URINARY SYSTEM

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14 URINARY SYSTEM

The urinary system has three critical functions: (1) to clear the blood of nitrogenous and other waste metabolic products by filtration and excretion; (2) to balance the concentration of body fluids and electrolytes, also by filtration and excretion; and (3) to recover by reabsorption small molecules (amino acids, glucose, and peptides), ions (Na⁺, C1⁻, Ca²⁺, PO^3–), and water, in order to maintain blood homeostasis (Greek homoios, similar; stasis, standing).

The kidneys regulates blood pressure by producing the enzyme renin. Renin initiates the conversion of angiotensinogen (a plasma protein produced in liver) to the active component angiotensin II.

The kidneys is also an endocrine organ. It produces erythropoietin, a stimulant of red blood cell production in bone marrow (for the role of erythropoietin, see Chapter 6, Blood and Hematopoiesis). It also activates 1,25-hydroxycholecalciferol, a vitamin D derivative involved in the control of calcium metabolism (see vitamin D metabolism in Chapter 19, Endocrine System).

Kidneys

The urinary system consists of paired kidneyss and ureters and a single urinary bladder and urethra. Each kidneys has a cortex (subdivided into outer cortex and juxtamedullary cortex) and a medulla (subdivided into outer medulla and inner medulla).

The medulla is formed by conical masses, the medullary pyramids, with their bases located at the corticomedullary junction. A medullary pyramid, together with the associated covering cortical region, constitutes a renal lobe. The base of the renal lobe is the renal capsule. The lateral boundaries of each renal lobe are the renal columns (of Bertin), residual structures representing the fusion of primitive lobes within the metanephric blastema. The apex of each renal lobe terminates in a conic-shaped papilla surfaced by the area cribrosa (the opening site of the papillary ducts). The papilla is surrounded by a minor calyx. Each minor calyx collects the urine from a papilla dripping from the area cribrosa. Minor calyces converge to form the major calyces which, in turn, form the pelvis.

Organization of the renal vascular system

The main function of the kidneys is to filter the blood supplied by the renal arteries branching from the descending aorta.

The kidneyss receive about 20% of the cardiac output per minute and filter about 1.25 L of blood per minute. Essentially, all the blood of the body passes through the kidneyss every 5 minutes.

About 90% of the cardiac output goes to the renal cortex; 10% of the blood goes to the medulla. Approximately 125 mL of filtrate is produced per minute, but 124 mL of this amount is reabsorbed.

About 180 L of fluid ultrafiltrate is produced in 24 hours and transported through the uriniferous tubules. Of this amount, 178.5 L is recovered by the tubular cells and returned to the blood circulation, whereas only 1.5 L is excreted as urine.

We start our discussion by focusing on the vascularization of the kidneys (Figure 14-1).

Figure 14-1 Vascularization of the kidneys

Oxygenated blood is supplied by the renal artery. The renal artery gives rise to several interlobar arteries, running across the medulla through the renal columns along the sides of the pyramids.

At the corticomedullary junction, interlobar arteries give off several branches at right angles, changing their vertical path to a horizontal direction to form the arcuate arteries, running along the corticomedullary boundary. The renal arterial architecture is terminal. There are no anastomoses between interlobular arteries. This is an important concept in renal pathology for understanding focal necrosis as a consequence of an arterial obstruction. For example, renal infarct can be caused by atherosclerotic plaques in the renal artery or embolization of atherosclerotic plaques in the aorta.

Vertical branches emerging from the arcuate arteries, the interlobular arteries, penetrate the cortex. As interlobular arteries ascend toward the outer cortex, they branch several times to form the afferent glomerular arterioles (see Figure 14-1).

The afferent glomerular arteriole, in turn, forms the glomerular capillary network, enveloped by the two-layered capsule of Bowman, and continues as the efferent glomerular arteriole. This particular arrangement, a capillary network flanked by two arterioles (instead of an arteriole and a venule) is called the glomerulus or arterial portal system. As discussed in Chapter 12, Cardiovascular System, the glomerular arterial portal system (Figure 14-2) is structurally and functionally distinct from the venous portal system of the liver.

Figure 14-2 Arterial and venous portal systems

Both the glomerulus and the surrounding capsule of Bowman form the renal corpuscle (also called the malpighian corpuscle). The smooth muscle cell wall of the afferent glomerular arteriole contains epithelial-like cells, called juxtaglomerular cells, with secretory granules containing renin. A few juxtaglomerular cells may be found in the wall of the efferent glomerular arteriole.

Vasa recta

Depending on the location of the renal corpuscle, the efferent glomerular arteriole forms two different capillary networks:

1. A peritubular capillary network, surrounding the cortical segments of the superficial uriniferous tubules. The peritubular capillary network, lined by fenestrated endothelial cells, drains into the interlobular vein converging to the arcuate vein. Arcuate veins drain into the interlobar veins, which are continuous with the renal vein.

2. The vasa recta (straight vessels), formed by multiple branching of the efferent arterioles located close to the corticomedullary junction. The descending components of the vasa recta (arterial capillaries lined by continuous endothelial cells) extend into the medulla, parallel to the medullary segments of the uriniferous tubules, make a hairpin turn, and return to the corticomedullary junction as ascending venous capillaries lined by fenestrated endothelial cells.

Note that the vascular supply to the renal medulla is largely derived from the efferent glomerular arterioles. The descending vasa recta bundles penetrate to varying depths of the renal medulla, alongside the descending and ascending limbs of the loop of Henle and the collecting ducts. Side branches connect the returning ascending vasa recta to the interlobular and arcuate veins. Remember the close relationship of the vasa recta with each other and adjacent tubules and ducts. This is the structural basis of the countercurrent exchange and multiplier mechanism of urine formation as we will discuss later.

Difference between lobe and lobule

A renal medullary pyramid is a medullary structure limited by interlobar arteries at the sides. The corticomedullary junction is the base and the papilla is the apex of the pyramid.

A renal lobule is a cortical structure that can be defined in two different ways (see Figure 14-1): (1) The renal lobule is a portion of the cortex flanked by two adjacent ascending interlobular arteries. Each interlobular artery gives rise to a series of glomeruli, each consisting of an afferent glomerular arteriole, a capillary network, and the efferent glomerular arteriole. (2) The renal lobule consists of a single collecting duct (of Bellini) and the surrounding nephrons that drain into it. The straight portions of the nephrons, together with the single collecting duct, is called a medullary ray (of Ferrein). A medullary ray is the axis of the lobule (Figure 14-3).

Figure 14-3 Medullary ray

Note that the cortex has many lobules and that each lobule has a single medullary ray.

The uriniferous tubule consists of a nephron and a collecting duct

Each kidneys has about 1.3 million uriniferous tubules surrounded by a stroma containing loose connective tissue, blood vessels, lymphatics, and nerves. Each uriniferous tubule consists of two embryologically distinct segments (Figure 14-4): (1) the nephron and (2) the collecting duct.

Figure 14-4 Uriniferous tubule

The nephron consists of two components: (1) the renal corpuscle (300 μm in diameter) and (2) a long renal tubule (5 to 7 mm long).

The renal tubule consists of several regions: (1) the proximal convoluted tubule, (2) the loop of Henle, and (3) the distal convoluted tubule, which empties into the collecting tubule.

Collecting tubules have three distinct topographic distributions: a cortical collecting tubule (found in the renal cortex as the centerpiece of the medullary ray), an outer medullary collecting tubule (present in the outer medulla), and an inner medullary segment (located in the inner medulla).

Depending on the distribution of renal corpuscles, nephrons can be either cortical or juxtamedullary. Renal tubules derived from cortical nephrons have a short loop of Henle that penetrates just up to the outer medulla. Renal tubules from juxtamedullary nephrons have a long loop of Henle projecting into the inner medulla (Figure 14-5).

Figure 14-5 Cortical and juxtamedullary nephrons

The renal corpuscle

The renal corpuscle, or malpighian corpuscle (Figure 14-6), consists of the capsule of Bowman investing a capillary tuft, the glomerulus.

Figure 14-6 Renal corpuscle

The capsule of Bowman has two layers: (1) the visceral layer, attached to the capillary glomerulus, and (2) the parietal layer, associated with the connective tissue stroma.

The visceral layer is lined by epithelial cells called podocytes, reinforced by a basal lamina. The parietal layer is covered by a basal lamina supported by simple squamous epithelium and is continuous with the simple cuboidal epithelium of the proximal convoluted tubule.

A urinary space (Bowman’s space or capsular space), containing the plasma ultrafiltrate (primary urine), exists between the visceral and parietal layers of the capsule. The plasma ultrafiltrate contains trace amounts of protein. The urinary space is continuous with the lumen of the proximal convoluted tubule at the urinary pole, the gate through which the plasma ultrafiltrate flows into the proximal convoluted tubule. The opposite pole, the site of entry and exit of the afferent and efferent glomerular arterioles, is called the vascular pole.

The glomerulus consists of two components (Figure 14-7):

1. The glomerular capillaries, lined by fenestrated endothelial cells.

2. The mesangium, formed by mesangial cells embedded in the mesangial matrix.

Figure 14-7 Components of the renal corpuscle visualized by light and electron microscopy

The renal corpuscle: Glomerular filtration barrier

The podocytes have long and branching cell processes that completely encircle the surface of the glomerular capillary. Both podocytes and fenestrated endothelial cells and their corresponding basal laminae constitute the glomerular filtration barrier.

The endings of the cell processes, the pedicels, from the same podocyte or adjacent podocytes, interdigitate to cover the basal lamina and are separated by gaps, the filtration slits. Filtration slits are bridged by a membranous material, the filtration slit diaphragm (Figure 14-8). Pedicels are attached to the basal lamina by α₃β₁ integrin.

Figure 14-8 Glomerular filtration barrier

The podocyte filtration slit diaphragm consists of the protein nephrin interacting with nephrin molecules in a homophilic manner, and with the nephrin-related transmembrane proteins Neph1 and Neph2. Nephrin is anchored to actin filaments (within the pedicel) by the proteins podocin and CD2-associated proteins (CD2AP). The interaction of nephrin in the middle of the slit creates a filtering structure retarding the passage of molecules crossing the endothelial fenestrations and the basal laminae.

In addition to the components of the glomerular filtration barrier, other limiting factors controlling the passage of molecules in the plasma ultrafiltrate are size and electric charge. Molecules with a size less than 3.5 nm and positively charged or neutral are filtered more readily. Albumin (3.6 nm and anionic) filters poorly.

Clinical significance: Glomerular filtration defects

The fenestrated endothelial cells of the glomerular capillaries are covered by a basal lamina to which the foot processes of the podocytes attach (see Figure 14-8). Podocytes produce glomerular endothelial growth factor to stimulate the development of the endothelium and maintenance of its fenestrations.

The endothelium is permeable to water, urea, glucose, and small proteins. The surface of the endothelial cells is coated with negatively charged glycoproteins that block the passage of large anionic proteins.

The endothelial cell basal lamina, closely associated with the basal lamina produced by podocytes, contains type IV collagen, fibronectin, laminin, and heparan sulfate as major proteins.

Each type IV collagen monomer consists of three α chains forming a triple helix. There are six chains (α1 to α6) encoded by six genes (COL4A1 through COL4A6). Two domains of each monomer are important: (1) the noncollagenous (NC1) domain at the C-terminal and (2) the 7S domain at the N-terminal. The NC1 and 7S domains, separated by a long collagenous domain, are cross-linking domains required for formation of the type IV collagen network. A correctly assembled network is critical for maintaining the integrity of the glomerular basal lamina and its permeability function.

Type IV collagens are directly involved in the pathogenesis of three diseases. (1) Goodpasture syndrome, an autoimmune disorder consisting in progressive glomerulonephritis and pulmonary hemorrhage, caused by anti-α3(IV) antibodies binding to the glomerular and alveolar basal laminae. (2) Alport’s syndrome, a progressive inherited nephropathy, characterized by irregular thinning, thickening, and splitting of the glomerular basal lamina. Alport’s syndrome is transmitted by an X-linked recessive trait, is predominant in males, and involves mutations of the COL4A5 gene. Patients with Alport’s syndrome—often associated with hearing loss (defective function of the stria vascularis of the cochlea) and ocular symptoms (defect of the lens capsule)—have hematuria (blood in the urine) and progressive glomerulonephritis leading to renal failure. The abnormal glomerular filtration membrane enables the passage of red blood cells and proteins. (3) Benign familial hematuria, caused by a dominant inherited mutation of the COL4A4 gene, which does not lead to renal failure.

Clinical significance: Congenital nephrotic syndrome

Congenital nephrotic syndrome is caused by a mutation in the nephrin gene leading to the absence or malfunction of the podocyte slit filtration diaphragm. About 70 different mutations have been described. Affected children have massive proteinuria even in utero and the nephrotic syndrome develops soon after birth. Infants display abdominal distention, hypoalbuminemia, hyperlipidemia, and edema. Congenital nephrotic syndrome, particularly common in Finland, is lethal.

Mesangium

The mesangium, an intraglomerular structure interposed between the glomerular capillaries, consists of two components: (1) the mesangial cells and (2) the mesangial matrix. In addition, mesangial cells aggregate outside the glomerulus (extra-glomerular mesangial cells; see Figures 14-7 and 14-15) in a space limited by the macula densa and the afferent and efferent glomerular arterioles. Intraglomerular mesangial cells may be continuous with extraglomerular mesangial cells.

Mesangial cells are specialized pericytes with characteristics of smooth muscle cells and macrophages.

Mesangial cells are (1) contractile, (2) phagocytic, and (3) capable of proliferation. They synthesize both matrix and collagen, and secrete biologically active substances (prostaglandins and endothelins). Endothelins induce the constriction of afferent and efferent glomerular arterioles.

Mesangial cells participate indirectly in the glomerular filtration process by:

1. Providing mechanical support for the glomerular capillaries.

2. Controlling the turnover of the glomerular basal lamina material by their phagocytic activity.

3. Regulating blood flow by their contractile activity.

4. Secreting prostaglandins and endothelins.

5. Responding to angiotensin II.

The glomerular filtration membrane does not completely surround the capillaries (Figure 14-9). Immunoglobulins and complement molecules, unable to cross the filtration barrier, can enter the mesangial matrix. The accumulation of immunoglobulin complexes in the matrix induces the production of cytokines by mesangial cells that trigger an immune response leading to the eventual occlusion of the glomerulus.