MAYA ADAM: 

Welcome to Health Compass. I'm your host, Maya Adam, director of Health Media Innovation at Stanford Medicine.

ALAN PAO: 

I think that's sort of the beauty of being a physician scientist, is that it's not just a theoretical problem, but there are patients that you take care of who have this problem. And so I think having the human face in your mind and the social interactions that you have is really what drives a lot of what we do is to say, well, we can use the science to really help people. And I think that that's probably why every physician goes into the field is to do that.

MAYA ADAM:

Kidney stones might seem like a small problem, something painful, yes. But we often think of them as being temporary and fixable. In reality, for millions of people, kidney stones are a source of debilitating pain and they can really interfere with people's lives. They come back without warning and they send people in and out of emergency rooms often without clear answers about why they happen or how to prevent them. Today's guest, Dr. Alan Pao, is a kidney specialist and a researcher at Stanford Medicine who's devoted much of his career to understanding an overlooked corner of human physiology, how the kidneys regulate minerals and maintain chemical balance in the body. Dr. Pao's work focuses on a little known molecule called citrate, and on a tiny transporter in the kidney that may hold clues to stopping stones before they ever form. His research bridges the clinic and the lab, giving him a unique vantage point on why kidney stones develop and what we can do to prevent them. Alan, thank you so much for joining us today.

ALAN PAO:

Thank you for having me.

MAYA ADAM:

I like to start by asking all of our guests to share a story with me, something that sort of gives us a little glimpse into what it's like to live in your world, both as a scientist but also as a person. Can you share an experience or something that's sort of helped shape the path that you're on today?

ALAN PAO:

So that's a really great question. I think for me, it wasn't a particular instant or experience -- singular experience that brought me into what I'm doing now, but a collection of different points in time in my life that drove me to become a kidney specialist as well as a physician scientist. So I tried to use what we discover in the laboratory and try to apply it to patient care. I think when I was young, my father was a scientist and I remember taking me to the science museums in St. Louis where I grew up and he would show me the periodic table. And I didn't know it at the time, but my father's favorite subject in school was chemistry. And so I was really fascinated by how the elements on the periodic table sort of are arranged by atomic number. And then when I got into high school, I actually really enjoyed chemistry and I also enjoyed mixing solutions together in the lab setting. And I think that kind of made me really excited to be in a laboratory environment. And then I think in medical school I went through a process of trying to find what I liked about medicine. And I think a lot of times people choose a particular field or specialty based on something that they like from before and they kind of incorporate that into the care of human patients. And for me that was again, chemistry. And I think nephrology is really sort of the field of chemistry of the human body. The kidneys are the organ that really controls the electrolyte composition of the blood. And so I think that really attracted me to the field. And then fast forward to residency, I did my residency training at UT Southwestern in Dallas and it was actually known for its nephrology historically. And I was an intern with my future mentor at the time. His name is Orson Moe, and he was doing a lot of research in the laboratory and then translating it to the care of patients with kidney disease. And so I think I wanted to be like him. And I think this is where modeling of people -- you go into a career sometimes by just the role models that you pick. And he was one of my role models. And then I think around that time, this was in the late 1990s, molecular biology was becoming commonplace in different fields, but I think for nephrology it was a little bit slower to adapt to sort of embracing molecular biology compared with other fields like neuroscience, oncology and cardiology. So I really wanted to learn molecular biology and really understand the molecular basis of disease. And so I went to train with my other mentor, David Pierce at UC San Francisco, and he basically taught me how to think through problems at the molecular level. So when I got to Stanford, I think I combined all of those interests to study kidney stone disease through both bench approaches, also translational approaches to really help my patients. But I would say, just tying it together, that it was after that I started to care for patients who had recurrent kidney stone disease that I realized that there was sort of a gap in terms of what we could do for them. And there are a couple of patients that I would see who were going through a lot of pain through having obstructing stones and they come to me for prevention and realized that we didn't have a lot of medicines or approaches that could help reduce the recurrence of the disease. And I think that's where I started to focus on different types of therapeutics that we could develop to help prevent those stones from recurring.

MAYA ADAM:

So I'm curious about that. Alan, can you tell us what's going on in the body when somebody experiences a kidney stone? What causes the pain? What causes the stone? Give us a little bit of the background there.

ALAN PAO:

Yeah, that's a great question. So kidney stones occur in about 10% of the general population throughout their lifetime. So it's fairly common. And the kidney stone forms generally in this area -- I'm going to show you where the kidney is. So this is the kidney and my finger is sort of the connection between the kidney and then the bladder would be right here. This is called the ureter. And the kidney stone generally forms in this area called the renal pelvis. It's where the ureter comes out of the kidney and it'll grow there and get larger and larger generally. And then at some point it will break off. And when it breaks off, it starts to go down the ureter and it gets stuck in generally two places: in the middle part of the ureter or the junction between the ureter and the bladder. And when it gets stuck there, the ureter is actually not just a tube, but it's actually a muscle that will kind of contract and kind of push the urine across the tube. And so when it gets plugged up, it starts to contract. And that contraction causes what we call renal colic. It causes the pain. And the pain can be very severe and usually will not stop unless if that stone is expelled. And most of the time if the stone is small enough, it can pass, but when the stone gets really big then it can't pass and it gets stuck. And that's when the urologists will see the patient and decide whether or not it needs to be removed. And so that's generally where people will have laser lithotripsies to try to remove the stone. But that doesn't necessarily get at the underlying reasons for why people have a kidney stone. And so I think there are things in the urine that will predispose patients to have these stones recur over time. And so when the minerals that are too high that can lead to stones like calcium oxalate or substances that are too low like citrate, which is an inhibitor of stones, those things can actually cause people to have more stones. And so we study why people might have lower amounts of citrate in the urine and try to come up with approaches to raise the citrate so that it can kind of inhibit future stones from happening.

MAYA ADAM:

Is that a genetic predisposition? Or what causes citrate to be low in people who predispose to kidney stones?

ALAN PAO:

It's interesting, even with the human genome project, we haven't identified a lot of families thus far who have an isolated decrease in citrate in the urine. There are patients who have what we call renal tubular acidosis that is due to a defect in acidification of the urine and they can have kidney stones. And as a byproduct of that, the citrate will be low, but it's not the primary reason. These types of diseases that are genetic that cause stones, those are generally monogenic diseases that are fairly rare. Most of the traits that lead to stone disease are generally the risk factors like having too much calcium in the urine, too much oxalate in the urine or citrate that it's too low. And those are just similar traits that are things like having high blood pressure. There can be a lot of genes that work together to make small changes that put people at risk.

MAYA ADAM:

And Alan, within families, is this something that runs generally within families? If my father had kidney stones, am I at a higher risk of having them as well?

ALAN PAO:

Yes. So generally that is the case. I think that when people come with recurrent stone disease, oftentimes they will have a family history of another person having a disease, kidney stones. And we know that that is a risk factor, so we do ask for that in the clinic. Having said that, that doesn't mean that you have one single gene that is responsible for that. It could still be a collection of genes that put you at risk. Alternatively, it could even be that families tend to eat similarly and so therefore that kind of sort of sociologic environmental trait might also get passed down. But it is probably true that there are multiple genes that can still be passed down to family members and then those over that collection is heritable and it is a risk factor. So yes.

MAYA ADAM:

And you mentioned the way families eat. On that note, what about preventive actions -- diet, any other lifestyle changes that could be made to protect the kidneys or prevent this kind of disease?

ALAN PAO:

Yeah, so another really great question. Dietary approaches is the cornerstone for how we should treat patients with recurrent stone disease. I think before we start medicines, we always try to take a detailed dietary history and really look at the urine that the patients will give us and correlate it with the diet. And generally the urine that is excreted by the patient largely is influenced by what they put into their body that day. So we can sort of infer how the patient is eating by looking at the urine, whether it's too much salt, whether it's too much meat. Those things we can actually see. And that is the first part that we look at. And so we'd have general recommendations to have patients drink more fluids to dilute their urine down. Other more targeted effects are looking at the level of sodium intake. And so if the sodium intake is too high, that can make the calcium in the urine also high. And so we really try to ask patients to counsel them to lower their salt intake so that their calcium and their urine is lower. In terms of citrate, if one eats too much animal meat, animal meat is sort of an acid load to the body and that can reduce citrate in the urine as well. So we also talk about animal protein intake as part of that prevention diet that we recommend to patients.

MAYA ADAM:

So just to summarize, make sure we're well hydrated -- is that just plain water? I mean people talk with kidneys, people often talk about cranberry juice and things like that. Are you saying just more water?

ALAN PAO:

Fluids in general is good, yeah. And you want to do fluids that maybe also ideally do not increase your weight. So I think sugary fluids, like soft drinks, things, like that probably aren't as helpful. Just water is actually quite good. And we try to recommend to patients to drink fluids that will generate about two and a half to three liters of urine a day. So it's quite a bit actually.

MAYA ADAM:

So how many glasses a day should we be drinking?

ALAN PAO:

Yeah, so if you're drinking eight ounce glass, that's basically about 10 to 12 glasses a day of fluid. Now having said that, one of the things that we also talk about is that people think that drinking lots of fluids is actually good for the body and good for the kidneys, but there doesn't seem to be a lot of evidence that that's helpful for kidney function. But it is very helpful for people with kidney stone disease. And so that is one thing that I think is important for patients to know is just that if you have kidney stone disease, that's not the same thing as chronic kidney disease. A lot of people are rightfully fearful that if they have kidney stone disease, they have kidney disease. But we as nephrologists differentiate the two. One is sort of a kidney function and the filtering function; kidney stone disease is just that the urine that you excrete tends to have minerals in it that promotes kidney stones to form after it's been excreted from the kidney. So that's a bit different. But yeah, we do recommend people to drink lots of fluids so that they can dilute their urine down. That's the one group of patients where it is beneficial to drink lots of fluids throughout the day.

MAYA ADAM:

And Alan, I watched a short video before this meeting and you were talking with a patient about that patient's experience of struggling with this for years and sort of the unpredictability of it, and the almost fear that it's going to disrupt their lives without any warning. Tell us a bit about what it's like for patients to manage this and this kind of psychological burden as well as the physical implications.

ALAN PAO:

So I think it starts with the fact that when you have a kidney stone, it can be extremely painful. And I think that it's one of those things that will not relent unless the stone passes. And so people who have an acute stone episode can go through days to weeks of having pain. And I think that pain is what's really, really problematic for many patients. And so I think that -- I had a patient this week who came to me who had a surgery every year, and I think it just grew really disruptful to patient lives. The pain keeps them out of work, and then they have to go through a process of getting the stone removed. When the stone is removed, there's a stent that is left in place typically, and that stent basically keeps open the ureter from the kidney all the way down to the bladder. But that tube is very irritating to the patient. So when it's in there for a week or so, it's really uncomfortable. And so I think a lot of my patients who come to me are really frustrated with that whole process of taking the stone out. And so I think it's not sufficient to just remove the stone without at least addressing why the patient is forming the stone in the first place. For many patients it may not be an issue if they only form stones once or twice in their life, but there are patients who have stones every few weeks to few months. And for those patients it's just almost debilitating they can't do anything else. So I think it's the preventative part that I think is an overlooked part for many clinicians who take care of kidney stone disease. And I think that's the part that we really focus on is try to help prevent that next stone.

MAYA ADAM:

Okay. So take us more, a little bit more into the science of what you're working on with that citrate molecule and what are the potential better solutions that we have in the future maybe?

ALAN PAO:

Sure. So yeah, so citrate is like my favorite molecule over the fast few years, and it's an amazing molecule in the sense that it's an organic compound that can bind to calcium. And we actually use citrate in different contexts to bind up calcium so that it doesn't activate blood clotting. It's used in the packed red blood cells to keep the blood from clotting. We use it for hemodialysis in the ICU where we prevent the filter from clotting because the citrate can bind up to the calcium and prevent clotting of the cascade -- the clotting factors in the coagulation cascade. In the kidney, citrate will also bind to calcium and keep it away from oxalate and keeping it away from phosphate. So calcium oxalate and calcium phosphate are the most common kidney stones that people will develop. And so having a citrate that is too low in the urine, again, is a risk factor about maybe a quarter to a third of patients might have that. And so the idea is that if we can increase citrate excretion into the urine, it'll bind up and keep calcium away from the stones that are comprised of calcium oxalate and calcium phosphate. So the way that we currently treat that in patients is that we give either potassium citrate or sodium bicarbonate. Both of those supplements will cause the kidney to excrete more citrate in the urine. Citrate is filtered by the kidney and then it's reabsorbed by the kidney tubules through this transporter. And this transporter is believed to be the only transporter that regulates citrate into the urine. And so when we give patients alkali, we think that we're actually turning off that transporter, and that's why the citrate goes up in the urine when we give patients either potassium citrate or sodium bicarbonate. This is the current therapy. But the problem with it is that when you give patients either of those two supplements, what will happen is that the kidney will metabolize that in the process of metabolism. It will actually sense that there's an alkali load to the body and the kidney will excrete bicarbonate into the urine and this raises the urine pH. And paradoxically, it increases your risk of having calcium phosphate stones. So even though when we're trying to treat somebody with a low urine citrate, in certain patients, that will be offset by a rise in the urine pH so that the patients might form more stones over time. And so this is a problem for many patients, those with what I talked about who had renal tubular acidosis, people who are taking medications like Topiramate, which is used to treat seizures, and also in women too. So women tend to form more alkaline urine compared with men in general. And so female patients sometimes will have calcium phosphate stones and low urine citrate, and those patients, if their pH is too high in the urine, they shouldn't actually be placed on potassium citrate or sodium bicarbonate. So I think what our project is trying to address is if we can turn off that transporter without giving them alkali. So that would require us to have a compound that can specifically inhibit the transport characteristics of that target. And that target is called NaDC1. And so we've been trying for the past few years to find compounds that can inhibit NaDC1 so that we can just directly turn off absorption of citrate from the kidney so that there's more citrate that is excreted into the urine.

MAYA ADAM:

And there's no risk that the kidney will somehow sense that that's being downregulated and upregulate the production of more transporters.

ALAN PAO:

Yeah, that's a great question. From what we know so far, there are no other transporters that are involved in the kidney to absorb citrate, as far as we know. I mean, this is an area that actually still needs a lot of work. And I think sort of a second question -- follow-up question that you're implying is whether or not it's okay to inhibit NaDC1, will there be other consequences that we don't know about? And that's a really good question, both from a scientific standpoint, but also from a clinical standpoint. If we're going to be developing these inhibitors that can inhibit NaDC1, is it safe to do so in patients? And so in the past year, we've collaborated with a group in Tulane where there are mice that are -- have the NaDC1 gene knocked out. And so we are now phenotyping characterizing that knockout mouse to make sure that there's nothing that is bad happening. And so far, these mice, they live normally, they behave normally, they reproduce fine. So it seems like there's some redundancy that can take away from some of the things that we're doing to the mouse so that they're not having the NaDC1. And they do increase -- they do have high citrate in the urine as well. So from the knockout mice, it looks like that they tend to be normal. And so our hope is that that's an encouraging kind of clue that it would be okay to try to inhibit this transporter without having any bad consequences.

MAYA ADAM:

Very interesting. I have so many more questions, but I'm going to shift a little bit because I want to ask you what it's like when you are interacting with a patient that has struggled with this for years, and you let them know that you're working on this very innovative solution that could be a long-term solution. What's that for the patient? What's that like for you as the physician? I noticed in the video that I watched that you mentioned that often the work -- the science you're doing is motivated by a sort of flashback to these discussions you have with the patients who are struggling with this problem. I think that's really wonderful and would love to hear more.

ALAN PAO:

So the patient that you're referring to -- he actually was one of the first patients that inspired me to go on this project. He had a problem where his citrate was too low and his urine pH was too high. And I do remember him asking me what other things that we can do to treat this so that he wasn't getting stones all the time. And then I did tell him that actually there wasn't anything that we had. And he asked me if there were ways that he could help to try to make that a possibility where we could develop some new treatment. And it was at that time that I was thinking about this project of inhibiting NaDC1, which would benefit him if it came to fruition. And so he has been really the face that I see when I think about hypocitraturia, I mean, he's always in my head. There are other patients that I have also that kind of pop into my head. And I think that's sort of the beauty of being a physician scientist is that it's not just a theoretical problem, but there are patients that you take care of who have this problem. And so I think having the human face in your mind and the social interactions that you have is really what drives a lot of what we do is to say, well, we can use the signs to really help people. And I think that that's probably why every physician goes into the field is to do that. And so I think he's definitely the person that I think of when I go through every day to look at the data. And then every Tuesday, I come to Stanford for my clinic. And so I see him periodically. I see a lot of my other patients who have a similar thing. And so I think it's a really special thing. And I think that's something that can take a lot of time to get to where you could kind of unite what you're learning in the lab to how you can actually treat them by the bedside.

MAYA ADAM:

Wow, that's inspiring. Alan, tell me, what are the biggest challenges? What are your toughest days? What do they look like?

ALAN PAO:

Toughest days? In what context? In the lab?

MAYA ADAM:

The work, the patient load, any of the above.

ALAN PAO:

Well, I think in the lab, many things don't pan out as you think that they will. I think, for example, right now we have a lot of candidate compounds that can work in cells. And what we're doing now is screening for those compounds to see which ones will actually get to the urine, and then also increase citrate in the urine. And so right now we're at the phase of translating the in vitro findings to the in vivo findings. And so there's a lot of compounds that don't work. And so I think that is disappointing when you spend all this time characterizing those compounds that they're not doing what you think they're doing, but the opportunities to find out why it's not working, and then to try to figure out how to change the compound so that it will work. And so we're at that stage right now where we have a few compounds where we think it works, but we want to make it better. And I think that that part is an iterative process that can be good on some days and sort of frustrating on other days. I used to think that going to the clinic sometimes can take away time from the laboratory, and I think that that makes for a long day when you're actually in the hospital, in the clinic, and then go back to the laboratory to check up on what's happening through the day. And I think that part was tiring. But I do think the benefits of that are twofold: One is that the day is more interesting. You're not just kind of in one place, but you're seeing patients, you're in the laboratory, and that's a really cool thing. I think it's always exciting. And so there's lots to do every day when you wake up in the morning. The other thing is is that again, seeing patients kind of remind you of the diseases that they have, their manifestations and then how best to help them. It kind of recharges the drive to try to find something in the lab. So I would say some things are frustrating, but it also can be very rewarding at the same time. So it's kind of two different sides of the same coin.

MAYA ADAM:

Lovely. That is a lovely note to end on, and I'm so happy that we got to speak. I'm so grateful to you for making the time. I learned so much, and I just wish you all the best. I hope that the experiments that you're working on come to fruition and very grateful to you for joining us, Alan.

ALAN PAO:

Great. Thank you Maya for asking all those great questions.

MAYA ADAM:

And to our listeners, thank you for spending part of your day with us on Stanford Medicine's Health Compass podcast. If you'd like to keep listening, just follow Health Compass on your favorite podcast app and we'll be back with more stories and conversations that aim to help us make sense of the science around us.