C (3:34)

Surprisingly, there is very little data of how to choose either glucocorticoid or miracorticoid replacement dose. The question of what is physiologic glucocorticoid dose is difficult to answer. It depends on the needle of cortisol at the time of the day, sensitivity to cortisol, metabolism of cortisol and other factors. There are several studies that investigated daily cortisol production rates in healthy individuals, individuals without adrenaline deficiency demonstrating mean Cortisol production rates between 7 and 11 milligrams per meter squared per day, which quite a bit of variability. The Endocrine Society guidelines for both congenital adrenal hyperplasia and primary adrenaline insufficiency recommend a dose of 15 to 25 milligrams a day, which is equivalent to 8.8 to 14.7 milligrams per meter squared per day, so higher than what has been shown to be the daily cortisol production in those healthy individuals. So why is that? Probably because endocrine society is really concerned about under replacement and adrenal crisis. Now how do we apply the data and the guidelines to the clinic? I think it's an art. Replacing glucocorticoids in patients with adrenaline sufficiency depends on personal circumstance, with most patients doing well on around 20 milligrams of hydrocortisone. Now as for blue drop cortisone, no standardized way to assess initial replacement dose has been ever studied to the best of my knowledge, but a starting dose of 100 micrograms and that's also according to the guidelines is usually chosen first, with clinical and biochemical biomarkers helping us with adjustments.

B (5:30)

Well, it sounds like this paper is a very appropriate topic for us to be discussing, and so that's great explanation of all the existing data and where this difficulty lies. So this paper aims to further cement the relationship between mineralocorticoid dose and renin, using renin specifically to guide our treatment. We know that mineralocorticoids act on the functioning nephron to retain sodium and water while excreting potassium, thus regulating our blood pressure and electrolytes at proper doses. Typically this is from our RAAS system, but in primary adrenal insufficiency that last step is lost. Current strategies for dose titration of mineralocorticoid focus on, like Irina said, the combination of potassium, sodium, systolic blood pressure and symptoms. Those symptoms of mineralocorticoid and glucocorticoid deficiency and overuse are sometimes difficult to distinguish what is related to the mineralocorticoid or glucocorticoid versus other things. The French Endocrine Society has a consensus statement encouraging renin levels to be used to better target mineralocorticoid dosing. And so I really wanted to ask why is there not a standard elsewhere? Why is this just the French Endocrine Society guidelines? And where are the challenges around designing one of these optimized replacement regimens in clinical practice?

C (6:57)

Recognizing significant under or over replacement with hydrocortida it's not that challenging. It's just not very common to have a patient who is in this severe under ovary placement stage. For example, a patient receiving very much suboptimal fluidrocortisone dose will have orthostasis report dissonance. Salt criping electrolytes may be abnormal with high potassium or high normal potassium and renin or renin plasma activity in this case would be quite elevated. So really multiple clinical and biochemical biomarkers will be very much indicative of suboptimal glucortisan replacement. On the other side, glutal cortisone over replacement that is significant will present with edema and hypertension and hypokalemia, leading to endocrinologists at least consider decreasing fluorocortis and do so. I would say most endocrinologists and even primary care physicians are very comfortable recognizing this. But what is challenging is to detect mild over an under replacement and especially to distinguish it from glucocorticoid under replacement. For example, sometimes symptoms of fluoride are confused with symptoms of Adrenaline sufficiency by patients themselves. Fatigue would be the most common symptom for both. Or occasionally we will have discordant symptoms or symptoms that are overlapping with other conditions. For example, edema and heart failure or a challenging combination is diagnosis of postural orthostatic tachycardia syndrome and primary adrenaline insufficiency were difficult to understand. What is orthostasis due to POTS and what is under replacement with sputrocortisone. And it is at that time we rely more heavily on biochemistries, electrolytes mainly, but also renin.

B (9:05)

Well, the purpose of this study is to determine if and how renin specifically could be used in clinical practice to adjust that dose of fujocortisone in these patients with primary adrenal incidents. Efficiency. So I will turn it over to Chase to discuss how they approach that.

A (9:22)

As we move into the methods. We'll start as we usually do. We're thinking about the study design that's used here. And though the authors don't describe their work this way, I think this best fits as a cross sectional study. And there's a few atypical features to where it's not obviously that. But to review what a cross sectional study is, is whenever you do one of those types of analysis and assessment, you get all of your data at once. So not only your exposure data, but also your outcome data. And sometimes it can be a little bit difficult, which should be the exposure, which should be the outcome. Sometimes it's a bit more obvious. But the key thing with this is that you're not following individuals over time. You're not splitting people in exposed or an unexposed group and then following them over time to wait for an outcome to occur to develop. You have the outcome information right away. What makes us a little bit weird is that for quite a few of the subjects, as we'll see in this study, there, there are multiple data points over time and often we think about that as being in a cohort study. However, I don't think that's what they're doing here. Primarily. They're not waiting for an outcome to occur. I think they are repeating the cross sectional study. So you can sometimes describe these as serial cross sectional studies. And I think that that fits best what's going on here. I think this has important implications as we consider the results that the authors find and the conclusions that they draw. So we will come back to that. First of all, though, we'll look at the study population for this particular investigation. So this is a study that's coming out of two tertiary centers in France. And they looked at adult patients with primary adrenal insufficiency who had at least one renin measurement while on treatment. So they were not looking at folks who had only renin measurements before they were started on steroid replacement. And they looked at patients between the years of 2008 and 2022. So we move on to thinking about exposures or potentially confounders. So this is how they're going to split folks into groups. The first big thing that they're looking at are doses. And so they're going to look at mineralocorticoid dose and glucocorticoid dose. And something else that they do is they try to put this into a similar measurement, and they describe that as a mineralocorticoid equivalent. The idea with that being is that different people are on different glucocorticoid regimens, and many glucocorticoid regimens have mineralocorticoid activity. So they're trying to standardize that and give that a single number. So, Rena, help us out with that, that calculation, how they did that. Is that a fairly standard way of doing that? Does that have any sort of clinical implication for us or is really just a necessary research technique that is utilized here?

C (11:48)

So office utilized the following conversions for 1 milligram of hydrocortisone. They considered that was equivalent to 2.5 of fludrocortisone. In other words, 10 milligrams of hydrocortisone would be 25 micrograms of fludrocortisone. For prednisone, they consider that to have 80% of melachorticoid activity of hydrocortisone. And I think it's absolutely arbitrary. There are no studies to show that this is true. Judging from the clinical practice, it is close to truth, I would say. But I'm not sure if 1 milligram of hydrocortisone equal to 2.5 microns of flutrocortisone versus 2 is so easy to distinguish clinically. But the rule of thumb, yes, if a person is on 40 to 50 milligrams of hydrocortisone, that is probably equivalent to 50 micrograms of fludrocortisone. Now, does this matter as far as not for hydrocortisone equivalency, but for prednisone? I think it probably would not affect the interpretation of this particular study just because the majority of patients have been on hydrocortisone. So whatever approach authors decided to use, it probably is applicable to all Groups.

A (13:03)

Studied other data that was measured again either as an exposure or confounder. So basic six, weight, height, blood pressure measurements, also blood pressure medication, electrolytes, bites as they were measured, and then also the cause of the primary adrenal insufficiency. Just want to discuss quickly as a group if there's anything else that we would have liked to have known that fits in this exposures or confounders category. One thing that jumped out to me is that though the authors note whether somebody was on blood pressure medications, it's curious perhaps about what blood pressure medications generally we think of in primary adrenal insufficiency, it's best to avoid things like diuretics. And maybe you wouldn't want to be on an ACE inhibitor, an R, because that would be largely ineffective though I think at least clinically speaking. And we see a lot of folks who end up on that, or maybe they were on that before they were diagnosed. So it would have been curious about that. Jill and Irina, anything else that you would want to have known that would fit into this exposure confounder category?

C (13:56)

Well, one thing that comes to mind is residual myocorticoid activity. Not all patients with primary adrenaline sufficiency have complete deficiency of my cortic reproduction. In fact, a small minority may not even meet fludrocortisone because they still have their own endogic aldosterone production. It is difficult to correct for that, but that's one of the things definitely that is potential confounding factor here. Another one is salt intake and volume intake at the time of measurement. If someone places me in the middle of the desert and I don't drink water for one day, my running hopefully sky high. On the other hand, if someone measures my Iranian after I drink couple of glasses of water, hopefully it's quite low. So renin production in patients with underlying sufficiency is not impaired. And aldosterone is not the only regulator of renin. So that I think I would have loved to see a bit more in the methodology section of this article, at least some attempt to standardize renin measurements in relation to fasting status and timing of the day as well as in relation to salt intake.

A (15:10)

And as we'll see in the discussion, the authors do acknowledge that they point that out is that that's something that they did not have access to and so we're not able to include in their methodology here. We'll move on to looking at the outcomes and I think this will be a key thing for us to pay attention to. We'll circle back to this in the discussion, but again thinking of this as a cross sectional study to where you have lots of exposures that are looked at. But I think at least the way the authors have described their analysis, I think the real outcome that they're looking for is the renin level. Now the authors do mention that this was done on multiple platforms, similar reference ranges, but maybe not done exactly the same way. And importantly, how they describe their outcomes, they do it as a continuous variable in some of their assessments. But one of the ways that they do it is utilizing those French guidelines that Jill told us about earlier. And so they group these renin results into three different categories based on the target range for treatment for individuals with primary adrenal insufficiency. So they have a group to where their reading level would be considered low or that would be an over treated group and so that would be less than 20. And then they have the normal range or probably better stated the AT goals. How the authors describe that between 20 and 60. And then they've got a group that would be considered high or under treated and so that would be above 60. So arena, help us out with that. So these units that are used here are different than I think most of us in the US and probably elsewhere are familiar with. So can you just give us a quick overview of how we should be thinking about those levels in terms of at least some of the ARENA measurements that we typically do.

C (16:43)

I needed some help with conversion as well. So what I've done, after I saw the units and the assay, I googled it and I found an article, a clinical chemistry article from 2004 that actually compared run into renin plasma activity. And for the audience here, I think it's important to give you some numbers now. So for the low over treated group, the 20 cutoff that authors used is equivalent to under 0.7 to 0.8 nanograms per milliliter per hour. So that would be suppressed binding plasma activity and that would be consistent also with how we diagnose primary aldosterone as you know, looking for suppressed run. And so I strongly agree that this group could be over treated. The next thing I slightly disagree with because the normal is equivalent to hardinoplasmic activity of 0.8 to 2 nanograms per milliliter per hour. And I'm not completely sure that's normal. I think it's a combination of people who are over treated and properly treated. And then finally the undertreated group with high renin above 60 is equivalent to above 2 retinoplasma activity about 2 nanocross per milliliter per hour. And I would not necessarily call it under treated. I would have loved for authors to have chosen a truly undertreated or likely undertreated group which would be, let's say, running plasma activity above 10 or above 20. That would be a bit more believable. Nevertheless, these three categories do give us a sense of where the patients lie as far as the renin.

A (18:25)

Well, several things for us to keep in mind, but I would argue that I think the key to understanding some of the conclusions is remembering that renin is the outcome here and everything else that it being looked at would be considered an exposure or at least a confounder. All right, enough of the methodology. I'm going to turn it back over to Jill and she is going to walk us through these results as the authors describe them.

B (18:44)

We looked at a total of 150 patients that were sampled. Average age of 44 majority female. Average age at diagnosis was listed as 29, with 37% of the individuals with primary adrenal insufficiency due to autoimmune disease, an additional 30% due to bilateral adrenalectomy and 24% from congenital adrenal hyperplasia. Largely generalizable population representing multiple etiologies and the majority female kind of fits with that autoimmune higher presence within the grouping. Both glucocorticoid and mineralocorticoid doses did vary widely, with the average equivalent dose hydrocortisone at 25 milligrams plus or minus 10 milligrams. However, the highest was up to 60 milligrams. Daily mineralocorticoid doses average 82 micrograms per day or 0.08 milligrams. These glucocorticoid and mineralocorticoid doses were then again combined to show that total equivalent mineralocorticoid dose. Using beer equation weighing the glucocorticoid effect at the mineralocorticoid receptor, the total equivalent Mineralocorticoid averaged about 136 micrograms per day and so for simplicity, 25 milligrams of hydrocortisone and 0.1 of flujocortisone would be equal to 162 micrograms, so the average for this population was about 20% under that dose. For a little bit of perspective, the baseline rins were called baseline after a one month stability on the respective doses trying to attain this true baseline of this baseline population on Treatment, renin was above the upper limit of normal, per their definition, in 45%, while 88% actually at that same time showed normal sodium, normal potassium. And when applying the French guidelines, only 29% of patients were in this ideal renin range, with 45% undertreated. Considering a high renin level and what Irina mentioned, that would be higher than a renin of 2. In our other clinical guidelines, renin did appear to be negatively correlated with sodium and systolic blood pressure and positively correlated with potassium. However, renin was not correlated with the fludrocortisone dose, hydrocortisone dose, or the equivalent mineralochort effect. The same patterns were seen when renin results were grouped into low, normal and high groups. 53 patients had data actually that were able to check three separate renin levels. So when comparing the trends in renin across this population, they did see a significant inverse correlation between renin and changes in the equivalent mineralocorticoid level, with higher doses occurring with a lower renin value. And that relationship seems to make sense where the higher amount of hydrocortisone effect resulting in a lower renin value. However, it did not show a trend between renin and electrolytes or renin and systolic blood pressure. There did exist a trend that mineralocorticoid doses did appear to increase over time in the 53 patients that were available for the follow up of renin levels. Those that had an unchanged dose though, had stable renin between checks. But even in the patients that had a dose adjustment, renin was not statistically changed. However, they did note a very wide variability. So a lot of different trends, a lot of different trajectories that I will let Chase kind of explain what we can glean from all of these.

A (22:49)

We will move on to the discussion and we'll start with what the authors, the way that they describe their findings. And before I quote them, I'll state that's probably the biggest area that I would disagree with the authors on some of their conclusions here, but I'll quote them first. And they say plasma renin concentration is a more sensitive marker than electrolytes and blood pressure for detecting over or under mineralocorticoid replacement dosing. The reason I would quibble on that is again, to go back to that study design, to where renin is the outcome, and then all of everything else that's measured, including the things the authors mentioned, the electrolytes and the blood pressure, those are all potential exposures. So whenever you're thinking about it that way, if Your renin is the definition of whether you are over or under replaced. It will always be a perfect indicator because of the way that you have set up your study design. So nothing else could ever be as good as that by design. A different way of saying that is instead of treating renin as the outcome, I think the way the authors have summarized it here, they're treating it as if they had measured it as an exposure with something else and the outcome. So that I think doesn't totally make sense, at least with the way that I have understood their study to be set up. Another way of describing their results, maybe the way that I would describe, which I think still has real value and gives us important information, is that the renin is far more likely to be abnormal in primary adrenal insufficiency than electrolytes or blood pressure are. And so I think that that's the main point that the authors are making and that I think I can definitely get behind. There's a few other findings that the authors point out as being really important and in a second we're going to get Irina to help us understand them. The first thing that they point out is what Jill told us already is that there was no correlation between the plasma renin and the flutrocortisone dose. They also point out that the changing of the dose of that mineralocorticoid equivalent did alter the renin levels, but there was not a correlation between the electrolytes or the blood pressure arena. Curious for your thoughts on this. If you were surprised for me, I'm not an expert in this like you are, but I was a little bit surprised by that. I would have just assumed that there was going to be a correlation between the renin level and the flutercortisone dose. So was that surprising to you? And then the authors do go into explanation of why this might be the case. So as a follow up question, I was curious as your thoughts on their explanation if that seemed to make sense or maybe there's still unanswered questions with that.

C (25:13)

To first address this particular question, I think we have to remember that fludrocortisone dose is, is very much predefined. It's either 50 or 100 or 150 micrograms. So there's not much variability between those cutouts to analyze, to have any association analysis to show significant results. So now in comparison to that, when you take the cortico exposure, which also accounts for hydrocortisone, now you have numbers on the continuum and yes, authors managed to show some significance, though not large. I guess that's not surprising to have a correlation between viral quarter code exposure and renin. But if I can, I would like to go back. What is a reference standard? It's what you've mentioned at the beginning in comparison to what? So, so, so why as a reader should I care about renin? Will my patient feel better if renin is low? Will I have lower blood pressure? What and why is it better? So again, there's no reference standard in this study. So I think it's important to put it in the context. It's not just this minor statistical significance that authors found, which I think is absolutely understandable. It's so what type of question.

A (26:33)

I think anticipating that that is where the authors go next. And they mention a couple of what I would describe as caveats and they point out very similar to what Irina was just alluding to is that it is difficult to confirm overdosing or under overdosing as there is really no gold standard marker of correct mineralocorticoid replacement. So just like what Irina was saying, so it's a Lorena is a little high, it's a little low. Does that really tell us that somebody's over replaced under replaced, Is that related to symptoms, any other outcomes that a patient would experience beyond simply a lab measurement? So I think the authors appropriately acknowledge that. And additionally they say that although imperfect, renin may be a good marker to evaluate mineralocorticoid replacement from an individual perspective. They go on to mention a few limitations, some of the ones that we have pointed out already and that the authors acknowledge here. So they point out this is a retrospective study and so it comes with plenty of limitations. They point out that follow up visits occurred at different times, so they were not standardized intervals. In between that follow up they point out that treatment adherence could not be assessed, that there was a variable frequency of hydrocortisone dosing. As we talked about before, they mentioned that the renin measurements were not standardized as ARENA told us already. The authors point out that we they did not have any information on the posture when the lab was drawn, what the current plasma volume variability was, what the daily sodium intake was, so potentially introduce a lot of variability there. And then as a final comment they mentioned that they could not assess with the effect of 11 beta hydroxysteroid dehydrogenase type 2. So we will wrap up with the author's conclusions. We'll give you our own thoughts here after I quote what the authors say. So they end their investigation report similar to how they started the discussion by saying that plasma renin is a more accurate marker than electrolytes or blood pressure to detect overdosing or underdosing of mineralocorticoid replacement. And then a few additional comments that the authors make. They point out something that Jill told us already is that there was wide variability of hydrocortisone replacement regimens. And finally, future prospective studies on a larger number of patients will also help determine the potential side effects of mineralocorticoid overdosing or underdosing with a target zone. That remains to be refined. So I think several things that we've talked about already before we think about whether this should change our practice, I'd like us to wrestle just a little bit more with the quality of this report overall. Jill, let's start with you. You spent quite a bit of time analyzing this article. So what are your thoughts about the quality of this report in general?

B (29:01)

You know, I think they used what they could and were attempting to navigate a lot of wide variable pieces. So I think I appreciate what they were attempting to do. I think it's just very difficult to navigate and I think it was just a very high reaching article trying to say, oh, we can say, yes, this is a concrete something we can look for. I don't think that that was there necessarily, but I appreciate their attempts to try and standardize it as much as they could with what they had.

A (29:38)

Marina, thoughts on the quality of this report overall?

C (29:41)

I completely agree. I realize how difficult it is to do studies like that, especially without significant funding. And yes, authors really tried to get whatever was available at different stages. I am concerned about the strong conclusions about superiority of Renin because I don't think the report demonstrated that, but certainly something that I will include in my clinical practice as far as considering some of the associations found.

A (30:16)

Yeah. So let's unpack that a little bit further. Irina, we'll end with you. So I want Jill to give us your thoughts. So just what arena stated as we think about how do we apply this clinically? Jill, you started us off at the very beginning by saying we don't have very much data on that. Irina confirmed that by giving us an overview of the medical literature as it stands. So this adds to the body of literature that we have. So what are we going to do do with this when we see patients, when we go to clinic later today and we see somebody in this exact situation? Jill, what are your thoughts on how we might be able to use this information to change our current clinical practice?

B (30:48)

Sure. I think it's another piece to the puzzle. I think we know the physiology. We know that symptoms very obvious, blatant, one side of over replaced, one side of under replaced are easy to see. But for those people that, that have more fatigue are more nuanced, I think that this is an additional piece. And if we individually know I can control how this patient's renin is drawn, I can have them try and hydrate, I can have them check at a certain time of day, I know more of the variables than maybe what these authors were able to do. Can I use that to convince me if I'm on the cusp of increasing a dose, does renin adjust that for me? Is that an additional piece that I can use to make me feel good about that clinical decision? And I think that that's what I will take away from this is nothing is perfect in the entire patient that didn't read the textbook necessarily. But using that additional piece and understanding that it's one of many considerations, I think is how clinically it can be the most productive.

A (31:58)

I agree. And even though I might describe the findings a little bit differently, I do think that main point is an important one, is that if something's going to be abnormal biochemically, it's almost certainly going to be the renin level. So that. That if your electrolytes are abnormal, then your renin was already going to tell you that anyway, so it's the one that's most likely to be abnormal. Now, again, how do we define that? What's truly normal, what's not abnormal? We don't know that. But. But I think that it's really helpful to put that in context of how likely that is to be abnormal compared to other biochemical that we're using here. Irina, let's finish with you. You alluded to it already. So how are you going to take this information when you see folks in clinic and you're trying to make adjustments to a mineralocorticoid regimen? What information do you think this provides to your clinical care?

C (32:42)

I don't think that this article changed my clinical practice. I think it emphasized that rhinin is not a miracle biomarker. That would trump clinical judgment, history, clinical exam, and a simple electrolyte measurement. I do think that it helps put that last dot on the clinical assessment. For example, if everything is telling me that the patient is over a place with ultracortisone, seeing granin that is suppressed reassures me that my clinical judgment is in line at least with biochemical assessment, or vice versa. If let's say I'm considering that patient's orthostasis may not be related to pludrocodes and under replacement. Seeing granite that is actually on the lower side reassures me that yes, potentially we should look for other causes of orthostasis. So I do think that it could be helpful in the clinical picture, but at the same time it would not trump my clinical judgment if everything goes for this is an optimal replacement and seeing that that high or low renin would not make me reach back to the patient say well actually despite all of the things that we've discussed during our appointment and a good report based on your renin, now I would like to increase or decrease your foot or cortisol. And just to add another thing, I think the study reminded me that we really do need studies on renin as well and replacement and adrenaline sufficiency that looks at patient important outcome and quality of life and a bit more than what is just sort of available at that cross sectional study visit.

A (34:23)

And with that I would like to thank Jill Wagner and Irina Baenkos for joining me for this month's edition of Interim Feedback Loop. I hope that you all learned as much as I did and that you will join us again next month. And now you're in the loop. This has been Endocrine Feedback Loop. Endocrine Feedback Loop is brought to you by the Endocrine Society with Production Oversight by Brandy Brown and Andrew Harmon. If you want to like and subscribe, you can find us on Apple, Spotify, or wherever you get your podcasts. We'd love to hear your feedback on this episode or the podcast itself. Please email us@podcastrine.org Endocrine Feedback Loop is a free service of the Endocrine Society. To learn more or to become a member, visit the society's website at www.endocrine.org.