Kidney Stones With Chlorthalidone Versus Hydrochlorothiazide

Areef Ishani, MD, is director of the primary and specialty care service line at the Minneapolis Veterans Affairs (VA) Health Care System and acting director of the VA Midwest Health Care Network (Veterans Integrated Services Networks 23) specialty care integrated care community. His late-breaking abstract at the National Kidney Foundation Spring Clinical Meetings 2025 (SCM25) compared chlorthalidone and hydrochlorothiazide for the prevention of kidney stones.

The results came from a secondary analysis from the Diuretic Comparison Project, a national study comparing the effects of the two thiazide-type diuretics on cardiovascular outcomes in older US veterans with hypertension. Joel Topf, MD, spoke with Dr. Ishani about kidney outcomes at SCM24 in Long Beach, California, and the two met again at SCM25 in Boston, Massachusetts, to discuss the kidney stone outcomes.

Dr. Topf: Joel Topf for Nephrology Times. I’m here with Areef Ishani. This is his second interview with Nephrology Times. We’re getting a lot of repeat customers today. It’s awesome. You’re here at the National Kidney Foundation Spring Clinical Meetings talking about the [Diuretic] Comparison Project again.

So, last year in Long Beach, you were talking about the kidney outcomes, correct? What have you got for us today?

Dr. Ishani: So again, to recap. It’s the Diuretic Comparison [Project]…. It’s a large, pragmatic randomized control trial—13,500 patients were randomized.

Dr. Topf: You didn’t say 13,000?

Dr. Ishani: Yes, I did—13,500 [were] randomized to chlorthalidone or hydrochlorothiazide. The overall study demonstrated no difference in cardiovascular outcomes.

Dr. Topf: Which was the primary outcome.

Dr. Ishani: [There was] no difference in cardiovascular outcomes. Last year, we talked about renal outcomes. There was no difference in renal outcomes between chlorthalidone and hydrochlorothiazide. This year, we’re looking at kidney stones following randomization, comparing chlorthalidone to hydrochlorothiazide.

The reason is, again, there was a meta-analysis that suggested that long-acting thiazide diuretics, chlorthalidone and adipamide, are better at reducing recurrent kidney stones compared to hydrochlorothiazide. I think there’s also a retro, smaller study where they looked at 24-hour urine collections, and chlorthalidone reduces 24-hour urine calcium to a greater degree.

Dr. Topf: In the shadow of the NOSTONE trial, where whoever took care of a kidney stone said, “Oh, of course, hydrochlorothiazide doesn’t do anything. It has to be chlorthalidone, right?” So, this is going to be a slam dunk, right? Chlorthalidone is going to have to be the drug that reduces it.

Dr. Ishani: Every time I come into these, I think, “This is an easy one. There’s no surprise that’s going to show up here.” So, it turns out, as you saw yesterday, there’s no difference between chlorthalidone and hydrochlorothiazide in the overall 13,000 population.

Dr. Topf: And again, the primary outcome for this analysis was…?

Dr. Ishani: For this analysis, [the primary outcome] was kidney stone occurrence.

Dr. Topf: Do you do this by chart review? What if it’s on the CT scan? Is that a positive?

Dr. Ishani: It is anywhere somebody has claimed for it. So, it’s either a physician goes in and, on the encounter, says there was a kidney stone. There’s a procedure code that somebody went in, smashed some stones, took some stones out. They show up in the emergency department with acute pain. Any of those things show up as an outcome.

Dr. Topf: So, it could be something as simple as they got a flat plate because they had belly pain, and then the doctor documented, “Oh, there was an incidental kidney stone,” that gets added to the problem. That’s going to count.

Dr. Ishani: That is going to count. Remember, the advantage here is [that] it’s randomized. So, if everybody’s getting flat plate, all the nonsense diagnoses should come out, balance out, and the ones that we care about are the ones that are different. But again, you know, most people aren’t going to get the kidney stones.

Dr. Topf: More people every year, though.

Dr. Ishani: Yes, indeed. But the study isn’t really designed overall to look at this. So, we did a subgroup analysis amongst those without kidney stones at baseline.

Dr. Topf: This study was started a long time ago. Are you continuing to accrue outcomes?

Dr. Ishani: We are. I should have said that. The original trial was a median duration of follow-up of 2.4 years. We extended follow-up for this analysis to the end of December 2024, so we have a follow-up of about 4.2 years. And then we did a subgroup analysis, so a subgroup of a subgroup. Remember, this is a secondary analysis, and now we’re doing a subgroup. We looked amongst those with and without kidney stones at baseline.

Dr. Topf: The same definition that we just talked about, as it establishes baseline. So, if they’ve ever, prior to the getting started in the trial, [prior to] the randomization, if they had kidney stones in their history—boom—make that a preexisting stone issue.

Dr. Ishani: Correct. The vast majority of the 13,000—about 12,500—never had a kidney stone, [representing] a low-risk population. In that population with no kidney stones, there’s no difference between chlorthalidone and hydrochlorothiazide. It’s about the same.  Then you look for a P for interaction, and there’s a very significant P for interaction here between getting treatment [and] treatment design randomized by baseline history of kidney stones.

Dr. Topf: This is getting exciting. Now we have a population where there is a signal, which you’ve been dying to find. [laughs]

Dr. Ishani: Let something be positive. So, the P for interaction is 0.005. What we see is, in people with a prior history of kidney stones, it’s the opposite of what we were thinking. Chlorthalidone had an increased risk of subsequent kidney stones. The hazard ratio is about 1.25, and it’s statistically significant.

Dr. Topf: It’s a pretty significant treatment effect, right?

Dr. Ishani: Negative treatment effect. Harm.

Dr. Topf: It’s a harm for being randomized to chlorthalidone. More stones in the chlorthalidone group than the hydrochlorothiazide [group]. Everybody’s brain is exploding, but you’re going to say, “I know the reason.” I know you don’t, but give me your theory.

Dr. Ishani: You see this, and you say, “Well, how am I going to explain? How am I writing this paper? I can’t write this paper.” Like, it’s worse. Everything I said in the introduction [indicates] it should be better, and now I’ve got it as worse.

The one thing is that, as we’ve shown consistently, chlorthalidone causes more hypokalemia. It’s about a 2% absolute increased risk of hypokalemia, defined as hospitalization for hypokalemia as a primary diagnosis—that’s bad—or a [inaudible] potassium less than 3.1 [mEq/L].

It turns out—and I didn’t know this prior to writing this paper—that hypokalemia drives hypocitraturia. I had forgotten that; it reminded me of that, so maybe that’s the reason. The more hypokalemic [a patient is, that] drives a low[er] urinary citrate, which then might increase the risk of kidney stones.

Dr. Topf: That’s good. That leaves obvious questions, then. You can look at the patients that have hypokalemia and that don’t have hypokalemia. Have you done that?

Dr. Ishani: We haven’t. That’s breaking randomization. What we wanted to do was preserve. This is a randomized analysis. Everybody’s included, so it’s intended to treat, and then it’s only about 13% of people who get hypokalemia. So, we haven’t done that yet, but that is our next analysis, looking specifically at hypokalemia as a risk factor for development.

Dr. Topf: That does open a can of worms because that’s—yes, I see.

Dr. Ishani: Because now we have to readjust Cox models—it’s a different analysis than what we wanted to do for this one.

Dr. Topf: Well, this is super interesting. This is the kind of thing that really can change how we start thinking about it. Maybe get off the urinary calcium and start looking at the serum potassium, right?

Dr. Ishani: I appreciate the 24-hour urine collection and looking at all these things, but I think ultimately, as NOSTONE shows, as this shows, you’ve got to look at outcomes.

Dr. Topf: I made a joke during your session yesterday, and I didn’t mean to make light of it, but are you guys going to look at bone outcomes?

Dr. Ishani: Absolutely. The advantage of these large pragmatic studies is that you can now use them. You’ve got the EMR, you’ve got extended follow-up. I think we’re going to do an extended follow-up for the cardiovascular outcomes, and we’re going to look at bone health and things like that.

Dr. Topf: Samuel Shem, who wrote The House of God, did 1 year of internship and has been living on that year of internship through 40 or 50 years. I look forward to you working on the Diuretic Comparison Project for the next decade. [laughs]

Dr. Ishani: That’s the goal.

Dr. Topf: Dr. Ishani, this was awesome.

Dr. Ishani: Thank you very much.

Dr. Topf: Take care.