CLEARANCE UNITS

The units of clearance are often confusing to the first-time reader, so let us be sure of the meaning. First, the units are volume per time (not amount per time). The easiest way to think of this is to ask what volume of plasma contains the amount excreted in a given time. Suppose 5 mg of a substance is excreted per hour and 200 mL of plasma contains 5 mg. Then the clearance of the substance is 200 mL/h, ie, 200 mL of volume has been completely cleared of the substance. Again, note the units: volume per time (ie, the volume of plasma from which a substance is completely removed [cleared]).
The general meaning and specific renal meaning of clearance can be illustrated by comparing how the body handles 2 substances with similar-sounding names but very different properties: insulin and inulin. Insulin is the familiar pancreatic hormone involved in regulating blood sugar (glucose). It is a protein with a molecular weight of 5.8 kDa and is small enough to be freely filtered by the glomerulus. Once in Bowman’s space, it moves along with every other filtered substance into the proximal convoluted tubule, where it is largely taken up by endocytosis and degraded into its constituent amino acids. Very little insulin escapes this uptake, and very little of the filtered insulin survives to be excreted in the urine. Thus, the kidney takes part in clearing insulin from the blood; however, because so little appears in the urine, the specific renal clearance is very low (<1 mL/min). However, the body has additional mechanisms for clearing insulin, and its metabolic clearance rate is quite high (half-life less than 10 min). Let us contrast this with inulin. Inulin is a polysaccharide starch of about 5 kDa molecular weight. Like insulin, it is freely filtered by the glomerulus, but it is not reabsorbed or secreted by the nephron. All the inulin that is filtered flows through the nephron and appears in the urine. Thus, inulin’s renal clearance is relatively large. Inulin in the blood is not taken up by other tissues, and the kidneys are the only excretion route. As we will see, this makes inulin a very special substance with respect to assessing renal function.

Clearance

One of the crucial functions of the kidneys is to remove metabolic wastes and excess amounts of ingested substances from the blood. Nitrogenous wastes such as urea and creatinine are generated by metabolism and removed from the body by the kidneys. The average excretion rate normally reflects the rate at which these substances are added to the blood by metabolic processes, thus keeping the body in balance for these substances. Other substances, those that are crucial for normal function, including sodium and potassium, enter the body by ingestion and are also removed from the body by the kidneys. These excretion rates parallel ingestion rate in the long term but are altered transiently to reflect other needs, such as the regulation of blood pressure or plasma osmolality.
Ridding the body of a substance is often called clearance. This term in a biomedical context has both a general meaning and a specific renal meaning. The general meaning of clearance is simply that a substance is removed from the blood by any of several mechanisms. For instance, a drug may be cleared by excretion in the urine or the feces, or it may be transformed by the liver and other peripheral tissues to an inactive form. Renal clearance, on the other hand, means that the substance is removed from the blood and excreted in the urine.

AUTOREGULATION

It is extremely important for the kidneys to keep the GFR at a level appropriate for the body because, as we have emphasized, the excretion of salt and water is strongly influenced by the GFR. We have also emphasized that the GFR is strongly influenced by renal arterial pressure. A rise in blood pressure causes an increased excretion of salt and water, a process called pressure natriuresis, whereas a fall in blood pressure diminishes excretion. These changes in excretion are mediated partly via changes in GFR. The effect is so strong that urinary excretion would tend to vary widely with the ordinary daily excursions of arterial pressure. Also, vascular pressure in the thin-walled glomerular capillaries is higher than in capillaries elsewhere in the body and hypertensive damage ensues if this pressure is too high.
Therefore, both to protect the glomerular capillaries from hypertensive damage and to preserve a healthy GFR, changes in GFR and RBF are severely blunted by mechanisms that we collectively call autoregulation. Consider first a situation in which mean arterial pressure rises 20%. Such a modest rise occurs many times throughout the day in association with changes in excitement level and activity. Pretend, for the moment, that all renal vascular resistances remain constant. By the basic flow equation (Q = ΔP/R), RBF would rise 20% also (actually slightly more if pressure in the renal vein is unaffected). What would this do to GFR? It would rise much more than 20%, in fact almost 50%. This is because net filtration pressure would rise almost 50%. In effect, fractional changes in upstream pressure (in the renal artery) are magnified in terms of net filtration pressure. Why is this? At the beginning of the glomerulus, capillary hydrostatic pressure is about 60 mm Hg and the pressures opposing filtration sum to 36 mm Hg, yielding a net filtration pressure of about 24 mm Hg. With an increase in arterial pressure to 120 mm Hg, capillary pressure would rise to about 71 m Hg, but there would be no increase in the pressures that oppose filtration–plasma oncotic pressure and Bowman’s capsule pressure. Therefore, net filtration pressure would rise to 71 – 36 = 35 mm Hg (an increase of almost 50%). The higher net filtration pressure would cause a parallel increase in GFR. (In turn, this would raise plasma oncotic pressure at the distal end of the glomerulus, tending to reduce filtration somewhat, but the total effect is still a major rise in GFR.) This emphasizes the crucial role of glomerular capillary pressure in glomerular filtration.
Now, what actually happens in the face of changes in mean arterial pressure? As is the case in many organs, blood flow does not change in proportion to changes in arterial pressure. The changes are blunted. A rise in driving pressure is counteracted by a rise in vascular resistance that almost offsets the rise in pressure. The word “almost” is crucial here. Higher driving pressures do indeed lead to higher flow but not proportionally. Within the range of mean arterial pressures commonly found in the human body4), RBF varies only modestly when mean arterial pressure changes. This is partly a result of a direct reaction of the vascular smooth muscle to stretch or relaxation—or the myogenic response—and partly the result of intrarenal signals that we describe shortly. The myogenic response is very fastacting and protects the glomeruli from short-term fluctuations in blood pressure. In addition to keeping changes in RBF fairly small, autoregulatory processes also keep changes in GFR fairly small. Again, GFR does rise with an increase in arterial pressure, just not substantially.

Autoregulation of renal blood flow (RBF). A similar pattern holds for glomerular filtration rate.

How do the intrarenal processes work? Much is by way of a process with the clumsy name of tubuloglomerular feedback. Tubuloglomerular feedback is feedback from the tubules back to the glomerulus (ie, an influence of events in the tubules that is exerted on events in the glomeruli). But for now the essence of tubuloglomerular feedback can be summarized as follows: As the filtration rate in an individual nephron increases or decreases, the amount of sodium that escapes reabsorption in the proximal tubule and the loop of Henle also increases or decreases. More sodium filtered means more sodium remaining in the lumen of the nephron and more sodium flowing from the thick ascending limb into the distal tubule. Recall that at the division between these nephron segments lies the macula densa, a special group of cells in the nephron wall where the nephron passes between the afferent and efferent arterioles. The macula densa cells sense the amount of sodium and chloride in the lumen. They act, in part, as salt detectors. One result of changing levels of luminal sodium chloride is to increase or decrease the secretion of transmitter agents into the interstitial space that affect the filtration in the nearby glomerulus. High levels of sodium flowing past the macula densa cause a decrease in filtration rate; low levels of sodium flowing past allow a higher filtration rate. It is as though each nephron adjusts its filtration so that the right amount of sodium remains in the lumen to flow past the macula densa. How can it adjust its filtration? The transmitter agents released by the salt-sensing macula densa cells produce vasoconstriction of the afferent arteriole, thereby reducing hydrostatic pressure in the glomerular capillaries. These same agents also produce contraction of glomerular mesangial cells, thereby reducing the effective filtration coefficient. Both processes reduce the single-nephron filtration rate and keep it at a level appropriate for the rest of the nephron.
In conclusion, we emphasize that autoregulation blunts or lowers the RBF and GFR responses to changes in arterial pressure but does not totally prevent those changes.

Filtered Load

A term we use in other chapters is filtered load. It is the amount of substance that is filtered per unit time. For freely filtered substances, the filtered load is just the product of GFR and plasma concentration. Consider sodium. Its normal plasma concentration is 140 mEq/L, or 0.14 mEq/mL. (Note: 1 mEq of sodium is 1 mmol.) A normal GFR is 125 mL/min, so the filtered load of sodium is 0.14 mEq/mL × 125 mL/min = 17.5 mEq/min. We can do the same calculation for any other substance, being careful in each case to be aware of the unit of measure in which concentration is expressed. The filtered load is what is presented to the rest of the nephron to handle. A high filtered load means a substantial amount of material to be reabsorbed. The filtered load varies with plasma concentration and GFR. A rise in GFR, at constant plasma concentration, increases the filtered load, as does a rise in plasma concentration at constant GFR.

Direct Determinants of GFR

Variation in GFR is a crucial determinant of renal function.
Everything else being equal, a higher GFR means greater excretion of salt and water. Regulation of the GFR is straightforward in terms of physical principles but very complex functionally because there are so many regulated variables. The rate of filtration in any of the body’s capillaries, including the glomeruli, is determined by the hydraulic permeability of the capillaries, their surface area, and the net filtration pressure (NFP) acting across them.

Rate of filtration 5 hydraulic permeability × surface area × NFP

Because it is difficult to estimate the area of a capillary bed, a parameter called the filtration coefficient (Kf ) is used to denote the product of the hydraulic permeability and the area. The net filtration pressure is the algebraic sum of the hydrostatic pressures and the osmotic pressures resulting from protein—the oncotic or colloid osmotic pressures —on the 2 sides of the capillary wall. There are 4 pressures to contend with: 2 hydrostatic pressures and 2 oncotic pressures. These are referred to as Starling forces, named after the physiologist who first described them. Applying this to the glomerular capillaries:

NFP = (PGC - πGC) - (PBC - πBC),

where PGC is glomerular capillary hydraulic pressure, πBC is oncotic pressure of fluid in Bowman’s capsule, PBC is hydraulic pressure in Bowman’s capsule, and πGC is oncotic pressure in glomerular capillary plasma.
Because there is normally little protein in Bowman’s capsule, πBC may be taken as zero and not considered in our analysis. Accordingly, the overall equation for GFR becomes

GFR = Kf (PGC − PBC − πGC).

Net filtration pressure in the renal corpuscle equals glomerular-capillary hydraulic pressure (PGC) minus Bowman’s capsule hydraulic pressure (PBC) minus glomerularcapillaryoncotic pressure (πGC).

Estimated forces involved in glomerular filtration in humans (these are the same values shown in Table 2–1). Net filtration pressure (NFP) = PGC − πGC − PBC.

Note that the hydraulic pressure changes only slightly along the glomeruli; this is because the very large total cross-sectional area of the glomeruli collectively provides only a small resistance to flow. Importantly, note that the oncotic pressure in the glomerular capillaries does change substantially along the length of the glomeruli. Water is moving out of the vascular space and leaving protein behind, thereby raising protein concentration and, hence, the oncotic pressure of the unfiltered plasma remaining in the glomerular capillaries. Mainly because of this large increase in oncotic pressure, the net filtration pressure decreases from the beginning of the glomerular capillaries to the end. The average net filtration pressure over the whole length of the glomerulus is about 17 mm Hg. This average net filtration pressure is higher than found in most nonrenal capillary beds. Along with a high value for Kf , it accounts for the enormous filtration of 180 L of fluid/ day (compared with 3 L/day or so in all other capillary beds combined).
As we have noted, the GFR is not fixed but shows marked fluctuations in differing physiological states and in disease. If all other factors remain constant, any change in Kf , PGC, PBC, or πGC will alter GFR. However, “all other factors” do not always remain constant, and so other simultaneous events may oppose the effect of any one factor. To grasp this situation, it is essential to see how a change in any one factor affects GFR under the assumption that all other factors are held constant.
Table 2–2 presents a summary of these factors. It provides, in essence, a checklist to review when trying to understand how diseases or vasoactive chemical messengers and drugs change GFR. In this regard, it should be noted that the major



cause of decreased GFR in renal disease is not any change in these parameters within individual nephrons but rather simply a decrease in the number of functioning nephrons.

Kf
Changes in Kf can be caused by glomerular disease and drugs, but this variable is also subject to normal physiological control by a variety of chemical messengers. The details are still not completely clear, but these messengers cause contraction of glomerular mesangial cells. Such contraction may restrict flow through some of the capillary loops, effectively reducing the area available for filtration and, hence, Kf. This decrease in Kf will tend to lower GFR.

PGC
Hydrostatic pressure in the glomerular capillaries (PGC) is the most complex of the variables in the basic filtration equation because it is itself influenced by so many factors. We can help depict the situation by using the analogy of a leaking garden hose. If pressure feeding the hose (pressure in the pipes leading to the faucet) goes up or down, this directly affects pressure in the hose and, hence, the rate of leak. Resistances in the hose also affect the leak. If we kink the hose upstream from the leak, pressure at the region of leak falls, and less water leaks out. However, if we kink the hose beyond the leak, this raises pressure at the region of leak and increases leak rate. These same principles apply to PGC and GFR. First, a change in renal arterial pressure will cause a change in PGC in the same direction. If resistances remain constant, PGC will rise and fall as renal artery pressure rises and falls. This is a crucial point because a major regulator of renal function is arterial blood pressure. Second, changes in the resistance of the afferent and efferent arterioles have opposite effects on PGC. An increase in resistance upstream from the glomerulus in the afferent arteriole (like kinking the hose above the leak) will lower PGC, whereas an increase in resistance downstream from the glomerulus in the efferent arteriole (like kinking the hose beyond the leak) will increase PGC. In contrast, a decrease in afferent resistance (RA) (resulting from afferent arteriolar dilation) will tend to raise PGC. Similarly, a decrease in efferent resistance (RE) (caused by efferent arteriolar dilation) tends to lower PGC. It should also be clear that when RA and RE both change simultaneously in the same direction (ie, both increase or decrease), they exert opposing effects on PGC.
It is possible for both resistances to rise by the same fraction, with the result that there is no effect on PGC (even though, in this case, RBF would fall). In contrast, when they change in different directions, they cause additive effects on PGC (and can have no effect on RBF). The real significance of this is that the kidney can regulate PGC and, hence, GFR independently of RBF. The effect of changes in RA and RE.

PBC
Changes in this variable generally are of very minor physiological importance. The major pathological cause of increased hydraulic pressure in Bowman’s capsule is obstruction anywhere along the tubule or in the external portions of the urinary system (eg, the ureter). The effect of such an occlusion is to increase the tubular pressure everywhere proximal to the occlusion, all the way back to Bowman’s capsule. The result is to decrease GFR.

Effects of afferent- and/or efferent-arteriolar constriction on glomerular capillary pressure (PGC) and renal blood flow (RBF). The RBF changes reflect changes in total renal arteriolar resistance, the location of the change being irrelevant. In contrast, the changes in PGC are reflected in which set of arterioles the altered resistance occurs. Pure afferent constriction lowers both PGC and RBF, whereas pure efferent constriction raises PGC and lowers RBF. Simultaneous constriction of both afferent and efferent arterioles has counteracting effects on PGC but additive effects on RBF; the effect on PGC may be a small increase, small decrease, or no change. Vasodilation of only 1 set of arterioles would have effects on PGC and RBF opposite those shown in parts B and C. Vasodilation of both sets would cause little or no change in PGC, the same result as constriction of both sets but would cause a large increase in RBF. Constriction of 1 set of arterioles and dilation of the other would have maximal effects on PGC but little effect on RBF.

πGC
Oncotic pressure in the plasma at the very beginning of the glomerular capillaries is, of course, simply the oncotic pressure of systemic arterial plasma. Accordingly, a decrease in arterial plasma protein concentration, as occurs, eg, in liver disease, will lower arterial oncotic pressure and tend to increase GFR, whereas increased arterial oncotic pressure will tend to reduce GFR.
However, now recall that πGC is identical to arterial oncotic pressure only at the very beginning of the glomerular capillaries; πGC then progressively increases along the glomerular capillaries as protein-free fluid filters out of the capillary, concentrating the protein left behind. This means that net filtration pressure and, hence, filtration progressively decrease along the capillary length. Accordingly, anything that causes a steeper rise in πGC will tend to lower average net filtration pressure and hence GFR.
This steep increase in oncotic pressure tends to occur when RPF is low. It should not be hard to visualize that the filtration of a given volume of fluid from a small total volume of plasma flowing through the glomeruli will cause the protein left behind to become more concentrated than if the total volume of plasma were large. In other words, a low RPF, all other factors remaining constant, will cause the πGC to rise more steeply and reach a final value at the end of the glomerular capillaries that is higher than normal. This increase in average πGC along the capillaries lowers average net filtration pressure and, hence, GFR. Conversely, a high RPF, all other factors remaining constant, will cause πGC to rise less steeply and reach a final value at the end of the capillaries that is less than normal, which will increase the GFR.
Another way of thinking about this is in terms of filtration fraction: the ratio GFR/RPF. The increase in πGC along the glomerular capillaries is directly proportional to the filtration fraction (ie, the more volume that is filtered from plasma, the higher is the rise in πGC). Therefore, if you know that filtration fraction has changed, you can be certain that there has also been a proportional change in πGC and that this has played a role in altering GFR.

Formation of Glomerular Filtrate

As stated in Chapter 1, the glomerular filtrate is nearly protein-free2 and contains most inorganic ions and low-molecular-weight organic solutes in virtually the same concentrations as in the plasma.
In order to form a glomerular filtrate, filtered fluid must pass through the glomerular filtration barrier. The filtration barrier separates the blood from the urinary space that topologically connects to the outside world via the renal tubules, ureters, bladder, and urethra. The route that filtered substances takes from the blood through the filtration barrier of a renal corpuscle into Bowman’s space is a 3-step process: through fenestrae in the glomerular-capillary endothelial layer, through the basement membrane, and finally through slit diaphragms between podocyte foot processes. The fraction of endothelial surface area occupied by fenestrae is about 10%. Both the slit diaphragm and basement membrane are composed of an array of proteins, and while the basement membrane may contribute to selectivity of the filtration barrier, integrity of the slit diaphragms is essential to prevent excessive leak of plasma protein (albumin). Some protein-wasting diseases are associated with abnormal slit diaphragm structure. Selectivity of the barrier to filtered solute is based on both molecular size and electrical charge. Let us look first at size.
The filtration barrier of the renal corpuscle provides no hindrance to the movement of molecules with molecular weights less than 7000 Da (ie, solutes this small are all freely filtered). This includes all small ions, glucose, urea, amino acids, and many hormones. The filtration barrier almost totally excludes plasma albumin (molecular weight of approximately 66,000 Da). (We are, for simplicity, using molecular weight as our reference for size; in reality, it is molecular radius and shape that is critical.) The hindrance to plasma albumin is not 100%, however, and so the glomerular filtrate does contain extremely small quantities of albumin, on the order of 10 mg/L or less. This is only about 0.02% of the concentration of albumin in plasma and is the reason for the use of the phrase “nearly protein-free” earlier. (Note: Some small substances are partly or mostly bound to large plasma proteins and are thus not free to be filtered, even though, when not bound to plasma proteins, they can easily move through the filtration barrier. This includes hydrophobic hormones of the steroid and thyroid categories and about 40% of the calcium in the blood.)
For molecules with a molecular weight ranging from 7000 and 70,000 Da, the amount filtered becomes progressively smaller as the molecule becomes larger. Thus, many normally occurring plasma peptides and small proteins are filtered to a significant degree. Moreover, when certain small proteins not normally present in the plasma appear because of disease (eg, hemoglobin released from damaged erythrocytes or myoglobin released from damaged muscles), considerable filtration of these may occur.
Electrical charge is the second variable determining filterability of macromolecules. For any given size, negatively charged macromolecules are filtered to a lesser extent, and positively charged macromolecules to a greater extent, than neutral molecules. This is because the surfaces of all the components of the filtration barrier (the cell coats of the endothelium, the basement membrane, and the cell coats of the podocytes) contain fixed polyanions, which repel negatively charged macromolecules during filtration. Because almost all plasma proteins bear net negative charges, this electrical repulsion plays a very important restrictive role , enhancing that of purely size hindrance. (For example, when neutral dextrans, the same size as plasma albumin, are administered to experimental animals, they are found to be 5–10% filterable rather than albumin’s 0.02%.) In other words, if albumin were not charged or the filtration barrier were not charged, even albumin would be filtered to a considerable degree. Certain diseases that cause glomerular capillaries to become “leaky” to protein do so by eliminating negative charges in the membranes.
It must be emphasized that the negative charges in the filtration membranes act as a hindrance only to macromolecules, not to mineral ions or low-molecularweight organic solutes. Thus, chloride and bicarbonate ions, despite their negative charge, are freely filtered.

FLOW, RESISTANCE, AND PRESSURE IN THE KIDNEYS

The basic equation for blood flow through any organ is as follows:

Q=ΔP/R,

where Q is organ blood flow, ΔP is mean pressure in the artery supplying the organ minus mean pressure in the vein draining that organ, and R is the total vascular resistance in that organ. Resistance is determined by the blood viscosity and the lengths and radii of the organ’s blood vessels, the arteriolar radii being overwhelmingly the major contributor. As described by Poiseiulle’s law, resistance of a cylindrical vessel varies inversely with the fourth power of vessel radius. It takes only a 19% decrease or increase in vessel radius to double or halve vessel resistance. The radii of arterioles are regulated by the state of contraction of the arteriolar smooth muscle.
The presence of 2 two sets of arterioles (afferent and efferent) and 2 sets of capillaries (glomerular and peritubular) makes the vasculature of the cortex unusual. (The vasculature of the medulla is even more unusual, but we concentrate on the cortex for now.) Normally, the resistances of the afferent and efferent arterioles are approximately equal and account for most of the total renal vascular resistance. Resistance in arteries preceding afferent arterioles (ie, cortical radial arteries) plays some role also, but we concentrate on the arterioles. Vascular pressures (ie, hydrostatic or hydraulic pressure) in the 2 capillary beds are quite different. The peritubular capillaries are downstream from the efferent arteriole and have a lower hydraulic pressure. Typical glomerular pressures are near 60 mm Hg in a normal unstressed individual, whereas peritubular pressures are closer to 20 mm Hg. The high glomerular pressure is crucial for glomerular filtration, whereas the low peritubular capillary pressure is equally crucial for the tubular reabsorption of fluid.
To repeat, total RBF is determined mainly by the mean pressure in the renal artery and the contractile state of the smooth muscle of the renal arterioles of the cortex. Now for a simple but very important point: A change in arteriolar resistance produces the same effect on RBF regardless of whether it occurs in the afferent arteriole or efferent arteriole. Because these vessels are in series, a change in either one has the same effect on the total. When the 2 resistances both change in the same direction, the most common state of affairs, their effects on RBF will be additive. When they change in different directions— one resistance increasing and the other decreasing—they exert opposing effects on RBF. We see in the next section that the story is totally different for GFR.

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?

Renal Innervation

The kidneys receive a rich supply of sympathetic neurons. These are distributed to the afferent and efferent arterioles, the JG apparatus, and many portions of the tubule. There is no significant parasympathetic innervation. The sensory endings of many afferent neurons are distributed throughout the kidneys as well, which feedback to the neural centers that regulate sympathetic outflow.

The Juxtaglomerular Apparatus

Reference was made earlier to the macula densa, a portion of the late thick ascending limb at the point where, in all nephrons, this segment comes between the afferent and efferent arterioles at the vascular pole of the renal corpuscle from which the tubule arose. This entire area is known as the juxtaglomerular (JG) apparatus. (Do not confuse the term juxtaglomerular apparatus with juxtamedullary nephron.) Each JG apparatus is made up of 3 cell types: (1) granular cells, also called juxtaglomerular cells, which are differentiated smooth muscle cells in the walls of the afferent arterioles; (2) extraglomerular mesangial cells; and (3) macula densa cells, which are specialized thick ascending limb epithelial cells.
The granular cells (so called because they contain secretory vesicles that appear granular in light micrographs) are the cells that secrete the hormone renin. Renin is a crucial substance for the control of renal function and systemic blood pressure. The extraglomerular mesangial cells are morphologically similar to and continuous with the glomerular mesangial cells but lie outside Bowman’s capsule. The macula densa cells are detectors of the luminal content of the nephron at the very end of the thick ascending limb and contribute to the control of glomerular filtration rate (GFR) and to the control of renin secretion.

Nephron Heterogeneity

As stated earlier, there are more than 2 million nephrons in the 2 human kidneys. These nephrons manifest significant differences in anatomic, biochemical, and functional characteristics beyond those described in the previous section. For simplicity, however, we generally ignore these complexities, many of which currently are not fully understood.

Categories of Nephrons

There are important regional differences in the various tubular segments of the nephron. All the renal corpuscles are in the cortex (accounting for its granular appearance) as well as the convoluted portions of the proximal tubule, cortical portions of Henle’s loops, distal convoluted tubules, connecting tubules, and cortical collecting ducts. The medulla contains the medullary portions of Henle’s loops and the medullary collecting ducts.

The renal microcirculation. The kidney is divided into a cortex and a medulla. The cortex contains an arterial network, glomeruli, a dense peritubular capillary plexus, and a venous drainage system. In the cortex, arcuate arteries, which run parallel to the surface, give rise to cortical radial (interlobular) arteries radiating toward the surface. Afferent arterioles originate from the cortical radial arteries at an angle that varies with cortical location. Blood is supplied to the peritubular capillaries of the cortex from the efferent flow out of superficial glomeruli. Blood is supplied to the medulla from the efferent flow out of juxtamedullary glomeruli. Efferent arterioles of juxtamedullary glomeruli give rise to bundles of descending vasa recta in the outer stripe of the outer medulla. In the inner stripe of the outer medulla, descending vasa recta and ascending vasa recta returning from the inner medulla run side by side in the vascular bundles, allowing exchange of solutes and water. The descending vasa recta from the bundle periphery supply the interbundle capillary plexus of the inner stripe, whereas those in the center supply blood to the capillaries of the inner medulla. Contractile pericytes in the walls of the descending vasa recta regulate flow. DVR, descending vasa recta.AVR, ascending vasa recta. (Used with permission from Pallone TL, Zhang Z, Rhinehart K.Am J Physiol Renal Physiol 2003;284:F253–F266.)

Nephrons are categorized according to the locations of their renal corpuscles in the cortex: (1) In superficial cortical nephrons, renal corpuscles are located within 1 mm of the capsular surface of the kidneys; (2) in midcortical nephrons, renal corpuscles are located, as their name implies, in the midcortex, deep relative to the superficial cortical nephrons but above (3) the juxtamedullary nephrons, which, as mentioned previously, have renal corpuscles located just above the junction between cortex and medulla. One major distinction among these 3 categories of nephrons is the length of Henle’s loop. All superficial cortical nephrons have short loops, which make their hairpin turn above the junction of outer and inner medulla. All juxtamedullary nephrons have long loops, which extend into the inner medulla, often to the tip of a papilla. Midcortical nephrons may be either short looped or long looped. The additional length of Henle’s loop in long-looped nephrons is due to a longer descending thin limb and the presence of an ascending thin limb. Finally, the beginning of the thick ascending limb marks the border between the outer and inner medulla; in other words, the thick ascending limbs are found only in the cortex and outer medulla.

BLOOD SUPPLY TO THE NEPHRONS

The kidneys receive an enormous amount of blood relative to their mass. Blood enters each kidney via a renal artery, which then divides into progressively smaller branches: interlobar, arcuate, and finally interlobular arteries (usually called cortical radial arteries because they radiate outward toward the kidney surface). As each of the interlobular arteries projects toward the outer kidney surface, a series of parallel arterioles branch off at right angles, each of which leads to a glomerulus. These are called afferent arterioles. Note that these arteries and glomeruli are found only in the cortex, never in the medulla.
Normally about 20% of the plasma (and none of the erythrocytes) entering the glomerulus is filtered from the glomerulus into Bowman’s capsule, leaving the remaining 80% to flow on to the next vascular segment. In most organs, capillaries recombine to form the beginnings of the venous system, but the glomerular capillaries instead recombine to form another set of arterioles called the efferent
arterioles. Thus, blood enters each glomerulus through a single afferent arteriole and leaves via a single efferent arteriole at the vascular pole of Bowman’s capsule. The afferent and efferent arterioles both penetrate Bowman’s capsule on the same side, with the thick ascending limb of the nephron that originated from that capsule passing between and in contact with each arteriole. The efferent arterioles soon subdivide into a second set of capillaries. These are usually the peritubular capillaries, which are profusely distributed throughout the cortex. The peritubular capillaries then rejoin to form the veins by which blood ultimately leaves the kidney.
The medulla receives much less blood than does the cortex, and in a quite different manner. There are no glomeruli in the medulla. In contrast to most efferent arterioles in the cortex, those from juxtamedullary glomeruli do not branch into peritubular capillaries, but rather descend downward into the outer medulla, where they divide many times to form bundles of parallel vessels that penetrate deep into the medulla. These are called descending vasa recta (Latin recta for “straight” and vasa for “vessels”). Although it is still uncertain, a small fraction of the descending vasa recta may branch off from the cortical radial arteries before the glomeruli, not after. The vasa recta on the outside of the vascular bundles “peel off” and give rise to interbundle plexi of capillaries that surround Henle’s loops and the collecting ducts in the outer medulla. Only the center-most vasa recta supply capillaries in the inner medulla; thus, limited blood flows into the papilla. The capillaries from the inner medulla re-form into ascending vasa recta that run in close association with the descending vasa recta within the vascular bundles. The structural and functional properties of the vasa recta are rather complex. The beginnings of the descending vasa recta are like arterioles, with pericytes containing smooth muscle in their walls, but become more capillary like as they descend. The ascending vasa recta have a fenestrated endothelium like that found in the glomerular capillaries. Therefore, the vasa recta, in addition to being conduits for blood, also participate in exchanging water and solutes between plasma and interstitium. The whole arrangement of descending and ascending blood flowing in parallel has major significance for the formation of both concentrated and diluted urine because plasma and medullary interstitial constituents exchange between descending and ascending vessels.

The Tubule

Throughout its course, the tubule, which begins at and leads out of Bowman’s capsule, is made up of a single layer of epithelial cells resting on a basement membrane. The structural and immunocytochemical characteristics of these epithelial cells vary from segment to segment of the tubule. A common feature is the presence of tight junctions between adjacent cells that physically link them together (like the plastic form that holds a 6-pack of soft drinks together).
Table 1–1 lists the names and sequence of the various tubular segments. Physiologists and anatomists have traditionally grouped 2 or more contiguous tubular segments for purposes of reference, but the terminologies have varied considerably. Table also gives the combination terms used in this text.


The proximal tubule, which drains Bowman’s capsule, consists of a coiled segment—the proximal convoluted tubule—followed by a straight segment—the proximal straight tubule—which descends toward the medulla, perpendicular to the cortical surface of the kidney.
The next segment, into which the proximal straight tubule drains, is the descending thin limb of Henle’s loop (or simply the descending thin limb). The descending thin limb is in the medulla and is surrounded by an interstitial environment that is quite different from that in the cortex. The descending thin limb ends at a hairpin loop, and the tubule then begins to ascend parallel to the descending limb. The loops penetrate to varying depths within the medulla. In long loops (see later discussion), the epithelium of the first portion of this ascending limb remains
thin, although different from that of the descending limb. This segment is called the ascending thin limb of Henle’s loop (or simply the ascending thin limb). Beyond this segment, in these long loops, the epithelium thickens, and this next segment is called the thick ascending limb of Henle’s loop (or simply the thick ascending limb). In short loops (see later discussion), there is no ascending thin limb, and the thick ascending limb begins right at the hairpin loop. The thick ascending limb rises back into the cortex. Near the end of every thick ascending limb, the tubule returns to Bowman’s capsule, from which it originated, and passes directly between the afferent and efferent arterioles, as they enter and exit that renal corpuscle at its vascular pole. The cells in the thick ascending limb closest to Bowman’s capsule (between the afferent and efferent arterioles) are specialized cells known as the macula densa. The macula densa marks the end of the thick ascending limb and the beginning of the distal convoluted tubule. This is followed by the connecting tubule, which leads to the cortical collecting tubule, the first portion of which is called the initial collecting tubule.
From Bowman’s capsule through the loop of Henle to the initial collecting tubules, each of the 1 million nephrons in each kidney is completely separate from the others. However, connecting tubules from several nephrons merge to form cortical collecting tubules, and a number of initial collecting tubules then join end to end or side to side to form larger cortical collecting ducts. All the cortical collecting ducts then run downward to enter the medulla and become outer medullary collecting ducts and then inner medullary collecting ducts. The latter merge to form several hundred large ducts, the last portions of which are called papillary collecting ducts, each of which empties into a calyx of the renal pelvis.

Standard nomenclature for structures of the kidney (1988 Commission of the International Union of Physiological Sciences). Shown are a short-looped and a long-looped (juxtamedullary) nephron, together with the collecting system (not drawn to scale). A cortical medullary ray—the part of the cortex that contains the straight proximal tubules, cortical thick ascending limbs, and cortical collecting ducts—is delineated by a dashed line. 1, renal corpuscle (Bowman’s capsule and the glomerulus); 2, proximal convoluted tubule; 3, proximal straight tubule; 4, descending thin limb; 5, ascending thin limb; 6, thick ascending limb; 7, macula densa (located within the final portion of the thick ascending limb); 8, distal convoluted tubule; 9, connecting tubule; 9*, connecting tubule of a juxtamedullary nephron that arches upward to form a so-called arcade (there are only a few of these in the human kidney); 10, cortical collecting duct; 11, outer medullary collecting duct; 12, inner medullary collecting duct. (Reproduced with permission from Kriz W, Bankir L. Am J Physiol 1988;254LF:F1–F8.)

The pathway taken by fluids flowing within a nephron always begins in the cortex (in Bowman’s capsule), descends into the medulla (descending limb of the loop of Henle), returns to the cortex (thick ascending limb of the loop of Henle), passes down into the medulla once more (medullary collecting tubule), and ends up in a renal calyx. Each renal calyx is continuous with the ureter, which empties into the urinary bladder, where urine is temporarily stored and from which it is intermittently eliminated. The urine is not altered after it enters a calyx. From this point on, the remainder of the urinary system serves only to maintain the fluid composition established by the kidney.
As noted earlier, the tubular epithelium has a one-cell thickness throughout.
Before the distal convoluted tubule, the cells in any given segment are homogeneous and distinct for that segment. Thus, eg, the thick ascending limb contains only thick ascending limb cells. However, beginning in the second half of the distal convoluted tubule, 2 cell types are found intermingled in most of the remaining segments. One type constitutes the majority of cells in the particular segment, is considered specific for that segment, and is named accordingly: distal convoluted tubule cells, connecting tubule cells, and collecting-duct cells, the latter known more commonly as principal cells. Interspersed among the segment-specific cells in each of these 3 segments are individual cells of the second type, called intercalated cells. There are actually several types of intercalated cells; 2 of them are called type A and type B. (The last portion of the medullary collecting duct contains neither principal cells nor intercalated cells but is composed entirely of a distinct cell type called the inner medullary collecting-duct cells.)

The Renal Corpuscle

The renal corpuscle consists of a compact tuft of interconnected capillary loops, the glomerulus (pl. glomeruli) or glomerular capillaries, surrounded by a balloonlike
hollow capsule: Bowman’s capsule. Blood enters and leaves Bowman’s capsule through arterioles that penetrate the surface of the capsule at the vascular pole. A fluid-filled space (the urinary space or Bowman’s space) exists within the capsule, and it is into this space that fluid filters. Opposite the vascular pole, Bowman’s capsule has an opening that leads into the first portion of the tubule.

Diagram of a longitudinal section through a glomerulus and its juxtaglomerular (JG) apparatus. The JG apparatus consists of the granular cells (GC), which secrete renin, the macula densa (MD), and the extraglomerular mesangial cells (EGM). E, endothelium of the capillaries; EA, efferent arteriole; AA, afferent arteriole; PE, parietal (outer) epithelium of Bowman’s space; PO, podocytes of Bowman’s capsule; GBM, glomerular basement membrane; US, “urinary” (Bowman’s) space. (Reproduced with permission from Kriz W et al. In: Davidson AM, ed. Proceedings of the 10th International Congress on Nephrology, Vol 1. London: Balliere Tindall; 1987.)

The filtration barrier in the renal corpuscle through which all filtered substances must pass consists of 3 layers: the capillary endothelium of the glomerular capillaries, a rather thick basement membrane, and a single-celled layer of epithelial cells. The first layer, the endothelial cells of the capillaries, is perforated by many large fenestrae (“windows”), like a slice of Swiss cheese, and

A, Anatomy of the glomerulus. B, Cross-section of glomerular membranes. US, “urinary” (Bowman’s) space; E, epithelial foot processes; GBM, lomerular basement membranes; End, capillary endothelium; Cap, lumen of capillary. (Courtesy HG Rennke. Originally published in Fed Proc 1977;36:2019; reprinted with permission.) C, Scanning electron micrograph of podocytes covering glomerular capillary loops; the view is from inside Bowman’s space. The large mass is a cell body. Note the remarkable interdigitation of the foot processes from adjacent podocytes and the slits between them. (Courtesy of C. Tisher.)

is freely permeable to everything in the blood except red blood cells and platelets. The middle layer, the capillary basement membrane, is not a membrane in the sense of a lipid bilayer membrane but is a gel-like acellular meshwork of glycoproteins and proteoglycans, with a structure like a kitchen sponge. The third layer consists of epithelial cells that rest on the basement membrane and face Bowman’s space. These cells are called podocytes. They are quite different from the relatively simple, flattened epithelial cells that line the outside of Bowman’s capsule. The podocytes have an unusual octopus-like structure. Small “fingers,” called pedicels (or foot processes), extend from each arm of the podocyte and are embedded in the basement membrane. Pedicels from a given podocyte interdigitate with the pedicels from adjacent podocytes. Spaces between adjacent pedicels constitute the path through which the filtrate, once through the endothelial cells and basement membrane, travels to enter Bowman’s space. The foot processes are coated by a thick layer of extracellular material, which partially occludes the slits, and extremely thin processes called slit diaphragms bridge the slits between the pedicels. Slit diaphragms are widened versions of the tight junctions and adhering junctions that link all contiguous epithelial cells together. These are like miniature ladders. The pedicels form the sides of the ladder, and the slit diaphragms are the rungs.
The functional significance of this anatomic arrangement is that it permits the filtration of large volumes of fluid from the capillaries into Bowman’s space but restricts filtration of large plasma proteins such as albumin.
Another cell type—the mesangial cell—is found in the central part of the glomerulus between and within capillary loops. Glomerular mesangial cells act as phagocytes and remove trapped material from the basement membrane. They also contain large numbers of myofilaments and can contract in response to a variety of stimuli in a manner similar to vascular smooth muscle cells. The role of such contraction in influencing filtration by the renal corpuscles is discussed.

THE NEPHRON

Each kidney contains approximately 1 million nephrons, one of which is shown diagrammatically. Each nephron consists of a spherical filtering component, called the renal corpuscle, and a tubule extending from the renal corpuscle. Let us begin with the renal corpuscle, which is responsible for the initial step in urine formation: the separation of a protein-free filtrate from plasma.

Relationships of component parts of a long-looped nephron, which has been “uncoiled” for clarity (relative lengths of the different segments are not drawn to scale). The combination of glomerulus and Bowman’s capsule is the renal corpuscle.

ANATOMY OF THE KIDNEYS AND URINARY SYSTEM

The 2 kidneys lie outside the peritoneal cavity close to the posterior abdominal wall, 1 on each side of the vertebral column. Each of the 2 kidneys is a beanshaped structure. The rounded, outer convex surface of each kidney faces the side of the body, and the indented surface, called the hilum, is medial. Each hilum is penetrated by a renal artery, renal vein, nerves, and a ureter, which carries urine out of the kidney to the bladder. Each ureter within a kidney is formed from funnel-like structures called major calyces, which, in turn, are formed from minor calyces. The minor calyces fit over underlying cone-shaped renal tissue called pyramids. The tip of each pyramid is called a papilla and projects into a minor calyx. The calyces act as collecting cups for the urine formed by the renal tissue in the pyramids. The pyramids are arranged radially around the hilum, with the papillae pointing toward the hilum and the broad bases of the pyramids facing the outside, top, and bottom of the kidney (from the 12-o’clock to the 6-o’clock position). The pyramids constitute the medulla of the kidney. Overlying the medullary tissue is a cortex, and covering the cortical tissue on the very external surface of the kidney is a thin connective tissue capsule.
The working tissue mass of both the cortex and medulla is constructed almost entirely of tubules (nephrons and collecting tubules) and blood vessels (capillaries and capillary-like vessels). Tubules and blood vessels are intertwined (something like a plateful of spaghetti) or arranged in parallel arrays (like bundles of soda straws) and, in either case, are always close to each other. Between the tubules and blood vessels lies an interstitium, which comprises less than 10% of the renal volume. The interstitium contains fluid and scattered interstitial cells (fibroblasts and others) that synthesize an extracellular matrix of collagen, proteoglycans, and glycoproteins.
The cortex and medulla have very different properties both structurally and functionally. On closer examination, we see that (1) the cortex has a highly granular appearance, absent in the medulla, and (2) each medullary pyramid is divisible into an outer zone (adjacent to the cortex) and an inner zone, which includes the papilla. All these distinctions reflect the arrangement of the various tubules and blood vessels.

A, The urinary system. The urine formed by a kidney collects in the renal pelvis and then flows through the ureter into the bladder, from which it is eliminated via the urethra. B, Section of a human kidney. Half the kidney has been sliced away. Note that the structure shows regional differences. The outer portion (cortex) contains all the glomeruli. The collecting ducts form a large portion of the inner kidney (medulla), giving it a striped, pyramid-like appearance, and these drain into the renal pelvis. The papilla is in the inner portion of the medulla.

FUNCTIONS

A popular view considers the kidney to be an organ primarily responsible for the removal of metabolic waste from the body. Although this is certainly a major function of the kidneys, there are other functions that are arguably more important.
Function 1: Regulation of Water and Electrolyte Balance
The balance concept states that our bodies are in balance for any substance when the inputs and outputs of that substance are matched. Any difference between input and output leads to an increase or decrease in the amount of a substance within the body. Our input of water and electrolytes is enormously variable and is only sometimes driven in response to body needs. For example, we drink water when thirsty but we drink much more because it is a component of beverages that we consume for reasons other than hydration. We also consume food to provide energy, but food often contains large amounts of water. The kidneys respond by varying the output of water in the urine, thereby maintaining balance for water (ie, constant total body water content). Minerals
like sodium, potassium, magnesium, and so on are components of foods and generally present far in excess of body needs. As with water, the kidneys excrete minerals at a highly variable rate that, in the aggregate, matches input. One of the amazing feats of the kidneys is their ability to regulate each of these minerals independently (ie, we can be on a high-sodium, low-potassium diet or low-sodium, high-potassium diet, and the kidneys will adjust excretion of each of these substances appropriately).

Function 2: Excretion of Metabolic Waste
Our bodies continuously form end products of metabolic processes. In most cases, those end products serve no function and are harmful at high concentrations. Some of these waste products include urea (from protein), uric acid (from nucleic acids), creatinine (from muscle creatine), the end products of hemoglobin breakdown (which give urine much of its color), and the metabolites of various hormones, among many others.

Function 3: Excretion of Bioactive Substances (Hormones and Many Foreign Substances, Specifically Drugs) That Affect Body Function
Drugs and hormones in the blood are removed in many ways, mostly in the liver, but a number of them are removed in parallel by renal processes. Physicians have to be mindful of how fast the drugs are excreted in order to prescribe a dose that achieves the appropriate body levels.

Function 4: Regulation of Arterial Blood Pressure
Although many people appreciate at least vaguely that the kidneys excrete waste substances like urea (hence the name urine) and salts, few realize the kidneys’ crucial role in controlling blood pressure. Blood pressure ultimately depends on blood volume, and the kidneys’ maintenance of sodium and water balance achieves regulation of blood volume. Thus, through volume control, the kidneys participate in blood pressure control. They also participate in regulation of blood pressure via the generation of vasoactive substances that regulate smooth muscle in the peripheral vasculature.

Function 5: Regulation of Red Blood Cell Production
Erythropoietin is a peptide hormone that is involved in the control of erythrocyte (red blood cell) production by the bone marrow. Its major source is the kidneys, although the liver also secretes small amounts. The renal cells that secrete it are a particular group of cells in the interstitium. The stimulus for its secretion is a reduction in the partial pressure of oxygen in the kidneys, as occurs, eg, in anemia, arterial hypoxia, and inadequate renal blood flow. Erythropoietin stimulates the bone marrow to increase its production of erythrocytes. Renal disease may result in diminished erythropoietin secretion, and the ensuing decrease in bone marrow activity is one important causal factor of the anemia of chronic renal disease.

Function 6: Regulation of Vitamin D Production
When we think of vitamin D, we often think of sunlight or additives to milk. In vivo vitamin D synthesis involves a series of biochemical transformations, the last of which occurs in the kidneys. The active form of vitamin D (1,25-dihydroxyvitamin D3) is actually made in the kidneys, and its rate of synthesis is regulated by hormones that control calcium and phosphate balance.

Function 7: Gluconeogenesis
Our central nervous system is an obligate user of blood glucose regardless of whether we have just eaten sugary doughnuts or gone without food for a week. Whenever the intake of carbohydrate is stopped for much more than half a day, our body begins to synthesize new glucose (the process of gluconeogenesis) from noncarbohydrate sources (amino acids from protein and glycerol from triglycerides). Most gluconeogenesis occurs in the liver, but a substantial fraction occurs in the kidneys, particularly during a prolonged fast.

Most of what the kidneys actually do to perform the functions just mentioned involves transporting water and solutes between the blood flowing through the kidneys and the lumina of tubules (nephrons and collecting tubules that comprise the working mass of the kidneys). The lumen of a nephron is topologically outside the body, and any substance in the lumen that is not transported back into the blood is eventually excreted in the urine. As we explore renal function in more detail, we will constantly refer to tubular structure and the surrounding vasculature. Therefore, in the following section, we present the essential aspects of renal anatomy that are necessary to understand function.