The February issue of the Journal of the American Society of Nephrology includes a science in renal medicine article that caught my eye:
If I ever teach metabolic alkalosis again, I have to revise my lecture!
Ever since loop diuretics became available in the 1960s, they have been a recognized cause of metabolic alkalosis. These drugs cause the kidney to excrete excess volume (Na + Cl + water), which is very useful if you have swelling from heart failure or liver disease or kidney problems. If the volume loss goes too far, the patient could develop alkalosis (too little acid/too much base in the blood). The major base in the blood is bicarbonate (HCO3-). Our "old-school" explanation of the pathophysiology follows. Volume depletion turns on aldosterone which controls a number of transporters in the distal nephron. The net effect of these transporters is retention of Na+ with concurrent excretion of K+ or H+. The latter would help perpetuate the alkalosis, because excreted H+ (acid) does not consume any of the blood's buffering bicarbonate. Restoring the patient's volume turns off aldosterone and allows the alkalosis to resolve.
How simple! How elegant! How wrong!!!!!
A number of human and animal studies are reviewed in the article. The alkalosis formerly known as contraction can be induced with diuretics plus dietary maneuvers. If volume is expanded without chloride, using albumin or other solutes, the alkalosis remains. If chloride is replenished without volume repletion, the alkalosis resolves (even though the subject remains volume depleted). Thus, this form of alkalosis is better described as chloride dependent (CDA).
The figure from the paper summarizes the new explanation. First note that unlike most tubular cartoons, the peritubular capillary is central in this one. Either side of the cells is a urinary space. The cortical collecting duct contains 3 cell types. Principal cells (middle of cellular column) reabsorb Na+ and excrete K+ to maintain electroneutrality in the luminal fluid. A-type intercalated cells (Acid secreting; top of cellular column) can transport H+ into the lumen. This activity during alkalosis with volume contraction may be driven against the H+ concentration gradient because of Na+ absorption by the principal cell, as in the old-school explanation above. Of more importance to the alkalosis, B-type intercalated cells (bicarbonate secreting; bottom of cellular column) express pendrin (Pn) on their luminal membranes. This protein transports bicarbonate into the luminal fluid while reabsorbing Cl-.
In states of chloride depletion (left side of cartoon), Cl- is not available to exchange with bicarbonate, so the latter cannot be excreted. After Cl- repletion (right side) this exchange can occur. Bicarbonate can be excreted to correct the alkalosis, without any alteration in the functions of the aldosterone-dependent transporters in the other cells.
Medical students have always been frustrated that we classify volume status by urine Na during "pure" volume depletion, but with urine Cl during metabolic alkalosis. Various explanations have been offered along the way, the most reasonable being that in periods of excess bicarbonate filtration (like alkalosis) a cation has to accompany it in the urine. Thus, urine Na may be falsely elevated in this setting. Turns out, the urine chloride concentration really is the critical component.
Will any clinical changes result from this new nomenclature? For the most part, no - when patients lose chloride and become alkalotic, they generally suffer volume depletion. We treat this with Na + Cl + water, repleting volume and chloride together. The paper summarizes a number of relatively recent studies and provides a great illustration of the shifting nature of established physiology.
There is always something new to discover.