Secretory Processes In The Proximal Straight Tubule

The proximal tubule has an important function in secreting many substances that can be regarded as metabolic by-products or potential toxins. Given normal rates of production of some metabolic byproducts, the body requires a renal secretory process to maintain acceptable plasma concentrations. Renal secretory processes serve a more important role in excreting exogenous toxic substances that are ingested in the diet. Secretion of these substances results in an excretion rate that exceeds their rate of filtration, and serves as a means of rapidly clearing them from the plasma. Secreted solutes include many organic acids and bases, creatinine, PAH, radiocontrast agents, and various drugs. In each case, the secretory process involves active accumulation of the solute into proximal tubule cells across the basolateral membrane from the plasma. This active accumulation is driven energetically in different ways, including Na+ cotransport and other cotransport and exchange processes. The accumulation of the solute in the cell provides a favorable electrochemical potential gradient for the solute to move into the tubular lumen, and various transporters located in the brush border membrane facilitate this movement. Secretion of these organic solutes occurs almost exclusively in the straight portion of the proximal tubule, and can produce luminal concentrations that are much higher than their plasma concentrations.

All of these secretory processes, because they are mediated by a fixed number of transporters, are saturable and exhibit the same Tm-limited rates of transport as the active reabsorptive processes discussed earlier. However, it is the rate of secretion rather than reabsorption that reaches a maximum as the plasma concentration increases.

Secretion of Para-Aminohippurate: Measurement of Renal Blood Flow

Of particular interest are those substances that are the most avidly secreted, including para-aminohippurate (PAH) and certain radiocontrast agents. At arterial plasma PAH concentrations of less than 10 mg/dL, blood flowing out of the kidney via the renal vein contains almost no PAH because it is all excreted in the urine. If PAH were cleared only by filtration, the amount excreted could be at most 20% of the amount flowing into the kidney. The greater clearance of PAH is achieved by its secretion from the peritubular capillaries into the lumen of the proximal straight tubule. This secretory process has such a high affinity for PAH that it can reduce the PAH concentration on the blood side of the epithelium to almost zero. Actually, however, the amount of PAH flowing out of the kidney is reduced not to zero but to about 10% of the amount delivered to the kidney via the renal artery. This residual amount is thought to be due to a fraction of the renal blood flow that is not exposed to filtration or secretion because it perfuses nontransporting structures such as the renal capsule.

The significance of the avid secretion of PAH is that this agent can be used as an indicator of renal plasma flow. If we assume that 100% of the PAH entering the kidney is excreted in the urine, then the amount excreted must be equal to the amount entering the kidney, which is the product of the renal plasma flow (RPF, mL/min) and

Excretion Pah

FIGURE 15 PAH secretion in the proximal tubule. The rates of PAH filtration, secretion, and excretion are plotted as a function of the plasma PAH concentration. In calculating the rate of filtration, a constant GFR of 130 mL/min is assumed. The excretion rate of PAH is always higher than the filtration rate because of the contribution of secretion in the proximal tubule; however, as the plasma PAH concentration rises above 10 mg/dL, the rate of secretion approaches a Tm of approximately 80 mg/mm. When the Tm is exceeded, the rate of excretion parallels the rate of filtration.

FIGURE 15 PAH secretion in the proximal tubule. The rates of PAH filtration, secretion, and excretion are plotted as a function of the plasma PAH concentration. In calculating the rate of filtration, a constant GFR of 130 mL/min is assumed. The excretion rate of PAH is always higher than the filtration rate because of the contribution of secretion in the proximal tubule; however, as the plasma PAH concentration rises above 10 mg/dL, the rate of secretion approaches a Tm of approximately 80 mg/mm. When the Tm is exceeded, the rate of excretion parallels the rate of filtration.

the arterial PAH concentration (PPAH, converted to units of mg/mL). The amount excreted will be the product of the urine PAH concentration (UPAH) and UF. Thus:

PpAH

In other words, the clearance of PAH is equal to the renal plasma flow. Actually, it is an underestimate by 10-15% because not all of the PAH entering the kidney is excreted. Nevertheless, this is a good index of the rate of renal blood flow.

As noted earlier, PAH is excreted completely only at arterial concentrations of less than 10 mg/dL. This is because the secretory process is saturable, as illustrated in Fig. 15. At concentrations less than 10 mg/dL, the rate of PAH excretion rises linearly with plasma concentration, and virtually all of the PAH entering the kidney is excreted. The rate of secretion of PAH, which is determined as the difference between the rate of excretion and the rate of filtration, thus also rises linearly. But above this plasma concentration, the rate of secretion falls off and reaches a maximum of about 80 mg/min, referred to as the secretory Tm. The Tm is reached when all the basolateral membrane transporters involved in the secretion of PAH are saturated. This Tm, as is the case for reabsorptive processes, is a function of the total number of functioning nephrons and decreases with the loss of nephrons in renal failure.

The renal plasma flow is an important clinical index. It can be decreased by partial occlusion of the renal vasculature or by a reduction in renal mass as occurs in renal failure. However, because of the difficulty in determining plasma PAH concentrations in the clinical laboratory, it is used primarily for laboratory or clinical research protocols. In clinical practice, it is more convenient to use the excretion of radiocontrast agents as rough indicators of renal plasma flow. Because these agents are secreted, their rate of clearance is proportional to the renal plasma flow and the functional renal mass. For example, the time required to excrete a bolus of the radiocontrast agent given during renal angiogra-phy is measured and compared with a standard to obtain an index of renal plasma flow. Radioisotope scans are also used for this purpose.

Urate

The renal excretion of urate is also determined largely by secretion into the proximal tubule, although in the normal individual, the rate of urate excretion is lower than its rate of glomerular filtration, indicating that it is reabsorbed along the nephron. However, the excretion of urate actually depends on the balance of opposing reabsorptive and secretory transport processes in the proximal tubule. Both processes involve active urate transport, and the net excretion of urate is determined by which process dominates. The secretory process is the one that is physiologically regulated to maintain a normal plasma urate concentration in the face of changing dietary intake and metabolic production. Thus, when there is an excess of urate, secretion is stimulated, and it is decreased when there is a deficit.

Secretion of Organic Acids and Bases

Many other organic acids and bases, including many not normally found in the body, can be secreted into the proximal tubule. Coupled with hepatic metabolism, renal filtration and secretion processes are essential for clearing potentially harmful substances from the blood. However, many drugs are also cleared rapidly from the body by secretion in the proximal tubule. Sometimes this is helpful, as in the case of diuretics. Because of tubular secretion, the most widely used diuretics reach an effective concentration in the tubular fluid without requiring potentially harmful plasma concentrations. In the case of other drugs such as salicylates, the penicillinlike antibiotics, and sulfonamides, secretion tends to clear the drug rapidly and can be a problem in achieving an optimal plasma concentration. In such cases, probe-necid, a competitive inhibitor of the secretory transporter, can be administered to reduce secretion.

Because the doses of most drugs are based on the assumption of normal renal function, care must be exercised in adjusting the doses for the patient with renal failure. Because of the reduction of functioning renal mass by disease, there is a decreased rate of filtration and secretion of drugs. For those drugs that are cleared from the plasma primarily by the kidney, dosages must be adjusted downward in consideration of the decreased renal clearance.

Suggested Reading

Berry CA, Ives HE, Rector FC Jr. Renal transport of glucose, amino acids, sodium, chloride, and water. In Brenner MB, ed. The kidney, 5th ed. Philadelphia: WB Saunders, 1996, pp 334-370.

Hamm LL, Alpern RJ. Cellular mechanisms of renal tubule acidification. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 1, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1935-1980.

Sackin H, Palmer LG. Epithelial cell structure and polarity. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 1, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 533-568.

Schafer JA. Transepithelial osmolality differences, hydraulic conductivities and volume absorption in the proximal tubule. Annu Rev Physiol 1990;52:709-726.

Weinstein AM. Sodium and chloride transport: Proximal nephron. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 2, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1287-1332.

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