This rat is salt deficient but is quite healthy. It is active, strong and bright eyed. Its fur is in prime condition. Its RENIN-ANGIOTENSIN-ALDOSTERONE-SYSTEM (RAAS) is extremely active and hangs onto every little particle of salt in its body. But it is neither potassium nor magnesium deficient.

This sorry little creature started out as a normal rat but was fed a diet deficient in magnesium. It is a very sick rat and just wants to be left alone. Its fur is falling out and although it is pretty miserable, its ability to handle salt is not affected.

When a person suffers from a salt losing syndrome, Bartter’s or Gitelman’s, the RAAS runs amok, the juxtaglomerular cells swell and increase in number and pour out renin.  Despite all this renin, the superactive RAAS cannot hold onto the salt and in addition, unlike our healthy salt deficient rat, potassium and chloride just seem to drain away.  Magnesium loss occurs in about twenty five percent of Bartter’s and in all Gitelman’s patients.  Of course, the whole thing was started off by the loss of salt and many patients crave salt, but giving the patients lots and lots of salt in most cases will make the disease far worse. 

Many years ago, so the story goes, our ancestors were little creatures who lived in the big salty sea.  When they decided that it was time to move on and inhabit dry land they took the salty sea with them but now they carried it inside.  If you want to know what was in the salty sea, you just have to look at the glomerular filtrate of a human with normal kidney function.  It’s minerals are pretty close approximations because no protein or large things like cells can get through and except for a few additions (mainly waste) there’s just sea water left!!!  We know, of course, that NORMALLY almost all the salt is reabsorbed and saved by the kidney tubules.  But sadly this effect does not hold true for either Bartter’s or Gitelman’s.

When life moved from the sea to dry land, nature was so determined to keep the salt from being lost that she developed the RAAS to be sure that its saltiness never changed.  Strangely, nature did NOT develop a similar system to retain potassium or magnesium or any other element you can think of.  Because of this fierce determination to retain salt, even in the presence of certain defects, nature was willing to sacrifice other elements just to maintain the salt level even if it resulted in the death of the individual.

Indeed, in severe cases, death has occurred in Bartter’s syndrome when small babies were “rehydrated” with intravenous sodium chloride solution to which the necessary potassium had not been added.  Nature told the body to keep all the sodium it could, but these attempts resulted in the loss of more and more potassium and then the death of the child.

Three defects causing salt loss in most cases of Bartter’s syndrome are described on pages 4 and 6.  These are defects occurring in the cotransporter of sodium, potassium and chloride, or in a defect in one of the 2 conducting channels in the affected cells.  We know that there are at least two other types of Bartter’s, a fourth accompanied by inherited deafness and a fifth due to a defect in a calcium-sensing receptor.  In addition, a Bartter-like syndrome accompanies congenital chloride diarrhea.

When sodium, potassium and chloride are lost, low salt at the macula densa stimulates the RAAS and this ultimately results in the “exchange” of sodium for potassium under the influence of aldosterone.  Nature has thrown away the potassium, the equivalent of throwing out the baby with the bathwater.  At this point you should look back to the previous page (12), especially the last part.  There it explains this SECONDARY loss of potassium brought about by the high aldosterone levels.  In the course of all this magnesium and calcium may also be lost (unexplained as yet).

Besides doing away with the potassium, the distal action of aldosterone makes the tissues absorb bicarbonate (producing baking soda) in the blood, one of the main causes of the  alkalosis of Bartter’s and Gitelman’s syndromes.

Because of the hyperactivity of the RAAS,  medications are being designed to cut down the secretion of renin itself or to chemically interfere with all the intermediaries between the secretion of renin and the secretion of aldosterone.  When salt is low at the macula densa cyclooxygenase-2 (Cox-2) is formed.  The Cox-2 stimulates the production of prostaglandin E2 around the JG cells and the JG cells increase their production of renin.  Look back and see the diagrams on page 7.

Another stimulus for renin secretion is the sympathetic nervous system which sends fine adrenergic filaments, to touch and innervate both granular (JG cells) and agranular cells in the afferent and efferent arterioles as well as proximal and distal tubular cells. To cut down this effect, beta adrenergic blockers have been used.  Patients who have tried them do not think much of them.  It is possible that although they cut down nervous impulses, prostaglandin E2 is still at work.

So, we are left walking a tightrope.  If we give a patient, especially a child, too much salt the loss of potassium can be fatal.  If we don’t give enough salt the child will also surely die.

Next time we will talk about blockers of the RAAS, a rather boring list of drugs so when the next page appears be prepared to be bored.