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+, PO3–), 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).

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).

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.

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:

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.

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.

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.

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:

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.

Clinical significance: Immuno mediated glomerular diseases

The damage to the glomerulus can be initiated by immune mechanisms. Antibodies against glomerular components (cells and basal lamina) and antibody-complement complexes circulating in blood in patients with systemic autoimmune diseases can cause glomerular injury such as membranoproliferative glomerulonephritis (Figure 14-10), membranous glomerulonephritis and immunoglobulin A nephropathy (Berger’s disease).

Antibody-antigen complexes are not immunologically targeted to glomerular components. They are trapped in the glomerulus because of the filtration properties of the glomerular filtration barrier. A complicating factor is that trapped antibody-antigen complexes provide binding sites to complement proteins, which also contribute to the glomerular damage (see Chapter 10, Immune-Lymphatic System, for a review of the complement cascade).

As we have seen, autoantibodies can target domains of type IV collagen, a component of the glomerular filtration barrier. The binding of antibodies to specific domains of type IV collagen generates a diffuse linear pattern detected by immunofluorescence microscopy. In addition, the deposit of circulating antibody-antigen complexes produces a granular pattern. Systemic lupus erythematosus and bacterial (streptococci) and viral (hepatitis B virus) infections generate antibody-antigen complexes circulating in blood.

Immune complexes can deposit between the endothelial cells of the glomerular capillaries and the basal lamina (subendothelial deposits, see Figure 14-10), in the mesangium, and less frequently between the basal lamina and the foot processes of podocytes (subepithelial deposits).

Immune complexes produced after bacterial infection can cause the proliferation of glomerular cells (endothelial and mesangial cells) and attract neutrophils and monocytes. This condition, known as acute proliferative glomerulonephritis, is observed in children and is generally reversible with treatment. This disease is more severe in adults: it can evolve into rapidly progressive (crescentic) glomerulonephritis (Figure 14-11).

A typical feature of crescentic glomerulonephritis is the presence of glomerular cell debris and fibrin, causing severe glomerular injury. The proliferation of parietal cells of the capsule of Bowman and migrating neutrophils and lymphocytes into the space of Bowman occur. Both the cellular crescents and deposits of fibrin compress the glomerular capillaries.