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Frank Maddux: Improving access to kidney transplantation on a worldwide basis is a vital next step for global healthcare. In this episode of dialogues, I talk with transplant expert, Dr. Ben Hippen, Clinical Professor of Medicine at the University of North Carolina at Chapel Hill, and a general and transplant nephrologist. As Senior Vice President of Transplant Medicine for Fresenius Medical Care, Dr. Hippen discusses the challenge and opportunities facing global transplant and why transplantation remains a vital therapy option for people living with advanced kidney disease.

Ben, thanks for being here.

Ben Hippen: Thank you for having me, Frank.

Frank Maddux: Our ambitions at Fresenius Medical Care have been to play a productive and credible role in the transplant world and expanding access to kidney transplantation. Can you give me your perspective on what the state of global transplant care looks like today?

Ben Hippen: Well, I think the first thing to say is that it’s struggling to recover from the Covid-19 crisis. In the United States, after a brief dip in the number of total organs procured for transplantation, the number of organs procured really bounced back substantially, and we’re at the highest rate of organ procurement and deceased donor transplantation we’ve ever been. Living donation had a similar trend in the United States, but around the world, that continues to be a challenge. In a recent study, they compared the US and France. The French really had a lot of difficulty rebounding during the Covid-19 crisis in the number of organs procured, and other countries had similar trends as well. The specifics of those trends are still a matter under study, but I think one of the things that we’ve learned from the Covid-19 crisis is the extent to which the organ procurement regime in the United States is and remains robust and offers opportunities for the rest of the world to learn how to cope with organ procurement under the duress of a pandemic.

Frank Maddux: Other than the procurement issues, did Covid-19 present transplant patients with any new or special issues, given their immunosuppression?

Ben Hippen: Absolutely. One that remains a conspicuous issue is responsiveness to vaccines. A recent study from Johns Hopkins reported that fewer than 10% of patients who are on an antimetabolite, that is a medication like mycophenolate mofetil or azathioprine, had a full response to the mRNA vaccine and only 50% had a partial response. There are a number of questions that emerge from that, such as whether or not - not having had a vaccine is the same as having had a vaccine and not manifesting an immune response, and whether or not booster shots after the usual two-shot regimen will improve IgG immunity in patients remaining immunosuppressed or not.

Frank Maddux: So we know in our kidney failure patients in general, they’re antibody immunity is limited to start with. But they seem to have some conferred benefit from other T-cell-related immunity or memory and so forth. Do transplant patients have a similar improvement with vaccination, independent of how many neutralizing, the level of neutralizing antibodies, they have produced?

Ben Hippen: We hope so, but I think that’s a question that’s still under consideration in the form of research. Unfortunately, I think we may discover the answer to this when we see another wave, possibly in the fall or winter, as people start to move back inside. We’ll really get a sense of whether or not there is, as it were, conspicuous or hidden immunity by virtue of mRNA vaccination. Of course, it’s not entirely apples to apples because, by that time certainly in the United States, well north of 50% of the adult population will have received at least one vaccine, and hopefully more. So it won’t be quite the same as it was in March of 2020, but hopefully the combination of some sort of surreptitious immunity from mRNA vaccination in addition to a large swatch of the immunocompetent population being vaccinated, will reduce the risk to those patients.

Frank Maddux: Let’s switch gears for a minute and talk a little bit about this changing reimbursement environment.  We know there’s been a lot of renal-related, kidney-related reimbursement changes and value-based care interests in the United States. Can you talk about the impact that either is having or may have on access to transplantation?

Ben Hippen: Yes, so there’s two types of value-based care initiatives that have been initiated by Medicare. The first is called the ESRD treatment choices model. It’s also known as the mandatory model, where selected hospital referral regions, or HRRs, have been selected to be enrolled in the ESRD treatment choices model and both nephrologists and dialysis providers will either be bonused or penalized financially based on the modality performance score, a component of which is something they call the transplant rate, which is a combination of the percent of patients who are on the waiting list, who are Medicare-eligible, as well as the number of patients who receive a living donor kidney transplant. Interestingly, the deceased donor kidney transplant rate was not included in that metric because of a recent change to the organ allocation system, and it was thought that local markets would not have as much control about who received a deceased donor kidney transplant, but might have more control over who received a living donor kidney transplant. There are also a series of voluntary models that also incentivize access to transplantation.

Frank Maddux: So let’s talk for a minute about the allocation system and, I think it would be useful for you to describe just in general what the allocation system is, how it was, and how it’s changed recently.

Ben Hippen: Certainly. So the kidney allocation system in particular has gone through a number of changes in the last decade. Prior to December of 2014, kidney allocation was largely based on waiting time by blood group. So patients who had blood type A were put on a waiting list and they would move up the waiting list based on their accumulated waiting time that started when they were actually evaluated and put on the waiting list. Starting in December of 2014 there were two changes to the allocation system. The first is that waiting time for candidates was backdated to their start date of ESKD. So even if a patient had been dialysis-dependent for three years prior to referral, once they were actually referred, evaluated, and waitlisted, their waiting time would be backdated all the way back three years or more, whenever they started dialysis. The other big change was the introduction of something called the KDPI, or the kidney donor profile index. This was a scoring system that was applied to deceased donor kidneys to give transplant professionals a sense of what the prognosis after transplantation of that particular kidney would be. So, in general, a kidney from a young, healthy donor had a low kidney donor profile index, which suggested a longer allograft half-life and a higher KDPI generally from an older, sicker donor with a shorter prognosis. And kidneys from the top 20% of the donor pool would be preferentially allocated to patients who had the highest estimated posttransplant survival, or ETPS score. The general idea is that kidneys that seem to confer the best survival would be given priority due to younger, healthier patients who would be likely to live long enough to enjoy all of that allograft half-life. And that was the organ allocation system for the next six years. Just very recently, in March of this year, another innovation was introduced to the kidney allocation system focusing on what were perceived to be geographic inequities in access to kidneys. A similar process had already been implemented for liver transplant allocation. In the case of kidney allocation, this expanded the geographic catchment from what were then called donor service areas, sort of states within states if you like, where organs were initially offered locally within a given donor service area, and then regionally and, ultimately, nationally, to a larger geographic swath of, in this case, 250 nautical miles from the donor hospital. So, for example, a kidney that was procured in Charlotte could be offered to patients who were lexically ordered on a waiting list as far as Tennessee to the west and as far south as Atlanta. So the effect of this has been to provide additional priority to candidates who had significant amounts of waiting time on the waiting list outside of the narrower geographic catchment of the donor service area, which also has the effect, at least in the short term, of increasing the median time to receiving an organ offer.

Frank Maddux: There are surely some unintended consequences of this particular change with the geography. How do you think that’s going to play in more rural areas, where there aren’t as many large transplant centers?

Ben Hippen: I think it will really come down to where patients who are in rural locales are waitlisted, whether they are waitlisted in a center that has an aggressive approach to organ acceptance behavior, whether they’re willing to take more risks on organs that are offered to them, and whether or not those patients are going to be able to get back and forth to those larger transplant centers typically in more population-dense areas. The other challenge that is already emerging in the new allocation system is a flood of organ offers to transplant centers that they otherwise would not have been offered before to patients who are now at the top of the individual center’s waiting list, largely based on extended waiting time. What that means is that transplant professionals, surgeons, nephrologists, coordinators are now fielding a multiple of higher number of organ offers than they were in the past, which results in a lot of time being taken to try and think through organ offers from centers that may be, or donor hospitals, that may be several states away, how much time it’s going to take to get the organ from the donor hospital to the recipient’s center, how much cold ischemia time that may amount to, and adding all of that into patients who have been on dialysis for a longer period of time and consequently have a lot of the vicissitudes and comorbidities of a long dialysis tenure. All of that is going to translate, I think, into more complications posttransplant, more episodes of delayed graft function, longer hospital stays, and increased cost.

Frank Maddux: You and I have looked at this together, but we’ve seen some recent interest from some of the pharma community in finding some potential compounds that might actually help with resolving increased cold ischemic time and delayed graft function. Do you think that is realistic? Do you think some of those things are actually looking promising at this point?

Ben Hippen: I do. You know, cold perfusion has been around for two decades now and it has allowed kidneys in particular to endure cold ischemia time sometimes north of 24 hours. The prevalence of cold perfusion is spotty, in part because it is more costly and more cumbersome. But I think as organs being offered are increasingly going to be coming from outside of the traditional donor service area and so will naturally have more cold ischemia time, things like cold perfusion pumping are going to be more important in terms of increasing the efficiency and speed of acceptance of organ offers, as well as reducing the prevalence of delayed graft function. Whether that actually translates into improved allograft survival or reduced cost, I think remains to be seen. But I do think that as this is the new normal, at least in the United States, there is going to be increased attention to novel technologies that will allow kidneys to endure more cold ischemia time.

Frank Maddux:  In your comment about allocation a minute ago, you mentioned the concept of equity a little bit. When we think about a recent study in JASN around some of the social, economic, and demographic factors that provide either access to transplant or not access to transplant, to what degree do you think we’ve got to deal with some of the health equity issues related to access to transplantation, acceptability of transplantation in some of the unusual demographics of both recipients wanting to get a transplant, but also organ donation in various populations?

Ben Hippen: I think addressing issues of equity is an imperative, and I’m happy to report that it is now front and center with the professional transplant societies, as well as with the United Network for Organ Sharing. While I listed a number of disadvantages of the new so-called geographic allocation system, it is really designed, geared, to address inequities in access to transplantation. I think it’s perhaps easy to the point of banal of saying that this is complicated. But it truly is. Transplant centers right now are laboring under a number of different pressures that make it difficult to provide equitable access to transplantation. On the one hand, there are powerful incentives to increase rates of referral to transplant centers, though centers themselves are variably equipped to handle all of those referrals and efficiently get those patients through the multidisciplinary evaluation process, which has multiple steps, all the way to waitlisting. Transplant centers are also disincentivized from having too many people on their waiting list because it’s very difficult to track them once they’re actually waitlisted, and they are penalized if patients are removed from the waiting list because they deteriorate or die. That is, removed for a reason other than successfully receiving a transplant. Furthermore, with these additional attentions that are required on the part of transplant centers to handle these additional organ offers that are coming their way as a result of the switch to the geographic emphasis on allocation, it means that it makes it a lot harder for them to process this deluge of new referrals and make sure that patients don’t fall off the path in the course of the evaluation. But all of this is sort of stacked on top of the challenges that were identified in this recent study that suggests that there has not been much change in the inequity in access to transplantation in the United States in the last 20 years, which is really built on a number of social determinants of health, including food insecurity, transportation insecurity, and reliable access to medications. So, yes, I think that insofar as our ambition is to become the provider of choice for patients throughout their entire continuum of their experience of kidney disease, from advanced CKD to ESKD to transplant and back again, we are going to have to figure out a way in which we can make a dent in these really daunting but crucial social problems that are maintaining these inequities in access to transplant.

Frank Maddux: So your responsibilities extend beyond the United States and we’ve been talking mostly about what has been happening in the United States. But let’s talk about some of the countries where transplant is not sort of a standard part of therapy, but it’s more of an emerging therapy. How do you think countries like India and others should begin to approach a growth in transplant, a growth in access to transplant? What are some of the things that we might be able to do to help with that?

Ben Hippen: There is actually, and I’m indebted to an excellent paper that was just published in the American Journal of Transplantation by Sunil Shroff and John Gill about the policy challenges of kidney and liver transplantation in India. In India, as is the case in many countries, living donor kidney transplantation is well-established and robust. Since India passed a Transplantation of Human Organs Act back in 1994, living donor kidney transplantation has really taken off. The challenge has been an equivalent improvement in rates of deceased donor kidney transplantation. The challenge there really is not for lack of potential donors. Unfortunately, the public health challenge of high rates of automobile and motorcycle accidents in India has not really translated into a robust organ procurement regime. Many organ transplant programs in India are located in private hospitals, which is where a lot of the personnel and expertise also reside, whereas many of the patients who could be potential deceased donors end up at local hospitals that don’t have the same either infrastructure or human expertise to proceed with deceased donor organ procurement. There are a handful of exceptions there, but that’s the main challenge. The other challenge, too, is financial, making sure that the some 200,000 Indian citizens who end up dying for lack of one type of renal replacement therapy or another are not left out while those who are of means and are able to afford access to kidney transplantation manage to do so. Approximately 15% to 20% of the living donor kidney donor transplantation in India is performed on non-Indian citizens who come to India specifically for the procedure and often bring a living donor candidate with them. Dr. Shroff and Dr. Gill have some very interesting ideas about how some cost shifting could transpire to not only ensure improved access to transplantation for those who currently don’t have it, but also begin to build the necessary infrastructure and human expertise for a more robust organ procurement process, which is something that I think, for example, the United States could provide support and expertise for because despite the many challenges with kidney transplantation in the United States with regard to inequities, this is one area where the United States definitely does shine.

Frank Maddux: The European Kidney Health Alliance recently had a roadmap on transplant-related activities to try to improve access to care, organ procurement, and so forth. Just briefly describe a little bit about your perspective on what the state of play is in Europe.

Ben Hippen: Europe has a robust social safety net. So for patients who make it to transplant, the ability to maintain that transplant is, I think, in many ways a model. The challenge in Europe these days seems to be the most current one being recovering from the Covid-19 pandemic and bouncing back in terms of rates of organ procurement as the pandemic slowly starts to burn itself out. But even before that, the EU was challenged by relatively slow rates of deceased donor organ procurement for lots of reasons. Among them is typically a lack of cooperation cross-border in terms of organ allocation, the lack of kidney paired exchange programs cross-border, and a low rate, at least in the EU, of utilization of donors after circulatory death. There the model is, I think, the UK which has a very high rate of organ procurement from donors after circulatory death and a recent study comparing the UK and the US in terms of organ procurement and utilization from so-called DCD donors definitely showed that the UK was more aggressive in terms of procurement and utilization, though interestingly, the average comorbidities in the DCD donor in the UK were slightly different than the US. In the US, a higher KDPI—remember this is the score that sort of grades the quality of donors—in the UK was generally driven by older age, whereas in the United States, the higher KDPI scores were generally driven by comorbidities like hypertension and diabetes. So it’s not clear that these are entirely apples to apples comparisons. But even if we take parts of the EU, such as France, and try and make apples to apples comparisons, it seems clear that there are certainly countries in the EU who are more aggressive and more successful in using kidneys from donors after circulatory death, and something that the US, I think, could learn from.

Frank Maddux: Well, Ben, Fresenius Medical Care is certainly interested in many aspects of transplantation and what our role can be in sort of building out our transplant participation services and activity in the field. I want to congratulate you and welcome you to the organization and to recognize that there is so much work to do, not only in organ availability and access to care, but also the survival of transplants and graft survival in the long term, what can we do to facilitate this. Any final comments before we end today on how you see the opportunities for us going forward?

Ben Hippen: I think transplantation is just a piece of our ambition at Fresenius to try and be deeply involved in every aspect of patient care, from advanced CKD to ESKD to transplant, because I think as we become more involved in each of these areas, we’re going to realize and teach the community that this is a long-term journey for patients, not just years, but decades. And the way to help them navigate it successfully is to build the infrastructure and care pathways that address their needs and care for them throughout their entire experience of kidney disease. And I’m excited to get started.