++
The working structures of the kidney are the nephrons and collecting tubules into which the nephrons drain. Figure 1–7 illustrates the meaning of several key words that we use to describe how the kidneys function. It is essential that any student of the kidney grasp their meaning.
++
++
Filtration is the process by which water and solutes in the blood leave the vascular system through the filtration barrier and enter Bowman's space (a space that is topologically outside the body). Secretion is the process of transporting substances into the tubular lumen from the cytosol of epithelial cells that form the walls of the nephron. Secreted substances may originate by synthesis within the epithelial cells or, more often, by crossing the epithelial layer from the surrounding renal interstitium. Reabsorption is the process of moving substances from the lumen across the epithelial layer into the surrounding interstitium.1 In most cases, reabsorbed substances then move into surrounding blood vessels, so that the term reabsorption implies a 2-step process of removal from the tubular lumen followed by movement into the blood. Excretion means exit of the substance from the body (ie, the substance is present in the final urine produced by the kidneys). Synthesis means that a substance is constructed from molecular precursors, and catabolism means the substance is broken down into smaller component molecules. The renal handling of any substance consists of some combination of these processes.
+++
Glomerular Filtration
++
Urine formation begins with glomerular filtration, the bulk flow of fluid from the glomerular capillaries into Bowman's capsule. The glomerular filtrate (ie, the fluid within Bowman's capsule) is very much like blood plasma, but contains very little total protein because the large plasma proteins like albumin and the globulins are virtually excluded from moving through the filtration barrier. Smaller proteins, such as many of the peptide hormones, are present in the filtrate, but their mass in total is miniscule compared with the mass of large plasma proteins in the blood. The filtrate contains most inorganic ions and low-molecular-weight organic solutes in virtually the same concentrations as in the plasma. Substances that are present in the filtrate at the same concentration as found in the plasma are said to be freely filtered. (Note that freely filtered does not mean all filtered. It just means that the amount filtered is in exact proportion to the fraction of plasma volume that is filtered.) Many low-molecular-weight components of blood are freely filtered. Among the most common substances included in the freely filtered category are the ions sodium, potassium, chloride, and bicarbonate; the uncharged organics glucose and urea; amino acids; and peptides such as insulin and antidiuretic hormone.
++
The volume of filtrate formed per unit time is known as the GFR. In a healthy young adult male, the GFR is an incredible 180 L/day (125 mL/min)! Contrast this value with the net filtration of fluid across all the other capillaries in the body: approximately 4 L/day. The implications of this huge GFR are extremely important. When we recall that the average total volume of plasma in humans is approximately 3 L, it follows that the entire plasma volume is filtered by the kidneys some 60 times a day. The opportunity to filter such huge volumes of plasma enables the kidneys to excrete large quantities of waste products and to regulate the constituents of the internal environment very precisely. One of the general consequences of healthy aging as well as many kidney diseases is a reduction in the GFR (see Chapter 3).
+++
Tubular Reabsorption and Tubular Secretion
++
The volume and composition of the final urine are quite different from those of the glomerular filtrate. Clearly, almost all the filtered volume must be reabsorbed; otherwise, with a filtration rate of 180 L/day, we would urinate ourselves into dehydration very quickly. As the filtrate flows from Bowman's capsule through the various portions of the tubule, its composition is altered, mostly by removing material (tubular reabsorption) but also by adding material (tubular secretion). As described earlier, the tubule is, at all points, intimately associated with the vasculature, a relationship that permits rapid transfer of materials between the capillary plasma and the lumen of the tubule via the interstitial space.
++
Most of the tubular transport consists of reabsorption rather than tubular secretion. An idea of the magnitude and importance of tubular reabsorption can be gained from Table 1–2, which summarizes data for a few plasma components that undergo reabsorption. The values in Table 1–2 are typical for a healthy young adult on an average diet. There are at least 3 important generalizations to be drawn from this table:
++
Because of the huge GFR, the quantities filtered per day are enormous, generally larger than the amounts of the substances in the body. For example, the body of a 70-kg person contains about 42 L of water, but the volume of water filtered each day may be as large as 180 L.
Reabsorption of waste products, such as urea, is partial, so that large fractions of their filtered amounts are excreted in the urine.
Reabsorption of most “useful” plasma components (eg, water, electrolytes, and glucose) is either complete (eg, glucose), or nearly so (eg, water and most electrolytes), so that very little of the filtered amounts are excreted in the urine.
++
++
For each plasma substance, a particular combination of filtration, reabsorption, and secretion applies. The relative proportions of these processes then determine the amount excreted. A critical point is that the rates of these processes are subject to physiological control. By triggering changes in the rates of filtration, reabsorption, or secretion when the body content of a substance goes above or below normal, these mechanisms regulate excretion to keep the body in balance. For example, consider what happens when a person drinks a large quantity of water: Within 1 to 2 hours, all the excess water has been excreted in the urine, partly as the result of an increase in GFR but mainly as the result of decreased tubular reabsorption of water. The body is kept in balance for water by increasing excretion.
+++
Metabolism by the Tubules
++
Although most sources list glomerular filtration, tubular reabsorption, and tubular secretion as the 3 basic renal processes, we cannot overlook metabolism by the tubular cells. The tubular cells extract organic nutrients from the glomerular filtrate or peritubular capillaries and metabolize them as dictated by the cells' own nutrient requirements. In so doing, the renal cells are behaving no differently than any other cells in the body. In addition, there are other metabolic transformations performed by the kidney that are directed toward altering the composition of the urine and plasma. The most important of these are gluconeogenesis, and the synthesis of ammonium from glutamine and the production of bicarbonate, both described in Chapter 9.
+++
Regulation of Renal Function
++
The most complex and least understood feature of the kidneys is regulation of renal processes. Details, to the extent known, will be presented in later chapters. Neural signals, hormonal signals, and intrarenal chemical messengers combine to regulate the processes described above in a manner to help the kidneys meet the needs of the body. Neural signals originate in the sympathetic celiac plexus. These sympathetic neural signals exert major control over renal blood flow, glomerular filtration and the release of vasoactive substances that affect both the kidneys and the peripheral vasculature. Known hormonal signals originate in the adrenal gland, pituitary gland, parathyroid glands, and heart. The adrenal cortex secretes the steroid hormones aldosterone and cortisol, and the adrenal medulla secretes the catecholamines epinephrine and norepinephrine. All of these hormones, but mainly aldosterone, are regulators of sodium and potassium excretion by the kidneys. The posterior pituitary gland secretes the hormone arginine vasopressin (AVP, also called ADH). ADH is a major regulator of water and urea excretion, as well as a partial regulator of sodium excretion. The heart secretes hormones—natriuretic peptides—that increase sodium excretion by the kidneys. Another complicated aspect of regulation lies in the realm of intrarenal chemical messengers (ie, messengers that originate in one part of the kidney and act in another part). It is clear that an array of substances (eg, nitric oxide, purinergic agonists, superoxide, and eicosanoids) influence basic renal processes. The precise roles of these substances are just now being elucidated.
++
Two points about regulation should be kept in mind. First, excretion of major substances is regulated by overlapping, redundant controls. Failure of one may be compensated by the operation of another. Second, control systems adapt to chronic conditions and may change in effectiveness over time.
++
In ensuing chapters of this book we discuss specific mechanisms of reabsorption and secretion. When describing regulation of these mechanisms we are also implying regulation of excretion because any substance present in the tubule and not reabsorbed is destined to be excreted.
+++
Overview of Regional Function
++
We conclude this chapter with a broad overview of the tasks performed by the individual nephron segments. Later, we examine renal function substance by substance and see how tasks performed in the various regions combine to produce an overall result that is useful for the body.
++
The glomerulus is the site of filtration—about 180 L/day of volume and proportional amounts of solutes that are freely filtered, which is the case for most solutes (large plasma proteins are an exception). The glomerulus is where the greatest mass of excreted substances enters the nephron. The proximal tubule (convoluted and straight portions together) reabsorbs about two thirds of the filtered water, sodium, and chloride. It reabsorbs all of the useful organic molecules that the body conserves (eg, glucose, amino acids). It reabsorbs significant fractions, but by no means all, of many important ions, such as potassium, phosphate, calcium, and bicarbonate. It is the site of secretion of a number of organic substances that are either metabolic waste products (eg, uric acid, creatinine) or drugs (eg, penicillin) that clinicians must administer appropriately to make up for renal excretion.
++
The loop of Henle contains different segments that perform different functions, but the key functions occur in the thick ascending limb. As a whole, the loop of Henle reabsorbs about 20% of the filtered sodium and chloride and 10% of the filtered water. A crucial consequence of these different proportions is that, by reabsorbing relatively more salt than water, the luminal fluid becomes diluted relative to normal plasma and the surrounding interstitium. During periods when the kidneys excrete dilute final urine, the role of the loop of Henle in diluting the luminal fluid is crucial.
++
The end of the loop of Henle contains cells of the macula densa, which sense the sodium and chloride content of the lumen and generate signals that influence other aspects of renal function, specifically the renin-angiotensin system (discussed in Chapter 7). The distal tubule and connecting tubule together reabsorb some additional salt and water, perhaps 5% of each. The cortical collecting duct is where several connecting tubules join to form a single tubule. Cells of the connecting tubule and cortical collecting duct are strongly responsive to and are regulated by the hormones angiotensin II and aldosterone, which enhance sodium reabsorption. ADH enhances water reabsorption in the collecting ducts. The degree to which these processes are stimulated or not stimulated plays a major role in regulating the amount of solutes and water present in the final urine.
++
The medullary collecting duct continues the functions of the cortical collecting duct in salt and water reabsorption. In addition, it plays a major role in the excretion of acids and bases, and the inner medullary collecting is important in regulating urea excretion. The final result of these various transport processes to keep the various plasma solutes close to the typical values is shown in Table 1–3.
++
++
++