The renal potassium secretory machinery is precisely regulated to proportionately alter K+ excretion with changes in dietary potassium intake or extracellular K+. For instance, a sequence of adaptive changes in distal nephron morphology, biochemistry and physiology take place in response to a chronic increase in dietary potassium, allowing a more effective and enhanced excretion of potassium. A similar adaptive process can maintain potassium excretion relatively constant in chronic kidney disease with declining GFR (until 5-10ml/min or otherwise provoked). In recent years, much has been described about the process, but central unresolved issues remain:
1. How minute changes in plasma potassium are communicated to the distal nephron to adjust potassium excretion is completely unknown. The role of aldosterone is well appreciated, but it is not sufficient to drive the adaptive process. Kaliuretic factors have been suggested, but none have been identified. Whether and how distal nephron cells respond directly to plasma potassium also remains an open question.
2. The intracellular signaling events that lead to enhanced activity and surface density of the potassium secretory machinery is not well defined.
3. How renal Na+ reabsorption and K+ excretion are coordinately regulated has long been a puzzle because aldosterone is required for both processes. In states of intravascular volume contraction, angiotensin II stimulates aldosterone release to maximize renal NaCl reabsorption and restore BP. On the other hand, when aldosterone is released in response to a rise in plasma K+ (e.g. high K+ diet), it stimulates maximum K+ excretion without major effects on renal Na+ handling.
Answering these fundamental unresolved issues will have immediate translational impact. The adaptive process has its limits. In fact, development of hyperkalemia is especially common in patients with cardiac or kidney disease who are receiving drugs that antagonize the renin-angiotensin-aldosterone system (RAAS). As the results of large-scale clinical demonstrate major benefits of RAAS blockade, the incidence of hyperkalemia has increased in clinical practice. Unfortunately, this carries a significant increase risk of mortality. Similarly, thiazide-induced hypokalemia (and hyperuricemia) has been suggested to play pivotal roles in the adverse effect of these widely used drugs, particularly in the exacerbation of the metabolic syndrome or increased risk of developing diabetes. Because potential benefits of RAAS blockers and thiazides support their use in high-risk patient populations, finding new ways to manage and prevent disorders of potassium balance has become timely and important.