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

Reabsorption of Organic Substances

Increased urinary excretion of amino acids (hyperaminoaciduria) can occur. Prerenal hyperaminoaciduria occurs when plasma amino acid concentrations are elevated (and reabsorption becomes saturated, as in A), whereas renal hyperaminoaciduria occurs due to deficient transport. Such a dysfunction may be specific (e.g., in cystinuria, where only L-cystine, L- arginine and L-lysine are hyperexcreted) or unspecific (e.g., in Fanconi’s syndrome, where not only amino acids but also glucose, phosphate, bicarbonate etc. are hyperexcreted).

Certain substances (lactate, sulfate, phosphate, dicarboxylates, etc.) are also reabsorbed at the proximal tubule by way of Na+ symport, whereas urea is subject to passive back diffusion (!p. 166). Urate and oxalate are both reabsorbed and secreted (!p. 160), with the predominant process being reabsorption for urate (FE !0.1) and secretion for oxalate (FE !1). If the urinary conc. of these poorly soluble substances rises above normal, they will start to precipitate (increasing the risk of urinary calculus formation). Likewise, the excessive urinary excretion of cystine can lead to cystine calculi.

Oligopeptides such as glutathione and angiotensin II are broken down so quickly by luminal peptidases in the brush border that they can be reabsorbed as free amino acids (!C1). Dipeptides resistant to luminal hydrolysis (e.g., carnosine) must be reabsorbed as intact molecules. A symport carrier (PepT2) driven by the inwardly directed H+ gradient (!p. 174) transports the molecules into the cells tertiary active H+ symport; !p. 26, 29 B4). The dipeptides are then hydrolyzed within the cell (!C2). The PepT2 carrier is also used by certain drugs and toxins.

Proteins. Although albumin has a low sieving coefficient of 0.0003 (!p. 154, 2400 mg/ day are filtered at a plasma conc. of 45 g/L (180 L/day · 45 g/L · 0.0003 = 2400 mg/day). Only 2 to 35 mg of albumin are excreted each day (FE !1%). In the proximal tubule, albumin, lysozyme, α1-microglobulin, "2-microglobulin and other proteins are reabsorbed by receptormediated endocytosis (!p. 28) and are “digested” by lysosomes (!D). Since this type of reabsorption is nearly saturated at normal filtered loads of proteins, an elevated plasma protein conc. or increased protein sieving coefficient will lead to proteinuria.

25-OH-cholecalciferol, which is bound to DBP (vitamin D-binding protein) in plasma and glomerular filtrate, is reabsorbed in combination with DBP by re- ceptor-mediated endocytosis (!p. 292).

Excretion of Organic Substances

tion curve reaches plateau, and slope of PAH excretion curve decreases). Some organic anions (e.g., urate and oxalate) and cations (e.g., choline) are both secreted and reabsorbed (bidirectional transport), which results in net reabsorption (urate, choline) or net secretion (oxalate).

The secreted organic anions (OA–) include indicators such as PAH (p-aminohippurate; !p. 150) and phenol red; endogenous substances such as oxalate, urate, hippurate; drugs such as penicillin G, barbiturates, and numerous diuretics (!p. 172); and conjugated substances (see above) containing glucuronate, sulfate or glutathione. Because of its high affinity for the transport system, probenecid is a potent inhibitor of OA– secretion.

The active step of OA– secretion (!B) occurs across the basolateral membrane of proximal tubule cells and accumulates organic anions in the cell whereby the inside-negative membrane potential has to be overcome. The membrane has a broad specificity carrier (OAT1 = organic anion transporter type 1) that transports OA– from the blood into the tubule cells in exchange for a dicarboxylate, such as succinate2– or α-ketoglutarate2 –; !B1). The latter substance arises from the glutamine metabolism of the cell (!p. 177 D2); the human Na+-dicarboxylate transporter hNADC-1 also conveys dicarboxylates (in combination with 3 Na+) into the cell by secondary active transport (!B2). The transport of OA– is therefore called tertiary active transport. The efflux of OA– into the lumen is passive (facilitated diffusion; !B3). An ATP-dependent conjugate pump (MRP2 = multi-drug resistance protein type 2) in the luminal membrane is also used for secretion of amphiphilic conjugates, such as glutathione-linked lipophilic toxins (!B4).

The organic cations (OC+) secreted include endogenous substances (epinephrine, choline, histamine, serotonin, etc.) and drugs (atropine, quinidine, morphine, etc.).

The active step of OC+ secretion occurs across the luminal membrane of proximal tubule cells (luminal accumulation occurs after overcoming the negative membrane potential inside the cell). The membrane contains (a) direct ATP-driven carriers for organic cations (mdr1; primary active OC+ transport; !C1) and (b) a multispecific OC+/H+ antiporter (tertiary active transport; !C2). The OC+ diffuse passively from the blood into the cell by way of a polyspecific organic cation transporter (OCT; !C3).

A. Secretion and excretion of p-aminohippurate (PAH)

B. Secretion of organic anions (OA–)

C. Secretion of organic cations (OC+)

Plate 7.7 Excretion of Organic Substances

161

7 Kidneys, Salt, and Water Balance

162

Plate 7.9 Water Reabsorption, Concentration of Urine I

165

Along the course of the distal convoluted tubule and, at the latest, at the connecting tubule, which contains aquaporins and ADH receptors of type V2 (explained below), the fluid in the tubule will again become isotonic (in osmotic balance with the isotonic interstice of the renal cortex) if ADH is present (!p. 168), i.e., when antidiuresis occurs. Although Na+ and Cl– are still reabsorbed here (!p. 162), the osmolality does not change significantly because H2O is reabsorbed (ca. 5% of the GFR) into the interstitial space due to osmotic forces and

166urea increasingly determines the osmolality of the tubular fluid.

Final adjustment of the excreted urine volume occurs in the collecting duct. In the presence of antidiuretic hormone, ADH (which binds to basolateral V2 receptors, named after vasopressin, the synonym for ADH), aquaporins (AQP2) in the (otherwise water-impermeable) luminal membrane of principal cells are used to extract enough water from the urine passing through the increasingly hypertonic renal medulla. Thereby, the Uosm rises about four

times higher than the Posm (Uosm/Posm !4), corresponding to maximum antidiuresis. The ab-

sence of ADH results in water diuresis, where

Uosm/Posm can drop to !0.3. The Uosm can even fall below the osmolality at the end of TAL,

since reabsorption of Na+ and Cl– is continued in the distal convoluted tubule and collecting duct (!p. 162) but water can hardly follow.

Urea also plays an important role in the formation of concentrated urine. A protein-rich diet leads to increased urea production, thus increased the urine-concentrating capacity of the kidney. About 50% of the filtered urea leaves the proximal tubule by diffusion (!C). Since the ascending limb of the loop of Henle, the distal convoluted tubule, and the cortical and outer medullary sections of the collecting duct are only sparingly permeable to urea, its conc. increases downstream in these parts of the nephron (!C). ADH can (via V2 receptors) introduce urea carriers (urea transporter type 1, UT1) in the luminal membrane, thereby making the inner medullary collecting duct permeable to urea. Urea now diffuses back into the interstitium (where urea is responsible for half of the high osmolality there) via UT1 and is then transported by UT2 carriers back into the descending limb of the loop of Henle, comprising the recirculation of urea (!C). The non-re-

absorbed fraction of urea is excreted: FEurea ! 40%. Urea excretion increases in water diuresis

and decreases in antidiuresis, presumably due to up-regulation of the UT2 carrier.

Urine concentration disorders primarily occur due to (a) excessive medullary blood flow (washing out Na+, Cl– and urea); (b) osmotic diuresis; (c) loop diuretics (!p. 172); (d) deficient secretion or effectiveness of ADH, as seen in central or peripheral diabetes insipidus, respectively.

Plate 7.10 Water Reabsorption, Concentration of Urine II