Presenting Author Weill Medical College New York, New York
The renal response to hyperkalemia is mediated by increased K secretion within connecting tubule (CNT), flux that is modulated by tubular effects (e.g. aldosterone) in conjunction with increased luminal flow. It is established that peritubular K blunts Na reabsorption in proximal tubule, thick ascending Henle limb, and distal convoluted tubule (DCT). While any such reduction may augment CNT delivery, the relative contribution of each is uncertain. The kidney model of this lab was recently advanced with representation of cortical labyrinth and medullary ray. This introduced additional communication between proximal and distal nephron, in addition to tubuloglomerular feedback (TGF). Model tubules capture the impact of hyperkalemia to blunt Na reabsorption, and augment luminal flow within each upstream segment. However, this forces the question of the extent to which increased Na delivery is transmitted past macula densa and its TGF signal. Beyond the effect of high luminal Na, peritubular K is predicted to raise cytosolic Cl and depolarize macula densa cells, so that it may also activate TGF. Thus, even though upstream reduction in Na transport may be larger, it appears that the DCT effect is critical to increasing CNT delivery. Beyond the flow effect, hyperkalemia reduces ammoniagenesis and reduced ammoniagenesis can enhance K excretion. What this model provides is a possible mechanism. When cortical NH4 is taken up via peritubular Na,K(NH4)-ATPase, it acidifies principal cells. Consequently, reduced ammoniagenesis is expected to increase principal cell pH, thereby increasing conductance of both ENaC and ROMK, further increasing K excretion.
NIH RO1-DK29857
Whole-kidney K flows (delivery) and fluxes (transport), in hyperkalemia, with TGF active. Negative or positive transport denotes reabsorptive or secretory flux. Bars correspond to incremental regulation: clear - unregulated hyperkalemia; backslash (\) - doubling ENaC and Na,K-ATPase in principal cells; forward slash (/) adds an 80% reduction in NCC density; cross hatch (X) adds halving ammoniagenesis. With each additional regulatory response there is a step up in K excretion.
