When I teach kidney pathophysiology to second year medical students every fall, I have to address two syndromes. Bartter's syndrome involves mutations in transporters in the Loop of Henle, a part of the kidney very important for salt and water balance. Gitelman's syndrome affects the NCC transporter in the distal convoluted tubule, responsible for approximately 10 per cent of sodium reabsorption in the nephron.
Both of these disorders present with salt loss, low potassium, and metabolic alkalosis, an accumulation of base in the body. Because of the different sites involved, Gitelman's patients usually have normal urine calcium, while Bartter's patients spill a lot of calcium. The easiest way for most doctors to remember the difference between these syndromes is that each mimics the effect of a common diuretic. Bartters's syndrome resembles a patient on a furosemide drip, while those with Gitelman's syndrome have issues similar to a thiazide diuretic.
In both cases, the kidney tries to compensate for the perturbation by stimulating the renin-angiotensin-aldosterone system. In addition to supplementing that which is low in the blood, we often inhibit this system to try and improve the biochemical milieu. Unfortunately, these patients tend to have low blood pressure, and blocking angiotensin may exacerbate this problem.
I was excited to see the following on today's schedule:
Inhibition of thiazide-sensitive sodium chloride cotransporter phosphorylation provokes a global compensatory response
P. R. Grimm1, Susan M. Wall2, Eric Delpire3, James B. Wade1, Paul A. Welling1
1Physiology, University of Maryland School of Medicine, Baltimore, MD,2Renal Division, Emory University School of Medicine, Atlanta, GA,3Anesthesiology, Vanderbilt School of Medicine, Nashville, TN
These investigators studied mice that lack SPAK, and enzyme that phosphorylates the sodium-chloride cotransporter (NCC). The NCC is mutated in Gitelman's syndrome and also the target of thiazide diuretics. They performed microarray studies on these and wild-type mice to see which genes were up- or down-regulated in the SPAK null mice. To no one's surprise, a number of these involved cellular transporters.
To understand the cool part, you need to know a little bit about the nephron segment just beyond the distal convoluted tubule (home of the NCC). The connecting tubule and cortical collecting duct have 3 cell types: Principal cells are aldosterone-responsive and house ENaC, the epithelial sodium channel. We will ignore them for now. There are two forms of intercalated cells in this area (see figure above), mixed about with the principal cells. Alpha cells have a hydrogen ATPase that allows them to secrete acid (as H+) into the urine, while the other cells contain pendrin, a molecule that secretes base (as OH-) into the urine in exchange for chloride. During chronic changes in acid-base metabolism, the number of these cells changes! Yes, if we feed rodent acid for a few weeks, they will have more acid secreting cells in their kidneys.
So the current investigators found an increase in transporters in these pendrin-positive cells. Patients with Gitelman's syndrome often have metabolic alkalosis, so this sounds like a perfectly expected change in response to this state. However, they also found coordinated regulation of a number of other molecules that could form an alternate, electroneutral sodium transport pathway, including:
- Solute carriers Slc26a; Slc4a8; Slc4a9
- Carbonic anhydrase 2 and 15
- V-type H+ATPase subunits
Now, they have more experiments planned. Are these events modulated by the renin-angiotensin-aldosterone system? Could other metabolic changes (see alkalosis, for example) modulate some of this gene regulation? How in the world do you look at some of this stuff?
Once again, you ask a question in science, you get a million more questions.
For a nice summary of the physiology of acid-base balance in the kidney, click here.