Urologist Nirmish Singla, MD, MSc, discusses kidney health for bladder cancer patients, and how "It's All Related" during the Johns Hopkins Greenberg Bladder Cancer Institute Grand Rounds in February 2022.
Hello everyone welcome to our series. Our team is grateful You're here of course seeing you in person be preferable. But given the ongoing response to managing the SARS cov two pandemic at Hopkins in our local communities. These virtual platforms are proving to be an efficient means of for sharing information and for education and discussion. Couple of updates. Next month, March eight I'm excited to announce that Dr Otis Brawley will be joining us to talk about bladder cancer prevention and control from a national perspective. Dr Brawley is a Bloomberg distinguished professor and serves john Hopkins as director of our community outreach for the Kimmel Cancer Center. A trained medical oncologist. Otis has served in leadership roles at Emory and the american Cancer Society. He's a much sought after expert and I'm sure you will enjoy hearing from him. You can find our updated programming and a new newsletter on the web google Greenberg bladder cancer institute. And I wanted again to draw attention to our evolving group of programs specifically tailored around the experiences of women with bladder cancer led by doctors are mean smith and jeanie Hoffman census and the program team of Pamela gets Samantha Rockler and Stephanie Cooper Greenberg. Again, all of these are up on our site and if we can help you directly we are only an email away at bladder cancer at j H M E dot edu. It is a pleasure to introduce you to norma's Singla who's joining us today for a conversation about kidney health and bladder cancer. Dr enormous single is an assistant professor of urology and oncology in the brady urological institute at johns Hopkins. He serves as the director of translational research in genital urinary oncology and helps lead the multidisciplinary kidney cancer program at johns Hopkins. As a urologic oncologist. Dr Singler is a close collaborator with our Greenberg team where he works alongside Dr Hoffman census in our upper track program, Dr Singla attended the University of michigan medical school before completing his residency training and urologic surgery at the University of texas Southwestern Medical Center in Dallas. He then completed a specialized clinical fellowship in urologic oncology at Memorial Sloan Kettering Cancer center in new york to the Society of Urologic Oncology before joining our faculty more than their incredible portfolio discovery numbers represents the very best of our institutes, focus and commitment to patients and families. I'm grateful for his service to our patients, families and larger community. Dr Singla, welcome and thank you for joining us. Today, Anonymous has agreed to speak for about 30 minutes or so and then we'll jump to a larger group discussion. I would ask for folks to bring their questions into the chat and after the conversation will have ample time for group discussion. Excellent. Well, I I really appreciate that kind introduction. Dr McConkey. Uh let me just go ahead and share my screen. Hopefully this will work. Okay, fantastic. Um so, good afternoon everybody. And again, it is truly my honor and privilege to be able to speak at today's G. B. C. I grand round sessions. Um But today I wanted to highlight a topic that I think deserves considerable discussion related to kidney health as it pertains to patients with your epithelial carcinoma. I think in the original flyer it's had bladder cancer but I did want to high highlight some particular nuances as it pertains also to a lesser common entity referred to as Upper Track with the little carcinoma as well. And so I wanted to just first discuss things for a little bit from my perspective and then have an opportunity to allow for this to be an interactive forum. Um so that if anyone has any questions pertaining to kidney out in europe, hello carcinoma and there will be ample opportunity to discuss the um and just to begin I have no relevant disclosures. Okay so the goal of today's talk would be largely to first start off by discussing what kidney health truly is. So this is a bit of a more fundamental introduction. But I think it would help set the stage for what it is that we refer to when we talk about kidney health. And then um I wanted to talk a little bit about the nuanced relevance of kidney health first as it pertains to bladder cancer and the treatment for bladder cancer and then talk about its relationship to U. T. U. C. Or upper track your cell carcinoma. So first what is can you help? So again this is probably fairly fundamental but just to kind of go from the ground up uh the kidneys as you know, our two about fist sized organs in the body that undertake a number of vital functions. These include things such as eliminating waste products and drugs and toxins into the urine, regulating electrolyte concentrations, fluid balance and blood pressure for the body, maintaining an acid base homeostasis and also producing important hormones that are relevant to both blood production as well as bone health. Now, when it comes to kidney health, we are essentially for the purposes of this talk referring to kidney function, a renal function. Now this is typically measured by what we refer to as estimated glamorous color filtration rate, which is a calculation that's based on um essentially blood work. Um serum creatinine is one of the most important surrogates for one's overall kidney function or kidney health. And furthermore the an assessment of the urine can also play an important role as the presence of protein in the urine. Can sometimes also signify potential dysfunction in the kidneys. Um Now I do want to also make the distinction between the role of various specialists when it comes to kidneys. Um as a urologist, my primary role tends to be largely surgical in nature when it comes to doing kidney surgery. However, we also tend to interface very closely with the nephrologist says who are internal medicine trained medical specialists who deal with the medical aspects of kidney health. And so in large part they would be the ones to monitor kidney function over time and also take into consideration aspects related to prevention of chronic kidney disease. Um and looking at aspects of medications and various interactions they may have that that could have some influence on kidney function. And so having that close interplay between different team members and engagement with the nephrologist is absolutely critical. And when we talk about overall kidney health worsening of renal function is what we refer to as CKD or chronic kidney disease. And this is entirely measured by the E G fr or again the globular filtration rate. And in general When we find that the e.g. falls below 60, that's when we start to get more concerned about stage three chronic kidney disease. And as we start to get closer and closer to 15 or less, that's when we start to worry about end stage renal disease. And considerations like dialysis become more pertinent at this stage. And so just to give some basic fundamental framework for our discussion today, there are a number of predisposing risk factors that have been identified for the development of CKD and these include things like underlying medical conditions such as diabetes, hypertension, cardiovascular disease and obesity, environmental exposures like tobacco use. Um even inherent genetics that may pertain to for example, african american race or having a family history of CKD congenital and acquired structural abnormalities um recurrent urinary tract infections, specifically pilot nephritis, which can sometimes lead to scarring in the long term chronic obstruction, Things related to, for example, kidney stones or other structural reasons for why there may be some obstruction that has developed and also an increased risk with advanced stage. Now, when it comes to symptoms of CKD, these generally tend to be very non specific, so there isn't necessarily a specific symptom per se that may suggest the presence of CKD. However, patients who do suffer from CKD may exhibit some constellation of symptoms that could include things like nausea and vomiting, loss of appetite, fatigue, weakness, changes in urine volume, which in some cases may involve decreased urine output more often. But in some cases even done, concentrated elevation of your volumes can also signify a potential issue related to the kidney beans, altered mental status or confusion, muscle cramps from electrolyte abnormalities, swelling that can develop from fluid retention, dryer, itchy skin and then other manifestations such as higher blood pressure, shortness of breath, chest pain or palpitations. Now, the reason why it's very important to manage CKD is because when left unchecked, there can sometimes be very serious sick, well related to CKD and these include things like, again, exacerbation of hypertension from fluid retention, electrolyte imbalances that could potentially lead to cardiovascular dysfunction. Um due to the importance of the kidneys in bone health and and blood production as well. There can sometimes be an increased risk of bone fractures or anemia, decreased sex drive and fertility related issues, um, altered mental status and potentially even seizures compromising the immune system. Even pregnancy complications for those who are currently or hoping to get pregnant. Um and then again, as the kidney function continues to deteriorate, there is this concern for development of end stage renal disease and potential um dependence on dialysis. Um it has also been found to be an independent predictor in and of itself of accelerated mortality to have chronic kidney disease. And for these reasons. Um we uh we do pay serious attention to one's kidney function. And so for these reasons, you know, we do want to look and see if there are ways in which we can help preserve kidney health overall and specifically the ways in which we can maybe prevent deterioration of kidney function, both in patients who have normal kidney health and baseline as well as those who may have some degree of compromise. And so some ways that that are important to keep in mind include medications and they're dozing the types of medications patients may beyond the way that they are cleared from the body as well as interactions with one another, maintaining a healthy lifestyle. So, from the standpoint of um, things like blood pressure control blood glucose control, maintaining an overall healthy weight avoidance of risk factors like tobacco and other exposures, um and then maintaining an adequate degree of hydration and then again, early consultation with the nephrologist can absolutely be paramount for patients who either may have some early signs or lab values that may suggest potential development of renal compromise or in patients who may have needed to have surgery that that either has amounted to removable of the kidney or may may result in some cryogenic compromise to the kidney function. And now also as being a kidney surgeon myself who almost routinely removes kidneys from the body. I do want to also answer a question that I often will get in the clinic which is um, you know, is it possible to live a but then also live a healthy normal life with just one kidney. And the answer to that is that it is in fact indeed very possible to live a normal healthy life with just one kidney. But the caveat is that it is important to pay attention to these factors on the slide and and ways in which we can try to prevent renal deterioration and making sure that, you know, if needed, early consultation with the nephrologist and monitoring of the kidney functions are implemented in those cases to help optimize outcomes in the long term. Okay, so now that now that you have sort of a nephrology, 101, fundamental basic about kidney health. Um I wanted to transition to sort of the meat and bones of this talk, which is the relationship of kidney health and your epithelial cancers. And again, I wanted to break up this talk by focusing primarily on bladder cancer but then having an opportunity to also discuss its relationship to you t you see. So with respect to bladder cancer and kidney health, these are absolutely intimately related for a number of reasons. The first consideration when approaching patients who have bladder cancer is to get a sense of what the baseline kidney health is and the reason for that is multifold first is to consider the types of treatments that patients may be eligible for. Since that is largely predicated on what the baseline kidney function was. Um in particular, one thing we very often think about is eligibility for certain systemic treatments because of the potential toxicities that some of our treatments will have on the kidneys. And I'll go into this in more detail momentarily. Um for patients who are requiring um definitive or extra operative surgery, I. E. Stephanie to remove the bladder. Uh the type of urinary diversion um that can be offered to a patient may also be influenced by what the baseline kidney function looks like. Um And then also CKD can be a surrogate assessment of one's overall general health and because of that, one's operative candidacy may be influenced by by whether or not there is CKD or other related comorbidities. At baseline. The other aspect to make mention of here also is that ideally when it comes to staging patients who are diagnosed with bladder cancer or your epithelial cancers in general. Um We we rely heavily on Io donated I. V. Contrast enhanced cross sectional images. And so the the unfortunate aspect of I. V. Contrast is that it does have potential deleterious effects on the the kidney or at the very least it's cleared from the kidney. And so for those who have a compromised baseline kidney function that may limit our ability to perform such imaging for for adequate staging imaging. Um But in addition to baseline keeping health, it's also pertinent to maintain keeping health both throughout the treatment course and then in the long run once treatment is complete. Um And the reason for this is also pertinent to these types of therapies that we use for bladder cancer a because of the systemic therapies which now more and more uh will incorporate either um platinum based natural toxic chemotherapies or uh and or the use of their immuno immuno therapies. And again I'll go into this in a bit more detail momentarily and then also some of the sequel from having a urinary diversion which is essentially a segment of bowel that then becomes the conduit or the palace by which urine can be eliminated from the body. Um We also continue to surveil images. Surveil patients long term using cross sectional imaging which may require the use of coordinated contrast and then patients with bladder cancer also have the potential for recurrence in the upper urinary tracts or developing ut you see and uh and again I have a segment of this talk dedicated to U. T. U. C. Specifically. But some of those treatments may also impact kidney function overall as well. So the first the first aspect related to bladder cancer treatment and eligibility for treatment is predicated on the use of chemotherapy. Um Now this I should mention this is specific to intravenous chemotherapy. So systemic chemotherapies and not so much for patients who maybe require topical chemotherapy installations into the bladder, which are not quite system systemically absorbed in the same manner as ivy chemotherapy would would expose the kidneys. But essentially for patients who either have non metastatic muscle invasive bladder cancer um who may benefit from neo adjuvant or preoperative strategies with chemotherapy or patients with metastatic bladder cancer who may benefit from induction chemotherapies. The current gold standard approach is to use a cis platinum platinum containing regimen. Now, the problem with this plan is that unfortunately it tends to be relatively harsher type of chemotherapy and in large part some of the toxicities associated with this plan are due to the kidneys. So baseline kidney function would determine whether or not a patient may be eligible to receive six plan but then also for patients who are eligible to receive this plan. And there may be some concerns as well related to how their kidneys Mayfair during and beyond the completion of treatment. Now there has been an immense body of literature that has emerged, particularly from the nephrology groups um that have looked at understanding the underlying mechanisms of metro toxicity amounting from CISplatin based chemotherapy. And there have actually been a number of different mechanisms proposed and shone through through a variety of basic science models and these include a combination of perhaps direct tubular injury. So direct injury of the agent to the african or the functional unit of the kidney, vascular injury and ischemic related complications from the agent apoptosis or essentially direct sido toxicity to the cells. Um oxidative stress and the generation of free oxygen radicals. And one thing that has garnered considerable contemporary interest is whether there is also an inflammatory and inflammatory role that chemotherapy may play in terms of potential rating renal damage. Another emerging type of systemic therapy that is starting to gain more and more attraction, especially for your epithelial cancers is something called immune checkpoint inhibitors and these are starting to play more of a role either in isolation or in combination with other um agents. And in general the benefit of these is that compared to for example, CISplatin based chemotherapy, um immune immune checkpoint inhibitors tend not to carry the same degree of renal toxicities. However, there have been some manifestations of renal injury that have been found to amount from the use of these types of immuno therapies in general. The main form of Renal dysfunction that has has been shown to be directly attributable to immunotherapy is is something called acute interstitial nephritis or essentially an inflammatory induced renal compromise and that may be seen in about anywhere from 2-5% of patients who who are on immuno therapies. However, there are also other mechanisms that name play a more minor role that may amount to renal dysfunction in patients who are on these therapies. And these include things like a tnR acute tubular necrosis, thrombin, arctic micro angioplasties and multiple glomeruli allergic diseases. Now, even though these are the types of um toxicities that are directly thought to be directly attributable to, you know, therapies, the overall quoted rate of patients who may have some form of renal dysfunction while on immunotherapy maybe even as high as say 15-17%. And these may be again more multifactorial and could be related to other causes as well. Mhm. Furthermore, you know, the the use of these immuno therapies may compound renal failure when there are other types of therapies being utilized or other medications that may pose risk factors for developing renal dysfunction. And generally if if a patient were to develop some form of a immuno toxicity from from these types of therapies. Uh Generally the first step would be to discontinue the offending agent. Uh and then secondarily if needed. Um consider means of immuno suppression to basically scale back on the on the body's innate immune response to to these agents that may be causing them to fry tous. Um So things like steroids or even stronger immune suppressing agents can be used as well. Um and I wanted to highlight this this complex interplay between the immune system and toxicities with respect to uh the use of these types of chemotherapy agents. Because this actually is an active area of engagement with some of our own investigators here at johns Hopkins. And I highlight here um some monumental work done by one of our transplant nephrologist who is also a basic scientist, dr Hamid rob who over the course of the last you know, 15 to 20 years has made quite a few discoveries in the world of of nephrology and and specifically um CISplatin based toxicities. Um and so uh one thing I wanted to highlight here is um some of his recent work looking at double negative T cells um and and their ability to perhaps protect against platinum induced renal dysfunction. These specific types of T cells are part of the immune system, but they are importantly an immuno suppressive type of model, a Torrey um group of cells. And so the thought is that there may be some form of a complex interplay between immune mediated mechanisms and platinum induced toxicities that we're finding that there could be a protective role when the immune system is able to be suppressed within the kidney. Uh and that essentially lends more evidence that this plant based toxicity to the kidney, maybe uh at least in part due to these these inflammatory mechanisms that this is absolutely an area of ongoing interest in the nephrology community. This also begs the question of whether there may be opportunities for further discovery of biomarkers to help predict renal dysfunction in patients who may require CISplatin based chemotherapy and indeed through partnerships between our group and others such as dr rob, I think that this absolutely highlights a very important role that interdisciplinary collaboration can play in terms of making more discoveries in this in this realm, shifting gears here. Um there's also some important aspects related to renal function as it pertains to surgical management of bladder cancer. Um So for those who do have typically either refractory non muslim, high risk, non Muslims cancer or those who have right or those who have or those who have muslim basic disease and require surgical extra patients. There needs to be a way in which the urine can exit from the body. And so in these patients we often will refashion a segment of bowel and create what's called the urinary diversion of which there are several types. Now the the caveat of urinary diversion is that it does involve the contact between a viable segment of bowel and urine as well. Um what this means is that there are implications with respect to re absorption of certain parts of the urine or secretion of other electrolytes into the urine that can sometimes alter the normal acid based balance within the body or amount to metabolic arrangements. So there are a few different types of urinary diversions. These include um an alien conduit which is the simplest form and involves the least amount of the whole. But then there are also other continent forms of urinary diversions as well. Uh And the the types of electrolyte abnormalities that can sometimes be seen with urinary diversions tend to be more more pronounced for patients who have these content diversions by virtue of having a larger surface area of contact between urine and bowel, but then also a longer duration of contact as well. Um The issues that also sometimes arises because of the inherent metabolic abnormalities that may arise from having these types of diversions patients may represent with issues related to dehydration or failure to thrive. And unfortunately this can sometimes further compound acute renal injuries. Um And so because of these reasons we actually do utilize baseline renal function as a means to stratify which patients may be appropriate for receipt of some of these types of diversions and in particular because of the more pronounced risk of of having uh electrolyte and metabolic arrangements with the continent diversions. Baseline renal dysfunction is often the contrary indication to constant diversions when we're counseling patients in the office. And I wanted to highlight this study. It was actually just published last month by one of my close colleagues on the West Coast because I thought this was this was actually very interesting um sort of analysis of renal function in patients who are undergoing radical suspecting me. And essentially, within the study, the investigators assessed factors associated with developing advanced chronic kidney disease, defined as essentially an e g f r of less than 30 or stage four and five CKD after undergoing a cyst ectomy across um, more than 3000 patients captured within the Veterans Affairs database spanning across about 15 years of data. Um, what was remarkable is that, well, over the course of five years, um, that they had assessed patients post operatively. There was an overall decline in kidney function in patients who had received, um, suspecting me, Emilio conduit or neo bladder. Uh, and in particular, the decline was most pronounced within the 1st 12 months of undergoing surgery. Now, the aspect that is more concerning is that nearly one third of patients are, about 30% of patients actually progressed to CKD stage four or five within those 1st 12 months. Uh, and now this may be certainly multifactorial as it may pertain also to other underlying health conditions or exposures that may predispose patients to forming bladder cancer that may also compound renal function. And so, the investigators also then performed a multi variable analysis to assess for any any factors that may be associated with development of advanced CKD post op in these patients. And they did identify that factors such as advanced age, preoperative hydro necrosis or obstruction of the kidneys at use of adjuvant chemotherapy, higher baseline co morbidity index, lower baseline kidney function all amounted to increased risk of developing CKD. Um, interestingly there was no difference based on whether a patient had received neo bladder or an illegal conduit, although some may argue that there could be some selection bias in selecting patients to receive a neo bladder based on baseline CKD. However, an important point that did emerge from their analysis is when looking at mortality risk, lower baseline tv function was significantly associated with a higher risk of death in patients undergoing suspect to me and as a result from the standpoint of patient counseling as well as understanding risk stratification for patients undergoing surgery. This should be um, a factor that is included within the counseling process. Yeah, switching gears here. I did want to talk a little bit also about less common form of cancer called upper tract epithelial carcinoma. Um, for those of you who attended one of our earlier gdc I. Grand round sessions, uh um, you may have received a little bit of background about this entity, so I won't go into too much detail, but uh, In general, as far as European carcinoma, there can arise anywhere along the lining of the urinary track from the kidneys down the orders all the way to the bladder. And whereas bladder cancer accounts for anywhere from 90 to 95% of all your ethereal Carson cancers. About 5-10% maybe of this flavor called U.T. you see and this is this is actually particularly nuanced as it relates to kidney health for a few reasons paralleling the earlier slide on bladder cancer. We first have to look at baseline kidney health because that does affect eligibility for certain treatments. We talked about the use of certain systemic therapies which in large part are mirrored in UT you see off of what's used in the bladder cancer space. But then also there are important, unique treatment strategies from a surgical standpoint for patients with beauty, you see as the gold standard approach typically entails the removal of a renal unit or a nephrology redirected me. Uh and there are emerging interests in in terms of renal sparing approaches to help maximize kidney function among these patients. Furthermore imaging cross sectional iota I automated contrast based imaging also plays an important role in staging these patients. But then again, aside from the baseline aspects related to kidney health for patients who are receiving treatment for you. T you see maintenance of kidney health is remains paramount as well. Again, due to the toxicities from the use of similar systemic therapies as is used in bladder cancer, but then also the fact that oftentimes if you do have to remove a kidney from a patient, how do we continue to maintain an appropriate health of the overall kidney state. Um, and so for that, um, it absolutely becomes even more paramount to engage with early consultation with nephrology specialist. Um Now with respect to U. T. You see, I'm just going to talk a little bit about the role for systemic therapies as we know for bladder cancer. There is a level one evidence that has supported the use of neo adjuvant or pre surgical chemo CISplatin based chemotherapy regimens prior to surgery in patients who have non metastatic muscle invasive bladder cancer in the space of UT you see. Um we lack the same level of evidence. However, there is absolutely a role for for the use of systemic therapies and the timing and the role have continued to be in flux and continued to evolve today. Um Unfortunately with you to see patients often at baseline tend to, on the average be a bit older, a bit sicker. And oftentimes have multiple factors that may predispose them to having baseline CKD. In fact, if you were to sort of look across a number of series anywhere from 37 to 58% of patients with you t you see may be eligible to receive chemotherapy. Even prior to undergoing any treatment of their U. T. You see. Unfortunately, that renders a substantial proportion of patients, nearly half of patients ineligible even before treating them as a result of the actuary legalization of platinum based chemotherapy is largely limited because of the because of the exclusion exclusionary factors related to the baseline health. And so when we treat patients with beauty, you see, it becomes a fine balance because on the one hand we perceive oncological benefit. So treatment of the cancer may benefit from use of the chemotherapy agents. But then on the other hand, there's also the concern about increased mortality, risk related to uh, to kidney failure. And so so trying to traverse that balance and finding the appropriate balance between Risking mortality from cancer versus risking mortality from end stage renal disease becomes a very nuanced discussion and one that often can can challenge the discussions that we have with patients in this space. The other aspect unique to this disease is that again, if the definitive gold standard approach for non metastatic treatment patients is to remove a kidney that um, that often will further compromise the kidney function. And so for patients who did not receive chemotherapy upfront, doing a surgery may further limit the ability to give chemotherapy adamantly or post operatively. And series quote only 15% or so patients may remain eligible. And so this has been this has actually been an active area of interest of mine back when I was in residency and between some of the studies that we looked at at the time as well as other contemporary groups, there have been quite a few studies that have emerged with interest in understanding predictors of outcomes and renal function after undergoing extensive surgery for for this type of disease. Um, and indeed, there has been ongoing efforts to sort of push the envelope as far as um, surgical approaches that may be able to spare the kidneys in as much as we can. Um, and so some of the work that we looked at tried to assess whether doing a radical hysterectomy or removing the kidney and ureter versus just removing a segment of your inspiring the kidney may may potentially impact kidney function. And what other factors are there associated with worsening function after undergoing extra operative surgery. Some of the findings we reported on included that adjuvant chemotherapy did appear to be the most significant predictor of new or worsening chronic kidney disease after undergoing surgery. And furthermore patients who have had some, some hydra necrosis or essentially obstruction of the side that's affected at baseline are those who are actually more likely to experience less of a decline in their tv function. And this makes sense logically, since uh, the the concept here is that these patients have likely been obstructed for some degree of time and has allowed for their other kidney too to accommodate some of the kidney function to some degree before that kidney is removed. This also actually for for better or for worse, does work in these patients favor because we've also noted that patients who demonstrate hydrogen fibrosis in UT you see often have characteristics associated with worse prognostic outcomes. And so these are the patients who are more likely to derive benefit from the use of chemotherapy. And so if we are able to um less likely impact their kidney function by removing the kidney at the very least, we can hope that their kidney function will remain relatively well preserved despite a surgical intervention. We also did a follow up systematic review. Shortly thereafter, systematic review and meta analysis assessing both oncological and renal functional outcomes based on the surgical approach. In other words, sparing the kidney versus removing the kidney and murder. And not um not surprisingly, it was in fact shown in the in the meta analysis that um, patients who did have the removal of the kidney compared to those who just had a segmental your directory or just removal of the affected segment of your order um, did have worse renal functional outcomes. Um, now I did also want to highlight that again. Um, the role for chemotherapy is one that continues to evolve in U. T. U. C. And given the relative rarity of this disease, it is actually rather challenging to um to conduct um good evidence sort of well controlled prospective trials in the space that being said a couple of years ago, there were there were two important clinical trials that were published first was one that was published in the adjuvant or postoperative state. This is something called the Ouch trial which is a phase three randomized controlled trial uh in this trial, patients would undergo enough for your directing me and receive either cis platinum or for those who are ineligible based on their kidney function. Carbon Platten versus surveillance strategy alone For locally advanced ut you see after surgery. And as it turned out from a cancer control perspective, patients who received chemotherapy exhibited a approximately 25% absolute benefit with respect to recurrence and mortality rates attesting to the benefit of chemotherapy in general for these patients. Now, there may be some who would say that, you know, with this trial based on what I showed earlier with respect to eligibility for chemotherapy, especially post before you directed me. Um, you know, there's a substantial handful of patients who may not even be eligible for this type of an approach and that served as the, as the underlying rationale to conduct a trial that was actually lead. It was a multi institutional trial but led here by Dr Hoffman senses herself termed the E Cog Akron 81 41 trial. This was a phase two single arm trial that included the use of neo adjuvant CISplatin based approaches or genocide. Being carbon planning for the few patients that were ineligible based on their kidney function for high grade U T U C. Prior to underlying network, you're directing you. This was actually um, noteworthy for certainly a few reasons but looking at what's called the pathologic complete response rate or the essentially the eradication of disease seen in the final specimen after it was removed. Uh, About 14% of patients actually had no residual disease after the use of chemotherapy Furthermore. They also had noted that over 60% of patients had been found to have non muscle invasive disease on their final specimen, either from presumably down staging from chemotherapy or perhaps in a subset of patients, even just inherently lower stage disease to begin with. And so this has largely become our institutional preference for patients who do present with higher risk you t you see that we often try to offer them chemotherapy in a neo adjuvant setting whenever they are eligible to receive it. Um Now I won't be labor, some of the ongoing work too much or get into the weeds too heavily here, but I did want to highlight that there are indeed a number of ongoing active research efforts here at johNS Hopkins to better understand the role for um kidney health in in ut you see again, as I mentioned earlier, in large part, we are trying to um discover ways in which we can better spare kidneys while also balancing that risk of cancer control. Uh And so just to highlight some of the ongoing efforts, um uh there are multi institutional collaborations that were involved with um one of which is being run by Dr Rahman at Penn State University looking at endoscopic management or you arthroscopic management alone for patients who present with you. T you see to better understand if this is a technique that can potentially be applied to high risk patients while minimizing um, the risk of cancer spread. Uh this is a technique that generally has been reserved for patients with lower grade disease. And yet we don't fully understand whether it's effective or not for higher grade disease. We also tend to reserve informations who are not great operative candidates. Other studies worth highlighting. There was there was a trial that that Johns Hopkins was a part of that led to the FDA approval for a mighty mice and continuing reverse thermal gel, currently marketed as jell Mido, particularly for patients with low grade you. T you see that um, that maybe endoscopic leon perceptible. The idea behind using this agent is hopefully to decrease the chance of recurrence in the future, but also offer an opportunity to spare the kidney. Um, we also have an upcoming trial that is currently undergoing regulatory review and we hope to have off the ground uh, if all goes smoothly within the next month or two, it is currently open at other sites and we're hoping to open our site here at johns Hopkins called the N Lighted Trial. This is a phase three trial using a novel um, laser technology essentially referred to as a vascular targeted photodynamic approach, in which we uh likewise hope to be able to better manage patients with low grade you, t you see more effectively and again be able to offer them uh, kidney sparing approaches to their to their care. And then there's also another trial that dr Hoffman census has been working on referred to as the renal retention trial for those who are either medically inoperable or who outright refused undergoing an effort to direct me as another means of retaining the kidney for kidneys. Um, there are other ongoing efforts as well in which we are involved related to U. T. U. C. And kidney health. Um, there is another trial that again, Dr Hoffman sense its can attest to. This is a similar in scope to the prior to trial that I mentioned before. This is like the ecology Akron 81 41 trial. This is the cog Akron 81 92 trial that involves a new agreement. Use of not just cis platinum containing chemotherapy, but also in combination with an immune checkpoint inhibitor called jarvela mob. And then there are other collaborative efforts with our colleagues at other institutions trying to better predict the postoperative decline in kidney function after undergoing neck for your directory. And we feel that this is absolutely pertinent to patient counseling when when we are considering surgery for for patients with you, t you see. And so just to sort of wrap things up and again, I do want to leave adequate time for questions. Just some concluding remarks. Um, you know, as as highlighted here absolutely maintaining kidney health is crucial to optimizing outcomes and survival in general, but then, especially within the realm of european, low carcinoma patients, kidney health are absolutely very intimately tied with with the management of both bladder cancer and you t you see and the reasons for this is because a baseline renal function influences treatment options that are available to patients but then be uh the treatments that we offer are also tightly tightly impact kidney function uh and specific to each disease state both bladder cancer and you t you see these carry inherent nuances with respect to keeping health that I outlined here in there. This is absolutely an active area of of academic interest to us with clinical, with practical applications clinically and so we um we are engaging in ongoing work both through collaborations internally and collaborations externally towards maximizing kidney function in patients affected by your Theodore carcinoma. And uh and I think hopefully this talk has highlighted the importance of engaging a multidisciplinary personalized approach to each patient specifically with easy access to um nephrology consultation given given the paramount role that they play for patients who have urethral carcinoma in the long term. Um and I'll also just utilize this opportunity to put in another plug for a recently implemented ut you see multidisciplinary clinic that was officially launched last year as a way to help streamline the ability to um to allow patients access to specialists both in nephrology and in other fields who may have this more complicated, intricate form of the disease that that would warrant care from not just the urologist and not just a multi medical oncologist, but perhaps other specialists as well. So on that, this is this is my last slide. I do want to thank you again for the, for the opportunity to present at today's Gdc. I grand round session and of course I'd be more than happy to uh, to answer any questions that, that, that the audience may have never miss. Maybe if you would, you could stop sharing your screen. Absolutely. So, I'm going to start with a question to rise in the chat and um, the question is, is bladder cancer or kidney stones a risk factor for CKD? It's a it's a very good question. Um, so, uh, you know, I think the, the nuances related to bladder cancer. I think that we discussed here in, I think are important to consider because absolutely, the treatment options that exist for bladder cancer can be directly related to the development of CKD, uh, the bladder cancer in and of itself. You know, the thing we tend to worry the most about when it comes to kidney function would be that sometimes bladder cancer can result in obstruction of a or both kidneys, either from the bladder itself or even potentially from enlarged lymph nodes or other sites of metastases. And so in those scenarios we do tend to have to worry about about kidney cancer, sorry about chronic kidney disease directly related to the bladder cancer itself with respect to the kidney stones. Um, that absolutely is something that is again entirely related with with kidney health. I didn't devote this talk towards kidney stones specifically because it does, I think warrant it's it's enough of a topic that I think could anyone could do an independent talk on that but with respect to kidney stones. So, the issues that may relate to that and kidney function would include obstruction of of the, of the urinary tract that can sometimes cause hydro necrosis or for worsening kidney function related to that as well as, um, the sometimes the repeated treatments that patients may require for kidney stones, repeated manipulation of the urinary tract, either through your arthroscopy or pro catania's national economy. That in and of itself can also sometimes cause urethral scarring over time if they're frequent stone formers extinguish. So, I'm going to go to the question answer now. Um, What no ephron sparing surgical approaches are available for patients with high grade humourous upper one third, mid one third, one third. Um, it's it's an excellent question. Uh, and you know, uh, at the moment, so, when we're thinking about high grade tumors, surgical management, the gold standard would be currently extra operative surgery. So, extractive. What does that actually mean? Uh, it means removal of the involved segment. So, you know, the gold standard typically would be um, certainly for a renal pelvis tumors or tumors within the proximal ureter generally in frou redirected. Now, there has been a contemporary interest in trying to see if there is the ability to remove the segment of your order and reconstruct the urinary tract in a way that we can still obtain um comparable oncological outcomes for patients who have a distal, you're doing something called a distal um directory or removing the last part of the order and then re implanting the the more proximal portion of the order of the upper part of the order back into the bladder is an is an acceptable approach and has actually been shown to carry uh similar oncological outcomes even in the setting of high grade disease. Um, the challenges that we start to face from a technical standpoint arise when we start to try this approach for patients who have tumors that are higher up. So even in the mid year, for example, we sometimes have to become more creative if we're going to try and make an aggressive approach of saving the kidney. Sometimes there are ways to make something called the blurry flap or essentially utilizing a flap of the bladder to help bridge the gap in the year that would result. Sometimes we have to do something called the sos hitch to basically mobilize the bladder and attack it up on the soas muscle to help it reach. There are also techniques such as the downward natural pixie. So mobilizing the kidney to make it come down a little bit to help reach the bladder. Um, there are other techniques as well that that may be subject to complications. Things that involve interposition, sometimes even using the balance segment. But we um for your epithelial cancers often take more pause when we try to apply these types of approaches. Um the practice of doing called something called the segmental, you redirect me where you just remove a segment of the order and then conjoined the orders back together. For benign strictures is is not as unreasonable but for cancer approaches maybe less desirable from the cancer control perspective. So when we start to see us higher up and we're looking at definitive surgery enough for your directory usually tends to be preferred. And then the other aspect would be. Again, we're looking at endoscopic approaches. We're trying to explore whether high grade disease can be as effectively managed through your microscopy and laser ablation or other techniques. Ancillary techniques. Um, and that is an ongoing question right now. Thanks Hamish. How long does it take for your literal obstruction to cause permanent decrease in renal function. That's an excellent question as well. So, um, we often, so there have been actually a number of studies that have on a basic science level that have looked at the time that it takes for obstruction of these are largely I think that the main interest was related to kidney stone studies, but essentially to see if you were to include the ureter, what would be the impact in terms of a kidneys function. And so, so even immediately there have there have been some changes that have been seen even as as even as soon as an hour after clamping for example, but but the relief of the obstruction in those cases may maybe amounting to more reversible changes, particularly in patients who have no other risk factors for developing chronic renal disease. The longer it remains obstructed, certainly the longer we start to worry, there are patients who present with kidney stones to the emergency room that we are often comfortable with simply a trial of passage which can last sometimes even a few weeks without going in and having to operate right away. However, you know, we when we often tend to see that that the stone hasn't passed after usually a few weeks then then we start to really think that we should go in and definitively treated because of the potential for irreversible damage to the kidney. The reversible damage sometimes can, can be present initially after the after the inciting event. But again, it often can be rectified sooner rather than later. Thank you. Since creatinine levels are critical to care and treatment options is their recent research on effective ways to help lower manage those levels are other than proper hydration. Um, so, so for the for the creatinine levels. So the issues largely amount to understanding what the what the inciting causes for for increasing the creatinine levels. So if it is an issue. So there's essentially 33 major categories of kidney dysfunction. There's a pre renal ideology. So that usually means, oftentimes the lack of hydration or profusion to the kidney, then there's an intrinsic cause, uh, to the kidney itself. These are often uh, related to things like medication effects that can sometimes impact the kidney directly. Or, um, there maybe even some other anomalies inherent to the different or the functional component of the kidney. And then there's the post renal or the obstructive causes. And so, if we're dealing with the pre renal causes, then usually hydration would be the main, the main stage. If we're dealing with some of the entrance, it causes the removal of the offending agent. Trying to understand the specific ideology would be ways to address the creating issue. And then if it's an obstructive issue, then, um, then relieving the obstruction or bypassing the obstruction, either with a stent or in the frosty tube would be ways that that the kidney function can be addressed in that manner. Thank you. What's the significance of suspicious urine cytology from the upper track for over two years, that changes from suspicious to a typical too negative. So it's like cytology. It's honestly, it's a bit of a moving target and specifically for the upper urinary tract we do tend to um, utilize it more from its aspect of specificity as opposed to sensitivity when we do see. So what I would say is when we do see that there is definitive, high grade your othello carcinoma in cytology specimen. Then often that is indicative that there is some form of a high grade you're hella carcinoma somewhere along the urinary tract. When we see um when we see a jump to sort of atypical or sometimes the non specific reads that we get on cytology, um we often don't necessarily make too much of them because it can be compounded by other aspects such as infections or inflammation that can impact what we see under the microscope. So like an atypical cytology is usually not one that tends to raise a lot of, I'm sorry, suspicious is kind of that middle ground that becomes a little bit harder to understand if it truly is significant or not. Um When we see that there is some significance, it's certainly something that we pay attention to and try to try to monitor more closely. But serial cytology is in and of themselves because of the low sensitivity of them, especially for the upper track, we don't often tend to place a lot of value on them when they do come back negative or equivocal and oftentimes if there is any suspicion, a direct assessment visually with the uterus copy would be the way to um more definitively assess that just to elaborate on that. We're working with colleagues at Hopkins and also here at Fox Fox Chase and other places to try to develop what we call a liquid biopsy in urine which might compliments cytology to help us make more accurate diagnoses that that's a way of liquid biopsies. A way of measuring your D. N. A. Usually through mutations by sequencing DNA from the urine. So stay tuned on that. So how can patients avoid or lessen the incidents of beauties or can they Is there anything one can do to avoid you? Tia? So uh you know U. T. I. S. It's it's a pretty complex topic because they tend often to be very multifactorial. There's a number of different types of beauty or flavors of U. T. I. S. People. And consequently there's a number of reasons why patients develop U. T. I. S. Uh And some of them can be more structurally related to the urinary track. Sometimes there can be um uh something more related to the activities one is doing that may end up amounting to an increased risk of U. T. I. S. And so when it comes to urinary tract infections um uh There are things that people have looked at. Two to better understand. You know is it an issue with respect to emptying the bladder properly? And if that's the case then maybe addressing outlet obstruction would be um the way to address that problem Or you know is it something that people have looked at? For example the ph balance in the urine. Is that something inherent to the development of U. T. I. S. Use of cranberry juice has also been explored. Um And so so it is a little bit of a nuanced question. But but indeed there are ways to potentially minimize U. T. I. S. But it largely depends on what the underlying cause or reason for the U. T. I. S. Are up front. Thank you. So and Hoffman wonders the most common treatment for non muslim invasive bladder cancer is BCG intra basically any connection between BCG and CKD. Yeah, so unfortunately um with with these within intra vertical therapies in general, the idea is that they're hopefully just a topical therapy with minimum systemic absorption. Uh and so in general when when applied in the strictest form and and if if there is no absorption then the presiding thighs that there should be no direct connection with with the kidneys um being that it's simply located in the lower urinary tract. Um now the mechanism of BCG is such that it does it does amount to a local inflammatory response within the bladder. And so whether or not that translates to any sort of inflammatory response to the kidneys, I don't think has actually been specifically studied. But I would suspect that unlike the case of for example, immuno therapies that are administered intravenously, there would be a less likelihood for a direct impact on the kidney function. Now that being said I will also put the caveat in that patients who received BCG sometimes are at risk of developing systemic side effects from absorption of the agent. And so one of the rare complications for example from BCG is something called um BCG sepsis or or other forms of BCG aosis where there could be some dissemination of the of the two essentially the tubercular um that's contained within the BCG. And so whether that may secondarily impact kidney function I think it is certainly a possibility but much very much a rare complication for topical therapies. Thank you. So when a person is underground removal of the bladder has a conduit, do U. T. I. S. Happen more frequently because of the new plumbing and why and how? Um Yeah. So when it comes to um when it comes to patients who require urinary diversion uh like I said a loop of a segment of bowel ends up becoming the route of urination, urine elimination. And so generally these become colonized especially for patients who have a comment categorize noblest Roma. Or importantly for patients who have illegal conduits they're going to be colonized with bacteria. So every time you get a your analysis or or even a culture from the urine from someone who has an illegal conduit? Um I would expect there to be a U. T. I. If you will because of that asymptomatic colonization that that essentially occurs. Um that being said there are also forms of pathogenic U. T. I. S. And these are the types that that do. So. So so I'll mention that for the asymptomatic bacteria area that that's often inherent. We don't tend to worry so much about necessarily treating them. But for patients who do generate pathogenic U. T. I. S. Or symptomatic U. T. I. S. Especially for those who may develop symptoms of pilot nephritis because the urine has the ability to sometimes go back up in the reverse direction towards the kidney. Those are situations in which treatment is warranted to help minimize potential sequel from the infection itself. Thank you. Do kidney transplants enter the work you do if so under what conditions? And are those with you too? You see candidates? Um Yeah, so so good question. So kidney transplantation has largely become under the umbrella of of our of our general surgery trained transplant surgeons. Now that's not necessarily the case everywhere across the country. Um So there are still urologists who partake in kidney transplantation more so in the past than today. You know, in my personal practice, I don't tend to do kidney transplants. However, I do work very closely with our transplant surgeons and the transplant team and they actually have established guidelines through their society in terms of when it's appropriate to offer a kidney transplant to patients who have had a history of cancer in general and it varies on the type of cancer and the overall prognosis from the cancer. But in general for patients who may be eligible, there's often a specific waiting period where they have to demonstrate freedom from cancer before they're eligible to potentially receive a transplant kidney. Uh, and so it does involve a number of factors from the screening perspective, as well as general baseline health perspective to see if someone may be appropriate to receive a kidney transplant. But again, this would be the reason why we we have the ability to collaborate on a multidisciplinary team to make sure that if if it's appropriate, then we can kind of have those discussions. Thank you. If a person has been diagnosed with muslim invasive, your othello cars number for bladder and the tumor is blocking the order. Should a stand on a frost amoebi considered in an effort to lower the creatinine clearance to allow for the CISplatin versus carbon platte. Absolutely. So it's actually not too uncommon that we, we may pursue that route because we do want to maximize the ability of a patient to receive what maybe life prolonging therapies. And so if we think that there could be some potential for kidney compromised due to obstruction from a tumor, then placing either than a frosty or even a stent would would potentially be a way that we can allow them to receive assist plan as opposed to having to receive carbon plan or another agent. Um, and so that's absolutely something that we do. We'll never finish. I see we've gone beyond the top of the hour. I wanted to thank you very much for sharing your wisdom with us today. I want to thank all of you for joining us on the zoom meeting today. And again, hopefully we'll be able to see all of you in a hybrid kind of zoom in person format very soon. Goodbye. Everyone have a good week and continue to save save. Thank you everyone. I appreciate it.