Confessions of a transplant patient: grateful, but unsatisfied.
Transplantation may have reached its peaked and it's time we start looking ahead.
Housekeeping:
Sorry all, it’s been a while since I posted here! Consider this a re-launch
Moving forward, this will be the substack I dedicate to all my science-related thoughts to.
TL;DR:
Transplantation is better than dialysis
But transplantation still sucks (for lack of a better word)
There is a limit to how much better it can get
So we need to consider if we have reached the peak, and maybe even change directions
We have a few options on the table - cell and tissue therapy - but we need to focus more on infrastructural problems. Cell and tissue generation is not the limiting factor here anymore (as sexy as it is)
If you want to chat more about this, email me adaobi@dividebio.com
It is often said that dialysis is an expensive and burdensome process, and this is true. It costs the US approximately ~$30B every year to pay for the ~550K kidney failure patients needing dialysis. Speaking from experience, dialysis made me temporarily infertile, severely nauseous, eliminated my appetite and significantly reduced my ability to travel. With every session I faced just how fragile my mortality really was.
Transplantation, however, is both cheaper and much less burdensome. It restored my fertility and appetite, eliminated my nausea and made it possible to travel again. It unequivocally eased the weight of my mortality and made life a little brighter.
The natural chain of thought on transplanations is
If transplantation is cheaper, and provides higher quality of life for patients, we should aim for everyone to receive transplantation
But we do not have enough organs to go around
Therefore we should focus on the problem of organ supply
Although this logic makes sense, it is not true. The unspoken, but assumed, fact is that transplantation is possible for all, and once done will give you back the life you once had. But transplantation, though a lifesaver, is not a life restorer. It has also introduced me to several new infections and chronic conditions. My fertility is restored, but restricted. My diet, strict and forever changed. There are places I can never go to again. It has given me, in a sense, a more manageable disease of a life. Is this really an improvement, or just.. difference?
You will never hear these truths because it would be impolite to state them so publicly. To save me, someone died. To ask for more would be ungrateful, so nobody does. With no demand for new treatment, and such high human cost of current treatment, first steps remained only, and all efforts for improvement became concentrated on simply finding better organ sources.
But permit me to be that ungrateful patient and say we can do more. I believe we deserve more, and that more is possible. To do so, however, first requires us to better understand the problems with transplantation today and why it, as a future, is not one we should be aspiring to.
Accessibility
The first myth is that transplantation is accessible to all, with the major constraint being the organ shortage. Although organ shortage is a major constraint of transplantation, it is not the only, nor the primary, reason why transplantation is not abundant. Only ~16% of US kidney patients make it to the waitlist (90,000 vs 550,000 total dialysis patients), and this low percentage seems to be fairly consistent across different countries (e.g UK - ~6400 on waiting list vs ~21,000 doing dialysis for kidney failure).
Iran, a country where compensation for live donation is legal, is often used as the strongest piece of evidence for focusing on increased live donation. I argue that it is the strongest piece of evidence against our focus on increased organ supply. Living donors in Iran are given cash to donate, along with expense reimbursement and income support. This increased organ supply effectively eliminated its waiting list time, going from years to months, with ~3000 kidney transplants performed in 2024 alone . However, despite increased organ availability, ~32,000 persons continue to do dialysis, maintaining a similar low rate of persons actually able to do transplantation*.
Although waitlist selection is multifactorial and mixed with heavy non-biological influences (bias, low referral from doctors, limited number of clinicians/beds, changing criteria across different centers etc), common and very real clinical barriers exist, including: risk of surgery from frailty and/or underlying disease, immunosuppression complications, and general inability to adhere to strict medication protocols. These issues have persisted since our first successful transplant in 1954. So long as these barriers remain, no amount of unlimited organ supply will change this (sorry xeno!).
Transplant surgeries, although routine, are not easy on the body. Kidney transplants remain the least invasive solid organ surgery. It does not require; a cut through the chest, a heart-lung machine, deep navigation through abdominal organs, removal of the failed organ and most importantly, only has a surgery time of 2-4 hours. And yet, the intensity remains. Why?
The cutting of muscle and connective tissue, large vessel clamping and general capillary destruction causes noticeable stress and dysregulation in the body. To prevent the transplanted organ from being immediately rejected, a high dose of immunosuppression drugs is given before and during the surgery. This interferes with the immune system’s repair work in response to the surgery, significantly impacting the time to heal and the ability to heal itself. Once the transplanted organ is attached to its new host, it restarts immediately, causing disruption and immune activation in the new organ (known as reperfusion injury). All of these things are reasons why to first be eligible for transplantation, the candidate must be extremely strong and healthy, making it a counterintuitive but necessary requirement.
Naturally, the elderly, severely diseased and frail already have dysregulated processes and weakened immune systems. Extra shocks and interferences such as these add additional risks that can be fatal on the surgery table or during recovery, making the risk-benefit reward just not worth it, even if they have a living donor willing and able.
But does this have to be the case?
Heart valve replacements were once plagued by this issue, but they overcame it with the introduction of transcatheter aortic valve replacement surgery (TAVR). TAVR removed the need to cut open the chest, instead, making a small incision near the groin and delivering the new heart valve via a small tube. Eliminating the need to cut through masses of muscle, connective tissue and most importantly, allowing the heart to maintain its function throughout the surgery, patients deemed inoperable suddenly weren’t so. To illustrate the impact of this, between 2008 and 2020 in Denmark, valve replacement surgery doubled yearly, going from 621 surgeries per year to 1256, with TAVR representing ~48% of surgeries. TAVR patients were not only older (81 vs 73), but sicker too (70% of them had more than 1 major comorbidity vs 50%). By 2020 91% of all patients aged 75+ had TAVR surgery .
Of course, it is much easier to address such problems with something as small as a heart valve. It is not entirely clear to me if the same can be said with large solid organs (but never say never!).
Complex drug management
Compared to dialysis, transplants look good. And people assume that having a transplant means life goes on as normal, apart from a few pills to pop. But this is wrong. The reality looks more like this:
You take between 4-8 pills daily (split at different times during the day), for the rest of your life.
One of the pills will run out unexpectedly as you’ve been suddenly told to consume a higher dose based on your previous blood tests.
You’ve been busy with work and now need to create time to collect the medication urgently.
Another of the medications (likely your blood pressure medication) requires constant monitoring of a certain marker (in this case your blood pressure) to ensure its efficacy.
You check this twice a day with a bulky blood pressure monitor you carry with you everywhere.
Your blood pressure has been stable for the last 2 months, so you stop checking religiously and continue on your current dosage.
During your next clinic appointment it’s noticed that your blood pressure is high, but you are not sure when this change occurred because you stopped checking.
You begin checking again to confirm this change is real.
You now begin an email thread with your nurse seeking advice on whether to increase your dosage.
Another appointment is scheduled, this time 2 weeks from your last one as they want to see you before increasing your dosage.
You attend the appointment and increase the dosage.
The increased dosage causes swelling in your feet.
You start another email thread with your nurse and have been advised to stop said medication.
You are now back at the clinic only 1 week later as you need to start a new blood pressure medication.
During this clinic appointment it is noticed your last blood test revealed elevated CRP levels (an infection marker), but you had no real symptoms because you are immunosuppressed. You are now on extra high alert.
You start general antibiotics and wait for the urine culture to grow so that they can give you the specific antibiotics you need. In other words, you will be back in the clinic next week.
The urine culture is positive for X and it only responds to a special antibiotic.
Treatment involves daily IV infusion as an outpatient for 7 days.
You now have to adjust the dosage of one of your immunosuppressants during this treatment.
Your new blood pressure medication is yet to bring down your blood pressure to safe levels, you are told to increase the dosage, and because of this, run out of medication ahead of time (again). You make an extra trip to your pharmacy to collect more medication.
Your most recent blood test reveals elevated glucose levels for the third time (thanks to your immunosuppression medication), you are now referred to the pre-diabetic clinic
Your blood test shows elevated CRP again, with your urine showing nitrates, likely another infection.
Your new blood pressure medication is causing severe dizziness. Another clinic appointment is scheduled.
You are started on another general antibiotic, whilst you wait to hear back from your doctor.
Another email thread regarding your glucose levels...
The list goes on every day, for the rest of one’s life.
Given the complexity of the drug management, most patients are assessed on their capability to keep up. Unsurprisingly, a lot of people fail this criterion.
Putting the difficulty of the regimen aside, there is also a mental burden that comes along with it. Every interaction with this system is an active reminder of health lost and how much time you have left. So it should not come as a surprise that adherence is a prominent issue. In a study of 153 patients 18 months into their kidney transplant, ~55% of patients were non-adherent in some shape or form, with the highest level of non-adherence being timing of dosage (something I admit I can relate to).
I don’t imagine the solution is simply a “better” way of managing these systems, but rather, a way to eliminate a lot, if not all of it. Will it require new types of drugs? Ones that can somehow sense and respond on their own? Or can we evolve transplantation to eliminate the need for some of these drugs?
Short organ lifespan
Contrary to popular belief, transplants do not last your whole life, nor do they start off being 100% functional. To use myself as an example, my kidney, deceased, started at 41%, which is not too far from the norm (eGFR for those more aware of the technical terms).
In order of longevity, it goes:
Living donor, kidney - 15-25 years
Deceased donor, kidney 10-15 years
Heart - 10 years
Liver - 10 years
Lungs - 3-5 years
This is due to issues like: the type of death from the organ donor, damage during surgery, damage during recovery, toxicity of immunosuppressants, introduction of new disease due to medication (high blood pressure & diabetes, ironically the two top causes of kidney failure in the first place), etc. In the case of kidney transplantation, nearly all patients will experience IFTA, a result of all the aforementioned damage, which ultimately leads to graft failure. Given the multifactorial cause of damage, it becomes extremely difficult to target and therefore solve.
This brings us to the ultimate question. If this is as good as it gets, is this still a path worth pursuing?
A future beyond transplantation?
So what could a future beyond transplantation look like? The obvious route is cell and tissue therapy, avoiding solid organ transplantation altogether. Although progress has been made in creating the material needed to regenerate organs, in my opinion, we have become overinvested in this when it is no longer the bottleneck. There are major infrastructural challenges that are overlooked, underinvested and need a lot more attention if we are truly serious about this future.
The biggest issues are;
Delivery of tissue
Environment for tissue engraftment
Tissue placement and orientation
Measuring engraftment
Rejection
Rejection detection
Delivery
Traditionally, there have been two main delivery mechanisms for cell/tissue therapy: IV of free-floating cells and direct injection/placement. Although accessible and low risk, the former results in ~ 90% of cells getting washed away (for solid organ transplants), making its clinical benefit a non-starter. The size of cells/tissue also means it is not possible to deliver using our standard drug delivery carriers (e.g lipid nanoparticles are ~100nm, compared to the size of a single cell being anywhere between 10,000 -100,000 nm).
The latter has been done more successfully (islet cells in liver, abdomen etc), but is organ dependent, as this influences surgical accessibility and bleeding, e.g., cell transplantation in the brain has a very different risk profile to transplantation in the abdomen. Given how many times one might need such therapy, it becomes a little concerning.
Environment for tissue engraftment
Only a few cell transplants have been truly successful - albeit to varying degrees - islet transplants, limbal stem cell transplants and bone marrow transplants. All three share the fact that the environment in which the new tissue was engrafted was new or “cleaned”. It is well known that environmental cues play a big role in cell health. Yet, tissue and cell therapy approaches of today continue to deliver to the same diseased environments.
Islet cell transplant solves this issue by being delivered to a completely new organ (typically the liver, but recently the abdomen too, see Sernova) rather than the pancreas. Although this works to varying degrees, this isn’t a strategy that can be adopted for most organs e.g you need your cardiac tissue in your heart to pump blood everywhere else. Sticking them in your abdomen is no help at all.
Bone marrow transplants address this issue by simply destroying the old environment and cells. This is an intense treatment that requires patient isolation due to the person’s destroyed immune system, but it is necessary for the engraftment of the new cells. If tissue regeneration and replacement therapy are going to exist, could we figure out how to do this locally and non-invasively?
The use of irradiation as preconditioning for hepatocyte transplant showed signs of promise in non-human primates using conformal radiation (11% engraftment vs standard 1-2% engraftement), but it ultimately didn’t translate well in humans.
Tissue placement and orientation
Assuming we can deliver our tissue to the right organ and right place, we need to make these tissues stick, integrate and work in this environment. The gold standard today is to promote blood vessel growth, increasing the odds of integration. The problem is we do so with no sense of direction or placement. This strategy only makes sense for tissues whose orientation is not absolutely crucial to their function, essentially, hormone-secreting tissues. For non-secreting tissues like the glomeruli - small filtering units in the kidney - the tissues it connects to and how it connects to them are very important to its job. It’s not clear how we solve for that on such a microscopic scale. My gut feeling is that some level of molecular suturing will need to be invented.
Measuring engraftment
If we figure out engraftment, how will we know? For islet cells we have C-peptide, for bone marrow transplants we use blood count, but what do we have for the multiple tissue types in the heart? The kidney? How will we know if the tissue is engrafted, but for some reason, isn’t restoring organ function? How can we better what we don’t measure?
As with transplantation, it is something that will need to be continuously monitored in the clinic. In theory you could argue we could do this via more regular, detailed scans and biopsies, but in reality, that is just not happening. Nobody is getting scanned every few weeks for the rest of their life, let alone having a biopsy done at that rate. Again, for secreting tissue this isn’t such a big deal, but for non-secreting tissue, it is.
Although clever tactics have been used in pre-clinical models (cell source from different gender, species etc) these are all histopathology dependent, which we have just established is not happening.
Measuring Rejection
Given the manufacturing complexities that exist with autologous transplantation, it is safe to assume that allogeneic transplantation will have a role to play in this future. But with that comes risks of rejection. For solid organ transplants, the most common rejection monitoring is that of donor-specific antibodies, and for the most part this is a very fine measurement of rejection. However, evidence continues to show that the same can not be said of cell transplants. They tend to be destroyed mainly via cell-driven mechanisms, with antibody levels being a poor predictor (see here for example).
One of the main reasons why detection of donor-specific antibodies works so well is because it’s done via blood test. The infrastructure is standardised and the procedure is easy, making it feasible to do repeatedly, which is necessary for long-term transplant monitoring. The same can’t be said for cellular-driven mechanisms. To state the obvious, we need a new assay that mimics the ease of blood tests.
Treating Rejection
To prevent and treat rejection today involves a variety of immunosuppression protocols. The administration and targeting of these drugs, however, work on a systemic level, making it hard to effectively target areas locally. Despite maintaining similar trough levels seen in solid organ transplants, rejection still happens. Increasing the dosage would likely come with more risks than reward, making the need for alternative, more targeted rejection therapy essential.
There is also the case of instant blood-mediated inflammatory reaction (IBMIR), which in plain english just means when the transplanted cells get exposed to the host’s blood, it experiences clotting, inflammation and a ton of other damage. Although not formally classified as rejection, it is still the body’s immune response to something foreign. In islet cell transplantation, estimates of immediate loss due to IBMIR range between 60-70%. While patients are given anti-clotting medication to reduce this process, it persists given its multifactorial nature. We need better drugs that can prevent and maintain cascades like this.
Making my point even clearer
If you have gotten this far, thanks for reading! I encourage you to also read this blog post, it’s less than a page. Ironically, it is meant to be a testimonial page about the life transplantation has given them, but if you remove the lens of gratefulness, you will see just how sad these stories are. And unfortunately, they aren’t uncommon.
I’m grateful for the life transplantation has afforded me, but I believe we can aim higher. With acknowledgement of the problem, better direction, focus and the right people I’m pretty confident a future beyond transplantation is possible. One that we are not only grateful for, but actually happy to live. I’ve started a company dedicated to creating this future and am always looking to talk to people about it. If you’d like to know more, please email me adaobi@dividebio.com
*The 32,000 number likely includes patients just doing short-term dialysis, however, a large majority will be permanent kidney failure patients, which is still in line with my point. High numbers of dialysis patients persist even though the waiting list has been brought down to essentially zero.
Thank you to Afiq Hatta and Yvonne Bajela for the feedback and edits