[Music] oh [Music] [Music] oh good afternoon everyone and welcome to this kidney action week session on APO L1 mediated kidney disease also known as am KD my name is Mike spigler and I'm the vice president of patient support and education for the American Kidney fund today's session will give you valuable insights into am KD and its impact on Kidney Health we also discuss existing research and initiatives being done by both the kidney health initiative and the American Kidney fund and most most
importantly we'll provide you with action steps that you should take to improve the care of your patients now let me introduce our speakers first is Dr Mona Doshi Dr Doshi is medical director of the living donor kidney transplant program at the University of Michigan Dr doshi's research interests include understanding the impact of the apo1 genotype on donor outcomes she is one of the primary investigators on the NIH sponsored Apollo study and is co-leading a work group on the psychosocial evalu
ation of living donors particularly those with a history of substance use disorder and mental health disorders Dr Doshi is passionate about removing Financial disincentives to living donations and works with state government efforts to remove some of those barriers next is Dr Abal Patel Dr Patel is chief medical officer at high bio prior to high bio he was the head of clinical renal and executive group director in early cvrm at astroica where he led early clinical strategy and development for a
wide range of Therapies that address several kidney diseases he previously led the kidney diseases domain at Gilead Sciences he currently also serves as chair of the board of directors for the Kidney Health Initiative as a faculty member at Duke University he led clinical and translational research programs to improve detection and management of kidney disease in populations we've got a lot of information to get to you so we're going to jump right in so I'll turn things right over to Dr DOI oh t
hank you thank you Mike and I would like to kick off by welcoming the audience and thank you to American Kidney fund for inviting me to share uh you know where research is so far with regards to apo1 mediated kidney disease here are my disclosure as Mike already alluded to I'm the pi on the ni sponsored Apollo study so next slide please okay so for today's talk I will give you an overview of apo1 Gene and it's rolled in develop of kidney disease thereafter we'll review the impact of people on ki
dney risk variants in different clinical settings so native kidney disease kidney transplants and then as it pertains to living donors and family members of those who have A1 mediated kidney disease at the end I will give you an overview about uh current research initiatives and lastly end with some action steps for the providers next slide please so as we all know right black Americans constitute only 133% of general population yet 35% of black Americans suffer from kidney disease and are on di
alysis the recent jwa study right which is looking at Gene association with diseases in 2010 found an association between apo1 genotypes and RIS risk of kidney disease seen in African-Americans next slide please and since 2010 if you see there have been several studies case control cohort studies population studies indicating that there is an association between apo1 kidney risk variants and development of kidney disease so let's talk a little bit about apo1 kidney risk variants next slide pleas
e so apo1 G is coded on chromosome number 22 okay and this Gene was mutated or change in that Gene occurred to protect human beings from trypanosomal infection so individuals in South Saharan Africa were succumbing to this infection that led to sleeping sickness and eventually death of that individual so mother nature is trying to protect us from this nasty infection and as a result individuals residing in subsaharan African region had a mutation in apo1 G and what you see here is if the individ
ual had one risk variant then they were able to fight off trypanosomal infection if individuals had two risk variants on the far right side you see they were also able to fight off oposal infection but unfortunately individuals who had two risk variants of apo1 Gene were also susceptible to kidney disease as you see the cartoon where the individual carrying two risk variants is now on dialysis so while apo1 Gene changes in apol1 gene occurred to protect individuals from sleeping sickness unfortu
nately individuals carrying two risk variants develop disease so down later on in the talk I refer to these individuals caring two risk alals as highrisk genotype because they are at high risk for developing kidney disease next slide please so what is the Prototype of this kidney disease right what is the Prototype of A1 mediated kidney disease so this is a microscopic picture of your kidney as you all know what is the role of the kidneys to clean your blood there are million nephrons a million
filters in your kidney that help to clean the blood okay and these circles that you see in the middle are those nephrons or filters right and the dark pink is not good stuff right it it indicates that the filters are damaged so originally we used to call kidney disease and black individuals with hypertension who had kidney disease who are landing upon dialysis and as it was mediated from hypertension therefore the name hypertensive NEOS sclerosis now it is known that it was not just hypertension
but it is the result of AP1 Gene variance that caused this prototype of disease where the individuals the filters are damaged as seen by this pink substance as a result they leak protein and they have premature kidney disease that that a lot of them need dialysis now AP1 Gene has been implicated to hasten the progression of fsgs focal segmental glal sclerosis that just indicates all this extra ping stuff in the nephrons or also is proposed to increase the uh hasten the development of HIV Associ
ated Ney shown in the extreme right hand side next slide please now let's look at the worldwide prevalence of A1 kidney risk variants so as I mentioned before apo1 Gene evolved to protect individuals living in subsaharan region from sleeping sickness right so the Green Dots here show where the APO one is absent and the dark magenta dots show where the individuals reside and they have care and these individuals carry highrisk variants so let's focus on where are these dark magenda dots and as you
see they are in West Africa but you also see them in Africans residing in North America Africans residing in Caribbean Africans residing in Brazil so what this map shows is the prevalence of apo1 risk variants is follows the migratory pattern of the individuals as they left subsaharan Africa and migrated to other parts of the world okay so just so the reason I wanted to highlight this is we just cannot look at a person's skin and assume that whether they have A1 or they don't while African-Amer
icans black individuals from America do carry this high-risk variants but such high-risk variants are also present in Black individuals from Brazil and as well as from Caribbeans so just just a point to make when you are taking care of patients in clinics next slide please so let's delve a little bit about this Gene right I told you why these the AP1 Gene had some changes was to protect individuals from infection so how we each one of us have two copies of apo1 Gene we get one from Mom and one f
rom Dad okay the variant are inherited in autosomal recessive pattern that means you need two copies of the change Gene to have kidney disease now apo1 risk variance Is An ancestry marker it does not have 100% penetrance that means not every individual carrying 2 A1 risk variance is going to develop kidney disease so if you look at this cartoon that I borrowed from from the Apollo study in the yellow box you see there are five individuals all five are carrying two apo1 risk variant but what you
see is four of them are not going to get kidney disease only one individual out of the five or are caring two risk variants is going to get kidney disease okay so unlike other diseases that have autosomal recessive pattern that means you need two copies of bad Gene to get kidney disease with regards to AAP oil one mediated kidney disease even if you have two copies of the mutated Gene not everybody will get kidney disease only one in five or 20% of folks carrying this highis varians will develop
kidney disease next slide please so what are the proposed theories for apo1 mediated kidney disease as I mentioned not every individual carrying these risk variants is going to get kidney disease there has to be a second hit the second hit can be a virus like HIV or Co infection a lot of individuals we had case reports of individuals black individuals who had worsening of their kidney function after covid infection developed actually collapsing fsgs and later on when we genotyped them we found
them to be carrying two apo1 risk variants and therefore viral infection like covid-19 was also thought to cause be responsible for apo1 Med kidney disease a role has been proposed by either environmental factor and even by genetic Factor recently there was a gene proposed that protects individual uh carrying two A1 risk variants from getting kidney disease so again why not all individuals caring this high-risk variance develop kidney disease is because you need a second hit for the individual c
aring two risk variants to manifest disease next slide please so how does apol1 how does carrying two apo1 risk variants in presence of a second hit cause kidney disease there are several theories proposed where it could be because of the mutation of AP1 gene causes increase in cation transport and as a result the cell does not causes injury to the cells in the kidneys particularly protocy it is thought to lead to mitochondrial dysfunction or caused to thought uh to lead to endoplasmic reticulum
stress so there are a lot of theories proposed but one of the most important theory that is thought to play an important role is thought due to that AP1 results in gain of function gain of channels that eventually cause premature death of ptoy pyes are the cells that surround those filters and prevent leakage of protein into the kidney space into the urinary space when these cells are damaged the protein leaks out from the capillaries from the filters and you see protein in the urine of the aff
ected individual next slide please so I wanted to share the effect of apol1 gene on the spectrum of kidney disease not all kidney disease diseases are affected by presence of apol1 apo1 seems to hasten the progress progression of certain kidney disease as shown on the left hand side showing the large effect right fsgs HIV HIV in Africa HIV in US hypertension related SRD seem to be influenced very very heavily by presence of apo1 genotype however on the extreme right where you see diseases where
apo1 has little or no effect IG aathy diabetic kidney disease it appears that apo1 does not have that strong of an influence in causing progression of kidney disease next slide please so with this background now I'm going to talk about what is the influence of apo1 uh high-risk variance or apo1 gen eye on progression of kidney disease in general population that means individuals with Native kidney disease right so next slide so the data comes from two major studies one first study is the ass stu
dy which is African-American study of kidney disease and hypertension so what this study did is it looked at progression of kidney disease or doubling of serum creatinin or need for dialysis in Black individuals followed from enroll to around 10 years post followup the genotype these individuals for the apo1 risk variants so you see on the left hand side let's first focus on the left hand uh panel of the figure figure a what this figure a shows is the percentage of patients free from doubling of
serum creatin or free from needing dialysis based on number of copies of apo1 risk variants so you see the two top Dash lines represent individuals carrying zero or one risk variant and the dark line at the bottom shows trajectory of people carrying two copies of AP1 risk variants or the higher RIS genotype what you see here is that individuals carrying two copies of AP L1 risk variants are much likely to progress to CKD much likely to double the serum creatin much likely to be on dialysis than
individuals carrying Z1 copies now apart from just carrying the copies whether these individuals have protein Uria or not also affects the outcome so let's move our attention to panel B on the right hand side which stratifies further stratifies individuals based on their proteinuria so on the very top line you see AP1 lowrisk group that means they carry zero or one risk variants and you're further stratifying them by protein UA so regardless of the risk variants individuals with no protein UA d
o far better than individuals with protein UA but within each of these subgroups whether with protein Uria or without protein Uria individuals carrying two high-risk carins or high-risk variants of a po1 genotype are more likely to progress to needing Di down the road next slide so next slide shows you the results of cek study the cek study included whites and blacks and the black participants were further genotype based on a one highrisk variants and lowrisk variants and again you see and here
this uh group looked at patients with diabetes on panel C and patients without diabetes on panel D what do you see is the white diabetics and the white non-diabetics had the best outcomes they were less likely to require dialysis however in the dark solid black line individuals black individuals carrying hris genotype were more likely to require dialysis at followup regardless of presence of diabetes so what I have shown you so far is in Black individuals with or without diabetes with or without
protein UA if they are carrying apol1 hris genotype then they are more likely to progress to kidney disease right so these individuals already have either hypertension or diabetes and some am some amount of kidney disease and if they have CKD then they're likely to progress so in Black individuals who have chronic kidney disease who have protein UA the apo1 high-risk genotype affects their or accelerates the kidney disease and they more likely to require dialysis down the road next slide please
and this slide shows that individuals what is the effect of standard blood pressure lowering treatment right so uh on panel C you're seeing individuals based on apo1 RIS genotype whether they were you know their blood pressure was controlled to standard goal of 140 by 90 or they had a more intensive blood pressure control more stricter blood control what we see here regardless of the blood control right the individuals carrying highis genotype showed in the red line did much poorly than individ
uals caring lowest genotype okay and as you all know ACE inhibitors ARB Inhibitors are the preferred choice of treatment for hypertension in Black individuals and despite being on a in bits right individuals carrying highrisk genotype seen in panel D with have inferior outcomes regardless of use of ace inhibitor so the current management of intensive blood pressure control of using a inhibitor does not seem to slow down the progression of kidney disease in individuals caring highis genotype next
slide so now we'll move from native kidney disease to kidney transplant next slide and I really think kidney transplant can nail some important issues why so kidney transplant gives us an opportunity to understand the pathophysiology of AP1 mediated kidney disease so apo1 protein is produced by the liver and locally within the kidney a A1 is produced by the vascular cells right so when an individual who has apol1 mediated kidney disease who's on dialysis that means his own kidneys are not worki
ng the apol and that individuals undergo kidney transplant then the apo1 that is present in that individual comes mainly from the liver right assuming that they got a kidney caring lowrisk genotype versus if an individual who is carrying low risis genotype gets a kidney from a high-risk donor then you know that the local apo1 production is responsible for the outcomes of the allograph right so in other words in this cartoon let's look at this cartoon here you have a donor kidney with lorus genot
ype and you which is transplanted into an individual who carries hrus genotype then here in this natural experiment you will be a able to figure out whether it is the circulating apol1 that is produced by the liver which is a p is affecting the outcome of the donor kidney which is not carrying apo1 highrisk variants right so I think kidney transplant allows us to better understand as to whether it is the circulating apol1 that affects the outcomes or whether it is the uh local apo1 that is produ
ced within the kidney causing adverse outcomes or is it he next slide please so let's first look at does the apol1 genotype of the diseased Kidney donor right does the apo1 genotype of the black donor who's caring you know who's donating the kidney right matter in allograph survival next slide please so the first the earliest report came out in 2011 right after the genovas study in 201 this was published by Wake Forest where Wake Forest did a single Center study of 136 kidney transplant recipien
ts okay they followed these recipients for at least five to six years as you see in the graph and the recipients was classified grouped based on the donor apo1 genotype and we are now only looking at outcomes of kidney transplant where the deceased donor was black was of black ancestry or African ancestry and all these donors were genotyped for apo1 risk variants and then they looked at the outcomes on the kidney transplant recipients so in blue line here you see the outcomes in the recipients w
ho got a kidney from a black donor that was not carrying uh two two copies of AP1 risk variants and in the red line you see outcomes and kidney transplant recipients that were carrying two copies of fap1 variants and what you see here is that mean followup of 26 months kidneys from donors with two copies of APO wus variants had much shorter graph survival the risk of graph loss was almost three-fold higher than individuals not receiving a kidney from donors not carrying hris genotype a third of
the gra will loss and when we look at the histology most of them had fsgs like pathology a pathology that I described before so while what I showed you this far here is that apo1 genotype of the donor matters and it causes premature graph loss but I also want to point out that not every kidney caring two risk variants failed right again there there has to be a second hit as a result only some failed prematurely maybe up to a third fa failed prematurely and others did just fine right you saw out
of the 22 eight failed prematurely 30% fail prematurely at two years but the remaining right I also want you to remember the point the remaining 14 did just fine next slide please so so then uh Dr Freedman at Hall expanded their studies to include over 110 transplant centers to include the number of participants to over thousand to see if AP1 risk variants in the diseased black diseased donor still mattered right so he confirmed his findings in a much larger study and here on the right hand side
you see the survival curves and the black line is the outcome in recipient from who received a kidney transplant from a black donor carrying zero or one kidney risk variants and in the blue line is from a donor black donor who carried highrisk variant or two G uh apo1 kidney risk variants and you see the recipient outcomes varied recipients getting a kidney from a black donor carrying two risk variants had a lower graph survival okay but again I want to point out 73% % of the graphs from highri
sk donors were still working so it's not an all or none phenomena while recipients getting a kidney from a black donor with two apo1 risk variants are at a higher risk for graph failure not every recipient loses the graph okay next slide please and as I mentioned before when they took a deeper dive as what caused the allograph failure it was the same FSG like Legion where you see a lot of pink within the filters and what caused what was the second hit in these patients next slide please was thou
ght to be due to rejection majority of the people who had fsgs like lesion had rejection preceding the graph loss and some of them also had viral infections as I showed was a possible set second hit in the native kidney disease too next slide now let's now look at whether the apo1 genotype of the kidney recipient matters right the person receiving the kidney does their genotype affect their kidney transplant outcomes next slide Dr fredman at Hall uh genotyped or 100 I think this was from yes the
y genotyped 119 kidney transplant recipients so now the recipients are being genotyped for ao1 risk variants and individuals carrying they were 58 out of the 119 roughly 50% carried two A1 risk variants shown in the dark black line and uh the remaining uh you know what is it 51 or 61 carried zero or one risk variance shown in the dash line and and as you see the two curves are superimposed on each other showing there is no difference in death censored elra survival based on the recipient a one s
tatus so until recently we thought only the deceased donor genotype matter but the recipient genotype did not matter next slide however this was challenged more recently in 2021 where uh uh Dr Menan from Yale University looked at two cohorts goar cohort and the seot cohort individuals getting you know with reip kidney transplant recipients carrying two AP1 risk variants is shown in the blue line and they genotyped both the donor and the recipient and showed that recipients caring two risk varian
ts of AP1 gene or highis genotype did have inferior outcome next slide please and there was another study uh from um Brams that also confirmed the findings that the recipient AP1 status did matter and did lead to poor outcomes after kidney transplant next slide please so and the in so in summary I think we have conflicting data whether the number of A1 kidney variants in the kidney transplant recipients affect the clinical outcomes after transplant and if they do some studies that proposed that
it is due to rejection or perhaps due to viral infection next slide please so now uh you know we all know that uh transplant from a living donor is far far better than getting a kidney from a diseased donor Which is far far better than remaining on dialysis right and uh generally you know it's your family members right or who want to donate a kidney to you who want to help you so now we are talking about you know among black individuals it's likely that their family members want to donate and it
is possible that the family members share that same genetic factors which is AP1 genotype and whether the apol1 genotype matters in living donor outcomes so you have an individual a young person who wants to donate to his dad and has apo1 genotype should you allow that young individual to donate yes no so we'll try to tackle to answer that question in the next few slides next slide please so first let's take a step back okay let's look at the risk of endstage kidney disease in living donors as
compared to healthy non- donors right we all know that the living donors undergo extensive testing before they're allowed to donate right you have a recipient a you know candidate who's already sick who's on dialysis right I cannot change the outcome for that patient but I don't want somebody otherwise healthy to donate and then risk their lives right as a result living donors go through extensive testing so it is not fair to compare the outcomes of an individual who's gone through extensive tes
ting and allowed to donate to just anybody right so as a result in this study Dr mzali at all he looked at outcomes you know likelihood of developing endstage kidney disease in living donors shown in the blue line and compared it to healthy non-donors that means these were individuals who did not donate but were screened for Good Health at Baseline right and the and their risk of end stage kidney disease or their risk of needing dialysis down the road is shown in the dark black lines right so yo
u're comparing the risk of end stage kidney disease or risk of needing dialysis down the road in living donors in Blue Line as compared to healthy non- donors in the black line and you're now doing this comparison across races so you have black individuals on the extreme left Hispanics in the middle and white individuals on the extreme right what you see is regardless of the race live kidney donors are more likely to develop endstage kidney disease or require dialysis than healthy non-donors rig
ht and the cumulative risk of endstage kidney disease is highest in Black like it's the tallest blue line is in the black cohort and the difference of development of pstage kidney disease between non- donors and living donors that is shown in that red line the Red Bracket is highest in the black living donors so not only the black living donors have a highest cumulative risk of developing in stage kidney disease but the absolute risk increase perhaps due to donation is highest in the blacks I al
so want to tell the audience that this risk is far far lower what you see it it's 70 per 10,000 donors for the black is far lower than what is seen in unscreened gender population for black individuals which is in the estimates of 300 per 10,000 right so while I'm showing you that the black donors have a slight increase the risk as compared to the general population is very very low okay next slide please so we want to go back and look at who are these black donors who are getting kidney disease
so this SL shows you comparison of you know outcomes between biologically related donors and biologically unrelated donors right so it's the recipient donor relationship that matters that affects the risk of post donation and development of endstage kidney disease which makes sense right the donors and the intended recipients are family members they share the same genetic and the familial and the environmental factors and there is a a result the donors mightly might be at a fer uh risk of devel
oping and stage kidney disease so we want to see if we can further you know uh rest stratify our donors who are biologically related to see if we can use some testing such as AP1 to further stratify the risk of kidney disease next slide please so myself and Dr ggins from Henry 4 we went and genotyped 136 black living donors who had donated at two centers in Detroit at harpa hospital and at Henry Ford and they had donated roughly 10 15 years ago we genotyped them so 19 donors carried two risk var
iants were labeled as highrisk genotype and 117 carried zero or one risk variants and were labeled as low RIS genotype so then we went back and looked at the outcomes in these two groups of donors next slide please and we published our results in uh Journal of American society of nephology so let's look at the figure on the left okay figure one so first we compared the pre and the post donation kidney function based on apo1 genotype so the first column on the left hand side where you see the red
graphs shows you outcomes in Black living donors who had donated and carried lowest genotype and the black figure on just on the right hand side shows you pre-donation kidney function and post donation kidney function among donors carrying highrisk genotype what you see here is individuals or living donors carrying highest genotype had lower kidney function prior to donation but that was acceptable and as a result also had a lower post donation kidney function at followup and that difference wa
s statistically significant as you see might be less than 0.05 two donors in the hris genotype group so we had 19 donors in the hris genotype group out of which two donors went to develop and Stage kidy disease now let's focus on the right hand side figure two as I mentioned previously donors carrying highis genotype have a lower GFR still normal within normal range had a lower GFR prior to donation had a low much lower GFR than the low risk Group after donation the question is do they have lowe
r GFR after donation because they started low or did they have a faster decline in the kidney function after donation right so to answer this question we compared the trajectory of GFR between the lowest group and the highest group so figure two shows trajectory of GFR after donation in the lowest group in the red line and the highest group in the right line right in the black line what you see is individuals not all some individuals in the hris genotype had a much faster decline in the kidney f
unction after donation than as compared to donors in the low risk group okay and that difference was statistic Ally significant again as I said we had a closer look at all the individuals in the hris genotype and not all 17 individuals who did not require dialysis had a nose dive in their kidney function some of them had stable kidney function years together so again showing that there has to be a second hit for some individuals who have donated who are caring hris genotype have an accelerated d
ecline in the kidney function after donation next slide so the question comes say does donation affect the outcome between AP1 Associated kidney disease or no in other words if an individual who has AP1 hris genotype if they were to donate does donation alter of the association between AP1 and kidney disease does it hasten the progression to answer that question we compared the GFR trajectory between non- donors shown in the black line in the two pictures and compared it to donors okay in the re
d line the non- donors were matched to donors based on age gender duration of followup family history of kidney disease and AP1 status so you see on the left hand side you have comparison in the lowest group in the right hand side you have comparison in the highest group what you see is the two curves are parallel suggesting that donation does not affect the outcome of apo1 associated kidney disease next slide please so we concluded apo1 hris genotype in Black living kidney tonor is associated w
ith lower pre and post donation kidney function and some donors may experience a faster decline in kidney function after donation not all donors with hris genotype had an accelerated decline in the kidney function while hus genotype you know in that last figure that I showed did not modify the association between donation and rate of decline in kidney function individuals with highrisk genotype who have lower GFR after kidney donation May experience faster decline in the kidney function and may
reach ESRD sooner so we need to perhaps we need to perhaps do AP1 testing and select donors and you know based on the risk factors perhaps recommend them not to donate a kidney donate their kidney sorry next slide please so what do we tell the healthy relatives of patients who are caring apo1 gene mutation what do we tell a person who's in your office who wants to donate to the loved one about A1 when they're otherwise totally healthy or what do we tell to our patient with CKD in the clinic who
wants to know what should they tell their loved ones at home whether they should whether their relatives should undergo genetic testing and how much should they worry about their future risk of kidney disease right so we're talking about healthy relatives of patients getting AP1 G mutation next slide please so what do we know what have we learned from the living donors right what are the risk factors of developing endstage kidney disease uh post donation right and this study was done by uh mzali
at all and he looked at risk of endstage kidney disease in donors stratified by Race So Dash lines represent black donors solid line represents non-black donors or white donors and the different colors represent the age of the donor right so the green lines let's just focus so uh the green line represents donors who are more than 45 years of age you see the dash lines and the solid lines are superimposed so young black donors right because if you see overall the dash donor the dash lines the ri
sk of endstage kidney disease is high highest that means in Black donors the risk of f stage kidney disease is highest and it's highest in the ones that are you know pink or blue and they are donors who are age 45 or under for donors who are age 45 and over shown in the green line there is no difference by Race So this slide suggest that perhaps the risk of pstage kidney disease is higher in the younger people who who have not had chance to manifest the disease right so we should be more careful
when we are selecting uh a young donor we are accepting a young donor uh to donate a kidney to the loved ones or to their family members next slide and this finding was further strengthened by Dr L's paper that was published in annals of surgery in 2018 in 2018 where they he she looked at all young individuals age 18 to 25 and who were healthy at Baseline had good kidney function did not have diabetes did not have hypertension and looked at the risk of kidney disease that means GFR less than 60
at 25 years of followup Hazard ratio gives you the risk of kidney disease right and let's focus at the very bottom you see apo1 risk group references European Americans so black young black individuals have higher risk of developing chronic kidney disease GFR less than 60 regardless of number of risk A1 risk variants they carry but the risk is highest in young black individuals carrying two risk variants shown in that last line at the bottom where the risk is almost fivefold higher right so aga
in this study exemplifies that young individuals who are good with good good Baseline Health are at higher risk for developing kidney disease if they are carrying two risk variants next slide please so this is a study that I recently did and is accepted in kidney medicine and will be published soon so to answer the same very question I was like thinking what about individuals who are 45 years old or about like so I looked at the Eric C which and select this Eric cohort has uh individuals has enr
olled individuals age 45 to 54 so in that middle age group out of that Eric cohort I limited my analysis to individuals who would be selected as living donors or would be accepted as living donors that means they had good kidney function at Baseline kidney function was more than 80 ml they did not have hypertension they did not have diabetes they were not obese they did not have any cancer and then looked at risk of pen stage kidney disease that follow up right so I compared the risk of pen stag
e kidney disease between the whites shown in the green line uh individuals with low risk group in the red line and those in the high risk group in the blue line what do you see it's all superimposed so the race doesn't matter and the genotype doesn't matter in older cohort because I believe that that older individual has had chance to manifest kidney disease if they were going to manifest one right so I think the apol1 genotype in the living donor particularly in the older cohort does not matter
next slide please so what about treatment right so I have shown you so far the Theo one genotype matters in individuals with kidney disease individuals that have already developed kidney disease particularly those with protein Uric kidney disease AP1 genotype does affect outcomes it is possible that the apo1 genotype of the diseased donor may affect transplant outcomes it is also possible that the apo1 genotype of the recipient may affect outcomes how can we treat this next slide please so ther
e are s so to understand treatment let's go back and look at H how does a gene cause effect right so you have apo1 Gene which is a DNA which is present on your DNA right which is present within the nucleus of the cell that DNA has to be converted to an mRNA so that is called the apo1 transcript so that codes that sends the coding outside the cell and outside sorry the nucleus for the cell to create a protein which to generate your AP1 protein right so the DNA has to be then converted into mRNA c
arry the cord to make the protein right so the current therapies are targeting either with crisper to alter the DNA or to create an anti-sense mRNA targeted therapy or currently there is a therapy that inhibits the action of apol1 protein so it's really exciting time when there are a lot of different treatment options targeting different time points that at the end ultimately results in formation of A1 Pro next slide please so uh this was uh a paper published in New England Journal of Medicine j
ust a year ago where they looked at in axip Palin uh for treatment of protein Uric disease this is a molecule that inhibits apol1 protein which is thought to create those pores in the protocy and cause damage to the protoy so in aipan was given to 13 patients as you see in in the box there uh who had proteinuric kidney disease had proteinuria anywhere from 3.3 and a 12 gr to 1.8 grams and after treatment with this drug what you see at week 13 they all had a reduction in protein UA at least by 47
% so this is really encouraging and uh there are next slide please there are clinical trials underway pH 2 phase three looking at the effectiveness of the small molecule in treatment of a one mediated kidney disease to see if we can halt the progression of this kidney disease this is so exciting to see a gene getting discovered just within the last 15 years and now you're to witness uh you know treatment already uh based on the alteration in the gene next slide please so where do we go from here
right we have some unanswered question at least in Native kidney disease world we know that individuals carrying hris genotype particularly if they have protein UA more likely to progress we discussed uh new treatment options that might be soon available to everyone for treatment there are studies underway to assess the efficacy and uh make sure that these treatments are safe uh unanswered question mainly remains in the realm of transplant and we believe that in trans uh that these transplant t
rials will also help us understand the second hit what is that second hit that causes some people to fail the kidney prematurely and other individuals who are carrying this high-risk variance to just fine right so next slide please so we have this Multi Center Apollo study uh currently underway that uh aims to study transplant outcomes of all kidney transplant all kidney transplants that have been perform uh using kidneys from black diseased donors so this study is again as I said Nationwide in
uh with 260 transplant programs are participating across the country 58 opos and to dat it have enrolled several thousands of uh deceased donor kidney transplant Pairs and have also enrolled several living donor pairs to answer this question as to whether the L1 genotype of the diseased donor affects recipient outcomes they're genotyping the recipients to see if the uh genotype AP1 genotype of the recipient affects the outcomes they're also genotyping the living donor to see if the transplant ou
tcomes based on the living donor genotype are also different uh next slide please and there are studies under way to see if the aort living donors also right to see if individuals or living donors carrying apo1 genotype have a more inferior outcomes with regards to the kidney function as compared to individuals not carrying such Iris genotype there are several other studies about identifying and exploring solutions to ethical challenges of apal one testing particularly in transplant setting wher
e such little is known currently and how do we uh inte a culturally competent A1 genetic testing program into living donor evaluation so the the I think uh a lot of studies great studies are underway and a lot more to come in the coming years next slide please so a little bit because so much is unknown I think it is very important to be transparent and to coun patients both before and after April one testing uh transplant counseling can be performed by a general nephologist transplant nephologis
t or a member of the transplant team or a genetic counselor it should definitely be offered before genetic counseling and again after obtaining results uh at least in the transplant World definitely acknowledge that there is lack of robust data and that not every individual again I really want to hone this down not every individual caring T risk variance is going to get kidney disease we need a second hit for the kidney disease to manifest the good news is there are newer treatment options to tr
eat individuals uh who are who have kidney disease due to ao1 mediated uh due to ao1 hyrus genotype the there are several work groups talking about how do you what how do you counsel what element should you uh cover during these counseling and these work groups support shed decision making between the transplant team and the donor at least for now and lastly the team wants to say isolated finding of two a PO one risk variants should not be sufficient to rule out an otherwise healthy candidate ex
cept like when you have a very young donor you know who's 20 or 30 years old has strong family history of kidney disease then perhaps you want to seek an alternative donor next slide please so I want to these are the main key takeaway from this talk and I've classified based on ative kidney disease transplant recipient living donors and what do we tell the healthy family members of uh you know uh individuals who have chronic kidney disease and have A1 Gene variance I think everybody should be in
formed about a pearl one genene across the board whether it is patient with Native kidney disease whether it's a recipient whether it's a living donor with whether it's the family member but testing for now should be just reserved for few if you have a patient with kidney disease proteinuric kidney disease with African ancestry then you should check them for po1 mutation and as I said there are treatment options under way which you could be off which you could offer to this individual in clinic
and selected living donors you know young those with some risk factors you know should be screened for A1 to better restoratif for their future risk of kidney disease okay and again I want to say not every individual caring A1 Gene will develop kidney disease and uh next slide please and I think that's the end of my talk Mike thank you very much Dr DOI I appreciate it and we're gonna jump right into Dr Patel to talk a little bit about the work that the Kidney Health Initiative is doing in this a
rea great thanks I just want to thank Mike jitra and everyone at akf for being part of this kidney action week it's uh very exciting and thanks to Dr DOI for a great overview of ail one and why it's so important that we need to discuss this sort of as a kidney Community next slide maybe to share a little bit about what Ki is doing I'll start with our mission statement which is to catalyze Innovation and development of safe and effective patient- centered therapies for people living with kidney d
isease um and really aligned with this Mission you see our 2024 goals are listed and advancing sort of collective efforts for a po1 Associated kidney disease is really important part of this next slide so how does ki do this um it really is um you know I invite you to look more at our website but in brief um it's a pre-competitive organization that seeks to raise the tide for all boats of individuals and organizations trying to develop new therapies for people with living with kidney disease we'
re fiercely patient centered community-led and Community developed and so you know as a public private partnership between the American sty methology and the FDA also work very closely with several key centers within the FDA focused on drugs biologics and devices next slide you heard a lot about um some of Dr fredman's work um I'm gonna skip this next um case presentation it's wonderful um i' recommend everybody go check it out um next slide it goes through the Journey of a lot of patients with
A1 who have strong family histories of developing kidney failure and um often initially show up with hypertension and wonder about um you know uh their their Journey um and so uh April one has really been a phenomenal Discovery in the kidney field and now we're on the verge of having therapies available so it's important to figure out how we're going to address this uh in terms of improving awareness detection and possible treatment next slide so a few years ago a bunch of folks got together and
try to examine the current sort of State of Affairs of um nephology views Community views and other key stakeholders and really found that there's pretty good awareness among kidney providers but not among a lot of other key stakeholders to sort of help make this something that's actionable particularly among the patient community and so low levels of awareness not only limit um the ability to detect but then have the ability to potentially be part of um studies that can help advance therapies
but then eventually when they're available even receive those therapies so this is something Ki wanted to address next slide really along the axis of awareness uh genetic testing and potentially study participation so a lot of different things to sort out um and with that next slide in 2022 we initiated a road map to establish sort of um ways to um increase awareness of ao1 increase access and awareness to genetic testing and the associated counseling to make that actionable and then also um fin
ding ways to empower patients to make informed decisions about clinical trial participation um this was a multi-stakeholder event um took a year to develop generated over 40 action items and they're meant to really prompt action among the community not any one individual stakeholder and it's nice to see akf picking up that that and and working with the community to sort of have this kidney action week and a number of other efforts focusing on a april1 mediate kidney disease next slide there's a
number of audiences that are relevant to this so I've invite everybody to go check out this road map online but maybe in the interest of time we'll we'll jump to the the a few slides forward to sort of why this road map is important um in the uh road map you'll see all of the different components the main challenges potential Solutions um but what I want to highlight is maybe go slide forward four slides now we're running over so I'm just trying to catch up here two three more or four more I thi
nk one of the the takeaways from this um road map is that it's really a call to action for the entire Community um and it's exciting to see this kidney action um related um effort um it's going to take Collective action and together we really think we can increase awareness of people of African ancestry increase AAL genetic testing and Empower those at risk to make informed decisions about participating in clinical studies whether or not that's a trial or just trying to learn more about the dise
ase process and risk factors like you heard about and um just two more slides forward I think will get us just kind of a summary slide that we can end on um really I think with the verge of these therapies being available it's important um to really um start to address this now so that they can have an impact in the community and um help reverse some of the U outcomes that you heard about by Dr jhi but also um a lot of other descriptions of how you know just April one might be responsible for al
most 70% of the excess burden you see among people with kidney failure who are of African ancestry so with that um I'll end and again thank the akf for the opportunity to share a little bit about what we're doing and look forward to working with you well thank you very much upall I really appreciate it um and we really appreciate the work that keny Health Initiative is doing I'm glad to be part of all the all the efforts there uh if I could just go through and talk a little bit about some of the
the resources that the American Kidney fund has uh regarding uh apo1 mediated kidney disease I think it's good for everyone to to be aware of what we've got next slide please so we um have done a lot in this area obviously this is one of many different things that we've been trying to do to raise awareness about am KD day uh am KD and one of those ways is through our amk awareness day which is coming up on April the 30th and I'm sure my team is probably already dropping into the chat way in whi
ch you can save the date and find out how you can participate in that um there are lots of other ways that your organization can help us do that um you know you either partner with us as pushing out for social media we have some states that we're looking for proclamations for for am KD awareness day and we have opportunity is proud to that on our website as well next slide please and then you know we also have uh resources for you as a clinician but also for your patients um Dr Doshi uh did anot
her professional webinar for us uh last year and we had uh a great overview fact sheet that is available on that site uh as well we've got patient testimonials you can hear from patients themselves with some video stories that we have on that site we have information on clinical trials that are happening now um not just on trials in general but you know akf has partnered with a company called antidote who uh presented it last year's kidney action week to really have a a a way for patients to to
search for clinical trials in ways that is Meaningful to them uh and make sense so you can find that on the akf website as well and then you know one of the things that we've uh been a great resource to healthc Care Professionals is providing patient resources to uh professionals to give to their patients um you know you all know how difficult it is when you you're you're trying to get the most key information to patients as quickly as possible in the amount of time that you have and we're here
to do that as a trusted resource so please know that you have those available to you lots of Education content on that we've animated explainer videos that you're welcome to use uh and guides for working with the genetic counselor which is a huge part of this you heard Dr weer talk about that in this morning's uh first presentation uh but the importance of having that genetic counselor piece attached to this as well next slide and I mentioned am KD Awareness Day on April the 30th again this is a
nationwide campaign to raise awareness about am KD uh we have lots of Partners already joining on on to help us with this you know again as I mentioned we are looking for those to help uh submit a proclamation for your state I think we're at like 20 or 24 States the last I heard so we've still got plenty of room uh and need your help to do that our uh government Affairs team can walk you through it but there's also a step-by-step guide on our website um and you know share resources with your pa
tients leading up to that day as well we want to do all we can as Dr Doshi said to at least raise awareness about this that is really the idea behind our work is to get this in front of as many patients as possible and whether or not they decide to get genetic testing will be a decision with their their their physician and their family and their genetic counselor um but we at least want to get the information out there next slide so again just some key takeaways um you know make sure you're educ
ating patients about am KD you know for in those cases where Dr Doshi talked about you know since living donors if you already have an active uh kidney disease at a young age and you're not reallying what's happening talk to your patients about genetic testing get them in touch with the genetic counselor uh to figure out you know what is best for patients make sure they understand any risk related to to uh life insurance disability insurance those kinds of things um and again just making sure th
at that you are talking to patients about all their their options related to the kidney disease and get them identified as early as possible and with that I think we have time for maybe just a couple of questions I know we're over just a little bit um but if Dr Doshi if you're willing I could just maybe send a couple questions I'll just ask my team if they've gotten any from sure the audience but um in the meantime um Dr DOI how do you see this uh relating to you know the kidney Precision medici
ne project you know what's the what's the crossover there with am KD and how that those things might relate and move forward I think has more and more Therapies come along you know genotype will be part of the panel when you see a patient with kidney disease right particularly with African ancestry and uh I think uh and then not just de1 as I mentioned recently there was a gene published that protected individuals with carrying apol1 from getting kidney disease so we might find those second hits
either other genes that protect individuals or genes that amplify the injury uh due to a well one uh highrisk variant so I think more to come and can you explain we had a question from someone in the audience uh about uh when you have a single apo1 risk V variant uh the question being does that mean one came from the mother and not the father or vice versa can you explain a little bit about kind of how that's passed down familiar yes so when you have one it either came from one other the parent
and because it's a recessive gene you need both copies so you need one want from each parent for you to be at high risk for A1 mediat kidney disease great okay let's see if we got any other questions in I think that may be it well Dr Doshi I want to thank you very much uh for your time today uh for everything that you've done uh and continue to do for the Apollo project and and for us at akf I really appreciate it uh and that is actually going to conclude our session for today um tomorrow we ha
ve our last day of kidney action week I can't believe it's here uh already um but we'll start uh tomorrow at 10: am eastern time um on our final day of kidney action week talking about Innovation so we're have eight different quick presentations uh about all the uh great things that are happening uh in the field of of Innovations in neology including some information on xenot transplantation you may have seen uh the news today that there was um the first uh Pig kidney transplanted into a patient
today we actually have one of the pioneers of of that work speaking tomorrow so please join us tomorrow uh as we close you will see a survey come up uh in uh the U in the chat box please fill it out let us know how we're doing um and we will see you all tomorrow thanks again to our speakers thanks to all of [Music] you [Music] [Music] [Music] [Applause] [Music] [Music] all [Music] [Applause] [Music] yeah
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