Figure 2.

Illustration of the pathogenesis of hypokalemia, hypomagnesemia, and hypocalcemia in leptospirosis kidney disease. (A) Sodium-potassium-2 chloride cotransporter (kidney-specific cation Cl- coupled cotransporter, NKCC2) is an important cotransporter that maintains the homeostasis of intraluminal cations and anions. (B) NKCC2 functions with potassium channels (ROMK) and paracellular selective protein channels of magnesium (main) and calcium (minor), called claudin 16 and 19, in order to maintain intraluminal positive electric charge. (C) Similar to pharmacological inhibition of NKCC2 by furosemide, loss of NKCC2 controlling due to tubular injury caused by Leptospira, leading to loss of intraluminal positive electric charge, which causes decreased reabsorption of magnesium and calcium. Thus, low levels of both magnesium (hypomagnesemia) and calcium (hypocalcemia) in circulation, in turn, provide positive feedback (green arrow) and enhance potassium excretion into the lumen to maintain homeostasis. In fact, the Ca/Mg receptor is located at the basolateral membrane so far called calcium sensing receptor (CaSR), which is the key molecular player involved in sodium, potassium, and chloride transport by the thick ascending limb. During hypocalcemia and/ or hypomagnesemia, inactivation of basolateral CaSR enhances ROMK. Eventually, a large amount of potassium will be lost in urine.