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Diuretic use in renal disease

Domenic A. Sica
Abstract | Diuretics are agents commonly used in diseases characterized by excess extracellular fluid, including chronic kidney disease, the nephrotic syndrome, cirrhosis and heart failure. Multiple diuretic classes, including thiazidetype diuretics, loop diuretics and K+sparing diuretics, are used to treat patients with these diseases, either individually or as combination therapies. An understanding of what determines a patients response to a diuretic is a prerequisite to the correct use of these drugs. The response of patients with these diseases to diuretics, which is related to the dose, is best described by a sigmoid curve whose contour can become distorted by any of the several sodiumretaining states that are directly or indirectly associated with renal disease. Diuretic actions are of considerable importance to patients who have renal disease, as their effective use assists in extracellular fluid volume control, reducing excretion of protein in urine and lessening the risk of developing hyperkalemia. Diureticrelated adverse events that involve the uric acid, Na + and K+ axes are not uncommon; therefore the clinician must be vigilant in looking for biochemical disturbances. As a result of diureticrelated adverse events, clinicians must be resourceful in the dose amount and frequency of dosing.
Sica, D.A. Nat. Rev. Nephrol. 8, 100109 (2012); published online 20 December 2011; doi:10.1038/nrneph.2011.175

Introduction
Diuretics are mainly used in patients with chronic kidney disease (CKD) for the treatment of edema, to assist in reducing blood pressure and to aid in lowering serum levels of K+ in patients with hyperkalemia (a second ary feature of their action). Diuretics also have other renal uses that will not be addressed in this Review, such as the treatment of patients with nephrogenic dia betes insipidus, syndrome of inappropriate antidiuretic hormone secretion, hypercalcemia or nephrolithiasis with calciumcontaining stones. Loop diuretics are the most commonly used diuret ics in patients with CKD and an understanding of their pharma cology (pharmacokinetics and pharmaco dynamics) is important for their efficient use. Abundant questions exist about the use of diuretics in such patients. Some of the most frequent questions include: when should a thiazidetype diuretic be converted to a loop diuretic during progression of renal failure; are all loop diuretics equipotent and how best is combination diuretic therapy employed; do diuretics accelerate the loss of renal function in CKD; can loop diuretics be safely and effectively used in patients on hemodialysis; what are the most worrisome adverse events with diuretic therapy in patients with CKD; and how are diuretics used in patients who are allergic to sulfonamide? These issues, among others, will be addressed in this Review. syndrome. For example, ~84% of patients in the Reduction of Endpoints in NonInsulinDependent Diabetes Mellitus with the AngiotensinII Antagonist Losartan (RENAAL) study (baseline serum creatinine ~145 mol/l and a median urine albumin:creatinine ratio of ~1,250) required diuretic therapy (among other antihypertensive medications) to achieve the blood pressure goal of <140/90 mmHg.1,2 A similarly high pro portion (>90%) of patients received diuretic therapy to reach the target blood pressure in the Irbesartan Diabetic Nephropathy Trial (IDNT; baseline serum creatinine ~130 mol/l and median daily urinary protein excretion of 2.9 g).3,4 For example, in the group of patients treated with amlodipine, the frequency of diuretic use was as follows: thiazidetype (33.9%), loop (72.5%), K+sparing (7.8%) and combination (8.1%); diuretics were by far the most common addon therapies, with some patients receiving more than one diuretic.4 Although diuretic use was not stratified according to blood pressure reduction and/or maintenance of a euvolemic state in these studies, it can be presumed that usage followed a standardofcare pattern for the components of diabetic nephropathy.

Clinical pharmacology of diuretics

An understanding of the factors that affect a patients response to diuretics is a prerequisite to the proper use of these drugs, regardless of the disease state. The site of action for all diuretics (with the exception of spirono lactone) is in the luminal space. Glomerular filtration has a minor role in diuretic entry into the urinary compart ment, largely because all diuretics are bound to protein. Diuretics are then delivered to their luminal site of action by organic anion transporters that are expressed in the straight segment of the proximal tubule.
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Diuretic usage pattern

Virginia Commonwealth University Health System, 1101 East Marshall Street, Sanger Hall, Room 8062, Richmond, VA232980160, USA. dsica@mcvhvcu.edu

Diuretics remain a mainstay in the treatment of hyper tension and extracellular fluid volume overload in the presence of renal insufficiency and/or the nephrotic
Competing interests The author declares no competing interests.

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The intrinsic secretory capacity of the proximal tubule controls the quantity of diuretic that enters the proximal tubule to then be carried to its distal site of action.5,6 An assortment of pharmacokinetic factors influence drug availability for tubular secretion, including dose, absolute bioavailability (for orally administered compounds) and specific delivery determinants such as systemic blood pressure and renal blood flow. Of note, furosemide is the most widely used looptype diuretic and is erratically absorbed with an absolute bioavailability of 49%17% and a bioavailability range of 12112%.7,8 The coefficients of variation for the absorption of different furosemide products varies from 25% to 43%; thus, switching from one formulation to another will probably not result in an improved and more predictable patient response to this loop diuretic. Therefore, bioavailability (together with conversion from intravenous to oral therapy) should be governed by the reduction in body weight and not by a formulaic ratio of the intravenous dose doubled.810 Once a drug is presented to the kidney, the intrin sic capacity for tubular transport comes into play. Importantly, the tubular transport capacity is linked to the level of renal function. In addition, competi tion for diuretic secretion can occur, for example, in patients with renal failure as a consequence of acidosis or retained organic anions or urates. With the excep tion of azotemia or conditions associated with notable absorptive abnormalities, diseaserelated changes in the pharmacokinetics of diuretics are minor considerations when contrasted with altered pharmacodynamics and do not usually account for diuretic resistance.6
Key points
Diuretic therapy is mainly used in renal disease to facilitate extracellular fluid volume control, lessen the tendency to develop hyperkalemia and lower blood pressure The response to a loop diuretic is optimized by a clinically relevant time course of urinary drug delivery; a number of aspects of renal failure alter this relationship Although thiazidetype diuretics can elicit a response in patients with a glomerular filtration rate <50 ml/min/1.73 m2, loop diuretics are generally the diuretic of choice in patients with renal insufficiency K+sparing diuretics should be used cautiously in patients with chronic kidney disease In patients with endstage renal disease who have some residual renal function, treatment with a loop diuretic can be a useful adjunct therapy to lessen interdialytic fluid restriction Diureticrelated adverse events are typically dosedependent and can be a particular problem when high diuretic doses are necessary to control excess extracellular fluid volume

Maximal response

a
Sodium excreton rate Dose Bioavailability Tubular secretory capacity Rate of absorption Time course of delivery

Ef

cie

nc

b
Altered doseresponse relationship Braking phenomenon

Pharmacodynamics
The natriuretic response to a loop diuretic is optimized at a unique and clinically relevant time course of urinary drug delivery. This optimum rate of delivery resides on the steep portion of a developed sigmoidshaped diuretic dose (diuretic excretion rate) response (Na+ excretion rate) curve and is situated between a threshold rate of excretion (or minimally effective dose) and the plateau excretion rate (or dose beyond which there is no further gain in effect) (Figure1). Although this curve might be shifted to the right or left in individual patients (varying the threshold for effect), it retains its patientspecific contour (that is, the maximum response is unchanged).11 Determining the threshold dose for diuretic effect is clini cally important, particularly in patients with renal failure. In so doing, doses can be tailored to the individual needs of a patient and excessive diuretic dosing can be avoided. A reduction in the glomerular filtration rate (GFR), and thus the filtered load of extracellular fluid and Na+, limits the maximum achievable response to any diuretic and is a particularly relevant consideration in patients with renal failure. However, although a reduced GFR limits the effect of a diuretic in patients with CKD, adaptive increases in fluid delivery from the proximal tubule, together with transporter overexpression (both in the loop of Henle and the distal tubule), preserves diuretic response even in patients with very advanced CKD.12,13 Patients with a GFR of ~15 ml/min/1.73 m2 secrete only 1020% of the
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Threshold Loop diuretic excretion rate

Figure 1 | Determinants of loop diuretic response. a | Pharmacokinetic determinants. b | Pharmacodynamic determinants. The blue line represents and altered doseresponse relationship, as is observed in a diureticresistant state. The rate of diuretic delivery needed to attain a threshold response can vary substantially among patients with diuretic resistance. Reproduced from Sica, D.A. & Gehr, T.W. Clin. Pharmacol. 30, 229249 (1996) with permission from Adis, a Wolters Kluwer business ( Adis Data Information 2011. All rights reserved).

amount of loop diuretic that is secreted into tubular fluid in similarly dosed patients with a normal GFR.14,15 Thus, in patients with advanced CKD, an increased diuretic dose must be given to ensure delivery of tubular fluid sufficient to elicit a diuretic response. In so doing, the response is then similar to what is observed in healthy volunteers, unless patients with CKD have a tendency to retain Na+, as might be the case if the patient also has heart failure or the nephrotic syndrome.16 Another pharmacodynamics question for diuretic dosing in CKD is what is the ceiling dose that can (or should) be given? In severe CKD, studies have shown that the maximal natriuretic response (~20% of the filtered Na+ load) is achieved with intravenous doses of furose mide, bumetanide and torasemide at 160200 mg, 68 mg and 80100 mg, repectively.17,18 Doses in excess of these will not result in an incremental natriuretic response. This
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Sodium excretion rate (mmol/min) 3 30

diu

ex

cre

tio

nr

ate

10

0 100 80 60 40 20 Glomerular ltration rate (% of normal)

0 0

Figure 2 | Decrease in overall sodium excretion from a maximally effective dose of a loop diuretic in renal insufficiency as a result of a decreased filtered load. Abbreviation: FENa+, fractional excretion of sodium. Permission obtained from American Physiological Society Shankar, S.S. & Brater, D.C. Am. J.Physiol. Renal Physiol. 284, F11F21 (2003).

FENa+ (%)

FENa+
So

20

origin of Na+ retention after administration of a diuretic, which can be ascribed to an increase in both proximal and distal tubular Na+ absorption.22,23 A volumeindependent component of the braking phenomenon has also been suggested that might be structural in nature.8,24 Structural hypertrophy in the distal nephron has been demonstrated in rats receiving prolonged infusions of loop diuretics.8 These structural changes are coupled to enhanced rates of distal nephron Na+ and Cl absorption and increased secretion of K+, processes that are only partially related to aldosterone. These nephron adaptations might contribute to retention of Na+ after administration of a diuretic and to tolerance of diuretics in humans, and possibly explain why Na + retention can persist for up to 2weeks after discontinua tion of a loop diuretic.25 In patients who have received chronic loop diuretic administration, initiation of thiazide therapy can reverse the structural adaptations produced by loop diuretics.26

process can be conceptualized in the following way; in a patient with a GFR of 20 ml/min/1.73 m2, 3035 mmol of Na+ will be excreted with a ceiling dose of a loop diuretic in consideration of the filtered load and an unimpeded maximal natriuretic response (Figure2). If the daily intake of Na+ is ~100 mmol then the ceiling dose of a loop diuretic will need to be given three times per day to main tain a neutral Na+ balance. However, in clinical practice a loop diuretic is seldom given three times daily in order to maintain Na+ balance, as adherence can be a problem with medications administered at this frequency. A normal doseresponse relationship for loop diuret ics, as might be present in patients with CKD who do not have edema, can be unfavorably distorted (a downward and rightward shift of the sigmoid curve) by a number of clinical conditions, ranging from volume depletion to the presence of heart failure or the nephrotic syndrome (disease state alterations), and by various drug thera pies, such as NSAIDs.5,6,19 NSAIDs are particularly likely to negatively rework this relationship, as inhibition of prostaglandin synthesis considerably blunts the effect of loop diuretics.20

Diuretic rotation
The rotation from one diuretic class to another and, occa sionally, rotation within a class might induce diuresis in a patient previously refractory to the diuretic effects of a particular compound given intravenously. This phenom enon has not been critically examined, however, and evi dence for this effect is anecdotal at best.27 Within a class, varied responses to orally administered diuretics is mostly attributable to differences in the rate of diuretic absorp tion and the gain from one diuretic being delivered to the tubules in a more efficient manner than another diuretic. In addition, differing hemodynamic circumstances might be present when a withinclass diuretic switch occurs and might be the basis for a perceived better response. Finally, a switch from a shortacting loop diuretic, such as furosemide, to a longacting compound, such as torasemide, quite logically would result in an increased net negative Na+ balance. The converse would possibly apply if the rotation was from torasemide to furosemide. This scenario would be most relevant in the setting of fairly normal renal function, as the pharmacokinetics of torasemide in patients with CKD (absence of accumula tion of torasemide) mean that the duration of action of torasemide is similar to that of furosemide.28

Tolerance of loop diuretics

The first few doses of a loop diuretic (either intravenous or oral) can be expected to each yield a recognizable diuresis. In most patients, this diuresis results in a net negative Na+ balance if Na+ intake is restricted; however, physiologic adaptations (also termed braking phenom enon) soon develop that preclude continued volume loss with successive doses (rightward shift of the dose response curve). In patients without edema, this adapta tion (after diuretic Na+ retention as might be induced by volume depletion) develops within days of being given a thiazide or loop diuretic, which limits weight loss to 12 kg.21 In patients with edema, this process might take somewhat longer to fully activate, enabling a greater net weight loss than that which occurs in patients without edema. A reduction in extracellular fluid volume and neurohumoral activation are important factors in the
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Alternative diuretics
Mannitol is a polysaccharide diuretic given intra venously that is freely eliminated by glomerular filtra tion. Mannitol is poorly reabsorbed along the length of the nephron and therefore has a dosedependent osmotic effect. This osmotic effect traps water and solutes in the tubular fluid, thus increasing excretion of Na+ and water. The halflife for plasma clearance of mannitol depends on the level of renal function, but is usually between 30 min and 60 min, thus its diuretic properties are very transient. As mannitol also expands the extracellular volume and can precipitate pulmonary edema in patients with heart failure, it should be used cautiously in these patients, if at all. Moreover, excessive mannitol administration, particularly in patients with a
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reduced GFR, can cause dilutional hyponatremia, hyper kalemia and/or acute renal failure.29 The last of these is dosedependent, is connected to afferent arteriolar vaso constriction and typically corrects with the systemic elimination of mannitol, as occurs with hemodialysis.30 Acetazolamide is the only carbonic anhydrase inhibi tor with notable diuretic effects. Acetazolamide is readily absorbed and undergoes renal elimination by tubular secretion. Its administration is usually marked by a brisk alkaline diuresis. Although carbonic anhydrase inhibi tors are proximal tubular diuretics (where the bulk of Na+ reabsorption occurs), their net diuretic effect is modest, as Na+ reabsorption in distal nephron segments offsets proximal Na+ losses. The use of acetazolamide is limited by its transient action and by the development of metabolic acidosis with extended administration. However, acetazolamide can correct the considerable metabolic alkalosis that occasionally occurs with loop diuretic therapy. Acetazolamide can be of some thera peutic use when given together with a loop diuretic and spironolactone, with this threedrug combination effect ing sequential nephron blockade and thus an additive to synergistic diuretic response.31
GFR (ml/min/1.73 m2) 130 90 Stage 1 Thiazides Stage 2 Thiazides

60 Stage 3 Thiazides Loop diuretics

30 Stage 4 Loop diuretics Combination treatment

15 Stage 5 Loop diuretics Combination treatment

Figure 3 | The stages of CKD showing classification of CKD and diuretic use according to the NKF K/DOQI guidelines. Increased rates of adverse events are generally seen at GFR <60 ml/min/1.73 m2. Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate; NKF K/DOQI, National Kidney Foundation Kidney Disease Outcomes Quality Initiative.

Chronic kidney disease

A loop diuretic is generally the diuretic of choice in patients with renal insufficiency. Although a thiazide type diuretic will initiate diuresis in patients with mild renal insufficiency, the response in patients with a GFR of <50 ml/min/1.73 m2 is less than that seen with a loop diuretic. Higher doses of thiazidetype diuretics are required in patients with renal insufficiency than in those with normal renal function, as these drugs need to reach the nephron lumen to be effective. Therefore, most instances of a patient with moderate to severe renal failure not responding to a thiazidetype diuretic are attribut able to underdosing rather than to resistance. As such, for hydrochlorothiazide a dose of 50100 mg (moderate CKD) or 100200 mg (severe CKD) would be required for a representative diuretic response (Figure3).32 Even if thiazidetype diuretics are correctly dosed for the level of renal function, their use is limited as they have low potency and a flat doseresponse curve. For example, if an individual with a GFR of 10 ml/ min/1.73 m2 (14.4 l per day) needs to excrete 200 mmol per day of Na+, ~10% of the filtered Na+ must appear in the final urine. The commonly used thiazide prepara tions, even given in high doses, are incapable of this level of inhibition of Na+ reabsorption. The thiazidetype diuretics metolazone and chlortalidone, although not more potent than other diuretics, are both longacting and heavily compartmentalized in red blood cells. These pharmacokinetic features lead to a lowlevel diuresis being sustained for a lengthier period of time than with other thiazides and enable the occasional successful use of either compound in patients with CKD.33

Hypertension in chronic kidney disease

Diuretics are useful in the management of most patients with CKD and hypertension. By reducing extracellular
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fluid volume, diuretics will lower blood pressure and potentiate the effects of angiotensinconvertingenzyme (ACE) inhibitors, angiotensinreceptor blockers (ARBs) and other antihypertensive agents, including calcium channel blockers. Thiazidetype diuretics given once daily are recommended in patients with stages 13 CKD. Limited information from controlled trials exists to guide diuretic dosing to control blood pressure in patients with stages 4 or 5 CKD; thus, such dosing is empiric and frequently determined by the elimination of edema (if present) and less so by control of blood pressure (Table1).34 The major outcomes data in patients with stage3 CKD and hypertension comes from the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) in which the thiazidetype diuretic chlortali done was compared with the ACE inhibitor lisinopril and the calciumchannel blocker amlodipine. In a posthoc evaluation of ALLHAT data, patients were stratified into three groups on the basis of their baseline GFR: normal or increased (90 ml/min/1.73 m2; n = 8,126 patients), mildly reduced (6089 ml/min/1.73 m 2; n = 18,109 patients) and moderately or severely reduced (<60 ml/ min/1.73 m2; n = 5,662 patients). A chlortalidonebased regimen (dose range of 12.525.0 mg per day) was equally as effective (if not superior) in reducing blood pressure in all groups of patients, as were lisinopril (dose range of 1040 mg per day) and amlodipine (dose range of 510 mg per day) in the main ALLHAT trial.35 In this posthoc evaluation, a low GFR independently predicted an increased risk of coronary heart disease. Neither amlodipine nor lisinopril were better than chlor talidone in preventing coronary heart disease, stroke or combined cardiovascular disease. Chlortalidone was superior to both amlodipine and lisinopril in preventing heart failure, independent of the level of renal function. Although the study design of ALLHAT confounds inter pretation of these findings (protocolspecific second line and thirdline drugs were required), the results do suggest that if a thiazidetype diuretic is to be used in patients with moderate to severe renal failure, outcomes and efficacy data support the use of chlortalidone rather than amlodipine or lisinopril.35 Loop diuretics, given once or twice daily, are recom mended in patients with stages 4 or 5 CKD. This regime of loop diuretics, in combination with thiazide diuretics,
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Table 1 | Pharmacokinetics of diuretics Diuretic
Loop Furosemide Bumetanide Torasemide Thiazide Bendroflumethiazide Chlortalidone Chlorothiazide Hydrochlorothiazide Hydroflumethiazide Indapamide Polythiazide Trichlormethiazide K+-sparing Amiloride Triamterene Spironolactone Active metabolites 50% >80 90% Unknown 1726 25 1.5 >15 100 Prolonged No change ND ND ND ND ND ND 64 3050 6575 73 93 ND ND 25 2455 1.5 2.5 625 1525 26 14 ND ND ND Increased ND ND ND 510 ND ND ND ND 628 ND ND ND 10100 80100 80100 1.52 1 34 2.8 1.6 45 2.7 1.3 6

Oral bioavailability (%)

Half-life (h) Healthy patients Patients with renal insufficiency Patients with heart failure

Abbreviation: ND, not determined. Permission obtained from Massachusetts Medical Society Brater, D.C. N. Engl. J. Med. 6, 387395 (1998).

can be used for patients with considerable extracellular fluid volume expansion and edema. 34 An important consideration in the treatment of hyper tension in patients with stages 4 or 5 CKD is that a loop diuretic is only as useful as its ability to bring a patient to target weight. In patients with CKD, expansion of the extra cellular volume is directly dependent on the degree to which the GFR is reduced and corresponds to ~510% of body weight, even in the absence of overt edema.36,37 Establishing a target weight in patients with CKD who do not have edema can be challenging; however, a gradual reduction in blood pressure in a patient with poorly con trolled hypertension that coincides with diureticrelated weight loss can be a useful clue that a target weight is being approached or has been reached.38 If control of blood pressure is inadequate and/or edema is present, patients who receive a fixeddose combination antihypertensive therapy that contains a thiazide diuretic should be considered for conversion to a loop diuretic (with the other fixeddose combina tion component given separately) when their GFR drops below 50 ml/min/1.73 m2. If a patient with CKD (irrespective of the stage) has good blood pressure control and does not have edema, fixeddose combina tion antihypertensive therapies with a thiazide diuretic component do not need to be changed. K+sparing diuretics, such as spironolactone and eplere none, are used more regularly than previously in the CKD population on the basis of their blood pressurereducing ability and their prominent antiproteinuric effect. 39 Mechanistically, spironolactone and eplerenone are dif ferent from amiloride and triamterene (which are also
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K+sparing diuretics) in that they work as aldosterone receptor antagonists (ARAs), whereas amiloride and tri amterene block the epithelial sodium channel. The onset of action for spironolactone is characteristically slow, with a peak response at 48 h after the first dose. This lag in the response is probably related to the time needed for the active metabolites of spironolactone to reach steadystate levels in plasma and/or tissue. Spironolactone can trigger a natriuretic response when it is given to patients with cirrhosis and ascites or heart failure, particularly if it is given in combination with a loop and/or a thiazidetype diuretic;40 however, when spironolactone is administered acutely to patients with hypertension who do not have edema it is not a particularly strong natriuretic agent, irrespective of CKD status. The package labels for both spironolactone and eplere none specifically state that these drugs should not to be used in patients with mild to moderate renal insuffi ciency. However, use (or not) of an ARA in patients with CKD is not merely a function of the level of renal function; rather, it should take into account the prob ability of clinically relevant hyperkalemia developing. 41 Hyperkalemia attributable to an ARA is connected with several factors, including dose, patient predisposition to hyperkalemia (as in the case of renal failure), dietary intake of K+ and/or volumedepleting illnesses that result in a decline in renal function. The risk of some change in serum levels of K+ when an ARA is used in patients with CKD should not be an absolute deterrent to the use of these drugs, but rather should prompt careful monitor ing for this potentially lifethreatening and unpredict able electrolyte disturbance. The frequency of such
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monitoring should be patientspecific and largely based on the number of risk factors for hyperkalemia that are present. Strategies to reduce the degree of proteinuria should always be pursued in patients with the nephrotic syn drome.50 This reduction can be best accomplished with ACE inhibitors, ARBs, ARAs and/or statin therapy.51 The cornerstone of therapy for edema related to the nephrotic syndrome is that of restricting the intake of salt and water. Dietary management of edema that accompanies the nephrotic syndrome often needs to be supported by diuretic therapy; however, the reduced response often requires increased dosing of a loop diuretic. The selec tion of a starting dose for a loop diuretic in patients with the nephrotic syndrome should take into consideration the level of renal function and the degree of albuminuria, while being mindful of the chance that renal function can decline if the rate of diuresis exceeds the refilling rate of the vascular compartment from the interstitial space. The latter is particularly the case in patients receiving moderate to high doses of an ACE inhibitor or an ARB. Failure to respond to monotherapy with a loop diuretic might prompt consideration of therapy with the combination of a thiazide and a loop diuretic.6 If these strategies fail and the patient is severely hypo albuminemic (serum levels of albumin <20 g/l), a mixture of loop diuretic and albumin can be given either premixed in a syringe or as separate albumin and loop diuretic infusions.52,53 However, how these approaches reproducibly generate a meaningful diuretic response is untested. In particular, administration of premixed loop diuretic and albumin in a syringe was studied in patients with cirrhosis and ascites (40 mg of furosemide and 25 g of albumin premixed exvivo versus 40 mg of furosemide); the premixing of albumin with furosemide did not enhance the natriuretic response.52

The nephrotic syndrome

The nephrotic syndrome often presents as a diuretic resistant state. Alterations in both the pharmacokinetics and pharmacodynamics of loop diuretics account for this blunting of the effects of diuretics. Patients with the nephrotic syndrome can also have their response to diuretic therapy blunted by orthostatic hemodynamic changes. Delivery of loop diuretics is impaired in patients with hypoalbuminemia, as the renal secretion of diuret ics is strongly dependent on the plasma concentration of albumin.42 Moreover, decreased renal secretion of a loop diuretic in patients with the nephrotic syndrome relates to the movement of these drugs from the intravascular to the interstitial compartment. For example, low serum values of albumin, as seen in the analbuminemic rat, can produce as much as a 10fold increase in the volume of distribution of furosemide.43 Finally, in addition to diminished secretion of loop diuretics in patients with the nephrotic syndrome, diuretic metabolism increases with an increased rate of glucuronidation, which is specific to furosemide.44 In addition to these noteworthy pharmacokinetic alterations, the pharmacodynamics of loop diuretics are also abnormal in patients with the nephrotic syndrome. In patients with decompensated nephrotic syndrome, the doseresponse relationship for the diuretic effect is shifted to the right (increased threshold for effect) and downwards (reduction in maximal response or decreased sensitivity) (Figure1). In patients with the nephrotic syndrome, the subnormal diuretic response occurs as a result of several factors. Diuretics can bind to albumin in the tubular fluid, which decreases the amount of unbound, active drug that is available to interact with its tubular receptor.45 When urinary concentrations of albumin are >4 g/l, as much as 65% of the diuretic that reaches the tubular fluid is bound to albumin. Consequently, starting with a dose that is two to three times higher than the normal dose is recommended in patients with the nephrotic syndrome to ensure delivery of adequate amounts of free drug to the site of action.5 However, a study has shown that sulfafurazole (a com pound that competes with furosemide for intraluminal albumin binding) does not enhance the natriuretic effect of furosemide when given to patients with the nephrotic syndrome.46 Moreover, patients with the nephrotic syndrome might have a diminished natriuretic response to a loop diuretic because of a primary decrease in cellular drug action and/or because excessive Na+ reabsorption occurs in proximal and/or more distal nephron segments.47,48 As regards excessive Na+ reabsorption, many (but not all) patients with the nephrotic syndrome have an activated reninangiotensin system with high circulating levels of angiotensinII and high concentrations of aldosterone, both of which are capable of increasing Na+ reabsorption in proximal and distal nephron segments.49
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Combination diuretic therapy

The use of diuretic combination therapies in patients who are resistant to diuretics is predicated on the ability of diuretics of different classes to affect sequential nephron blockade, which generates an additive natri uretic response. This additive response is connected to several factors, including an increased delivery of Na+ to the more distal thiazidesensitive segments of the kidney and changes in distal tubular cell structure and/or func tion as a result of exposure to a thiazidetype diuretic. Although all permutations of diuretic combinations have been tried, a thiazide and a loop diuretic with or without a K+sparing diuretic is the most commonly used combination in clinical practice.6 The metolazone furosemide combination is particularly useful when a large volume removal is needed, as might be the case in patients with CKD and the nephrotic syndrome.5456 The diuretic response to the combination of a loop diuretic and metolazone is often unpredictable, as meto lazone has a slow and erratic pattern of absorption.6,57 Achieving a systemic concentration of metolazone adequate to effect its synergy with a loop diuretic might require multiple doses, and thus a lag of several hours or days, before the effect of the drug combination is fully manifested.6,57 When a diuretic response is urgently needed, an oral loading dose of metolazone in the range
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of 1020 mg can be given, usually in the hospital setting. Such an approach provides a large amount of the drug, thereby eliminating the rate and extent of metolazone absorption as a potential confounder to the response.57 In the outpatient setting, when circumstances are not generally urgent, 2.55.0 mg of metolazone per day or every other day can be administered with a loop diuretic. Dependent on the clinical need, upward dose titration of metolazone can be considered. With the initiation of combination therapy, the dosage of the loop diuretic is typically kept constant until a response has occurred; although some suggest that the loop diuretic dose should be simultaneously reduced with the introduction of metolazone.58 Once a diuretic response has been elicited, the frequency at which metolazone is administered can be decreased to two or three times a week; a substantial reduction in the loop diuretic dose is also typically indi cated. In all cases, judicious monitoring of the diuretic response is paramount to avoid excessive diuresis and notable electrolyte depletion. If either occurs, both drugs must be discontinued and therapeutic measures begun in anticipation of continued diuresis, as the half life of metolazone is extremely prolonged in the setting of reduced renal function.59 Although decreased renal function might offer some protection from an excessive diuretic response, this is not an observation that can be relied on.32,55 have any beneficial effect on the removal of nitrogenous waste products. If loop diuretic therapy is contemplated in patients on hemodialysis, large doses or combination therapy is needed to achieve the desired effect.56 For example, in one study, 13 patients on hemodialysis were treated with a fixed daily dose of furosemide of 2501,000 mg. Although urine volume increased by 60%, this response diminished after 3months and a decline in creati nine clearance occurred. 61 The Dialysis Outcomes and Practice Pattern Study (DOPPS) examined prac tice patterns for the use of diuretic therapy in 16,420 patients on hemodialysis. In this prospective observa tional study, overall use of loop diuretics ranged from 9.2% in the US to 21.3% in Europe, whereas use within 90days of dialysis initiation ranged from 25.0% (US) to 47.6% (Japan). Not unexpectedly, use of diuretics was associated with a reduced interdialytic weight gain and a lower probability of developing hyperkalemia (levels of K+ >6.0 mmol/l) than was not receiving a diuretic. Patients with residual renal function (defined as a daily urine output of 200 cm 3) on diuretic therapy were almost two times more likely to retain residual renal function after 1year in the study than were patients not receiving diuretics.62

Dialytic removal
Hemodialysis and hemofiltration do not influence the pharmacokinetics of loop diuretics. As a result of the high plasma protein binding, which is common to all diuretics, <10% of a loop diuretic that is in the body is eliminated by dialysis. Therefore, patients with ESRD can be given diuretics without undue concern that the diuretic will be removed during dialysis or that dosing will be required after dialysis.56

Diuretic infusions
A loop diuretic administered as an infusion is another method that can potentially improve response in patients with diuretic resistance. In a randomized crossover study comparing continuous infusion to bolus bumetanide in patients with severe renal insufficiency (mean GFR 17 ml/min/1.73 m 2), a greater net Na+ excretion was observed during continuous infusion than with a bolus administration despite comparable total 14 h drug excretion.60 The rate of urinary bumetanide excretion remained constant when infused. With intermittent administration, peak bumetanide excretion was observed within the first 2 h and tapered thereafter. When continu ously infused, the pattern of bumetanide can be expected to produce more efficient drug utilization than with a bolus administration. However, this approach has not been proven to be successful in all patients in whom it has been studied.

Diuretic-related adverse events

The list of diureticrelated adverse events is lengthy and so they can not all be discussed here. Diureticrelated adverse events can be separated into those with estab lished mechanisms (such as electrolyte and/or metabolic abnormalities) and those that have less clear mecha nisms, as is the case with impotence or idiosyncratic drug reactions.63 Electrolyte changes are the most common adverse events with diuretics and presumably are most promi nent with loop diuretics owing to their greater overall potency. However, the potency of a diuretic might not be as important to electrolyte adverse events as its duration of action. For example, thiazidetype diuretics, such as chlortalidone and metolazone, although less potent than a loop diuretic can still cause noteworthy hypokalemia and hypomagnesemia as a consequence of their very long duration of action.64 Diureticrelated electrolyte adverse events are readily picked up with periodic blood testing, which simplifies management of the abnormality. Six wellestablished electrolyte adverse events that arise from diuretic use in patients with CKDhyponatremia, hypo kalemia, hyperkalemia, hyperuricemia, hypercalcemia and hypocalcemiawarrant specific discussion.
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End-stage renal disease

Weight gain between dialysis sessions is an expected phenomenon in patients with endstage renal disease (ESRD) and is ordinarily controlled by having the patient restrict their fluid intake. However, fluid intake in some patients is inordinately high, which results in considerable interdialytic weight gain. Such patients are candidates for loop diuretic therapy if sufficient residual renal function exists to enable a meaningful diuretic effect. Although loop diuretics might be an effective adjunctive therapy in patients with ESRD, an increase in the time interval between hemodialysis sessions is not possible with loop diuretics, as these drugs do not
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Hyponatremia Hyponatremia is an uncommon but potentially serious complication of diuretic therapy in patients with CKD. The considerably reduced GFR of patients with stages 4 and 5 CKD contributes to an increased prob ability of hyponatremia developing in these patients.56 Hyponatremia is more likely with thiazide diuretics than with loop diuretics. Loop diuretics inhibit Na+ trans port in the renal medulla, which means that a maximal osmotic gradient can not be achieved. Thus, loop diuret ics impair the ability to produce concentrated urine. By contrast, thiazidetype diuretics increase Na+ excretion, prevent maximal dilution of the urine and maintain the innate concentrating capacity of the kidney. Although hyponatremia attributable to diuretics usually occurs shortly after therapy begins (within the first 2weeks), it can appear after several years of therapy.63 Several methods, which are not mutually exclusive, exist to manage mild asymptomatic hyponatremia (typically levels of Na+ of 125135 mmol/l) as a result of diuretic therapy, including withholding the diuretic that caused the hyponatremia, restricting free water intake and/or correcting hypokalemia if present. When a thiazidetype diuretic is associated with hyponatremia, substituting a loop diuretic is an option if diuretic therapy is felt to be necessary. In the past 5years, vasopressin receptor antagonists have become available for the management of patients with hyponatremia. These compounds mainly act on the V2 vasopressin receptor. The compounds in this class, including conivaptan, lixivaptan and tolvaptan, all improve renal water handling and correct hyponatremia in conditions associated with water retention. Optimal doses and dosing frequencies in patients with CKD are yet to be established for these compounds. The avail ability of V2 vasopressin receptor antagonists simplifies the management of hyponatremia, particularly when an excess of vasopressin is implicated.65 Hypokalemia and hyperkalemia A serum level of K+ of <3.5 mmol/l, which is the most common criterion for a diagnosis of hypokalemia, occurs variably in patients who are treated with loop and/or thi azide diuretics.66 The mechanisms that contribute to the development of hypokalemia during diuretic use include: increased flowdependent distal K+ secretion (more often observed when Na+ intake is high); a fall in distal tubule luminal Cl concentration; metabolic alkalosis; and secondary hyperaldosteronism. To effectively treat hypokalemia as a result of diuretic therapy, Na+ intake needs to be restricted whether or not CKD is present. When conservative approaches, such as using the lowest possible diuretic dose and restricting Na+ intake, prove inadequate, K+ supplements and/or K+sparing compounds can be used (even in patients with CKD). A number of K+sparing drugs are avail able, including compounds that reduce the activity of the reninangiotensin system such as ACE inhibitors, ARBs or direct renin inhibitors, and K+sparing diuret ics such as triamterene, amiloride, spironolactone and
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eplerenone. In general, K+sparing diuretics are much more effective in minimizing urinary K+ losses as a result of diuretic therapy than are ACE inhibitors or ARBs. On average, serum levels of K+ increase by 0.51.0 mmol/l in patients with late stage3, stage4 or stage5 CKD who are treated with a K+sparing diuretic; however, the occa sional patient has a much greater rise in serum levels of K+ with these compounds.67 K + sparing diuretics (such as triamterene and amiloride) and aldosteronereceptor antagonists (such as spironolactone and eplerenone) might cause noteworthy hyperkalemia. Hyperkalemia is more likely to develop in patients treated with K+sparing diuretics who also have a reduced GFR (especially the elderly), in those also receiving K+ supplements or salt substitutes (K+ at 60 mmol/15 ml), in patients on an ACE inhibitor, ARB or an NSAID, or in other situations that predispose to hyperkalemia such as metabolic acidosis, hyporeninemic hypoaldosteronism, administration of trimethoprim/ sulfamethoxazole, or heparin therapy (including sub cutaneous heparin regimens).68 Of note, a Ushaped relationship between serum levels of K+ and mortality has been observed, with mortality risk greater at serum values of K+ 4.0 mmol/l than at values 4.05.5 mmol/l in a cohort of 820 patients with an average GFR of 25.4 ml/ min/1.73 m2.69

Hyperuricemia The concentration of serum urate can be increased by as much as 35% with the use of thiazide diuretics. This effect is attributable to decreased clearance of urate by the kidney, and is more likely to occur in patients who have the highest values of urate clearance before therapy is ini tiated.70 Decreased clearance of urate might be associated with increased reabsorption secondary to a reduction in the extracellular fluid volume that is related to the use of a diuretic and competition for tubular secretion, as tubular secretion of thiazide diuretics and urate is medi ated by the same organic anion transporter pathway.71,72 Hyperuricemia as a result of diuretic therapy is dose dependent and is important for several reasons, such as increasing the probability of a gouty flare; however, an attack of gout is not usually precipitated by hyper uricemia following use of a diuretic unless the patient is predisposed to the development of gout or serum concentrations of urate are in excess of 714 mol/l.71 Hyperuricemia itself has been linked to hypertension, cardiovascular events, and perhaps the development and progression of renal failure; however, it is unclear how these events specifically relate to hyperuricemia brought on by diuretic therapy.73,74 Hypercalcemia and hypocalcemia In patients with CKD, the use of loop diuretics is associ ated with hypercalciuria, increased levels of parathyroid hormone and increased odds of secondary hyper parathyroidism compared with no diuretic treatment. These associations are attenuated in patients who are coadministered thiazidetype diuretics. The choice of which diuretic is used is a potentially modifiable
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determinant of secondary hyperparathyroidism in patients with CKD.75 Conversely, thiazidetype diuretics reduce the excretion of urinary calcium and are effective therapies for nephrolithiasis and useful adjunct therapies for osteoporosis.76,77 which furosemide is infused should not exceed 4 mg/min and serum concentrations should be maintained below 40 g/ml. Patients with renal failure and those receiving concomitant aminoglycoside therapy are at greatest risk of developing ototoxicity.80

Diuretic-related allergic reactions Photosensitivity dermatitis can occur during therapy with a thiazide or furosemide. Hydrochlorothiazide is more likely to cause photosensitivity than are other thiazides.78 Diuretics might occasionally cause serious generalized dermatitis and sometimes even necrotizing vasculitis. Crosssensitivity with sulfonamide drugs can occur with all diuretics except etacrynic acid, which is not structurally related to sulfonamide drugs. Severe nec rotizing pancreatitis is an additional serious, but rare, lifethreatening complication of thiazide therapy, as is acute allergic interstitial nephritis, a disease state marked by fever, rash and eosinophilia. This state might result in permanent renal failure if drug exposure is prolonged. Etacrynic acid is chemically dissimilar from the other loop diuretics and can be safely substituted in patients treated with a diuretic who experience any one of a number of these allergic complications.79 Ototoxicity Ototoxicity as a result of loop diuretic therapy usually occurs within 20 min of infusion and is typically revers ible, although permanent deafness has been reported, particularly with etacrynic acid. Ototoxicity is clearly connected with both the rate of infusion and the peak serum concentrations of the loop diuretic. Etacrynic acid, furosemide and bumetanide with both intra venous and oral administration have been associated with ototoxicity.80 The frequency of ototoxicity seems to be higher with furosemide than with bumetanide, and even higher with etacrynic acid.80 In general, the rate at
1. Brenner, B.M. etal. Effects of losartan on renal and cardiovascular outcomes in patients with type2 diabetes and nephropathy. N.Engl. J.Med. 345, 861869 (2001). Bakris, G.L. etal. Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch. Intern. Med. 163, 15551565 (2003). Lewis, E.J. etal. Renoprotective effect of the angiotensinreceptor antagonist irbesartan in patients with nephropathy due to type2 diabetes. N.Engl. J.Med. 345, 851860 (2001). Berl, T. etal. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type2 diabetes and overt nephropathy. Ann. Intern. Med. 138, 542549 (2003). Brater, D.C. Diuretic therapy. N.Engl. J.Med. 339, 387395 (1998). Sica, D.A. & Gehr, T.W. Diuretic combinations in refractory oedema states: pharmacokinetic pharmacodynamic relationships. Clin. Pharmacokinet. 30, 229249 (1996). Almeshari, K. etal. A volumeindependent component to postdiuretic sodium retention in man. J.Am. Soc. Nephrol. 3, 18781883 (1993). Ellison, D.H., Velzquez, H. & Wright, F.S. Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietary

Conclusions
Diuretics are mainstays of therapy in patients with CKD, as they can treat edema as well as facilitate reductions in blood pressure. Understanding the determinants of the doseresponse relationship for diuretics is impor tant to their efficient use. The rate and extent of diuretic absorption has some involvement in the soughtafter natriuretic response.81 In addition, although diuretic infusion therapy is trendy, at least in patients with heart failure, it has not proven superior to traditional loop diuretic bolus therapy.82,83 Diuretics can be given alone and in combina tion, with the latter sometimes proving effective if diuretic resistance exists. Also, diuretics can be used in patients with ESRD who have residual renal function and therein decrease the fluid pull during dialysis runs. Many adverse events exist with diuretics that are either physio logical or nonphysiological in nature; however, despite the potential for adverse events with these compounds, they remain vital components of the treatment plan for the majority of patients with CKD.
Review criteria
Material for this article was found by searching the PubMed search engine using the terms, chronic kidney disease, diuretics, loop diuretics, nephrotic syndrome, endstage renal disease, pharmacokinetics and pharmacodynamics. Only Englishlanguage articles published after 1970 were included.

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Sequential nephron blockade breaks resistance to diuretics in edematous states. J.Cardiovasc. Pharmacol. 29, 367372 (1997). 32. Wollam, G.L., Tarazi, R.C., Bravo, E.L. & Dustan,H.P Diuretic potency of combined . hydrochlorothiazide and furosemide therapy in patients with azotemia. Am. J.Med. 72, 929938 (1982). 33. Dargie, H.J., Allison, M.E., Kennedy, A.C. & Gray,M.C. High dosage metolazone in chronic renal failure. Br. Med. J. 4, 196198 (1972). 34. Kidney Disease Outcomes Initiative (K/DOGI). K/ DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am. J.Kidney Dis. 43 (5Suppl. 1), S1S290 (2004). 35. Rahman, M. etal. Cardiovascular outcomes in highrisk hypertensive patients stratified by baseline glomerular filtration rate. Ann. Intern. Med. 144, 172180 (2006). 36. Vasavada, N. & Agarwal, R. Role of excess volume in the pathophysiology of hypertension in chronic kidney disease. Kidney Int. 64, 17721779 (2003). 37. Dorhout Mees, E.J. 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