Thank you for the introduction and I am delighted to be here. I think the only reason I'm here

is that somebody didn't tell Felix that I left Yale 20 years ago, so he thinks I'm

still a Yale faculty member. But it's a great, great privilege to be here and especially

to follow Gerhard Gebisch to talk about potassium transport because as Dr. Muir said, he's really

the pope of potassium transport and has really described the outlines of everything that

we know about how the kidney handles potassium. And I think that my comments are going to

grow directly out of all of what he introduced. And so it really, I think it's all based

upon what Gerhard has taught us over the years. So it's a great, great privilege to be following

Gerhard on a symposium like this and like to thank the organizers for letting me participate

in this. So I'm going to try and provide you with, like Peter said, sodium transport and

water transport is an active field. I'm going to try and convince you that potassium transport

is a very active field too and there are some new things that we, I think, are learning

about this. So this is a general introduction slide from some work from many years ago by

David Young in which he carefully showed the impact of plasma potassium and plasma aldosterone

on potassium excretion and argued that the combination of these two factors has a multiplicative

effect on potassium excretion that maybe is best, so is seen here, so that if aldosterone

goes up there's an increase in potassium secretion or excretion here and if plasma potassium

goes up there's an increase in urinary potassium excretion but if both go up the impact of

both is multiplicative. It's much greater than either alone and that's shown on the

right where here he fixed aldosterone levels in dogs and then varied plasma potassium and

you can see that there's this dramatic relationship between potassium excretion and plasma potassium

even at constant aldosterone levels but this is dependent on the presence of aldosterone

because if there's no aldosterone around potassium secretion is almost absent. So I think we've

been interested in what kind of factors mediate that and I'll talk more about that in a minute.

Gerhard introduced the concept of a feed forward versus a feedback regulation. This is a graph

from a figure from a review last year in the New England Journal of Medicine that just

talks about the differences. Gerhard's emphasized this already and I'll so I don't want to I

won't be able to resolve this question but I've been impressed over the years that although

these this distinction is made most of the time when potassium excretion goes up significantly

there are substantiate there are detectable differences in plasma potassium concentration.

So this is one of this is one of the papers that's been used to suggest that there are

plasma potassium independent factors regulating potassium excretion and I kind of think it

actually argues the opposite. These are these are human data that I've redrawn from from

Rabalink and colleagues where they fed humans either a hundred millimolar K diet or K meal

or a 25 millimolar K meal and you can see that when they ate the high K meal urinary

potassium excretion went up a lot but look what happened to plasma potassium it actually

went up a bit and and and and the body sensed that by increasing aldosterone secretion and

so that all that goes together with this multiplicative relationship. On the other hand when they when

the folks ate a very modest K intake in a meal there was a still probably a rise in

plasma potassium. Now this would be declared statistically insignificant but I would argue

that's a type 2 error. There's not much of an increase in urinary K and aldosterone doesn't

go up. So this concept that there's all the time changes in potassium excretion that are

unrelated to plasma potassium I think is is is probably true but may not be as true as

as some would argue. I would say the one exception to that is it's very true and I'm not going

to go into this right now that there's circadian variation in how we excrete potassium and

I think that's also a lot of what's going on. Alright so so as you noticed in Gerhard's

trip down the nephron in terms of the cells he showed he didn't show a distal convoluted

tubule cell and and that's probably because we think of a distal convoluted tubule as

as emphasized in some of the talks yesterday as really being a sodium chloride reabsorbing

tubule segment not a segment that's related to secreting potassium and really the only