fetal kidneys. They don't mature. If they grow them longer
in vitro they just turn into fibrotic masses and die. They're not profused, so how do you
really test for function? You need profusion to then look at urine production, glomerular
filtration, and then tubular function. So we are working with groups like this now in the
lymph node. That to me is really exciting work, and of course, the challenge is always
getting external funding agencies to be as excited. That's one piece that I'm working on.
The other piece is I've fallen in love with the bladder. I never knew I would fall in love
with the bladder, but I have. And it's a very important organ if you're a nephrologist. If
you don't have a functioning bladder your kidneys aren't going to be very happy. And,
actually, there's a real lack of intensive research at a basic science level looking at
bladder disease. Urologists are very talented people, but they're mostly clinically
focused. Whether it's they're straight up clinicians, or focused on clinical research. Not
really interested in laboratory research as much.
So, there's a real big problem out there, which is that bladder injury happens a lot. One
example is cyclophosphamide. A great drug, helps cure patients that have lymphomas,
or that have bad types of glomerular disease, or rheumatic disease. But, there are
problems with it. And one is that a toxin called acrolein accumulates in the urine, and it
leads to direct bladder toxicity. Leading to hemorrhagic cystitis, and more importantly,
There was a large survivor study, patients with lymphoma, 6000 of them that overall
had a 4.5 fold increased risk of bladder cancer. If you stratify them by dose, those that
get the highest dose, which is 50 grams of more, had a 15 fold increased risk of bladder
cancer. This is despite all the stuff we're currently doing. Mesna, which binds acrolein,
hydration. What we're doing isn't working. And no one's really looked at this. How does
acrolein cause bladder toxicity? What does it do, and is there anything we can do about
We have some really interesting, I think, interesting research looking at exactly that
topic. We are specifically interested in how fibroblast growth factor receptors might
play a role in disease, or even in therapy for patients that have this bladder disease.
Well, why would that be the case? It's been known for some time that keratinocyte
growth factor, FGF-7, is a potent epithelial mitogen; and if you give too much, that
actually can cause hypoplasia and even cancer. But it's also been shown in many wound
healing studies, oral mucositis, lung alveoli injury, gut injury models. Both preclinical and
some clinical models, that if you give patients keratinocyte growth factor, patients or
animals, that it largely ameliorates injury.
So we started looking at that in the context of the bladder. There was actually a paper,
the last one in 1997, that's the last one. That somebody looked at this, and there was a
paper, a preclinical model, that suggested you give a patient Cytoxan, give a mouse, give
a rat Cytoxan, they get horrible hemorrhagic cystitis. You give them a single dose of
keratinocyte growth factor before Cytoxan, and they said you largely regenerate the
urothelium. You accelerate the regeneration.
We started looking at this and they're not quite right. What actually happens is, and
we've shown this same thing, it's incredible. If you give a mouse a single
intraparenchymal dose of cyclophosphamide, a dose that's equivalent or similar to what
you'd give a person, they get horrible cystitis. And we actually have to look at the
females, because the males do, as is most often the case, much worse than the females.
We weren't even looking at the males, we're looking at the females. And even they have
terrible hemorrhagic cystitis.
If we give a single, one, single, one, subcutaneous, which is like giving an IV dose of
keratinocyte growth factor, we almost completely block the injury. Block the injury.
That's the key. It's not accelerated regeneration. We block the injury. So, what we find is
that actually the acrolein, which hits the superficial cells in the bladder, the urothelium...
The outermost layer, there's a necrotic cell death they slough off, and we don't block
that. That happens within the first 0 to 6 hours. But from 6 to 24 hours, there's a second
wave of death called apoptosis. That is almost completely blocked by keratinocyte
growth factor. In those that don't have KGF... The urothelium is a multilayered
epithelial, you go down to just your basal layer, and sometimes completely denude
everything, and in our KGF-treated it's amazing. There's almost no apoptosis.
We've been carrying these studies forward to look at... Well, you might say, "Are you
protecting cells that you should let die?" The answer seems to be no, so far. We've
carried the studies out to 3 days, and now 28 days we're looking to see what the
architecture is. And so far it looks pretty good, but stay tuned with that. The backside of
this, is what happens if you knockout the receptor that binds to KGF? What happens to
the urothelium then? Well, so as it turns out, if you do that, if you knockout the
receptor, specifically, we can use fancy mouse targeting techniques to knock it out just
in the urothelium. And we can do it in indusial fashion.
So we let these mice... they're born, they're fine. We give them a hit of Tamoxifen,
which induces the deletion of this receptor. And in the quiescent state they don't care.
It's fine. But we hit those with Cytoxan and they don't do very well, they're not very
happy. What happens is we have a maladaptive regenerative response. What happens
is, the basal layers, which is where the progenitors are... Normally in a quiescent state
there are very few progenitors. After injury, they spread across the entire basal layer,
and in the controls, the proliferate upwards and replace the damaged tissue. But it's not
a simple replacement. There's a lot of DNA damage that happens, so they're sloughing
the damaged cells, making new ones. Sloughing, making, sloughing, making, and this
happens all the way out to... Even at 28 days it's not finished.
Our poor mutants on the other hand, they make the progenitors spread across the basal
layer, but they are ineffective at producing progeny to replace the damaged urothelium.
What they do is they get trapped in a process called endoreplication. Well, what is that?
They go through the cell cycle, but they bypass mitosis. So they make big, fat nuclei,
they make more DNA, but they don't divide. So they get these giant cells, with these
giant nuclei, that don't divide.
We find this very fascinating and, actually, we are starting to even understand the
mechanisms by which this occurs. We're understanding now that they're different, of
course, these receptors signal through different downstream pathways. The KGF
overdrive anti injury protective effect seems to be on one pathway called AKT. The
problem with regeneration in the mutants seems to be irk mediated. In other words, irk
So, anyway. This is where we are with that. Probably more detail and depth than you
wanted to hear.
Stephanie: I am so happy that you're in love with the bladder. I have merely made peace with my
bladder, and learned to live with it every day. But that was more thinking about bladder
cellular activity than I think I've ever had in my entire career.
John: It is clear that you are passionate about your research, and I think it's really cool that
you highlighted the different areas from really basic, how are things forming and
developing in the kidney which lead to these kidney diseases in kids, and how are
medicines that we use injuring the kidney or bladder, and what are the mechanisms,
and how could that be intervened in. And then how we can maybe make new kidneys
instead of the treatments we have now. Just a final point, your division, I think, really
focuses a lot on research and education, right? That's a little unusual for a pediatric
Carlton: Yeah. So, first of all we have 10 MD nephrologists, and 2 PhDs in our faculty; which puts
us at one of the largest in the country. I can't say we're the largest. But it isn't just the
numbers that I think is impressive. We have four in our division that are really dedicated
to patient care. That really come to work to see patients and stamp out kidney disease.
And they do a wonderful job. And then the rest have other activities, mostly focused on
discovery and research. And what I love is it's really diverse.
We have my basic science program, but I'm not the only one. We have junior faculty
doing really exciting things, our one funded research focused on the role of Micronase in
patterning the kidney, and podocytes in the glomerulus. We have people working on
how the microvasculature is important in response to acute kidney injury, and how
alterations in metabolism related to the microvasculature is important in acute kidney
injury. We have people working on understanding the mechanisms of nephronophthisis,
which is a degenerative cystic kidney disease. Looking at how aberrant DNA damage
response plays a role. Which, again, has potentially high clinical relevance. We have
people looking at altered membrane traffic of proteins in diseases such as nephrotic
There are lots of kinds of nephrotic syndrome we don't know how to treat, we don't
understand that pathophysiology, but this is a novel approach, an outside the box
thought that aberrant trafficking of proteins contributes to this. And, while we have this
fairly solidly established basic science program, we have this growing patient oriented
research program that I'm very excited about. We have a faculty member whose a dual
critical care pediatric nephrologist, who submitted what's called a K Award, which is a
career development award. She's likely to be funded, she got a very good score. Looking
at novel biomarkers that would predict poor outcomes in patients with congenital heart
disease that go for heart surgery, some of these adult general heart patients get their
surgery. About half have full kidney failure requiring intervention. Half don't. We have
no idea to predict whose going to do what, which would then help us determine how
close we would follow up on care we would give. She has some very innovative data,
looking like this thing's likely to be funded.
We have a faculty member that created a high density patient database from the
intensive care unit from a five year period. Granular level detail, and has identified novel
associations between antibiotics and acute kidney injury that really weren't very
appreciated. Pip-Tazo, Zosyn, actually fell out as very highly associated with acute
kidney injury. Vancomycin did not, which was surprising. So, this is a current Kapplication that's in review. We have other fellows, I'm very proud to say we're 1 of only
5 pediatric nephrology programs that has a dedicated T32 to training pediatric
nephrology fellows. Only 5 in the country, and of the 13 fellows that have been on the
T32, 6 are committed to becoming clinician scientists. And I actually heard rumors that
one that's a junior person, the 7th, is very interested. And the topics they're looking at
range from hardcore basic science work, one doing induced pluripotent and stem cell
work, all the way to patient-oriented research related to databases and other things.
I'm very proud of the research focus in our program.
Stephanie: So it sounds like there's a lot going on with kidneys, ureters, bladders, and urethras here
in Pittsburgh. We're so happy that you were able to take the time to join us on the
podcast today and share this knowledge with us.
John: It's really been a pleasure to have Carl Bates, chief of pediatric nephrology to tell us
about the exciting research and clinical care in his division. I'm John Williams, we'll see
you next time on That's Pediatrics.
Stephanie: And I'm Steph Dewar. Thanks for joining us.
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