On the biology of sodium excretion: The search for a natriuretic hormone.

One of the foremost functional attributes of the mammalian kidney in health is its ability to regulate the excretion of sodium with sufficient precision to allow for the maintenance of a constant content of sodium in the extracellular fluid (ECF). In essence, whatever quantity of sodium enters the ECF from dietary intake must be excreted by the kidney, and this commitment must be upheld regardless of the range over which sodium intake varies. The capability of the kidney to maintain the equality between excretion rates and acquisition rates of sodium must also be preserved in the face of advancing nephron loss if either salt retention or salt depletion is to be prevented. Thus when the nephron population is reduced progressively in the course of advancing renal disease, the residual nephrons must increase their individual excretion rates of sodium in inverse proportion to the glomerular filtration rate. The complexity of regulating the excretion rate of sodium in health and the increasing complexity of this regulation in advancing renal disease make it extremely unlikely that the mechanisms of control reside entirely within the nephron. Rather, it seems essential that a biologic control system exists that has the general design shown in Fig. 1. A detector element is shown that has the capability of monitoring the rate of sodium entry into the ECF. The evidence is clear that the detector element does not perceive changes in the concentration of the sodium ion (i.e., it does not operate as a "sodium electrode"). Rather, it appears that what is detected is a translocation from the steady state of some property of the ECF volume. A widely held view is that the derivative of ECF that is monitored is the "effective arterial blood volume" and that receptors, possibly sensitive to pressure or volume, are distributed diffusely throughout small subdivisions of the vascular tree. If detector elements do exist throughout the body, then it becomes essential that there be an integrator element, presumably located in the central nervous system and having the ability to collate the messages arising from the multiple detector components. The basis for this becomes evident when one examines the potential impact on a sodium control system imposed by the sequestration of extracellular fluid in a localized area of the body. If, for example, there is localized edema formation in one limb, the detector elements in that limb would see an expanded ECF volume, which would necessitate an increase in the rate of sodium excretion by the kidney. However, the effective ECF volume in the rest of the body would be diminished by virtue of the loss of fluid into the affected limb, and detector elements in the nonaffected areas would see a decrease in ECF volume, which would be interpreted as a need to decrease the rate of sodium excretion. An integrator element would analyze the various stimuli arising from all of the detector elements throughout the