REVIEW OF RENAL STRUCTURE AND FUNCTION

The numbers indicate the PowerPoint slide that goes with the notes.

2] The kidneys are paired organs on either side of the aorta and inferior vena cava. They are retroperitoneal; that is, they are located behind the parietal peritoneum and are located outside of the peritoneal cavity. If we enter the body through the posterior body wall we can perform surgery on the kidneys without entering the peritoneal cavity. The kidneys are only partially protected by the 11th and 12th ribs, but have other means of protection. The right kidney is slightly lower than the left due to the space taken up by the liver. Each kidney is surrounded by a connective tissue capsule called the renal capsule. A thick layer of adipose tissue (fat) surrounds each kidney to protect it from blows and to anchor it in place. The adipose capsule is then surrounded by the renal fascia which also serves to hold the kidney in place within the body.

3] Picture: observe the location of the kidney in relation to the parietal peritoneum, and find the renal fascia,  the adipose capsule and the ribs.

4] Another view of the kidneys. Again, observe the location of the kidney in relation to the parietal peritoneum and the surrounding organs.

5] Each kidney is a bean-shaped structure. On the medial side of each there is the hilum - the small area where the renal artery enters the kidney and the renal veins and ureter leave the kidney. Each kidney has an outer cortex and inner medulla. Within the medulla the renal pyramids - triangular areas of tissue- can be seen. Each pyramid drains toward the point of the triangle, the area called the renal papilla. The rest of the medulla is made up of tubules that drain the urine. The renal papillae open into minor calyces which join to form major calyces. The major calyces drain into the renal pelvis which empties into the ureter.

6] Find the structures listed above. The renal columns are extension of the tissue of the cortex that run down between the renal pyramids.

7] The ureters connect the kidneys to the urinary bladder. They have smooth muscle in their walls and can move urine through peristalsis. Hydrostatic pressure and gravity also help to move urine toward the urinary bladder. They also have many sensory nerves that can make the passage of a kidney stone extremely painful (as bad or worse than childbirth!) Urine is stored in the urinary bladder, and then sent outside the body through the urethra. Where the urethra joins the bladder are two sphincters- an internal (involuntary) and an external (voluntary) sphincter. It females the urethra is short, only about 4 cm long. In the male it is much longer, and also serves to carry semen. The male urethra is divided into three parts: the prostatic urethra (as it passes through the prostate gland - the swelling of which can disturb urine flow)  the membranous urethra (as it pass through the urogenital diaphragm)  and the spongy or penile urethra (as it passes through the corpus spongiosum).

8] Observe the location of the kidneys, the ureters, urinary bladder and urethra.

9] Even though the kidneys make up only 1 % of the body mass, they receive 15-30% of the total cardiac output.
    The kidneys have two major functions:
    They remove metabolic wastes from the body, especially those containing nitrogen. Remember that nitrogenous wastes are produced by the breakdown of proteins (primarily - also nucleic acids).

10]The second major function of the kidneys is regulation:
       - of blood volume and composition (under the influence of ADH, aldosterone and atrial natriuretic peptide.)
       - of electrolytes, especially sodium, but also potassium and calcium.
       - of blood pH. The kidneys are the most effective regulators of pH in the body. They can eliminate acids from the     body, preserve bicarbonate ion and produce new bicarbonate ion. If the kidneys fail, pH balance fails.
    - blood pressure is extremely important to the ability of the kidneys to produce urine. If the blood pressure to the kidneys gets too low, they will produce renin, which activates the renin-angiotensin system to raise blood pressure.
    - remember the kidney also regulates the production of red blood cells through the production of the hormone erythropoietin.(EPO). This increases when oxygen levels in the kidney drop.

11] The basic functional unit of the kidney is the nephron. There are approximately 10⁶ nephrons/ kidney.
The three major processes that occur in the nephron are filtration, tubular reabsorption and tubular secretion. The nephron is composed of the renal corpuscle and a series of tubules. The renal corpuscle is composed of the glomerulus, which is a small tuft or ball of fenestrated capillaries,  and the glomerular or Bowman's capsule which surrounds the glomerulus.

12] The glomerulus produces a filtrate of blood, which is received into Bowman's capsule. This filtrate is then modified into urine as it passes through the kidney tubules. The first segment is called the proximal convoluted ("twisted") tubule. The major process that occurs here is reabsorption of water and solutes. A small amount of tubular secretion also take place here. The next section is the nephron loop or loop of Henle. This looks like a hair pin, and has descending and ascending limbs. This section allows for the body to produce a concentrated urine. The final sections are the distal convoluted tubules and collecting ducts. Here water and electrolytes are reabsorbed and the urine  is modified under the influence of ADH (antidiuretic hormone from the posterior pituitary gland), aldosterone from the adrenal cortex, and ANP produced by the right atrium. Here we can also rid the body of substances we want to get rid of by tubular secretion - actively secreting those substances into the urine, so that the concentration of these substances in the urine may be much higher than in the blood.

13] Diagram of a nephron. Notice that there are two types cortical nephrons which lie in the superficial regions of the cortex, and have short nephron loops which penetrate only a short distance into the renal medulla. These  make up 80-85 % of the nephrons. The remaining 15 -20 % of the nephrons are juxtamedullary nephrons which have long nephron loops which reach nearly to the renal papilla. These are important in regulating water balance. Once urine leaves the collecting duct at the renal papilla the urine is formed and is not modified again. The rest of the kidney and urinary system is just "plumbing" that transports urine outside the body.

14] Diagram of a nephron. Identify the renal corpuscle, glomerulus, glomerular (Bowman's) capsule, the proximal convoluted tubule, the nephron loop, the distal convoluted tubule and collecting duct.

15] This is a close-up of the glomerulus, and also shows the difference in the inner and outer layers of Bowman's capsule.  Notice the pores or fenestrations in the capillaries of the glomerulus. These allow easy passage of large amounts of fluid out of the capillary, but retain the cells within the capillary. The inner layer of Bowman's capsule, the layer that surrounds the glomerular capillaries, is made up of a modified simple squamous epithelium whose cells are called podocytes. The podocytes produce extensions called pedicels that wrap around the capillaries. In between the pedicels is a thin membrane called the slit membrane.

16] Blood enters the kidney through the renal artery, which divides down to the afferent arterioles that enter the renal corpuscle and form the glomerulus. There is an efferent arteriole that leaves the renal corpuscle, and then divides down into a second capillary network that surrounds the renal tubules. This allows substances to move from the tubules back into the capillaries and for substances in the capillaries to be secreted into the tubules. Notice the peritubular capillaries. The relatively straight capillaries around the loop of Henle are called the vasa recta.

17] The first process necessary for the formation of urine is filtration. This occurs only in the renal corpuscle. Most substances in plasma easily pass the glomerular filter. However, blood cells and most proteins are not normally filtered.
    The capillary endothelium and the podocytes form the endothelial-capsular (filtration) membrane. There are three basic layers to this membrane. The first layer is the fenestrated endothelium of the glomerulus. This prevents the passage of blood cells, but allows the passage of all other blood components. The second layer is the basement membrane of the glomerulus. This layer prevents the passage of the larger proteins. The third impediment is the slit membranes. The podocytes of Bowman’s capsule produce extensions that wrap around the glomerular capillaries, called pedicels. In between the pedicels are filtration slits. Over the filtration slits is a thin membrane called slit membrane which prevents the passage of medium sized proteins.

18] Forces that influence filtration: There are several opposing forces at work here.
    One force promotes glomerular filtration:
                glomerular blood hydrostatic pressure (GBHP). 55 mm Hg
    Two forces oppose glomerular filtration:
                capsular hydrostatic pressure (CHP) 15 mm Hg
                blood colloid osmotic pressure (BCOP) average is 30 mm Hg

19] Diagram of the forces that influence filtration. The numbers may be slightly different, but the net result is the same -  a force of only 10 mm Hg promotes filtration.

20] Glomerular filtration rate is the volume of plasma filtered per unit of time. Glomerular filtrate amounts to about 180 liters of fluid per day. However, most (99%) of this is usually reabsorbed, and urine output is about 1-2 liters/day. This large amount of fluid is filtered because the filter is porous and thin, the glomerular capillaries are long (have a large surface area), and the capillary blood pressure is high. This last is due to the fact that the afferent arteriole is larger in diameter than the efferent arteriole.

21] Diagram of amount of fluid filtered by kidneys vs. actual urine output.

22] The glomerular filtration rate (GFR) is influenced by several factors:
 -   the blood pressure and blood flow to the kidney. (If this drops, the kidney will try to increase it)
-    obstruction to urine outflow - like we saw in the heart, if the urine can not flow freely out of the kidney, the pressure of the urine can back up and increase the hydrostatic pressure inside Bowman's capsule, decreasing or stopping urine production.
-    Loss of protein-free fluid - this alters the osmotic pressure in the capillaries and so alters the net filtration.
- Hormonal regulation:
    Renin, a hormone produced by the kidneys, activates angiotensin I which is converted to angiotensin II which is a potent vasoconstrictor. This raises the systemic blood pressure so that there is increased blood flow to the kidneys.
    Aldosterone is the sodium (and water) retaining hormone. It causes sodium to be reabsorbed from the DCT and Collecting ducts, and where sodium goes, water follows. This only holds true here if ADH is pressent.
    ADH affects the permeability of the DCT and collecting ducts to water. If ADH is not present, these tubules may as well be plastic pipes, because virtually no water is reabsorbed into the body. When ADH is produced, water channels are placed into the membranes of the cells of the DCT and collecting ducts, and water can be reabsorbed. ANP or atrial natriuretic peptide, is the sodium and water losing hormone. It is produced by the right atrium when blood pressure is too high there. This causes the body to lose water, decreasing blood volume and thereby blood pressure.

23] In each nephron, the region of the final portion of the ascending nephron loop (of Henle) or the beginning of the distal convoluted tubule makes contact with the afferent arteriole serving its renal corpuscle. The tubule epithelial cells in this area are tall and crowded and are called the macula densa. These cells monitor the stretch and the sodium and chloride ion concentrations in the fluid in the tubule. Next to the macula densa, the wall of the afferent arteriole contains modified smooth muscle fibers call juxtaglomerular cells. These cells plus the macula densa make up the juxtaglomerular apparatus. The JGA senses Na +, Cl- and water. Under conditions of low blood pressure there is less of these substances in the loop of Henle. The JGA is inhibited from releasing its vasoconstrictor, and the afferent arteriole dilates, increasing the blood pressure to the glomerulus. The opposite occurs for high BP.  The JGA helps regulate arterial blood pressure and the rate of filtration by the kidneys. These cells secrete renin when BP falls.

24] Picture of the location of the juxtaglomerular apparatus.

25]Close-up of the JGA

26] Tubular reabsorption takes place in both the proximal convoluted tubules and the distal convoluted tubules. For right now, let's concentrate on the proximal convoluted tubules.
    The volume of fluid that enters the proximal convoluted tubule in half an hour is greater than the total plasma volume. As the filtrate passes through the tubules and collecting ducts 99% of it is reabsorbed returned to the bloodstream.
    The wall of the entire renal tubule consists of a single layer of epithelial cells and a basement membrane. The epithelium is modified in different portions of the tubule. In the proximal convoluted tubule the cells are cuboidal and have microvilli to increase their surface area for reabsorption and secretion. About 65% of the water and 100% of some filtered solutes are reabsorbed here. Reabsorbed substances include glucose, amino acids,urea, and ions, such as sodium, chloride, potassium, and bicarbonate.
    Especially important is the reabsorption of sodium. More sodium passes through the filter than any other substance except water. Sodium passively diffuses into the lumen side of the cell, and is actively pumped out the back side into the interstitial fluid. From there it diffuses into a capillary. This promotes the reabsorption of water by osmosis, and the reabsorption of other substances, esp. negatively charged ions, by passive diffusion. ("Where sodium goes, water follows.")
    There are several other factors that aid in the reabsorption of sodium and water. The peritubular capillaries are under relatively low pressure, the blood having already passed through the glomerular capillaries. The wall of the peritubular capillaries is more permeable than that of other capillaries. And finally, the protein concentration of the plasma in the capillaries is relatively high due to the removal of fluid through filtration, and this high concentration helps to pull fluid and sodium back into the capillaries.

27] Picture: Relationship of the kidney tubules to the surrounding capillaries.

28] Diagram of substances reabsorbed into the blood.

29] In addition to reabsorption, tubular secretion also occurs here.  Substances move from the peritubular capillaries into the tubules. This is a second chance to remove substances from the blood.

30] Diagram of tubular secretion and reabsorption in the proximal convoluted tubule.

31] By the end of the proximal convoluted tubule we have reabsorbed about 60 -70 % of the water and sodium that was present in the filtrate; about 90% of the potassium, bicarbonate ion, calcium and  uric acid;and about 100% of the glucose and amino acids.
    Normally, all the glucose and amino acids are removed from the filtrate by active transport or facilitated diffusion. Because this type of transport depends on carrier molecules, only a limited number of molecules can be transported in a given amount of time. The maximum amount of a substance that can be reabsorbed per unit time is called the transport maximum (Tm), and is measured in mg/min. When blood concentrations are abnormally high, the transport maximum may be exceeded, and some of that substance will be passed in the urine. (mental image- The old "I Love Lucy" episode where she is working at the candy factory. Everything is fine until the conveyor belt starts moving too fast with too many chocolates - Lucy ends up eating them and stuffing them in her clothes, but some of the bad ones still get away from her - she has exceeded her transport maximum! ) The plasma concentration for a substance at which it exceeds the Tm is called the renal threshold. Excess solutes will always cause the urine volume to be larger than normal (diuresis) because solutes increase the osmotic concentration of the urine. This explains the sugar in the urine and increased urine output in diabetes mellitus.

32] The loop of Henle or the nephron loop is used to produce a more concentrated urine. To produce a urine which is more concentrated than blood plasma, we have to rely on the long loops of Henle in the juxtamedullary nephrons. Here we can produce a filtrate that is 4X more concentrated than plasma. The way that this occurs is that the countercurrent mechanism establishes an osmotic concentration gradient in the interstitial fluid of the renal medulla. This enables production of concentrated urine when ADH is present.

33] Watch what is happening here: as the urine enters the descending limb of the nephron loop the urine is isotonic with the blood. As the urine flows through the descending limb, water can move out into the surrounding fluid in the medulla of the kidney, and sodium can enter the descending limb. The ascending limb actively pumps sodium out of the tubule, and by the time the ascending limb leaves the medulla, the urine is LESS concentrated than when we started!! As it passes through the distal convoluted tubule in the cortex, the urine again equilibrates with the blood. When it again enters the medulla through the collecting duct, the tonicity is the same as when we started. But, the action of the nephron loop was to produce this concentration gradient in the renal medulla. As long as ADH is present and water can be reabsorbed, as the urine flows through the collecting duct water is drawn into the surrounding fluid and the urine in the collecting duct becomes progressively more concentrated. Remember that after the urine leaves the collecting duct, it remains unchanged until it leaves the body.

34] What happens in the distal convoluted tubules and collecting ducts depends on whether or not ADH is present. In the proximal convoluted tubules water can be absorbed at any time. In the distal convoluted tubule we have facultative water reabsorption - in other words, it depends on how much water the body needs to reabsorb and how much the body can afford to lose. Aldosterone increases the reabsorption of sodium (and water), but causes potassium to be lost in the urine. Parathyroid hormone will increase the reabsorption of calcium.

35] Again, when ADH is not present, the DCT and collecting ducts do not reabsorb water, and a very dilute urine is produced.  When ADH is present, a very concentrated urine can be produced as the urine passes through the concentration gradient formed by the counter-current mechanisms in the loop of Henle.

36] Tubular secretion in the distal convoluted tubules and collecting ducts acts to rid the body of excess substances such as potassium, hydrogen ion, urea, ammonia, creatinine and certain drugs.  The secretion of hydrogen ion (acid) helps to maintain blood pH. Remember that the kidneys can reabsorb bicarbonate ion, and also make more as needed.

37] Diagram of tubular reabsorption and secretion in the DCT.

38] Renal diagnostic procedures:
    Urinalysis is a non-invasive and inexpensive way to determine what is going on in the body. We have studied urine extensively, and its normal properties are well known and easily measured.

39] The pH of urine is normally 4.6- 8.0, it is higher in alkalosis and lower in acidosis. Diabetes and starvation cause a more acidic urine, and urinary infections can cause higher pH, since organisms like pseudomonas and proteus are urea splitters. (They break urea into ammonia, which increases the pH). Lower pH helps to prevent bladder infections by inhibiting the growth of microorganisms.

40]Normal urine has a specific gravity of 1.025 to 1.032, but can range from 1.001-1.035. (The specific gravity of water is 1.000) High specific gravity can cause precipitation of solutes and formation of kidney stones. When the tubules are damaged urine specific gravity approaches that of the glomerular filtrate (1.010) If specific gravity remains fixed at this level it is a sign that at least 2/3 of the nephron mass has been lost.

41]  Diabetes insipidus is a condition caused by the lack of ADH. Since water is not reabsorbed, the specific gravity is low =1.003

42] Examination of urine under the microscope can tell us a lot about what is happening in the kidneys.  We should see few or no red blood cells. Large numbers of red blood cells in the urine is called hematuria, and often indicates a problem with the glomerulus, since normally the filtration membrane will retain blood cells. There are several conditions that can also show blood in the urine and mislead you:  be careful if your patient is menstruating or has been traumatized by catheterization. An inflamed prostate gland or a bladder infection or bladder stones can also cause bleeding that has nothing to do with the kidney itself.
   

43] Casts are the impressions of the tubules formed when the pressure of the urine forces substances against the tubules, where these substances make "casts" of the tubules. Red cell casts would indicate bleeding in the tubules. White blood cell casts would indicate inflammation of the tubules. Epithelial cell casts would indicate degeneration of the tubules, or necrosis (death) of the tubule cells.

44] Crystal may form as the urine cools, especially if concentrations of substances are high. The presence of cystals may indicate inflammation, or infection or kidney stones.

45] The presence of white blood cells in the urine is called pyuria (or pus in the urine) and usually indicates a urinary tract infection, as would the presence of bacteria in the urine. Urine itself is virtually sterile under normal circumstances, but bacteria may contaminate the sample from the external genitalia or last section of the urethra. Casts, cells and bacteria are normally found only in trace amounts.

46] Substances not normally found in urine include acetone, albumin, bile and glucose. However, with individuals on the Atkin's diet, we may be seeing increases in ketones such as acetone. These are products that are formed when lipids are incompletely metabolized for energy, and are often seen in diabetics. Those on the Atkin's diet will also restrict their carbohydrate intake until ketones are formed. Glucose in the urine is also a sign of diabetes mellitus.
    Proteins, such as albumin, could indicate renal disease involving the glomerulus since the filtration membrane retains most proteins. Increased proteinuria and decreased serum albumin can lead to edema in the extremities.

47] Blood Urea Nitrogen or BUN
    Urine normally contains mineral ions such as sodium, chlorine and potassium, nitrogenous wastes such as ammonia, creatinine, urea and uric acid. Catabolism of protein produces about 30 milligrams of urea each day. Uric acid is produced from nucleic acids. BUN is the amount of urea found in blood. It is the end product of protein breakdown, and the amount produced is influenced by diet (consuming raw meat with blood, for example), dehydration, and hemolysis (breakdown of blood cells). About 50% is passively reabsorbed by the kidney tubules, but the rest is excreted in the urine. The normal range is 10-20 mg/dL. BUN is used as a good general screen for abnormal renal function. If the GFR decreases with renal disease or due to a blockage, BUN rises.

48] Creatinine occurs in blood as the end product of muscle metabolism, the breakdown of creatine. Since muscle mass is usually constant, and is not affected by extrarenal factors such as diet, creatinine is produced at a relatively constant rate. It is normally 0.7-1.5 mg/dL in plasma. The creatinine in the blood can be compared to the creatinine in the urine collected over a 24 hour period to determine the creatinine clearance.

49] Creatinine clearance is an indirect measure of GFR and renal blood flow. Creatinine is neither reabsorbed nor is it actively secreted, just freely filtered. The amount excreted is equal to the amount filtered. Creatinine clearance is a useful test to monitor changes in chronic renal function. It does increase in conditions where there is trauma with massive muscle breakdown.

50] We can use the clearance rates of chemicals not normally found in the body diagnostically. Inulin is a substance which is not reabsorbed or secreted and its clearance is equal to the GFR. A certain amount of inulin is injected into the patient and the clearance is measured. The clearance of PAH (para-aminohippuric acid) is equal to the renal plasma flow since this substance is not reabsorbed and is actively secreted.