GLOMERULAR FILTRATION AND RENAL BLOOD FLOW

The kidneys receive an enormous blood flow: more than 1 L/min, or about
20% of the cardiac output. This blood flow is far in excess of the kidney’s
metabolic need and provides the kidneys with the flexibility to alter their
blood flow in response to physiological demand. All of this blood flows through
glomeruli in the cortex.1 The vast majority continues on (via efferent arterioles) to peritubular capillaries in the cortex and then into the renal venous system. A much smaller fraction, about 5–10%, flows from efferent arterioles down into the medulla. This medullary blood derives from juxtamedullary glomeruli that are situated near the corticomedullary border. Consider some typical numbers. A normal hematocrit is 0.45, ie, 45% of the blood volume is composed of red blood cells and the remaining 55% is almost entirely plasma. Typical renal blood flow (RBF) is 1.1 L/min. The renal plasma flow (RPF) 5 0.55 × 1.1 L/min 5 605 mL/min. As stated in Chapter 1, a typical glomerular filtration rate (GFR) is about 125 mL/min. Thus, of the 605 mL of plasma that enters the glomeruli via the afferent arterioles, 125 mL, or 20%, filters into Bowman’s space. The remaining 480 mL passes via the efferent arterioles into the peritubular capillaries. This ratio—GFR/RPF—is known as the filtration fraction. Because freely filtered substances are passing into Bowman’s space along with the water, about 20% of all freely filtered substances (eg, sodium) that enter the kidney also move into Bowman’s space.

Overview of Regional Function

We conclude this chapter with a broad overview of the tasks performed by the various 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 enter the nephron. The proximal tubule (convoluted and straight portions) reabsorbs about two thirds of the filtered water, sodium, and chloride. The proximal convoluted tubule reabsorbs all of the useful organic molecules that the body wishes to conserve (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, urate, creatinine) or drugs (eg, penicillin) that physicians must replace 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 (a region that begins in the outer medulla for all nephrons and continues outward into the renal cortex until it reaches the renal corpuscle from which the tubule arose (which can, depending on the nephron, be near the corticomedullary border or close to the cortical surface)). 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 senses or assays the sodium and chloride content of the lumen and generates signals that influence other aspects of renal function, specifically the renin-angiotensin system.
The distal tubule and connecting tubule together reabsorb some additional salt and water, perhaps 5% of each.
The cortical collecting tubule is where several (6–10) connecting tubules join to form 1 tubule. Cells of the cortical collecting tubule are strongly responsive to and are regulated by the hormones aldosterone and ADH. Aldosterone enhances sodium reabsorption and potassium secretion by this segment, and ADH enhances water reabsorption. 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. With large amounts of ADH present, most of the water remaining in the lumen is reabsorbed, leading to concentrated, low-volume urine. With little ADH present, most of the water passes on to the final urine, producing dilute, high-volume urine.
The medullary collecting tubule continues the functions of the cortical collecting tubule in salt and water reabsorption. In addition, it plays a major role in regulating urea reabsorption and in acid-base balance (secretion of protons or bicarbonate).

Regulation of Renal Function

By far, the most difficult aspect of renal physiology for students (and authors alike) is regulation of renal function. Neural signals, hormonal signals, and intrarenal chemical messengers combine to regulate the basic renal processes presented previously in a manner to help the kidneys meet the needs of the body. Unfortunately, our collective knowledge on much of this is, as yet, incomplete. Of necessity, much of the coverage in this textbook will attempt to draw an overview of renal function without an emphasis on nuance and detail that is more appropriate for advanced texts.
As with many organs, signals regulating the kidney arise from both neural and hormonal input. Neural signals originate in the sympathetic celiac plexus. Sympathetic signals exert major control over renal blood flow, glomerular filtration, and the release of vasoactive substances (the renin-angiotensin system, described later). Hormonal signals originate in the adrenal gland, pituitary gland, 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 kidney. The pituitary gland secretes the hormone arginine vasopressin (also called ADH). ADH is a major regulator of water excretion, and via its influence on the renal vasculature and possible collecting-duct principal cells, probably sodium excretion as well. The heart secretes hormones, natriuretic peptides, that contribute to signaling increased excretion of sodium by the kidneys. The most difficult 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, various eicosanoids) influence basic renal processes, but, for the most part, the role of these substances is beyond the scope of this text.

Metabolism by the Tubules

Although renal physiologists traditionally list glomerular filtration, tubular reabsorption, and tubular secretion as the 3 basic renal processes, we cannot overlook metabolism by the tubular cells. For example, the tubular cells may extract organic nutrients from the glomerular filtrate or peritubular capillaries and metabolize them as dictated by the cells’ own nutrient requirements. In doing so, the renal cells are behaving no differently from any other cells in the body. In contrast, other metabolic transformations performed by the kidney are not directed toward its own nutritional requirements but rather toward altering the composition of the urine and plasma. The most important of these are the synthesis of ammonium from glutamine and the production of bicarbonate.

Tubular Reabsorption and Tubular Secretion

The volume and solute contents of the final urine that enters the renal pelvis 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 peritubular capillaries in the cortex or cappillary-like vessels in the medulla, a relationship that permits rapid transfer of materials between the capillary plasma and the lumen of the tubule via the interstitial space.
The most common relationships among these basic renal processes, glomerular filtration, tubular reabsorption, and tubular secretion, are shown in the hypothetical. Plasma, containing 3 low-molecular-weight substances (X, Y, and Z), enters the glomerular capillaries, and approximately 20% of the plasma is filtered into Bowman’s capsule. The filtrate contains substances X, Y, and Z in the same concentrations as the plasma (ie, each one is freely filtered). The filtrate enters the proximal convoluted tubule and begins its flow through the rest of the tubule. Simultaneously, the remaining 80% of the plasma, with its substances X, Y, and Z in the same concentrations as they had when entering the kidney, leaves the glomerular capillaries via the efferent arterioles and enters the peritubular capillaries.
Suppose the cells of the tubular epithelium can secrete all the peritubularcapillary substance X into the tubular lumen but cannot reabsorb substance X. Thus, by the combination of filtration and tubular secretion, all the plasma that originally entered the renal artery is cleared of substance X, which leaves the body via the urine. Now suppose the tubule can reabsorb some of substance Y. The amount of substance Y reabsorbed is small, so most of the filtered substance Y escapes from the body in the urine. In contrast, let substance Z be reabsorbed fully. Therefore, no substance Z is lost from the body. Hence, the processes of filtration and reabsorption have canceled each other, and the net result is as though substance Z had never entered the kidney at all.
As we will see, 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. are at least 3 important generalizations to be drawn from this table:
1)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 contains about 40 L of water, but the volume of water filtered each day may be as large as 180 L. If reabsorption of water ceased but filtration continued, the total plasma water would be urinated within 30 min.
2)Reabsorption of waste products, such as urea, is incomplete, so that large fractions of their filtered amounts are excreted in the urine, like substance Y in our hypothetical example.
3)Reabsorption of most “useful” plasma components (eg, water, electrolytes, and glucose) varies from essentially complete, so that urine concentrations should normally be undetectable (eg, glucose), to almost complete (eg, water and most electrolytes), so that the amounts excreted in the urine represent only very small fractions of the filtered amounts.

Average values for several substances handled by filtration and reabsorption

Renal manipulation of 3 hypothetical substances, X,Y, and Z. Substance X is filtered and secreted but not reabsorbed. Substance Z is filtered but is completely reabsorbed.

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 at which the relevant processes proceed for many of these substances 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 can regulate excretion to keep the body in balance. For example, consider what happens when a person drinks a large quantity of water: Within 1–2 h, 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. By keeping the body in balance, the kidney is the effector organ of a reflex that maintains body water concentration within very narrow limits.

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. However, it contains very little total protein. The large plasma proteins like albumin and 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. 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 neutral organics glucose and urea; amino acids; and peptides like insulin and antidiuretic hormone (ADH).
The volume of filtrate formed per unit time is known as the GFR. In a normal
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 aging and of many renal pathologies is a reduction in the GFR.

BASIC RENAL PROCESSES

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 moving 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. In most cases, reabsorbed substances then move from the interstitium into surrounding blood vessels, so that the term reabsorption implies a 2-step process of removal from the 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 3 basic renal processes. Only the directions of reabsorption and secretion, not specific sites or order of occurrence, are shown. Depending on the specific substance, reabsorption and secretion can occur at various sites along the tubule.

The renal handling of any substance consists of some combination of the justmentioned processes. If we can answer the following questions, we can know what the kidney does with a given substance. Is it filtered? Is it secreted? Is it reabsorbed? Is it synthesized? Is it catabolized?