Reabsorption, Secretion and the Proximal Tubule
In a healthy adult, ∼180 L of filtrate enters the proximal tubules daily. A significant component must be reabsorbed to prevent the loss of water and solutes. The filtrate is progressively modified as it passes through the nephron by the reabsorption of substances into the blood.
The proximal tubule (Fig. 33a)
Most glucose, amino acids, phosphate and bicarbonate is reabsorbed in the proximal tubule, together with 60–70% of Na+, K+, Ca2+, urea and water. The secretion of H+ and reabsorption of HCO3 are disand secretion into the tubular fluid. The net reabsorption or secretion of any substance can be determined from its clearance (Chapter 32).
Tubular transport processes
Reabsorption and secretion involve the transport of substances across the tubular epithelium; this occurs either by diffusion through tight junctions and lateral intercellular spaces (paracellular pathway), driven by concentration, osmotic or electrical gradients, or by active cussed in detail in Chapter 36.
Sodium. The concentration of Na+ in the filtrate is ∼140 mmol/L (= plasma Na+ concentration), but is much lower in the cytosol of epithe- lial cells (∼10–20 mmol/L), which is also negatively charged. The electrochemical gradient therefore favours the movement of Na+ from the filtrate into the cells, providing the driving force for the secondary transport of other substances. About 80% of Na+ entering proximal tubular cells exchanges for H+ (Na+–H+ antiporter). The secretion of transport through the epithelial cells themselves (transcellular path H+ in the proximal tubule plays a critical role in HCO3 Reabsorption ways) (Fig. 33a). The latter usually involves an active process on either the apical or basolateral cell membrane, with passive diffusion across the opposite membrane driven by the concentration gradient so created. The movement of solutes between the peritubular space and capillaries is by bulk flow and diffusion (Chapter 11); the movement (Fig. 33a; Chapter 36). Na+ is removed from tubular cells by Na+ pumps primarily on the basolateral membrane, thus transporting Na+ into the interstitial fluid. However, only ∼20% of transported Na+ diffuses into the capillaries, as there is significant backflux into the tubule via paracellular pathways. of water is influenced by Starling’s forces (Chapter 23).
Water. Water is not actively reabsorbed. As Na+ and HCO3 are Active transport involves proteins called transporters that trans- locate substances across the cell membrane (Fig. 33b; Chapter 4). Primary active transport uses adenosine triphosphate (ATP) directly, e.g. the Na+–K+ ATPase (Na+ pump). Secondary active transport uses the concentration gradient created by primary active transport as an energy source. This is most commonly the Na+ gradient created by the Na+ pump, and the latter therefore plays a critical role in renal reabsorption and secretion. Symporters (or cotransporters) transport substances in the same direction as (for example) Na+, whereas antiporters transport in the opposite direction (Chapter 4; Fig. 33b).
The rate of diffusion across cell membranes is enhanced by ion channels and uniporters (transporters carrying only one substance), which effectively increase membrane permeability to specific sub- stances; this is termed facilitated diffusion, and may be modulated by hormones or drugs.
Tubular transport maximum
There is a limit to the rate at which any transporter can operate, and so, for any substance, there is a maximum rate of reabsorption or secretion, called the tubular transport maximum (Tm). For example, glucose is normally completely reabsorbed in the proximal tubule and none is excreted in the urine (see below). However, when the filtrate glucose concentration rises above the renal threshold, the transporters start to saturate, and glucose appears in the urine (Fig. 33c). Once Tm is reached, excretion increases linearly with filtration. The threshold concentration is somewhat lower than that required to reach Tm because of the variation in transport maxima between nephrons; this is called splay. Secretory mechanisms also exhibit Tm. For example, at low concentrations, para-aminohippuric acid (PAH) is almost completely removed from capillary blood by filtration and secretion (Chapter 32). At higher concentrations secretion becomes saturated, and further excretion is limited to the filtered load (Fig. 33d). transported from the tubule into the peritubular interstitial fluid, the osmolality of the latter increases, whilst that of the tubular fluid decreases. This osmotic pressure difference causes the reabsorption of water via both transcellular and paracellular pathways.
The reabsorption of water increases tubular concentrations of Cl−, K+, Ca2+ and urea, which therefore diffuse down their concentration gradients into the peritubular space, largely via paracellular pathways, although the route for Ca2+ may be transcellular. The final two-thirds of the proximal tubule has increased permeability to Cl−, facilitating Cl− reabsorption. This makes the lumen more positive, enhancing the reabsorption of cations. As the reabsorption of Na+, Cl−, K+, Ca2+ and urea in the proximal tubule is closely coupled to the reabsorption of water, their concentrations (and the total osmolality) are similar in the fluid leaving the proximal tubule to those in the filtrate and plasma, although their total quantity and the fluid volume are decreased by ∼70%.
Glucose. Glucose is reabsorbed by cotransport with Na+ across the apical membrane of epithelial cells, and then diffuses out of the cells into the peritubular interstitium. The Tm for glucose is ∼380 mg/min (∼21 mmol/min), and the renal threshold is ∼11 mmol L−1. The appearance of glucose in the urine reflects hyperglycaemia (high plasma glucose), a sign of diabetes mellitus.
Amino acids. Amino acids are reabsorbed by several Na+-linked symporters, specific for acidic, basic and neutral amino acids.
Phosphate. Phosphate is cotransported with Na+ across the epithelial apical membrane. Its Tm is close to the filtered load, and so an increase in plasma concentration leads to excretion. Phosphate reab- sorption is decreased by parathyroid hormone. Organic acids and bases. These include metabolites (e.g. bile salts, urate, oxalate) and drugs (e.g. PAH, penicillins, aspirin) and are secreted. Organic acids are transported from the peritubular fluid into tubular cells by cotransport with Na+, and diffuse into the tubule in exchange for anions (e.g. Cl−, HCO −). Organic bases are actively extruded from the apical membrane in exchange for Na+ or H+.