Excretion tubular transporters

A plot of rate of transport against solute concentration in the tubule (Figure 8.3) shows fm, the tubular transport maximum to be analogous with Vmax for an enzyme, which is a maximum rate of solute transport across tubular cells. Assuming a fixed GFR, the point at which the plotted line begins to deviate from linearity, indicates that the substance exceeds a critical threshold concentration and begins to be excreted in the urine. When the plotted line reaches a plateau indicating that saturation point, that is tm has been reached, the rate of excretion is linear with increase in plasma concentration. The concept of fm as described here for tubular reabsorption applies equally well to carrier-mediated secretory processes. If the fm value for a particular is exceeded for any reason, there will be excretion of that solute in the urine. 

Excretion of a solute occurs if its rate of delivery to the tubules exceeds the 1, . Figure 8.3 tm tubular transport kinetics... 

It is important to appreciate that these tubular transport mechanisms are not as well developed in the neonate as in the adult. In addition, their functional capacity may be diminished in the elderly. Thus, compounds normally eliminated by tubular secretion will be excreted more slowly in the very young and in the older adult. This age dependence of the rate of renal drug secretion may have important therapeutic implications and must be considered by the physician who prescribes drugs for these age groups. 

During the first 3 h after Intravenous injection of 1 that followed administration of thiamine, urinary excretion of the oxime was about 12.7% below that during the corresponding period of the control experiment during the remainder of the run, it was 62.2% above that during the same period of the control experiment. Inasmuch as intravenous injection of 900 mg of sodium jg-aminohippurate with I decreased by only 6.3% the urinary excretion of I during the first 3 h after its administration, the tubular transport mechanisms for 1 and for jg-amino-hippurate probably are different. 

Spironolactone also increases Ca excretion through a direct effect on tubular transport. In relatively high concentrations, it can inhibit the biosynthesis of aldosterone. 

Spironolactone competitively inhibits the physiologic effects of the adrenocortical hormone aldosterone on the distal tubules, thereby producing increased excretion of sodium chloride and water, and decreased excretion of potassium, ammonium, titratable acid, and phosphate. Spironolactone is a potassium-sparing diuretic that has diuretic activity only in the presence of aldosterone, and its effects are most pronounced in patients with aldosteronism. Spironolactone does not interfere with renal tubular transport mechanisms, and does not inhibit carbonic anhydrase. 

Roch-Ramel F, Besseghir K, Murer H. Renal excretion and tubular transport of organic anions and cations. In Handbook of physiology, section 8 renal physiology. Windhager EE (editor). Oxford University Press, NewYork/Oxford 1992 p. 2189-2262. Guggino SE, Aronson PS. Paradoxical effects of py razinoate and nicotinate on urate transport in dog renal microvillus membranes. J Clin Invest 1985 76 543-547. 

Cystinuria is an autosomal recessive condition in which there is excessive urinary excretion of cystine because of a defect in proximal renal tubular reabsorption. In the most common form of the disease there is also excess excretion of the dibasic amino acids (lysine, ornithine, and arginine). These share the same renal tubular transporter although their presence in excess in urine appears benign. More rarely, isolated cystinuria is seen. The reader should note that cystinuria should not be confused with cystinosis, which is a condition associated with intracellular accumulation of cystine but not excess urinary excretion of cystine. 

A decline in the urinary excretion of uric acid to a level below the rate of production leads to hyperuricemia and an increased miscible pool of sodium urate. Almost all the urate in plasma is freely filtered across the glomerulus. The concentration of uric acid appearing in the urine is determined by multiple renal tubular transport processes in addition to the filtered load. Evidence favors a four-component model including glomerular filtration, tubular reabsorption, tubular secretion, and postsecretory reabsorption. ... 

As noted previously, nucleosides and nucleoside analogs are used to treat HIV infection as well as certain types of cancers (Table 9.8). Many of these drugs are readily excreted by the kidney. Gonsequently, renal tubular transport of these hydrophilic compounds involves various transport systems. 

Cystinuria is a hereditary disease characterized by the excessive excretion of cystine, lysine, ornithine, and arginine in the urine, probably resulting from a deficiency in the renal tubular transport mechanism. Sir Archibald E. Garrod postulated that cystinuria resulted from a metabolic block involving the oxidation of cystine to sulfate. Later investigations of the pathogenesis of cystinuria demonstrated that the hereditary deficiency does not involve a metabolic block. If a metabolic impairment existed, cystine would be expected to accumulate in the plasma of cystinurics, but plasma levels of cystine are normal or low in cys-... 

Dietary habits and tubular transport defects of urate explain the excessive uric acid excretion of patients with RCN. An alteration of the renal handling of uric acid may be suspected when hyperuricosuria concurs with hypouricemia normal serum uric acid does not exclude a tubular transport defect of urate. 

Four of the subjects with neoplastic disease were studied in more detail (Table 3 and Table 4). In each subject, the ratio of urate creatinine found to be increased (Table 3). There was no evidence of renal glucosuria, hyperphosphaturia, or bicarbonate wasting, which would suggest a generalized defect of tubular transport in these patients (Table 4). One patient, however, patient W.G., had a generalized amino aciduria and another, patient A.H., had an increase in alanine excretion. Two of the patients, J.L. and W.G., with neoplastic disease and an increased Curate/ creatinine ratio had evidence of obstructive jaundice, with plasma bilirubin levels of 15 and 20 mg/100 ml, respectively. In these same two patients with extensive hepatic involvement there was also an increase in the urinary excretion of oxypurines (Table 4). 

Pritchard JB, Miller DS (1992) Proximal tubular transport of organic anions and cations. In Seldin DW, Giebisch G (eds) The kidney physiology and pathophysiology, vol 2, 2nd edn. Raven, New York, p 2921 Rabinowitz MB, Kopple JD, Wetherill GW (1976) Kinetic analysis of lead metabolism in healthy humans. Clin Invest 90 700-706 Roels HA, Boeckx M, Ceulemans E, Lauwerys RR (1991) Urinary excretion of mercury after occupational exposure to mercury vapor and influence of the chelating agent meso-2,3-dimercaptosuccinic acid (DMSA). Br J Ind Med 48 247-253... 

Familial iminoglycinuria is an inborn error in which there is increased excretion of proline, hydroxyproline and glycine in the urine. It is due to defective renal tubular transport of these... 

An imino acid excreted in the urine in large amounts, along with hydroxyproline and glycine, in the inborn error, familial imino-glycinuria. This is due to abnormal renal tubular transport of these compounds. 

The co-administration of drugs which inhibit the transporters involved in renal tubular secretion can reduce the urinaty excretion of drugs which are substrates of the transporter, leading to elevated plasma concentrations of the drugs. For example, probenecid increases the plasma concentration and the duration of effect of penicillin by inhibiting its renal tubular secretion. It also elevates the plasma concentration of methotrexate by the same mechanism, provoking its toxic effects. 

Excretion via the kidney can be a straightforward question of glomerular filtration, followed by passage down the kidney tubules into the bladder. However, there can also be excretion and reabsorption across the tubular wall. This may happen if an ionized form within the tubule is converted into its nonpolar nonionized form because of a change in pH. The nonionized form can then diffuse across the tubular wall into plasma. Additionally, there are active transport systems for the excretion of lipophilic acids and bases across the wall of the proximal tubule. The antibiotic penicillin can be excreted in this way. 

An essential requirement for diffusion of Na+ ions is the creation of a concentration gradient for sodium between the filtrate and intracellular fluid of the epithelial cells. This is accomplished by the active transport ofNa+ ions through the basolateral membrane of the epithelial cells (see Figure 19.4). Sodium is moved across this basolateral membrane and into the interstitial fluid surrounding the tubule by the Na+, K+-ATPase pump. As a result, the concentration of Na+ ions within the epithelial cells is reduced, facilitating the diffusion of Na+ ions into the cells across the luminal membrane. Potassium ions transported into the epithelial cells as a result of this pump diffuse back into the interstitial fluid (proximal tubule and Loop of Henle) or into the tubular lumen for excretion in the urine (distal tubule and collecting duct). 

Tubular secretion is the transfer of substances from the peritubular capillaries into the renal tubule for excretion in urine. This process is particularly important for the regulation of potassium and hydrogen ions in the body it is also responsible for removal of many organic compounds from the body. These may include metabolic wastes as well as foreign compounds, including drugs such as penicillin. Most substances are secreted by secondary active transport. 

Potassium ion secretion. Potassium ions are secreted in the distal tubule and the collecting duct. These ions diffuse down their concentration gradient from the peritubular capillaries into the interstitial fluid. They are then actively transported up their concentration gradient into the tubular epithelial cells by way of the Na+, K+ pump in the basolateral membrane. Finally, potassium ions exit the epithelial cells by passive diffusion through K+ channels in the luminal membrane and enter tubular fluid to be excreted in the urine. 

Male rats are sensitive to renal tubular nephropathy after exposure to hexachloroethane. The lesions observed are characteristic of hyaline droplet nephropathy. They are most likely the result of hexachloroethane or one of its metabolites binding to the excretory protein 2p-globulin, altering its kidney transport, and leading to the formation of hyaline droplets. This protein is synthesized by male rats and accounts for 26% of their urinary protein excretion (Olson et al. 1990). It is not excreted in female rats except in minimal quantities. Since some effects are also seen in kidneys of female rats and in male and female mice that do not synthesize 2p-globulin, hexachloroethane must also have milder adverse effects on the kidney through a different mechanism. 

These active secretory systems are important in drug excretion because charged anions and cations are often strongly bound to plasma proteins and therefore are not readily available for excretion by filtration. However, since the protein binding is usually reversible, the active secretory systems can rapidly and efficiently remove many protein-bound drugs from the blood and transport them into tubular fluid. 

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

A nephron, showing the major sites and percentage (in braces) of sodium absorption along with other features of solute transport. The filtered load = GFR (180 L/day) Xplasma Na+ (140 mEq/L) or 25,200 mEq/day. About 1% of this amount is excreted in voided urine. Sites where tubular fluid is isosmotic, hypertonic, or hypotonic relative to plasma are shown. POT, proximal convoluted tubule LH, loop of Henle DOT, distal convoluted tubule CCD, cortical collecting duct TAL, thick ascending loop. 

The uricosuric drugs (or urate diuretics) are anions that are somewhat similar to urate in structure therefore, they can compete with uric acid for transport sites. Small doses of uricosuric agents will actually decrease the total excretion of urate by inhibiting its tubular secretion. The quantitative importance of the secretory... 

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