Brenner and Rector's The Kidney, 8th ed.

CHAPTER 46. Diuretics

David H. Ellison   Christopher S. Wilcox



Individual Classes of Diuretics, 1646



Carbonic Anhydrase Inhibitors, 1646



Osmotic Diuretics, 1648



Loop Diuretics, 1648



Thiazides and Thiazide-like Diuretics (Distal Convoluted Tubule Diuretics), 1652



Distal Potassium-Sparing Diuretics, 1654



Miscellaneous Agents, 1655



Adaptation to Diuretic Therapy, 1655



Diuretic Braking Phenomenon, 1655



Humoral and Neuronal Modulators of the Response to Diuretics, 1657



Diuretic Resistance, 1659



Diuretic Combinations, 1659



Adverse Effects of Diuretics, 1659



Fluid and Electrolyte Abnormalities, 1659



Metabolic Abnormalities, 1663



Other Adverse Effects, 1664



Clinical Uses of Diuretics, 1665



Edematous Conditions, 1665



Nonedematous Conditions, 1670

This chapter reviews the mechanisms of action, physiologic adaptation, adverse effects, and clinical uses of diuretics. The major transport targets for diuretic drugs have been defined and their genes cloned. The effects of disease on diuretic kinetics are discussed because this predicts the required dosage modifications. Loop and thiazides are the most widely used diuretics, and the physiologic adaptations to their prolonged use are described. Diuretic resistance, its management, and the major adverse effects of therapy are discussed. This provides a framework for the design of strategies to maximize the desired actions while minimizing the unwanted effects. The chapter concludes with a discussion of the practical use of diuretics in the treatment of specific clinical conditions.

Other chapters discuss the treatment of hypertension by diuretic drugs ( Chapter 45 ), diuretic-induced changes in potassium excretion ( Chapter 15 ), acid-base disturbances ( Chapter 14 ), divalent cation excretion and nephrolithiasis ( Chapters 16 and 37 ), the syndrome of inappropriate antidiuretic hormone (SIADH) secretion ( Chapter 13 ), and acute kidney injury (AKI; Chapter 29 ). Diuretics have been reviewed extensively. [1] [2] [3] [4] More extensive and historical references appeared in the last edition; the interested reader is referred to the seventh edition, for more detailed references.


The major sites of action of diuretics and the fraction of filtered Na+ reabsorbed at the corresponding nephron segments are summarized in Figure 46-1 .

FIGURE 46-1  Nephron diagram shows the primary sites of diuretic action and the approximate fraction of filtered sodium reabsorbed at each.


Carbonic Anhydrase Inhibitors

Sites and Mechanisms of Action.

In the kidney, carbonic anhydrase inhibitors (CAIs) act primarily on proximal tubule cells to inhibit bicarbonate absorption ( Fig. 46-2 ). An additional, more modest, effect along the distal nephron, however, is also observed.[5]Carbonic anhydrase (CA), a metalloenzyme containing one zinc atom per molecule, is important in sodium bicarbonate reabsorption and hydrogen ion secretion by renal epithelial cells. The biochemical, morphologic, and functional properties of CA have been reviewed [6] [7] (see Chapter 7 ).

FIGURE 46-2  Mechanisms of diuretic action in the proximal tubule: The figure presents a functional model of proximal tubule (PT) cells. Many transport proteins are omitted from the model, for clarity. Carbonic anhydrase (CA) catalyzes inside the cell the formation of HCO3 from H2O and CO2. This is the result of the two-step process. Bicarbonate leaves the cell via the Na-HCO3, cotransporter.464,465 A second pool of carbonic anhydrase is located in the brush border (CA). This participates in disposing of carbonic acid, formed from filtered bicarbonate and secreted H+. Both pools of CA are inhibited by acetazolamide and other CA inhibitors (see text for details).


CA is expressed by many tissues, including erythrocytes, kidney, gut, ciliary body, choroid plexus, and glial cells. Although at least 14 isoforms of CA have been identified, two play predominant roles in renal acid/base homeostasis. CA II is widely expressed, comprising the enzyme expressed by red blood cells and a variety of secretory and absorptive epithelia. CA II is a cytoplasmic protein expressed in the kidney, making up 95% of renal CA.[7] It is present in proximal tubule cells and intercalated cells of the aldosterone-sensitive distal nephron (ASDN).[7] CA IV is expressed at the luminal border of the cells of the proximal, thick ascending limb (TAL) of the loop of Henle and α-intercalated cells of the ASDN.[8]

CAIs block the catalytic dehydration of luminal carbonic acid at the brush border of the proximal tubule, decrease the intracellular generation of H+ required for countertransport with Na+, and decrease the peritubular capillary fluid uptake.[9] CAIs are also also weak inhibitors of reabsorption in the TAL,[10] but the natriuretic efficacy of CAIs and loop diuretics (see later) is additive, which confirms their mainly independent mechanisms of action.[11] CAIs also inhibit bicarbonate reabsorption along the distal tubule, presumably by interfering with the action of α-intercalated cells.[7]

The first administration of a CAI causes a brisk alkaline diuresis. The excretion of Na+, K+, HCO3-, and PO42- increases, whereas titratable acid and NH4+ decrease sharply. Excretion of Ca2+ remains essentially unchanged. There is substantial kaliuresis, owing to the presence of nonreabsorbable HCO3- and high flow rates in the distal nephron. However, hypokalemia is uncommon, because acidosis partitions K+ out of cells.

Chronic CAI administration causes only a modest natriuresis, despite the magnitude of CA-dependent proximal Na reabsorption. Several factors account for this. First, CA is required for reabsorption of HCO3-, whereas about two thirds of the proximal Na+ reabsorption is accompanied by Cl-. Second, some proximal HCO3- reabsorption persists even after apparently full inhibition of CA.[12] Third, some of the HCO3- that is delivered from the proximal tubule can be reabsorbed at more distal sites.[12] Fourth, the metabolic acidosis that develops limits the filtered load to HCO3- and thereby curtails the natriuresis. Fifth, the increased delivery of filtered Na+ to the macula densa elicits a tubuloglomerular feedback (TGF)–induced reduction in the glomerular filtration rate (GFR).[13] Micropuncture studies of mice with deletion of the proximal Na/H ex-changer, NHE3, show that inhibition of proximal Na reabsorption is largely balanced by reduced GFR,[14] supporting this mechanism.

Most diuretics have some CAI action.[15] This contributes to the weak inhibition of proximal reabsorption by furosemide and chlorothiazide and to the relaxation of vascular smooth muscle cells by high-dose furosemide.[15]


Acetazolamide (Diamox) is readily absorbed. It is eliminated with a half-life (t1/2) of 13 hours by tubular secretion, which is diminished during hypoalbuminemia.[16] Methazolamide (Neptazane) has less plasma protein binding, a longer t1/2, and greater lipid solubility, all of which favor penetration into aqueous humor and cerebrospinal fluid (CSF). It has less renal effect and, therefore, is preferred for treatment of glaucoma.

Clinical Indications.

The use of CAIs as diuretics is limited by their transient action, the development of metabolic acidosis, and a spectrum of adverse effects. They can be used with NaHCO3 infusion to initiate an alkaline diuresis that increases the excretion of weakly acidic drugs (e.g., salicylates and phenobarbital) or acidic metabolites (urate). Chloride-responsive metabolic alkalosis is best treated by administering Cl- with K+ or Na+. However, if this produces unacceptable extracellular volume (ECV) expansion, acetazolamide (250–500 mg/day) and KCl can be used to increase HCO3- excretion.

Metabolic alkalosis owing to loop diuretics or thiazides can depress respiration in patients with chronic respiratory acidosis, for example, due to chronic obstructive pulmonary disease (COPD). This provides a rationale for a CAI. Indeed, the administration of acetazolamide to such subjects can reduce their arterial partial pressure of arterial carbon dioxide (Paco2) and improve their partial pressure of oxygen (Pao2). Since both Paco2 and plasma bicarbonate concentration (Phco3) decrease, there is little change in blood pH.[17] However, a reduction in Phco3 limits the buffer capacity of blood. CAIs can increase the Paco2 during metabolic acidosis or exercise perhaps by depressing hypoxic ventilatory drive[18] and hypoxic pulmonary vasoconstriction,[19] and can cause ventilation-perfusion imbalance.[20] Nevertheless, acetazolamide (250 mg bid) can improve blood gas parameters in patients with COPD.[21]Careful surveillance is required when CAIs are administered to such patients.

When used to treat glaucoma, CAIs diminish the transport of HCO3- and Na+ by the ciliary process, thereby reducing the intraocular pressure.[22] CAIs also limit formation of CSF[23] and endolymph.[24]

Acute mountain sickness is characterized by headache, nausea, drowsiness, insomnia, shortness of breath, dizziness, and malaise after an abrupt ascent. Acetazolamide improves the performance of a mountaineer.[25] It is useful in a dose of 250 mg twice daily as prophylaxis against mountain sickness, probably through stimulating respiration and diminishing cerebral blood flow and CSF formation. [26] [27] In established mountain sickness, acetazolamide improves oxygenation and pulmonary gas exchange.[28] It can stimulate ventilation in patients with central sleep apnea.[29]

CAIs are effective in prophylaxis of hypokalemic periodic paralysis because they diminish the influx of K+ into cells.[30] Paradoxically, they are also useful in the treatment of hyperkalemic periodic paralysis.[31]

Adverse Effects.

Patients may complain of weakness, lethargy, abnormal taste, paresthesia, gastrointestinal distress, malaise, and decreased libido. These symptoms can be diminished by NaHCO3, but this increases the risk of nephrocalcinosis and nephrolithiasis.[32] Overall, symptomatic metabolic acidosis develops in half of glaucoma patients treated with CAIs.[33]

Elderly patients or those with diabetes mellitus or chronic kidney disease (CKD) can develop a serious metabolic acidosis.[33] An alkaline urine favors partitioning of renal ammonia into blood rather than its elimination in urine. An increase in blood ammonia may precipitate encephalopathy in patients with liver failure.[34]

Acetazolamide increases the risk of nephrolithiasis by more than 10-fold.[35] CAIs occasionally cause allergic reactions, hepatitis, and blood dyscrasias.[36] They can cause osteomalacia when used with phenytoin or phenobarbital.[37]

Osmotic Diuretics

Sites and Mechanisms of Action.

Omsotic diuretics are substances that are freely filtered but poorly reabsorbed.[38] Mannitol is the prototypic osmotic diuretic, although sorbitol and glycerol have similar actions. In the water-permeable nephron segments of the proximal nephron and the thin limbs of the loop of Henle, fluid reabsorption concentrates filtered mannitol sufficiently to diminish tubular fluid reabsorption. Ongoing Na+ reabsorption lowers the tubular fluid [Na+] and creates a gradient for back-flux of reabsorbed Na+ into the tubule. Increased distal flow stimulates K+ secretion.

Mannitol is a hypertonic solute that abstracts water from cells. The increase in total renal blood flow (RBF) relates in part to hemodilution and a decrease in blood hematocrit and viscosity. Mannitol increases the medullary blood flow and decreases the medullary solute gradient, thereby preventing urinary concentration. The rise in renal plasma flow and fall in plasma colloid osmotic pressure can increase the GFR.[39]

Pharmacokinetics and Dosage.

Mannitol is distributed in extracellular fluid (ECF). It is filtered freely at the glomerulus. Consequently, the t1/2 for plasma clearance depends on the GFR and is prolonged from 1 to 36 hours in advanced kidney failure.[40] It can be infused intravenously in daily doses of 50 to 200 g as a 15% or 20% solution or 1.5 to 2.0 g/kg of 20% mannitol over 30 to 60 minutes to treat raised intraocular or intracranial pressure.[38]

Clinical Indications.

Mannitol has been evaluated for the prophylaxis of AKF, but controlled trials of patients at risk for AKF have not been positive. [41] [42] The rationale for such trials includes mannitol's ability to expand the ECV, block TGF, maintain GFR, increase RBF and tubule fluid flow, prevent tubule obstruction from shed cell constituents or crystals, reduce renal edema, redistribute blood flow from the outer cortex to the relatively hypoxic inner cortex and outer medulla, and scavenge oxygen radicals. [38] [39] It can protect against AKF in cadaveric kidney transplant recipients.[38] The use of diuretics to convert oliguric to nonoliguric AKF is discussed later (see Clinical Uses of Diuretics, Nonedematous Conditions, and Acute Kidney Failure).

A trial of mannitol therapy for cerebral edema complicating hepatic failure demonstrated a markedly improved survival of 47%, compared with only 6% in the control group.[43] Mannitol is recommended for management of severe head injury.[44] It is more effective than loop diuretics or hypertonic saline in reducing brain water content.[45] Mannitol can reverse the dialysis disequilibrium syndrome.

Adverse Effects.

The effects of mannitol on plasma electrolyte concentrations are complicated. The osmotic abstraction of cell water initially causes hyponatremia and hypochloremia. Later, when the excess ECF is excreted, the decrease in cell water concentrates K+ and H+ within cells, which increases the gradient for their diffusion into the ECF, leading to hyperkalemic acidosis. These electrolyte changes are normally rapidly corrected by the kidney, provided that renal function is adequate. Later, hypernatremic dehydration may develop if free water is not provided, because urinary concentrating ability is inhibited.

Expansion of ECV, hemodilution, and hyperkalemic metabolic acidosis occur in patients with renal failure who cannot eliminate the drug. Circulatory overload, pulmonary edema, central nervous system depression, and severe hyponatremia require urgent hemodialysis.[46] Doses above 200 g/day can cause renal vasoconstriction and AKF.[38]

Loop Diuretics

Sites and Mechanisms of Action.

The prime action of loop diuretics occurs from the luminal aspect of the TAL ( Fig. 46-3 ). An electroneutral Na+/K+/2Cl- cotransporter, termed NKCC2, is located at the luminal membrane. [47] [48] This cotransporter, a member of the solute carrier family 12 (SLC12A1), mediates Na+ and Cl- movement across the cell. A high luminal K+ conductance, via the ROMK channel, allows the majority of K+ to recycle across the luminal membrane.[49] Coupled with electrogenic exit of Cl- across the basolateral membrane, the activity of the NKCC2 generates a transepithelial voltage, oriented with the lumen positive, relative to interstitial fluid. The primary energy for transport across TAL cells is provided via the basolateral Na+,K+-ATPase, which maintains a low intracellular [Na+]. Additional details concerning mechanisms of solute reabsorption by TAL cells can be found in Chapter 5 .

FIGURE 46-3  Mechanisms of diuretic action along the loop of Henle. Figure presents a model of thick ascending limb (TAL) cells. Na and Cl are reabsorbed across the apical membrane via the loop diuretic-sensitive Na-K-2Cl cotransporter, NKCC2. Loop diuretics bind to and block this pathway directly. Note that the transepithelial voltage along the TAL is oriented with the lumen positive relative to blood (circled value, given in millivolts [mV]). This transepithelial voltage drives a component of Na (and calcium and magnesium, see Fig. 46-4 ) reabsorption via the paracellular pathway. This component of Na absorption is also reduced by loop diuretics because they reduce the transepithelial voltage.


Loop diuretics are organic anions that bind to the NKCC2 from the luminal surface. Early studies showed that [3H] bumetanide binds to membranes that express the NKCC proteins and that Cl- competes for the same binding site on the transport protein.[50] More recently, studies using chimeric NKCC molecules have investigated sites of bumetanide binding and interactions with ions by determining effects on ion transport of heterologously expressed NKCC proteins. Using this approach, it was shown that changes in amino acids that affect bumetanide binding are not the same as patterns of changes affecting the kinetics of ion translocation. [51] [52] Nevertheless, the second membrane spanning segment of NKCC2 does appear to participate in both anion and bumetanide affinity. [51] [52] A clearer picture of the details of diuretic and ion interaction with the NKCC protein must await a crystal structure.

NKCC2 is expressed on the apical membranes of medullary and cortical TALs and macula densa segments. [53] [54] Its abundance is increased by prolonged infusion of saline or furosemide.[53] A closely related gene, NKCCl, encodes a protein that is widely expressed in transporting epithelia.[47] It is implicated in uptake and secretion of Cl- and NH4+ at the basolateral membrane of the medullary CDs.[55]

Hormones that stimulate cyclic adenosine monophosphate (cAMP), such as arginine vasopressin (AVP), enhance TAL reabsorption and should enhance the response to loop diuretics. In contrast, those that stimulate cyclic guanosine monophosphate (cGMP), such as nitric oxide and atrial natriuretic peptide (ANP), or those that increase intracellular [Ca2+], such as 20-hydroxyeicosatetraenoic acid (20-HETE), or those that activate the Ca2+ (polyvalent cation)-sensing protein[56] inhibit TAL reabsorption and reduce the response to loop diuretics.[57] These hypotheses await clinical trial.

The rat TAL also transports NH4+58 that can substitute for K+ on the Na+/K+/2Cl- cotransporter. In the rat, there is a luminal Na+/H+ countertransporter that contributes to tubular fluid acidification. Loop diuretics block the luminal entry of Na+ via NKCC2, but not the peritubular exit via the Na+,K+-ATPase, and thereby reduce the intracellular [Na+] sufficiently to promote luminal Na+ uptake via the Na+/H+ countertransport process. This is one reason that furosemide stimulates acid excretion in the rat.[59] In some studies, furosemide has not affected net acid excretion or urine pH in normal human subjects.[60]

Loop diuretics reduce proximal fluid reabsorption modestly. This has been ascribed to a weak CAI action. However, furosemide depresses proximal reabsorption in tubules perfused with HCO3--free solutions.[61] Moreover, bumetanide, which is a much less potent inhibitor of CA, also impairs proximal fluid reabsorption.[62]

Furosemide exerts two contrasting effects on reabsorption in the superficial distal tubule. Increased delivery to the unsaturated distal tubule reabsorption process increases Na+ reabsorption.[59] However, Velazquez and Wright[63]perfused rat distal tubules in vivo to obviate the confounding effects of altered delivery. They concluded that furosemide, but not bumetanide, was a weak inhibitor of the thiazide-sensitive Na+/Cl- cotransporter (NCC). Loop diuretics also inhibit NaCl transport in short descending limbs of the loop of Henle[64] and collecting ducts.[65] Although the TAL is clearly the major site of action of loop diuretics, actions at other nephron segments contribute to the natriuresis by blunting the expected increase in reabsorption in the proximal tubule (in response to volume depletion) and the distal nephron (in response to increased load).

Reabsorption of solute from the water-impermeable TAL segments dilutes the tubular fluid and concentrates the interstitium. Its inhibition by loop diuretics impairs both free water excretion during water loading and free water reabsorption during dehydration.[66]

Loop diuretics increase the fractional excretion of Ca2+ by up to 30%.[67] The predominant mechanism is by decreasing the magnitude of the lumen-positive transepithelial potential ( Fig. 46-4 ; see also Fig. 46-3 ). A large fraction of transepithelial Ca2+ transport along the TAL traverses a paracellular pathway involving paracellin (claudin 16) and driven by the lumen-positive transepithelial potential. By reducing its magnitude, loop diuretics reduce passive calcium absorption along this segment. A second mechanism has been observed in some experiments, involving active Ca2+ transport. This pathway may also be affected by loop diuretics.[68]

FIGURE 46-4  Possible mechanisms of diuretic effects on calcium and magnesium excretion. Typical cells from the proximal tubule (PT), thick ascending limb (TAL), and distal convoluted tubule (DCT) are shown. Calcium reabsorption occurs along the DCT largely via a transient receptor potential channel (TRPV5). Magnesium reabsorption occurs along the DCT largely via a transient receptor potential channel (TRPM6). Transepithelial voltages (representative but arbitrary values, given in millivolts [mV]) are shown. Net effects on electrolyte excretion are shown at the bottom. Normal conditions are at the left. Treatment with loop diuretics (LDs) is shown in the middle; treatment with DCT diuretics is shown on the right. LDs reduce the magnitude of the lumen-positive transepithelial voltage, thereby retarding passive calcium and magnesium reabsorption. Passive calcium and magnesium reabsorption appears to traverse the paracellular pathway. Chronic treatment, especially with DCT diuretics, increases proximal Na and Ca reabsorption; thus, less calcium is delivered distally. Enhanced distal calcium absorption, driven by DCT diuretics, also occurs. Effects of DCT diuretics to increase magnesium excretion remain incompletely understsood.


The loop of Henle is the major nephron segment for reabsorption of Mg2+.[67] Mg2+ transport along the TAL, like Ca2+ traverses a paracellular pathway that involves paracellin and is driven by the transepithelial potential difference. Loop diuretics can increase fractional Mg2+ excretion by more than 60%[69] by diminishing voltage-dependent paracellular transport[67] (see Figs. 46-3 and 46-4 [3] [4]) (see Adverse Effects, later).

Loop diuretics initially increase urate excretion by inhibiting proximal urate transport.[70] However, a succeeding reduction in urate clearance is largely secondary to volume depletion, which enhances proximal fluid and urate reabsorption.[71]

The total RBF is maintained or increased and the GFR is little changed during administration of loop diuretics to normal subjects.[72] However, there is a marked redistribution of blood flow from the inner to the outer cortex.[73]The fall in papillary plasma flow is dependent on angiotensin II (AII).[74] Furosemide increases the renal generation of prostaglandins (PGs).[75] Blockade of cyclooxygenase (COX) prevents furosemide-induced renal vasodilation.[76]

The macula densa participates importantly in both renin secretion and TGF-mediated control of GFR. NaCl entry into macula densa cells regulates both processes; thus, loop diuretics affect both TGF and renin secretion. When the luminal NaCl concentration at the macula densa rises, as during ECV expansion, NaCl entry into macula densa cells leads to the production of adenosine, which interacts with adenosine 1 receptors on vascular smooth muscle and/or extraglomerular mesangial cells, activating phospholipase C. This leads to depolarization and activation of voltage-dependent Ca channels, which contracts afferent arterioles, and reduces GFR (the TGF response).[77] NaCl transport across the luminal membrane of macula densa cells traverses the NKCC2.[54] Loop diuretics, by blocking NaCl entry into macula densa cells, block the TGF completely.[78] This is one reason that loop diuretics tend to preserve GFR, despite ECV depletion.

Loop diuretics also stimulate renin secretion, both acutely and chronically. Although this effect results in part from ECV depletion, a major component results from direct effects of loop diuretics on the macula densa. NaCl uptake into macula densa cells inhibits renin secretion acutely and inhibits renin synthesis chronically.[79] Macula densa cells were shown to express COX-2. Schnermann and colleagues[79] showed that lowering medium NaCl concentration bathing a macula densa cell line increased the release of PGE2, and caused a delayed induction of COX-2 expression. A similar stimulation of COX-2 expression was also caused by furosemide and bum-etanide. A lowering of medium Cl concentration was followed by rapid phosphorylation of p44/42 and p38 MAP kinases, and the presence of p44/42 and p38 inhibitors prevented the stimulation of COX-2 expression by low chloride. In summary, a decrease in luminal NaCl concentration activates and transcriptionally induces COX-2, causing PGE2 release, and EP4-mediated stimulation of renin secretion and renin synthesis. Nitric oxide synthase (NOS) inhibition with L-nitroarginine methylester (L-NAME) has been found to completely block the increase in renin mRNA after administration of furosemide for 4 days by minipump infusion.[80] Similarly, the increase in renin content in renal microvessels caused by a 5-day furosemide treatment was completely prevented by L-NAME.[81] Yet, mice made deficient in both the neuronal and the endothelial forms of NOS display relatively normal renin responses to loop diuretics.[82] These data have been interpreted to suggest that nitric oxide synthesis plays a permissive role in macula densa-mediated renin secretion.

Pharmacokinetics and Differences Between Drugs.

Loop diuretics are absorbed promptly after ingestion, but their bioavailability varies. Because bumetanide and torsemide are more completely absorbed than furosemide, changing from intravenous to oral dosing requires doubling the furosemide dose, but a lesser increase in the bumetanide or torsemide doses. Moreover, there is considerable variation in furosemide absorption, both between patients and over time,[83] that is accentuated by food intake. [84] [85]

Once absorbed, loop diuretics circulate largely bound to albumin (91% and 99%), which greatly limits their clearance by glomerular filtration. The diuretic volume of distribution varies inversely with the serum albumin concentration,[86] but this is not usually a major determinant of diuretic responsiveness (see later).[87]

The metabolism of loop diuretics comprises both hepatic and renal mechanisms; the relative fractions that are cleared by each mechanism differ between agents. Loop diuretics, thiazides, and CAIs are all secreted avidly by a probenecid-sensitive organic anion transporter in proximal tubule cells ( Fig. 46-5 ). [88] [89] Diuretics gain access to tubular fluid almost exclusively by proximal secretion. Recent studies have characterized this weak organic anion (OA-) transport process. Four isoforms of an OA transporter (OAT) have been cloned and are expressed in the kidney. [89] [90] Peritubular uptake by an OAT is a tertiary active process (see Fig. 46-5 ). Energy derives from the basolateral Na+, K+-ATPase that provides a low intracellular [Na+] that drives an uptake of Na+ coupled to α-ketoglutarate (aKG-) to maintain a high intracellular level of aKG-. This in turn drives a basolateral OA-/aKG-countertransporter. OAT translocates diuretics into the proximal tubule cell where they can be sequestered in intracellular vesicles. They are secreted across the luminal membrane by a voltage-driven OA transporter[91] and by a countertransporter in exchange for urate or OH-.[90] OAT1 is expressed on the basolateral membrane of the S2 segment of the proximal tubule.[92] Recently, a mouse colony deficient in OAT1 was generated and shown to exhibit dramatically impaired renal organic anion secretion and furosemide resistance.[93] Thus, OAT1 plays a central role in mediating loop diuretic secretion by proximal cells.

FIGURE 46-5  Mechanisms of diuretic secretion by proximal tubule cells. Cell diagram of the S2 segment of the proximal tubule shows secretion of anionic diuretics, including loop diuretics and distal convoluted tubule (DCT) diuretics. Peritubular uptake by an organic anion transporter (primarily OAT1, although OAT3 may play a smaller role) is in exchange for α-ketoglutarate. α-Ketoglutarate is brought into the cell by the Na-dependent cation transporter, NaDC-3. Luminal secretion can be via a voltage-dependent pathway or in exchange for luminal hydroxyl (OH-) or urate. A portion of the luminal transport traverses the multidrug resistance protein-2.466


Approximately 50% of furosemide is eliminated by renal metabolism to the inactive glucuronide. Only the unmetabolized and secreted fraction is available to inhibit NaCl reabsorption. In contrast, bumetanide and torsemide are metabolized in the liver. [94] [95] Slow-release furosemide is more effective in reducing blood pressure and treating edema, highlighting the importance of pharmacokinetics in diuretic responsiveness.[96] The duration of torsemide action is approximately twice as long as that of furosemide,[97] whereas the duration of bumetanide action is shorter than that of furosemide. These differences may be clinically relevant, [98] [99] [100] but large controlled trials are lacking.

Unlike bumetanide or torsemide,[97] the elimination of furosemide, in patients with CKD is greatly reduced because its metabolism to the inactive glucuronide occurs in the kidney. In contrast, metabolic inactivation of bumetanide and torsemide occurs mainly in the liver, and therefore, they are unaffected by uremia.[101] This prolongs the t1/2 of furosemide in CKD, leading to drug accumulation. However, the fraction of a dose excreted unchanged in patients with CKD is greater for furosemide, leading to an enhanced natriuretic response ( Fig. 46-6 ). There is, therefore, a tradeoff when selecting a loop diuretic in CKD: Furosemide can accumulate and cause ototoxicity at high doses, whereas bumetanide retains its metabolic inactivation but is, therefore, somewhat less potent.

FIGURE 46-6  Comparison of the pharmacokinetics and dynamics of furosemide (F, 160 mg; metabolically inactivated in the kidney) and bumetanide (B, 4 mg; metabolically inactivated in the liver) in 10 subjects with chronic renal insufficiency (mean creatinine clearance 12±2 mL/minute). Significance of difference: *, P<.05; ***, P<.005.  (Redrawn from data in Voelker JR, Cartwright-Brown D, Anderson S, et al: Comparison of loop diuretics in patients with chronic renal insufficiency. Kidney Int 32:572–578, 1987.)



Renal clearance of the active form of loop diuretics is reduced in CKD in proportion to the creatinine clearance.[102] There is competition both for peritubular uptake[89] and for luminal secretion[91] with other OA-, including urate that accumulates in uremia. Metabolic acidosis depolarizes the membrane potential (Em) of proximal tubule cells,[103] which decreases OA- secretion,[91] which may explain why diuretic secretion is enhanced by alkalosis.[104]Therefore, the increased plasma levels of OA- and urate and the metabolic acidosis of CKD impair proximal tubule secretion of diuretics and, hence, impair their delivery to their active sites in the nephron.

Proximal secretion of active furosemide is potentiated by albumin.[105] In the rabbit, an equal fraction of administered furosemide is taken up by probenecid-sensitive mechanisms in the S2 (secretory) or the S1 segment of the proximal tubule, where it is conjugated and excreted as the inactive glucuronide[106] ( Fig. 46-7 ). Unlike the uptake and secretion of active furosemide by the S2 segment, uptake and metabolism by the S1 segment is enhanced by a fall in albumin concentration. Therefore, a low serum albumin concentration enhances furosemide metabolism,[107] yet decreases tubular secretion of active diuretic.[105] The consequences of this are described later (see Clinical Uses of Diuretics and Nephrotic Syndrome).

FIGURE 46-7  Diagrammatic representation of the disposition of intravenous furosemide and the effects of hypoalbuminemia or probenecid in normal or hypoalbuminemic rabbits. After intravenous furosemide, 15% is metabolized by uridine diphosphate glucoronyl transferase (UDPGT) in the liver and gut to the inactive furosemide gluconide (F-GC). Of the remainder, 85% is transported by the kidney. Some 42% is taken up in the Sl segment of the proximal tubule (PT-Sl) and metabolized to the inactive gluconide, and the remainder is taken up by the S2 segment (PT-S2) and secreted in active form into the lumen. Both uptake processes are inhibited by probenecid. Plasma albumin concentration facilitates uptake and secretion by PT-S2 but inhibits uptake and metabolism by PT-S1.  (Drawn from data in Pichette V, Geadah D, du Souich P: The influence of moderate hypoalbuminemia on the renal metabolism and dynamics of furosemide in the rabbit. Br J Pharmacol 119:885, 1996.)



The relationship between fractional sodium excretion and the log of the serum diuretic concentration is sigmoidal. A similar sigmoidal relation between fractional sodium excretion and the log of the urinary diuretic concentration exists ( Fig. 46-8 ). Inhibition of proximal secretion with probenecid shifts the plasma dose response to the right, but does not perturb the relationship between natriuresis and diuretic excretion.[108] Thus, natriuresis is related to the urinary, but not the plasma, diuretic concentration. The administration of indomethacin or other nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the responsiveness of the tubule to furosemide.[109] This is due predominantly to reduced generation of PGE2, because a natriuretic response to furosemide can be restored in indomethacin-treated rats by infusion of PGE2.[110] Both a reduced dietary salt intake and repeated administration of furosemide during salt restriction[111] diminish the renal tubular response to furosemide (see Fig. 46-8 ).

FIGURE 46-8  Relationship between excretion of Na. and furosemide (log scale) following a bolus intravenous injection of 40 mg furosemide in normal subjects on a normal NaCl intake (1), for a normal NaCl intake after indomethacin (2), for a low Na. intake (20 mmol/24 hr) (3), and for the 3rd day of furosemide administration on a low Na. intake (4).  (Redrawn from data in Wilcox CS, Mitch WE, Kelly RA, et al: Response of the kidney to furosemide. J Lab Clin Med 102:450, 1983; and Chennavasin P, Seiwell R, Brater DC: Pharmacokinetic-dynamic analysis of the indomethacin-furosemide interaction in man. J Pharmacol Exp Ther 215:77, 1980.)



Clinical Indications.

These are described under Clinical Uses of Diuretics.

Adverse Effects.

These are discussed under Adverse Effects of Diuretics.

Thiazides and Thiazide-like Diuretics (Distal Convoluted Tubule Diuretics)

Sites and Mechanisms of Action.

Thiazides and thiazide-like diuretics are moderately active drugs that increase excretion of sodium, chloride, and potassium while reducing calcium excretion. The major site of action of thiazide and thiazide-like diuretics is the distal convoluted tubule (DCT), where they block coupled reabsorption of Na+ and Cl- ( Fig. 46-9 ). [63] [85] [112] The true thiazides (benzothiadiazines) comprise chlorothiazide, hydrochlorothiazide, bendroflume-thiazide, and others. Subsequent to their development, nonthiazide drugs with similar activities were developed. Substitution of the ring sulfone in the thiazides with a carbonyl group provides a group of quinazolinones with diuretic activity that is similar to that of the thiazides (c.f., metolazone). Chlorthalidone is a substituted benzophenone with strong CAI activity and a prolonged half-life that has seen widespread use as an antihypertensive.

FIGURE 46-9  Mechanisms of distal convoluted tublue (DCT) and collecting duct (CD) diuretics. A, Mechanism of action of DCT diuretics. In rat, mouse, and human, two types of DCT cells have been identified, referred to here as DCT-1 and DCT-2. Na and Cl are reabsorbed across the apical membrane of DCT-1 cells only via the thiazide-sensitive Na-Cl cotransporter (NCC). This transport protein is also expressed by DCT-2 cells where Na can also cross through the epithelial Na channel, ENaC (see text for details). Thus, the transepithelial voltage along the DCT-1 is near to 0 mV, whereas it is finite and lumen-negative along the DCT-2. B, Mechanism of action of CD diuretics. The late DCT cells (DCT2 cells) and connecting (CNT) or CD cells are shown. Na is reabsorbed via the ENaC, which lies in parallel with a K channel (ROMK). The transepithelial voltage is oriented with the lumen negative, relative to interstitium (shown by the circled value), generating a favorable gradient for transepithelial K secretion. Drugs that block the epithelial Na channel reduce the voltage toward 0 mV (effect indicated by dashed line), thereby inhibiting K secretion.


The predominant effect of the thiazide diuretics is to inhibit the thiazide-sensitive Na-Cl cotransporter (NCC, gene symbol SLC12A3). This protein is expressed in the DCT [113] [114] and is inhibited directly by thiazides (see later). Several thiazides and thiazide-like drugs (e.g., chlorothiazide, hydrochlorothiazide, and chlorthalidone) inhibit CA, contributing to their natriuretic efficacy.[115] Yet, patients with Gitelman syndrome, who have a loss-of-function mutation in the NCC, demonstrate a dramatically impaired natriuretic response to thiazides,[116] confirming that the principal effect of these drugs is to inhibit NCC. Further, Na reabsorption by the proxi-mal tubule is enhanced during chronic treatment with thiazides, even when the drug has significant CA-inhibiting capacity.[117]

Like loop diuretics, DCT diuretics, including the thiazides, are organic anions that bind to the transport protein from the luminal surface. The mechanism(s) of NCC inhibition have been studied using two approaches. First, Fanestil and colleagues [118] [119] showed that [3H] metolazone binds avidly to kidney membrane proteins; its binding is inhibited competitively by Cl-, suggesting that Cl- and diuretic compete for the same binding site. These results are reminiscent of those that utilized [3H] bumetanide to study properties of the NKCC proteins and were used to develop a kinetic model for the NCC.[120] More recently, Gamba and colleagues[121] have expressed chimeras of the NCC in Xenopus oocytes and determined thiazide affinity based on transport inhibition. The results suggest a more complicated picture. They conclude that thiazide diuretic affinity is conferred by transmembrane segments 8-12, whereas transmembrane segments 1-7 affect chloride affinity. Both segments are involved in determining Na+ affinity. These data suggest that that the affinity of thiazide diuretics for binding to the transport protein is in a region distinct from that that participates in Cl- transport.

Thiazides increase potassium excretion, but they do not augment K+ secretion by DCTs directly. [85] [122] Instead, their effects on K+ secretion result from their tendency to stimu-late aldosterone secretion, to increase distal flow, and to increase calcium reabsorption.[123] Mineralocorticoids, glucocorticoids,[124] and estrogens[125] enhance thiazide binding and tubular actions.

Thiazides reduce Ca2+ excretion. Three potential and nonredundant mechanisms have been postulated (see Fig. 46-4 ).[126] First, blockade of luminal NaCl entry reduces the tubule cell [Na+] sufficiently to enhance the basolateral Na+/Ca2+ exchange.[127] Second, thiazides block luminal NaCl entry and reduce cell [Cl-] concentrartion, thereby hyperpolarizing the membrane voltage (making the interior of the cell more negative, electrically). Hyperpolarization increases calcium entry via the transient receptor potential channel subfamily V, member 5 (TRPV5), which is expressed at the apical membrane of DCT and connecting tubule cells. [128] [129] Third, thiazides stimulate proximal reabsorption of Ca2+ owing to ECV depletion.[130] The importance of this proximal effect has been highlighted recently because thiazides reduce Ca2+ excretion, even when the TRPV5 channel has been knocked out and the major distal calcium reabsorptive pathway is absent.[131] Thiazides produce a sustained reduction in renal Ca2+ excretion, which is accompanied by a small rise in serum Ca2+ concentration (SCa).

Mg2+ excretion is enhanced by thiazide diuretics, at least during prolonged therapy[132] (see Fig. 46-4 ). Recently, it was shown that TRPM6 is a magnesium channel in the distal nephron. [133] [134] Chronic thiazide treatment of mice diminishes TRPM6 mRNA expression modestly and reduces TRPM6 protein abundance by approximately 80%. Such changes would be expected to reduce magnesium reabsorption along the distal nephron, leading to Mg2+wasting. Mg2+ depletion that can occur during chronic thiazide administration may be augmented by K+ depletion.[132] Thiazides reduce urate clearance secondary to ECV depletion[71] and competition for tubular uptake.[88]

Aquaporin-2 (AQP2) expression begins at the junction between the DCT and the connecting tubule. Thus, the NCC-expressing DCT makes up the terminal diluting segment of the kidney. Thiazides impair maximal urinary dilution, but not maximal urinary concentration.[135] Thiazides also enhance water absorption from inner medullary collecting ducts in an AVP-independent manner.[136] This effect is correlated with an increase in AQP2 expression during chronic thiazide treatment.[137] These effects may contribute to the tendency of thiazide diuretics to produce hyponatremia. Central effects on thirst, however, may also contribute (see Adverse Effects, later).

Pharmacokinetics and Differences Between Drugs.

Thiazides are readily absorbed. They are extensively bound to plasma proteins. They are eliminated largely by secretion by the S2 segment of the proximal tubule, largely via the OAT1. [88] [138] The t1/2 is prolonged in renal failure and in the elderly, which reduces natriuretic efficacy.[139] The more lipid-soluble drugs (e.g., bendroflumethiazide and polythiazide) are more potent, have a more prolonged action, and are more extensively metabolized.[140]Chlorthalidone has a particularly prolonged action.[140] Indapamide is sufficiently metabolized to limit accumulation in renal failure.[140]

Clinical Indications.

These are described under Clinical Uses of Diuretics.

Adverse Effects.

These are described under Adverse Effects of Diuretics.

Distal Potassium-Sparing Diuretics

Distal K+-sparing diuretics comprise those that directly block the epithelial Na+ channel (ENaC; amiloride and triamte-rene) and antagonists of aldosterone (spironolactone and eplerenone).

Sites and Mechanisms of Action.

Distal K+-sparing diuretics act on the cells in the late DCT, connecting tubule, and the cortical collecting duct (the ASDN), where they inhibit luminal Na+ entry via the ENaC (see Fig. 46-9 ). [141] [142] They depolarize the lumen-negative transepithelial voltage, diminishing the electrochemical gradient for K+ and H+ secretion. [141] [142]

Both amiloride and triamterene are organic cations that block ENaC directly from the luminal surface. Amiloride also inhibits the Na/H exchanger of the proximal tubule (NHE3), but the affinity of amiloride for NHE3 is low enough that the distal effects predominate in clinical use. In experimental work, congers of amiloride that are more selective for either ENaC or NHE3 have been developed, but these have not been employed clinically. Amiloride appears to bind ENaC in its conducting pore and is thus a pore blocker.[143] Amiloride binding is sensitive to the electric field and amiloride appears to compete with Na+ for binding to the pore of the channel.[144] Amiloride may interact with several regions on the ENaC protein, but one amiloride-binding region composes a short amino acid stretch within the extracellular loop.[145]

Spironolactone and eplerenone are competitive antagonists of the mineralocorticoid receptor. Aldosterone antagonists were developed when it was discovered that aldosterone is an 18-aldehyde derivative of corticosterone and that progesterone increases Na+ excretion by blocking exogenously administered mineralocorticoid. Eventually, spironolactone was developed. It was found not to have any effect on urinary Na+ or K+ excretion directly, but instead to competitively block the mineralocorticoid receptor. Structurally, spirolactone strongly resembles aldosterone. Eplerenone was developed as an attempt to find an aldosterone antagonist with fewer estrogenic side effects.

These drugs were employed for many years primarily to reduce the excretion of K+ and net acid, especially when used in combination with other diuretics.[146] Amiloride and triamterene reduce the excretion of Ca2+ and Mg2+.[147] [148] These drugs cause a very modest natriuresis. Under certain circumstances, however, their natriuretic efficacy can be significant. For example, spironolactone is more effective than furosemide in reducing cirrhotic ascites.[149] Further, spironolactone is often an effective adjunct in the treatment of resistant hypertension.[150] Spironolactone has achieved an important role in the treatment of congestive heart failure (CHF) caused by systolic dysfunction,[151] although the mechanisms by which it achieves protection continue to be debated.


Triamterene is well absorbed. It is rapidly hydroxylated to active metabolites.[152] The drug and its metabolites are secreted by the organic cation pathway in the proximal tubule,[1] with half-lives of 3 to 5 hours. Triamterene and its active metabolites accumulate in patients with cirrhosis because of decreased biliary secretion,[153] and in the elderly, [139] [152] and in those with CKD[139] because of decreased renal excretion.

Amiloride is incompletely absorbed. Its duration of action is approximately 18 hours. It is secreted into the tubular fluid by the organic cation transport pathway.[154] Other organic cations, such as cimetidine, inhibit its secretion and prolong its half-life.[154] It accumulates in renal failure[155] and may worsen renal function.[156]

Spironolactone is readily absorbed and circulates bound to plasma proteins. Its intrinsic half-life is short, but it is metabolized to active compounds with considerably prolonged actions. Spironolactone is metabolized to canrenones (t1/2=16 hr) and to sulpher-containing metabolites, predominantly 7 alpha-thiomethylspirolactone (t1/2=13 hr).[157] Canrenones are metabolized by the cytochrome P-450IIIA system.[158] Clinically, spironolactone has a t1/2 of approximately 20 hours. It takes 10 to 48 hours to become maximally effective.[159] It is lipid soluble and enters distal renal tubules from the plasma.[160] Eplerenone has fewer antiandrogenic and proestrogenic effects. [161] [162]However, it is metabolized with a half-life of 3 hours and, therefore, should be given twice daily.[163]

Clinical Indications.

Distal K+-sparing agents are used to prevent or treat hypokalemic alkalosis, especially in combination with a thiazide diuretic.[164] Amiloride can prevent amphotericin-induced hypokalemia and hypomagnesemia.[165]Spironolactone is indicated as first-line therapy for ECV expansion in the setting of cirrhotic ascites, where it is more effective than daily furosemide. [149] [166] [167] It is indicated for heart failure associated with systolic dysfunction, where its effects may include renal and extrarenal mineralocorticoid receptor blockade[168] and where recommended doses are limited to 25 and 50 mg/day. It is also commonly used to treat hypertension associated with hyperaldosteronism and for resistant hypertension [150] [169] [170] and may reduce proteinuria in CKD[171] (although see the cautions, later). Eplerenone is indicated for systolic dysfunction is the setting of recent myocardial infarction (MI).[172]

Adverse Effects and Drug Interactions.

Hyperkalemia is the most common complication of these drugs. The risk is dose-dependent and increases considerably in patients with CKD or in those receiving K+ supplements, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), NSAIDs, β-blockers, heparin, or ketoconazole.[173] The incidence of hyperkalemia-associated morbidity and mortality in Canada rose sharply after the publication of the Randomized Aldactone Evaluation Study (RALES), and may relate to the widespread use of aldactone in patients with CHF and impaired renal function.[174] It is important to note that the original RALES study specifically excluded patients with several of these comorbidities. Renal failure appears to be another complication in this group.[175]

Gynecomastia may occur in men, especially as the dose is increased[176] but even at low doses[177]; decreased libido and impotence have also been reported. Women may develop menstrual irregularities, hirsutism, or swelling and tenderness of the breast. Impaired net acid excretion can cause metabolic acidosis,[178] which worsens hyperkalemia.

Amiloride and triamterene accumulate in renal failure [152] [155] and triamterene accumulates in cirrhosis.[153] Therefore, these drugs should be avoided in these situations. Triamterene occasionally precipitates in the urinary collecting system and causes obstruction.[179] It can cause acute kidney injury when given with indomethacin.[180]

Miscellaneous Agents

Dopaminergic Agonists.

When given to normal subjects in low doses (1–3 mg/kg/min), dopamine causes a modest increase in the GFR, reduces proximal reabsorption via a cAMP-induced inhibition of the Na+/H+ antiporter and increases Na+ excretion.[181] Fenoldopam is a selective dopamine type 1 (DA1) receptor agonist with little cardiac stimulation.[181] Unfortunately, these beneficial effects are reduced in patients who are critically ill and/or receiving vasopressors.[167] A comprehensive review of the literature has concluded that controlled trials have universally failed to demonstrate improved renal outcomes in patients at high risk for AKF given low-dose dopamine[167] and, in the largest trials, had no effect on renal function, need for dialysis, or mortality in critically ill patients with early renal dysfunction. Thus, there is currently no justification for the use of low-dose dopamine for renal protection. Higher rates of dopamine infusion have a role as a pressor agent in septic shock or refractory heart failure, but any benefits are offset by arrhythmias.[167]

Adenosine Type I Receptor Antagonists.

Aminophylline is an adenosine receptor antagonist that inhibits NaCl reabsorption in the proximal tubule and diluting segments and causes a modest increase in GFR.[182] Highly selective adenosine 1 (A1) receptor antagonists are natriuretic[183] and antihypertensive and potentiate furosemide-induced natriuresis in normal humans[184] and in patients with diuretic-resistant CHF. A1 antagonists disrupt glomerulotubular balance and TGF, thereby decreasing proximal reabsorption and increasing GFR.[183]

Vasopressin Antagonists.

Nonpeptide, orally active vasopressin V2 receptor antagonists cause free water diuresis without appreciable natriuresis in water-deprived human subjects.[185] They increase urine volume, free water clearance, and serum sodium concentration (SNa) in hyponatremic patients with SIADH.[186] One such agent, lixivaptan, is an oral V2 antagonist that increases SNa in patients with SIADH, CHF, or cirrhosis.[187] Tolvaptan is another agent that has been subjected to two controlled trials in patients; it increased the urine volume on the first day and reduced the body weight and corrected the hyponatremia over 25 days.[188] In the second study of hospitalized patients with an ejection fraction less than 40%, it reduced the body weight on the first day. Although it did not modify CHF outcomes at 2 months, it corrected hyponatremia and appeared beneficial in subgroups of patients with azotemia or those with clinical signs of congestion at baseline. Conivaptan is a combined V2 and V antagonist. In a controlled trial of patients with CHF, it increased urine volume and reduced the pulmonary capillary wedge pressure (PCWP).[189] Thus, AVP antagonists appear to be an effective means to treat acute or chronic conditions associated with dilutional hyponatremia.


Diuretics entrain a set of homeostatic mechanisms that limit their fluid-depleting actions and contribute to diuretic resistance and adverse effects.

Diuretic Braking Phenomenon

The first dose of a diuretic normally produces a reassuring diuresis. However, in normal subjects, a new equilibrium is attained within several days, when body weight stabilizes and daily fluid and electrolyte excretion no longer exceeds intake.[111]

The patterns of Na+ excretion during 3 days of loop diuretic administration to normal human subjects are shown in Figure 46-10 . [111] [190] [191] [192] During a high Na+ intake (270 mmol/24 hr), furosemide causes a large negative Na+ balance over the ensuing 6 hours (dark blue in Fig. 46-10A ) followed by 18 hours when Na+ excretion is reduced well below intake (postdiuretic Na+ retention), which results in positive Na+ balance (green in Fig. 46-10A ) that offsets the preceding negative Na+ balance. The natriuresis caused by the third daily dose of furosemide is comparable with the first dose and is also followed by a restoration of Na+ balance. Consequently, at high levels of Na+intake, subjects regain neutral Na+ balance within 24 hours of each dose of furosemide and maintain their original body weight. A similar diuretic braking phenomenon occurs during established furosemide therapy.[193]

FIGURE 46-10  Effects of dietary salt intake on diuretic braking phenomenon shows renal Na. excretion (mmol/6 hr) for 24 hours before and after the first (F1) and third (F3) daily doses of furosemide (40 mg intravenously) or bumetanide (B, 1 mg intravenously) in groups of 8 to 10 normal subjects equilibrated to fixed daily Na. intakes. The average level of Na. intake (mmol/6 hr) is shown by the broken horizontal line. Negative Na. balance is indicated by the dark blue and positive Na. balance by the green shading. The mean±standard error of the mean (SEM) values for diuretic-induced increases in Na. excretion above baseline values for 6 hours after the administration of the diuretic are shown at the top.  (Redrawn from data in Wilcox CS, Mitch WE, Kelly RA, et al: Response of the kidney to furosemide. J Lab Clin Med 102:450, 1983.)



During severe dietary Na+ restriction (20 mmol/24 hr), the first dose of furosemide produces a blunted natriuresis (see Fig. 46-10C ). Na+ balance cannot be restored because of the low level of dietary Na+ intake. Consequently, virtually all the Na+ lost during the diuretic phase is represented as negative Na+ balance for the day. Unlike the high-salt protocol, tolerance manifests as a 40% reduction in the natriuretic response to the drug over 3 days. However, despite a blunted initial response and the development of tolerance, all subjects lose Na+ and body weight.

A loop diuretic (bumetanide, 1 mg daily) given during an Na+ intake of 120 mmol/24 hours (equivalent to a salt-restricted diet) causes Na+ loss, but this is curtailed by a combination of postdiuretic renal salt retention and diuretic tolerance (see Fig. 46-10B ).[192]

Furosemide kinetics and GFR are unchanged over 3 days of furosemide administration. What, then, mediates diuretic tolerance? During a low NaCl intake, the relationship between natriuresis and furosemide excretion is shifted to the right by the 3rd day of diuretic administration (see Fig. 46-8 ), indicating a blunting of tubular diuretic responsiveness.

One month of furosemide therapy for hypertension reduces the natriuretic response to a test dose of furosemide by 18%.[193] This tolerance cannot be ascribed to aldosterone, nor to a fall in plasma or ECV, because tolerance to furosemide is not prevented by spironolactone and does not develop during thiazide therapy, which causes similar reductions in body fluids. In fact, the natriuretic response to a test dose of a thiazide is augmented during furosemide therapy. Thus, tolerance to furosemide is class-specific and is depen-dent on increased NaCl reabsorption at a downstream, thiazide-sensitive nephron site.

Furosemide activates the renin-angiotensin-aldosterone (RAA) axis and sympathetic nervous system (SNS). However, postdiuretic Na+ retention in normal subjects is not blunted by doses of an ACEI, which prevents any changes in plasma AII or aldosterone concentrations, [194] [195] [196] or by prazosin, which blocks adrenergic receptors even when given in combination.[197]

Micropuncture studies have shown that the blunted natriuretic response to furosemide during repeated administration to rats can be attributed to three factors: a reduced NaCl delivery to the site of furosemide action; a limited inhibition of NaCl reabsorption by furosemide in the loop of Henle; and an enhanced ability of the distal tubule to reabsorb the extra NaCl load delivered during furosemide's upstream action.[198]

Rats receiving prolonged infusions of loop diuretics have considerable structural hypertrophy of the DCT, connecting tubule, and intercalated cells of the collecting duct[199] that are partially dependent on AII.[200] The DCT and collecting duct have a large increase in messenger RNA (mRNA) for insulin-like growth factor-binding protein-1[201] and increased Na+,K+-[202] and H+-ATPase.[203] The Na+,K+-ATPase activity of rat cortical collecting duct segments increases abruptly following an increase in cellular [Na+], owing to mobilization of a latent pool of enzyme.[204] There is doubling of NCC expression in the distal tubules of rats adapted to diuretics.[205] Microperfusion studies of rats adapted to prolonged diuretic infusion have shown enhanced aldosterone-independent distal Na+ and Cl- absorption and K+ secretion.[206] Therefore, diuretics induce structural and functional adaptations of downstream nephron segments, apparently in response to increased rates of NaCl delivery and, to some extent, on RAA axis activation. Nephronal adaptation could underlie the inappropriate renal Na+ retention that can persist for up to 2 weeks after abrupt cessation of diuretic therapy.[207]

Normal subjects fully eliminate a modest (100 mmol) NaCl load over 2 days.[208] However, when challenged with the same NaCl load delivered after administration of bumetanide during simultaneous infusion of sufficient fluid, Na+, K+, and Cl- to prevent any losses, the elimination of the load is prevented.[208] Thus, diuretics can entrain an ECV-independent NaCl retention; this is apparent when distal delivery is enhanced, as during high NaCl intake.

Even a single dose of loop diuretic causes a Cl- depletion “contraction” alkalosis.[60] In a study of normal subjects with a mild metabolic alkalosis produced by equimolar substitution of NaHCO3 for NaCl, bumetanide-induced natriuresis was reduced during alkalosis despite enhanced delivery of bumetanide to the urine ( Fig. 46-11 ).[104] This implies a profound defect in tubular responsiveness to the diuretic. Several mechanisms may contribute. First, the Na+/K+/2Cl- cotransporter has affinities for Na+, K+, and Cl- of 7.0, 1.3, and 67 μM, respectively. Thus, the [Cl-] of tubular fluid may be sufficiently low during Cl- depletion alkalosis to limit reabsorption by this transporter and thereby to limit the responsiveness to loop diuretics. Second, alkalosis causes glycosylation of the bumetanide-sensitive cotransporter that could alter its transport function.[53] Third, thiazide-sensitive cotransporters in the rat DCT are increased by 40% during NaHCO3 administration.[209] These mechanisms may contribute to diuretic tolerance and the braking phenomenon.

FIGURE 46-11  Mean±SEM values for plasma bicarbonate concentration, increase in Na. excretion with bumetanide (1 mg intravenously), and rate of bumetanide excretion in normal subjects (n=8) after equilibration to equivalent diets containing 100 mmol/24 hr of NaCl (control, blue boxes), NH4Cl (mild metabolic acidosis, red boxes), or NaHCO3 (mild metabolic alkalosis, green boxes). Compared with control: *P<.05; **P<.01.  (Redrawn from Loon NR, Wilcox CS: Mild metabolic alkalosis impairs the natriuretic response to bumetanide in normal human subjects. Clin Sci (Colch) 94:287, 1998.)



There are several clinical implications from these studies. First, dietary salt intake must be restricted, even in subjects receiving powerful loop diuretics, to obviate postdiuretic salt retention and to ensure the development of a negative NaCl balance. Second, during prolonged diuretic administration, subjects may be particularly responsive to another class of diuretic. Third, diuretic therapy should not be stopped abruptly unless dietary salt intake is curtailed, because the adaptive mechanisms limiting salt excretion persist for days after diuretic use. Fourth, selection of a diuretic with a prolonged action, or more frequent administration of the diuretic, will enhance NaCl loss by limiting the time available for postdiuretic salt retention. Indeed, a continuous infusion of a loop diuretic is somewhat more effective than the same dose given as a bolus injection in volunteers,[210] in patients with cardiac disease,[211] and in those with chronic kidney failure (CKF)[212] despite a similar delivery of diuretic to the urine. Fifth, prevention or reversal of diuretic-induced metabolic alkalosis may enhance diuretic efficacy.

There are similar patterns of furosemide-induced K+ loss followed by renal K+ retention[213] associated with an increase in the transtubular K+ gradient.[214] In contrast, loop diuretics induce ongoing renal K+ losses during severe salt restriction owing to hyperaldosteronism[213] that can be countered by distal, K+-sparing diuretics.[214]

Humoral and Neuronal Modulators of the Response to Diuretics

Renin-Angiotensin-Aldosterone Axis.

Diuretic therapy increases plasma renin activity (PRA) and serum aldosterone concentrations (SACs), as described previously. The initial increase in PRA with loop diuretics is independent of volume depletion or the SNS and is related to inhibition of NaCl reabsorption at the macula densa.[215] Loop diuretics also stimulate renal prostacyclin release, which promotes renin secretion.[216] Later, renin secretion is dependent on ECV depletion and the SNS.

Activation of the RAA axis in patients treated with diuretics and salt restriction for edema limits the natriuresis.[217] In a study of patients with CHF, angiotensin-converting enzyme (ACE) inhibition potentiated the diuretic and natriuretic responses to furosemide despite a fall in blood pressure.[218] However, severe volume depletion and azotemia can complicate overzealous therapy with ACEIs, particularly in patients with CHF receiving high doses of diuretics or in those with stenosis of both renal arteries or the artery to a single or dominant kidney.[219] Thus, the combination of diuretics and ACEIs can be highly effective but requires careful surveillance.

During stimulation of the RAA axis by severe dietary salt restriction, further diuretic-induced increases in SAC promote renal K+ losses.[220] ACEIs counter diuretic-induced increases in SAC and blunt diuretic-induced hypokalemia.[213]


PGE2 acting on luminal prostaglandin type 4 (EP4) receptors inhibits NaCl reabsorption via the Na+,K+,2Cl- cotransporter[221] and inhibits free water and Na+ reabsorption in the CDs via changes in cAMP ( Fig. 46-12 ).[222]

FIGURE 46-12  Mean±SEM values for change in Na+ excretion for 11 normal subjects given 40 mg of furosemide IV after placebo (blue box) or after each of three nonsteroidal; anti-inflammatory drugs (NSAIDs): ibuprofen, 600 mg/6 hr for three doses (red box), naproxen, 375 mg/12 hr for two doses (green box) or sulindac, 200 mg/12 hr for two doses (gold box). Compared with placebo: *, P<.05.  (Drawn from data from Brater DC, Anderson S, Baird B, Campbell WB: Effects of ibuprofen, naproxen, and sulindac on prostaglandins in men. Kidney Int 27:66–73, 1985.)



Loop diuretics, thiazides, triamterene, and spironolactone increase PGs substantially.[223] Inhibition of PG synthesis by NSAIDs can diminish the natriuresis and diuresis induced by furosemide,[224] hydrochlorothiazide,[225]spironolactone,[223] or triamterene (see Fig. 46-12 ).[226] Microperfusion of the loop segment with PGE2[110] restores the response to furosemide in indomethacin-treated rats. Indomethacin also blunts furosemide-induced renal[227]and capacitance vessel vasodilation[228] and stimulation of renin.[229] The blunting of furosemide-induced natriuresis by NSAIDs is potentiated by salt depletion[230] and is prominent in edematous patients.[224] The NSAIDs ibuprofen, naproxen, and sulindac blunt furosemide-induced natriuresis similarly (see Fig. 46-12 ). A COX-2 inhibitor blocks furosemide-induced renin secretion and natriuresis, but not natriuresis ( Fig. 46-13 ). Although other studies show an effect of COX-2 inhibition on Na reabsorption,[231] it is COX-1 that facilitates natriuresis in the distal nephron.[232] Salt-sensitive hypertensives have a blunted natriuretic re-sponse to furosemide that may be related to a paradoxical reduction in renal production of 20-HETE ( Fig. 46-14 ). Thus, COX-1 products mediate a part of furosemide-induced natriuresis whereas COX-2 products mediate renin secretion. 20-HETE may be an important positive modulator of salt excretion.

FIGURE 46-13  Mean±SEM values for six normal subjects equilibrated to a 69 mmol/24 hr Na+ intake and studied before (blue boxes) and after (red boxes) furosemide, 20 mg IV. Data shown are for plasma renin activity (panel A) and Na+ balance over 24 hr (panel B) without pretreatment, or after the Cox-2 inhibitor rofecoxib.  (Drawn with data from Kammerl MC, Nüsing RM, Schweda F, et al: Low sodium and furosemide-induced stimulation of the renin system in man is mediated by cyclooxygenase 2. Clin Pharmacol Ther 70:468–474, 2001.)



FIGURE 46-14  Mean±SEM values for Na+ balance (panel A) and change in 20-hydroxyeicosatetraenoic acid (20-HETE) excretion (panel B) in response to three doses of furosemide (40 mg q 4 hr) during dietary salt restriction. Data compare 11 salt-resistant hypertensives (blue boxes) with 12 salt-sensitive hypertensives (red boxes).  (Drawn with data from Laffer CL, Lanaido-Schwartzman M, Wang MH, et al: 20-HETE and furosemide-induced natriuresis in salt-sensitive essential hypertension. Hypertension 41:703–708, 2003.)



Loop diuretics also increase the excretion of the thromboxane A2 (TxA2) metabolite TxB2. Inhibition of TxA2 synthesis or receptors in the rat increases furosemide diuresis[233] and diminishes the renal vasodilation.[234] Thus, TxA2 may antagonize the actions of loop diuretics.

Arginine Vasopressin.

AVP increases after administration of furosemide.[235] This may be a response to a reduced blood volume. Plasma AVP is increased in many edematous states, such as CHF,[236] especially in those who develop hyponatremia during thiazide treatment.[237] AVP stimulates K+ secretion in the rat distal tubule.[238] Diuretic-induced AVP release contributes to hypokalemia, because the kaliuretic response to furosemide is reduced by 40% in subjects whose AVP release is suppressed by a water load.[220]

Catecholamines and Sympathetic Nervous System.

The first dose of furosemide increases the heart rate and plasma catecholamine concentrations. [104] [190] Blockade of α1-adrenergic receptors with prazosin does not modify the ensuing renal salt retention[190] but blockade of β-adrenergic receptors blunts the renin release.[215] Short-term, furosemide-induced ECV depletion in the conscious rat activates sympathetic nerve activity that stabilizes the blood pressure.[239]

Atrial Natriuretic Peptide.

Diuretics are often used to treat patients who have an expanded blood volume and elevated levels of ANP. Administration of furosemide to dogs with CHF reduces ANP levels.[240] Infusion of ANP in this dog model promotes furosemide-induced natriuresis and blunts the activation of the RAA axis and the fall in GFR. Thus, a fall in ANP contributes to postdiuretic renal NaCl retention.[240]

Diuretic Resistance

Diuretic resistance implies an inadequate clearance of edema despite a full dose of diuretic. The principal causes are summarized in Table 46-1 . The first step is to select the appropriate target response (e.g., a specific body weight) and to ensure that the edema is due to inappropriate renal NaCl and fluid retention rather than to lymphatic or venous obstruction or redistribution ( Fig. 46-15 ). Diuretics do not prevent edema caused by dihydropyridine calcium channel blockers.[241] The next step is to exclude noncompliance, severe blood volume depletion, or concurrent NSAID use. Thereafter, dietary NaCl intake should be quantitated. In the steady state, this can be assessed from measurements of 24-hour Na+ excretion. For patients with mild edema or hypertension, a daily Na+ intake of 100 to 120 mmol may be sufficient. For patients with diuretic resistance, the help of a dietitian is usually necessary to reduce daily Na+ intake to 80 to 100 mmol.

TABLE 46-1   -- Common Causes of Diuretic Resistance



Incorrect diagnosis

Venous or lymphatic edema

Inappropriate NaCl intake

Na+ intake > 120 mmol · d-1

Inadequate drug reaching tubule lumen in active form:



 Dose inadequate or too infrequent

 Poor absorption

Uncompensated CHF

 Decreased renal blood flow

CHF, cirrhosis of liver, elderly

 Decreased functional renal mass

AKF, CKD, elderly


Nephrotic syndrome

Inadequate renal response:

 Low GFR


 Decreased effective ECV

Edematous conditions

 Activation of RAA axis

Edematous conditions

 Nephron adaptation

Prolonged diuretic therapy


Indomethacin, aspirin


AKI, acute kidney injury; CHF, congestive heart failure; CKD, chronic kidney disease; ECV, extracellular fluid volume; GFR, glomerular filtration rate; NSAIDs, nonsteroidal anti-inflammatory drugs; RAA, renin-angiotensin-aldosterone.




FIGURE 46-15  Diagrammatic representation of an approach to the management of a patient with resistance to a loop diuretic. CD, collecting duct diuretic (e.g., amiloride, triamterene, or spironolactone). DCT, distal convoluted tubule diuretic (e.g., thiazide); PT, proximal tubule diuretic (e.g., acetazolamide).  (From Ellison DH, Wilcox CS: Diuretics: Use in edema and the problem of resistance. In Brady HR, Wilcox CS [eds]: Therapy in Nephrology and Hypertension, 2nd ed. London, Elsevier Science, 2003.)

The diuretic dose must be above the natriuretic threshold (the steep part of the dose-response curve in Fig. 46-8 ). Outpatients should be able to detect an increase in urinary volume within 4 hours of an administered dose; urine volume can be measured directly when patients are hospitalized. If a diuresis does not occur, the next step is to double the dose until an effective dose, or the maximum safe dose, is reached. The next step is to give two daily doses of the diuretic. Bumetanide or furosemide acts for only 3 to 6 hours. Two daily doses, by interrupting postdiuretic salt retention, produce a greater response than the same total dose given once daily, as long as both are above the diuretic threshold. Concurrent disease may impair the absorption of the diuretic. Thus, a more bioavailable diuretic, such as torsemide, may be preferable to furosemide.[100] Diuretic resistance is often accompanied by a pronounced metabolic alkalosis.[104] This may be reversed by KCl or by adding a distal K+-sparing diuretic.

A progressive increase in diuretic dosage may produce an inadequate reduction in body fluids because of activation of NaCl-retaining mechanisms. ACEIs can sometimes restore a diuresis in resistant patients with CHF,[217] but a fall in blood pressure often limits the response. Adaptive changes in downstream nephron segments during prolonged diuretic therapy [72] [199] provide a rational basis for combining diuretics (see the next section). Highly resistant patient can be admitted for a trial of intravenous loop diuretic infusion or ultrafiltration.[242]

Diuretic Combinations

Full doses of diuretics acting on the same transport mechanism are less than additive, whereas diuretics acting on a separate mechanism may be synergistic. [5] [243]

Loop Diuretics and Thiazides.

A loop diuretic and a thiazide or thiazide-like drug (e.g., hydrochlorothiazide or metolazone) are synergistic in normal subjects and in those with edema or renal insufficiency. [243] [244] [245] [246] [247] Metolazone is equivalent to bendrofluazide in enhancing NaCl and fluid losses in furosemide-resistant subjects with CHF or the nephrotic syndrome.[248] During prolonged furosemide therapy, the responsiveness to a thiazide is augmented.[72] Patients with advanced CKD (GFR<30 mL/min) who are unresponsive to thiazide alone have a marked natriuresis when a thiazide is added to loop diuretic therapy,[246] probably by blockade of enhanced distal tubular Na+ reabsorption.[249]However, such combination therapy should be initiated under close surveillance because of a high incidence of hypokalemia, excessive ECV depletion, and azotemia.[250]

Loop Diuretics or Thiazides and Distal Potassium-Sparing Diuretics.

Amiloride or triamterene increases furosemide natriuresis only modestly but curtails the excretion of K+ and net acid[59] and preserves total body K+.[251] Distal K+-sparing agents are generally contraindicated in renal failure because they may cause severe hyperkalemia and acidosis.


Although diuretic therapy is generally well tolerated, a Medical Research Council (MRC) trial showed that the following adverse effects occurred more frequently with thiazide than with placebo: impaired glucose tolerance, gout, impotence, lethargy, nausea, dizziness, headache, and constipation.[252] However, the withdrawal rate of those receiving a thiazide was similar to that for a β-blocker, and the dose of thiazide was higher than that used currently.

Fluid and Electrolyte Abnormalities

Extracellular Volume Depletion and Azotemia.

Diuretics normally do not decrease the GFR. [72] [253] However, renal failure can be precipitated by vigorous diuresis in patients with impaired renal function, severe edema, or cirrhosis and ascites. A rise in the ratio of blood urea nitrogen to creatinine suggests ECV depletion. This change can be ascribed to decreased renal urea clearance because of increased urea reabsorption in the distal nephron[254] and to increased urea appearance due to increased arginine uptake by the liver with metabolism by arginase. [255] [256] [257]


Several mechanisms may play a role. One, illustrated in a self-experiment by McCance[258] ( Fig. 46-16 ) of severe salt depletion by a salt-free diet and forced perspiration, shows that the loss of the first 2 L of body fluid occurs isotonically. However, further obligated NaCl losses are not accompanied by corresponding fluid losses, leading to progressive hyponatremia, likely a consequence of AVP release in response to severe plasma volume depletion. Despite salt depletion, the degree of hyponatremia is mild.

FIGURE 46-16  Data from normal volunteers subjected to progressive salt depletion over 12 days (followed by 3 days of salt repletion) caused by a zero salt intake and forced perspiration. Results shown are for changes in total body Na. (red line), body weight (blue line), plasma sodium concentration, and serum urea nitrogen.  (Drawn from data in McCance RA: Experimental sodium chloride deficiency in man. Proc R Soc Lond B Biol Sci 119:245–268, 1936.)



A second mechanism is illustrated in the study of Clark and colleagues.[259] They showed that older age and thiazide diuretics are additive in impairing maximal free water excretion following a water load ( Fig. 46-17 ). This effect is relatively specific for thiazides, which inhibit urinary dilution, whereas loop diuretics inhibit urinary concentration and dilution.[260] Indeed, thiazides are 12-fold more likely than loop diuretics to cause hyponatremia.[261]Thiazide-induced hyponatremia usually entails an inappropriate fluid intake and an expanded total body water. [261] [262] Estradiol enhances the expression of the thiazide-sensitive cotransporters in the DCT.[263] Eighty percent of thiazide-induced hyponatremia occurs in females,[264] most of whom are elderly.[265] As noted previously, thiazide diuretics also increase AVP-independent water reabsorption along the medullary collecting duct and increase AQP2 expression when administered chronically. [136] [137]

FIGURE 46-17  Mean±SEM values for positive free water clearance during water loading. Data shown compare values in younger (blue boxes) and older (red boxes) normal volunteers given placebo or hydrochlorothiazide. Note that older age and thiazide diuretics both impair free water excretion.  (Redrawn from Clark BA, Shannon RP, Rosa RM, Epstein FH: Increased susceptibility to thiazide-induced hyponatremia in the elderly. J Am Soc Nephrol 5:1106, 1994.)



Hyponatremia can develop during rechallenge with a thiazide. [262] [266] It often develops within the first 2 weeks of thiazide therapy. [261] [266] Mild, asymptomatic hyponatremia can be treated by withdrawing diuretics, restricting the daily intake of free water to 1.0 to 1.5 L, restoring any K+ and Mg2+ losses, and replenishing NaCl if the patient is clearly volume-depleted. [261] [267] Severe, symptomatic hyponatremia complicated by seizures is an emergency requiring intensive treatment. The ideal management remains controversial. [264] [268] Central pontine myelinolysis has been related to overcorrection of hyponatremia[268] or to a rapid corrective of SNa by over 12 and 18 mmol/L in the first 48 hours. [264] [267] [269]

In one series, eight elderly patients with severe diuretic-induced hyponatremia (average SNa=110 mmol/L) and neurologic manifestations received 3% NaCl at 35 to 50 mL/hr and 20 mg furosemide intravenously after 6 and 24 hours of infusion. The SNa was corrected over an average of 29 hours to 132 mmol/L at a rate of 0.8 mmol/L/hr. Seven patients recovered from their neurologic deficit, and none died from hyponatremia.[270] However, there is a high rate of permanent neurologic damage in patients with severe, symptomatic hyponatremia due to thiazide therapy that has been corrected slowly over 18 to 56 hours.[266] For symptomatic patients, some recommend an initial rate of infusion of 3% NaCl at 2 mL/kg/hr for 3 hours. This must be reduced sharply when the SNa has increased by 6 to 8 mEq/L or if symptoms have abated.[261]


Furosemide inhibits the coupled reabsorption of Na+/K+/2Cl- at the luminal border of the TAL. A luminal K+ conductance provides for rapid secretion of reabsorbed K+ and thereby completes a futile cycle. The outcome is little net K+ retrieval from tubular fluid in the TAL.[142] Thiazides inhibit the coupled reabsorption of Na+/Cl- in the early DCT. Therefore, hypokalemia with these agents cannot be ascribed to their direct effects on K+ transport.

Four mechanisms have been identified that increase renal K+ elimination during therapy with thiazides or loop diuretics. First, flow-dependent K+ secretion by the distal nephron provides a universal mechanism for increased K+secretion in response to diuretics that act more proximally.[142] Recently, it has been shown that the basal and flow-dependent components of K+ secretion are largely mediated by distinct channels. Whereas basal secretion traverses ROMK (see earlier), flow-dependent K secretion is mediated by calcium-activated maxi K+ channels. [271] [272] Normally, a flow-dependent increase in K+ secretion during increased water intake is offset by a fall in AVP concentration that diminishes distal K+ secretion ( Fig. 46-18 ). Diuretic therapy is unusual because it combines increased distal tubule flow with maintained or increased AVP release due to nonosmotic stimulation. Indeed, inhibition of AVP release in normal human subjects undergoing a furosemide diuresis inhibits the kaliuresis.[220] Nonosmotic AVP release is common in edematous subjects.[267] Enhanced release of AVP and enhanced distal tubule fluid delivery combine to promote ongoing K+ losses during diuretic therapy for edema.

FIGURE 46-18  Contrasting effects of increased water or salt intakes with diuretic action on potassium secretion by the distal nephron. AVP, arginine vasopressin; DT, distal tubule.  (From Wilcox CS: Metabolic and adverse effects of diuretics. Semin Nephrol 19:557–568, 1999.)



Diuretic-induced aldosterone secretion promotes distal K+ secretion and provides a further mechanism for K+ secretion. [142] [238] [273] The effects of flow and aldosterone on distal K+ secretion are normally counterbalanced during changes in salt intake just as are the effects of flow and AVP induced by changes in water intake ( Fig. 46-19 ). Diuretic treatment, however, uncouples the two because it enhances the secretion of aldosterone and AVP during periods of diuretic-induced increases in distal flow, thereby accounting for the particular importance of aldosterone and AVP in promoting K+ loss with diuretics.[220]

FIGURE 46-19  Diagrammatic representation of mechanisms that partition K. into cells or increase K. excretion by the collecting ducts (CDs) during therapy with a thiazide or loop diuretic, and strategies for prevention or treatment with angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), aldosterone antagonists (e.g., spironolactone), distal K.-retaining diuretics (amiloride or triamterene), or KCl supplements. Diuretics stimulate the renin-angiotensin-aldosterone (RAA) axis, increase distal tubule flow, increase release of arginine vasopressin (AVP), increase the chloride concentration of distal tubule (DT) fluid, and generate a metabolic alkalosis, all of which enhance K. secretion in the collecting ducts.


Lastly, diuretic-induced alkalosis enhances distal secretion of K+.[142]

The serum K+ concentration (SK) of patients not receiving KCl supplements falls by an average of 0.3 mmol/L with furosemide and by 0.6 mmol/L with thiazides.[274] This 20% fall in SK is accompanied by a fall in total body K+that averages less than 5%.[274] Moreover, in normal subjects receiving daily doses of loop diuretics, there is no detectable change in K+ balance despite a reproducible fall in SK of about 0.5 mmol/L.[220] This implies that the primary cause of hypokale-mia during diuretic administration is a redistribution of K+ into cells likely related to the accompanying metabolic alkalosis. [60] [104]

Mild diuretic-induced hypokalemia (SK 3.0–3.5 mmol/L) increases the frequency of ventricular ectopy.[275] Some authors [276] [277] have shown that thiazide-induced hypokalemia does not pose a risk of clinically significant cardiac dysrhythmia even in large populations of hypertensive patients. In contrast, others[278] report a dose-dependent risk of cardiac arrest in patients receiving thiazides that is prevented by therapy with a K+-sparing diuretic such as amiloride.

Adverse effects of hypokalemia are clearly important in certain circumstances. First, severe hypokalemia (SK<3.0 mmol/L) requires treatment because it is associated with a doubling of serious ventricular dysrhythmias, muscular weakness, and rhabdomyolysis.[279] Second, mild hypokalemia can precipitate dangerous dysrhythmias in patients with cardiac dysfunction owing to left ventricular hypertrophy, coronary ischemia, CHF, prolonged QT interval, anoxia, or ischemia and in those with a known dysrhythmia. Third, hypokalemia enhances the toxicity of cardiac glycosides by diminishing the renal tubule secretion of digoxin and by enhancing its binding to cardiac Na+,K+-ATPase and thereby exaggerates its actions on the heart. Fourth, hypokalemia stimulates renal ammoniagenesis. This is dangerous for patients with cirrhosis and ascites who are prone to develop hepatic encephalopathy owing to hyperammonemia. Moreover, the accompanying diuretic-induced alkalosis partitions ammonia into the brain. Fifth, catecholamines partition K+ into cells and lower SK. MI provokes sufficient catecholamine release to lower SK by approximately 0.5 mmol/L, which is potentiated in patients who have received prior thiazide therapy.[280] Sixth, hypokalemia impairs insulin release and predisposes to hyperglycemia.[281] Seventh, hypokalemia limits the antihypertensive action of thiazides.[282] In a placebo-controlled study of hypokalemic subjects receiving thiazide diuretics, coadministration of KCl that restored SK reduced blood pressure significantly.[282] Diuretic-induced hypokalemia can be easily prevented and the adverse consequences can be clinically significant. Therefore, it is prudent to prevent even mild degrees of hypokalemia.

Hypokalemia can be prevented by increasing intake of K+ with Cl- (see Fig. 46-19 ), but this often requires 40 to 80 mmol daily. Moreover, in the presence of alkalosis, hyperaldosteronism, or Mg2+ depletion, hypokalemia is quite unresponsive to dietary KCl. A more effective, convenient, and predictable strategy is to prescribe a combined therapy with a distal K+-sparing agent such as amiloride or triamterene that maintains SK during short- or long-term hydrochlorothiazide therapy.[283] It also prevents diuretic-induced alkalosis and provides further natriuresis and antihypertensive efficacy. An alternative strategy is to administer an ACEI, an ARB, or an aldosterone antagonist to counter angiotensin-induced hyperaldosteronism that promotes distal K+ secretion. The further fall in blood pressure and the beneficial cardiovascular actions of these agents are clearly a further advantage.


Diuretics acting in the ASDN decrease K+ secretion and predispose to hyperkalemia. [273] [284] As noted previously, this complication has been observed more frequently recently, associated with an increased use of distal K+-sparing diuretics.


Loop diuretics inhibit Mg2+ reabsorption in the TAL [67] [69] by reducing the transepithelial voltage (Tm) that drives Mg2+ and Ca2+ paracellularly (see Fig. 46-4 ).[285] Thiazides first enhance Mg2+ uptake in the DCT, but during prolonged therapy, there is enhanced renal Mg2+ excretion.[132] Although this has been attributed to a fall in cellular [Na+] stimulating basolateral Na+/Mg2+ exchange,[285] more recent molecular data suggest that chronic thiazide use leads to down-regulation of the predominant apical Mg2+ channel of the distal nephron.[131] Distal K+-sparing agents and spironolactone diminish Mg2+ excretion. During prolonged therapy with thiazides and loop diuretics, serum Mg2+ concentration (SMg) falls by 5% to 10%. Diuretic-induced hyponatremia and hypokalemia cannot be reversed fully until any Mg2+ deficit is replaced.[286] Mg2+-depleted rats secrete K+ inappropriately into the distal tubule, independent of aldosterone.[287]


Thiazides increase the serum concentrations of total and ionized calcium (Sca). During established thiazide treatment, parathyroid hormone (PTH) concentrations are inversely related to ionized Sca.[288] The increased Sca can be ascribed primarily to enhanced Ca2+ reabsorption (the mechanism is discussed previously). Persistent hypercalcemia should prompt a search for a specific cause, for example, an adenoma of the parathyroid glands.[288] Loop diuretics increase calcium excretion and can be used, together with saline, to treat hypercalcemia.

Acid-Base Changes.

Metabolic alkalosis induced by thiazides or loop diuretics is an important adverse factor in patients with hepatic cirrhosis and ascites, in whom the alkalosis may provoke hepatic coma by partitioning ammonia into the brain, and in those with underlying pulmonary insufficiency, in whom the alkalosis diminishes ventilation.[289] The generation of metabolic alkalosis with loop diuretics results from contraction of the extracellular HCO3- space by the excretion of a relatively HCO3--free urine. [60] [290] The maintenance of metabolic alkalosis involves increased net acid excretion in response to hypokalemia-induced ammoniagenesis and mineralocorticoid excess during continued Na+delivery and reabsorption at the distal nephron sites of H+ secretion.[291] Diuretic-induced metabolic alkalosis is best managed by administering KCl, but a distal K+-sparing diuretic,[292] or occasionally a CAI, should be considered.[293] Metabolic alkalosis impairs the natriuretic response to loop diuretics[104] (see Fig. 46-11 ) and may thereby contribute to diuretic resistance.

CAIs produce metabolic acidosis. Spironolactone, eplerenone, amiloride, and triamterene can cause hyperkalemic metabolic acidosis, especially in elderly patients, those with renal impairment, and those receiving KCl supplements.

Metabolic Abnormalities


Diuretic therapy, especially with thiazides, impairs carbohydrate tolerance and occasionally precipitates diabetes mellitus. [252] [294] The increase in blood glucose concentration is greatest during initiation of therapy. In one study, hydrochlorothiazide given to patients with non-insulin-dependent diabetes mellitus increased the fasting serum glucose concentration by 31% at 3 weeks. This was attributed to decreased hepatic glucose utilization.[295]Hyperglycemia persists,[296] but is reversed rapidly after diure-tic discontinuation, even following 14 years of thiazide therapy.[297] The increase in blood glucose provoked by thiazides is worsened by concurrent β-adrenergic receptor blockade.[295]

Thiazides impair glucose uptake into muscle [298] [299] and liver.[295] This effect is more pronounced during initiation of therapy. It has been ascribed to a diuretic-induced reduction in cardiac output with reflex activation of the SNS and catecholamine secretion leading to reductions in hepatic glucose uptake, muscle blood flow, and muscle glucose uptake ( Fig. 46-20 ). During sustained thiazide therapy, there is decreased insulin release that can be corrected by reversal of hypokalemia with KCl,[300] hypomagnesemia with magnesium oxide[301] or administration of spironolactone. Experimental K+ deficiency causes glucose intolerance and impairs insulin secretion in the absence of diuretics.[302]

FIGURE 46-20  Hypothesis for the hyperglycemic actions of thiazide diuretics. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ECV, extracellular fluid volume; SNS, sympathetic nervous system.  (From Wilcox CS: Metabolic and adverse effects of diuretics. Semin Nephrol 19:557–568, 1999.)



Hydrochlorothiazide and ACEIs have opposite effects on glucose disposal attributed to opposing effects on SK.[299] The increase in serum glucose levels that occurs with thiazide therapy is more pronounced in obese patients and correlates with a fall in intracellular [K+] or [Mg2+].[303] It can be prevented by reducing the thiazide dosage[281] or by KCl replacement.[300] Therefore, care should be taken to monitor blood glucose during thiazide therapy, particularly in obese or diabetic patients, and to prevent hypokalemia.

Thiazide-induced hyperglycemia should be anticipated and prevented. Measures include coadministration of a distal, K+-sparing diuretic, spironolactone, ACEI, or ARB, prescribing extra KCl, or reducing the thiazide dosage. Thiazide diuretics are not contraindicated in patients with diabetes. Indeed, diuretics produce an even greater reduction in the absolute risk for cardiovascular events in hypertensive patients who are diabetic.[304] Therefore, diabetes mellitus is an indication for close surveillance and attention to coadministration of agents designed to prevent hypokalemia (see Fig. 46-20 ).


Administration of loop diuretics or thiazides increases the plasma concentrations of total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol but reduces high-density lipoprotein (HDL) cholesterol. These adverse changes average 5% to 20% during initiation of therapy.[305] The mechanism is uncertain; it may relate to ECV depletion because severe dietary NaCl restriction has similar metabolic effects,[306] whereas increasing NaCl intake lowers serum cholesterol. Alternatively, it may relate to hypokalemia because this impairs insulin secretion. [300] [303] Importantly, most studies have shown that serum cholesterol returns to baseline over 3 to 12 months of thiazide therapy. [305] [307] In fact, when combined with lifestyle management, 4 years of thiazide therapy for hypertension is associated with a modest improvement in lipid profile. [308] [309]


Prolonged thiazide therapy for hypertension increases the serum urate concentration by approximately 35%. Renal urate clearance falls because of competition for secretion between urate and the diuretic[70] and because of ECV depletion-induced urate reabsorption[71] (see Fig. 46-5 ). Hyperuricemia is dose-related and occasionally can lead to gout. A very long-term outcome analysis of 3693 patients detected no adverse effects of diuretic-induced hyperuricemia in hypertensive subjects who did not have gout.[310] However, recent studies have correlated raised serum urate with cardiovascular death rate.[311]

Other Adverse Effects


In the MRC trial of 15,000 hypertensive subjects, impotence was much commoner in those receiv-ing a thiazide.[252] In the Treatment of Mild Hypertension Study, erection problems were twice as high in those re-ceiving a thiazide. A controlled trial demonstrated the efficacy of sildenafil in reversing impotence in hyperten-sives receiving multiple antihypertensive agents including diuretics.[312]


Loop diuretics can cause deafness that may occasionally be permanent.[313] The risk is greater with ethacrynic acid than with other loop diuretics and is greater when a loop diuretic is combined with another ototoxic drug (e.g., an aminoglycoside). It is especially common during high-dose bolus intravenous therapy in patients with renal failure in whom plasma levels are increased and in hypoalbuminemic subjects.[314] In a crossover trial, no ototoxicity was noted in patients with severe CHF when given an infusion of 250 to 2000 mg of furosemide over 8 hours, whereas reversible deafness occurred in 25% when the same dose was given as a bolus.[315]

Hazards in Pregnancy and Newborns.

Diuretics do not prevent preeclampsia. There is little effect on perinatal mortality.[316] Thiazides can be maintained during pregnancy in those whose hypertension has been controlled by them or used to treat pulmonary edema.[317]

Intensive therapy with loop diuretics for neonates with respiratory distress syndrome increases the prevalence of patent ductus arteriosus because of increased PG generation,[318] cholelithiasis, secondary hyperparathyroidism, bone disease, and drug fever.[319] Prolonged furosemide therapy in preterm infants can cause renal calcification.[320] Diuretics can be transferred from the mother to the infant in breast milk[320] and can cause serious fluid and electrolyte abnormalities in the infant.[321]

B Vitamin Deficiency.

Diuretics increase the excretion of water-soluble vitamins.[322] Long-term diuretic therapy for CHF reduces folate and vitamin B1 (thiamine) levels[323] and increases plasma homocysteine. Thiamine can improve left ventricular function in some patients with CHF treated with furosemide.[324]

Drug Allergy.

A reversible photosensitivity dermatitis occurs rarely during thiazide or furosemide therapy.[325] High-dose furosemide in renal failure can cause bullous dermatitis.[326] Diuretics may cause a more generalized dermatitis, sometimes with eosinophilia, purpura, or blood dyscrasia. Occasionally, they cause a necrotizing vasculitis or anaphylaxis.[327] Acute allergic reactions to sulfonamides are mediated via immunoglobulin E, whereas delayed-onset hypersensitivities are mediated by antibodies to specific protein epitopes.[328] Severe necrotizing pancreatitis is a rare complication.[329]

Acute interstitial nephritis with fever, skin rash, and eosinophilia may develop abruptly some months after initiation of therapy with a thiazide or, less often, furosemide. [330] [331] Ethacrynic acid is chemically dissimilar from other loop diuretics and can be a substitute.


There is a 50% increased risk of renal cell carcinoma associated with prolonged diuretic use.[332] This risk, however, has been attributed to associated hypertension and not to the diuretic itself. [333] [334] The risk for colon cancer is also increased modestly by thiazides.[335]

Adverse Drug Interactions.

Hyperkalemia in patients receiving distal K+-sparing diuretics, spironolactone, or eplerenone can be precipitated by concurrent therapy with KCl, ACEIs, ARBs, heparin, ketoconazole, trimethoprim, or pentamidine. Therefore, these drugs should not normally be prescribed in combination, especially in patients with impaired renal function or diabetes. ACEIs increase the risk of severe hyperkalemia in patients with decompensated CHF receiving spironolactone.[336] [337] Loop diuretics and aminoglycosides potentiate ototoxicity and nephrotoxicity. [314] [338] Diuretic-induced hypokalemia increases digitalis toxicity fourfold.[339] Plasma lithium concentrations increase during loop diuretic therapy[340] because of increased proximal lithium reabsorption.[341] NSAIDs may impair the diuretic, natriuretic, antihypertensive, and venodilating responses to diuretics and predispose to renal vasoconstriction and a fall in GFR (see Adaptation to Diuretic Therapy). Used together, indomethacin and triamterene may precipitate renal failure.[342]


Edematous Conditions

The first aim when treating edema is to reverse the primary cause by restoring hemodynamics and cardiac output in patients with heart failure (e.g., use of vasodilators or elimination of cardiac depressant drugs); by improving hepatic funtion in patients with cirrhosis and ascites (e.g., stopping alcohol intake); or by diminishing proteinuria in patients with the nephrotic syndrome (e.g., administration of ACEIs or ARBs).

Although the GFR is not reduced by low-dose diuretic therapy in normal subjects, it can be reduced in those with CKD, or if there is an abrupt fall in blood pressure, especially if this is complicated by orthostatic hypotension. Moreover, overzealous diuresis decreases the cardiac output, blood pressure, and renal function and stimulates the RAA axis, the SNS, PGs, and AVP, all of which may compromise the desired hemodynamic and renal responses.[343]Therefore, diuretic therapy for edema should be initiated with the lowest effective dose. Additional drugs can be used to counteract unwanted actions. For example, ACEIs, ARBs, or mineralocorticosteroid antagonists (MCAs) can prevent the expression of an activated RAA axis and enhance fluid losses, yet diminish K+ depletion (see Fig. 46-19 ). The use of a second diuretic can produce a synergistic action, whereas the use of a distal K+-sparing agent may counteract unwanted hypokalemia, alkalosis, or Mg2+ depletion (see Adaptation to Diuretic Therapy).

Dietary Na+ intake should be restricted to 2.5 to 3 g daily (corresponding to 107-129 mmol/24 hr) in patients with mild edema. Increasingly severe Na+ restrictions to 2 g daily (86 mmol/24 hr) is required for patients with refractory edema.

Some resistance to diuretic therapy should be anticipated in all patients with CKD and those with more than mild edema ( Fig. 46-21 ).

FIGURE 46-21  Effects of chronic renal insufficiency (A) or uncompensated edema (B) on the relationship between the absolute and fractional sodium excretion and the quantity of furosemide delivered to the urine in healthy controls (continuous lines) or patients (broken lines). CHF, congestive heart failure.


Congestive Heart Failure

The therapeutic approach for cardiac failure depends on the cause. [344] [345]

Acute Ischemic Left Ventricular Failure.

Patients with acute MI require the rapid establishment of coronary reperfusion (e.g., by thrombolysis or percutaneous transluminal coronary angioplasty) and treatment of arrhythymias. The aim of concomitant treatment is to counter the increase in left ventricular end-diastolic pressure, which enhances wall tension and O2 usage, and the accumulation of pulmonary edema without further curtailing the cardiac output. Judicious use of diuretics may meet these requirements. In one study, intravenous furosemide for left ventricular failure (LVF) complicating acute MI reduced the left ventricular filling pressure from 20 to 15 mm Hg within 5 to 15 minutes and increased the venous capacitance by 50%.[346] This rapid venodilation is blocked by NSAIDs[228] and ACEIs.[347] The ensuing diuresis reduces left ventricular end-diastolic pressure further.

A study of first-line therapy for 48 patients with acute LVF following MI compared the response to intravenous furosemide with a venodilator (isosorbide dinitrate), an arteriolar dilator (hydralazine), or a positive inotrope (prenalterol).[348] The venodilator and furosemide both reduced left ventricular filling pressure while maintaining the cardiac index and heart rate. The authors concluded these were the best first-line agents but that they should be combined with an arteriolar vasodilator.

In contrast, a study randomized 110 patients with acute LVF to high-dose isosorbide dinitrate (3 mg IV every 5 min) or to high-dose furosemide (80 mg IV every 15 min).[349] An adverse end point occurred more frequently in those randomized to furosemide (46%) than to nitrate (25%). The authors cautioned against the use of high-dose furosemide in acute LVF.

Although intravenous furosemide decreases left ventricular filling pressure in patients with LVF, the shape of the Frank-Starling ventricular function curve predicts little change in cardiac output at elevated filling pressures. Nevertheless, most investigators recommend a trial of loop diuretics after ECV depletion and preload-dependent right heart failure have been ruled out by targeted volume boluses.[350]

Furosemide can be given as an intravenous bolus of up to 100 mg or as a short-term infusion to limit the risk of ototoxicity. Although controversial, an intermittent infusion produces a slightly less natriuresis in most comparative studies.[351] Ideally, lower doses are used initially and titrated up to a good effect, for example, a PCWP of 16 mm Hg.[351]

Decompensated Chronic Congestive Heart Failure.

Acute decompensation often results from an imbalance in the neurohumoral systems that regulate cardiac and renal function.[352] Therefore, it is rational to target these mechanisms with selective therapy. These patients often respond to intravenous vasodilators, which counteract the effects of baroreceptor-dependent increases in sympathetic tone, AII and aldosterone, endothelin, and AVP. Venodilation and diuresis evoked by intravenous furosemide may be useful. In a study of 15 patients with severe decompensated CHF, however, intravenous furosemide led to an abrupt increase in systemic vascular resistance and blood pressure and a decrease in the cardiac index.[353] Over the next 2 hours, a diuresis occurred that decreased the left ventricular filling pressure and right atrial pressure and reversed the adverse hemodynamic changes. The authors concluded that intravenous furosemide had activated neural and humoral mechanisms of vasoconstriction that had contributed to acute pump dysfunction. In contrast, subsequent studies in patients with severe heart failure show that therapy with vasodilators and diuretics aimed at improving overall hemodynamic status led to rapid neurohumoral improvement when central filling pressure declined.[354] Moreover, longer-acting loop diuretics, such as torsemide[355] or azosemide,[356] produce less neurohumoral activation and may be preferable.

If a patient becomes resistant to loop diuretics, but maintains an adequate blood pressure, additional therapy with metolazone[357] or hydrochlorothiazide[315] can increase fluid losses by an average of 7 to 8 kg. Low-dose dopamine infusion (1–3 mg/kg/min) or fenoldopam, which is a dopamine type 1 receptor agonist, are modest diuretics that are often used in diuretic-resistant patients. These agents, however, can have adverse arrhythmogenic effects and, in comparative trials in patients with decompensated heart failure, have generally not been superior to vasoconstrictors. Moreover, dopamine does not provoke natriuresis in furosemide-resistant patients.[351] The use of higher and inotropic doses of dopamine, how-ever, remains an integral part of treating refractory systolic dysfunction.

Nesiritide is a recombinant human brain natriuretic peptide (BNP) that was approved by the U. S. Food and Drug Administration (FDA) for the treatment of acute decompensated CHF.[358] Studies of natriuretic peptide receptor A-deficient mice implicate this system in the natriuretic response to blood volume expansion[359] and provide a rationale for BNP in the treatment of decompensated CHF. Nesiritide given short-term to patients with decompensated CHF can reduce PCWP.[360] However, subsequent studies have shown that nesiritide is not a diuretic in patients with heart failure and, when compared with placebo, may increase the risk of death and worsening renal function. [361] [362] [363] Until more data are available, nesiritide cannot be recommended as a primary therapy for decompensated CHF.

Chronic Stable Congestive Heart Failure.

Diuretics are extremely useful in the long-term management of chronic stable CHF. Avid renal NaCl and fluid retention leads to pulmonary edema that limits ventilation. Cardiac dilation limits cardiac function and increases wall tension and O2 usage. This can create a spiral of decreasing oxygenation and cardiac output. In a study of 13 patients with severe edema due to CHF, furosemide therapy increased stroke volume by 15% and decreased peripheral vascular resistance despite reducing body weight by an average of 10 kg.[364] In another study, combined therapy with a diuretic and a vasodilator reduced left and right atrial volumes, corrected atrioventricular valvular regurgitation, and improved stroke volume by 64%.[348] A meta-analysis of trials for CHF concluded that the odds ratio was reduced to 0.25 for mortality and 0.31 for hospitalization for those randomized to diuretics.[365] These remarkable data strongly support the use of diuretics in CHF.

Conversely, because the failing heart has a decreased capacity to regulate its contractility in response to changes in venous return, if diuretic therapy is too abrupt or severe, patients suffer from a decreased effective blood volume (orthostatic hypotension, weakness, fatigue, decreased exercise ability, and prerenal azotemia). Therefore, salt-depleting therapy requires continual reassessment and judicious use of other measures (e.g., vasodilators, ACEIs, ARBs, or aldosterone antagonists). As noted previously, diuretics must be used cautiously in patients with diastolic dysfunction.

The RALES study concluded that patients with severe CHF caused by left ventricular dysfunction have improved outcomes if randomized to spironolactone (25–50 mg/day), even if they are receiving concurrent ACEI therapy.[366]Current American College of Cardiology guidelines indicate that aldosterone antagonists are reasonable in patients with moderately severe to severe CHF symptoms and reduced left ventricular function who can be carefully monitored for kidney function and Sk. The guidelines exclude men with creatinine concentrations higher than 2.5 mg/dL and women with creatinine concentrations higher than 2.0 mg/dL.[367]

Diuretic kinetics are impaired in decompensated CHF. [368] [369] The bioavailability of furosemide, unlike that of bumetanide or torsemide, is erratic in CHF.[370] This, and a longer duration of action, may account for a 50% reduction in the requirement for readmission to hospital in patients with CHF randomized to torsemide, compared with furosemide.[100] Diuretic bioavailability is normal in patients with decompensated CHF but absorption may be markedly delayed. There is a decreased plasma clearance because of a decreased RBF.[368] Together, these can limit the peak diuretic concentration in the tubular fluid to the foot of the dose-response curve and, thereby, diminish the response.

There is impaired diuretic responsiveness in patients with advanced CHF, as shown by a shift to the right in the natriuresis/excretion relationship of diuretics[369] (see Fig. 46-21 ). Thus, resistance should be anticipated in patients with severe CHF and the diuretic dosage increased accordingly.

Mild CHF often responds to dietary Na+ restriction (100–120 mmol/day) and low doses of a thiazide diuretic. As cardiac failure progresses, larger, more frequent doses of loop diuretics and tighter control of dietary salt (80–100 mmol/day) are required. For the refractory patient, the addition of a second diuretic acting at the proximal tubule (e.g., acetazolamide) or a downstream site (e.g., a thiazide) can produce a dramatic diuresis, even in individuals with impaired renal function.[371] Although earlier reports suggested that resistant patients have a satisfactory diuresis after addition of spironolactone (25–100 mg/day),[372] recent reports of excess morbidity from hyperkalemia during spironolactone use lessen the enthusiasm for this approach and suggest that aldosterone antagonist use should remain within guidelines. Aldosterone antagonists and loop diuretics improve ventricular remodeling. [372] [373]

Admission to the hospital for an escalating continuous intravenous infusion of loop diuretic can improve fluid loss and symptoms.[374] As patients progress through this treatment strategy, the risks of volume depletion, azotemia, and electrolyte abnormalities increase sharply. Therefore, new therapies are required, because a decrement in renal function predicts a bad outcome in patients treated for CHF.[375] Indeed, furosemide therapy for CHF often reduces renal function. Renal dysfunction can be ameliorated by an ARB, providing that the blood pressure is maintained, or by an adenosine type 1 receptor antagonist,[376] if this becomes available. Decompensated CHF stimulates the RAA axis and AVP,[353] predisposing to hypokalemia, hypomagnesemia, hyponatremia, and arrhythmias. Hypokalemia potentiates the binding of digitalis to cardiac myocytes,[377] decreases its renal elimination,[378] and enhances its cardiac toxicity.[379] Hypokalemia should be prevented in patients with CHF (see Adverse Effects of Diuretics).

Right Ventricular Failure.

The requirement for diuretic therapy in patients with pure right heart failure or cor pulmonale is not compelling. A decrease in venous return induced by vigorous diuresis may worsen right heart function. Furosemide administration increases AII-induced hypoxic pulmonary vascular resistance.[379] Therefore, the emphasis should be on reversal of chronic hypoxemia.

Cirrhosis of The Liver

Most patients with cirrhotic ascites and peripheral edema have expansion of the ECV owing to arteriolar underfilling caused by peripheral vasodilation and impaired cardiac function [380] [381] [382] ( Fig. 46-22 ). Diuretic therapy for this group is rational and is usually well tolerated. In some patients, however, the reduced serum albumin and an increased portal venous pressure coupled with preexisting diuretic use lead to true “underfill edema.” Diuretic therapy for this group is complicated by hypotension, azotemia, and electrolyte dysfunction.

FIGURE 46-22  Comparison of clinical and biochemical characteristics and responses in patients with nephrotic syndrome and underfill vs. overfill edema. ANP, atrial natriuretic peptide; AVP, arginine vasopressin; ECV, extracellular fluid volume; GFR, glomerular filtration rate; PA, plasma aldosterone; PRA, plasma renin activity.  (Redrawn from Schrier RW, Fassett RG: A critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome. Kidney Int 53:1111, 1998.)



Studies in patients with cirrhosis demonstrate increases in proximal reabsorption in response to a diminished effective arterial blood volume.[383] These patients also have an increased natriuretic response to a thiazide and increased serum aldosterone concentrations.[384] Thus, diuretics acting on the distal nephron and aldosterone antagonists are rational for cirrhosis.[385]

Ascitic fluid is largely cleared by lymphatics. Diuretics increase thoracic duct lymph flow.[386] Thus, diuretics decrease ascites formation by decreasing the venous and portal hydraulic pressures, concentrating the plasma proteins,[387] and increasing ascites absorption. [276] [386]

The maximal daily ascites drainage into the systemic circulation is limited to 300 to 900 mL.[388] Therefore, the maximum daily weight loss in nonedematous patients should not exceed 0.3 to 0.5 kg. In patients with ascites and edema, daily diuretic-induced weight losses of 1 to 3 kg do not perturb the plasma volume or renal function.[389] The same diuretic regimen maintained after the peripheral edema has cleared, however, or given to nonedematous patients, reduces plasma volume by as much as 24% and increases the risk of hyponatremia, alkalosis, and azotemia. Thus, a diuretic prescription that is initially safe must be reviewed continuously.

Mild edema can be treated by dietary restriction of Na+ (100 mmol/day). Dietary fluid restriction is not necessary when treating most patients with cirrhotic ascites.[390] Guidelines developed by the American Association for the Study of Liver Disease recommend fluid restrictcion only if the SNa falls below 120 to 125 mmol/L. [390] [391] Patients with moderate ascites require diuretics. Spironolactone (50–200 mg/day) or eplerenone (50–200 mg/day) or, occasionally, amiloride (5–10 mg/day) has been recommended first-line agents,[381] although amiloride has been shown to be less effective than a spironolactone derivative.[392] Spironolactone has also been shown to be more effective than furosemide in nonazotemic cirrhotic patients, in which 19 of 20 responded favorably to spironolactone but only 11 of 21 responded to furosemide.[385] The American Association for the Study of Liver Disease practice guidelines suggest an initial regiment of 40 mg of furosemide and 100 mg of spironolactone, with titration upward maintaining the same diuretic ratio.[391] Maximally recommended doses of spironolactone are 400 mg and 160 mg of furosemide. Patients with cirrhosis and ascites cannot normally tolerate ACEIs or ARBs because of a fall in blood pressure.[392a]

The most common problems with furosemide in cirrhosis patients are electrolyte disturbances and volume depletion. Hypokalemia is related to preexisting K+ depletion and hyperaldosteronism and can be countered by the use of spironolactone, eplerenone, or a distal K+-sparing agent, as noted previously. However, patients with cirrhosis can develop hyperkalemic metabolic acidosis with spironolactone.[393]

More severe diuretic resistance requires paracentesis. Controlled trials in patients with refractory ascites have shown that large-volume paracentesis is more effective than diuretic therapy in reducing hospital stay and electrolyte complication but does not influence the mortality.[394] Even repeated, large-volume paracenteses (4–6 L/day) are safe if intravenous albumin (40 g with each procedure) is administered.[394] Most investigators, however, recommend paracentesis only for patients who are relatively resistant to diuretics and dietary Na restriction[391] ( Fig. 46-23 ).

FIGURE 46-23  Treatment algorithm for management of fluid retention in patients with hepatic cirrhosis and ascites.  (From Ellison DH, Wilcox CS: Diuretics: Use in edema and the problem of resistance. In Brady HR, Wilcox CS [eds]: Therapy in Nephrology and Hypertension, 2nd ed. London, Elsevier Science, 2003.)

Patients with mild cirrhosis of the liver have a normal or reduced natriuretic response to furosemide with little change in diuretic kinetics.[395] However, in those with advanced disease, furosemide absorption is slowed,[396] its volume of distribution is increased because of hypoalbuminemia and an expanded ECV, and its elimination is delayed because of hypoalbuminemia that limits proximal tubule diuretic secretion and a low RBF that limits renal clearance.[395]

Loop diuretic resistance in early cirrhosis is largely due to decreased responsiveness to the drug, which correlates with an elevated serum aldosterone.[385] With the development of ascites, a further decrease in natriuretic response correlates with decreased delivery of furosemide to the urine[397] and with further stimulation of the RAA axis.[385]

Diuretic resistance is common in advanced cirrhosis. In addition to the usual causes (see Table 46-1 ), it may herald the development of infection, bleeding, or a critical fall in cardiac output. Patients who are refractory and disabled by recurrent paracentesis may respond to body compression[398] or a transjugular intrahepatic portosystemic shunt.[399]

Nephrotic Syndrome

Renal albumin losses and reduced hepatic synthesis in the nephrotic syndrome eventually lead to hypoalbuminemia. The ensuing fall in plasma oncotic pressure increases the flux of fluid into the interstitial spaces, leading to under-fill edema. [401] [402] In addition, a primary renal salt retention can lead to overfill edema (see Fig. 46-22 ). Patients with minimal-change disease often have a contracted plasma volume and a stimulated RAA axis, whereas those with diabetes and hypertension usually have an expanded plasma volume and a suppressed RAA axis.[402] Micropuncture studies of sodium-retaining animal models of the nephrotic syndrome demonstrate pronounced NaCl reabsorption in the distal nephron and TAL. [404] [405] The proteinuric kidney of a rat model of unilateral nephrotic syndrome has an enhanced Na+ reabsorption in the collecting ducts[405] and a diminished response to ANP.[406]Hyperaldosteronism reinforces NaCl reabsorption at these sites. Renin and aldosterone levels are highly variable in patients with the nephrotic syndrome.[407]

Hypoalbuminemia decreases the binding of furosemide to plasma proteins and thereby increases its volume of distribution.[408] Whereas one study reported that premixing furosemide with albumin in the syringe prior to intravenous injection enhanced the diuresis of patients with the nephrotic syndrome,[409] this has not been confirmed. [87] [411] [412] Indeed, two studies have shown that patients with a serum albumin of 2 g/dL can deliver normal quantities of furosemide into the urine. [409] [413] Iso-oncotic plasma volume expansion with albumin in patients with the nephrotic syndrome fails to induce negative NaCl balance[413] or to enhance the response to furosemide[410] and is not generally recommended for treatment of resistant nephrotic syndrome. [411] [415]

A more logical approach to diuretic resistance is to limit albuminuria with an ACEI or ARB or both, which may also combat the associated coagulopathy, dyslipidemia, edema, and progressive loss of renal function. The addition of a loop diuretic to an ACEI or an ARB reduces proteinuria further but increases the serum creatinine concentration.[415]

The secretion of CAIs[16] and loop diuretics[106] by the S2 segment of the proximal tubule is dependent on albumin. However, in the rabbit, the uptake of loop diuretics into the S1 portion of the proximal tubule, where furosemide is inactivated by glucuronidation, is inhibited by albumin [107] [417] (see Fig. 46-7 ). Albumin infusion into nephrotic patients does indeed increase renal furosemide excretion, whereas hypoalbuminemia enhances its metabolic clearance.[417]

The interaction of furosemide with its receptor in the lumen of the TAL is restricted by binding to filtered albumin.[418] Addition of albumin to the tubular perfusate of the loop of Henle attenuates the response to perfused furosemide because of binding to albumin and is reversed by coperfusion with warfarin, which displaces it from its albumin binding site.[419] However, Agarwal and colleagues[420] found that displacing furosemide from albumin by coadministration of sulfisoxazole did not affect natriuresis in patients with the nephrotic syndrome. This study is not definitive as these patients did not have diuretic resistance.

Animal studies demonstrate six mechanisms that could impair the responsiveness to loop diuretics in patients with the nephrotic syndrome ( Table 46-2 ). Clinical studies confirm that nephrotic patients have an impaired tubular response to loop diuretics (see Fig. 46-21 ).

TABLE 46-2   -- Some Identified Mechanisms and Their Possible Solutions for Limited Response to Loop Diuretics in Patients with the Nephrotic Syndrome

Limitation of Response


Potential Solution

Decreased renal diuretic delivery

Decreased albumin increases VD and reduces renal delivery

Premix diuretic with albumin in syringe[*]

Decreased tubular secretion of active diuretic

Decreased albumin limits proximal secretion

Reduce albuminuria with ACEI or ARB

Increased renal metabolism of furosemide

Decreased albumin increases tubular uptake and glucuronidization

Consider bumetanide or torsemide, which are hepatically metabolized

Decreased blockade of tubular NaCl reabsorption

Filtered albumin binds free drug[†]

Reduce albuminuria with ACEI or ARB

Enhanced NaCl reabsorption in downstream segments

Functional and structural adaptation in distal nephron

Coadministration with thiazide or    -sparing diuretic

Enhanced reabsorption in the collecting ducts

ANP resistance

Increase dose of diuretic, add    -sparing


ACEI, angiotensin-converting enzyme inhibitor; ANP, atrial natriuretic peptide; ARB, angiotensin receptor blocker; VD, volume of distribution.



Little evidence of efficacy, if serum albumin ≥2 g/dL.467

Little evidence of importance for human resistance.468


Nephrotic edema is best managed by dietary salt and fluid restriction. Most patients respond initially to a loop diuretic when required. Spironolactone or eplerenone is effective in some patients.[401] Decreasing renal function[235] or administration of indomethacin[224] causes marked resistance to loop diuretics in these patients. The combination of a thiazide diuretic with furosemide dissipates edema but at the expense of marked kaliuresis.[421]

Idiopathic Edema

Idiopathic edema affects women predominantly. It causes fluctuating salt retention and edema, exacerbated by orthostasis.[422] The effects of diuretic withdrawal during controlled salt intake were studied in 10 such patients.[423]Although their body weight increased by 0.5 to 5.0 kg within 2 to 8 days, 7 returned to their original weight by 3 weeks without reinstituting diuretics. The authors concluded that diuretic abuse could cause idiopathic edema. However, this has been challenged.[424] Remarkably, 83% of habitual furosemide abusers who consume high doses over prolonged periods develop medullary nephrocalcinosis and tubulointerstitial fibrosis.[425] Patients are best treated by salt restriction.

Nonedematous Conditions


This is discussed in Chapter 42 .

Acute Kidney Injury.

A review of 11 randomized trials of loop diuretics or mannitol for prophylaxis or treatment of established AKI found no benefit.[426] Diuretics can be used to convert patients to nonoliguric AKI. A sustained diuresis can be provoked in most patients given 1 g furosemide orally three times daily, but this very large dose produced deafness in two patients, which was permanent in one,[427] and therefore, cannot be recommended. Both observational and randomized studies have indicated that furosemide does not improve the prognosis of AKI. [429] [430] [431] Furosemide can reduce the need for dialysis by diminishing hyperkalemia, acidosis, or fluid overload.[426] One protocol is to give 40 mg of furosemide, 1 mg of bumetanide, or 25 mg torsemide intravenously and to double the dose each 60 minutes if there is no response, up to a total daily dose of 1 g of furosemide or equivalent.[426] Bumetanide and torsemide are hepatically metabolized and, therefore, may be preferred to furosemide, which is metabolized by the kidney and, thus, accumulates to a greater degree in patients with renal insufficiency (see Fig. 46-6 ).

Chronic Kidney Disease.

This has been reviewed recently. [4] [432] In subjects who are in balance, the fractional reabsorption of NaCl and fluid by the renal tubules is reduced in proportion to the fall in GFR. The renal clearance of loop diuretics falls in parallel with the GFR because of a decreased renal mass and the accumulation of organic acids that compete for proximal secretion.[432] Thus, although the maximal increase in fractional excretion of Na+ produced by furosemide is maintained quite well in CKD [5] [434] [435] the absolute response to diuretics is limited by a reduced absolute rate of NaCl reabsorption and a reduced delivery of the diuretic to its target (see Fig. 46-21 ). Although CKD decreases proximal reabsorption, there is enhanced fractional reabsorption in the loop segment, distal tubule, and collecting ducts[435] with a relative increase of three- to fourfold per residual nephron in the expression of the Na+/K+/2Cl-transporter in the TAL and the Na+/Cl--transporter in the DCT.[436]

Torsemide has the greatest oral bioavailability in CKF.[95] For refractory patients, a loop diuretic infusion (e.g., bumetanide, 1 mg/hr for 12 hr) produces a greater natriuresis and less myalgia than two bolus injections.[211] Thiazides, when used alone, become relatively ineffective in patients with creatinine clearance below 35 mL·min-1. When used in combination with a loop diuretic that increases NaCl delivery and reabsorption at the distal tubule, larger doses of thiazides are effective in patients with moderate azotemia but at the cost of a sharp further rise in the serum creatinine and blood urea nitrogen concentrations and a high incidence of hypokalemia and electrolyte disorders[250] (Fig. 46-24 ). Moreover, high plasma levels of furosemide can cause ototoxicity.[437] Therefore, care should be taken not to exceed the ceiling dose [434] [435] ( Table 46-3 ). Mechanisms of impaired diuretic response in CKD are outlined in Table 46-4 .

FIGURE 46-24  Mean±SEM values in eight azotemic patients with resistant hypertension shows systolic blood pressure (SBP), body weight, serum creatinine, and blood urea nitrogen. Subjects were studied while receiving high-dose furosemide (Fur) alone (mean 176 mg/day), after doubling the furosemide dose, and after addition of hydrochlorothiazide (mean dose 70 mg/day).  (Drawn from data in Wollam GL, Tarazi RC, Bravo EL, et al: Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. Am J Med 72:929–938, 1982.)



TABLE 46-3   -- Ceiling Doses (in mL) of Loop Diuretics








IV or PO

IV or PO

Chronic kidney disease:





 Moderate (GFR 20–50 mL·min- 1)





 Severe (GFR <20 mL·min- 1)





Nephrotic syndrome with normal GFR





Cirrhosis with normal






CHF with normal GFR





Data from references 5, 7, and 8.

CHF, congestive heart failure; GFR, glomerular filtration rate; IV, intravenous; PO, oral.




TABLE 46-4   -- Some Identified Mechanisms and Their Possible Solutions for Limited Response to Loop Diuretics in Patients with Renal Insufficiency

Limitation of Response

Potential Mechanism

Potential Solution

Decreased renal diuretic delivery

Decreased RBF

Optimize BP and body fluids to restore RBF

Decreased basal fractional NaCl reabsorption

Limits effects of less active diuretics

Select a loop diuretic

Decreased proximal tubule diuretic secretion

Competition with urate and organic anions for basolateral uptake by OAT

Correct uremic milieu and hyperuricemia

Acidosis impairs secretion

Correct acidosis

Competition with drugs for tubular secretion by OAT

Avoid co-dosing with probenecid, NSAIDs, β-lactam and sulfonamide antibiotics, valproic acid, methotrexate, cimetidine, and antivirals

Maintained metabolic, but decreased renal clearance (furosemide only)

Hepatic metabolism of bumetanide and torsemide preserved

Avoid furosemide to prevent accumulation and ototoxicity

Enhanced NaCl reabsorption in downstream segments

Enhanced distal tubule fluid and NaCl delivery

Use thiazide or metolazone with loop diuretic in resistant patients

Enhanced NCC expression


BP, blood pressure; NCC, thiazide-sensitive Na+/Cl- transporter; NSAIDs, nonsteroidal anti-inflammatory drugs; OAT, organic anion transporter; RBF, renal blood flow.




Epidemiologic studies have correlated diuretic use with end-stage renal disease,[438] but this may be an epiphenomenon.[439] Epidemiologic studies have also raised the possibility that long-term diuretic use is associated with excess renal cell carcinoma.[440]

Renal Tubular Acidosis.

Furosemide increases the distal delivery of NaCl and fluid and stimulates aldosterone secretion and phosphate elimination, which enhance acid elimination.[441] Furosemide increases renal acid excretion in patients with distal renal tubular acidosis.[442] Patients with type IV renal tubular acidosis can be managed with diuretics or mineralocorticoid therapy depending on whether they have high or low blood pressure.[443]


Ca2+ excretion is increased by osmotic or loop diuretics but decreased by thiazides and distal agents. Hypercalcemia activates the Ca2+ (polyvalent cation)-sensing protein [445] [446] that inhibits fluid and NaCl reabsorption in the TAL and impairs renal concentration. The ensuing ECV depletion further limits Ca2+ excretion by reducing the GFR and enhancing proximal fluid and Ca2+ reabsorption. Therefore, the initial therapy for hypercalcemia is volume expansion with saline. Thereafter, an infusion of a loop diuretic (e.g., 80–120 mg of furosemide every 1-2 hr) causes the loss of approximately 80 mg of Ca2+ per dose. Fluid and electrolytes should be replaced quantitatively.[446]


Thiazides reduce stone formation in hypercalciuric and even normocalciuric patients by reducing excretion of Ca2+ and oxalate.[447] Some patients continue to form stones and require additional citrate therapy.[448] Ca2+ excretion can be reduced by addition of amiloride[449] or a low-salt diet. KHCO3 produces a greater reduction in Ca2+ excretion than KCl when given with hydrochlorothiazide.[450]


Bone cells express an Na+/Cl- cotransporter[451] that, when blocked by a thiazide, enhances bone Ca2+ uptake.[452] Thiazides inhibit osteocalcin, an osteoblast-specific protein that retards bone formation.[453] They inhibit bone reabsorption[454] and augment bone mineralization, independent of PTH.[455] Thus, thiazides may promote bone mineralization both by reducing renal Ca2+ excretion and by direct effects on bone. Indeed, thiazide therapy is associated with an increase in bone mineral density and a reduction in hip fractures in elderly persons.[456] In a placebo-controlled trial in postmenopausal women,[457] hydrochlorothiazide (50 mg/day) slowed cortical bone loss significantly. Surprisingly, despite opposite effects on Ca2+ excretion, a thiazide and a loop diuretic both enhance bone formation in postmenopausal women, at least in the short term.[458]

Diabetes Insipidus.

Thiazides can reduce urine flow by up to 50% in patients with central or nephrogenic diabetes insipidus.[459] Antidiuresis in nephrogenic diabetes insipidus is related to a decreased GFR, enhanced water reabsorption in the proximal and distal nephron, [461] [462] and an increase in papillary osmolarity leading to distal water reabsorption. Amiloride is effective treatment for lithium-induced diabetes insipidus. [463] [464]


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