Chronic Kidney Disease – A Window into Understanding Health Disparities – Neil Powe

Eric Green:
Well, good afternoon, everyone. I’m Eric Green, director of the National Human Genome
Research Institute. I wanted to welcome you to the Genomics and Health Disparities lecture
series. I’m just going to give a general introduction about the series, and then I’ll
turn this over to a colleague to introduce today’s speaker. I just want to remind you
this is the second lecture in a series we have dedicated to looking at genomics and
health disparities. This series is really designed to educate and to encourage conversations
about how genomics research and genomic technologies can really affect health disparities research
and the opportunities we see going forward in this very important area, and we’ve deliberately
selected speakers to — who approach the problem of studying heath disparities from different
perspectives, from genomics research with an emphasis but also making sure we’ve covered
a full spectrum across the research landscape from basic science to population genomics
as well as translational and clinical research. Now, reflecting the broad interest in this
area and our institute, NHGRI has been fortunate to have four co-sponsors to this lecture series.
The National Institute of Diabetes and Digestive and Kidney Diseases; the National Heart, Lung,
and Blood Institute; the National Institute on Minority Health and Health Disparities;
and also the Office of Minority Health at the Food and Drug Administration, the FDA.
Now, the series started with the first lecture by Dr. Carlos Bustamante, a well-known population
genomicist from Stanford University whose research focused on analyzing genome-wide
patterns of genomic variation within and between species and how that is used to address fundamental
questions in biology, anthropology, and medicine, and today’s speaker will very nicely complement
what we heard from Carlos and I think again in many ways set up some of the issues and
problems we’ll be hearing about in subsequent lectures. So, to introduce today’s speaker, I’d
like to turn the podium over to my good friend and colleague, Dr. Griff Rodgers, who is the
director of the National Institute of Diabetes and Digestive and Kidney Diseases. Griff. [applause] Griffin Rodgers:
Well, thanks Eric, and I’m certainly pleased to be here, and I want to welcome you to this
— to this lecture series. It certainly gives me great pleasure to introduce my good friend
and colleague to be a part of this session, Dr. Neil Powe. Dr. Powe earned his medical
degree at Harvard Medical School and his master’s in public health at the Harvard School of
Public Health. He subsequently went on to University of Pennsylvania, where he completed
his residency and a Robert Wood Johnson Clinical Scholar, and during that period of time received
an MBA degree at the Wharton School at Penn, and after spending many years at Johns Hopkins,
where he was the head of the Welch Center, Dr. Powe moved to San Francisco, where as
you can see he is the chief of medicine at the Priscilla Chan and Mark Zuckerberg San
Francisco General Hospital. That’s important to point out. He’s also the Constance B.
Wofsy distinguished professor and vice chair of medicine at the University of California
at San Francisco. Dr. Powe’s research unites medicine and
public health with the goals of saving and improving the quality of human lives, and
his major interests have been in improving discovery, education, and clinical practice
of medicine, propelling academic organizations to function effectively and efficiently, and
developing future talents and leadership in the health profession, and this is actually
where we work very closely together in the current Harold Amos medical faculty development
program, the erstwhile Robert Wood Johnson minority medical faculty program, where I’ve
worked with Neil for more than 20 years now. Dr. Powe is remarkably creative and innovative
thinker in the area of kidney disease and public health, looking at many different factors
including the role of race and gender in treatment settings. One of — a recent paper, a JAMA
paper that he published entitled “Why Don’t Physicians Follow Clinical Practice Guidelines?”
It’s a framework for improvement that he published in 1999, and it has over 3,000 citations.
In addition, Dr. Powe was part of team that discovered the genetic variant on chromosome
22 that confers a significant risk of kidney disease and is found exclusively in individuals
of African origin. He continues to study this APOL1 gene and its role in ESRD or end-stage
renal disease and health disparities. Dr. Powe has been a recipient of numerous
NIH grants and has received many honors and awards. Just to name a few, he’s a member
of the National Academy of Medicine and erstwhile IOM. He’s a master at the American College
of Physicians. He’s received the Diversity Award from the Association of Professors of
Medicine, the John M. Eisenberg Award for career achievement research from the Society
of General Internal Medicine, and the Belding H. Scribner Award from the American Society
of Nephrology. My colleague, Dr. Green, mentioned that at least at the NIH — the — this series
is cosponsored by four institutes, and I’m pleased to say that all four institute directors
are here present at your — at your talk. So, without further ado, please help me in
welcoming Dr. Powe for this lecture. [applause] Neil Powe:
Thank you, Griff. It’s always nice when you’ve known somebody for 40 — over 40
years and they can give that kind of introduction to you, and I’m really glad he said the
things I’m most proud of and didn’t say the things that — [laughter] — I’m not most proud of. So, thank you,
Griff, and I thank everybody for attending. I want to thank the institute directors for
sponsoring this session, and this is one of the first times I’ve been able to show this
slide, you know, with the Zuckerberg San Francisco General, as we’re now know due to a generous
donation, the largest generation — largest donation to a public hospital in the country. So, what I’m going to talk about is my — one
of my favorite subjects, and that is disparities from the viewpoint of chronic kidney disease.
So, I’m going to start with a case illustrating racial and ethnic disparities in kidney disease.
Then, I’m going to put forth a premise about disparities as a focal point in science and
medicine, talk about definitions in a framework for how I try to understand disparities, and
talk a little through the lens of my research on the science of disparities, of why kidney
disease occurs more often in minorities. Then, hopefully we’ll have — may have some time
for questions at the end. So, let me start with a case. This is a common
occurrence, a 46-year-old African American male who presents to the emergency room for
generalized weakness, nausea, and vomiting. His history of present illnesses — he had
increased lower extremity edema for two months. He was seen by a private physician, a physician
who cared for his mother. There was no lab work done, but he was placed on a diuretic.
His edema improved but he — worsening weakness and 15-pound weight loss over two months,
and then he presented to the emergency room with nausea and vomiting of three days’
duration. In his past medical history, he had no history
of kidney disease or other chronic diseases. He did have a family history of diabetes and
hypertension, and he took no medications, including over the counter medications. On
physical exam, he was chronically ill appearing young man in no acute distress. His vital
signs were normal. Notably, his blood pressure was 141 over 76, and his exam was really unremarkable,
but his laboratory examination was remarkable in that he had a bicarbonate of 19, a NIN
gap of 28, a calcium of 5.8, phosphorus of 13, and a high BUN in creatinine 240 in 28,
and so he was admitted and seen by the nephrology service, and a temporary catheter was placed,
and he was immediately started on hemodialysis. So, what this case illustrates is an African
American patient with kidney failure — not uncommon, the late presentation for care,
where there’s little opportunity to prepare for kidney failure and urgent initiation of
hemodialysis, probably limiting optimal treatment for end-stage renal disease. So, this is — this
is my premise, that science on disparities, clinical care with diverse patients, and education
about disparities enhances all of medicine and human health. Now, why? Because learning
about disparities allows the examination of complex interactions that contribute often
unequally for different clinical problems to human health. So, interactions between
biology and the environment, between environment and social conditions, between biology and
social conditions, and so examining disparities allows us to look at a variety of different
determinants of disease. I like to — I like to show this slide about
the racial and ethnic composition of the United States, of California, and then the hospital
that I practice at. In the U.S. now, minorities make up about 31 percent of the population,
and if you look at projections — in 2050, minorities are projected to make up — be
a majority of the population. We passed that in California in 2005, where minorities make
up a large portion of the population, and that’s even larger in the city that I practice
and live in, San Francisco, and then if you look at the population at my county hospital
that serves the underserved, in fact we have a very diverse ethnic group, almost 20 to
30 percent of the population in different ethnic groups, and so we do a lot of — we
do clinical care. We do educations to students and residents, and we do a tremendous amount
of research on our diverse and vulnerable populations. So, last year was a year of anniversaries.
On December 1, 1955, that was the year that I was born — I shouldn’t tell my age, and
Griff’s age, too, since I’ve known him for — well, Rosa Parks changed the course
of history and inspired all of us by the steps that she took when she came on a bus, but
it was also another year of anniversaries. In September 1985, the U.S. Department of
Health and Human Services issued the landmark Heckler Report, and I remember this because
I was a fellow at that time, and it was — it was an amazing report because I think for
the first time it documented health disparities in the United States among racial and ethnic
minorities, and it said, “Disparities are an affront both to our ideals and to the ongoing
genius of American medicine,” and so this report served as a driving force for ending
health disparities and advancing health equity in America. There was very little disparities
research before this report was issued I think going on in the whole country. So, disparities — what do we mean by disparities?
Disparity is a difference or a lack of equality, and the Institute of Medicine said that health
care should not only be safe, effective, patient-centered, timely, and efficient, but also equitable.
That is, providing care that does not vary in quality because of personal characteristics,
such as gender, ethnicity, geographic location, or socioeconomic status, and race — I know
this is an emotionally charged term in our society. Nowhere else in the world is — are
we preoccupied with race, and the different — these are different definitions of race. Webster defines race as “a group of people
united or classified together on the basis of common history, nationality, or geographic
distribution,” and the Institute of Medicine defines race as a “construct of human variability
based on perceived differences in biology, physical appearance, and behavior, not a biological
reality,” and then I like Mike Bamshad’s definition of both — that about — “information
about genetic group membership captured by notions of race is in general less than that
obtained by making inferences of ancestry from geographic or explicit genetic data,”
and this schematic shows what the thinking is on this, showing genetic relatedness among
different ethnic groups, and I think, you know, showing that in fact we all are — makeup
of different ancestry, whether that’s African American, European, or Asian ancestry, and
what’s really remarkable is that the genetic distance between individuals within the same
population is larger than the genetic distance between individuals from different populations.
So, we are really all one and the same. So, since the Heckler Report there’s really
been a plethora of data that has shown that there’s non-uniformity of health among racial
and ethnic groups in the United States. If you look at life expectancy, the differences
are about a 10-year gap for black men versus whites, five years of difference for women.
The infant mortality rate is higher for blacks and Native Americans. The death rate is harder
— is higher for a variety of diseases for blacks and Hispanics compared to whites, and
for most ethnic minorities there — they have higher rates of kidney failure that I’ll
talk about and also many other diseases, and these disparities persist even after accounting
for socioeconomic status, for insurance, lifestyle factors, and clinical factors. I’m just
going to — I’ll show you some of the evidence for chronic kidney disease, and the toll is
really that — it’s shown in this article by my former colleague, Tom LaVeist and Darrel
Gaskin is that the combined cost of health inequalities and premature death in the United
States were $1.24 trillion. I always like to say, you know, that could have paid for
health-care reform, that — the $1.24 trillion. And this is a striking article, that I thought
— published several years ago by Chris Murray, who showed that we live in eight Americas,
and he investigated mortality disparities across races and counties and race counties
in the United States, and so he looked at the — at eight Americas: America that the
top — where Asians live, where the average income per capita is $21,000 and where 80
percent of folks completed high school; and then looked at northland, low-income rural
whites, and you can see the average per capita income, and percent completing high school;
and if you go all the way down the list and you see actually western Native Americans,
per capita income half of that of Asians or middle America, and the graduation rate from
high school very low; and then blacks in middle America; then blacks in southern low-incomer
rural communities, again, $10,000 and 61 percent completing high school; and then high-risk
urban blacks. And strikingly he looked at the mortality
over many years in these groups, and they’re rated in the order that I’ve shown you,
but striking that the high — that the urban blacks here at the bottom, you know — I’m
sorry, here at the top — wait, no, sorry — at the bottom had a lower life expectancy
at birth, and this is true for — you can see this relationship across these eight Americas
is similar for males as for females, so the females having less mortality. So, just looking
at the impact I think both of race and of socioeconomic status in America. So, let me turn to kidney failure — the area
that I’ve worked a lot in, and we know that kidney failure — end-stage renal disease
— that you — it needs to be treated with dialysis or transplantation, some form of
renal replacement therapy and — if you are to live — is up to 2.9 times higher in racial
and ethnic minorities. This is data from the United States renal data system, and it shows
that in 2013, the incidence of kidney failure was 825 per million population in African
Americans compared to 282 per million population in whites, and the mean onset of end-stage
renal disease is about five years earlier. So, it strikes minorities earlier, and the
rate is higher, you can see, in most minorities. That includes Native Americans and Asian,
though not as — not as dramatic as in African Americans — and also higher in Hispanics,
and it occurs earlier than in the Caucasian population. So, why is this bad? Treating ESRD is costly,
both personally and financially. Age 50 to 54-year-old person — they’re expected remaining
lifetime in the general population is 30 years, but if you’re a dialysis patients, it’s
eight years — or a transplant patient, if you’re lucky to get one, is 20 years, and
the annual Medicare expenditures are — you can see eight times higher for someone in
the — who’s a — who is on dialysis than if you’re in the general population, and
quality of life is poor, although if you’re lucky to get a transplant, it can restore
quality of life compared to the general population. So, there’s really the need to preempt illness
upstream through molecular knowledge, through clinical therapeutics, and through behavioral
interventions, and that’s what I’ve been trying to do after studying ESRD for many
years is to focus on chronic kidney disease, and one of the projects I’m involved in
is a CDC surveillance project — a CKD surveillance project that’s sponsored by the Centers
for Disease Control where we track kidney disease in the United States, so one in 10
adults have chronic kidney disease. As we’ve shown from NHANES over 20 million individuals
in the United States have chronic kidney disease, and what we do is we chart statistics for
the nation, including for healthy people 20 on, chronic kidney disease prevalence incidence,
awareness, risk factors, health consequences, quality of care, and how well our health system
is prepared to care for individuals with chronic kidney disease. So, we look at trends, and this shows data
from the United States Renal Data System funded by the NIDDK on the incidence rate of ESRD
by race, and you can see — there — we really thought there was an epidemic in the 1980s,
in the 1990s, but recently it looks as if we’ve begun to make a difference, and in
fact this — the rate of ESRD is declining, although it is still dramatically higher in
African Americans compared to the general population. You can see down here — lower
— but we recently did some work that we presented to the last American Society of Nephrology
to see if actually the prevalence of earlier stages of kidney disease — chronic kidney
disease is defined by an EG — estimated glomerular filtration rate less than 60 for albuminuria.
It’s prevalence was declining, and it looks as if — actually, that it is declining, although
there’s a concern here in this — shown in the blue line that in African Americans
that rate of decline has not continued. So, you know, one of the things that’s interesting
is I think we have no or very few therapies today — and I think this slide from the African
American kidney disease study — I like to illustrate that, and it — this was an, as
you know, NIDDK-funded study of African Americans with kidney disease — early stage kidney
disease, and it compared ACE inhibitors to non-ACE inhibitors, and here you see that
during the trial, in fact, the rate of the endpoint, which was a combined endpoint of
ESRD as well as death or doubling of serine/creatinine, it was lower in the ACE group than in the
non-ACE group, but what happened after the trial is you see that more than 50 percent
individuals despite being on ACE inhibitors still progressed toward the endpoint, showing
that our therapies are really halfway therapies if at — if at all, and that there is a great
need to identify why this happens and to develop therapies to prevent this. Recently, my colleague Carmen Peralta published
a study that showed — shows that actually the decline in early stage kidney disease
at early ages is faster among African Americans than whites, and this is — this shows it
by age, eGFR and the top line in blacks who have a higher eGFR as measureable by cystatin,
but you see that this rate of decline is much greater in African Americans. The slope here
is greater than in whites over — with age, suggesting that in fact there is a higher
rate of progression of disease among African Americans, and a large study was done in Kaiser
in Southern California, and a large number of individuals — over a million individuals
in Kaiser Permanente, where they followed — they measured, actually, individuals’
kidney function at baseline and then followed them over several years, one, three, and five
years, and what they showed is that in both African Americans and Hispanics, the odds
of progression to kidney failure were higher, and for blacks that’s true at any entry
GFR. For Hispanics, it was high only for those individuals who had a lower GFR that — starting
in Asians, even a suggestion of rapid progression. So, this is what we think now — is that the
higher incidence of kidney failure among African Americans appears due to a faster rate of
disease progression rather than a greater prevalence of early stage disease, that in
fact blacks are more likely to progress toward damage and kidney failure, and the issue is,
what are the contributing factors to this acceleration? So, I want to talk a little
bit about that — about how I think the field has dissected these factors. I try to think
of them as susceptibility initiation and progression factors that contribute to the excess ESRD
incidence. They could be biological, environmental, behavioral, such as lifestyle or even the
quality or adequacy of the medical care that we deliver. So, let’s talk about biology. Observations
were made by individual — by investigators in the south and southeast United States,
and they went into dialysis units, and they asked 26,000 individuals who were starting
dialysis in the southeast United States, “Do you have a first- or second-degree relative
who is also being treated for ESRD?”, and they found that actually 22 percent — 23
percent of the individuals in dialysis units had a first- or second-degree relative. Huge,
really, really, huge. Almost one in four, but that — this was much more striking among
African Americans than among whites, and this was replicated in about 12,000 U.S. residents
from a larger number of states — and in fact the rate was higher among African Americans
than among whites, although not as dramatic in this earlier study. So, that raised the issue of genetic factors,
and several years ago — it was 1995 — we started a study called the “Choices for
Healthy Outcomes in Caring for ESRD” study, and it was a national prospective cohort study
comparing the effectiveness of hemodialysis and peritoneal dialysis. We had set this up
to look at treatment, but we recruited an interesting population of 1,000 new-onset
— probably the first study of new-onset or incident adult ESRD patients throughout clinics
in the United States, and we followed them for up to nine years. This has been a great
study that we’ve had multiple grants and has supported a lot of individuals’ careers,
and my colleague, Joe Coresh at Johns Hopkins had the wisdom in 1995 when we got this study
started to set up a specimen bank far before this was popular, and so we did measurements
of serum and plasma and DNA at multiple time points during the follow-up of these patients,
and this has allowed — this allowed us to address a variety of factors considering that
in the choice study we’d looked at risk factors for prevention, diagnosis, etiology,
and genetics. That’s what I’m going to talk about — the work that Griff referred
to — and therapy prognosis, CKD complications, access to care, quality, and even resource
use and cost. And so this was the study that my late colleague,
Linda Kao and also Rulan Parekh, who’s in Canada now, did on — in the family investigation
of nephropathy and diabetes research group using data from choice. They did a case control
design to look at associations of genetic markers with kidney disease and found that
MYH9 locus was associated with non-diabetic end-stage renal disease in African Americans,
but as Griff said, he actually was wrong. We got it wrong, and in fact a variety of
other studies emerged also looking at MYH9 — looking not only at non-diabetic kidney
disease but focal segmental glomerulosclerosis, HIV associated nephropathy, as well as hypertensive
nephropathy, showing this association with MYH9, but I think more importantly, APOL1
because what we found out is that the real culprit is the APOL1 gene that is a 14.5 kilobase
gene on chromosome 22, but it’s located downstream of MYH9, in fact was in linkage
disequilibrium with MYH9, and it codes for a product that’s 398 amino acids, and the
mutant form or the mutant alleles actually confer a survival advantage against sleeping
sickness, trypanosomiasis, but they also confer a risk of — an increased risk for non-diabetic
kidney disease. The mechanism we don’t understand, although
there are a number of potential candidates out there, and this is the structure of the
product of APOL1. It’s a 43-kilodaltin protein — the apolipoprotein family. It’s bound
to circulating HDL particles, and what’s interesting — it’s expressed in various
organs, including kidney podocytes, renal tubular cells, and glomerular endothelial
cells, and it’s involved in the autophagy pathway. What’s even interesting, if you look at
where these mutant alleles are in the population in Africa, it’s not quite a one-to-on overlap,
but it suggests that in fact the area where the tsetse fly, the vector for sleeping sickness,
is most prevalent, suggesting that there is this — there was this selection factor for
this mutant allele, and so other studies funded by NIDDK, the CRIC study and the AST study
have shown that the powerful effect of the APOL1 mutant alleles and the CKD progression
in longitudinal studies following up from case control studies — rapid case control
studies that were done showing that two copies, not one, but two copies of the mutant alleles
confers risk, and this is true whether individuals have proteinuria or don’t have proteinuria,
a potent risk factor for progression of kidney disease. So, I’ll come back to the APOL1 in a minute,
but let’s talk about environmental factors. Could they contribute? Several years ago,
I was asked by Raynard Kington to get involved in a study in Baltimore funded by the National
Institute of Aging called the “Healthy Aging in Neighborhoods of Diversity Across the Lifespan,”
and we designed a study that went into neighborhoods in Baltimore, where we could recruit both
whites and African Americans, but interestingly, African Americans of higher socioeconomic
status and white Americans of lower socioeconomic status in equal proportions to allow us to
try to tease out the effects of biology and socioeconomic status and race, and my colleague
at Hopkins, Deirdre Cruse, did this study that showed that individuals who had lower
socioeconomic status were more likely to have chronic kidney disease than those with higher
socioeconomic status, but this was really profound for African Americans than for whites. And so, you know, it shows that there’s
also a powerful effect of socioeconomic status, something that Paul Kimmel — I know I saw
Paul here — has studied tremendously and cares a lot about, but there’s also behavioral
factors, and we did this study several years ago, and actually Paul Eggers had a lot to
do with this study because he worked at the then-CMS and allowed us to link the NHANES
survey with the Medicare registry to provide a longitudinal look at individuals of whether
they progressed to kidney disease, and so we did this study looking at race, and in
— what this shows is the relative risk for blacks versus whites in progression of kidney
disease, and if you control for age and sex there was an almost threefold higher risk,
but if you control for SES, you could explain about 12 percent of the excess risk, and then
if you control for other lifestyle factors like physical activity, BMI, alcohol, and
smoking status, you could explain about a quarter of the risk, so in fact not only socioeconomic
status but lifestyle factors influence the progression of kidney disease. Recently, we did — we used this kind of linkage
study linking again the NHANES study with the ESRD registry, and where we looked at
the exposure of dietary acid load determined by a 24-hour dietary recall questionnaire,
and we measure NHANES participants, whether they developed ESRD over 14 years of follow
up, and we had a variety of data to control for potential confounders, and I know this
slide is busy, but I want to — I just want to illustrate and tell you what it shows.
It shows that those who have a high net acid excretion or a high dietary load of — high
dietary acid load — blacks are much more likely than whites to have a high acid load.
Mexican Americans, as well, and those who are in poverty — this is a poverty-income
ratio — also have a high dietary acid load — that high dietary acid load is a diet that
is not high in fruits and vegetables but more animal products, and it’s also true that
those of lower socioeconomic status, less than a high school education, had a higher
dietary acid load. But in linking this to — let’s see — to
the ESRD registry, this is what we found, that actually having a high dietary acid load
was associated — this was a cumulative probability of ESRD versus a low dietary acid load, so
in fact both behavioral factors, including diet, may be an important risk factor for
disease. Well, what about the quality and adequacy
of CKD care? One thing is — we know that having control of blood pressure helps to
prevent progression, and so this is a slide from NHANES in a study that we did looking
at minorities in the U.S. with chronic kidney disease, and this shows the percentage of
participants with uncontrolled blood pressure, and you can see that compared to whites, African
Americans shown here either with CKD or without CKD have higher levels of uncontrolled blood
pressure, and this is — this just makes it more dramatic if you use a stricter definition
of blood pressure control, which some argue for in chronic kidney disease. So, in fact,
how we treat individuals may also contribute to progression. So, back to this slide, then, if you look
at care quality as measured by controlled diabetes, hypertension, cardiovascular history,
or cholesterol, you can explain about a 33 percent of the excess risk reduction in the
study that I showed you before, and if you put all those factors together, we could explain
over half of the excess risk, but there’s still a considerable amount of risk that is
still there, and maybe is that APOL1 or other genes? Could we have — if we had had data
back then about APOL1, in this study could we have explained 100 percent? So, these are some questions to ponder. How
does — how much does APOL1 or other genes contribute to the disparity in ESRD incidence
between African Americans and whites? How important is this gene in comparison to other
modifiable risk factors? This is the slide that Joe Coresh leant me — Morgan Grams did,
and this shows actually the prevalence of CKD by APOL1 risk variance, and this is in
blacks: blacks high risk, blacks low risk, and then here in the green whites, and what
you see is that there’s a wide distribution in risks, even among those who have high risk
— that is, two mutant alleles, so it’s not that everyone who has those alleles is
going to have the same risk. So, there’s something here that we have not — we don’t
understand why, in fact, some people, even if you have the risk alleles, develop kidney
disease faster than others. So, other questions: Are APOL1 risk variants
more susceptible to known kidney injury agents? Do APOL1 variants alter response to an environmental
factor or to treatment? And I think most importantly, does knowing APOL1 risk status lead to better
outcomes? What can be done? Is better blood pressure control, diabetes avoidance and nephrotoxins,
less acid diets — would that — would that help in such individuals? And there are lots
of controversies about the decision to be a live kidney donor and donor outcomes, and
that’s a whole issue of great import. What about the mechanism? Well, APOL1 has
an endogenous function — does APOL1 have an endogenous function in the podocyte that’s
necessary to resist environmental stress and maintain podocyte health? In the path — could
the pathways be dysregulating in the presence of two risk variants where clinical disease
manifests with the introduction of environmental stress? Could there be gene-gene interactions
that may explain that — you know, there could be modifier loci that explain the difference
between different kidney pathologies, and then gene environment interactions, so-called
second hits. Could it be viruses or antiviral pathways that might explain the gaps that
we see in lifetime risks with individuals with the same genetic background? What about — is APOL1 — is the risk — does
the risk come from circulating or APOL1 or APOL1 expressed in the kidney? Is this apoptosis
as a mechanism in podocytes? Lots of — lots of information. I think these kinds of studies
illustrate how we can learn from researching diverse race and ethnic groups, and this recent
study that I did with my colleague — I released a thought piece with Steven Bouchard [spelled
phonetically] — illustrates that. You know, in breast cancer, we’ve been able to show
differences in Native American ancestry at the estrogen receptor locus led to discovery
of a genetic variant that was protective against breast cancer in Latinas. In heart theory,
we know that the data about fixed-dose combinations of hydralazine and isosorbide dinitrate suggested
that blacks but not whites had a significant reduction in mortality. The increased preterm
birth rate due to endocrine-disrupting chemicals — it’s more common among minorities. Stevens-Johnson
syndrome, kidney diseases I mentioned, and then response to antiretroviral agents that
may be due to differences in genetic polymorphisms in the cytochrome pathway. So, these are the kinds of insights I think
that diversity is teaching us about. What about — I want to talk a little bit about
downstream, where I did a lot of early work in quality and adequacy of CKD care, and this
data came also from the TROY [spelled phonetically] study where we looked at in our cohort the
timing of specialist evaluation and chronic kidney disease and mortality, and what we
found is that over one third of black dialysis patients prior to ESRD received a late evaluation
by a nephrologist, so this is white males, 25 percent received a late evaluation, but
45 percent of black males received late evaluation — thirty-eight percent of black females and
30 percent white females, and in fact others have shown as well as us that when you have
a late evaluation, you’re really poorly prepared for dialysis. You’re nutritional
status is reflected by serum albumin is worse when you have a late evaluation. You’re
hematocrit is lower, and you’re less likely to have therapy for anemia. So, it’s shown in a variety of studies now,
and I think what was remarkable is that when we looked at whether you had an early, intermediate,
or late evaluation, among African Americans having a late evaluation was seven times higher
risk of mortality with ESRD. So, why is this important? Because poorly prepared patients
miss opportunities to make informed treatment decisions — treatments about hemodialysis
or peritoneal dialysis and transplant. We saw that in the patient that I presented,
who was, I like to say, found in the emergency room rather than prepared for ESRD, and choice
of therapy matters. The risk of death for hemodialysis versus
peritoneal dialysis in the first year is equivalent. In — but hemodialysis may yield better long-term
outcomes. More frequent dialysis at home may be better, and self-care modalities enhance
quality of life, and transplants yield better length and quality of life as I showed you
earlier. Live donor transplants are better and preemptive transplants even better, and
African Americans versus whites are less likely to be waitlisted and transplanted. They’re
less likely to receive live kidney transplants, less likely to have knowledge of kidney replacement
therapies, less knowledge of transplant prior to a dialysis initiation. They have lower
health literacy, and health literacy has been associated with transplantation, and they’re
less knowledgeable when being evaluated for a transplant, even when knowledge isn’t
counted for race differences — well, knowledge as counted for race differences in transplant
evaporate. So, let me summarize. I know that’s a lot
of information. What I tried to show you is illustrate the African American patient with
late presentation for care who had poor preparation for ESRD and had urgent hemodialysis initiation,
and treating disease at end stage is costly both personally and financially and limits
access to optional therapies, and the biologic, socioeconomic, behavioral, and clinical determinants
conspire to compromise health and health care for minorities, and we need to develop and
rigorously test interventions to address determinants to human health and learn how to preempt all
this through molecular knowledge, through therapeutics and behavioral interventions.
And disparities research allows the examination of these complex interactions that contribute,
often unequally, to health or different diseases, and so a growing proportion of Americans are
not fully benefitting from clinical and biomedical advances since racial and ethnic minorities
make up 40 percent of the United States population, and most physicians and scientist, including
myself, are informed by research that is extrapolated from a largely homogenous population, and
ignoring diversity of the U.S. population is a missed scientific opportunity to understand
factors that lead to disease or health. And U.S. biomedical research in steady populations
must better reflect the country’s changing demographics. So, that’s my premise that
science on disparities, clinical care with diverse patients, and education about disparities
enhances all of medicine and human health. So, thank you for your attention, and thank
you for the Heckler Report issued by your department some 30 years ago that got us on
this journey. [applause] Griffin Rodgers:
Well, thanks, Neil, for that great talk. I would point out that actually this is very
timely. March is actually National Kidney Month, and March 11 is World Kidney Day, so
this is a very timely talk in this series. Neil Powe:
The only problem with that is Marv, who would have given me heckle for that because it’s
devoted to children. Griffin Rodgers:
I was going to say [laughs] [inaudible] — Neil Powe:
The theme this year is kidney disease in children, and I didn’t say anything about children. Griffin Rodgers:
All right, but we have time for some questions if there are some. Male Speaker:
Thank you, Neil. That was not only a lovely talk, but it was an extremely important talk,
I think. I have an observation and a question. So, the observation is that over the last
probably decade, I’ve become increasingly interested in the prenatal environment and
perinatal environment and the idea of malnutrition, poverty, maternal fetal dysfunction in setting
up the idea for the lower nephron number, which may be differentially expressed in different
populations, and I think that’s a very important consequence because CKD may actually start
shortly after birth or at birth, so I think that’s — should be added to your very beautiful
presentation. Neil Powe:
I agree. It’s a — it’s a wonderful area. It’s really been understudied, and for a
variety of reasons, it’s very hard to get information like that — Male Speaker:
Right. Neil Powe:
— in a large number of individuals to look at this, but certainly an intriguing area,
again, an area that brings together both biology and environmental factors — Male Speaker:
Right. Neil Powe:
— some of which I tried to meet. So thank you — Male Speaker:
Right. Neil Powe:
That’s a very important, I think, area for future discovery. Male Speaker:
Epigenetics and actions, sort of. But the question is — and I know you’ve probably
struggled with because I think people in the dialysis world have struggled with this for
30 years since Fritz Port’s observation is that the survival in black Americans and
the end-stage renal disease program and hemodialysis is superior the survival of white populations,
and I’ve often thought that this must be associated with psychosocial factors and differential
perceptions of quality of life or other factors associated with families, but the two questions
would be, why is it only in this population specially out of all the chronic disease — and
we haven’t really licked the issue. I think there’s an important biological interactive
message there that we haven’t been able to elucidate, and I’m wondering what your
thoughts are about that. Neil Powe:
Right, so that — yeah, that’s a very — what Paul’s referring to is that an African American
patient who gets ESRD has a far better survival than their white counterparts — paradoxical.
So, you know, I’ve done some work to try to look at this, and what Paul is saying is
that — is this actually environmental and socioeconomic? We’ve kind of done work to
look at whether it’s biological, whether in fact, you know, remember several years
ago I did a study to try to look at that those who actually get onto dialysis — is there
selection? Maybe African Americans with more comorbidity are left behind and didn’t have
an opportunity for dialysis, but that’s not true in our country because Medicare provided
insurance for everyone to — if they develop end-stage renal disease to get dialysis, and
we’ve actually showed that using some data. And then there’s the other side, which is
are more African Americans — are African Americans less likely — because they’re
less likely to get a transplant, does that mean that in fact when you compare them to
Caucasians, the Caucasians have more comorbid disease that were contraindications to a transplant
or at least there was some subtle selective factors for people who got a transplant, meaning
that the African Americans left behind may be healthier? And there’s some suggestion
of that, although not perfect, and then the other side, which, you know, I have not seen
a lot of data about is the — are there environmental or, as you say, behavioral related issues
that may affect human health and your survival to be on dialysis? It’s something we don’t
understand, another area for — ripe for discovery. Male Speaker:
More research. It was a lovely talk. Thank you, Neil. Hia Sudontis:
Hello. Thank you so much for your talk. My name Hia Sudontis [spelled phonetically].
I am a postgrad student and actually a prospect medical student. My question for you is, knowing
all of this information, you know, the correlations and the factors related to certain disease
and how health disparities is related to that, you know, as you mentioned in the end how,
for example, even though African Americans are more likely to need a transplant, they
actually have more barriers to receiving a transplant. This information — how can it
actually translate into doctors actually providing better patient care? Neil Powe:
Well, you know, what’s interesting is we’ve known a lot of this. I could have showed you
a slide that showed those transplant disparities. It’s been 10 years, and we have not made
any difference in who gets waitlisted or who gets transplanted. I mean, we’ve tried to
tinker a little with the factors in the wait listing algorithm. So, you’re absolutely
right. I think this is a failure. I think it’s a failure of our profession to correct
this because it shouldn’t be that individuals have different [unintelligible] and may have
to do with how we evaluate individuals for transplant. We also know that for living related donors
that if — I showed you the data that actually shows that African Americans have relatives
who have kidney disease, so maybe that limits the potential live kidney donors in their
family or friends, and how do you factor that in? So, we have — we have a lot of reflection
to do, and I think even more action to turn this around. Hia Sudontis:
Okay. Neil Powe:
Thanks for your question. Hia Sudontis:
Thank you. Neil Powe:
And I would say also that thanks for the wonderful questions I had. I met with some of the trainees
here today that are doing really exciting work in different laboratories throughout
the NIH, and it was fabulous to hear all the wonderful and exciting areas that they’re
working, and — Griffin Rodgers:
This is the last one. Male Speaker:
Hi, Dr. Powe. Thank you for your interesting talk. I was wondering, after a diagnosis or
the beginning of dialysis in patients, do you know if there’s a difference in how
dramatic their lifestyle behavior changes after — you know, when they — in conjunction
with their diagnosis or beginning of dialysis therapy, and if so, if that makes a difference
in their survival rate? Neil Powe:
So, you’re — if I got the question right, do — you know, after someone has had a serious
illness, could there be differences by ethnic group in how you respond to that illness that
leads to behaviors that may influence outcome. I think that’s understudied. I haven’t
seen work in that area. It’s a good question. Male Speaker:
Yeah, like for example, if, you know, I know I’m going to get kidney disease, I’ll
probably start eating better or exercising far more or — Neil Powe:
We do know that, yeah, and you’ll get tortured — Male Speaker:
Yeah. Neil Powe:
— to do that, too, by your — by your doctors and your family, definitely. In fact, if you
look at, you know, smoking rate, something that my colleague Ellis Sayre [spelled phonetically]
studied, if you look at smoking rates and chronic kidney disease, the more severe your
kidney disease gets, the less people smoke. We’ve looked at that in national data, so
— Male Speaker:
Great. Neil Powe:
Well, thank you very much. I appreciate it. [applause] [end of transcript]

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