The kidney is designed to perform a number of essential functions. First, it contributes importantly to the maintenance of the extracellular environment that is essential for normal cellular function. The kidney achieves an optimal extracellular environment through excretion of waste products such as urea, creatinine, uric acid, and other substances. Balanced excretion of water and electrolytes is another important role of the kidney. Second, the kidney regulates systemic and renal hemodynamics through the production of various hormones, as well as the regulation of salt and water balance. Hormones such as renin, angiotensin II (AII), prostaglandins (PGs), endothelin, nitric oxide, adenosine, and bradykinin regulate vascular reactivity and renal blood flow. Third, the kidney produces other hormones that influence various end-organ functions. Red blood cell production is stimulated by renal erythropoietin synthesis, which is controlled by a highly regulated oxygen sensor in the proximal nephron. Hence the kidney can be viewed as a “critmeter”, which monitors and controls red blood cell production and the hemoglobin and hematocrit. Bone metabolism is influenced by renal production of calcitriol, as well as proper balance of calcium and phosphorus. Finally, the kidney participates in gluconeogenesis during fasting to prevent hypoglycemia. It also contributes to the catabolism of various peptide hormones filtered by the glomerulus such as insulin.
To perform these functions, the kidney is uniquely constructed to filter, reabsorb, and secrete a variety of substances in a very precise manner through integrated regulation of renal hemodynamics and tubular handling of water and solutes. Secretion of hormones such as erythropoietin and calcitriol closely link kidney function with control of red cell mass and bone metabolism. Metabolism of peptide hormones and clearance of medications is another important kidney function to maintain health. Disturbances in these processes lead to several harmful and potentially life-threatening clinical syndromes.
MORPHOLOGY OF THE KIDNEY
Gross examination of the kidney reveals an outer portion, the cortex, and inner portion, the medulla (Figure 1.1). Blood is supplied to the kidney via the renal artery (or arteries) and is drained via the renal vein. As is discussed next, the glomeruli, which are the filtering units of the nephron, are found within the cortex. Tubules are located in both cortex and medulla. The medulla consists of an inner and outer stripe. Collecting tubules form a large part of the inner medulla and papilla. Urine is formed by glomerular filtration and modified by the tubules, leaves the collecting ducts and drains sequentially into the calyces, renal pelvis, ureter, and finally into the bladder.
FIGURE 1-1. Anatomy of the kidney. Shown are the cortex, medulla, calyces, renal pelvis, and ureter.
The nephron is the basic unit of the kidney. There are approximately 1.0 to 1.3 million nephrons in the normal adult kidney. The nephron consists of a glomerulus and a series of tubules (Figure 1.2). The glomerulus is composed of a tuft of capillaries with a unique vascular supply. Glomerular capillaries are interposed between an afferent and efferent arteriole. They reside in the cortex and corticomedullary junction. Within the tubular lumen glomerular filtrate is modified by tubular cells. Tubules are lined by a continuous layer of epithelial cells, each of which possesses characteristic morphology and function depending on its location in the nephron. The tubules are present both in cortex and medulla.
FIGURE 1-2. The nephron. The nephron consists of a glomerulus and series of tubules. Nephrons can be subdivided into those in cortex and those in the juxtamedullary region. The glomerulus is composed of a capillary tuft interposed between the afferent and efferent arteriole. Tubules are supplied by a peritubular capillary network that includes the vasa recta, which runs parallel to the loop of Henle.
An ultrafiltrate of plasma is formed by the glomerulus and passes into the tubules where it is modified by reabsorption (removal of a substance from the ultrafiltrate) and secretion (addition of a substance to the ultrafiltrate). Different tubular segments alter fluid contents by varying reabsorption and secretion. Division of the nephron is based on morphology, as well as permeability and transport characteristics of the segments. For example, the proximal tubule and loop of Henle reabsorb the bulk of filtered water and solutes. In the distal nephron, and particularly in collecting tubules, fine adjustments in urinary composition are undertaken. Also, there is heterogeneity of cell types within the cortical collecting tubule. In this segment, the principal cell reabsorbs sodium and secretes potassium while the intercalated cell secretes hydrogen ion and reabsorbs potassium.
The formation of urine occurs as glomerular filtrate is sequentially modified in tubular segments. Plasma is ultrafiltered by the glomerulus and passes from the Bowman space into the proximal tubule. This nephron segment consists anatomically of an initial convoluted segment, followed by a straight segment, and the pars recta that enters the outer medulla. The loop of Henle, which possesses a hairpin configuration, follows the pars recta and includes a thin descending limb, and thin and thick ascending limb. The loops of Henle are not uniform in their length. Approximately 40% are short loops that don’t enter the medulla or enter only the outer medulla. These loops do not have a thin ascending limb and are located predominantly in outer cortex. The remaining loops of Henle are long and extend into the medulla and may reach the inner medulla and papilla. Long loops are located in the juxtamedullary region. Both short and long loops are found in midcortex.
The thick ascending limb of the loop of Henle has a cortical segment that returns to its own glomerulus. This tubule, which has specialized epithelial cells known as the macula densa, approximates the afferent arteriole, forming the juxtaglomerular (JG) apparatus. As is discussed later, the JG apparatus participates importantly in regulation of GFR.
Four cortical tubular segments follow the macula densa. They are the distal convoluted tubule, the connecting segment, the initial collecting tubule, and the cortical collecting tubule. The connecting segments drain into a single cortical collecting tubule, which then connects to the medullary collecting tubule. In cortex, initial collecting tubules drain into collecting ducts, whereas deeper connecting tubules drain into connecting segments. These are called arcades. From this segment, urine drains into the calyces, renal pelvis, ureters, and bladder.
Renal blood flow exceeds most other organs and, on average, the kidneys receive approximately 20% of the cardiac output. This calculates to approximately 1 L/min of blood and 600 mL of plasma. Of this, 20% of plasma is filtered into the Bowman space, giving a filtration rate of approximately 120 mL/min. Renal arteries carry blood into the kidney where it passes through serial branches, which include the interlobar, arcuate, and interlobular arteries. Blood enters the glomerulus through the afferent arteriole. A plasma ultrafiltrate is formed within the capillary tuft and passes into the Bowman space. Blood remaining in the capillaries exits the glomerulus via the efferent arteriole. In cortex, blood in postglomerular capillaries flows adjacent to the tubules, while branches from the efferent arterioles of juxtamedullary glomeruli enter the medulla and form the vasa recta capillaries. Blood exits the kidney through a venous system into the systemic circulation.
The circulatory anatomy within the kidney determines the final urine composition. First, GFR importantly influences the amount of solute and water that is excreted. Second, peritubular capillaries in cortex modify proximal tubular reabsorption and secretion of solutes and water. They also return reabsorbed solutes and water to the systemic circulation. Third, creation of the counter-current gradient for water conservation is dependent on vasa recta capillary function. These capillaries also return reabsorbed salt and water to the systemic circulation.
As stated previously, the glomerulus is comprised of a capillary network with an afferent and efferent arteriolar circulation. This design sets the glomerular circulation apart from other organ systems and allows modification of urine composition to meet the demands of various, often extreme diets. The glomerular capillary tuft sits within the parietal epithelial cell space, known as the Bowman capsule. The parietal epithelium is continuous with the visceral epithelial cells (podocytes), which cover the glomerular capillary tuft. The glomerular capillary loop is comprised of endothelial cell, glomerular basement membrane (GBM), and podocyte, all of which are supported structurally by mesangial cells. The GBM consists of a fusion of endothelial and visceral epithelial cell basement membrane components, which include type IV collagen, laminin, nidogen, and heparan sulfate proteoglycans. It functions to maintain normal glomerular architecture, anchor adjacent cells, and restrict passage of various macromolecules. The podocyte is attached to the GBM by discrete foot processes, which have pores containing slit diaphragms. The slit diaphragm is a thin membrane that acts as the final filtration barrier.
A key function of the glomerulus is to act as a filtration barrier that permits the passage of water and other solutes and restricts the movement of certain molecules. For example, filtration of water, sodium, urea, and creatinine are integral to proper toxin clearance, volume balance, and electrolyte homeostasis. In contrast, restriction of filtration of large proteins (albumin, immunoglobulin G) prevents the development of hypoalbuminemia, negative nitrogen balance, and infection. The glomerular capillary wall restricts solute movement by using both size and charge selectivity.
Size selectivity is maintained by GBM and podocyte foot process slit diaphragms. The GBM contributes to size selectivity through the creation of functional pores present in the spaces between the cords of type IV collagen. Two populations of pores are present in glomerular capillary wall: a more common small pore (radius 42 Â) and a less numerous larger pore (70 Â). Other capillary loop elements, however, provide additional size selectivity. This is known because isolated GBM studies demonstrate more permeability in GBM than intact glomerulus, suggesting an important role of glomerular epithelial cells. Also, molecules that pass through the GBM are restricted from passage into the Bowman space by epithelial slit diaphragms. A number of podocyte proteins (nephrin, podocin, synaptopodin, podocalyxin, α-actin 3) interact to form the slit diaphragms and maintain podocyte integrity as a filtration barrier. Mutation in genes that synthesize these proteins as well as effacement of foot processes by disease states is associated with filtration barrier loss and the development of proteinuria. Glomerular endothelial cells, however, contribute very little to size selectivity, as their fenestrae are wide and do not restrict macromolecules until they reach a radius larger than 375 Â.
Macromolecule filtration is also prevented by charge selectivity. Electrostatic repulsion is created by anionic sites in the GBM and endothelial cell fenestrae. Heparan sulfate proteoglycans, which are synthesized by glomerular endothelial and epithelial cells, provide the bulk of negative charge. The charge barrier was first noted when the differential effect of similar-sized dextrans with various charges (neutral, cationic, anionic) on filtration was noted. Neutral and cationic dextrans undergo greater filtration than anionic dextrans, despite similar molecular weight (Figure 1.3). This finding supports a glomerular charge barrier. In humans, albumin is restricted from filtration based on both size and charge selectivity. When glomerular injury occurs, impairment of both size and charge selectivity results. An increased number of larger pores, the development of rents and cavities in the GBM, and a defect in charge selectivity allow proteinuria in diseases such as membranous nephropathy, diabetic nephropathy, and focal glomerulosclerosis. Loss of charge selectivity plays a major role in the protein leak that occurs with minimal change disease, although loss of size selectivity may contribute. It is interesting to note that small solute and water clearance are impaired in this setting, likely a result of loss of capillary surface area, while protein losses continue through large pores unimpeded because of loss of anionic charge repulsion.
FIGURE 1-3. Filtration curves for neutral, cationic, and anionic dextrans. The curves show that filtration of anionic dextrans is impeded by negative charge in the glomerular capillary wall supporting the conclusion that the glomerular capillary wall impedes protein movement via a charge and size barrier. (From Brenner BM, Bohrer MP, Baylis C, and Deen WM. Kidney Int. 12:229-237, 1977, with permission.)