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Physical Medicine and Rehabilitation

Recent Breakthroughs with the APOL1 Nephropathy Gene Risk Variant

Recent Breakthroughs with the APOL1 Nephropathy Gene Risk Variant


– The last year, I’ve seen
tremendous translational research breakthroughs
in the nephrology section at Wake Forest Baptist. In my mind, one of the
most important findings in nephrology research in recent times was discovery of the APOL1 gene and its role in nondiabetic kidney disease in African-derived populations, African Americans particularly. APOL1 is the most impressive gene associated with any common
complex human disease. It’s amazing the role that it’s played, and 20 years we first
postulated that there was a kidney failure gene in certain African American families that predisposed to more than one type of kidney disease. We noted 20 years ago that there were African American families
that had four and five members on dialysis. One of them would have focal sclerosis. One of them would have HIV infection associated with kidney disease. One had, what was thought
to be, kidney disease due to essential hypertension. And other members with diabetes, lupus, other disorders, all of whom had kidney disease,
required dialysis therapy, but different diseases. And we noticed this
tremendous familial clustering of kidney disease, and
we’re the first ones to describe that more than
30% of African Americans starting dialysis had other
relatives already on dialysis. This was an amazing observation. There are many more
members of these families with mild to moderate kidney disease. I’m talking 30% had relatives already receiving dialysis therapies. We postulated back in the early 1990s that there was an overarching
kidney failure gene that these families inherited and multiple other second hits that would trigger the
development of kidney disease. Well I’ve spent 20 years
looking for that gene, and in 2010, working with
a team of investigators, some at the National Institutes Of Health, some at Harvard University,
the APOL1 gene was discovered. And the risk of developing
severe kidney disease is increased 10-fold in individuals with two risk variants in this gene. What’s most striking is
that the risk variants in this gene are limited to
people of African decent. They’re virtually absent
in people from Europe, European Americans, and Asians. This suggested that there was something selecting for the
presence of these variants that are now associated
with kidney disease, but they must have
protected from something. And as part of that
breakthrough work in 2010, it was discovered that one
copy of that risk variant protected from African Sleeping Sickness, which is a disease associated
with trypanosomal infection which is transmitted by the Tsetse fly. Turns out that if you had one copy of the APOL1 risk
variant you are protected from certain forms of
African Sleeping Sickness. So people survived waves of infection five or 10,000 years ago
in Sub-Saharan Africa, and the gene was selected for. However, if you were unlucky
and got two risk variants of this gene, one from your
mother, one from your father, your risk of severe kidney
failure goes up 10-fold. This is an amazing finding, and it’s very similar to
malaria and sickle-cell disease. If you have one copy of
the sickle-cell gene, you’re relatively protected from malaria, so that gene was common. But if you got two copies
of the sickle-cell gene, you develop sickle-cell
anemia and became very sick also protecting from a
parasitic disease in Africa. So it’s an amazing finding, but as I said, this is one of the most
striking genetic associations in human disease. Some of the things we’ve
been able to demonstrate in the last year are that
African American donated kidneys for transplantation have long been known to function for shorter periods of time than kidneys donated by
non-African Americans. This finding’s never been understood. We were able to show at Wake
Forest Baptist Nephrology that African American
deceased donor kidneys that had two copies of that risk variant functioned for significantly
shorter periods of time than African American donated kidneys without two risk variants. So this observation
suggests there was nothing about being African American
that led to the loss of kidney function in
transplanted kidneys, it’s solely due to this genetic variant. In fact, African American kidney donors who didn’t have two risk
variants in the APOL1 gene, those kidneys survived equally well as European Americans and
others who donate kidneys. So an amazing breakthrough
where we were able to translate the major
genetic identification of APOL1, which happened only
a little over a year ago, and we were fortunate
to play a role in that, is our now translation
into the transplant arena to suggest that certain
kidneys that are transplanted and have two risk copies of
this gene won’t work as well. This has tremendous
potential implications. The effect of having two
copies of this risk variant were greater than all these
standard accepted criteria for things we try and fix and select for in a kidney transplant. So for example, we try and
reduce the amount of time a kidney’s out of the body
called the cold ischemia time. We try and improve HLA
matching so that the kidneys are close to the HLA
type of the recipient. All these factors were compared, and the APOL1 risk variant
was a far stronger predictor of outcome than the
conventional risk factors we normally think about. This is led by calls from
others in transplant nephrology in the United States
that all African American potential kidney donors should be screened for variation in the APOL1 gene. Number one, we think it’s very likely to improve the outcomes in that kidney once it’s transplanted,
and if the kidney donor doesn’t have two copies
of that risk variant, the kidneys may function far longer. That would be very good for the recipient. The other important aspect though is if you have two risk
copies of the APOL1 gene, you may need both of your kidneys later so that you don’t develop
kidney failure in your lifetime. So this has the potential
to benefit kidney donors and the recipients of those kidneys. So that’s from the live transplant side. The data that we published was developed from deceased kidney donors, and I think it’s very likely that APOL1 genotyping
will soon be incorporated into the selection criteria
for kidneys selected for transplantation. This basic finding just
a couple of years ago is likely to improve kidney function after transplantation in all Americans. The unique capabilities
of our nephrology division here at Wake Forest to extend
this genetic observation in the transplant arena developed because of number one, our close interaction with the Wake Forest Solid
Organ Transplant program headed by Dr. Robert Stratta. This is one of the 20 most active kidney transplant programs
in the United States, and because of the large
number of transplants that are performed here historically, we were able to go back into the archives and get DNA samples from large numbers of African American donors and track their outcomes in all transplants done at Wake Forest Baptist Medical Center. This is a unique aspect
as other medical centers have not yet been able to
replicate these findings. I should say we’re eagerly
awaiting replication of these findings by other groups, but the ability of us to
take an initial observation that we participated in and extend it into the clinical arena derives from our close interaction with
the transplant program.

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