Perspectives in Biology and Medicine

Perspectives in Biology and Medicine 43.3 (2000) 399-405

Diuresis and Diarrhea: Is the gut a Misunderstood Nephron?

A. R. Michell *

Introduction

The preponderant constituent of the body is water, and the cellular environment is essentially saline with bicarbonate. The most serious clinical disturbances of this extracellular fluid (ECF), which includes plasma, are sodium depletion (causing hypovolemia), water loss (causing hypernatremia), and bicarbonate depletion (by titration or external loss) causing metabolic acidosis. Of itself, hypovolemia causes disproportionate water retention, resulting in hyponatremia [1].

The almost universal axiom of physiology textbooks is that the regulation of sodium, water, and bicarbonate is entrusted to the kidneys. Yet the common cause, whether in humans or animals, of serious fluid and electrolyte disturbances is not renal disease but acute diarrhea. In the early stages of diarrhea renal function is distorted, and in the advanced stages it is compromised ("pre-renal" failure). Hence, restoration of circulating volume to a sufficient degree to allow improved renal regulation of plasma composition is the primary objective of fluid therapy [2]. In recent years the most effective way of achieving this has become oral, rather than parenteral, rehydration [3].

But fluid and electrolyte disturbances are not simply effects of diarrhea --they are the fundamental underlying defect. And oral rehydration is not simply symptomatic therapy but a treatment which attacks the essential life-threatening disturbance. Diarrhea is a failure of net enteric sodium and water absorption which exceeds the compensatory capacity of the colon. Multiple factors can act as triggers, including bacteria, viruses, toxins, and villus damage, but defective net absorption remains the essential outcome and, in the case of oral rehydration, the direct therapeutic target [3].

The trusted axioms of textbooks should arouse the suspicion of scientists; as recently as the 1960s the new certainty was that hormonal sodium [End Page 399] regulation was entrusted to aldosterone and that hormones with the opposite effect--natriuretic hormones--were fantasies or artifacts: the 1980s consigned aldosterone to a lesser role in sodium regulation, alongside angiotensin II and other hormones, and indeed a more persuasive case can be made for its primary role as a potassium regulating hormone [1]. The kidney, after all, can escape its sodium-conserving effects (via counter-regulation in the proximal tubule) but not its potassium-excreting effects, unless proximal reabsorbtion is so excessive (in severe hypovolemia) that solute delivery to the distal nephron becomes insufficient to sustain the kaliuretic effects of aldosterone [1]. In sheep, sodium intake is often so exorbitant that even during pregnancy sodium balance is successfully regulated in the absence of changes--or even detectable plasma concentrations--of aldosterone [4]. Above all, the 1980s saw natriuretic hormones emerge as the most flourishing aspect of research on sodium regulation, conferring an endocrine role on the heart as well as adding to the endocrine function of the brain and, perhaps, the adrenal cortex [1].

So the main cause of fluid and electrolyte disturbances is the gut, and the main treatment hinges on stimulation of a vital aspect of enteric physiology, namely sodium absorption. This in turn restores circulating volume and renal function, which is substantially impaired even in some comparatively mild diarrheas [5]. Yet nephrologists are strikingly uninterested in diarrhea [6]. Sadder still, most nephrologists remain unaware that in a wide range of species the gut is not only the main source of fluid and electrolyte disturbances but the primary regulator of sodium and water balance. Indeed most of those who first observed this were too daunted by the consensus of the textbooks to comment upon it [1].

We all recall that the kidneys and the gut make common cause in birds and other vertebrates via the cloaca. In mammals the interconnection is not anatomical but functional; the interplay between the gut and the kidneys is crucial to the understanding and treatment of fluid and electrolyte disturbances. Almost as important is the interplay with thirst (which in most animals which drink water rather than flavored fluids is the primary regulator of water balance) and hepatic function (an important influence on acid-base...