Chronic Adaptations

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When diuretics reduce ECF volume effectively, NaCl balance gradually returns to neutral despite continued diuretic administration (see Fig. 1 [13, 42]). This "braking phenomenon" occurs when the magnitude of natriuresis following each diuretic dose declines. Several factors, acting in concert, may participate in chronic adaptation (see Fig. 3). A critical factor that is necessary for the braking phenomenon to occur is a decline in the ECF volume. Wilcox and coworkers showed that the magnitude of each diuretic-induced natriuresis declined during ECF volume depletion induced by once daily furosemide treatment of humans consuming a low NaCl diet. In contrast, when dietary NaCl intake was high, ECF volume depletion did not occur, and the magnitude of diuretic-induced natriuresis did not decline [42]. Relative or absolute ECF volume contraction limits NaCl excretion by reducing the amount of NaCl that is filtered and by increasing the amount of NaCl that is reabsorbed. In experimental animals, declines in renal blood flow occur during chronic diuretic

FIGURE 3. Physiological control mechanisms affecting natriuresis following loop diuretic administration. Factors tending to increase NaCl excretion are shown on white background. Factors tending to retard NaCl excretion are shown on a shaded background. Effects are arbitrarily classified as "early" and "late," although overlap of these effects does occur. Early effects of loop diuretic administration primarily predispose to natriuresis. In addition to direct blockade of tubular NaCl transport along the thick ascending limb (-lljNaci), both increased secretion of prostaglandins and suppression of the tubuloglomerular feedback mechanism tend to increase Na excretion. Later effects of loop diuretic predominate once loop diuretic concentrations in tubule fluid decline. These effects include increases in renin, angiotensin, and aldosterone, decreases in atrial natriuretic peptide, increased renal sympathetic activity, declines in glomerular filtration rate, and distal nephron hypertrophy. These changes predispose to increases in renal Na reabsorption.

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treatment, but declines in glomerular filtration rate are usually modest, unless volume depletion is extreme or renal perfusion is otherwise compromised by drugs or physical factors, such as renal artery stenosis. The effects of diuretics on glomerular filtration and renal blood flow (RBF) are not caused primarily by changes in mean arterial pressure, as the renal autoregulatory response tends to maintain glomerular filtration rate and renal blood flow relatively constant when arterial pressure changes. Instead, ECF volume contraction itself leads to decrements in renal blood flow and glomerular filtration rate; because renal blood flow declines proportionately more than glomerular filtration rate, ECF volume contraction increases the filtration fraction (GFR/RBF).

The role of the proximal tubule in diuretic adaptation has been documented clearly in rats treated chronically with thiazide diuretics and in animals and humans treated with loop diuretics. In the case of thiazide treatment, micro-puncture studies showed that hydrochlorothiazide initially inhibited Na and CI absorption along both the proximal tubule (by inhibiting carbonic anhydrase) and the distal tubule (by inhibiting Na/Cl cotransport) of rats (see Fig. 4 [39]). After 7-10 days of treatment, however, ECF volume contraction led to increases in proximal solute reabsorption, thereby limiting delivery of Na and CI to the distal sites of thiazide action. During the chronic phase of treatment, inhibition of NaCl transport along the distal nephron (the predominant site of thiazide action) counterbalanced the reduction in distal NaCl delivery; under

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FIGURE 4. Comparison of effects of acute and chronic thiazide administration on fractional ion delivery along the nephron. Compared with control (■), acute thiazide administration ( ) increases ion delivery out of the proximal tubule (Prox) and into the early distal tubule (ED). Because distal ion reabsorption is inhibited, ion delivery to the late distal tubule (LD) is increased, leading to increased fractional excretion (FE) (data from [24]). In contrast, after 7-10 days of diuretic treatment ( ), ion delivery out of the proximal tubule is reduced, delivery to the early distal tubule is reduced, and, because transport along the distal tubule is inhibited, delivery to the late distal tubule is similar to control conditions (data from [39]).

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FIGURE 4. Comparison of effects of acute and chronic thiazide administration on fractional ion delivery along the nephron. Compared with control (■), acute thiazide administration ( ) increases ion delivery out of the proximal tubule (Prox) and into the early distal tubule (ED). Because distal ion reabsorption is inhibited, ion delivery to the late distal tubule (LD) is increased, leading to increased fractional excretion (FE) (data from [24]). In contrast, after 7-10 days of diuretic treatment ( ), ion delivery out of the proximal tubule is reduced, delivery to the early distal tubule is reduced, and, because transport along the distal tubule is inhibited, delivery to the late distal tubule is similar to control conditions (data from [39]).

these conditions, at steady state, urinary NaCl was equal to dietary NaCl intake because enhanced proximal NaCl absorption and inhibited distal NaCl absorption counterbalanced [39]. Loop diuretics such as furosemide have also been shown to inhibit Na and CI absorption by the proximal tubule, although the mechanism is unclear. However, as with distal convoluted tubule (DCT) diuretics, chronic treatment with loop diuretics leads to ECF volume contraction and enhanced proximal NaCl reabsorption. That effects on proximal absorption require decrements in ECF volume was shown by comparing NaCl delivery out of the proximal tubule during furosemide administration with and without volume replacement. Only when the ECF volume was permitted to decline was proximal absorption stimulated [7],

Many of the same effector systems that participate in postdiuretic NaCl retention also may participate in chronic adaptations to diuretic drugs.

Physical Factors

A rise in filtration fraction increases the protein oncotic pressure in peritubular capillaries (more protein free filtrate is formed per milliliter of blood flow, thereby contracting the plasma volume around a constant amount of serum protein). The increased peritubular oncotic pressure increases solute and fluid reabsorption especially in the proximal tubule, where physical factors play a prominent role in regulating solute and fluid reabsorption. ECF volume contraction also enhances proximal solute and fluid reabsorption by decreasing the renal interstitial pressure during chronic diuretic treatment.

Sympathetic Renal Nerve Activity

Efferent sympathetic nerves innervate the renal vasculature, the macula densa, and essentially all segments of the nephron. Stimulation of sympathetic nerves reduces urinary NaCl excretion by reducing renal blood flow, by stimulating renin release at the macula densa, by stimulating tubule NaCl reabsorption along the nephron, and by interacting with hormonal modulators of NaCl transport. Renal nerves may contribute to NaCl retention in edematous disorders, and renal nerve activity is stimulated when furosemide is administered either to normal or to volume depleted animals [8]. Yet experimental models of chronic diuretic administration have failed to substantiate a central role for renal nerve activity in adaptive processes. Chronic sympathectomy or blockade of a-\ receptors inhibits the compensatory increase in proximal NaCl reabsorption that occurs during furosemide induced ECF volume depletion, but these maneuvers did not lead to an enhanced natriuretic response to furosemide [33]. This indicates that the inhibition of proximal solute reabsorption that occurs secondary to adrenergic blockade is compensated by increased reabsorption distally. Use of systemic pharmacological sympathetic blockade to study the role of renal nerves in diuretic adaptation is limited because of drug-induced systemic hypotension, but Petersen and DiBona showed that even anatomical renal denervation in normal rats does not abrogate the compensatory response to chronic furosemide administration [31]. Although it seems clear that renal nerves do not play a critical role in mediating compensation to chronic diuretic use in normal humans and animals, the consistent observation that diuretics do stimulate renal nerve activity does suggest the renal nervous activity may contribute to diuretic adaptation in some patients. In patients suffering from edematous disorders, distal Na reabsorption may already be stimulated; denervation in this situation might lead to significant impairment in adaptation to diuretic drugs.

Renin/Angiotensin/ Aldosterone

A third factor participating in chronic adaptation to diuretic drugs is the renin/ angiotensin/aldosterone system. Diuretics stimulate renin secretion via several mechanisms. First, loop diuretics stimulate renin secretion by inhibiting NaCl uptake into macula densa cells. Sodium chloride uptake via the loop diuretic sensitive Na/K/2C1 cotransport system is a central component of the macula densa mediated pathway for renin secretion [36]. Macula dense cells express both the loop diuretic-sensitive Na/K/2C1 transport pathway and a constitutive isoform of nitric oxide synthase (NOS, type 1 [30]); blocking Na/K/2C1 uptake at the macula densa stimulates renin secretion directly leading to a volume independent increase in angiotensin II and aldosterone secretion. Second, loop diuretics stimulate renal production of prostacyclin. Cyclooxygenase inhibitors (nonsteroidal anti-inflammatory drugs) inhibit the increase in renin secretion that results from loop diuretic administration, suggesting that the increased secretion of prostaglandins plays a critical role in diuretic-induced renin release [10]. Third, ECF volume contraction stimulates renin secretion via vascular effects on juxtaglomerular cells; diminished stretch is believed to hyperpolarize juxtaglomerular cells, thereby closing calcium channels and reducing intracellular calcium concentrations. Reduced cellular calcium appears to stimulate renin secretion. Fourth, renal nerves (see above) directly stimulate renin secretion via interaction with /3 adrenergic receptors on juxtaglomerular cells that affect cellular production of cAMP. Fifth, extracellular fluid volume contraction inhibits secretion of atrial natriuretic peptide. Among its other effects, atrial natriuretic peptide inhibits renin release. Renin acts on angiotensinogen to generate angiotensin I, which is converted to angiotensin II by converting enzyme. Angiotensin II stimulates aldosterone secretion from the adrenal cortex; aldosterone stimulates salt reabsorption by the distal nephron. In addition, however, angiotensin II directly stimulates Na reabsorption along both the proximal and the distal tubule by stimulating Na/H exchange activity [40]. Thus, diuretic drugs frequently result in stimulation of the renin/angiotensin/aldosterone system and the Na retention that occurs during diuretic treatment may result in part from this. As is the case with renal nerves, it has been difficult to show conclusively that the renin/angiotensin/aldosterone system plays a critical role in chronic adaptation to diuretic drugs. Yet as with renal nerves, the systemic effects of inhibition of the system, with either angiotensin I converting enzyme inhibitors, angiotensin II receptor blockers, or competitive aldosterone blockers, make it difficult to exclude a role for this hormonal system in the compensation to diuretic therapy.

Epithelial Hypertrophy and Hyperplasia

Other factors that can enhance renal NaCl reabsorptive capacity are structural and functional changes in the nephron itself. When a diuretic is administered, solute delivery to segments that lie distal to the site of diuretic action increases, leading to load dependent increases in solute reabsorption, as discussed above. When solute delivery and solute reabsorption increase chronically, epithelial cells undergo both hypertrophy and hyperplasia (see Fig. 5). Infusion of furo-semide into rats continuously for 7 days increased the percentage of renal cortical volume occupied by distal nephron cells (see Fig. 5). Distal convoluted tubule cell volume increased by nearly 100% with accompanying increases in luminal membrane area per length of tubule, in basolateral membrane area per length of tubule, and in mitochondrial volume per cell (see Fig. 6 [9, 18, 19]). Biochemical and functional correlates of these structural changes are shown in Fig. 7. Chronic loop diuretic administration increases the Na/K ATPase activity in the distal convoluted and cortical collecting tubules [35, 38] and increases the number of thiazide-sensitive Na/Cl cotransporters, measured as the maximal number of binding sites for [3H]metolazone [6, 29]. In one study, chronic furosemide treatment increased expression of mRNA encoding the thiazide-sensitive Na-Cl cotransporter, as detected by in situ hybridization (see Fig. 7) [29], In another study, however, mRNA expression of the thiazide-sensitive Na/Cl cotransporter as well as the ouabain sensitive Na/K ATPase was not affected by chronic furosemide infusion, when detected by Northern analysis [27]. Distal tubule cells that express high levels of transport proteins and are hypertrophic have a higher Na and CI transport capacity than normal tubules. Compared with tubules from normal animals, tubules of animals treated chronically with loop diuretics can absorb Na and CI up to 3 times more rapidly than control animals, even salt and water delivery is fixed by microperfusion (Fig. 7). When distal tubules are presented with high NaCl loads, as occurs during loop diuretic administration in vivo, Na and CI absorption rates approach those commonly observed only in the proximal tubule [9]. Recently, it has been observed

FIGURE 5. Effects of chronic loop diuretic administration on distal convoluted tubule cells of rats. Rats received furosemide continuously for 7 days. (A and B) Electron micrographs (X 10,000) of distal convoluted tubule cells from control (B) and furosemide (A) infused animals. Note that furosemide increases the size of the cell, the size of the nucleus, the amount of mitochondrial volume, and the amount of basolateral membrane area. (C and D) Photomicrographs of kidney cortices from control (D) and furosemide (C) infused animals (X480). D indicates distal convoluted tubule, CN indicates connecting tubule, CD indicates cortical collecting duct, tal indicates thick ascending limb. Note thickening of the epithelium in all distal segments. Photomicrographs are used with permission from Ellison, D.H. et al, Journal of Clinical Investigation 83:113126, 1989.

FIGURE 5. Effects of chronic loop diuretic administration on distal convoluted tubule cells of rats. Rats received furosemide continuously for 7 days. (A and B) Electron micrographs (X 10,000) of distal convoluted tubule cells from control (B) and furosemide (A) infused animals. Note that furosemide increases the size of the cell, the size of the nucleus, the amount of mitochondrial volume, and the amount of basolateral membrane area. (C and D) Photomicrographs of kidney cortices from control (D) and furosemide (C) infused animals (X480). D indicates distal convoluted tubule, CN indicates connecting tubule, CD indicates cortical collecting duct, tal indicates thick ascending limb. Note thickening of the epithelium in all distal segments. Photomicrographs are used with permission from Ellison, D.H. et al, Journal of Clinical Investigation 83:113126, 1989.

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FIGURE 6. Effects of continuous loop diuretic infusion in rats on distal convoluted tubule cells. Diuretic treatment increased the fraction of cortical volume occupied by distal convoluted tubule cells (VcelI), the area of luminal membrane relative to cortical volume (Bim), the area of basolateral membrane relative to cortical volume (BbIm), and the volume of mitochondria relative to cortical volume (Vml„). All changes were statistically significant. Drawn from Kaissling &r Stanton, Am. J. Physiol. 255:F1256-F1288,1988.

that chronic treatment of rats with loop diuretics also results in significant hyperplasia of cells along the distal nephron. Whereas mitoses of renal tubule epithelial cells are infrequent in adult kidneys, distal tubules from animals treated with furosemide chronically demonstrate prominent mitoses; increased synthesis of DNA in these cells was confirmed by showing increases in labeling of distal convoluted tubule cells with bromodeoxyurindine and proliferating cell nuclear antigen [25].

The diuretic-induced signals that initiate changes in distal nephron structure and function are poorly understood. Several factors, acting in concert, may contribute to these changes; these include diuretic induced increases in Na and CI delivery to distal segments, effects of ECF volume depletion on systemic hormone secretion and renal nerve activity, and local effects of diuretics on autocrine and paracrine secretion. Increased production of angiotensin II or increased secretion of aldosterone resulting from increases in renin activity may contribute to hypertrophy and hyperplasia. Angiotensin is a potent mitogen; angiotensin II receptors have not been localized definitively to DCT cells but recent functional studies do suggest that DCT cells express angiotensin II receptors. Aldosterone also promotes growth of responsive tissues under some circumstances [20]: when salt delivery to the collecting duct is increased in the presence of high levels of circulating aldosterone, principal cell hypertrophy

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