Well, diuretics to treat hypertension may fit best certain patient profiles. What are those patient profiles? So, there are certain types of hypertension for which specific drugs are recommended. For the average run of the mill hypertension. As we just discussed, any of the classes of drugs, any of the three classes we mentioned is probably fine. In patients who have chronic kidney disease, especially advanced chronic kidney disease, there is no question that those patients have blood pressure elevations that are driven largely by excess extracellular fluid volume, which means excess salt. So, in patients with chronic kidney disease, we especially emphasize the use of diuretic drugs. And if those patients become resistant to their hypertensive regimen, we absolutely will escalate the use of diuretics. Now traditionally, in chronic kidney disease, we turn to loop diuretics to treat hypertension, rather than thiazide diuretics. Because what's taught to medical students for many years is that thiazide diuretics lose their potency as one’s kidney function begins to deteriorate. What we used to teach people is you needed to switch from a thiazide diuretic to a loop diuretic, as the glomerular filtration rate got below, say 50. I think that view has changed recently because a very nice study done by Rajiv Agarwal at Indiana University and published recently in the New England Journal of Medicine. He took patients with advanced chronic kidney disease, stage four chronic kidney disease, and instead of using loop diuretics, he added a thiazide diuretic chlorthalidone, which is a very good thiazide diuretic. He also pushed the doses a little bit higher than we typically use for treating run of the mill hypertension. But he was able to show strong efficacy of chlorthalidone even in patients with advanced chronic kidney disease to reduce their blood pressure. So, I guess I'd summarize that aspect by saying this. In patients with chronic kidney disease, usually their blood pressure is volume-driven. Usually, it's salt-driven. Dr. David Ellison, MD.: And so, we strongly emphasize the use of diuretics. And while loop diuretics are effective, we now think that thiazide diuretics and especially chlorthalidone, should be a good alternative and should be considered in these patients. The second class or second type of hypertensive patient where a specific diuretic is indicated in patients who have primary aldosterone problems, either from an aldosterone tumor or more importantly from hyperplasia of the adrenal gland, which is the more common type of high aldosterone problem. In those patients, it's really important to block the specific actions of aldosterone. And most commonly, we would do that with spironolactone, which blocks the actions of aldosterone. You can also use Eplerenone, which has fewer side effects than Spironolactone. But Eplerenone is probably a little less effective at the end of the day. So those are two specific situations. The third situation, which is really important to emphasize, is that we now recognize that in patients who have resistant hypertension, whether or not they have hyperaldosteronism, they still respond very well to the use of Spironolactone. Or alternatively to amiloride, the direct sodium channel blocking drugs, drugs that work in the collecting duct. Dr. David Ellison, MD.: And so, patients with resistant hypertension, and this is another beautiful randomized trial called the PATHWAY trial published a couple of years ago in the Lancet, in which they examined several different classes of drugs in patients with resistant hypertension. And they found that Spironolactone or amiloride, parenthetically, but Spironolactone specifically, was the most effective add-on drug for patients with resistant hypertension. And again, if you look at the data, it's very clear that you don't have to have elevated aldosterone levels in order to respond to Spironolactone with a positive reduction in blood pressure. Dr. David Ellison, MD.: And so even though we recommend screening everybody for primary aldosteronism, and if you have it definitely treated with spironolactone. Even if you don't have it, if your blood pressure is difficult to treat, now we recommend adding Spironolactone to your regimen. And it's quite effective. One of the other things we've recognized recently, in terms of this interaction between sodium, potassium, and aldosterone and blood pressure that we didn't recognize before, is that serum potassium level is the most important regulator of the cyanide-sensitive sodium chloride co-transporter. So, the transporter that's blocked by thiazide diuretics is actually regulated by the serum potassium level. And it turns out that the transporter is turned on when the serum potassium level goes down. Dr. David Ellison, MD.: And so, we know that this is important for the body's homeostatic regulation of the ability to get rid of potassium. But this actually can contribute to the hypertension that develops when people don't eat enough potassium because it activates their thiazides sensitive transporter, and they retain more salt. But that also explains why, if you give a thiazide diuretic, and the patient becomes hypovolemic and has a low serum potassium level that then turns on the thiazide-sensitive transporter, and essentially counteracts the effects of thiazides. So, the side effect actually is blocked when one develops hypokalemia. And that's why we think it's very important to prevent hypokalemia when you're treating a patient with a thiazide diuretic. We also now know that one of the reasons that amiloride and spironolactone are effective at lowering blood pressure is not just because they block the actions of aldosterone on the distal nephron and block the sodium channel in the distal nephron. Because they raise blood potassium, they also inhibit the thiazide-sensitive cotransporter. So, they really block two different transporters in the kidney. They block the sodium channel in the collecting duct, and they block the thiazide-sensitive transporter in the distal convoluted tubule. So, you really get to kill two birds with one stone, if you will. So that's one of the reasons these drugs are really so effective. It is because of that dual-action. That's why we often add them on top. If somebody develops hypokalemia when they're on a thiazide diuretic, you can just add a little bit of Spironolactone or amiloride and raise the blood potassium. That's really an effective approach to treating hypertension.