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on therapy in renal disease. Arch Intern Med 1981;141:1039–41. Clinical use of diuretics 4Turner MW, Hutchinson TA, Barre PE, Richard S, Jothy S. A prospective study on Liam Plant MB MRCPI FRCPE , Consultant the impact of the renal biopsy in clinical exhibit high affinity for the chloride- Renal Physician, Department of Renal management. Clin Nephrol 1986;26:217–21. binding site of the sodium-potassium-2 5Cohen AH, Nast CC, Adler SG, Kopple JD. Medicine, Cork University Hospital, Cork, chloride (Na-K-2Cl) transporter. Bind- Clinical utility of kidney biopsies in the Ireland ing directly inhibits sodium and chloride diagnosis and management of renal disease. reabsorption. This indirectly leads to Am J Nephrol 1989;9:309–15. Clin Med 2003;3:517–20 6Farrington K, Levison DA, Greenwood RN, decreased reabsorption of calcium and Cattell WR, Baker LR. Renal biopsy in magnesium, and interferes with urine patients with unexplained renal impair- What are diuretics? concentrating and diluting mechanisms. ment and normal kidney size. Q J Med How do they work? Up to 20% of filtered sodium can be 1989;70: 221–33. excreted using these agents. 7Richards NT, Darby S, Howie AJ, Adu D, Michael J. Knowledge of renal histology Diuretics are widely used in clinical med- Ethacrynic acid is a rarely used loop alters patient management in over 40% of icine, particularly in hypertensive and diuretic indicated in patients known to cases. Nephrol Dial Transplant oedematous states. By inhibiting sodium have had hypersensitivity reactions to 1994;9:1255–9. reabsorption at different sites along the sulphonamides and related agents. 8Tomson C, Porter T. Asymptomatic micro- nephron, they increase natriuresis with scopic or dipstick haematuria in adults: consequent clinical benefit. 1 However, which investigations for which patients? A Thiazide and related diuretics 1–3 review of the evidence. BJU Int 2002;90: clinical goals may not always be easily 185–98. achieved. Diuretics of another class, the thiazides 9McGregor DO, Lynn KL, Bailey RR, Robson Site of action classifies the commonly and related compounds (egbendro- RA, Gardner J. Clinical audit of the use of used agents (Table1). 1–3 Although most flumethiazide, hydrochloroth iazide, renal biopsy in the management of isolated microscopic hematuria. Clin Nephrol 1998; (60–70%) filtered sodium is reabsorbed chlorthalidone, indapamide , metola- 49:345–8. in the proximal tubule, agents acting at zone), are also organic anions secreted in 10 Nakao N, Yoshimura A, Morita H, Takada this site (eg acetazolamide) are of rela- the proximal tubule. They act in the M et al. Combination treatment of tively little clinical use in oedematous distal tubule and connecting segment. angiotensin-II receptor blocker and states because the increased sodium loss They bind to a number of transporters, angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOP- is offset by increased reabsorpti on principally the sodium-chloride cotrans- ERATE): a randomised controlled trial. further down the nephron in the thick porter (Na-Cl-CT), directly inhibiting Lancet 2003;361:117–24. ascending loop of Henle. The same sodium reabsorpti on. This indirectly 11 Feehally J. Treating IgA Nephropathy – principle applies to the proximal tubular increases calcium reabsorpti on. The Who, When and How? Nephron Clin Pract effect of some thiazide diuretics. maximum natriuresis is less than that 2003;93:C47–8. 12 Iseki K, Iseki C, Ikemiya Y, Fukiyama K. achieved with loop diuretics, but combi- nation of these classes can be especially Risk of developing end-stage renal disease Loop diuretics 1–3 in a cohort of mass screening. Kidney Int potent. 1996;49:800–5. Loop diuretics (eg furosemide, 13 Kasiske BL. Relationship between vascular bumetanide, torasemide) are organic disease and age-associated changes in the Potassium-sparing diuretics1-3 human kidney. Kidney Int 1987;31:1153–9. anions, secreted into the tubular lumen 14 Ball S, Cook T, Hulme B, Palmer A, Taube in the proximal tubule. They act on the The potassium-sparing diuretics include D. The diagnosis and racial origin of 394 thick ascending loop of Henle where they amiloride, triamterene and spironolac- patients undergoing renal biopsy: an associ- ation between Indian race and interstitial nephritis. Nephrol Dial Transplant 1997; Key Points 12:71–7. Diuretics cause natriuresis in oedematous and hypertensive states

Dietary salt intake restriction is essential with diuretic use

Rapid adaptation by the tubule blunts the initial response to diuretic therapy

Application of pharmacokinetic and pharmacodynamic principles improves the achievement of clinical objectives

Sequential nephron blockade is effective in advanced chronic renal failure and heart failure

KEY WORDS: diuretics, heart failure, kidney, nephron, oedema, pharmacodynamics, pharmacokinetics, potassium, sodium

Clinical Medicine Vol 3No 6 November/December 2003 517 CME Renal Medicine tone. The first two are organic cations, prescribe a reduction in dietary salt intake Secretion into the nephron is secreted in the proximal tubule and in those taking diuretics, but it may be predominantly of bound drug. In inhibiting the luminal epithelial sodium difficult to achieve. Unfortunately, many patients with hypoalbuminaemia, channels of the principal cells in the cor- patients find diets containing less than this will lead to a decrease in tubular tical collecting duct. Spironolact one 80 mmol/day unpalatable, and most salt diuretic excretion and also allow free inhibits the effect of aldosterone on the intake occurs because of addition in food diuretic to pass out of the vascular intracellular aldosterone receptor in processing. space. Hypoalbuminaemia may these cells. Unexpected failure to lose weight/ECF therefore result in a smaller dose Diuretics may have actions at other volume in a patient on a seemingly reaching the kidney for secretion sites, for example many interfere with appropriate diuretic dose should prompt into the lumen. Increasing the dose urate absorption and secretion in the enquiry into salt intake. Measurement of or taking the steps above may be proximal tubule. 24-hour sodium excretion may help. A indicated. patient passing 150 mmol/day or more • Low glomerular filtration rate (GFR): but not losing weight is likely to have an delivery of diuretic to the kidney will When are diuretics indicated? excess intake. be decreased in heart failure and How are they most effectively Pharmacokinetic and pharmacody- renal failure (as will the initial 1–3 used? namic considerations are the other main filtered sodium load). Increasing the 1,3 Diuretics are primarily indicated in reasons why patients fail to respond. dose, taking the steps above or pathophysiological states (renal failure, Pharmacokinetics are important in initi- enhancing cardiac output by other cardiac failure, hepatic failure, nephrotic ating natriuresis, pharmacodynamics in means (egangiotensin-converting syndrome) in which retention of sodium sustaining it. enzyme inhibitors (ACEI)) may is a central problem. The objective of Since the natriuretic response is pro- help. therapy is to initiate and sustain an portional to the rate at which diuretic • Competition for secretion in the increased natriuresis until the patient has is excreted in the tubular fluid, consider- proximal tubule: many organic ions returned to clinical euvolaemia. It is ation should be given to the barriers accumulate in liver and renal failure; easier to maintain homeostasis at the present between administr ation and they compete for secretion, new desired steady state, particularly if excretion. Exceeding the natriuret ic decreasing the amount of diuretic attention has been paid to dietary salt threshold may be difficult in the presence reaching the tubular lumen. Certain intake.1 of: medications (egcimetidine) also To achieve a decrease in total body salt • Decreased bioavailability: furosemide have this effect. Avoiding such and water requires an excess of excretion has an oral bioavailability of about agents and taking the steps above over intake. Dietary salt intake frequently 60%. This may be decreased with an may help. exceeds 100 mmol/day (~6 g salt/day). oedematous gastrointestinal tract. It was formerly speculated that diuretic Increased sodium avidity occurs when the Increasing the oral dose, switching excretion was increased if the drug was diuretic is not active. For example, to lose to intravenous administration or administered with albumin, and that 5kg of excess extracellular fluid (ECF) using oral bumetanide (higher proteinuria might decrease the effective volume requires a net sodium loss of bioavailability) may be chosen. tubular concentration by binding free 650 mmol over and above that needed to • Increased volume of distribution: drug within the tubule. More recent balance daily intake. It is irrational not to diuretics are highly protein-bound. studies do not support these views. 4,5

Table 1. Diuretic agents.

Diuretic class Examples Principal site of action Comments

Loop Furosemide Thick ascending loop of Henle *Greater oral bioavailability Bumetanide* **Indicated if sulphonamide hypersensitivity Torasemide Ethacrynic acid** Thiazide Bendroflumethiazide Distal convoluted tubule; Also used in management of urolithiasis Hydrochlorothiazideconnecting segment More likely to cause hyponatraemia, Chlorthalidone hypomagnesaemia and hypercalcaemia Indapamide than loop diuretics Metolazone Potassium-sparingTriamterene Principal cells, cortical May be needed to correct hypokalaemia Spironolactone + collecting duct due to combination of loop and thiazide diuretics Amiloride Consider in severe heart failure +Specific benefits in advanced heart failure

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It is most important to increase the be time-cons uming and treatment –hypomagnesaemia (similarly) initial dose or otherwise overcome prolonged. –hypokalaemia (most common pharmacokinetic problems to initiate with combinations of loop and natriuresis. Giving an ineffective dose Are there other specific thiazide diuretics), usually more frequently will not help. In difficult indications? manifest within 5–7 days of cases, measurement of 24-hour sodium establishing therapy; ‘routine excretion may guide dosing. The hypocalciuric effects of thiazides screening’ is not indicated in the In a short time (days) after diuretic may be used to reduce the frequency of absence of changes in clinical administration more distal parts of the stone events in some hy percalciuric circumstances, dose or other tubule will increase reabsorpti on of patients, but not all patients benefit. medications sodium, thereby blunting the natriuretic Other measures to achieve this should –hyponatraemia (more common effect. This is principally a local response also be used. These include: increasing in the elderly), the incidence of to increased delivery of tubular sodium the fluid intake to achieve urine output which may be reduced by to these segments. This pharmacody- greater than three litres per day, restric- avoiding a high water intake namic adaptation should be anticipated tion of dietary salt intake, moderate (>1.5l/ day) and strategies for this may include: restriction of dietary calcium intake, • Metabolic alkalosis due to chloride Use of adequate dose more frequently: avoidance of calcium-containing supple- loss and ECF volume contraction • ments and restriction of dietary oxalate furosemide acts for about sixhours. Hyperuricaemia – tubular handling intake. • No enhanced natriuresis will occur of uric acid is complex, with both In some clinical circumstances, the for the rest of the day. Twice or reabsorption and secretion choice of agent may be informed by thrice daily dosing, once the initial occurring in the proximal tubule. other outcomes; for example, patients dose has been demostrated to have Diuretics (particularly thiazides) can with heart failure, particularly with more exceeded the ‘natriuretic threshold’ interfere with either of these marked left ventricular impairment and leading to increased sodium processes, the usual consequence low/normal serum potassium concentra- excretion, allows for a higher daily being hyperuricaemia. This effect is tions, may have an excess mortality if dose until blunting of the response usually dose-dependent and potassium-sparing diuretics are not begins. Studies indicate that frequently asymptomatic. used.9 In addition, spironolactone may continuous infusion may achieve a Combination therapy with ACEIs or have specific beneficial effects in some greater cumulative loss than angiotensin-receptor blockers may patients with severe heart failure. 10 repeated boluses. 6 blunt the effect. Clinical gout is Diuretics do not alter outcomes in Sequential nephron blockade: a more likely if the patient is also ECF • acute renal failure (ARF), 11 and are in fact structured inhibition of the distal volume depleted. more likely to increase the frequecy with nephron sites is indicated as the which ARF occurs when used in protocols Hypersensitivity reactions such as response to loop diuretics declines. • to diminish anticipated nephrotoxicity. skin rashes and interstitial nephritis. Initially, thiazide diuretics should be • Ototoxicity is a major, but administered, and subsequently uncommon, potential side effect. It potassium-sparing agents. The What are the side effects of diuretics? occurs with high dose loop diuretic latter may in fact be required therapy. It has been reported with quickly. Combination therapy with Side effects are common and include: high-dose (>2g/ day) infusion the other diuretic classes markedly ECF volume depletion and raised therapy in patients with renal increases potassium loss which may • urea concentrations because of renal failure. The mechanism is believed be an additional limiting factor. hypoperfusion. Typically, serum to be mediated via the Na-K-2Cl Sequential strategies have been creatinine concentrations (a more transporter in the inner ear. shown to be successful even in sensitive marker of GFR) are Diuretics should be avoided in preg- patients with advanced chronic renal unchanged or do not increase by nancy. They can cross the placenta and failure or heart failure. 7 In crossover more than 10–20% of baseline may cause fetal electrolyte disturbances. studies there appears to be little values. Urea concentrations may rise Placental perfusion may be compro- difference in the response to dramatically. (GFR is relatively mised, and diuretics enter breast milk. equipotent doses of different preserved due to autoregulation, but thiazides8 – personal choice may be impaired renal blood flow causes the best guide. References enhanced tubular urea Careful application of these principles reabsorption.) 1Brater DC. Diuretic therapy. Review. N Engl J Med 1998;339:387–95. should achieve the treatment objectives, Electrolyte disturbances , for example: • 2Brater DC. Pharmacology of diuretics. although in difficult cases therapy –hyponatraemia (commoner with Review. Am J Med Sci 2000;319:38–50. adjustments and clinical evaluation may thiazides) 3Ellison DH. Diuretic drugs and the treat-

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ment of edema: from clinic to bench and back again. Review. Am J Kidney Dis 1994; When should atheromatous renal artery 23:623–43. 4Fliser D, Zurbruggen I, Mutschler E, stenosis be considered? Bischoff I et al. Coadministration of albumin and furosemide in patients with the nephrotic syndrome. Kidney Int 1999; A guide for the general physician 55:629–34. 5Agarwal R, Gorski JC, Sundblad K, Brater DC. Urinary protein binding does not John Main MB ChB FRCP MD , Consultant raphy make definitive investigation sim- affect response to furosemide in patients Nephrologist, James Cook University pler and safer than traditional angiog- with nephrotic syndrome. J Am Soc Nephrol Hospital, Middlesbrough 2000;11:1100–5. raphy. Duplex scanning of the renal 6Rudy DW, Voelker JR, Greene PK, Esparza artery may have a role, but it is highly FA, Brater DC. Loop diuretics for chronic Clin Med 2003;3:520–5 operator-dependent and can be impos- renal insufficiency: a continuous infusion is sible in obese subjects even in skilled more efficacious than bolus therapy. Ann hands. Intern Med 1991;115:360–6. Atheromatous renal artery stenosis 7Fliser D, Schroter M, Neubeck M, Ritz E. (ARAS) is common – it is present in The introduction of angiotensin-con- Coadministration of thiazides increases the 15–30% of otherwise unselected patients verting enzyme inhibitors (ACEIs) and efficacy of loop diuretics even in patients with coronary, peripheral or cerebral angiotensinII receptor antagonists with advanced renal failure. Kidney Int vascular disease. 1 It is easy to find; in our (AIIRA) has both unearthed previously 1994;46:482–8. silent cases of ARAS and made the diag- 8Channer KS, McLean KA, Lawson-Matthew unit, about 75% of cases selected only on P, Richardson M. Combination diuretic clinical clues and basic ultrasonography nosis more important. Drugs of both treatment in severe heart failure: a ran- have some degree of ARAS at angio- classes abolish AII mediated glomerular domised controlled trial. Br Heart J 1994; graphy. However, it is much more diffi- efferent arteriolar constriction which is 71:146–50. cult to identify patients in whom ARAS vital to maintain glomerular filtration 9Cooper HA, Dries DL, Davis CE, Shen YL, rate (GFR) when renal perfusion pres- Domanski MJ. Diuretics and risk of is contributing to morbidity because all arrhythmic death in patients with left ven- the possible clinical manifestations of sure is reduced. This loss of GFR is inde- tricular dysfunction. Circulation 1999;100: ARAS can also be caused by other com- pendent of the cause of reduced renal 1311–5. plications of atheromatous disease blood flow and is also seen in the pres- 10 Pitt B, Zannad F, Remme WJ, Cody R et al. (Table 1). ence of hypotension or hypovolaemia of The effect of spironolactone on morbidity any cause as well as in renal artery and mortality in patients with severe heart This article will discuss clinical sce- failure. Randomized Aldactone Evaluation narios in which ARAS should be consid- stenosis. The effect of these drugs is dose Study Investigators. N Engl J Med 1999; ered with a view to revascularisation. dependent to some extent, and their 341:709–17. The increasing refinement and avail- effect on renal function in ARAS may 11 Mehta RL, Pascual MT, Soroko S, Chertow ability of computed tomography (CT) also be masked by intravascular volume GM; PICARD Study Group. Diuretics, overload and/ or hypertensio n. If the mortality, and nonrecovery of renal func- and magnetic resonance (MR) angiog- tion in acute renal failure. JAMA 2002;288: 2547–53. Key Points

Atheromatous renal artery stenosis (ARAS) is common in arteriopaths

All the clinical manifestations of ARAS have more common causes in arteriopaths

ARAS and chronic renal failure (CRF) often co-exist, but the CRF is not usually due to the ARAS (and therefore not improved by revascularisation)

The role of intervention in preventing end-stage renal failure remains unclear

The response to intervention in hypertension is usually no better than mild improvement

When pulmonary oedema is due to ARAS, the response to intervention can be dramatic

When acute oliguric renal failure occurs as a consequence of renal artery occlusion, excellent renal recovery can occur after intervention

KEY WORDS: atheromatous renal artery stenosis, ischaemic nephropathy, athero-embolic nephropathy, renovascular hypertension

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