Oliver Gilan

Kidney Crisis

In the time it takes you to read this post at least one person will have died waiting for a kidney transplant. Kidney disease is the 10th biggest killer in the US and is estimated to rise to the 4th or 5th biggest by 2040. About 1 in 7 people suffer from some form of kidney disease and over 800,000 Americans are living with total kidney failure also known as end-stage renal disease (ESRD). For many of these patients death is the most likely outcome but that may change in the next 10 years.

I was born with one kidney but I was not aware of the implications of that until recently when I had a health scare two years ago. I had always just assumed kidney disease was a solved problem with transplants and dialysis but what I’ve learned that’s far from the case. In this post I want to share some of the issues and exciting new developments I’ve learned about over the past year and a half.

Causes of Kidney Failure #

The most common cause of kidney failure is diabetes which accounts for nearly half of the new cases in the U.S. Nephron cells in the kidney responsible for filtering blood are damaged when exposed to repeated high blood sugar and high blood pressure so it should not come as a surprise that kidney disease is on the rise at the same time that obesity and diabetes is exploding in the US. Unless semaglutide reveals itself to be safe over long periods of time, becomes cheaply and widely available, and proves effective at preventing diabetes then we can expect this trend of kidney failure to continue. As of 2020, kidney disease is the fastest-growing noncommunicable disease in the U.S.

Kidney failure doesn’t happen overnight and it’s estimated most individuals suffering with partial kidney failure are not even aware of it and many people never realize they are experiencing total kidney failure and die from lack of treatment. Kidney health is assessed by measuring the total glomerular filtration rate (GFR) which just amounts to the total amount (ml) of blood your kidneys are filtering per minute. The stage of kidney disease a patient is experiencing depends on their GFR with a value below 90 indicating the beginning of kidney disease, a value below 30 indicating severe reduction in capability of the kidneys, and a value below 15 indicating a patient is experiencing ESRD with a requirement for dialysis. These numbers can vary depending on age, sex, and body size.

GFR is usually measured with a complex procedure using blood plasma or monitoring urinary clearance over an entire day so doctors generally do not measure it directly and instead estimate it using a person’s creatinine and cystatin C level in combination with factors such as age, race, and gender. This estimate usually shows up on routine blood exams performed at an annual checkup with a PCP under the label eGFR. Being aware of this value over time is important to understand if you should make lifestyle changes early on to prevent kidney disease from progressing.

Treatment #

I was born with one kidney but never gave it much thought because I, like many people, went my whole life assuming kidney failure wasn’t a big deal anymore. I thought the advent of kidney transplants meant that if necessary I could simply get another kidney if mine failed and the odds that I would be compatible with a family member willing to donate one is — or at least was in my estimation — high. This turns out not to be as great of a solution as I first thought.

The transplant solution in which the kidney of a living or decreased donor is matched with a patient and then surgically implanted into their body is the best solution we currently have for people experiencing kidney failure. Only a minority of lucky patients will benefit from it though. There were only 26 thousand kidney transplants performed in 2022 and of the 130,000 new patients diagnosed with ESRD that year only a little more than 3,000 of them received a transplant. The rest went on dialysis.

If you’re lucky enough to get a transplant you will need to take immunosuppressant drugs for the rest of your life. Just like any organ transplant the body is immediately aware that the tissue of the new organ originated from outside itself and will begin to attack it with the immune system unless suppressed. These drugs are costly and need to be taken every single day for the rest of your life. Your immune system will be compromised from these drugs making you a patient and at-risk for events like COVID for the rest of your life.

The real kicker? Kidney transplants don’t last forever. Even with the immunosuppressants the half-life for a transplanted kidney is 11 years and only 7 when from a deceased donor. There is also a chance of your body suddenly rejecting the kidney far sooner even with the help of drugs. This is usually not seen as an issue because most patients experiencing total kidney failure are older but as kidney disease begins affecting people at younger ages it will become more common to get a transplant and then end up back at square one when the transplant expires.

If you are not fortunate enough to get a transplant you are put on the waitlist and your only other option in the meantime is dialysis. Hemodialysis is generally performed in a clinic 3 to 4 times a week in sessions of 4 to 5 hours and involves incrementally removing all the blood from the body, running it through a series of semipermeable tubes surrounded by a dialysis liquid which separates the toxins from the blood through the principle of diffusion.

Dialysis works in the sense that it can keep you alive (barely) but chances are you will not be able to live a normal life while relying on it. Nearly half of patients who reach ESRD and receive hemodialysis are under the age of 65 (working age) and 71% of them are unemployed despite being employed prior to dialysis. If you can maintain employment and a normal routine during treatment then it may not be for long. Of all the patients receiving hemodialysis 68% of them die in the first 5 years. The survival rate of patients on long-term dialysis has even been shown to be shorter than many cancers. The supposed solution to kidney failure that I’d heard about my whole life is less of a solution and more of a bandaid on a gaping wound. You do not want to find yourself in a position where dialysis is necessary to survive because odds are, you won’t.

There is a newer form of dialysis called peritoneal dialysis which uses a similar concept to hemodialysis but is much easier to perform. It involves pumping dialysate into the abdominal cavity and relying on osmosis to pull toxins from the blood into the dialysate before draining it. This can usually be performed by the patient themselves at home or on the go which allows for more continuous treatment of the blood. Because the blood is filtered more often the survival rate is higher than hemodialysis but only a little (52% over 5 years).

Revolutions in Waiting #

The most surprising part of my reading and talking to people in the field over the past year and a half was learning just how few resources are available to solve this problem. Since 1987 the standard treatment for kidney failure has remained largely the same we’ve simply increased the scale at which that treatment is available. Kidney disease was considered a solved problem with the widespread availability of dialysis and nephrology became viewed as a boring field of medicine as a result. Most of the nephrology training programs in the US could not fill all their vacant spots in 2018 and the MDs matching in nephrology declined by 12%. The vast majority of funding and attention goes towards flashier parts of the body such as the brain and heart. Only in recent years has the government realized the shortcomings of dialysis and committed to spending more on better solutions. As a result many private startups and labs have begun experimenting with next generation treatments.

There are three main branches of progress in the space: better dialysis, growing/harvesting real kidneys, and building an artificial kidney.

Better Dialysis #

The better dialysis branch of progress is centered on just that: creating better methods for performing dialysis. This generally boils down to making it easier for a patient to perform dialysis on themselves so that they can do it more regularly, or even constantly, with less chance of error. There is some progress in this area with promising results of small dialysis machines worn like a backpack as well as small bedside machines that can be used while sleeping. In the end, though, many of these solutions fail to pass final FDA approval and generally do not receive enough funding to reach mass market. The reliance on dialysate also imposes a challenge on miniaturization as it is a consumable liquid that needs to be constantly replaced as it is used.

It would be great to see progress in this branch reach the mass markets but I’m skeptical that this approach can deliver significantly better outcomes than it already does.

Growing Kidneys #

A much more fascinating branch of progress is in growing kidneys themselves. While dialysis focuses on treating the problem that arises with kidney failure growing kidneys aims to solve the transplant supply bottleneck because transplanted kidneys have much better mortality outcomes than dialysis.

One way to grow kidneys is to let nature do it for us and then just harvest them which is what researchers have been trying to do with pigs and it’s shown some promise. Researchers at NYU and the University of Alabama have both successfully transplanted genetically modified pig kidneys into humans while maintaining functionality. All of these transplants have taken place in brain-dead patients but the latest experiment has shown the kidney to be functional for 32 days after transplant. The genetic modification is necessary to prevent immediate rejection by the host body but otherwise it seems that pig kidneys are close enough in function and throughput to act in place of failed human ones. This could dramatically increase the supply of kidneys available for transplant but it certainly raises some ethical concerns and as a Jewish man I’m not sure I’d want a kidney from a pig. It’s also not an optimal solution because far more immunosuppressants are required to make this work than for a normal kidney. It’s likely that these kidneys will have a shorter half-life after transplantation and leave the patient in a weaker state than a regular human kidney but if the outcomes are still better than dialysis that could be a worthwhile tradeoff.

The second approach to growing real kidneys is to quite literally grow them in a lab using stem cells. This approach is still in its infancy and although there has been progress I would not expect this to be available to patients for another couple decades at least. Ultimately this could be the holy grail: a full human kidney, grown for little cost in a lab with customized antibodies to prevent rejection completely without the use of immunosuppressants. This is the approach that is furthest from being ready but it is the ideal and should be invested in far more than it is today. The science is still young and the hurdles to making this a reality are massive but it’s a moonshot that we should chase.

Building an Artificial Kidney #

The last approach, and the one I’m particularly excited about, similarly aims to solve the transplant supply issue while being financially cheaper than both transplanted kidneys and dialysis and also being available far sooner than grown kidneys. The efforts to design and build an artificial kidney are being led by Dr. Shuvo Roy and William Fissell, MD at UCSF and Vanderbilt respectively. The idea is that when it comes to filtering the blood within the human body you don’t need a full biological kidney and a silicon-based implantable device can be manufactured for cheap and replace the need for human kidney donors.

The device consists of two main parts: a hemofilter and biochamber which respectively work to separate toxins from the blood and produce urine just like a normal kidney would. The hemofilter is built around a semipermeable silicon wafer with slit-shaped pores just 7nm in width. When blood flows over this membrane it is partitioned at a molecular level as big protein molecules — such as albumin — cannot pass through the pores while water, salt, and small toxins can. Using photolithography and other techniques used in the manufacturing of computer chips it’s possible to design these semipermeable membranes with the precision and scale that’s required for this selective filtration.

The albumin and other proteins that don’t pass through the membrane are immediately recycled back into the blood stream while the water, salt, and toxins dissolved in them are passed into the biochamber. The biochamber is the only part of the device containing biological material and consists of human renal tubular cells which are responsible for reabsorption of the salt and water. The cells transport these water and salt molecules to a separate channel where they are recycled back into the blood just like they do in a real kidney. This leaves only the toxins remaining where they condense as urine and are passed directly into the bladder.

The beautiful part of this device is the lack of a power source. The internal blood pressure of a patient is enough to push blood through the device just like a regular kidney so no pump is needed which means this can be implanted in a human much easier than other solutions. The lack of dialysate also means there is no consumable element of this device so as long as the semipermeable membrane remains structurally sound and the renal cells remain alive this device can remain in the patient for the rest of their life.

Further, because only the dissolved water, salt, and toxins are entering the biochamber the patient’s immune systems won’t even be aware of the presence of external cells. The only organic part of the device is completely separated from the rest of the blood by the silicon membrane. This would allow a patient to not only restore their kidney functionality but also keep their immune system intact.

The challenges — of which there are many — come down to ensuring that no part of the device — especially the semipermeable membrane — form blood clots over time, culturing the renal cells, making sure they stay alive within the patient, and monitoring the performance of the device. The problem with silicon is that it’s naturally not very hemocompatible and blood clots will form on the membrane over time. To prevent this Dr. Roy and his team applied a polyethylene glycol (PEG) coating to the membrane which successfully prevented blood from clotting but was not durable over time longer time periods. PEG is aqueous so it’s not a great candidate for durability in the human body. More recently they experimented with polysulfobetaine methacrylate which showed extremely little erosion over time, is non-toxic, and prevented blood clotting even better than PEG. The existence of these coatings and the ability to find new, better coatings, will only improve and I’m confident that this part of the device is already at a stage where it can be commercialized.

The bigger challenges surround the renal cells. For the renal cells to perform their task they need to be cultured to the point of differentiation which is where they express specific genes to perform the function they are designed for. Typically renal cells have been difficult to differentiate in a lab which means they would not actually perform their jobs of transporting the water and salt ions but Dr. Roy and his team have not only discovered how to do it effectively they’ve even tested these cells in a device implanted in a pig and they performed as expected. The key then is to ensure they can handle the throughput necessary for a human. In a real kidney these cells perform many functions beyond the reabsorption of salt and water but in this artificial device we only need that one function. By genetically engineering these cells to be more efficient at reabsorbing salt and water we can make them capable of handling human loads. Dr. Roy and his team are working to optimize that process now.

And then in the end we need to monitor the device so that any loss of functionality or structural damage can be diagnosed and dealt with. Once a device is in a patient it will not be easy to inspect the device but low-powered onboard chips and sensors can be used to wirelessly transmit important diagnostics for monitoring. These chips would need to be powered by the human body as the device will not have a power source itself.

Just about all of the remaining problems to overcome for this artificial kidney are engineering in nature and do not require a deep insight. I’m confident that with enough funding and time Dr. Roy and his team will be able to create a fully functioning form of this device at a scale for humans to use.

Path to Market #

I’m hopeful about the future of ESRD treatment because we are seeing a convergence of many different solutions all at once but also because the non-technological factors at play are coming together in a way that should make progress possible. For any of these treatments to reach real patients and make a dent on the problem they need to pass regulatory bodies and be financially viable for companies to both invest in and for patients to pay for. When it comes to solving the non-technological problems of reaching patients I believe an artificial kidney is best positioned to win and here’s why.

The Tech #

When it comes to the tech better dialysis is just that. Quite frankly better dialysis would be great but in comparison to fully restoring a patients functionality and reducing adverse outcomes, it’s sorely lacking.

On the other hand growing real kidneys is extremely technologically advanced. Too much so. Growing a kidney custom for each patient so that the immune system fully accepts it is the holy grail but it’s still a question if that’s even possible or not. Either way, the tech for that is far out and unproven. Harvesting a kidney from an animal seems to work and is already being tried in real patients — brain-dead patients but patients altogether — but can be considered equal or worse than getting a human kidney transplant. You still need to suppress your immune system (even more so than for a regular transplant) but at least this option seems viable. If you do not care about the optics of having an animal’s organ in your body then getting a pig’s kidney could definitely be preferable over dialysis if those are the only two options.

And then there’s an artificial kidney which wouldn’t require suppressing the immune system at all and could in theory last the entire lifetime of the patient. Even if it had a lifetime of 20 years that could still be a superior option to anything else. The technology here is has been tested in both dogs and pigs for varying periods up to 30 days and is simple which reduces costs and reduces the chance of something going wrong. Unlike better dialysis or kidney harvesting the technology here is superior but it’s also far more viable and mature than custom grown kidneys.

The challenges remaining for the artificial kidney are almost fundamentally engineering in nature and not requiring immense scientific breakthroughs. Money can solve engineering problems but it can’t increase the speed at which new insights are attained. This bears well for the artificial kidney.

The Regulatory Environment #

The regulatory environment is also uniquely aligned to bring these new technologies to market. One of the big changes was President Trump signing Executive Order 13879 on Advancing American Kidney Health which explicitly aims to open the door towards tackling the kidney crisis. Among other initiatives to improve preventative care the Order explicitly calls for policy to “increase patient choice through affordable alternative treatments for ESRD by encouraging higher value care, educating patients on treatment alternatives, and encouraging the development of artificial kidneys."

The Order goes on to explicitly call for regulatory bodies such as the FDA and Congress to increase their support and collaboration with the private sector to develop an artificial kidney.

Sec. 6. Encouraging the Development of an Artificial Kidney. Within 120 days of the date of this order, in order to increase breakthrough technologies to provide patients suffering from kidney disease with better options for care than those that are currently available, the Secretary shall:

(a) announce that the Department will consider requests for premarket approval of wearable or implantable artificial kidneys in order to encourage their development and to enhance cooperation between developers and the Food and Drug Administration; and

(b) produce a strategy for encouraging innovation in new therapies through the Kidney Innovation Accelerator (KidneyX), a public-private partnership between the Department and the American Society of Nephrology.

Dr. Roy and his team has been awarded multiple prizes by KidneyX for their work on the artificial kidney and has been in contact with the FDA for years now, ironing out what it would take to get to clinical trials. The FDA granted Dr. Roy’s device Breakthrough Device designation which speeds up the regulatory review process during premarket development and in discussions with Dr. Roy he’s described to me the criteria the FDA has laid out before they grant approval for clinical trials:

  1. The device must not produce blood clots
  2. The device must not activate the immune system
  3. The device must successfully produce urine.

If they device can be shown to fulfill all of the above for a duration of 30 continuous days in a pig without breaking and without any assistance from the pig’s natural kidneys then they will grant clinical trial approval.

Because the components of the device have been developed in different stages each part of the criteria has been tested to varying degrees. Animal ethics boards will not allow you to test a full device for 30 days right out the gate so instead each experiment needs to be tested for 3 days, then 7 days, then 30 days. The semipermeable silicon membrane was developed first and has thus been tested for 30 days successfully. The biochamber was developed second and has been shown to not trigger the immune system for up to 7 days successfully. The last component of the biochamber which is the proper functionality of the renal cells to produce urine has been shown to successfully work for up to 3 days in a pig. The last few experiments for those components are in the process of happening as his lab waits for more funding. In the meantime they are working to improve the throughput of the device to meet the scale of a human body. It’s very possible this device will enter clinical trials within a couple years.

It’s so rare for medical devices and medical innovations with such a large potential impact on the world to have the bureaucratic machine removing roadblocks for it. This isn’t just limited to the work of Dr. Roy but it does inspire confidence that if this technology fails to reach the markets it won’t be because the FDA killed it prematurely.

Financial Viability #

The last component that determines whether a technology will reach the market is its financial viability. This includes both how much it’ll cost to develop it as well as how much it’ll cost to produce it once developed. I am less familiar with the financial environment for other branches of progress but I can talk about what it looks like for the artificial kidney and the market as a whole.

Dr. Roy has been working on the artificial kidney for nearly two decades by relying exclusively on federal grants, private donors, and university funding. He believes today that he only needs $10m to achieve approval for clinical trials. To date his lab has raised around $13m over the past two decades. These are paltry numbers compared to the investments VC’s regularly pour into startups and the potential impact of such a device vastly outstrips the potential of said startups. This is also an order of magnitude cheaper than it would cost to develop the science to grow real kidneys in a lab. In terms of R&D the science around developing a silicon-based artificial kidney is far cheaper than the R&D for fully growing a kidney.

Once it is developed Dr. Roy believes early versions of the artificial kidney will be comparable in price to normal transplants which puts it at around $200k but the ongoing lifetime cost of the device is far less than a transplant because the patient will not require expensive immunosuppressants. It’s not unreasonable to believe this price will go down as production of the device is scaled and I can envision a world where this price is driven down to be even cheaper than dialysis.

The interesting wrench in the market around the device is who the buyer actually is. Namely, it’s not the patient who’s paying for the device and it’s not necessarily even their insurance. It’s Medicare. To understand how kidney treatment works today you need to go back to 1972 when Congress passed the Social Security Amendments that guaranteed coverage for treatment of ESRD regardless of age effectively making Medicare the biggest customer in this market. This move was in large part due to the mistaken idea that dialysis was “the cure” and that by heavily subsidizing it the government could prevent a large chunk of the population from dying or being unproductive. Unfortunately now most dialysis patients still die and are not economically productive until that happens.

Medicare pays for dialysis treatments after 3 months for anyone with ESRD, subsidizes kidney transplants, and pays for immune-suppressing drugs for 3 years (EDIT: Comprehensive Immunosuppressive Drug Coverage for Kidney Transplant Patients Act passed in 2020 extends coverage to the lifetime of the patient) post surgery even if they are under the age of 65. In 2019 Medicare spent nearly $90,000 per patient with ESRD totaling $37 billion in costs. These patients make up 1% of the Medicare beneficiaries but account for 7% of total Medicare costs. The cost per patient living with a kidney transplant averages $30,000 per year just to pay for their immune drugs. These staggering costs is a large reason why the government is actively trying to encourage better solutions to the kidney crisis and Dr. Roy’s team, in conjunction with a medical economist, concluded that even conservative estimates show their artificial kidney would save Medicare $10 billion annually.

This subsidization by Medicare screws up the incentives for any product or service trying to enter the market. Insurance companies do not feel the need to find or fund a solution because once a patient reaches ESRD they can pawn them off to the government and the pharmaceutical companies are happy to sell the immunosuppressants no matter who is buying. Any solution that aims to reach the market needs to get the stamp of approval from Medicare so that it can be reimbursed or payed for by the government just like dialysis is so Dr. Roy has tried to get this approval ahead of time but their answer is clear: they want a better solution and are open to changing the rules around what’s covered but they need to see clinical approval first. So for now, it’s all about developing the device further to get it tested in real patients.

Looking Forward #

The kidney crisis is a problem that threatens the health of the nation. It drains our Medicare system of its funds, it takes hundreds of thousands (and soon millions) of people out of work, and leaves our country weaker. When speaking to Dr. Roy it’s obvious that he’s passionate about this problem and his team has been making incredible progress the past two decades. Besides him there are incredible researchers and doctors working around the world to materialize a revolution in kidney treatment with many of them showing promise. I personally believe an artificial kidney such as the one that Dr. Roy is designing offers the best potential outcomes with the most achievable hurdles to overcome. I’m hopeful that in my lifetime (and hopefully quite soon!) we can see the kidney crisis become a thing of the past and I hope if I ever find myself in need of another kidney to complement the one I have that I can reach for a solution that gets me back to full health without compromises.