Diabetes Insipidus: Central & Nephrogenic

Don't be intimidated by just how long this one is. There's a *LOT* of anatomy to digest, but it's by far the coolest (and easiest to relate to) disease I've covered yet! When we think 'diabetes' we usually think can't handle sugar. But in reality, diabetes just means you have any condition that makes you urinate too much. In typical diabetics that's due to the sugar. . . but this is diabetes *insipidus* and it's . .. very interesting.

Short 'n Sweet: Disruption in proper function of the body's water-regulatory pathway resulting in excessive thirst and urination.

Background Anat&Physio:
Sodium ion (Na+) is an extraordinarily important ion for human beings. Many cell functions rely on an electro-chemical gradient (like an osmotic gradient, but based on ion-charges [Na+,K+,Ca2+, etc.]across the membrane). The concentration of sodium (amount of dissolved element divided by amount of fluid) outside the cell in the water part of the bloodstream (or 'plasma') is the major ion for maintaining the gradient and as such the plasma concentration of Na (P[Na]) must be strictly maintained.

In the brain, there are sensors that detect changes in P[Na] and then try to regulate it. As I mentioned earlier, concentration = solute/solvent. So for the body to change its P[Na], it must change the amount of water (solvent) in the bloodstream! If P[Na] is too high (like after eating potato chips), then we need to take in more water to go back to normal. At this point the brain reacts by making you thirsty, and also by cutting secretion of a critical hormone: Anti-Diuretic Hormone (ADH). "Diuretic" literally just means something that makes you urinate more, so ADH makes you urinate less. The ADH gets secreted from the brain, then circulates through the blood all the way to the kidneys. Here it binds at its receptor (the ADH-receptor) and causes Aquaporins (literally: 'water holes') to appear in the kidney's collecting tubules (the tubes through which urine runs and is concentrated in the kidneys). When our kidneys filter out water to pee, these aquaporins at the end will absorb (actually called 'reabsorbtion') that water back into the blood stream so that your body retains it. This keeps P[Na] from growing any higher - remember: solute/solvent, so water-up, means P[Na] down, until eventually it gets back to normal.

ADH is very good at what it does. At normal P[Na], when there's no need to conserve water, or to get rid of it, the body still needs to urinate out sodium and other ions for other reasons. The concentration of our urine is determined by how much water we end up excreting to dilute those ions. With very high ADH, we can have up to 1200 mOsm of solute per Liter of water, conversely, with minimal to no ADH, our urine can be so dilute that we have 50mOsm/L (300 is normal). And thus, in general, the body's control of water balance is *very* effective.

And with that understanding, you're ready to learn about one of the coolest conditions we've covered yet!


What goes wrong?:
So now we've got this happy system. . .let's break it ! Diabetes is a term that means "increase in urination" - this includes Diabetes Mellitus (glucose issues, the one we all know). In Diabetes Insipidus, there's a problem with the ADH-pathway. If the problem is that the hormone cannot be secreted from the brain (central nervous system) it is termed "Central Diabetes Insipidus". On the other hand, if the ADH-receptors no longer function properly - either due to toxic damage or genetic problems - it is termed Nephrogenic Diabetes Insipidus (or 'kidney-generated' DI).

So now let's see what happens. Our patient is happy with a normal P[Na] of 140. In central DI, the brain senses this and says "all's well in the neighborhood" and tries to put out a normal level of ADH to maintain it; but it can't excrete the ADH. In nephrogenic DI, the brain does secrete this basal-level of ADH, but when it gets to the kidney, it can't bind the ADH-receptor to do its job. The kidney, of course, can only interpret this lack of ADH action as the body purposefully withholding ADH, as it would do if the P[Na] was too low and needed to be increased. The kidney's interpret it as ADH being witheld, and rather than preserving that desperately needed water, they continue to excrete *MAXIMALLY DILUTED* urine. This hyper-concentrates the sodium in the bloodstream, and bringing the P[Na] up! Now our P[Na] is high - say 150! The brain sees this and freaks out - quick, make more ADH! Bind that receptor, let out the aquaporins! But the body doesn't respond, and P[Na] goes higher and higher. . . .
Why it's cool:
Remember how I said there were *two* things the body did to respond to an increase in P[Na]? The automatic one is to make sure it doesn't get much worse with ADH. . . but eventually we'll need more water to dilute the extra sodium. So the brain makes you feel thirsty. It's an interesting fact about thirst actually, the impulse of thirst is so strong, that -given a functioning impulse and access to water- no healthy mammal will ever accidentally suffer from P[Na] elevation due to poor diet. It can even wake you from your sleep .
Well our diabetes mellitus patient doesn't have the ability to stop losing water, thus increasing his P[Na], but he *does* have intact thirst, and the ability to decrease his P[Na] by water intake. Thus patients with this condition will frequently be exceedingly thirsty and find themselves forced to keep drinking water all the time! An average person excretes about 600mOsm/day, and this maximally-diluted urine is, say, 50mOsm/L; so our patient is peeing out 12Liters of water a day. Twelve liters that she intensely needs - and is mentally compelled- to replace by drinking that much back. She's got to drink 12L of water a day!
Then there's the other factor - the volume. Sure, she's unable to concentrate her urine and so thorughout the day she's gonna drink and pee 12L. But think about it - we can't exactly pee 3 liters at a time here - a bladder can only hold so much ! Though there's a lot of variation between men and women and individual to individual, the urge to urinate typically starts at around 200mL. . . and is impossible to mentally override /control at 600mL. BTW, these numbers are generous. So say she holds it till about 400mL every time, this means 12000/400=30 trips to the bathroom every day!

Treatment:
The first step is kinda cool - you've got to figure out whether the problem is in her head or in her kidneys. The simplest way (and one commonly done) is to give an artificial version of ADH (called DDAVP). If the receptors are healthy and functioning, we should see a more concentrated urine instead of the abnormally dilute kind. If not, then we can conclude that ADH is present, but not working.
If it's central, then the patient continues taking synthetic ADH; though it's important not to take too much, as unlike the brain's sensors, our patient has no way to instantly tell their P[Na] and regulate it with more or less water. As a rule, less is better than more. If it's nephrogenic, then quite honestly I'm not sure what the treatment is even if it's there at all.
Its important to realize that. No matter how infuriating or frustrating it doubtlessly is to the patient, there are much worse things in life and in kidney-disease than having to go to the bathroom every hour and drink a ton of water.


That's probably the coolest thing about this disease: in terms of ion-balance, heart function, toxin removal, blood pressure, and all the other super-important body-physiology things, your just fine. But if you find yourself without water for an hour, and suddenly get a large increase in salt/potassium/chloride/electrolytes, then God help you!