Kok

c T3

Reabsorption of Organic Substances

The filtered load of a substance is the product of its plasma concentration and GFR. Since the GFR is high (ca. 180 L/day), enormous quantities of substances enter the primary urine each day (e.g., 160 g/day of D-glucose).

Fractional excretion (FE, ^ p. 154) of D-glu-cose is very low (FE ~ 0.4%). This virtually complete reabsorption is achieved by secondary active transport (Na+-glucose symport) at the luminal cell membrane (^ B and p. 29 B1). About 95% of this activity occurs in the proximal tubule. If the plasma glucose conc. exceeds 10-15 mmol/L, as in diabetes mellitus (normally 5 mmol/L), glucosuria develops, and urinary glucose conc. rises (^ A). Glucose reabsorption therefore exhibits saturation kinetics (Michaelis-Menten kinetics; ^ p. 28). The above example illustrates prerenal glucosuria. Renal glucosuria can also occur when one of the tubular glucose carriers is defective.

Low-affinity carriers in the luminal cell membrane of the pars convoluta (sodium-glucose transporter type 2 = SGLT2) and high-affinity carriers (SGLT1) in the pars recta are responsible for D-glucose reabsorption. The co-transport of D-glucose and Na+occurs in each case, namely at a ratio of 1 : 1 with SGLT2 and 1 : 2 with SGLT1. The energy required for this form of secondary active glucose transport is supplied by the electrochemical Na+ gradient directed towards the cell interior. Because of the co-transport of two Na+ ions, the gradient for SGLT1 is twice as large as that for SGLT2. A uniporter (GLUT2 = glucose transporter type 2) on the blood side facilitates the passive transport of accumulated intracellular glucose out of the cell (facilitated diffusion, ^ p. 22). D-galactose also makes use of the SGLT1 carrier, while D-fructose is passively absorbed by tubule cells (GLUT5).

The plasma contains over 25 amino acids, and about 70 g of amino acids are filtered each day. Like D-glucose, most L-amino acids are reabsorbed at proximal tubule cells by Na+-coupled secondary active transport (^ B and p. 29 B3). At least 7 different amino acid transporters are in the proximal tubule, and the specificities of some overlap. Jmax and Km (^ p. 28) and, therefore, saturability and reabsorption capacities vary according to the type of amino acid and carrier involved. Fractional excretion of most amino acids ~ to 1% (ranging from 0.1% for L-valine to 6% for L-histidine).

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, theywill start to precipitate (increasing the risk ofurinarycalculus formation). Likewise, the excessive urinaryexcretion of cystine can lead to cystine calculi.

Oligopeptides such as glutathione and angio-tensin II are broken down so quickly by luminal peptidases in the brush border that they can be reabsorbed as free amino acids (^ C1 ). Dipep-tides resistant to luminal hydrolysis (e.g., car-nosine) 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 dipep-tides 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 (180L/day-45 g/L-0.0003 = 2400mg/day). Only 2 to 35 mg of albumin are excreted each day (FE ~ 1%). In the proximal tubule, albumin, lysozyme, ^-microglobulin, ^-microglobulin and other proteins are reabsorbed by receptor-mediated 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 receptor-mediated endocytosis (^ p. 292).

i- A. Reabsorption of glucose and amino acids -.

glucose

Maximum reabsorption Reabsorbed 2 rate__

glucose

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