J Clin Pathol: first published as 10.1136/jcp.34.11.1267 on 1 November 1981. Downloaded from J Clin Pathol 1981;34:1267-1275 Modern diuretics and the kidney AF LANT From the Department of Therapeutics, Westminster Medical School, London SWIP 2AP It is particularly appropriate to discuss the pharma- THE DISTRIBUTION OF GLOMERULAR cology and mechanisms of action of diuretic drugs FILTRATION BETWEEN OUTER CORTICAL in a symposium on diseases of the kidney, since AND JUXTAMEDULLARY NEPHRONS diuretics were the first group of drugs to be devel- The functional unit of each kidney comprises oped for the control and manipulation of selected approximately one million nephrons which lack aspects of renal function. Despite a relatively short homogeneity in their structure. About 80% of history of less than three decades since the discovery them are in the outer cortex, have short loops of of the first orally acting diuretic, chlorothiazide, Henle, and have relatively low reabsorptive capacity modern diuretic therapy continues to enjoy an ever- for sodium. The remaining 20% are juxtamedullary, expanding clinical demand: worldwide expenditure possessing long loops of Henle, and are largely has been estimated at around US $800 million responsible for creating the hyperosmotic inter- per annum during the last five years. Though stitium in the medulla which meditates the process originally introduced for the treatment of oedema- of urine concentration. Redistribution of blood flow tous conditions it is interesting that application of from outer cortical to juxtamedullary nephrons diuretics to the treatment of hypertension has out- can contribute to abnormal sodium retention, stripped their use in oedema. This has happened whilst predominance of the effect of outer cortical notwithstanding the parallel discoveries of other nephrons may lead to saluresis. A reduction in blood copyright. major antihypertensive agents such as the beta- flow to the outer part of the cortex has been found adrenoceptor blocking drugs and powerful vaso- to occur in some sodium-retaining states. Conversely, dilators. a drug which could shift blood flow from juxta- The advent of novel, orally effective diuretics medullary to outer cortical nephrons would reduce following on the prototype benzothiadiazine, chloro- sodium reabsorption and result in an effective thiazide, has had a major influence in stimulating diuretic response. progess in the basic sciences relating to nephrology or electrolyte transport in body tissues in general. HAEMODYNAMIC AND PHYSICAL FACTORS3 http://jcp.bmj.com/ Advances in fundamental knowledge have in turn Changes in physical forces within the peritubular given the impetus to further discoveries of new and, capillaries have been shown to be important de- in some cases, unique substances possessing diuretic terminants of renal sodium reabsorption, especially activity. Byand large these compounds have attained a in the proximal tubule. Thus, for example, renal remarkable degree of sophistication while, at the arteriolar dilatation may, by increasing the hydro- same time, remaining relatively safe during long static pressure in the vasa recta, decrease net tubular term treatment of patients. The widespread use and, reabsorption of sodium with resulting natriuresis, at times, the regrettable abuse of any group of on October 1, 2021 by guest. Protected drugs whose primary effect is directed toward while the reverse occurs with any increase of plasma interference with the renal handling of electrolytes oncotic pressure. It seems probable that changes must inevitably generate secondary disturbances in in the oncotic or hydrostatic pressures within the body homeostasis which have particular relevance peritubular blood vessels achieve their effects on to the chemical pathologist. To understand these, net tubular reabsorption of sodium by influencing demands an understanding of how diuretics work the resistance of the intercellular channels or "shunt" in the context of modern views of the functional paths through which sodium ions pass to reach the organisation of the kidney. peritubular capillaries. Renal regulation of sodium excretionl 2 HORMONAL FACTORS A number of hormonal mechanisms operate singly Four main mechanisms are believed to be involved or together in encouraging sodium retention by the in the control of sodium excretion by the kidney. kidney. 1267 J Clin Pathol: first published as 10.1136/jcp.34.11.1267 on 1 November 1981. Downloaded from 1268 Lant Renin-angiotensin-aldosterone4 5 FEEDBACK CONTROL SYSTEMS INVOLVING The role of this humoral system in renal sodium THE MACULA DENSA9 regulation is considerable. Yet, because of the slug- A fourth intrarenal regulating system which has gish characteristics of the system, it is unlikely been proposed is that of a servo-mechanism operat- that these hormones, especially aldosterone, are ing between the macula densa cells of the ascending involved in fine "moment to moment" modulation. limb of Henle's loop and the glomerulus of the Aldosterone influences epithelial transport of sodium same nephron. This system functions by the release through activation of DNA-dependent RNA syn- of renin and angiotensin It locally in response to thesis, and the response to it follows a significant the sodium concentration in the tubular fluid lag period which corresponds to the time needed for impinging on the macula densa, the feedback the induction of new protein synthesis; this may loop being completed by appropriate alterations in amount to an hour or more in experimental systems. both GFR and proximal tubular reabsorption. The Yet it is clear that changes in sodium excretion detailed mechanisms involved in such an auto- in vivo may be induced abruptly by various ma- regulatory system which couples distal salt delivery noeuvres. Moreover, whenexcessive amounts ofaldos- to the filtration rate in individual nephrons remain terone or other mineralocorticoids are given experi- incompletely understood. mentally sodium retention occurs, but is transient. The "escape" from the action of aldosterone cannot Organisation of tubular function'° 11 be accounted for by changes in glomerular filtration rate or renal blood flow, and it is one of the pieces Diuretic drugs have actions on ion-transporting of evidence supporting the presence of another tissues as diverse as amphibian skin, intestinal humoral substance stimulating natriuresis-called epithelium, red and white blood cells and cornea. Third Factor or natriuretic hormone. The primary target for the action of these drugs however is the kidney, where they promote the Natriuretic hormone6 excretion of water and certain electrolytes such as sodium and chloride by interfering with tubularcopyright. A growing body of evidence supports the existence reasorptive mechanisms. Because these reabsorptive of a natriuretic humoral agent which promotes mechanisms vary according to the degree of sophisti- the renal elimination of sodium, by inhibiting sodium cation of different portions of the epithelium lining reabsorption in the proximal tubule. It may also the tubule, a brief survey of the organisation of work in harmony with the renin-angiotensin- is to understanding aldosterone system to provide fine control of tubular functions relevant sodium excretion by an action exerted mainly on diuretic action (Fig. 1). the collecting ducts. The chemical characterisation of the natriuretic hormone remains incomplete GLOMERULUS AND PROXIMAL TUBULE In normal man each day the renal glomeruli producehttp://jcp.bmj.com/ and its role in the sodium-retaining states is also approximately 180 litres of filtrate, and urine is uncertain. finally produced by the progressive reabsorption of 99% of this ultrafiltrate at various stages along Prostaglandins and kinins7 8 the nephron. About two-thirds of the glomerular Many experimental studies have demonstrated filtrate is reabsorbed iso-osmotically in the proximal the ability of renal tissues to generate prostaglandins tubule as a result of the active reabsorption of and kinins. Whereas renin, angiotensin and aldos- sodium chloride and sodium bicarbonate from the terone, like prostacyclin, are transported primarily tubular lumen into the peritubular fluid. The on October 1, 2021 by guest. Protected in the vascular compartment, kallikrein-kinin and mechanisms involved in transcellular ion movement prostaglandins of the E series are associated with are complex and involve a variety of energy- the renal interstitium and tubular lumen. One or dependent ion pumps as well as transfer paths or more prostaglandins, primarily PGE2, is probably channels in between the loose-fitting cells of the responsible for mediating the increase in medullary proximal tubule. The resistance to these intercellular blood flow that occurs in response to various stimuli shunts of ions is influenced considerably by changes including surgical trauma, salt loading, and the in the oncotic and hydrostatic pressures within the action of "loop" diuretics. The generation of peritubular capillaries. kinins in the distal tubules and collecting ducts results in the release of prostaglandins which in ASCENDING LIMB OF HENLE'S LOOP turn inhibit the local effects of antidiuretic hormone (MEDULLARY DILUTING SEGMENT)1213 (ADH) and thereby contribute to the tubular There are two morphologically distinct kinds of excretion of solute-free water. nephron, namely the outer cortical nephrons, J Clin Pathol: first published as 10.1136/jcp.34.11.1267 on 1 November 1981. Downloaded from Modern diuretics