Publisher Summary

Sodium regulation provides the central focus of renal physiology and related research. This chapter describes renal sodium regulation. Regulation of sodium excretion depends not only on the individual mechanisms characterizing successive segments of the nephron but also on a normal balance of function between segments. Even mild hypovolemia potently distorts renal function by enhancing proximal reabsorption and reducing distal delivery of sodium. The basis of normal renal function is an adequate glomerular filtration rate. This rests on autoregulation of renal perfusion and tubulo-glomerular feedback. The key determinants of glomerular filtration rate (GFR) are the following: (1) filtration pressure within the glomerular capillaries; this can be increased by constriction of the efferent arteriole or the relaxation of the afferent arteriole, (2) oncotic gradient between plasma and primitive urine, (3) renal blood flow, (4) packed cell volume (PCV), (5) capillary permeability and other factors affecting the ultrafiltration coefficient and (6) factors affecting the tone of mesangial cells. GFR is the dominant influence on renal function because it dictates the necessary workload associated with sodium reabsorption and because various renal gradients or exchanges are sensitive to flow rate, especially if it is either very low or very high.

Introduction

Two processes provide the basis of most of the non-endocrine functions of the kidneys; glomerular filtration and tubular reabsorption of sodium. They are inextricably linked and it could not be otherwise: if a 70 kg animal has a glomerular filtration rate (GFR) of 125 ml/min and a plasma sodium concentration of 145 mmol/l, a 1% mismatch between filtration and reabsorption would take only four days to reduce extracellular fluid (ECF) volume (14 l) by 50%—in fact, the animal would already be dead. The task of regulating external sodium balance also requires daunting precision; if the same 70 kg animal has a sodium intake of 0.65 mmol/kg/day (slightly above maintenance requirement, Chapter 5), its entire daily intake appears in primitive urine (glomerular filtrate) in less than 2 min; the daily primitive urine contains over 2 years’ supply of sodium.

It is not perhaps surprising, therefore, that the great majority of renal energy consumption is expended on a single function, sodium reabsorption; it is, however, bizarre that such a huge reabsorptive workload should be the price of such a minute excretory outcome. Moreover, to the extent that 50% of GFR can be sacrificed with impunity (and some two-thirds without the onset of clinical symptoms), this is a profligate system; no energy-conscious engineer would design it that way.

Inevitably, sodium regulation provides the central focus of renal physiology and related research. As with many aspects of renal physiology, it is fairly easy to define what the kidney does; most of the controversy concerns how it is accomplished. The detail of such controversies, in particular with sodium the pumps, carriers and membrane potentials operating in different segments of the nephron, tends to obscure the fundamental importance of the appropriate balance of function between segments.

Segmental Distribution of Sodium Reabsorption

In its essentials, renal sodium regulation is as simple as depicted in Fig. 2.1. The proximal tubule receives glomerular filtrate in large volumes and reabsorbs perhaps two-thirds. The process therefore achieves high volumes of reabsorption rather than high concentration gradients (except for non-reabsorbed solutes which rise in concentration as the volume of tubular fluid falls; these include end-products of protein catabolism such as creatinine). Since the reabsorbed fluid greatly resembles plasma, especially in its sodium and potassium concentration, it is almost ideal for the replenishment of plasma volume, should it be subnormal. The main extra-renal determinant of proximal tubular reabsorption is circulating volume; reabsorption is accelerated during hypovolaemia, and suppressed during volume expansion (e.g. due to excess salt intake or parenteral fluid therapy). While this is appropriate for sodium balance, it means that the excretion of excess sodium will also cause losses of calcium and magnesium, since their reabsorption parallels that of sodium in the proximal tubules. Though incidental, such losses may become clinically significant, e.g. calcium in post-menopausal women on high salt intakes (Chapter 9). While it is usual to emphasise the role of the kidneys in defending circulating volume, there is also evidence to suggest that ECF volume as a whole, i.e. including interstitial fluid (ISF), can be the determinant. Thus, saline expansion of ECF volume is more natriuretic than the equivalent volume of blood and the natriuresis persists even in the face of hypotension (Kirchner and Stein, 1994).

Some of the early studies on the effect of volume receptors in the great veins and left atrium can now be reinterpreted in the light of effects on atrial natriuretic peptide (ANP) secretion (see below and Chapter 7). Nevertheless, there is substantial evidence for neural responses, including those involving cardiac nerves, e.g. failure of natriuresis following cardiac denervation, despite rises in ANP (Kirchner and Stein, 1994). There could well be species differences, especially between primates and quadrupeds. As well as volume receptors on the venous side, baroreceptors on the arterial side of the circulation influence renal sodium excretion, notably those in the carotid sinus and the afferent arteriole of the kidney (Seldin, 1990). Renal baroreceptors respond to increases in arterial or venous pressure and interstitial pressure (Moss, 1989). Other possible sites for volume receptors include the liver (Chapter 4) and brain. Intracarotid or intraventricular hypertonic saline is more natriuretic than systemic infusions and hypotonic saline within the cerebral ventricles reduces sodium excretion. ECF volume depletion reduces the sodium concentration in cerebrospinal fluid (CSF) (Kirchner and Stein, 1994). Reduction of haematocrit, provided ECF volume is not expanded, also reduces sodium excretion; this is true when plasma is used as the diluent, i.e. there is no effect on oncotic pressure.

The other determinant of proximal reabsorption, necessarily, is GFR. Glomerulo-tubular balance describes the mechanism whereby changes in GFR, provided they are not too fast or extreme, are virtually matched by parallel changes in tubular reabsorption of sodium and water. Tubuloglomerular feedback describes mechanisms whereby ‘distal delivery’ of sodium is monitored (by the macula densa) and GFR adjusted accordingly to prevent excessive loss of sodium. In both cases, the description is simple but the explanation remains complex and controversial. The combination of these mechanisms ensures that variations in GFR do not prejudice the regulation of sodium balance. This is just as well, since small perturbations can potentially have a drastic impact on sodium excretion. Equally, it implies that the regulation of sodium excretion rests on control of tubular reabsorption rather than GFR. An important stabilising influence on GFR is autoregulation of renal blood flow, i.e. over a certain range glomerular perfusion remains stable despite hypovolaemia or hypotension. Tubuloglomerular feedback contributes to this, but is only part of the explanation (Steinhausen et al., 1988).

In the loop of Henlé, active removal of salt (perhaps 25% of filtered load) but not water in the ascending thick limb produces the dilute urine necessary for excretion of excess water. It also creates the concentrated interstitial fluid characteristic of the renal medulla; this is the basis of water conservation during dehydration. Antidiuretic hormone (ADH) is released in response to the resulting rise in plasma sodium concentration (or, in more severe dehydration, the fall in circulating volume) and, by making the collecting duct more permeable, it allows the concentrated medullary interstitial fluid to extract water from the final urine and achieve a high concentration and a low volume. The loops are thus the basis of both dilution and concentration of urine (excretion and conservation of water). Inability to secrete appropriate amounts of ADH or to respond to it normally cause diabetes insipidus (central or nephrogenic, respectively). Species particularly adapted to arid environments are characterised by long loops of Henlé. In contrast, some species living in or close to water (e.g. beaver, hippopotamus) have many nephrons with short loops that do not even reach the medulla; carnivores have none and humans are intermediate (Bankir et al., 1989).

The effectiveness of the renal concentrating mechanism depends particularly on: