Tolvaptan: Exciting Progress for Polycystic Kidney Disease

Lynda A. Szczech, MD; Donal J. O'Donoghue, MB ChB


January 16, 2013

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Donal J. O'Donoghue, MB ChB: Hi. I am Donal O'Donoghue, a kidney doctor in Salford, in Manchester, United Kingdom, and National Clinical Director of Kidney Care in England. Welcome to this Skype chat. Joining me on the chat this evening is Lynda Szczech. We are going to talk about the recent tolvaptan trial in autosomal polycystic kidney disease (the TEMPO study).[1] The results are very interesting. What are the implications [of this trial], what are we telling our patients, how are we interpreting the study, how generalizable is it? At the ASN (American Society of Nephrology) meeting, the tolvaptan trial was the trial to talk about. [Results showed] positive benefit [of tolvaptan] in terms of slowing the rate of progression of kidney disease and also reducing the rate of growth of the kidney size. How do you interpret those findings? How will this change your practice in clinic, Lynda?

Lynda A. Szczech, MD: That is a really good question. I am Lynda Szczech, immediate Past President of the National Kidney Foundation and a kidney doctor in North Carolina. The findings [of this study] are fabulous. First, the study was very well done. We have had [a large number] of negative trials in nephrology since the 1990s. Methodologically, I think we have learned a lot. This trial was very well done, with the vast majority of the patients making it to the end, with very good compliance, giving us interpretable data. We can learn quite a lot from this study. I worry that the casual reader will underestimate the importance of this trial by just looking at the numbers. Remember, very large numbers of patients were followed for a period of about 3 years, and the difference in the kidney growth size [between the treatment and control groups] was statistically significant. The difference in the decrement in kidney function was statistically significant. When you look at the actual numbers, the difference was about 1 mL per minute per year difference in the decrement in creatinine clearance. Superficially, that may seem small, and I would I hate for the casual reader to miss the importance of this trial. Was this discussed during the ASN meeting?

Dr. O'Donoghue: There was a lot of discussion about the dropout rate and the tolerability of tolvaptan at the ASN meeting. There was less discussion about the relatively mild progression in the control group, which may well relate to the advice [they received] to remain well hydrated. If you look at the [side effects] from hydrating, the symptom profile in the placebo group was similar to that of the tolvaptan group. This raises that question of [whether the results were related to] the tolvaptan. Is it the receptor blockade, or is it the switching off of ADH (antidiuretic hormone) via high fluid intake? That opens another set of questions.

To my mind, this trial opens a new era in the management of polycystic kidney disease. It is the first in a number trials, which is great news for the kidney community. It is great to have positive trials, fabulous news for patients and families with polycystic kidney disease, but it raises a whole series of questions that we do not yet have the answers to. What is striking is the rate of progression in the active [treatment] group. If we had that rate of progression, [similar to that of the active treatment group], over the decades towards end-stage kidney disease, we would see a big difference in outcomes. We do not have the long-term studies yet, but we are positioned to begin those experiments or to begin collecting those data from registries. The ability to run a trial over 2 or 3 decades clearly would be a real challenge to the system. Like you, I am less worried about the fact that, superficially, the difference is relatively small, because the study was well designed. It used the [highly accurate] CRISP [approach to measure] kidney volume size, which is methodologically sound, and demonstrated a clear separation between the active [treatment] group and the placebo group, despite a roughly 20% dropout rate in the active group. (Perhaps this is to be expected for this medicine because it makes you pee so much.)

Dr. Szczech: All those points make me think that the next set of questions needs to focus on subgroups because clearly you have to conduct a study in order to do patients good. A large number of patients with a smaller follow-up time is practically the perfect way to go. This difference [in creatinine clearance] of 1 cc per minute per year over 3 years does not seem like a heck of a lot, but there may be subgroups that will benefit based on the information we have from this study. That is important because, at some point, someone is going to raise the issue of limited resources in the healthcare economic bucket. The provision of these medications is for prolonged periods of time, and the research questions and then the clinical questions we as a healthcare community need to face are: Who will benefit from long-term tolvaptan, according to these data? What can we say right now? The answers may guide our clinical decisions as well as the research agenda in this particular area. Donal, what were your thoughts about which subgroups would be most attractive for treatment [with this drug]?

Dr. O'Donoghue: In terms of the biology, the people with the larger kidneys, those who already have hypertension [may benefit from tolvaptan]. We hope [the hypertension is] adequately treated. I would also look at family history and the age at which family members have developed end-stage renal failure. That is a good guide [for when to start treatment]. There is a whole series of additional legitimate scientific questions in terms of the characteristics of people who will comply with the therapy. There are the healthcare costs of lifelong tolvaptan, which will be a high cost now, while the drug is on patent, but probably a considerably lower cost in not so many years' time. What is a real waste is when it has been prescribed but not taken because people cannot tolerate it but maybe [do not admit this because they] do not want to disappoint the doctor. I think we have a responsibility to let patients know what the impact of a medicine like this would be. We need to make them aware that they will have to go to the bathroom to urinate [quite a lot] and that they will likely be up at night [because of that]. And if they decide to embark on that, what are the strategies we can use to encourage people to stay the course? We can use a whole range of media and support through the new technologies as well as traditional means of encouragement.

What does it mean in terms of who should get an MRI of their kidneys? How frequently should that be done? Thinking in terms of patients enrolled in a program of care with tolvaptan, how frequently would they wish to see the results, to know if they are doing well? There is little change in an individual patient over that period of time, and the patient may become a bit disappointed with the slow progress. If you plot those lines out to significant renal impairment and the patient stays along that trajectory, then even this modest but tiny statistically significant reduction in rate of progression may translate into years, if not decades, of reasonable kidney function, which has enormous cost saving implications as well as major implications for the individual.

Dr. Szczech: We are all aware of how incredibly motivated this particular segment of the population with kidney disease is, how educated these patients are, how they reach out and use the Internet and other social media to get additional information. It will be very important to educate them and help them get to this technology. As I was reading this article, I was thinking about the membranous nephrology literature and about the people with a greater degree of proteinuria who were more likely to progress. The fact that you have progressed means that you are more likely to progress. That truism, that people who have progressed, who have the larger kidneys, the presence of hypertension perhaps as a marker for increased parenchymal disease, these patients have a very subtle suggestion of a greater benefit, not statistically significant but fairly consistent. As you talk about patient expectations, that could be very important -- perhaps those people who do not have the larger kidneys should be counseled that the natural history of their particular disease, their mutation, may not be as aggressive, and they may not see a tremendous benefit, but how would they know? They would see stable kidney function [rather than small increments of progression].

Dr. O'Donoghue: We need to work out the protocols to identify and manage people [with polycystic kidney disease]. In the United Kingdom, we haven't identified everyone with polycystic kidney disease as early as we might in part for the legitimate reason that disease labeling may have an impact on occupational chances, health and life insurance policies, mortgages, and so on. What gain other than blood pressure control would be achieved, we wonder? We have also been reluctant to say this is a condition that we should have cascade screening for. But every year in every single kidney unit in the United Kingdom, we have at least 1 and probably up to 5 people who arrive with advanced chronic kidney disease who have a known family history of polycystic kidney disease. We are missing the opportunities to intervene, and perhaps this [study] will be a stimulus for us to say, "Well, hey, we have specific treatments." Ethically, we have to have the dialogue with people about what those treatments might mean, even though we have lots of uncertainty. We'll soon have the mTOR [mammalian target of rapamycin] inhibitor trials coming through, but with all that said, we have a treatment. Yes, [tolvaptan] does have an effect on your volume of urine, but its side-effect profile is reasonably tolerable. It is far different from the side-effect profile we might expect with treatment of membranous nephropathy.

Dr. Szczech: When you said this is a new era, I don't think you could have been more correct, definitely in the United Kingdom but even more so in the United States with Obamacare. We still have a lot of discussion and controversy about Obamacare, but it is the law now. Not being penalized for having a preexisting condition in healthcare, in combination with the fact that now we have a disease-specific therapy for people with polycystic kidney disease [is a big improvement]. The only thing that we now have to tackle is the life insurance issue. This changes all of those conversations we have been having over the last 10 to 15 years with patients who have polycystic kidney disease. You could screen your children, but why don't we just watch their blood pressures and do all of the nonspecific things that we would do, operating under the assumption that they also have it but not label them with it? In the new era of the Obamacare law, and with the emergence of a disease-specific therapy, I think here in the United States, we will have to rethink our approach to our concerns about diagnosing early disease.

Dr. O'Donoghue: That is a very interesting perspective. From the UK perspective, people are not disadvantaged, from a healthcare perspective, knowing they had polycystic kidney disease, in terms of access to therapy. However, they may be disadvantaged if they carry psychological burden with that.

Dr. Szczech: Sure.

Dr. O'Donoghue: As an aside, we hear a lot of "noise" in the system about labeling of CKD (chronic kidney disease) and all the negative effects of that in the general population, which has not been substantiated by evidence one way or the other. People have not done the studies. My prejudice in the general CKD population is that most individuals already have other disease labels, and [having a CKD "label"] is not going from a state of health to a state of unhealth. But clearly, with polycystic kidney disease, although it is not going from a state of health to a state of unhealth, it has far more implications, and I think we need to explore the characteristics of the patients who benefit and those who do not but might come to some harm from the label even though we have treatments. This issue is not going to be a one-size-fits-all. It is a fabulous era to be entering, to think we can settle the studies to answer the questions, so that in 5-10 years' time we will know so much more about the population. The end in sight is really slowing disease progression down so much that people will live a full life and die with systemic kidney disease but not with a decade or more on renal replacement therapy. It is a testament to all the hard work and effort of the TEMPO researchers and the polycystic kidney disease community. The third sector of the charitable community in the United Kingdom has been a real force for pushing government into supporting research and convening research meetings and asking very, very taxing questions about how we will tackle this very, very important disease area.

Dr. Szczech: In your honor, my English friend, I raise my cup of tea to dying with cysts in your kidney but not having to live with a graft in your arm.

For Donal O'Donoghue, I am Lynda Szczech, and I want to thank everyone so much for joining us again on this Skype chat. We have reviewed the recent TEMPO study of tolvaptan in patients with polycystic kidney disease and are both absolutely thrilled at both the clinical as well as the potential policy implications of this very well done study. Thanks again for joining us.