Renal processing

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The kidneys selectively secrete dead-end products of nutrient metabolism, such as urea and uric acid metabolize nutrients and other compounds, and regulate blood volume and acid-base balance. The list of nutrients and nutrient-like compounds whose availability is at least partly determined by the kidney includes vitamin D, creatine, sodium, chloride, potassium, calcium, phosphate, and magnesium.

Abbreviations

Renal anatomy

The kidneys are a pair of bean-shaped organs, which contain about a million individual microscopic functional units, the nephrons. Each nephron consists of a tangle of capillaries inside a capsule (Bowman's capsule) connected to a series of tubules (proximal tubule, loop of I lenle, distal tubule, collecting duct) that eventually drain into the ureter.

The filtering layer of the glomerulus is formed by the fenestrated capillary endothelium, an extracellular glomerular basement membrane, and a layer of specialized epithelial cells called podoeytes (Smoyer and Mundet, 1998). The podocyte foot processes are tightly connected to the basement membrane in a typical interlaced pattern. Small slit-like areas between the foot processes are thinned to a narrow diaphragm formed of rod-like units with some similarity to the tight junctions connecting tubular epithelial cells. This arrangement allows the unhindered passage of w ater and solutes up to a molecular weight of about 5-6 kDa. As their size increases, molecules are less likely to pass through the slits. Only a negligible percentage of albumin and similarly sized proteins crosses into the ultraflltrate (Rose. 1989). The resulting ultraflltrate passes into Bowman's space and from there into the proximal tubule. The amount of ultraflltrate produced per minute is the glomerular filtration rate (GFR). Healthy kidneys in young women produce about 95ml of ultraflltrate per minute. Men produce slightly more (I20ml minute), because they are heavier on average. GFR declines with age. both due to non-specific processes and disease-typical glomerular deterioration.

A healthy 70 kg man w ith a GI R of 120ml. minute produces about 1731 ofullraliltrate per day, which contains large amounts of small solutes. This corresponds to many times a typical day's intake not only of water, but also of essential nutrients such as sodium (5f>0g). potassium (>25 g), calcium l>8g), or vitamin 15 (>1000|lg).

rhe proximal tubule extends from the glomerulus to the loop of Henle, Characteristics of its epithelial cells change from the early convoluted segment (SI cells), to the

PTH RBP TAUT VBP

ANP AQP GFR

atrial natriuretic peptide aquaporin glomerular filtration rate 25-hydroxy-vitamin D 1,25-dihydroxyvitamin D parathyroid hormone retinol-binding protein taurine transporter (SLC6A6) vitamin D*bindmg protein macula densa macula densa

Pars Recta

late convoluted segment and early straight (pars recta) segment (S2 cells), and laic straight segmeni (S3 cells). The apical membrane facing the tubular lumen is folded (microvilli) and covered by protrusions (brush border). The basolateral membrane is adjacent to the interstitium and peritubular capillaries. Tight junctions, strand-like structures, seal the space between the epithelial cells near the luminal side. The light junctions of the proximal tubular epithelial cells arc more permeable for water and electrolytes than the tight junctions downstream (Gumbiner, 19X7), About 1001 d of water (two-thirds of the amount littered by the glomeruli) is reabsorbed from the proximal tubule, along with electrolytes, minerals and trace elements, glucose, amino acids, vitamins, and other filtered plasma constituents.

The loop of I lenle is a hairpin arrangement that extends from the renal cortex into the medulla and consists of the narrow-bore descending and thin ascending limbs followed by the thick ascending limb. Adjacent to the loops are the vasa recta, which start from glomeruli near the cortex medulla interface, extending into the medulla, and returning into the cortex along with the ascending limb of the loop. The capillaries are fully permeable to small and medium-sized molecules. This is the site where further sodium chloride and water is reabsorbed by countercurrent exchange. Intraluminal osmolality greatly increases towards the tip of the loop, reaching as much as 12(K)mosmol I. High intracellular concentrations of osmolytes, including sorbitol.

myoinositol, taurine and betaine, protect the Henle loop epithelia from the potentially disastrous effects of an excessive osmolar gradient. The import of myoinositol and betaine is mediated hy their respective transporters, sodium-dependent myo-inositol transporter (SLC5A3) and betaine transporter BGTl (SLC6A12, sodium chloride dependent); taurine is taken up via the taurine transporter (TAUT. SLC6A6); sorbitol is produced locally (Bitoun et <//.. 2001).

The distal tubule extends from the macula densa (an important site for blood volume regulation) to the connecting segment. The tight junctions between ils epithelial cells, as those of the following segments, prevent most uncontrolled paracellular movement of electrolytes from the highly concentrated luminal lluid into blood. Another 5"i> of the originally filtered sodium chloride is reabsorbed here. Residual amino acids and other complex organic compounds can still be recovered from this nephron segment.

The connecting segment contributes to calcium recovery (driven by a calcium-transporting ATPase at the basolateral membrane), absorbs some sodium, and reabsorbs calcium.

About two-thirds of cells forming the cortical collecting tubule are principal cells with the ability to further modify the electrolyte content of the luminal contents. Intercalated cells, the remainder of the cells in the conical collecting tubule, contribute to sodium-independent acid-base balance. Intercalated cells differ from more proximal tubular cells in that their ATPases (proton and potassium-transporting) are located at the luminal rather than the peritubular membrane.

The medullary collecting tubule modifies urine composition further by adjusting its water, electrolyte and proton content as needed. Water recovery from the inner medullar segment is Under the control of antidiuretic hormone.

Salvage of complex nutrients

Complex nuirients are recovered very efficiently from ultraflltrate in the proximal renal lumen as long as intake levels are modest and renal function is normal. Some of this reabsorptive activity continues in parts of the distal tubule. The luminal side of the tubular epithelial cells has a brush border membrane with numerous specific transport systems that mediate the uptake of carbohydrates, proteins and amino acids, vitamins and most other essential nutrients. In many instances these are the same systems that also mediate nutrient uptake across the small intestinal brush border membrane. The major driving force for uptake from the lumen into the tubular epithelial cells is the low intracellular sodium concentration that is maintained by sodium/potassium ATPase at the basolateral membrane of both proximal and distal tubular cells. Additional gradients involved in tubular reuptake include protons, formate, and an electric potential difference which favors inflow of cations. Receptor-mediated pinocytosis is another important mechanism of concentrative transport.

In most cases a distinct set of transporters and channels then mediates the transport oui of the epithelial cell across the basolateral membrane, this time mainly driven by the concentration gradient of the transported molecules, by anliport mechanisms, or by active transport. Once they have reached the basolateral intercellular space the molecules can then move into the luminal space of peritubular blood capillaries by simple diffusion. Neither the basement membrane adjacent to the tubular cell layer nor the (fenestrated) epithelium of the capillaries constitutes a significant barrier to this last step of solute transfer from tubular lumen to capillary lumen. Carbohydrates. The sugar content of the ultra filtrate reflects the composition of plasma, since these small molecules are readily filtered. Recovery of D-glucose and D-galaetosc from the lumen via sodium/glucose cotransporters proceeds with high capacity and low affinity in segments SI and S2 of the proximal tubule, and with low capacity but high affinity in segment S3. Glucose salvage becomes noticeably incomplete (i.e. glucose appears in urine) when the concentration in blood exceeds about 180mg dl; this threshold rises asGI R decreases (Rose. IMS'). 102 .1). Fructose crosses the brush border membrane v ia its own transporter. GLUT? (Mate et al., 2001). D-mannose uptake across the brush border membrane proceeds via a sodium-dependent transporter distinct from the sodium-glucose transporters. Its renal recovery is a critical element for the regulation of D-mannose homeostasis (Blasco ft ul.. 20U0),

Alt major sugars are transferred across the basolateral membrane by the glucose transporter 2 (GLUT2),

Citrate: I he sodium dicarboxylate cotransporter (NalX'-l, SLC13A2) in the proximal tubule mediates citrate recovery. The efficiency of tilts process is determined by actd base balance, increasing with acidosis. Since citrate competes with phosphate and oxalate for binding to calcium, its residual concentration in urine contributes to protection against calcium oxalate and calcium phosphate stone formation (Coe and Parks, 1988) Daily citrate excretion typically is several hundred milligrams (Schwille eft//.. 1979),

Proteins and ammo aads: Several specific proteins, including retinol-binding protein, vitamin D-binding protein, transcobalamin-H, insulin, and lysozyme, are taken up intact by megalin-mediated endocytosis as described in more detail below.

Most of the smaller proteins are hydrolyzed by various brush border exoenzymes, including membrane Pro-X carboxypcptidase (EC 3.4.17.1 (i) and angiotensin I-converting enzyme (ACE; EC3.4,15.1).

Two distinct sodium peptide eotransportcrs then mediate the tipuike of di- and tripepiides. but not of free amino acids. Sodium peptide cotransporter I (PepTl, SLC15AI) in the SI segment of the proximal tubule has lower affinity for the oligopeptides than sodium peptide cotransporter 2 (PepT2. SLCI5A2) in the S3 segment (Shen ct al., 1999).

Neutral amino acids enter epithelial cells mainly via the sodium-dependent neutral amino acid transporters B (Avissar et al.. 2001). ASCT2, and B *. Glutamate and aspartate use the HA ACL X transport system. The sodium-dependent transporters (JAT-1 and GAT-3, which are better know n for their role m neurotransmitter recov ery in brain, ferry gamma-ami no butyric acid (GABA). hypotaurine. and beta-alanine across the proximal tubular brush border membrane (Vluth et ul.. 1998). Proline, hydroxy proline, taurine, and beta-alanine arc taken up by the sodium-dependent imino transporter (Urdaneta et ul.. 1998), and helaine enters via the sodium- and chloride-dependent betaine transporter (SLC6A12). Taurine uptake via the taurine transporter (TAUT, SLC6Ab) is sodium- and chloride-dependent (Chesney et ul., 1990). High peptides peptides proteins, lipids vitamins

Enterocyie [Na ] low

Intestinal lumen [Na ] high

Brush border membrane proteins, lipids vitamins

Intestinal lumen [Na ] high

Ca2' ATPase

^ sugars, amino acids, vitamins sugars, ammo acids, vitamins amino acids

3 Na

3 Na amino acids amino acids

Enterocyie [Na ] low

Brush border membrane

Baso late ral membrane

Capillary endothelium

Capillary lumen [Na ] high receptor-mediated

ATP-driven transpon antiport, exchanger

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