книги студ / color atlas of physiology 5th ed[1]. (a. despopoulos et al, thieme 2003)

7 Kidneys, Salt, and Water Balance

168

the secretion of ADH from the posterior lobe of the pituitary (!p. 280). ADH decreases urinary H2O excretion (!p. 166). The likewise hypertonic cerebrospinal fluid (CSF) stimulates central osmosensors in the hypothalamus, which trigger hyperosmotic thirst. The perception of thirst results in an urge to replenish the body’s water reserves. Peripheral osmosensors in the portal vein region and vagal afferent neurons warn the hypothalamus of water shifts in the gastrointestinal tract.

Water excess (!A2). The absorption of hypotonic fluid reduces the osmolality of ECF. This signal inhibits the secretion of ADH, resulting in water diuresis (!p. 166) and normalization of plasma osmolality within less than 1 hour.

Water intoxication occurs when excessive volumes of water are absorbed too quickly, leading to symptoms of nausea, vomiting and shock. The condition is caused by an undue drop in the plasma osmolality before adequate inhibition of ADH secretion has occurred.

Volume regulation. Around 8–15 g of NaCl are absorbed each day. The kidneys have to excrete the same amount over time to maintain Na+ and ECF homeostasis (!p. 168). Since Na+ is

170the major extracellular ion (Cl– balance is maintained secondarily), changes in total body

Na+ content lead to changes in ECF volume. It is regulated mainly by the following factors:

Renin–angiotensin system (RAS) (!p. 184). Its activation promotes the retention of Na+ via angiotensin II (AT II; lowers GFR), aldosterone (!A4) and ADH.

Atriopeptin (atrial natriuretic peptide; ANP) is a peptide hormone secreted by specific cells of the cardiac atrium in response to rises in ECF volume and hence atrial pressure. ANP promotes the renal excretion of Na+ by raising the filtration fraction (!p. 152) and inhibits Na+ reabsorption from the collecting duct.

ADH. ADH secretion is stimulated by (a) increased plasma and CSF osmolality; (b) the

Gauer-Henry reflex, which occurs when stretch receptors in the atrium warn the hypothalamus of a decrease ("10%) in ECF volume (~ atrial pressure); (c) angiotensin II (!p. 184).

Pressure diuresis (!p. 172), caused by an elevated arterial blood pressure, e.g. due to an elevated ECF volume, results in increased excretion of Na+ and water, thereby lowering ECF volume and hence blood pressure. This control circuit is thought to be the major mechanism for long term blood pressure regulation.

Salt deficit (!A3). When hyponatremia occurs

in the presence of a primarily normal H2O content of the body, blood osmolality and therefore ADH secretion decrease, thereby increas-

ing transiently the excretion of H2O. The ECF volume, plasma volume, and blood pressure consequently decrease (!A4). This, in turn, activates the RAS, which triggers hypovolemic thirst by secreting AT II and induces Na+ retention by secreting aldosterone. The retention of Na+ increases plasma osmolality leading to secretion of ADH and, ultimately, to the retention of water. The additional intake of fluids in response to thirst also helps to normalize the ECF volume.

Salt excess (!A4). An abnormally high NaCl content of the body in the presence of a normal

H2O volume leads to increased plasma osmolality (thirst) and ADH secretion. Thus, the ECF volume rises and RAS activity is curbed. The additional secretion of ANP, perhaps together with a natriuretic hormone with a longer half-life than ANP (ouabain?), leads to

increased excretion of NaCl and H2O and, consequently, to normalization of the ECF volume.

Diuresis and Diuretics

Increases in urine excretion above 1 mL/min (diuresis) can have the following causes:

Pressure diuresis occurs when osmolality in the renal medulla decreases in the presence of increased renal medullary blood flow due, in most cases, to hypertension (!p. 170).

Diuretics (!A) are drugs that induce diuresis. Most of them (except osmotic diuretics like mannitol) work primarily by inhibiting NaCl reabsorption (saluretics) and, secondarily, by decreasing water reabsorption. The goal of therapeutic diuresis, e.g., in treating edema and hypertension, is to reduce the ECF volume.

Although diuretics basically inhibit NaCl transport throughout the entire body, they have a large degree of renal “specificity” because they act from the tubular lumen, where they become highly concentrated due to tubular secretion (!p. 160) and tubular water reabsorption. Therefore, dosages that do not induce unwanted systemic effects are therapeutically effective in the tubule lumen.

Diuretics of the carbonic anhydrase inhibitor type (e.g., acetazolamide, benzolamide) decrease Na+/H+ exchange and HCO3– reabsorption in the proximal tubule (!p. 174ff.). The overall extent of diuresis achieved is small because more distal segments of the tubule reabsorb the NaCl not reabsorbed upstream and because the GFR decreases due to tubuloglomerular feedback, TGF (!p. 184). In addition, increased HCO3– excretion also leads to non-respiratory (metabolic) acidosis. Therefore, this

172type of diuretic is used only in patients with concomitant alkalosis.

Loop diuretics (e.g., furosemide and bumetanide) are highly effective. They inhibit the bumetanide-sensitive co-transporter BSC

(!p. 162 B6), a Na+-2Cl–-K+ symport carrier, in the thick ascending limb (TAL) of the loop of Henle. This not only decreases NaCl reabsorption there, but also stalls the “motor” on the concentration mechanism (!p. 166). Since the lumen-positive transepithelial potential (LPTP) in the TAL also falls (!p. 162 B7), paracellular reabsorption of Na+, Ca2+ and Mg2+ is also inhibited. Because increasing amounts of non-reabsorbed Na+ now arrive at the collecting duct (!p. 181 B3), K+ secretion increases and the simultaneous loss of H+ leads to hypokalemia and hypokalemic alkalosis.

Loop diuretics inhibit BSC at the macula densa, thereby “tricking” the juxtaglomerular apparatus (JGA) into believing that no more NaCl is present in the tubular lumen. The GFR then rises as a result of the corresponding tubuloglomerular feedback (!p. 184), which further promotes diuresis.

Thiazide diuretics inhibit NaCl resorption in the distal tubule (TSC, !p. 162 B8). Like loop diuretics, they increase Na+ reabsorption downstream, resulting in losses of K+ and H+.

Potassium-sparing diuretics. Amiloride block Na+ channels in the principal cells of the connecting tubule and collecting duct, leading to a reduction of K+ excretion. Aldosterone antagonists (e.g., spironolactone), which block the cytoplasmic aldosterone receptor, also have a potassium-sparing effect.

Disturbances of Salt and Water

Homeostasis

When osmolality remains normal, disturbances of salt and water homeostasis (!B and p. 170) only affect the ECF volume (!B1 and 4). When the osmolality of the ECF increases (hyperosmolality) or decreases (hypoosmolality), water in the extraand intracellular compartments is redistributed (!B2, 3, 5, 6). The main causes of these disturbances are listed in B (orange background). The effects of these disturbances are hypovolemia in cases 1, 2 and 3, intracellular edema (e.g., swelling of the brain) in disturbances 3 and 5, and extracellular edema (pulmonary edema) in disturbances 4, 5 and 6.

rier (!p. 162) reabsorbs NH4+ (instead of K+) so that it remains in the renal medulla. Recirculation of NH4+ through the loop of Henle yields a very high conc. of NH4+ NH3 + H+ towards the papilla (!D3). While the H+ ions are then actively pumped into the lumen of the collecting duct (!A2, D4), the NH3 molecules arrive there by non-ionic diffusion (!D4). The NH3 gradient required to drive this diffusion can develop because the especially low luminal pH value (about 4.5) leads to a much smaller NH3 conc. in the lumen than in the medullary interstitium where the pH is about two pH units higher and the NH3 conc. is consequently about 100-times higher than in the lumen.

Disturbances of acid–base metabolism (see also p. 142ff.). When chronic non-respiratory acidosis of non-renal origin occurs, NH4+ excretion rises to about 3 times the normal level within 1 to 2 days due to a parallel increase in hepatic glutamine production (at the expense of urea formation) and renal glutaminase activity. Non-respiratory alkalosis only decreases the renal NH4+ production and H+ secretion. This occurs in conjunction with an increase in filtered HCO3– (increased plasma concentration, !p. 144), resulting in a sharp rise in HCO3– excretion and, consequently, in osmotic diuresis (!p. 172).

decreased) plasma PCO2 levels result in increased (or decreased) H+ secretion and, thus, in increased (or decreased) HCO3– resorption.

The kidney can also be the primary site of an acid– base disturbance (renal acidosis), with the defect being either generalized or isolated. In a generalized defect, as observed in renal failure, acidosis occurs because of reduced H+ excretion. In an isolated defect with disturbance of proximal H+ secretion, large portions of filtered HCO3– are not reabsorbed, leading to proximal renal tubular acidosis. When impaired renal H+ secretion occurs in the collecting duct, the urine can no longer be acidified (pH !6 despite acidosis) and the excretion of titratable acids and NH4+ is consequently impaired (distal renal tubular acidosis).

C. Excretion of titratable acids

4

0 >0.99 0.8 0.6 0.4 0.2 <0.01

[HPO42–]/total phosphate

1

H+ excretion with phosphate (titratable acidity)

H+

pH

8

7

6

5

4

0 >0.99 0.8 0.6 0.4 0.2 <0.01

[HPO42–]/total phosphate

2

Back titration with NaOH yields amount of H+-Ionen

The Kidney and Acid–Base Balance II