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.