Introduction to the kidneys

Extrinsic Control of Renal Blood Flow

*Sympathetic nervous system activity* is the most important extrinsic regulator of renal blood flow. There is little sympathetic tone at rest. Activation of the sympathetic system due to hemorrhagic shock, for example, can decrease renal blood flow to 10% of normal as renal vessels constrict. Thus, blood can be shunted to more critical areas of the body such as the brain. Several humoral factors can influence renal vascular resistance. Catecholamines are very potent vasoconstrictors of afferent and efferent arterioles. They also constrict renal veins leading to various hemodynamic changes. Serotonin and antidiuretic hormone (ADH) are also vaso-constrictors of the renal vascular bed, but only at relatively high concentrations. These high concentrations are seen only in conditions such as hemorrhagic shock. The kinins, ANF (sometimes termed ANP) and several prostaglandins are very potent vasodilators (predominantly of the afferent arteriole (dilation)) in the renal bed and function to control GFR.

Summary Table-Processing of the Ultrafiltrate under Normal Conditions

*You start with PCT; it reabsorbs 2/3rd of the water isoosmotically!* (He repeated this, so know it!) Only 5% of the water is reabsorbed in Loop of Henle and depending on whether you are in the descending or ascending limb, the filtrate can be hypertonic or hypotonic. In the DCT/CCT, reabsorption of water is about 8% and the osmolarity is *hypotonic*. In the collecting duct, water reabsorption is about 20% and its osmolarity depends on whether Antidiuretic Hormone (ADH) is present. If ADH is present, the osmolarity would be greater than 1. If it is absent, it is less than 1 and you would excrete diluted urine.

Major Functions of the Kidney

1. Regulation of water and electrolyte balance 2. Excretion of metabolic waste 3. Excretion of bioactive substances 4. Regulation of arterial blood pressure 5. Regulation of red blood cell production 6. Regulation of vitamin D production: Kidneys convert the inactive form of vitamin D3 to the active form, 1,25 dihydroxyvitamin D3. 7. Gluconeogenesis : doesn't do it often, only during periods of extended fasting. While most gluconeogenesis occurs in the liver, a substantial fraction occurs in the kidneys particularly during a prolonged fast.

clearance technique

A technique used to determine the rate of total blood flow to the entire kidney (not regional distribution of blood flow) is to apply the clearance concept. The clearance principle takes into account the type of substance being studied and gives an indication of how the kidney is handling a particular substance (reabsorbing, secreting, or filtering). One can determine the clearance rate of a particular substance such as para amino hippuric acid (PAH) and indirectly measure total renal blood flow. More on the use of the clearance technique will be presented in an upcoming lecture.

Intercalated Cells

Alpha Intercalated Cells: *secrete hydrogen* but *do not reabsorb sodium*. These alpha Intercalated Cells play a significant role in acid-base balance. A counterpart of the alpha cells is the beta Intercalated Cells. The *beta cells* specialize in *secreting bicarbonate* under appropriate conditions. Thus, the beta cells also play a significant role in acid-base balance.

Intrinsic Control-Scribe notes

BP <80 mm Hg - renal blood flow and GFR increases with increasingly arterial pressure while resistance remains constant BP > 80 mm Hg - vascular resistance then increases as a function of increasing arterial pressure and renal blood flow and GFR is kept constant. Between 60 mmHg to 150 mmHg of arterial pressure, renal blood flow (and thus GFR) stays relative constant. This is due to the smooth muscles cells in the afferent arterioles. The smooth muscle cells get activated and thus constricts. Thus, with increasing pressure in this range, the diameter of the blood vessel decreases. BP > 180 mm Hg - resistance at its maximum so higher pressures cause resumption of increasing renal blood flow and GFR. Myogenic regulation stops working at this high pressure system.

What percentage of cardiac output is sent to the kidneys?

Blood flow to both kidneys about 20% of the cardiac output. Kidney is responsible for filtering *plasma* thus it needs a great deal of cardiac output. Renal tissue does require a relatively large amount of oxygen per gram of tissue but blood flow > that required to meet the kidney's metabolic need. The renal vascular system is designed to very rapidly process blood (plasma) so that homeostatic regulation of the total body solvent and solute content can be rapidly accomplished.

Nephron heterogeneity: There are at least two subpopulations of nephrons within the kidney, what are they?

Cortical Nephron Juxtamedullary nephron

Cortical Nephron

Cortical nephrons are found primarily within the *renal cortex* and comprise about *85% of the total nephron population*. The PCT, most of the loop of Henle and DCT of cortical nephrons are physically located within the cortex. The tip of the cortical nephrons loops of Henle enter the outer zone of the renal medulla but do not significantly penetrate the inner zone of the renal medulla. The *efferent arterioles form a meshwork* around the nephron called the *peritubular capillary network* (different than juxtamedullary nephron).

How much does each glomerulus filter a day?

Each glomerulus filters 75 μL/day. The kidneys contain 2.5 million glomeruli, thus kidneys forms approximately 187 liters of filtrate per day!!

Proximal Convoluted Tubule (PCT), what does it look like histologically? Why would it look like this?

Histologically, the cells of this section contain numerous mitochondria and their luminal surfaces possess extensive microvilli to increase surface area. From all appearances, they are extremely energetic cells. This segment receives the entire 187 L/day of ultrafiltrate! By the time the ultrafiltrate reaches the end of the PCT, *2/3* or approximately 120 L/day, *are reabsorbed* and transported back to the intravascular space.

Intrinsic Regulation of Renal Blood Flow

Intrinsic control results in *autoregulation*. The myogenic theory is the most plausible explanation of renal autoregulation. Cells in the wall of afferent arterioles are sensitive to stretch. When blood pressure is below 80 mm Hg, there is not enough tension in the walls to stimulate contraction of the smooth muscle cells in the vessels so flow increases with increasing pressure while resistance remains constant. Above 80 mm Hg, tension is exerted against the vessel walls and they respond by contracting. Only a slight decrease in radius is needed to greatly increase resistance. Vascular resistance then increases as a function of increasing arterial pressure and renal blood flow is kept constant. At about 180 mm Hg, the smooth muscles of vessels have contracted as much as they can. Resistance is thus at its maximum so higher pressures cause resumption of increasing renal blood flow.

What drives the fluid through the remainder of the nephron? How do you regulate this pressure? How do you regulate this pressure?

Note that the hydrostatic pressure within Bowman's capsule drives the fluid through the remainder of the nephron. You regulate the hydrostatic pressure by constricting or dilating efferent and afferent arterioles.

There are two types of cells that make up the cortical collecting tubules and the collecting ducts what are they?

Principal Cells and Intercalated cells

The distribution of blood flow in the kidney is actually heterogeneous, how so?

The amount of blood per gram of tissue depends upon the *anatomy of the vasculature* and the *physiologic function* of the region being perfused. For example, the renal medulla is a specialized region of the kidney that has a very specific function. It is where a very high osmotic gradient is maintained so that the kidney can produce very concentrated urine when the need arises. The rate of blood flow to this region is critically maintained *low* so that function can be attained.

Renal Blood Supply Anatomy

The renal artery enters the kidney through the hilum and then branches progressively to: 1. segmental arteries 2. interlobar arteries 3. arcuate arteries 4. radial/interlobular arteries 5. afferent arterioles 6. glomerular capillaries: Kidney has two sets of arterioles so glomerular capillaries converge afferent arterioles (incoming) to efferent arterioles (outgoing) 7. efferent arterioles 8. peritubular capillaries Peritubular capillaries empty into interlobular/radial vein which empties into the arcuate vein, the interlobar veins and finally the renal vein.

juxtamedullary nephron

These comprise approximately *15% of all nephrons*. The glomeruli are still located within the cortex as are the PCT and DCT, but the *loop of Henle dips deeply down into the inner zone of the renal medulla*. Efferent arterioles form a specialized peritubular network termed the *vasa rectae* which is *important in maintaining the osmotic gradient in the medulla*.

Principal Cell

This cell is involved in the reabsorption of sodium (Na+), chloride (Cl-), potassium (K+) and water (H2O)

Why is this arrangement important?

This precise arrangement of afferent arterioles insures that every glomerulus in the kidney is provided with approximately the same hydrostatic force and is thus equally perfused. The loss of pressure along the interlobular artery as it courses upward toward the capsule is offset by the changing angles of the afferent arterioles. The afferent arterioles are part of a network of parallel circuits which offer less resistance than do vessels in series. The different angles with which the afferent arterioles branch from the interlobular arteries cause differences in energy loss and in resistance. Blood from the afferent arteriole then flows through the glomerular capillary tuft, back out the efferent arteriole, through the peritubular capillary network, and into the venous system which parallels the arterial system. Scribe notes: This offsets the change in pressure. The anatomy (angles of the arterioles) is compensating for the change in pressure, because pressure decreases as you go up. Thus, the increased angle near the cortico-medullary boundary provides more of a resistance to the flow than does the straight angle of the arterioles near the capsule of the cortex.

What are the two capillary beds of the kidney and are they arranged in series or parallel?

Thus the renal circulation is unique in that it has two capillary beds, the glomerular and the peritubular capillaries, which are arranged in series and separated by the efferent arterioles. By adjusting the resistance of the afferent and efferent arterioles, the kidneys can regulate the hydrostatic pressure in both the glomerular and the peritubular capillaries, thereby changing the rate of glomerular filtration, tubular reabsorption, or both in response to the body needs.

Distal Convoluted tubule is divided into what two parts?

We can functionally divide the distal convoluted tubule into two sections: the *early DCT* and the second half of the DCT will be referred to as the *cortical collecting tubule* or CCT.

Filtration

bulk movement of solutes and solvent across some semi-permeable membrane In the glomerulus, fluids and solutes are transported across a semi-permeable membrane by the *hydrostatic pressure*

Excretion

elimination of a solute or solvent from the body within the urine. Excretion = Filtration - Reabsorption + Secretion

Juxtamedullary nephrons are associated with what vessels?

juxtamedullary nephrons are surrounded by a very small peritubular capillary network: *vasa rectae*, a specialized peritubular capillary bed, which is only associated with juxtamedullary nephrons. Vasa rectae act as a counter-current exchange mechanism working with the juxtamedullary nephron's loop of Henle this countercurrent exchange design allows medullary region to remain properly hyperosmotic-which allows the collecting ducts to effectively concentrate the urine.

Reabsorption

term used to describe the *direction of movement* of solute or solvent. It is the movement of materials from the inside of the tubule (tubular lumen) into the interstitial space and eventually back into the bloodstream via the peritubular capillaries. Reabsorption does not tell you how the material is moved but rather the direction in which it was moved.

Blood flow in the kidney is proportional to what

Blood flow in kidney is proportional to the distribution of the nephrons in the kidney. 80% of the total renal blood at any instant is within the renal cortex where about 85% of the total nephron population is located- blood flow about 4 to 5 mls per minute per gram. cortex has the highest blood flow, because this is where all of the cortical nephrons are (85% of total) outer medulla has a flow rate of about 0.7 to 1 mls/minute/gram of tissue inner medulla receives a very low rate of flow of about 0.2 to 0.25 mls/minute/gram 15% of the total renal blood volume is located within the juxtamedullary region of renal cortex where 15% of the nephrons are located overall only 3% of the total renal blood volume is located within the medullary region - flow courses through the vasa rectae, a specialized peritubular capillary network within the renal medulla-blood flow through this area must remain relatively low to keep the area hyperosmotic. Too much blood flow per unit time will cause the movement of solute from the interstitial space into the blood plasma and then out of the kidney and as a result, will reduce the medullary osmolarity. About 2% of the renal blood volume flows through the adipose tissue in the kidney. The distribution of blood flow through the kidney is changed in various pathologies as flow is shunted among the three areas: medulla, juxtamedullary area and cortex. This leads to changes in overall renal function.

Loop of Henle

By the time the tubular fluid enter the loop of Henle, approximately two-thirds of the solute and water have reabsorbed and the fluid is still iso-osmotic with plasma. The loop of Henle is a very specialized structure. The cells in this structure are relatively flat, with *few mitochondria*. Different regions of the Loop of Henle have varying permeability to water. The descending limb of the loop is very permeable to water. *In contrast the ascending limp of the loop is completely impermeable to water at all times*. Specialized area of the nephron where salts are separated from water. Fluid leaving the loop is always hypotonic to plasma.

Cortical Collecting Tubule

Following the early distal convoluted tubule is a segment of the DCT that attaches the nephron to the collecting duct. It is termed the cortical collecting tubule (CCT). This is an area of additional solute and solvent transport that is *under hormonal control*. The CCT is normally *impermeable to the passive movement of water* as well as to the *passive movement of urea*, a product of protein catabolism. Under conditions of hormonal stimulation (antidiuretic hormone, *ADH*), the CCT becomes *permeable to water but not to urea*. This differential permeability plays an important role in the ability of the kidneys to produce *concentrated urine*.

Secretion

The directional opposite of reabsorption, movement of materials from the interstitial space or the capillaries around the nephron into the tubular lumen. Again, it is a term that indicates direction, not mechanisms. Keep in the mind that the carriers that do this are sitting on the cells that make up the tubular lumen. By transporting things in and out, you change the interstitial concentration and the interstitial fluid equilibrates with the peritubular capillaries. So, really what you are doing is pulling things out of the tubule into the interstitium and then into the peritubular capillaries depending on the osmolarity and concentration gradients.

The *Early* Distal Convoluted Tubule

The epithelial cells in the early DCT have microvilli and many mitochondria indicating a degree of high metabolic activity. These cells in this region of the DCT are not significantly under the control of hormones but do have significant transport mechanisms for various solutes. There is a somewhat automatic regulation of the transport mechanisms in this segment. The PCT reclaimed two-thirds of the ultrafiltrate indiscriminately, whereas the early DCT and other parts of the distal nephron are responsible for "fine-tuning", or making the final adjustments to the composition of the urine. The early DCT is associated with Na+ and Cl- reabsorption. There is also H+, K+, and ammonia secretion in this area. *This area is normally impermeable to the passive movement of water*.

How is fluid in the Proximal Convoluted tubule reabsorbed?

The fluid in this segment is reabsorbed *iso-osmotically* (for every osmotic particle reabsorbed, one H20 molecule follows) so the *concentration of most materials doesn't change along the length of the PCT*. A great deal of transport activity is observed in the PCT. It is the site of Na+, K+, and urea reabsorption. Solutes are transported by both active and passive mechanisms. HCO3- reabsorption and H+ secretion also occur in this area.

What is the functional unit within the kidney?

The functional unit within the kidney is the NEPHRON. There are approximately 1.25 million nephrons in each human kidney (total of 2.5 million). Anatomically, the nephron is divided into two general areas: a filtering unit called the glomerulus and the tubular unit (proximal convoluted tubule, loop of Henle, distal convoluted tubule, and cortical collecting tubule). Each nephron empties into a collecting duct which serves multiple nephrons. Begins with an afferent arteriole which enters Bowman's capsule - divides into *parallel* capillaries within the glomerulus, known as the glomerular capillaries.

The Glomerulus

The glomerulus begins with an afferent arteriole which enters the glomerular capsule (Bowman's Capsule). The afferent arterioles possess smooth muscle cells which can alter vascular resistance in this segment. The afferent arteriole breaks into a series of parallel capillary loops within the glomerulus. The glomerulus acts as a *selective filter* which allows solvent (water) and small solutes to move from the vascular space into the tubular part of the nephron. Materials must pass through/between the endothelial cells of the capillary and then pass through the glomerular basement membrane. On the other side of the basement membrane are *podocytes* which represent a *barrier to the bulk* movement of various kinds of solutes. Materials which do get through the filtration barrier end up in *Bowman's space* which is enclosed by Bowman's capsule. This filtrate of the plasma contains *no plasma proteins*.

granular cell mechanism- systemic reflex

The granular cell mechanism is also used in a more systemic reflex. Under conditions when the systemic blood pressure drops significantly, GRF decreases, the granular cells, which are sensitive to this decrease in stretch, release tremendous quantities of renin. This renin is not released into the interstitium but directly into the vascular system where it leads to production of angiotensin I and II, vasoconstriction in many peripheral beds, and the resultant release of aldosterone from the adrenal cortex. This systemic reflex in response to hypotension acts to retain Na+ and thereby water in the body, increases systemic blood pressure and stimulates salt appetite.

What is a lobe in the kidney? Why is interesting and important about their anatomy?

The human kidney is composed of 9 -12 lobes that are anatomically discrete and almost functionally independent of one another. There are very few interconnections between lobes and very few anastomoses of blood vessels between the lobes. This independence of each lobe allows other lobes to function even if one is severely damaged.

The juxtaglomerular apparatus is another mechanism responsible for the autoregulation of renal blood flow but may be more related to the autoregulation of what?

The juxtaglomerular apparatus is another mechanism responsible for the autoregulation of renal blood flow but may be more related to the autoregulation of the *glomerular filtration rate*.

Osmolarity Differentials in Kidney

The kidney, unlike most other tissue in the body, has a region that is not iso-osmotic with the plasma - the renal medulla. In the renal cortex, where the PCT, DCT, and all the glomeruli are located, the interstitial space is approximately 285-300 milliosmolar (mOsm). The interstitial space in the cortex is equilibrated with the plasma at all times. Within the human renal medulla, there is an osmotic gradient which ranges from 300 mOsm/L to about 1200 mOsm/L water in the presence of antidiuretic hormone, which is an extremely hypertonic area. This area must maintain its hypertonicity or the kidney cannot concentrate urine. All of the collecting ducts in the kidney must pass through this extremely hypertonic region before they enter the renal pelvis. As will be discussed later, this renal medullary hyperosmolarity is the mechanism for concentrating the final urine. The mechanisms responsible for the establishment and maintenance of the osmotic gradient will be discussed in later lectures.

juxtaglomerular apparatus

The response is local and rapid. The earliest portion of the distal convoluted tubule (DCT) associates with its own glomerulus and makes contact in the area where the afferent and efferent arterioles enter and exit, respectively. Specialized cells in the wall of the DCT called *macula densa cells* are in direct contact with specialized cells in the *afferent arteriole* called *granular cells*. Granular cells make and release *renin*, *adenosine* and perhaps *vasoconstrictor prostaglandins* into the interstitium *around the afferent arteriole*. This release of the enzyme renin results in the production of angiotensin II which constricts the efferent arteriole. Adenosine, ATP and vasoconstrictive prostaglandins can directly constrict the afferent arteriole as well. The net effect of the system is to control the amount of tubular fluid that emerges from the loop of Henle. The DCT cannot handle as much material per unit time as the PCT. The DCT gets overloaded quite easily and will not reabsorb the necessary constituents from the tubular fluid and they would be lost in the urine. The juxtaglomerular apparatus (macula densa and granular cells) adjusts the amount of fluid flowing through the nephron by controlling the *hydrostatic pressure* via the *renal arterioles*. Experimental studies suggest that a *decrease in glomerular filtration rate* (GFR) slows the flow rate in the loop of Henle, causing an increase in reabsorption of Na+ and Cl- in the ascending loop of Henle thereby reducing the concentration of NaCl at the macula densa cells. This initiates a signal from the macula densa cells that has two effects as shown in the figure: (1) it *decreases resistance* to blood flow in the afferent arterioles, which inturn *increases hydrostatic pressure* and acts to *increase GFR* (2) it also increases renin release which acting through angiotensin II to constrict the efferent arteriole, *increases glomerular hydrostatic pressure* and as a result the *GFR*.

Collecting Ducts

These structures are not technically part of the nephron per se but are *shared by a number of nephrons*. They are not inert collecting channels, but accomplish the final "polishing" of the tubular fluid. They are under very intense hormonal control for both solute and water transport. The collecting ducts begin in the renal cortex and course downward through the renal medulla toward the renal pelvis. Numerous nephrons empty into the cortical aspects of the collecting duct. Anatomically, it is the combination of the nephron being located in part within the renal cortex and in part within the renal medullary area together with the collecting ducts that must pass through the renal medullary area that allows the kidneys to concentrate the urine. Area where the final concentration of the urine is set. The collecting ducts can reabsorb solute and, depending upon the nature of hormonal influences, can reabsorb variable amounts of water.