Physiology_Levy

Physiology_Levy. A large variety of diseases impair kidney function and result in renal failure. In some instances the impairment in renal function is transient, but in many cases renal function declines progressively. Patients in whom the glomerular filtration rate (GFR) is less than 10% of normal are said to have end-stage renal disease (ESRD) and must receive renal replacement therapy in the form of either dialysis or kidney transplantation to survive. To understand the mechanisms that contribute to renal disease, it is first necessary to understand the normal physiology of renal function. Thus in the following chapters in this section of the book, various aspects of renal function are considered. Functional Anatomy of the Kidneys Structure and function are closely linked in the kidneys. Consequently an appreciation of the gross anatomical and histological features of the kidneys is a prerequisite for understanding their functions.


Physiology_Levy

Physiology_Levy. The kidneys are paired organs that lie on the posterior wall of the abdomen behind the peritoneum on either side of the vertebral column. In an adult human, each kidney weighs between 115 and 170 g and is approximately 11 cm long, 6 cm wide, and 3 cm thick. The gross anatomical features of the human kidney are illustrated in Fig. 33.1 . The medial side of each kidney contains an indentation through which pass the renal artery and vein, nerves, and pelvis. If a kidney were cut in half, two regions would be evident: an outer region called the cortex and an inner region called the medulla. The cortex and medulla are composed of nephrons (the functional units of the kidney), blood vessels, lymphatics, and nerves. The Kidney disease is a major health problem worldwide. In the United States alone: CKD affects over 23 million patients and accounts for more than 90,000 deaths annually. Kidney diseases represent the ninth leading cause of death.


Physiology_Levy

Physiology_Levy. CKD affects over 23 million patients and accounts for more than 90,000 deaths annually. Kidney diseases represent the ninth leading cause of death. The health care cost for CKD in Medicare patients alone exceeds $44 billion per year. Each year, kidney disease is diagnosed in over 3 million new patients. Over 500,000 people are treated for ESRD every year. Approximately 275,000 patients with ESRD are maintained on either hemodialysis or peritoneal dialysis. Diabetes and hypertension are the leading causes of ESRD. ESRD secondary to diabetes is increasing at an annual rate of more than 11% per year. More than 17,000 kidney transplants are performed each year. Unfortunately, in excess of 100,000 patients are awaiting kidney transplants.


Physiology_Levy

Physiology_Levy. Urinary tract infections (8.3 million visits annually), urolithiasis (i.e., kidney and urinary tract stones; 1.3 million visits annually), interstitial cystitis (i.e., inflammation of the urinary bladder; 700,000 patients), and urinary incontinence (13 million adults affected, mostly older than 65) are also major health care problems. Individuals with ESRD must undergo renal replacement therapy, which includes peritoneal dialysis, hemodialysis, and kidney transplantation. Both peritoneal dialysis and hemodialysis, as their names suggest, rely on the ability to remove small dialyzable molecules from the blood—including metabolic waste products normally removed by intact kidneys—via diffusion across a selectively permeable membrane into a solution lacking these substances, thereby mitigating both their accumulation and associated adverse health effects. In addition, dialysis helps reestablish both fluid and electrolyte balance via removal of excess fluid, correction of acid-base


Physiology_Levy

Physiology_Levy. both their accumulation and associated adverse health effects. In addition, dialysis helps reestablish both fluid and electrolyte balance via removal of excess fluid, correction of acid-base changes, and normalization of plasma electrolyte concentrations). In peritoneal dialysis, the peritoneal membrane lining the abdominal cavity acts as a dialyzing membrane. Several liters of a defined dialysis solution are typically introduced into the abdominal cavity, and small molecules in blood diffuse across the peritoneal membrane into the solution, which can then be iteratively removed, discarded, and replaced. In hemodialysis, a patient’s blood is pumped through an extracorporeal artificial kidney in which blood is separated from a defined dialysis solution by an artificial semipermeable membrane that allows small molecules to diffuse from the blood down their concentration gradient into the dialysis solution, thereby removing small molecules associated with adverse health effects if


Physiology_Levy

Physiology_Levy. membrane that allows small molecules to diffuse from the blood down their concentration gradient into the dialysis solution, thereby removing small molecules associated with adverse health effects if allowed to accumulate in patients without functioning kidneys. Patients who are candidates for renal transplantation are often treated with dialysis until an appropriate donor kidney can be procured. Although anemia has historically been a significant problem in ESRD patients owing to severely reduced endogenous erythropoietin production, this problem can now be easily corrected in patients undergoing chronic dialysis via administration of erythropoiesis-stimulating agents (e.g., recombinant human erythropoietin).


Physiology_Levy

Physiology_Levy. CHAPTER 33 Elements of Renal Function 583 • Fig. 33.1 Structure of a human kidney, cut open to show the internal structures. (Modified From Boron WF, Boulpaep EL. Medical Physiology. 2nd ed. Philadelphia: Saunders Elsevier; 2009.) medulla in the human kidney is divided into conical masses called renal pyramids. The base of each pyramid originates at the corticomedullary border, and the apex terminates in a papilla, which lies within a minor calyx. Minor calyces collect urine from each papilla. The numerous minor calyces expand into two or three open-ended pouches, the major calyces. The major calyces in turn feed into the pelvis. The pelvis represents the upper expanded region of the ureter, which carries urine from the pelvis to the urinary bladder. The walls of the calyces, pelvis, and ureters contain smooth muscle that contracts to propel the urine toward the urinary bladder.


Physiology_Levy

Physiology_Levy. Blood flow to the two kidneys is equivalent to about 25% (1.25 L/min) of the cardiac output in resting individuals. However, the kidneys constitute less than 0.5% of total body weight. As illustrated in Fig. 33.2 (left), the renal artery branches progressively to form the interlobar artery, the arcuate artery, the interlobular artery, and the afferent arteriole, which leads into the glomerular capillaries. The glomerular capillaries come together to form the efferent arteriole, which leads into a second capillary network, the peritubular capillaries, which supply blood to the nephron. The vessels of the venous system run parallel to the arterial vessels and progressively form the interlobular vein, arcuate vein, interlobar vein, and renal vein, which courses beside the ureter. Ultrastructure of the Nephron


Physiology_Levy

Physiology_Levy. Ultrastructure of the Nephron The functional unit of the kidneys is the nephron. Each human kidney contains approximately 1.2 million nephrons, which are essentially hollow tubes composed of a single epithelial cell layer. The nephron consists of a renal corpuscle, proximal tubule, loop of Henle, distal tubule, and collecting duct system (Fig. 33.3


Physiology_Levy

Physiology_Levy. Fig. 33.2 ). The renal corpuscle consists of glomerular capillaries enclosed within Bowman’s capsule. The proximal tubule exits this structure and initially forms several coils, followed by a straight piece that descends toward the medulla. The next segment is the loop of Henle, which is composed of aThe organization of the nephron is actually more complicated than presented here. However, for simplicity and clarity of presentation in subsequent chapters, the nephron is divided into five segments. The collecting duct system is not actually part of the nephron. However, again for simplicity, we consider the collecting duct system part of the nephron. bAlthough the renal corpuscle is composed of glomerular capillaries and Bowman’s capsule, the term glomerulus is commonly used to described the renal corpuscle.


Physiology_Levy

Physiology_Levy. • Fig. 33.2 Left, Organization of the vascular system of the human kidney. 1, interlobar arteries; 1a, interlobar vein; 2, arcuate arteries; 2a, arcuate veins; 3, interlobular arteries; 3a, interlobular veins; 4, stellate vein; 5, afferent arterioles; 6, efferent arterioles; 7a, 7b, glomerular capillary networks; 8, descending vasa recta; 9, ascending vasa recta. Right, Organization of the human nephron. A superficial nephron is illustrated on the left and a juxtamedullary (JM) nephron is illustrated on the right. The loop of Henle includes the straight portion of the proximal tubule (PT), descending thin limb (DTL), ascending thin limb (ATL), and thick ascending limb (TAL). B, Bowman’s capsule; CCD, cortical collecting duct; DT, distal tubule; IMCD, inner medullary collecting duct; MD, macula densa; OMCD, outer medullary collecting duct; P, pelvis. (Modified from Kriz W, Bankir LA. Am J Physiol 1988;254:F1; and Koushanpour E, Kriz W. Renal Physiology: Principles, Structure, and


Physiology_Levy

Physiology_Levy. MD, macula densa; OMCD, outer medullary collecting duct; P, pelvis. (Modified from Kriz W, Bankir LA. Am J Physiol 1988;254:F1; and Koushanpour E, Kriz W. Renal Physiology: Principles, Structure, and Function. 2nd ed. New York: Springer-Verlag; 1986.) the straight part of the proximal tubule, the descending thin limb (which ends in a hairpin turn), the ascending thin limb (only in nephrons with long loops of Henle), and the thick ascending limb. Near the end of the thick ascending limb, the nephron passes between the afferent and efferent arterioles of the same nephron. This short segment of the thick ascending limb abutting the glomerulus is called the macula densa (see


Physiology_Levy

Physiology_Levy. Figs. 33.2 33.3 ). The distal tubule begins a short distance beyond the macula densa and extends to the point in the cortex where two or more nephrons join to form a cortical collecting duct. The cortical collecting duct enters the medulla and becomes the outer medullary collecting duct and then the inner medullary collecting duct. Each nephron segment is made up of cells that are uniquely suited to perform specific transport functions (see


Physiology_Levy

Physiology_Levy. Each nephron segment is made up of cells that are uniquely suited to perform specific transport functions (see Fig. 33.3 ). Proximal tubule cells have an extensively amplified apical membrane (the ultrafiltrate or urine side of the cell) called the brush border, which is present only in the proximal tubule. The basolateral membrane (the interstitial or blood side of the cell) is highly invaginated. These invaginations contain many mitochondria. In contrast, the descending and ascending thin limbs of the loop of Henle have poorly developed apical and basolateral surfaces and few mitochondria. The cells of the thick ascending limb and the distal tubule have abundant mitochondria and extensive infoldings of the basolateral membrane. The collecting duct is composed of two cell types: principal cells and intercalated cells. Principal cells have a moderately invaginated basolateral membrane and contain few mitochondria (see


Physiology_Levy

Physiology_Levy. The collecting duct is composed of two cell types: principal cells and intercalated cells. Principal cells have a moderately invaginated basolateral membrane and contain few mitochondria (see Fig. 33.3 ). Principal cells play an important role in reabsorption of NaCl (see ) and secretion of K+ (see ). Intercalated cells, which play an important role in regulating acid-base balance, have a high density of mitochondria (see Fig. 33.3 ). One population of intercalated cells secretes H+ (i.e., reabsorbs HCO3 −), and a second population secretes HCO3 − (see ). The final segment of the nephron, the inner medullary collecting duct, is composed of inner medullary collecting duct cells, which have poorly developed apical and basolateral surfaces and few mitochondria. All cells in the nephron except intercalated cells have in their apical plasma membrane a single nonmotile primary cilium that protrudes into the tubule fluid (


Physiology_Levy

Physiology_Levy. All cells in the nephron except intercalated cells have in their apical plasma membrane a single nonmotile primary cilium that protrudes into the tubule fluid ( Fig. 33.4 ). Primary cilia are mechanosensors (i.e., they sense changes in the rate of flow of tubule fluid) and chemosensors (i.e., they sense or respond to compounds in the surrounding fluid), and they initiate Ca++-dependent signaling pathways, including those that control kidney cell function, proliferation, differentiation, and apoptosis (i.e., programmed cell death).


Physiology_Levy

Physiology_Levy. Fig. 33.2 ), with approximately 10 superficial nephrons for each juxtamedullary nephron. The 585 • Fig. 33.3 Diagram of a nephron including cellular ultrastructure. Inner medulla collecting duct Ascending thin limbThick ascending limb Descending thin limb Proximal tubule Macula densa Cortical collecting duct Distal tubule Principal cell Intercalated cell OutermedullaInner medulla Cortex • Fig. 33.4 Scanning electron micrograph illustrating primary cilia (C, ≈2 to 30 µm long and 0.5 µm in diameter) in the apical plasma membrane of principal cells in the cortical collecting duct. Note that intercalated cells (IC1 and IC2) do not have cilia but have numerous microvilli. CD, collecting duct principal cells with short microvilli (arrowhead); straight ridges (open arrow) represent the cell borders between principal cells; IC1 and IC2, intercalated cells with numerous long microvilli in the apical membrane. (From Kriz W, Kaissling B. Structural organization of the mammalian kidney. In:


Physiology_Levy

Physiology_Levy. borders between principal cells; IC1 and IC2, intercalated cells with numerous long microvilli in the apical membrane. (From Kriz W, Kaissling B. Structural organization of the mammalian kidney. In: Seldin DW, Giebisch G [eds]. The Kidney: Physiology and Pathophysiology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2000.) glomerulus of each superficial nephron is located in the outer region of the cortex. The corresponding loops of Henle are short, and associated efferent arterioles branch into peritubular capillaries that surround its associated nephron segments as well as adjacent nephrons. This capillary network conveys oxygen and important nutrients to the nephron segments in the cortex, delivers substances to individual nephron segments for secretion (i.e., movement of a substance from blood into tubular fluid), and serves as a pathway for return of reabsorbed water and solutes to the circulatory system. A few species, including humans,


Physiology_Levy

Physiology_Levy. Polycystin 1 (encoded by the PKD1 gene) and polycystin 2 (encoded by the PKD2 gene) are expressed in the membrane of primary cilia and mediate entry of Ca++ into cells. PKD1 and PKD2 are thought to play an important role in flow-dependent K+ secretion by principal cells of the collecting duct. As described in more detail in Chapter 36, increased flow of tubule fluid in the collecting duct is a strong stimulus for secretion of K+ . Increased flow bends the primary cilium in principal cells, which activates the PKD1/PKD2 Ca++-conducting channel complex and allows Ca++ to enter the cell and increase intracellular [Ca++]. The increase in [Ca++] activates K+ channels in the apical plasma membrane, which enhances secretion of K+ from the cell into the tubule fluid.


Physiology_Levy

Physiology_Levy. Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, occurring in about 1 in 1000 people. Approximately 12.5 million people worldwide have ADPKD, which is caused primarily by mutations in PKD1 (85%–90% of cases) or PKD2 (≈15% of cases). The major phenotype of ADPKD is enlargement of the kidneys due to the presence of hundreds or thousands of space-occupying renal cysts that can be as large as 20 cm in diameter. Cysts are also seen in the liver and other organs in this condition. About 50% of patients with ADPKD progress to renal failure by the age of 60. Although it is not clear how mutations in PKD1 and PKD2 cause ADPKD, renal cyst formation may result from defects in Ca++ uptake that alter Ca++-dependent signaling pathways, including those controlling kidney cell proliferation, differentiation, and apoptosis. also possess very short superficial nephrons whose loops of Henle never enter the medulla.


Physiology_Levy

Physiology_Levy. also possess very short superficial nephrons whose loops of Henle never enter the medulla. The glomerulus of each juxtamedullary nephron is located in the region of the cortex adjacent to the medulla (see Fig. 33.2, right). When compared with superficial nephrons, juxtamedullary nephrons differ anatomically in two important ways: the loop of Henle is longer and extends deeper into the medulla, and the efferent arteriole forms not only a network of peritubular capillaries but also a series of accompanying vascular loops called the vasa recta.


Physiology_Levy

Physiology_Levy. Fig. 33.2 (left), the vasa recta descend into the medulla, where they form capillary networks that surround the collecting ducts and ascending limbs of the loop of Henle. The blood returns to the cortex via the ascending vasa recta. Although less than 0.7% of the renal blood flow (RBF) enters the vasa recta, these vessels serve important functions in the renal medulla that include (1) conveying oxygen and important metabolic substrates to support nephron function, (2) delivering substances to the nephron for secretion, (3) serving as a pathway for return of reabsorbed water and solutes to the circulatory system, and (4) concentrating and diluting urine (urine concentration and dilution are discussed in more detail in Ultrastructure of the Glomerulus


Physiology_Levy

Physiology_Levy. Ultrastructure of the Glomerulus The first step in urine formation begins with passive movement of a plasma ultrafiltrate from the glomerular capillaries (i.e., glomerulus) into Bowman’s space. The term ultrafiltration refers to this passive movement of fluid—similar in composition to plasma, except for the fact that the ultrafiltrate protein concentration is much lower than that in the plasma—from the glomerular capillaries into Bowman’s space. To appreciate this process, one must understand the anatomy of the glomerulus, which consists of a network of capillaries supplied by the afferent arteriole and drained by the efferent arteriole ( Figs. 33.5 33.6 ). During embryological development, the glomerular capillaries press into the closed end of the proximal tubule, forming Bowman’s capsule. As the epithelial cells thin on the outside circumference of Bowman’s capsule, they form the parietal epithelium (see


Physiology_Levy

Physiology_Levy. Fig. 33.5 ). The epithelial cells in contact with the capillaries thicken and develop into podocytes, which form the visceral layer of Bowman’s capsule ( Figs. 33.7–33.9 ). The visceral cells face outward at the vascular pole (i.e., where afferent and efferent arterioles enter and exit Bowman’s capsule) to form the parietal layer of Bowman’s capsule. The space between the visceral layer and the parietal layer is Bowman’s space, which at the urinary pole (i.e., where the proximal tubule joins Bowman’s capsule) of the glomerulus becomes the lumen of the proximal tubule. The endothelial cells of glomerular capillaries are covered by a basement membrane surrounded by podocytes. The capillary endothelium, basement membrane, and foot processes of podocytes form the so-called filtration barrier (see Figs. 33.5 and 33.7–33.9 ). The endothelium is fenestrated


Physiology_Levy

Physiology_Levy. Fig. 33.5 Anatomy of the glomerulus and juxtaglomerular apparatus. The juxtaglomerular apparatus is composed of the macula densa (MD) of the thick ascending limb, extraglomerular mesangial cells (EGM), and renin-and angiotensin II–producing granular cells (G) of the afferent arterioles (AA). BM, basement membrane; BS, Bowman’s space; EA, efferent arteriole; EN, endothelial cell; FP, foot processes of the podocyte; M, mesangial cells between capillaries; P, podocyte cell body (visceral cell layer); PE, parietal epithelium; PT, proximal tubule cell. (Modified from Kriz W, Kaissling B. Structural organization of the mammalian kidney. In Alpern RJ, Moe OW, Caplan M [eds]: Seldin and Giebisch’s The Kidney, 5th ed. London, Elsevier, 2013. Figure in that source based on Kriz W, Sakai T, et al. [1988]. Morphological aspects of glomerular function. In “Nephrology,” A. M. Davison, Vol. 1, Proceedings of the 10th International Congress of Nephrology, 323. Bailliere Tindall, London.)


Physiology_Levy

Physiology_Levy. Fig. 33.6 Scanning electron micrograph of the interlobular artery, afferent arteriole (af), efferent arteriole (ef), and glomerulus. The white bars on the afferent and efferent arterioles indicate that they are about 15 to 20 µm in diameter. (From Kimura K et al. Am J Physiol 1990;259:F936.) • Fig. 33.7 A, Electron micrograph of a podocyte surrounding a glomerular capillary. The cell body of the podocyte contains a large nucleus with three indentations. Cell processes of the podocyte form the interdigitating foot processes (FP). The arrows in the cytoplasm of the podocyte indicate the well-developed Golgi apparatus, and the asterisks indicate Bowman’s space. C, capillary lumen; GBM, glomerular basement membrane. B, Electron micrograph of the filtration barrier of a glomerular capillary. The filtration barrier is composed of three layers: the endothelium, basement membrane, and foot processes of the podocytes. Note the filtration slit diaphragm bridging the floor of the filtration


Physiology_Levy

Physiology_Levy. The filtration barrier is composed of three layers: the endothelium, basement membrane, and foot processes of the podocytes. Note the filtration slit diaphragm bridging the floor of the filtration slits (arrows). CL, capillary lumen. (From Kriz W, Kaissling B: Structural organization of the mammalian kidney. In: Alpern RJ, Moe OW, Caplan M [eds]: Seldin and Giebisch’s The Kidney, 5th ed. London, Elsevier, 2013.) (i.e., contains 700-Å holes, where 1 Å = 10−10 m) and freely permeable to water, small solutes (e.g., Na+ , urea, glucose), and most proteins but is not permeable to red blood cells, white blood cells, or platelets. Because endothelial cells express negatively charged glycoproteins on their surface, they minimize the filtration into Bowman’s space of albumin, the most abundant plasma protein, and most • Fig. 33.8 A, Scanning electron micrograph showing the outer surface of glomerular capillaries. This is the view that would be seen from Bowman’s space. Processes (P) of


Physiology_Levy

Physiology_Levy. plasma protein, and most • Fig. 33.8 A, Scanning electron micrograph showing the outer surface of glomerular capillaries. This is the view that would be seen from Bowman’s space. Processes (P) of podocytes run from the cell body (CB) toward the capillaries, where they ultimately split into foot processes. Interdigitation of the foot processes creates the filtration slits. B, Scanning electron micrograph of the inner surface (blood side) of a glomerular capillary. This view would be seen from the lumen of the capillary. The fenestrations of the endothelial cells are seen as small 700-Å holes. (From Kriz W, Kaissling B: Structural organization of the mammalian kidney. In: Alpern RJ, Moe OW, Caplan M [eds]: Seldin and Giebisch’s The Kidney, 5th ed. London, Elsevier, 2013.) other plasma proteins. In addition to their role as a barrier to filtration, the endothelial cells synthesize a number of vasoactive substances (e.g., nitric oxide [NO], a vasodilator, and endothelin 1 [ET-1], a


Physiology_Levy

Physiology_Levy. proteins. In addition to their role as a barrier to filtration, the endothelial cells synthesize a number of vasoactive substances (e.g., nitric oxide [NO], a vasodilator, and endothelin 1 [ET-1], a vasoconstrictor) that are important in controlling renal plasma flow (RPF). The basement • Fig. 33.9 Electron micrograph of the mesangium, the area between the glomerular capillaries containing mesangial cells. C, glomerular capillaries; cGBM, capillary glomerular basement membrane surrounded by foot processes of podocytes (PO) and endothelial cells; M, mesangial cell that gives rise to several processes, some marked by stars; mGBM, mesangial glomerular basement membrane surrounded by foot processes of podocytes and mesangial cells; US, urinary space. Note the extensive extracellular matrix surrounded by mesangial cells (triangles) (×4100). (From Kriz W, Kaissling B: Structural organization of the mammalian kidney. In: Alpern RJ, Moe OW, Caplan M [eds]: Seldin and Giebisch’s The Kidney,


Physiology_Levy

Physiology_Levy. surrounded by mesangial cells (triangles) (×4100). (From Kriz W, Kaissling B: Structural organization of the mammalian kidney. In: Alpern RJ, Moe OW, Caplan M [eds]: Seldin and Giebisch’s The Kidney, 5th ed. London, Elsevier, 2013.) membrane, which is a porous matrix of negatively charged proteins (type IV collagen, laminin, the proteoglycans agrin and perlecan, and fibronectin), is an important filtration barrier to plasma proteins. The basement membrane is thought to function primarily as a charge-selective filter in which the ability of proteins to cross the filter is based on charge.


Physiology_Levy

Physiology_Levy. The podocytes, which are endocytic, have long finger-like processes that completely encircle the outer surface of the capillaries (see Figs. 33.7 33.8A ). The processes of the podocytes interdigitate to cover the basement membrane and are separated by apparent gaps called filtration slits (see Figs. 33.7 33.8A ). Each filtration slit is bridged by a thin diaphragm that contains pores with a dimension of 40 × 140 Å. The filtration slit diaphragm, which appears as a continuous structure when viewed by electron microscopy (see Fig. 33.7B ), is composed of several proteins, including nephrin (NPHS1), NEPH-1, and podocin (NPHS2), and intracellular proteins that associate with the slit diaphragm, including α-actinin-4 (ACTN4) and CD2-AP (


Physiology_Levy

Physiology_Levy. Figs. 33.10 33.11 ). Filtration slits, which function primarily as a size-selective filter, minimize the filtration of proteins and macromolecules that cross the basement membrane from entering Bowman’s space. Because both the basement membrane and filtration slits contain negatively charged glycoproteins, some proteins are held back (i.e., not filtered into Bowman’s space) on the basis of size and charge. For molecules with an effective molecular radius between 18 and 42 Å, cationic molecules are filtered more readily than anionic molecules. Another important component of the renal corpuscle is the mesangium, which consists of mesangial cells and the mesangial matrix (see


Physiology_Levy

Physiology_Levy. Another important component of the renal corpuscle is the mesangium, which consists of mesangial cells and the mesangial matrix (see Fig. 33.9 ). Mesangial cells, which possess many properties of smooth muscle cells, provide structural support for the glomerular capillaries, secrete extracellular matrix, exhibit phagocytic activity by removing macromolecules from the mesangium, and secrete prostaglandins and proinflammatory cytokines. Because they also contract and are adjacent to glomerular capillaries, mesangial cells may influence GFR by regulating blood flow through the glomerular capillaries or by altering the capillary surface area. Mesangial cells located outside the glomerulus (between the afferent and efferent arterioles) are called extraglomerular mesangial cells.


Physiology_Levy

Physiology_Levy. The nephrotic syndrome is produced by a variety of disorders and is characterized by increased permeability of the glomerular capillaries to proteins and by loss of normal podocyte structure, including effacement (i.e., thinning) of foot processes. The augmented permeability to proteins results in increased urinary protein excretion (proteinuria). Thus the appearance of proteins in urine can indicate kidney disease. Individuals with this syndrome often develop hypoalbuminemia as a result of the proteinuria. In addition, generalized edema is commonly seen in nephrotic individuals. Mutations in several genes encoding either slit diaphragm proteins (see


Physiology_Levy

Physiology_Levy. Figs. 33.10 33.11), including nephrin, NEPH-1, and podocin, or intracellular proteins that functionally interact with slit diaphragm proteins, such as CD2-AP and α-actinin 4 (ACTN4), result in proteinuria and kidney disease. For example, mutations in the nephrin gene (NPHS1) in congenital nephrotic syndrome lead to abnormal or absent slit diaphragms, causing massive proteinuria and renal failure. In addition, mutations in the podocin gene (NPHS2) cause autosomal recessive, steroid-resistant nephrotic syndrome. These naturally occurring mutations and knockout studies in mice demonstrate that nephrin, NEPH-1, podocin, CD2-AP, and α-actinin-4 play key roles in normal glomerular podocyte structure and function.


Physiology_Levy

Physiology_Levy. • Fig. 33.10 Anatomy of podocyte foot processes. This figure illustrates the proteins that make up the slit diaphragm between two adjacent foot processes. Nephrin and NEPH1 are membrane-spanning proteins that have large extracellular domains that interact. Podocin, also a membrane-spanning protein, organizes nephrin and NEPH1 in specific microdomains in the plasma membrane, which is important for signaling events that determine the structural integrity of podocyte foot processes. Many of the proteins that compose the slit diaphragm interact with adapter proteins inside the cell, including CD2-AP. The adapter proteins bind to the filamentous actin (F-actin) cytoskeleton, which in turn binds either directly or indirectly to proteins such as α3β1 and MAGI-1 that interact with proteins expressed by the glomerular basement membrane (GBM). α-act-4, α-actinin 4; α3β1, α3β1 integrin; α-DG, α-dystroglycan; CD2-AP, an adapter protein that links nephrin and podocin to intracellular proteins;


Physiology_Levy

Physiology_Levy. by the glomerular basement membrane (GBM). α-act-4, α-actinin 4; α3β1, α3β1 integrin; α-DG, α-dystroglycan; CD2-AP, an adapter protein that links nephrin and podocin to intracellular proteins; FAT, a protocadherin that organizes actin polymerization; MAGI-1, a membrane-associated guanylate kinase protein; NHERF-2, Na+-H+ exchanger regulatory factor 2; P, paxillin; P-Cad, P-cadherin; Synpo, synaptopodin; T, talin; V, vinculin; Z, zona occludens. (Adapted from Mundel P, Shankland SJ. J Am Soc Nephrol 2002;13:3005.)


Physiology_Levy

Physiology_Levy. Mesangial cells are involved in development of immune complex–mediated glomerular disease. Because the glomerular basement membrane does not completely surround all glomerular capillaries (see Fig. 33.9 ), some immune complexes can escape the blood and enter the mesangium without crossing the glomerular basement membrane. Accumulation of immune complexes induces mesangial infiltration of inflammatory cells and promotes local proinflammatory cytokine and autocoid production. These cytokines and autocoids enhance the immune complex– initiated inflammatory response, which can ultimately lead to mesangial expansion, scarring, and obliteration of the glomerulus. Ultrastructure of the Juxtaglomerular Apparatus The juxtaglomerular apparatus is one component of an important feedback mechanism, the tubuloglomerular feedback mechanism, described later in this chapter. Structures that make up the juxtaglomerular apparatus (see Fig. 33.5 ) include: 1.


Physiology_Levy

Physiology_Levy. Fig. 33.5 ) include: 1. the macula densa of the thick ascending limb 2. 3. reninand angiotensin II–producing granular cells of the afferent arteriole


Physiology_Levy

Physiology_Levy. 3. reninand angiotensin II–producing granular cells of the afferent arteriole Alport syndrome is characterized by hematuria (i.e., blood in the urine) and progressive glomerulonephritis (i.e., inflammation of the glomerular capillaries), and it accounts for 1% to 2% of all cases of ESRD. Alport syndrome is caused by mutations in type IV collagen, a major component of the glomerular basement membrane. In about 80% of patients with Alport syndrome the disease is X-linked with mutations in the COL4A5 gene. Some 15% of patients also have mutations in type IV collagen genes (COL4A3 and COL4A4); six have been identified, but the mode of inheritance is autosomal recessive. The remaining 5% of patients with Alport syndrome have autosomal dominant disease that arises from heterozygous mutations in the COL4A3 or COL4A4 genes. In Alport syndrome, the glomerular basement membrane becomes irregular in thickness and fails to serve as an effective filtration barrier to blood cells and protein.


Physiology_Levy

Physiology_Levy. The cells of the macula densa represent a morphologically distinct region of the thick ascending limb. This region passes through the angle formed by the afferent and efferent arterioles of the same nephron. The cells of the macula densa contact the extraglomerular mesangial cells and the granular cells of the afferent arterioles. The granular cells of the afferent arterioles contain smooth muscle myofilaments and—importantly—manufacture, store, and release renin in response to signals associated with decreased effective • Fig. 33.11 Overview of the major proteins that form the slit diaphragm. Nephrins (red) from opposite foot processes interdigitate in the center of the slit. In the slit, nephrin interacts with NEPH1 and NEPH2 (blue), FAT1 and FAT2 (green), and P-cadherin. The intracellular domains of nephrin, NEPH1, and NEPH2 interact with podocin and CD2-AP, which connect these slit diaphragm proteins with ZO-1, α-actinin 4, and actin. (Modified from Tryggvason K et al. N Engl J


Physiology_Levy

Physiology_Levy. domains of nephrin, NEPH1, and NEPH2 interact with podocin and CD2-AP, which connect these slit diaphragm proteins with ZO-1, α-actinin 4, and actin. (Modified from Tryggvason K et al. N Engl J Med 2006;354:1387.) circulating volume and reduced renal perfusion. Renin is involved in proteolytic generation of angiotensin II and ultimately in secretion of aldosterone (see ). The juxtaglomerular apparatus is one component of the tubuloglomerular feedback mechanism involved in autoregulation of RBF and GFR.


Physiology_Levy

Physiology_Levy. Innervation of the Kidneys Renal nerves regulate RBF, GFR, and salt and water reabsorption by the nephron. The nerve supply to the kidneys consists of sympathetic nerve fibers that originate in the celiac plexus. There is no corresponding parasympathetic innervation. Adrenergic fibers innervating the kidneys release norepinephrine and lie adjacent to the smooth muscle cells of the major branches of the renal artery (interlobar, arcuate, and interlobular arteries) as well as the afferent and efferent arterioles. In addition, sympathetic nerves innervate the renin-producing granular cells of the afferent arterioles. Renin secretion is stimulated by increased sympathetic activity. Nerve fibers also innervate the proximal tubule, loop of Henle, distal tubule, and collecting duct; activation of these nerves enhances Na+ reabsorption by these nephron segments. Assessment of Renal Function


Physiology_Levy

Physiology_Levy. Assessment of Renal Function The coordinated actions of the nephron’s various segments determine the final amount of a substance that appears in urine. This represents three general processes (1) glomerular CHAPTER 33 Elements of Renal Function This relationship permits quantification of the amount of substance x excreted in urine versus the amount returned to the systemic circulation in renal venous blood. Thus for any substance that is neither synthesized nor metabolized, the amount that enters the kidneys is equal to the amount that leaves the kidneys in urine plus the amount that leaves the kidneys in renal venous blood. The principle of renal clearance emphasizes the excretory function of the kidneys; it considers only the rate at which a substance is excreted into urine and not its rate of return to the systemic circulation in the renal vein. Therefore in terms of mass balance (


Physiology_Levy

Physiology_Levy. Eq. 33.1 ) the urinary excretion rate of substance x (Ux × V̇ ) is proportional to the plasma concentration of substance x ( Equation 33.2 To equate the urinary excretion rate of substance x to • Fig. 33.12 Mass balance relationships for the kidney. See text for definition of symbols. its renal arterial plasma concentration, it is necessary to determine the rate at which it is removed from plasma by filtration, (2) reabsorption of the substance from tubular the kidneys. This removal rate is the clearance (Cx): fluid back into blood, and (3) (in some cases) secretion of Equation 33.3 the substance from blood into tubule fluid. The first step in P × C = U × V˜ urine formation by the kidneys is production of an ultrafil-xa x x trate of plasma across the glomerulus. The process of glo-If


Physiology_Levy

Physiology_Levy. Eq. 33.3 is rearranged and the concentration of merular filtration and regulation of GFR and RBF substance x in renal artery plasma ( ) is assumed to beare discussed later in this chapter. The concept of renal clearance, which is the theoretical basis for measurement of GFR and RBF, is presented in the following section. Reabsorption and secretion are discussed in subsequent chapters. The concept of renal clearance is based on the Fick principle (i.e., mass balance or conservation of mass). Fig.


Physiology_Levy

Physiology_Levy. The concept of renal clearance is based on the Fick principle (i.e., mass balance or conservation of mass). Fig. 33.12 illustrates the various factors required to describe the mass balance relationships of a kidney. The renal artery is the single input source to the kidney for substances not synthesized by this organ, whereas the renal vein and ureter constitute the two principal output routes. In other words a nonmetabolized substance entering the renal circulation via the renal artery may only exit this circulation via the renal vein (i.e., the unfiltered fraction plus any filtered amount subsequently reabsorbed back into blood) or the ureter (the combined filtered and secreted fractions less any tubular reabsorption). The following equation defines the mass balance relationship: Equation 33.1 where identical to its concentration in a plasma sample from any peripheral blood vessel (Px), the following relationship is obtained: Equation 33.4


Physiology_Levy

Physiology_Levy. Equation 33.1 where identical to its concentration in a plasma sample from any peripheral blood vessel (Px), the following relationship is obtained: Equation 33.4 Clearance has the dimensions of volume/time, and it represents a volume of plasma from which all the substance has been removed and excreted into urine per unit time. This last point is best illustrated by considering the following example. If a substance is present in urine at a concentration of 100 mg/mL and the urine flow rate is 1 mL/min, the excretion rate for this substance is calculated as follows: Equation 33.5 If this substance is present in plasma at a concentration of 1 mg/mL, its clearance according to Eq. 33.4 is as follows: Equation 33.6 are the concentrations of substance x in the renal artery and renal vein plasma, respectively


Physiology_Levy

Physiology_Levy. Eq. 33.4 is as follows: Equation 33.6 are the concentrations of substance x in the renal artery and renal vein plasma, respectively RPFa and RPFv are renal plasma flow rates in the artery and vein, respectively In other words, 100 mL of plasma will be completely Ux is the concentration of substance x in urine cleared of substance x each minute. The definition of clearV̇ is the urine flow rate ance as a volume of plasma from which all the substance . UCr x V Amount filtered PCr x GFR = Amount excreted UCr x V .


Physiology_Levy

Physiology_Levy. Amount filtered PCr x GFR = Amount excreted UCr x V . • Fig. 33.13 Renal handling of creatinine. Creatinine is freely filtered across the glomerulus and is, to a first approximation, not reabsorbed, secreted, or metabolized by the nephron. Note that all the creatinine coming to the kidney in the renal artery does not get filtered at the glomerulus (normally, 15%–20% of plasma creatinine is filtered). The portion that is not filtered is returned to the systemic circulation in the renal vein. PCr, plasma creatinine concentration; RPF, renal plasma flow; Ucr, urinary concentration of creatinine; V., urine flow rate. has been removed and excreted into urine per unit time is somewhat misleading because it is not a real volume of plasma; rather it is a virtual volume. The concept of clearance is important because it can be used to measure GFR and RPF and determine whether a substance is reabsorbed or secreted along the nephron.


Physiology_Levy

Physiology_Levy. The concept of clearance is important because it can be used to measure GFR and RPF and determine whether a substance is reabsorbed or secreted along the nephron. The GFR is equal to the sum of the filtration rates of all functioning nephrons. Thus it is an aggregate index of kidney function. A fall in GFR generally means the kidney disease is progressing, whereas recovery generally suggests recuperation. Thus serial assessment of a patient’s GFR is essential to evaluate the severity and course of kidney disease.


Physiology_Levy

Physiology_Levy. Creatinine is a byproduct of normal skeletal muscle creatine metabolism and is freely filtered across the glomerulus into Bowman’s space. It is normally generated by the body at a fairly constant rate, and—to a first approximation—it is not appreciably reabsorbed, secreted, or metabolized by the cells of the nephron after its filtration. Accordingly the amount of creatinine excreted in urine per minute is fairly constant at steady state (i.e., when [creatinine] is constant) and equals the amount of creatinine filtered at the glomerulus each minute ( Fig. 33.13): cFor most substances cleared from plasma by the kidneys, only a portion is actually removed and excreted in a single pass through the kidneys. Equation 33.7 where PCr = plasma concentration of creatinine UCr = urine concentration of creatinine V̇ = urine flow Eq. 33.7 is solved for GFR: Equation 33.8 This equation is the same form as that for clearance (see Eq.


Physiology_Levy

Physiology_Levy. Eq. 33.7 is solved for GFR: Equation 33.8 This equation is the same form as that for clearance (see Eq. 33.4 ). Thus measured creatinine clearance (CrCl) can be used clinically to determine GFR at steady state. Clearance has the dimensions of volume/time, and it represents an equivalent volume of plasma from which all of the substance has been removed and excreted into urine per unit time. Creatinine is not the only substance that can be used to measure GFR; any substance that meets the following criteria can serve as an appropriate marker. The substance must: 1. 2. be freely filtered across the glomerulus into Bowman’s space 3. not be reabsorbed or secreted by the nephron 4. not be metabolized or produced by the kidney 5.


Physiology_Levy

Physiology_Levy. 2. be freely filtered across the glomerulus into Bowman’s space 3. not be reabsorbed or secreted by the nephron 4. not be metabolized or produced by the kidney 5. Not all creatinine (or other substances used to measure GFR) that enters the kidney in renal arterial plasma is filtered at the glomerulus. Likewise not all plasma coming into the kidneys is filtered. Although nearly all plasma that enters the kidneys in the renal artery passes through the glomerulus, approximately 10% does not. The portion of filtered plasma is termed the filtration fraction and is determined as: Equation 33.9 Under normal conditions the filtration fraction averages 0.15 to 0.20, which means that only 15% to 20% of the plasma that enters the glomerulus is actually filtered. The remaining 80% to 85% continues on through the glomerular capillaries and into the efferent arterioles and peritubular capillaries before finally returning to the systemic circulation via the renal vein.


Physiology_Levy

Physiology_Levy. The first step in the formation of urine is ultrafiltration of plasma by the glomerulus. In normal adults, GFR ranges from 90 to 140 mL/min in males and from 80 to 125 mL/ min in females. Thus in 24 hours as much as 180 L of plasma is filtered by the glomeruli. The plasma ultrafiltrate is devoid of cellular elements (i.e., red and white blood cells and


Physiology_Levy

Physiology_Levy. Creatinine clearance (CrCl) is used to estimate GFR in clinical practice. It is synthesized at a relatively constant rate, and the amount produced is proportional to the total muscle mass. However, creatinine is not a perfect substance for measuring GFR because it is secreted to a small extent by the organic cation secretory system in the proximal tubule (see ). The error introduced by this secretory component is approximately 10%. Thus the amount of creatinine excreted in urine exceeds the amount expected from filtration alone by 10%. However, the method used to measure the plasma creatinine concentration (PCr) overestimates the true value by 10%. Consequently the two errors cancel each other, and in most clinical situations, CrCl provides a reasonably accurate measure of GFR.


Physiology_Levy

Physiology_Levy. A fall in GFR may be the first and only clinical sign of kidney disease. Thus measuring GFR is important when kidney disease is suspected. A 50% loss of functioning nephrons reduces GFR only by about 25%. The decline in GFR is not 50% because the remaining nephrons compensate. Because measurements of GFR are cumbersome, kidney function is usually assessed in the clinical setting by measuring the plasma concentration of creatinine (PCr),which is inversely related to GFR ( Fig. 33.14 ). However, as


Physiology_Levy

Physiology_Levy. Fig. 33.14 shows, GFR must decline substantially before an increase in PCr can be detected in a clinical setting. For example, a fall in GFR from 120 to 100 mL/min is accompanied by an increase in PCr from 1.0 to 1.2 mg/dL. This does not appear to be a significant change in PCr, but GFR has actually fallen by almost 20%. In the clinical setting, estimated GFR (eGFR) also includes consideration of several other factors in addition to the plasma concentration of creatinine, including age, sex, body size, and race. A free app to calculate eGFR can be downloaded at: https://www.kidney.org/apps/professionals/ platelets) and is essentially protein free. The concentration • Fig. 33.14 Relationship between GFR and plasma [creatinine] (Pcr). The amount of creatinine filtered is equal to the amount excreted; thus GFR × PCr = UCr × V. Because the production of creatinine is constant, excretion must be constant to maintain creatinine balance. Therefore if GFR falls from 120 to 60 mL/min, PCr must


Physiology_Levy

Physiology_Levy. excreted; thus GFR × PCr = UCr × V. Because the production of creatinine is constant, excretion must be constant to maintain creatinine balance. Therefore if GFR falls from 120 to 60 mL/min, PCr must increase from 1 to 2 mg/dL to keep filtration of creatinine and its excretion equal to the production rate.


Physiology_Levy

Physiology_Levy. 1.0 0.8 0.6 0.4 of salts and organic molecules (e.g., glucose, amino acids) is similar in plasma and the ultrafiltrate. Starling forces drive ultrafiltration across the glomerular capillaries, and changes in these forces alter GFR. GFR and RPF are normally held within very narrow ranges by a phenomenon called autoregulation. The next sections of this chapter review the composition of the glomerular filtrate, the dynamics of its formation, and the relationship between RPF and GFR. In addition, factors that contribute to autoregulation and regulation of GFR and RBF are discussed. Determinants of Ultrafiltrate Composition The glomerular filtration barrier determines the composition of the plasma ultrafiltrate. It restricts filtration of molecules on the basis of both size and electric charge (


Physiology_Levy

Physiology_Levy. Fig. 33.15 ). In general, neutral molecules with a radius smaller than about 0.2 • Fig. 33.15 Influence of the size and electric charge of dextran on its filterability. A value of 1 indicates that it is filtered freely, whereas a value of zero indicates that it is not filtered. The filterability of dextrans between approximately 18 and 42 Å depends on charge. Dextrans larger than 42 Å are not filtered regardless of charge, and polycationic dextrans and neutral dextrans smaller than 18 Å are freely filtered. The major proteins in plasma are albumin and immunoglobulins. Because the effective molecular radii of immunoglobulin (Ig)G (53 Å) and IgM (>100 Å) are greater than 42 Å, they are not filtered. Although the effective molecular radius of albumin is 35 Å, it is a polyanionic protein, so it does not cross the filtration barrier to a significant degree.


Physiology_Levy

Physiology_Levy. 18 Å are freely filtered, molecules larger than about 42 Å are not filtered, and molecules between about 18 and 42 Å are filtered to varying degrees.


Physiology_Levy

Physiology_Levy. Fig. 33.15 shows how electric charge affects filtration of macromolecules (e.g., dextrans) by the glomerulus. Dextrans are a family of exogenous polysaccharides manufactured in various molecular weights. They can be electrically neutral or have either negative (polyanionic) or positive (polycationic) charges. As the size (i.e., effective molecular radius) of a dextran molecule increases, the rate at which it is filtered decreases. For any given molecular radius, cationic molecules are more readily filtered than anionic molecules. The reduced filtration rate for anionic molecules is explained by the presence of negatively charged glycoproteins on the surface of all components of the glomerular filtration barrier. These charged glycoproteins repel similarly charged molecules. Because most plasma proteins are negatively charged, the negative charge on the filtration barrier restricts filtration of anionic proteins more than the filtration of neutral and polyanionic proteins with a


Physiology_Levy

Physiology_Levy. most plasma proteins are negatively charged, the negative charge on the filtration barrier restricts filtration of anionic proteins more than the filtration of neutral and polyanionic proteins with a molecular radius between approximately 18 to 42 Å. For example, serum albumin, an anionic protein that has an effective molecular radius of 35.5 Å, is poorly filtered. Because the small amount of filtered albumin is normally reabsorbed avidly by the proximal tubule, almost no albumin appears in urine.


Physiology_Levy

Physiology_Levy. The importance of the negative charges on the filtration barrier in restricting filtration of plasma proteins is shown in Figs. 33.15 33.16 . Removal of the negative charges from the filtration barrier causes proteins to be filtered solely on the basis of their effective molecular radius ( Fig. 33.16 ). Hence at any molecular radius between approximately 18 and 42 Å, filtration of polyanionic proteins will exceed the filtration that prevails in the normal state (in which the filtration barrier has anionic charges). In a number of glomerular diseases the negative charges on the filtration barrier are reduced because of immunological damage and inflammation. As a result, filtration of anionic proteins between approximately 18 and 42 Å in radius is increased. When the filtered proteins exceed the ability of the proximal tubule to reabsorb and catabolize them, anionic proteins begin to appear in urine (proteinuria), which is a marker of kidney disease. Dynamics of Ultrafiltration


Physiology_Levy

Physiology_Levy. Dynamics of Ultrafiltration The forces responsible for glomerular filtration of plasma are the same as those in other capillary beds. Ultrafiltration occurs because the Starling forces (i.e., hydraulic and oncotic pressures) combine to drive fluid from the lumen of glomerular capillaries across the filtration barrier and into Bowman’s space (


Physiology_Levy

Physiology_Levy. Fig. 33.17 ). The hydraulic pressure inside the glomerular capillary (PGC) is oriented to promote movement of fluid from the glomerular capillary into Bowman’s space. Because the glomerular ultrafiltrate is essentially protein free under normal conditions, owing in large part to the paucity of proteins in serum smaller than 18 Å in radius 1.0 0.8 0.6 0.4 0.2 0 • Fig. 33.16 Reduction of the negative charges on the glomerular wall results in filtration of proteins on the basis of size only. In this situation the relative filterability of proteins depends only on the molecular radius. Accordingly, excretion of polyanionic proteins (18–42 Å) in urine increases because more proteins of this size are filtered.


Physiology_Levy

Physiology_Levy. that can be effectively filtered, the reflection coefficient (σ) for proteins across the glomerular capillary is essentially 1. Thus the oncotic pressure in Bowman’s space (πBS) is near zero. Therefore PGC is the principal force favoring filtration. In contrast, the hydraulic pressure in Bowman’s space (PBS) and the oncotic pressure in the glomerular capillary (πGC) both oppose filtration.


Physiology_Levy

Physiology_Levy. Fig. 33.17 , a net ultrafiltration pressure (PUF) of 17 mm Hg exists at the afferent end of the glomerulus, whereas at the efferent end it is 8 mm Hg (where PUF = PGC − PBS −πGC). Two additional points concerning Starling forces and this pressure change are important. First, PGC decreases slightly along the length of the capillary because of the resistance to flow along the length of the capillary. Second, πGC increases as plasma is filtered while protein is retained within the glomerular capillary, thereby progressively increasing the protein concentration along the length of the capillary. GFR is proportional to the sum of the Starling forces that exist across the capillaries [(PGC − PBS) −σ(πGC −πBS)] multiplied by the ultrafiltration coefficient (Kf). That is: Equation 33.10


Physiology_Levy

Physiology_Levy. Equation 33.10 Kf is the product of the intrinsic permeability of the glomerular capillary and the glomerular surface area available for filtration. The rate of glomerular filtration is considerably greater in glomerular capillaries than in systemic capillaries, mainly because Kf is approximately 100 times greater in glomerular capillaries. Furthermore PGC is approximately twice as great as the hydraulic pressure in systemic capillaries.


Physiology_Levy

Physiology_Levy. GFR can be altered by changing Kf or by changing any of the Starling forces. In normal individuals, GFR is regulated by alterations in PGC that are mediated mainly by changes • Fig. 33.17 Idealized glomerular capillary and the Starling forces across it. The reflection coefficient (σ) for protein across the glomerular capillary is approximately 1. PBS, hydraulic pressure in Bowman’s space; PGC, hydraulic pressure in the glomerular capillary; PUF, net ultrafiltration pressure; πBS, oncotic pressure in Bowman’s space; πGC, oncotic pressure in the glomerular capillary. The negative signs for PBS and πGC indicate that these forces oppose formation of the glomerular filtrate. in afferent or efferent arteriolar resistance. PGC is affected in three ways: 1. Changes in afferent arteriolar resistance: A decrease in resistance increases PGC and GFR, whereas an increase in resistance decreases PGC and GFR. 2.


Physiology_Levy

Physiology_Levy. Changes in afferent arteriolar resistance: A decrease in resistance increases PGC and GFR, whereas an increase in resistance decreases PGC and GFR. 2. Changes in efferent arteriolar resistance: A decrease in resistance reduces PGC and GFR, whereas an increase in resistance elevates PGC and GFR. 3. Changes in renal arteriolar pressure: An increase in blood pressure transiently increases PGC (which enhances GFR), whereas a decrease in blood pressure transiently decreases PGC (which reduces GFR). Blood flow through the kidneys serves several important functions: 1. 2. modifies the rate of solute and water reabsorption by the proximal tubule 3. participates in concentration and dilution of urine 4. delivers O2, nutrients, and hormones to cells along the nephron and returns CO2, reabsorbed fluid, and solutes to the general circulation 5. Blood flow through any organ may be represented by the following equation:


Physiology_Levy

Physiology_Levy. Blood flow through any organ may be represented by the following equation: A reduction in GFR in disease states is most often due to decreases in Kf because of the loss of filtration surface area. GFR also changes in pathophysiological conditions because of changes in PGC, πGC, and PBS. 1. Changes in Kf: Increased Kf enhances GFR, whereas decreased Kf reduces GFR. Some kidney diseases reduce Kf by decreasing the number of filtering glomeruli (i.e., diminished surface area). Some drugs and hormones that dilate the glomerular arterioles also increase Kf. Similarly, drugs and hormones that constrict the glomerular arterioles also decrease Kf. 2. Changes in PGC: With decreased renal perfusion, GFR declines because PGC falls. As previously discussed, a reduction in PGC is caused by a decline in renal arterial pressure, an increase in afferent arteriolar resistance, or a decrease in efferent arteriolar resistance. 3.


Physiology_Levy

Physiology_Levy. 3. Changes in πGC: An inverse relationship exists between πGC and GFR. Alterations in πGC result from changes in protein synthesis outside the kidneys. In addition the protein loss in urine caused by some renal diseases can lead to a decrease in the plasma protein concentration and thus in πGC. 4. Changes in PBS: Increased PBS reduces GFR, whereas decreased PBS enhances GFR. Acute obstruction of the urinary tract (e.g., a kidney stone occluding the ureter) increases PBS. Equation 33.11 organ R = resistance to flow through that organ Accordingly, RBF is equal to the pressure difference between the renal artery and the renal vein divided by renal vascular resistance: Equation 33.12


Physiology_Levy

Physiology_Levy. Accordingly, RBF is equal to the pressure difference between the renal artery and the renal vein divided by renal vascular resistance: Equation 33.12 The afferent arteriole, efferent arteriole, and interlobular artery are the major resistance vessels in the kidneys and thereby determine renal vascular resistance. Like most other organs, the kidneys regulate their blood flow by adjusting vascular resistance in response to changes in arterial pressure. As shown in


Physiology_Levy

Physiology_Levy. Fig. 33.18 these adjustments are so precise that blood flow remains relatively constant as arterial blood pressure changes between 90 and 180 mm Hg. GFR is also regulated over the same range of arterial pressures. The phenomenon whereby RBF and GFR are maintained relatively constant between blood pressures of 90 and 180 mm Hg, namely autoregulation, is achieved by changes in vascular resistance, mainly through the afferent arterioles of the kidneys. Because both RBF and GFR are regulated over the • Fig. 33.18 Relationship between arterial blood pressure and RBF and between arterial blood pressure and GFR. Autoregulation maintains GFR and RBF relatively constant as blood pressure changes from 90 to 180 mm Hg. same range of pressures and because RBF is an important determinant of GFR, it is not surprising that the same mechanisms regulate both flows.


Physiology_Levy

Physiology_Levy. same range of pressures and because RBF is an important determinant of GFR, it is not surprising that the same mechanisms regulate both flows. Two mechanisms are responsible for autoregulation of RBF and GFR: one mechanism that responds to changes in arterial pressure and another that responds to changes in [NaCl] in tubular fluid. Both regulate the tone of the afferent arteriole. The pressure-sensitive mechanism, the so-called myogenic mechanism, is related to an intrinsic property of vascular smooth muscle: the tendency to contract when stretched. Accordingly, when arterial pressure rises and the renal afferent arteriole is stretched, the smooth muscle contracts in response. Because the increase in resistance of the arteriole offsets the increase in pressure, RBF, and therefore GFR, remains constant. (That is, RBF is constant if ΔP/R is kept constant [see Eq. 33.11


Physiology_Levy

Physiology_Levy. The second mechanism responsible for autoregulation of GFR and RBF is the [NaCl]-dependent mechanism known as tubuloglomerular feedback. This mechanism involves a feedback loop in which a change in GFR leads to alteration in the concentration of NaCl in tubular fluid, which is sensed by the macula densa of the juxtaglomerular apparatus and converted into signals that affect afferent arteriolar resistance and thus the GFR (Fig. 33.19 ). For example, when the GFR increases and causes [NaCl] in tubular fluid in the loop of Henle to rise, more NaCl enters the macula densa cells in this segment (Fig. 33.20 ). This leads to an increase in formation and release of adenosine triphosphate (ATP) and adenosine (a metabolite of ATP) by macula densa cells, which causes vasoconstriction of the afferent arteriole and normalization of GFR. In contrast, when GFR and [NaCl] in tubule fluid decrease, less NaCl enters the macula densa cells, and both ATP and adenosine • Fig. 33.19 Tubuloglomerular


Physiology_Levy

Physiology_Levy. arteriole and normalization of GFR. In contrast, when GFR and [NaCl] in tubule fluid decrease, less NaCl enters the macula densa cells, and both ATP and adenosine • Fig. 33.19 Tubuloglomerular feedback. An increase in GFR (1) increases [NaCl] in tubule fluid in the loop of Henle (2). The increase in [NaCl] is sensed by the macula densa and converted to a signal (3) that increases the resistance of the afferent arteriole (RA) (4), which decreases GFR. A decrease in GFR has the opposite effects. (Modified from Cogan MG. Fluid and Electrolytes: Physiology and Pathophysiology. Norwalk, CT: Appleton & Lange; 1991.) production and release decline. The fall in [ATP] and [adenosine] results in afferent arteriolar vasodilation, which returns GFR to normal. NO, a vasodilator produced by the macula densa, attenuates tubuloglomerular feedback, whereas angiotensin II enhances tubuloglomerular feedback. Thus the macula densa may release both vasoconstrictors (e.g., ATP and adenosine) and a


Physiology_Levy

Physiology_Levy. macula densa, attenuates tubuloglomerular feedback, whereas angiotensin II enhances tubuloglomerular feedback. Thus the macula densa may release both vasoconstrictors (e.g., ATP and adenosine) and a vasodilator (e.g., NO) that oppose each other’s action at the level of the afferent arteriole. Production plus release of either vasoconstrictors or vasodilators ensures exquisite control over tubuloglomerular feedback.


Physiology_Levy

Physiology_Levy. Fig. 33.20 also illustrates the role of the macula densa in controlling renin secretion by granular cells of the afferent arteriole. This aspect of function of the juxtaglomerular apparatus is considered in detail in Because animals engage in many activities that can change arterial blood pressure, mechanisms that maintain RBF and GFR relatively constant despite changes in arterial pressure are highly desirable. If GFR and RBF were to rise or fall suddenly in proportion to changes in blood pressure, urinary excretion of fluid and solute would also change suddenly. Such changes in excretion of water and solutes without comparable changes in intake would alter fluid and electrolyte balance (the reason for which is discussed in ). Accordingly, autoregulation of GFR and RBF provides an effective means for uncoupling renal function from arterial pressure, and it ensures that fluid and solute excretion remain relatively constant.


Physiology_Levy

Physiology_Levy. Three points concerning autoregulation should be noted: 1. Autoregulation is absent when arterial pressure is less than 90 mm Hg.


Physiology_Levy

Physiology_Levy. • Fig. 33.20 Cellular mechanism whereby an increase in delivery of NaCl to the macula densa causes vasoconstriction of the afferent arteriole of the same nephron (i.e., tubuloglomerular feedback). An increase in GFR elevates [NaCl] in tubule fluid at the macula densa. This in turn enhances uptake of NaCl across the apical cell membrane of macula densa cells via the 1Na+-1K+-2Cl− (NKCC2) symporter, which leads to an increase in [ATP] and [adenosine] (ADO) release. ATP binds to P2X receptors and adenosine binds to adenosine A1 receptors in the plasma membrane of smooth muscle cells surrounding the afferent arteriole, both of which increase intracellular [Ca++]. The rise in [Ca++] induces vasoconstriction of the afferent arteriole, thereby returning GFR to normal levels. Note that ATP and adenosine also inhibit renin release by granular cells in the afferent arteriole. This too results from an increase in intracellular [Ca++] as a reflection of electrical coupling of the granular and


Physiology_Levy

Physiology_Levy. adenosine also inhibit renin release by granular cells in the afferent arteriole. This too results from an increase in intracellular [Ca++] as a reflection of electrical coupling of the granular and vascular smooth muscle (VSM) cells. When GFR is reduced, [NaCl] in tubule fluid falls, as does uptake of NaCl into macula densa cells. This in turn decreases release of ATP and adenosine by the macula densa, which decreases intracellular [Ca++] in smooth muscle cells and thereby increases GFR and stimulates renin release by granular cells. In addition a decrease in entry of NaCl into macula densa cells enhances production of PGE2, which also stimulates renin secretion by granular cells. As discussed in detail in , renin increases plasma [angiotensin II], a hormone that enhances NaCl and water retention by the kidneys. (Modified from Persson AEG et al. Acta Physiol Scand 2004;181:471.) 2.


Physiology_Levy

Physiology_Levy. Autoregulation is not perfect; RBF and GFR do change slightly as arterial blood pressure varies. 3. Despite autoregulation, RBF and GFR can be changed by several hormones and by alterations in sympathetic nerve activity that change in response to alterations in the extracellular fluid volume (ECFV) ( Table 33.1 Regulation of Renal Blood Flow and Glomerular Filtration Rate Table 33.1 ). As already discussed, the myogenic mechanism and tubuloglomerular feedback play key roles in maintaining RBF and GFR constant when blood pressure is greater that 90 mm Hg and ECFV is in the normal range. However, when the ECFV changes sympathetic nerves, angiotensin II, prostaglandins, NO, endothelin, bradykinin, ATP, and adenosine exert major control over RBF and GFR. Fig. 33.21 shows how changes in efferent and afferent arteriolar resistance, mediated by changes in the hormones listed in Table 33.1 , modulate both RBF and GFR.


Physiology_Levy

Physiology_Levy. Fig. 33.21 shows how changes in efferent and afferent arteriolar resistance, mediated by changes in the hormones listed in Table 33.1 , modulate both RBF and GFR. The afferent and efferent arterioles are innervated by sympathetic neurons; however, sympathetic tone is minimal when ECFV is normal (see ). When ECFV is reduced, sympathetic nerves release norepinephrine and dopamine, and circulating epinephrine (a catecholamine-like norepinephrine and dopamine) is secreted by the adrenal medulla. Norepinephrine and epinephrine cause vasoconstriction by Sympathetic nerves ↓ ECFV ↓↓ Angiotensin II ↓ ECFV ↓↓ Endothelin ↑ Stretch, A-II, bradykinin, epinephrine; ↓ ECFV ↓↓ Prostaglandins (PGE1, PGE2, PGI2) ↓ ECFV; ↑ shear stress, A-II No change/↑↑ Nitric oxide (NO) ↑ Shear stress, acetylcholine, histamine, bradykinin, ↑↑ ATP Bradykinin ↑ Prostaglandins, ↓ ACE ↑↑ Natriuretic peptides (ANP, BNP) ↑ ECFV ↑ No change


Physiology_Levy

Physiology_Levy. ATP Bradykinin ↑ Prostaglandins, ↓ ACE ↑↑ Natriuretic peptides (ANP, BNP) ↑ ECFV ↑ No change A-II, angiotensin II; ACE, angiotensin-converting enzyme; ECFV, extracellular fluid volume. Tubuloglomerular feedback (TGF) is absent in mice that do not express the adenosine receptor (A1). This underscores the importance of adenosine signaling in TGF. Studies have shown that when GFR increases and causes the concentration of NaCl in tubular fluid at the macula densa to rise, more NaCl enters cells via the 1Na+-1K+-2Cl− symporter (NKCC2) located in the apical plasma membrane (see Fig.


Physiology_Levy

Physiology_Levy. Fig. 33.20 ). Increased intracellular [NaCl] in turn stimulates release of ATP via ATP-conducting ion channels located in the basolateral membrane of macula densa cells. In addition, adenosine production is also enhanced. Adenosine binds to A1 receptors and ATP binds to P2X receptors located on the plasma membrane of smooth muscle cells in the afferent arteriole. Both hormones increase intracellular [Ca++], which causes vasoconstriction of the afferent artery and therefore a fall in GFR. Although adenosine is a vasodilator in most other vascular beds, it constricts the afferent arteriole in the kidney. binding to α1-adrenoceptors, which are located mainly in afferent arterioles. Activation of α1-adrenoceptors decreases RBF and GFR. Dehydration or strong emotional stimuli (e.g., fear, pain) also activate sympathetic nerves and reduce RBF and GFR.


Physiology_Levy

Physiology_Levy. Angiotensin II is produced systemically as well as locally within the kidneys. It constricts the afferent and efferent arterioles and decreases both RBF and GFR. Fig. 33.22 shows how norepinephrine, epinephrine, and angiotensin II act together to decrease RBF and GFR and thereby dThe efferent arteriole is more sensitive than the afferent arteriole to angiotensin II. Therefore with low concentrations of angiotensin II, constriction of the efferent arteriole predominates, and GFR increases and RBF decreases. However, with high concentrations of angiotensin II, constriction of both afferent and efferent arterioles occurs, and GFR and RBF both decrease (see Fig. 33.21


Physiology_Levy

Physiology_Levy. Fig. 33.21 Individuals with renal artery stenosis (narrowing of the lumen of the artery) caused by atherosclerosis, for example, often have elevated systemic arterial blood pressure mediated by the renin-angiotensin system. Pressure in the renal artery proximal to the stenosis is increased, but pressure distal to the stenosis is normal or reduced. Autoregulation is important in maintaining RBF, PGC, and GFR in the presence of this stenosis. Administration of drugs to lower systemic blood pressure also lowers the pressure distal to the stenosis; accordingly, RBF, PGC, and GFR fall. Significant hemorrhage decreases ECFV and arterial blood pressure and therefore activates sympathetic innervation of the kidneys via the baroreceptor reflex (


Physiology_Levy

Physiology_Levy. Significant hemorrhage decreases ECFV and arterial blood pressure and therefore activates sympathetic innervation of the kidneys via the baroreceptor reflex ( Fig. 33.22 ). Norepinephrine causes intense vasoconstriction of the afferent and efferent glomerular arterioles and thereby decreases both RBF and GFR. The rise in sympathetic activity also increases release of epinephrine and angiotensin II, which cause further vasoconstriction and a fall in RBF. The rise in vascular resistance of the kidneys and other vascular beds increases total peripheral resistance. The resulting tendency for blood pressure to increase (blood pressure = cardiac output × total peripheral resistance) offsets the tendency of blood pressure to decrease in response to hemorrhage. Hence this system works to preserve arterial pressure at the expense of maintaining normal RBF and GFR. increase blood pressure and ECFV (e.g., as would occur with hemorrhage).


Physiology_Levy

Physiology_Levy. increase blood pressure and ECFV (e.g., as would occur with hemorrhage). Prostaglandins do not play a major role in regulating RBF in healthy resting individuals. However, during • Fig. 33.21 Relationship between selective changes in resistance of either the afferent arteriole or the efferent arteriole on RBF and GFR. Constriction of either the afferent or efferent arteriole increases resistance, and according to


Physiology_Levy

Physiology_Levy. Eq. 33.11 (Q =ΔP/R), an increase in resistance (R) decreases flow (Q) (i.e., RBF). Dilation of either the afferent or afferent arteriole increases flow (i.e., RBF). Constriction of the afferent arteriole (A) decreases PGC because less of the arterial pressure is transmitted to the glomerulus, thereby reducing GFR. In contrast, constriction of the efferent arteriole (B) elevates PGC and thus increases GFR. Dilation of the efferent arteriole (C) decreases PGC and thus decreases GFR. Dilation of the afferent arteriole (D) increases PGC because more of the arterial pressure is transmitted to the glomerulus, thereby increasing GFR. (Modified from Rose BD, Rennke KG. Renal Pathophysiology: The Essentials. Baltimore: Williams & Wilkins; 1994.) pathophysiological conditions such as hemorrhage and reduced ECFV, prostaglandins (PGI2, PGE1, and PGE2) are produced locally within the kidneys and serve to increase RBF without changing GFR. Prostaglandins increase RBF by dampening the


Physiology_Levy

Physiology_Levy. hemorrhage and reduced ECFV, prostaglandins (PGI2, PGE1, and PGE2) are produced locally within the kidneys and serve to increase RBF without changing GFR. Prostaglandins increase RBF by dampening the vasoconstrictor effects of both sympathetic activation and angiotensin II. These effects are important because they prevent severe and potentially harmful vasoconstriction and renal ischemia. Synthesis of prostaglandins is stimulated by ECFV depletion and stress (e.g., surgery, anesthesia), angiotensin II, and sympathetic nerves. Nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen and naproxen, potently inhibit prostaglandin synthesis. Thus administration of these drugs during renal ischemia and hemorrhagic shock is contraindicated because, by blocking the production of prostaglandins, they decrease RBF and increase renal ischemia. Prostaglandins also play an increasingly important role in maintaining RBF and GFR as individuals age. Accordingly, NSAIDs can significantly reduce


Physiology_Levy

Physiology_Levy. they decrease RBF and increase renal ischemia. Prostaglandins also play an increasingly important role in maintaining RBF and GFR as individuals age. Accordingly, NSAIDs can significantly reduce RBF and GFR in the elderly.


Physiology_Levy

Physiology_Levy. NO, an endothelium-derived relaxing factor, is an important vasodilator under basal conditions, and it counteracts the vasoconstriction produced by angiotensin II and catecholamines. When blood flow increases, greater shear force acts on endothelial cells in the arterioles and increases production of NO. In addition a number of vasoactive hormones, including acetylcholine, histamine, bradykinin, and ATP, facilitate release of NO from endothelial cells. Increased production of NO causes dilation of the afferent and efferent arterioles in the kidneys. Whereas increased levels of NO decrease total peripheral resistance, inhibition of NO production increases total peripheral resistance.


Physiology_Levy

Physiology_Levy. Abnormal production of NO is observed in individuals with diabetes mellitus and hypertension. Excess renal NO production in diabetes may be responsible for glomerular hyperfiltration (i.e., increased GFR) and damage to the glomerulus, problems characteristic of this disease. Elevated NO levels increase glomerular capillary pressure secondary to a fall in resistance of the afferent arteriole. The ensuing hyperfiltration is thought to cause glomerular damage. The normal response to an increase in dietary salt intake includes stimulation of renal NO production, which prevents an increase in blood pressure. In some individuals, however, NO production may not increase appropriately in response to an elevation in salt intake, so blood pressure rises.


Physiology_Levy

Physiology_Levy. Endothelin is a potent vasoconstrictor secreted by endothelial cells of the renal vessels, mesangial cells, and distal tubular cells in response to angiotensin II, bradykinin, epinephrine, and endothelial shear stress. Endothelin causes profound vasoconstriction of the afferent and efferent arterioles and decreases GFR and RBF. Although this potent vasoconstrictor may not influence GFR and RBF in resting subjects, production of endothelin is elevated in a number of glomerular disease states (e.g., renal disease associated with diabetes mellitus). Kallikrein is a proteolytic enzyme produced in the kidneys. Kallikrein cleaves circulating kininogen to bradykinin, which is a vasodilator that acts by stimulating the release of NO and prostaglandins. Bradykinin increases RBF and GFR.


Physiology_Levy

Physiology_Levy. 600 SECTION7Berne & Levy Physiology • Fig. 33.22 Pathway by which hemorrhage activates renal sympathetic nerve activity and stimulates production of angiotensin II. (Modified from Vander AJ. Renal Physiology. 2nd ed. New York: McGraw-Hill; 1980.) Hemorrhage ˜ Arterial blood pressure ˜ RBF and GFR (Intrarenal receptors) ° Renin secretion ° Plasma and renal renin ° Activity of renal sympathetic nerves ° Plasma and renal angiotensin II ° Constriction of renal arterioles Carotid sinus and aortic arch reflexes ° Tubular sodium and water reabsorption ˜ Renal excretion of sodium and water Adenosine is produced within the kidneys and causes vasoconstriction of the afferent arteriole, thereby reducing RBF and GFR. As previously mentioned, adenosine plays an important role in tubuloglomerular feedback.


Physiology_Levy

Physiology_Levy. Secretion of atrial natriuretic peptide (ANP) by the cardiac atria and brain natriuretic peptide (BNP) by the cardiac ventricle increases when ECFV is expanded and myocardial wall tension is increased. Both ANP and BNP dilate the afferent arteriole and constrict the efferent arteriole. Therefore ANP and BNP produce a modest increase in GFR with little change in RBF. Cells release ATP into the renal interstitial fluid. ATP can have bidirectional effects on both RBF and GFR. Under some conditions, ATP constricts the afferent arteriole, reduces RBF and GFR, and may play a role in tubuloglomerular feedback. Under other conditions, ATP may stimulate NO production and have directionally opposite effects, increasing both RBF and GFR. Administration of therapeutic doses of glucocorticoids increases GFR and RBF.


Physiology_Levy

Physiology_Levy. Administration of therapeutic doses of glucocorticoids increases GFR and RBF. Local release of histamine modulates RBF during the resting state and during inflammation and injury. Histamine decreases the resistance of the afferent and efferent arterioles and thereby increases RBF without elevating GFR. The proximal tubule produces the vasodilator substance dopamine. Dopamine has several actions within the kidney, such as increasing RBF and inhibiting renin secretion. • Fig. 33.23 Examples of the interactions of endothelial cells with smooth muscle and mesangial cells. ACE, angiotensin-converting enzyme; AI, angiotensin I; AII, angiotensin II. (Modified from Navar LG et al. Physiol Rev 1996;76:425.) Smooth muscle cell or mesangial cellVasodilation PGI2 PGE2 Nitric oxide Stretch Histamine Acetylcholine Bradykinin ATP A I A II Endothelin A C E Endothelial cell Vasoconstriction Finally, as illustrated in


Physiology_Levy

Physiology_Levy. Fig. 33.23 , endothelial cells play an important role in regulating the resistance of the renal afferent and efferent arterioles by producing a number of paracrine hormones, including NO, prostacyclin (PGI2), endothelin, and angiotensin II. These hormones regulate contraction or relaxation of smooth muscle cells in afferent and efferent arterioles and mesangial cells. Shear stress, acetylcholine, histamine, bradykinin, and ATP stimulate production of NO, which increases GFR and RBF. Angiotensin-converting enzyme (ACE), located on the surface of endothelial cells lining the afferent arteriole and glomerular capillaries, converts angiotensin I to angiotensin II, which decreases GFR and RBF. Angiotensin II is also produced locally by granular cells in the afferent arteriole and by proximal tubular cells. PGI2 and PGE2 release by endothelial cells is stimulated by both sympathetic nerve activity and angiotensin II, resulting in increased GFR and RBF. Finally, endothelin release from


Physiology_Levy

Physiology_Levy. tubular cells. PGI2 and PGE2 release by endothelial cells is stimulated by both sympathetic nerve activity and angiotensin II, resulting in increased GFR and RBF. Finally, endothelin release from endothelial cells decreases both RBF and GFR.


Physiology_Levy

Physiology_Levy. ACE proteolytically inactivates the vasodilatory hormone bradykinin and converts angiotensin I, an inactive hormone, to angiotensin II, an active vasoconstrictive hormone. Thus ACE increases angiotensin II levels and decreases bradykinin levels. ACE inhibitors (e.g., lisinopril, enalapril, and captopril) are used clinically to reduce systemic blood pressure in patients with hypertension by decreasing angiotensin II levels and elevating bradykinin levels. Both effects lower systemic vascular resistance, reduce blood pressure, and decrease renal vascular resistance, thereby increasing GFR and RBF. Angiotensin II receptor antagonists (e.g., losartan) are also used to treat hypertension. As their name suggests, they block the binding of angiotensin II to the angiotensin II receptor (AT1). These antagonists block the vasoconstrictor effects of angiotensin II on the afferent arteriole; thus they increase RBF and GFR. In contrast to ACE inhibitors, angiotensin II receptor antagonists do not


Physiology_Levy

Physiology_Levy. antagonists block the vasoconstrictor effects of angiotensin II on the afferent arteriole; thus they increase RBF and GFR. In contrast to ACE inhibitors, angiotensin II receptor antagonists do not inhibit kinin metabolism (e.g., bradykinin).


Physiology_Levy

Physiology_Levy. 1. The first step in urine formation is passive movement of a plasma ultrafiltrate from the glomerular capillaries into Bowman’s space. The term ultrafiltration refers to passive movement of a plasma-like fluid that has a very low concentration of proteins from the glomerular capillaries into Bowman’s space. The endothelial cells of glomerular capillaries are covered by a basement membrane that is surrounded by podocytes. The capillary endothelium, basement membrane, and foot processes of podocytes form the so-called filtration barrier. 2. The juxtaglomerular apparatus is one component of an important feedback mechanism (i.e., tubuloglomerular feedback) that regulates RBF and GFR. The structures that make up the juxtaglomerular apparatus include the macula densa, extraglomerular mesangial cells, and reninand angiotensin II–producing granular cells. 3. Clinically, GFR is frequently estimated using measures of plasma [creatinine] or CrCl. 4.


Physiology_Levy

Physiology_Levy. 3. Clinically, GFR is frequently estimated using measures of plasma [creatinine] or CrCl. 4. Autoregulation allows GFR and RBF to remain constant despite changes in arterial blood pressure between 90 and 180 mm Hg. When ECFV is altered, sympathetic nerves, catecholamines, angiotensin II, prostaglandins, NO, endothelin, natriuretic peptides, bradykinin, and adenosine exert substantial control over GFR and RBF. Patel A. The primary cilium calcium channels and their role in flow sensing. Pflugers Arch. 2015;467:157-165. Pollak MR, et al. The glomerulus: the sphere of influence. Clin J Am Soc Nephrol. 2014;9:1461-1469. Schlondorff J. How many Achilles’ heels does a podocyte have? An update on podocyte biology. Nephrol Dial Transplant. 2015;30: 1091-1097. Schnermann J. Concurrent activation of multiple vasoactive signaling pathways in vasoconstriction caused by tubuloglomerular feedback: a quantitative assessment. Annu Rev Physiol. 2015;77:301-322.


Physiology_Levy

Physiology_Levy. Schnermann J. Concurrent activation of multiple vasoactive signaling pathways in vasoconstriction caused by tubuloglomerular feedback: a quantitative assessment. Annu Rev Physiol. 2015;77:301-322. Taylor AE, Moore TM. Capillary fluid exchange. Adv Physiol Educ. 1999;22:s203-s210. Arendshorst WJ, Navar LG. Renal circulation and glomerular hemodynamics. In: Schrier RW, et al., eds. Diseases of the Kidney and Urinary Tract. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2012. Dworkin LD, et al. The renal circulations. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012. Kriz W, Kaissling B. Structural organization of the mammalian kidney. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Philadelphia: Academic Press; 2012.


Physiology_Levy

Physiology_Levy. Lafayette RA, et al. Laboratory evaluation of renal function. In: Schrier RW, et al., eds. Diseases of the Kidney and Urinary Tract. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2012. Madsen K, et al. Anatomy of the kidney. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012. Upon completion of this chapter the student should be able to answer the following questions: 1. What three processes are involved in the production of urine? 2. What is the composition of “normal” urine? 3. What transport mechanisms are responsible for NaCl reabsorption by the nephron? Where are they located along the nephron? 4. How is water reabsorption “coupled” to NaCl reabsorption in the proximal tubule? 5. Why are solutes but not water reabsorbed by the thick ascending limb of Henle’s loop? 6. What transport mechanisms are involved in secretion of organic anions and cations? What is the physiological relevance of these transport processes?


Physiology_Levy

Physiology_Levy. 6. What transport mechanisms are involved in secretion of organic anions and cations? What is the physiological relevance of these transport processes? 7. What is glomerulotubular balance, and what is its physiological importance? 8. What are the major hormones that regulate NaCl and water reabsorption by the kidneys? What is the nephron site of action of each hormone? 9. What is the aldosterone paradox? he formation of urine involves three basic processes: (1) ultrafiltration of plasma by the glomerulus, (2) reabsorption of water and solutes from the ultra-filtrate, and (3) secretion of selected solutes into tubular fluid. Although an average of 115 to 180 L/day in women and 130 to 200 L/day in men of essentially protein-free fluid is filtered by the human glomeruli each day, less than 1% of the filtered water and sodium chloride (NaCl) and variable amounts of other solutes are typically excreted in urine (


Physiology_Levy

Physiology_Levy. Table 34.1 ). By the processes of reabsorption and secretion, the renal tubules determine the volume and composition of urine ( Table 34.2 ), which in turn allows the 1Normal glomerular filtration rate (GFR) averages 115–180 L/day in women and 130–200 L/day in men. Thus the volume of the ultrafiltrate represents a volume that is approximately 10 times that of the extracellular fluid volume (ECFV). For simplicity, we assume throughout the remainder of this section that GFR is 180 L/day. kidneys to precisely control the volume, osmolality, composition, and pH of the extracellular and intracellular fluid compartments. Transport proteins in cell membranes of the nephron mediate reabsorption and secretion of solutes and water in the kidneys. Approximately 5% to 10% of all human genes code for transport proteins, and genetic and acquired defects in transport proteins are the cause of many kidney diseases (


Physiology_Levy

Physiology_Levy. Table 34.3 ). In addition, numerous transport proteins are important drug targets. This chapter discusses NaCl and water reabsorption, transport of organic anions and cations, the transport proteins involved in solute and water transport, and some of the factors and hormones that regulate NaCl transport. Details on acid-base transport and on K+ , Ca++ , and inorganic phosphate (Pi) transport and their regulation are provided in through 37. Solute and Water Reabsorption Along the Nephron The general principles of solute and water transport across epithelial cells were discussed in Quantitatively, reabsorption of NaCl and water represent the major function of nephrons. Approximately 25,000 mEq/day of Na+ and 179 L/day of water are reabsorbed by the renal tubules (see Table 34.1).


Physiology_Levy

Physiology_Levy. Table 34.1). In addition, renal transport of many other important solutes is linked either directly or indirectly to reabsorption of Na+ . In the following sections, the NaCl and water transport processes of each nephron segment and their regulation by hormones and other factors are presented. The proximal tubule reabsorbs approximately 67% of filtered water, Na+ , Cl− , K+ , and most other solutes. In addition the proximal tubule reabsorbs virtually all the glucose and amino acids filtered by the glomerulus, as well as most of the HCO3 − . The key element in proximal tubule reabsorption is Na+,K+-ATPase in the basolateral membrane. Reabsorption of every substance, including water, is linked in some manner to the operation of Na+,K+-ATPase.


Physiology_Levy

Physiology_Levy. WaterL/day1801.5178.599.2Na+ mEq/day25,20015025,05099.4K+ mEq/day72010062086.1Ca++ mEq/day5401053098.2HCO3− mEq/day43202431899.9+ Cl− mEq/day18,00015017,85099.2Glucosemmol/day8000800100.0Ureag/day56282850.0 aThe filtered amount of any substance is calculated by multiplying the concentration of that substance in the ultrafiltrate by the glomerular filtration rate (GFR); for example, the filtered load of Na+ is calculated as [Na+]ultrafiltrate (140mEq/L) × GFR (180L/day) = 25,200mEq/day. The composition and volume of urine can vary widely in the healthy state. These values represent average ranges. Normal water excretion typically ranges between 0.5 and 1.5L/day.Data from Valtin HV. Renal Physiology. 2nd ed. Boston: Little, Brown; 1983.


Physiology_Levy

Physiology_Levy. Na+ is reabsorbed by different mechanisms in the first and the second halves of the proximal tubule. In the first half of the proximal tubule, Na+ is reabsorbed primarily with bicarbonate (HCO3 −) and a number of other solutes (e.g., glucose, amino acids, Pi, lactate). In contrast, in the second half, Na+ is reabsorbed mainly with Cl− . This disparity is mediated by differences in the Na+ transport systems in the first and second halves of the proximal tubule and by differences in the composition of tubular fluid at these Bilirubin50–130mEq/L20–70mEq/L30–50mEq/L5–12mEq/L2–18mEq/L50–130mEq/L20–40mEq/L200–400mmol/L6–20mmol/L5.0–7.0500–800mOsm/kgH2O0000000 sites. In absolute terms the first half of the proximal tubule reabsorbs significantly more Na+ than the second half.


Physiology_Levy

Physiology_Levy. In the first half of the proximal tubule, Na+ uptake into the cell is coupled with either H+ or organic solutes, includ ing glucose (Fig. 34.1 ). Specific transport proteins mediate entry of Na+ into the cell across the apical membrane. For example, the Na+/H+ antiporter, NHE3, (see Fig. 34.1A ) couples entry of Na+ with extrusion of H+ from the cell. H+ secretion results in reabsorption of sodium bicarbonate (NaHCO3) (see ). Na+ also enters proximal tubule cells via several symporter mechanisms, including Na+/glucose (SGLT2), Na+/amino acid, Na+/Pi, and Na+/ lactate (see


Physiology_Levy

Physiology_Levy. Fig. 34.1B ). The glucose and other organic solutes that enter the cell with Na+ leave the cell across the basolateral membrane via passive transport mechanisms. Any Na+ that enters the cell across the apical membrane leaves the cell and enters the blood via Na+,K+-ATPase. Thus reabsorption of Na+ in the first half of the proximal tubule is coupled to that of HCO3 − and a number of organic molecules, and this generates a negative transepithelial voltage across the proximal tubule that provides the driving force for the paracellular reabsorption of Cl− . Reabsorption of many organic molecules, including glucose and lactate, is so avid they are almost completely removed from the tubular fluid in the first half of the proximal tubule (


Physiology_Levy

Physiology_Levy. Fig. 34.2 ). Reabsorption of NaHCO3 and Na+–organic solutes across the proximal tubule establishes a transtubular osmotic gradient (i.e., the osmolality of the interstitial fluid bathing the basolateral side of the cells is a few mOsm/L higher than the osmolality of tubule fluid) that provides the driving force for the passive reabsorption of water by osmosis. Because more water than Cl− is reabsorbed in the first half of the proximal tubule, the [Cl−] in tubular fluid rises along the length of the proximal tubule (see Fig. 34.2 In the second half of the proximal tubule, Na+ reabsorption is largely accompanied by Cl− reabsorption via both transcellular and paracellular pathways ( Fig. 34.3 ). Na+ is primarily reabsorbed with Cl− rather than organic solutes or HCO3 − as the accompanying anion because the Na+ transport mechanisms in the second half of the proximal tubule


Physiology_Levy

Physiology_Levy. Fig. 34.3 ). Na+ is primarily reabsorbed with Cl− rather than organic solutes or HCO3 − as the accompanying anion because the Na+ transport mechanisms in the second half of the proximal tubule There are over 300 different solute transporter genes that form the so-called SLC (solute carrier) family of genes.AD, autosomal dominant; AR, autosomal recessive; TAL, thick ascending limb of Henle’s loop; XLR, X-linked recessive.Modified from Nachman RH, Glassock RJ. NephSAP 2010;9(3). differ from those in the first half, and because the tubular fluid that enters the second half contains very little glucose or amino acids. In addition the high [Cl−] (140 mEq/L)


Physiology_Levy

Physiology_Levy. differ from those in the first half, and because the tubular fluid that enters the second half contains very little glucose or amino acids. In addition the high [Cl−] (140 mEq/L) Fanconi syndrome, a renal disease that is either hereditary in tubule fluid, which is due to preferential reabsorption − or acquired, results from an impaired ability of the proximal of Na+ with HCO3 and organic solutes in the first half − tubule to reabsorb HCO3, Pi, amino acids, glucose, and of the proximal tubule, facilitates reabsorption of Cl− low-molecular-weight proteins. Because other downstream with Na+ . nephron segments cannot reabsorb these solutes and The mechanism of transcellular Na+ reabsorption in the protein, Fanconi syndrome results in increased urinary excretion of HCO3− , amino acids, glucose, Pi, and low- second half of the proximal tubule is shown in Fig. 34.3 molecular-weight proteins.


Physiology_Levy

Physiology_Levy. Na+ enters the cell across the luminal membrane primarily via the parallel operation of a Na+/H+ antiporter (NHE3) •Fig. 34.1 Na+ transport processes in the first half of the proximal tubule. These transport mechanisms are present in all cells in the first half of the proximal tubule but are separated into different cells to simplify the discussion. A, Operation of the Na+/H+ antiporter (NHE3) in the apical membrane and the Na+,K+-ATPase and HCO3− transporters, including the Na+/HCO3− symporter (NBC1; see also ) in the basolateral membrane mediates reabsorption of NaHCO3. Carbon dioxide and water combine inside the cells to form H+ and HCO3− in a reaction facilitated by the enzyme carbonic anhydrase (CA). B, Operation of the Na+/glucose symporter (SGLT2) in the apical membrane, in conjunction with Na+,K+-ATPase and the glucose transporter (GLUT2) in the basolateral membrane, mediates Na+-glucose reabsorption. Inactivating mutations in the GLUT2 gene lead to decreased glucose


Physiology_Levy

Physiology_Levy. conjunction with Na+,K+-ATPase and the glucose transporter (GLUT2) in the basolateral membrane, mediates Na+-glucose reabsorption. Inactivating mutations in the GLUT2 gene lead to decreased glucose reabsorption in the proximal tubule and glucosuria (i.e., glucose in the urine). Though not shown, Na+ reabsorption is also coupled with other solutes, including amino acids, Pi, and lactate. Reabsorption of these solutes is mediated by the Na+/amino acid, Na+/Pi, and Na+/lactate symporters, respectively, located in the apical membrane and the Na+,K+-ATPase, amino acid, Pi, and lactate transporters, respectively, located in the basolateral membrane. Three classes of amino acid transporters have been identified in the proximal tubule: two that transport Na+ in conjunction with either acidic or basic amino acids and one that does not require Na+ and transports basic amino acids.


Physiology_Levy

Physiology_Levy. •Fig. 34.2 Concentration of solutes in tubule fluid as a function of length along the proximal tubule. [TF] is the concentration of the substance in tubular fluid; [P] is the concentration of the substance in plasma. Values above 100 indicate that relatively less of the solute than water is reabsorbed, and values below 100 indicate that relatively more of the substance than water is reabsorbed.


Physiology_Levy

Physiology_Levy. •Fig. 34.3 Na+ transport processes in the second half of the proximal tubule. Na+ and Cl− enter the cell across the apical membrane through the operation of parallel Na+/H+ (NHE3) and Cl−-base (e.g., formate, oxalate, and bicarbonate) antiporters (CFEX). More than one Cl−-base antiporter is involved in this process, but only one is depicted. The secreted H+ and base combine in the tubular fluid to form an H-base complex that can recycle across the plasma membrane. Accumulation of the H-base complex in tubular fluid establishes a H-base concentration gradient that favors H-base recycling across the apical plasma membrane into the cell. Inside the cell, H+ and the base dissociate and recycle back across the apical plasma membrane. The net result is uptake of NaCl across the apical membrane. The base may be hydroxide ions (OH−), formate (HCO2−), oxalate, HCO3− , or sulfate. The positive transepithelial voltage in the lumen, indicated by the plus sign inside the circle in the tubular