Renal Blood Flow and Glomerular Filtration Notes

Glomerular Filtration And Renal Blood Flow Notes

The first step in the formation of urine by the kidneys is the production of an ultrafiltrate of plasma across the filtration barrier.

The process of glomerular filtration and regulation of the glomerular filtration rate (GFR) and renal blood flow (RBF) are discussed in this chapter.

The concept of renal clearance, which is the theoretical basis for the measurements of GFR and RBF, also is presented.

Renal Clearance

The concept of renal clearance is based on the Fick principle (i.e., mass balance or conservation of mass).

Illustrates the various factors required to describe the mass balance relationships of a kidney.

The renal artery is the single input source to the kidney, whereas the renal vein and ureter constitute the two output routes.

The Following Equation Defines The Mass Balance Relationship: \(\mathrm{P}_x^{\mathrm{a}} \times \mathrm{RPF}^{\mathrm{d}}=\left(\mathrm{P}_{\mathrm{x}}^{\mathrm{v}} \times \mathrm{RPF}^v\right)+\left(\mathrm{U}_{\mathrm{x}} \times \dot{\mathrm{V}}\right)\)(eq 1)

where \(P_x^a\) and \(P_x^y\) are concentrations of substance x in the renal artery and renal vein plasma, respectively, \(R P F^a\) and \(R P F^v\) are renal plasma flow (RPF) rates in the artery and vein, respectively, \(U_x\) is the concentration of x in the urine, and V is the urine flow rate.

This relationship permits the quantification of the amount of x excreted in the urine versus the amount returned to the systemic circulation in the renal venous blood.

Thus for any substance that is neither synthesized nor metabolized by the kidneys, the amount that enters the kidneys is equal to the amount that leaves the kidneys in the urine plus the amount that leaves the kidneys in the renal venous blood.

The principle of renal clearance emphasizes the excretory function of the kidneys; it considers only the rate at which a substance is excreted into the urine and not its rate of return to the systemic circulation in the renal vein.

Therefore in terms of mass balance (equation 1), the urinary excretion rate of x (\(U_x \times V\)) is proportional to the plasma concentration of \(x\left(\mathrm{P}_{\mathrm{x}}^{\mathrm{a}}\right)\): \(\mathrm{P}_x^2 \propto \mathrm{U}_{\mathrm{x}} \times \dot{\mathrm{V}}\)(eq 2)

To equate the urinary excretion rate of x to its renal arterial plasma concentration, it is necessary to determine the rate at which x is removed from the plasma by the kidneys. This removal rate is the clearance \(\left(C_x\right)\).

∴ \(\mathrm{P}_{\mathrm{x}}^1 \times \mathrm{C}_{\mathrm{x}}=\mathrm{U}_{\mathrm{x}} \times \dot{\mathrm{V}}\)(eq 3)

If equation 3 is rearranged and the concentration of x in the renal artery plasma \(\left(P_x^a\right)\) is assumed to be identical to its concentration in a plasma sample from any peripheral blood vessel, the following relationship is obtained:

∴ \(\mathrm{C}_{\mathrm{x}}=\frac{\mathrm{U}_{\mathrm{x}} \times \dot{\mathrm{V}}}{\mathrm{P}_{\mathrm{x}}^4}\) (eq 4)

Clearance has the dimensions of volume/time, and it represents a volume of plasma from which all the substances have been removed and excreted into the urine per unit of time.

The last point is best illustrated by considering the following example.

If a substance is present in the urine at a concentration of 100 mg/mL and the urine flow rate is 1 mL/min, the excretion rate for this substance is calculated as follows:

Excretion rate = \(\mathrm{U}_{\mathrm{x}} \times \dot{\mathrm{V}}=100 \mathrm{mg} / \mathrm{mL} \times(1 \mathrm{~mL} / \mathrm{min})\)

= \(100 \mathrm{mg} / \mathrm{min}\) (eq 5)

If this substance is present in the plasma at a concentration of 1 mg/mL, its clearance according to equation 4 is as follows:

∴ \(\mathrm{C}_{\mathrm{x}}=\frac{\mathrm{U}_{\mathrm{x}} \times \dot{\mathrm{V}}}{\mathrm{P}_{\mathrm{x}}^a}=\frac{100 \mathrm{mg} / \mathrm{min}}{1 \mathrm{mg} / \mathrm{mL}}=100 \mathrm{~mL} / \mathrm{min}\) (eq 6)

In other words, 100 mL of plasma are completely cleared of substance x each minute.

The definition of clearance as a volume of plasma from which all the substance has been removed and excreted into the urine per unit of time is somewhat misleading because it is not a real volume of plasma; rather, it is an idealized volume.

The concept of clearance is important because it can be used to measure the GFR and RPF and determine whether a substance is reabsorbed or secreted along the nephron.

Glomerular Filtration Rate

The GFR of the kidney is equal to the sum of the filtra¬tion rates of all functioning nephrons. Thus it is an index of kidney function.

A decrease in GFR generally means that kidney disease is progressing, whereas movement toward a normal GFR generally suggests recuperation.

Thus knowledge of the patient’s GFR is essential in eval¬uating the severity and course of kidney disease.

Creatinine, which is a byproduct of skeletal muscle creatine phosphate metabolism, can be used to measure the GFR.

Creatinine is freely filtered across the glomerular filtration barrier into Bowman’s space, and to a first approximation, it is not reabsorbed, secreted, or metabolized by the cells of the nephron.

Accordingly, the amount of creatinine excreted in the urine per minute equals the amount of creatinine filtered across the filtration barrier each minute:

Amount filtered = Amount excreted \(\mathrm{GFR} \times \mathrm{P}_{\mathrm{Cr}}=\mathrm{U}_{\mathrm{Cr}} \times \dot{\mathrm{V}}\) (eq 7)

where \(P_{C r}\) is plasma concentration of creatinine, \(U_{C r}\) is urine concentration of creatinine, and \(\dot{V}\) is the urine flow rate.

If equation 7 is solved for the GFR:

GFR = \(\frac{\mathrm{U}_{c x} \times \dot{\mathrm{V}}}{\mathrm{P}_c}\) (eq 8)

This equation is the same form as that for clearance (equation 4).

Thus the clearance of creatinine provides a means for determining the GFR.

Clearance has the dimensions of volume/time, and it represents a volume of plasma from which all the substances have been removed and excreted into the urine per unit of time.

Creatinine is not the only substance that can be used to measure the GFR. Any substance that meets the following criteria can serve as an appropriate marker for the measurement of GFR.

The Substance Must:

1. Be freely filtered across the filtration barrier into Bowman’s space
2. Not be reabsorbed or secreted by the nephron
3. Not be metabolized or produced by the kidney
4. Not alter the GFR

Creatinine is used to estimate GFR in clinical practice. It is synthesized at a relatively constant rate, and the amount produced is proportional to the muscle mass.

However, creatinine is not a perfect substance for measuring GFR because it is secreted to a small extent by the organic cation secretory system in the proximal tubule.

The error introduced by this secretory component is approximately 10%. Thus the amount of creatinine excreted in the urine exceeds the amount expected from filtration alone by 10%.

However, the method used to measure the plasma creatinine concentration \(\left(P_{C_r}\right)\) overestimates the true value by 10%. Consequently, the two errors cancel, and in most clinical situations creatinine clearance provides a reasonably accurate measure of the GFR.

A decrease in GFR may be the first and only clinical sign of kidney disease. Thus measuring the GFR is important when kidney disease is suspected. A 50% loss of functioning nephrons reduces the GFR by only about 25%.

The decline in GFR is not 50% because the remaining nephrons compensate. Because measurements of GFR are cumbersome, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Kidney Foundation, and the American Society of Nephrology all recommend estimating GFR from the plasma creatinine concentration \(P_{C r}\), which is inversely related to the GFR.

However, the GFR must decline substantially before an increase in the P Cr can be detected in a clinical setting.

For example, a decrease in GFR from 120 to 100 mL/min is accompanied by an increase in the \((P_{C r}\) from 1.0 to 1.2 mg/dL.

This situation does not appear to represent a significant change in the \(P_{C r}\), but the GFR actually has fallen by almost 20%. illustrates how a decrease in GFR by 50% causes a doubling of \(P_{C r}\).

Initially, when GFR is reduced, the excretion of creatinine declines because the amount of creatinine that is filtered (i.e., GFR × \(P_{C r}\)) and excreted (i.e., \(U_{C r}\) × V˙) decreases.

Because creatinine production is constant and its production transiently exceeds filtration and excretion, creatinine accumulates in the extracellular fluid until the amount filtered equals the amount produced (i.e., GFR × \(P_{C r}\) = production).

At this point, \(P_{C r}\) remains stable but elevated.

Not all of the creatinine (or other substances used to measure the GFR) that enters the kidney in the renal arterial plasma is filtered at the glomerulus.

Likewise, not all of the plasma coming into the kidneys is filtered. Although nearly all of the plasma that enters the kidneys in the renal artery passes through a glomerulus, approximately 10% does not.

The portion of the filtered plasma is termed the filtration fraction and is determined as:

Filtration fraction = GFR/RPF (eq 9)

Under normal conditions, the filtration fraction averages 0.15 to 0.20, which means that only 15% to 20% of the plasma that enters the glomerulus is actually filtered.

The remaining 80% to 85% continues through the glo¬merular capillaries and into the efferent arterioles, peritubular capillaries, and the vasa recta. It is finally returned to the systemic circulation in the renal vein.

Glomerular Filtration

The first step in the formation of urine is ultrafiltration of the plasma by the glomerulus. In healthy adults, the GFR ranges from 90 to 140 mL/min for men and from 80 to 125 mL/min for women.

Thus in 24 hours as much as 180 L of plasma is filtered by the glomeruli.

The plasma ultrafiltrate is devoid of cellular elements (i.e., red and white blood cells and platelets) and has a very low concentration of proteins.

The concentrations of salts and of organic molecules, such as glucose and amino acids, are similar in the plasma and ultrafiltrate.

Starling forces drive ultrafiltration across the glomerular capillaries, and changes in these forces alter the GFR.

The GFR and RPF normally are held within very narrow ranges by a phenomenon called autoregulation.

The next sections of this chapter review the composition of the glomerular filtrate, the dynamics of its formation, and the relationship between RPF and GFR.

In addition, the factors that contribute to the autoregu¬lation and regulation of GFR and RBF are discussed.

Determinants Of Ultrafiltrate Composition

The glomerular filtration barrier determines the composition of the plasma ultrafiltrate. It restricts the filtration of molecules primarily on the basis of size.

In general, molecules with a radius smaller than 20 Å are filtered freely, molecules larger than 42 Å are not filtered, and molecules between 20 and 42 Å are filtered to various degrees.

For example, serum albumin, an anionic protein that has an effective molecular radius of 35.5Å, is filtered poorly.

Because the filtered albumin and other small proteins normally are reabsorbed avidly by the proximal tubule, almost no protein appears in the urine of persons with normal renal function.

A reduction in GFR in disease states is most often due to decreases in the ultrafiltration coefficient (\(K_f\)) because of the loss of filtration surface area.

The GFR also changes in pathophysiologic conditions because of changes in the hydrostatic pressure in the glomerular capillary (\(P_\mathrm{GC}\)), oncotic pressure in the glomerular capillary (\(\pi_\mathrm{GC}\)), and hydrostatic pressure in Bowman’s space (\(P_BS\)).

1. Changes In \(K_f\): An increased \(K_f\) enhances the GFR, whereas a decreased \(K_f\) reduces the GFR. Some kidney diseases reduce the \(K_f\) by decreasing the number of filtering glomeruli (i.e., diminished surface area).

Some drugs and hormones that dilate the glomerular arterioles also increase the \(K_f\). Similarly, drugs and hormones that constrict the glomerular arterioles also decrease the \(K_f\).

2. Changes in \(P_\mathrm{GC}\): With decreased renal perfusion, the GFR declines because the \(P_\mathrm{GC}\) decreases.

As previously discussed, a reduction in the \(P_\mathrm{GC}\) is caused by a decline in renal arterial pressure, an increase in afferent arteriolar resistance, or a decrease in efferent arteriolar resistance.

3. Changes in \(\pi_\mathrm{GC}\): An inverse relationship exists between the \(\pi_\mathrm{GC}\) and the GFR. Alterations in the \(\pi_\mathrm{GC}\) result from changes in protein synthesis outside the kidneys.

In addition, protein loss in the urine caused by some renal diseases can lead to a decrease in the plasma protein concentration and thus in the \(\pi_\mathrm{GC}\).

4. Changes in \(P_\mathrm{BS}\): An increased \(P_\mathrm{BS}\) reduces the GFR, whereas a decreased \(P_\mathrm{BS}\) enhances the GFR. Acute obstruction of the urinary tract (for example, a kidney stone occluding the ureter) increases the \(P_\mathrm{BS}\).

Dynamics Of Ultrafiltration

The forces responsible for the glomerular filtration of plasma are the same as those in all capillary beds. Ultrafiltration occurs because the Starling forces (i.e., hydrostatic and oncotic pressures) drive fluid from the lumen of glomerular capillaries, across the filtration barrier, and into Bowman’s space.

The hydrostatic pressure in the glomerular capillary (\(P_\mathrm{GS}\)) is oriented to promote the movement of fluid from the glomerular capillary into Bowman’s space.

Because the reflection coefficient (σ) for proteins across the glomerular capillary is essentially 1, the glomerular ultrafiltrate has a very low concentration of proteins, and the oncotic pressure in Bow-man’s space (\(\pi_\mathrm{BS}\)) is near zero.

Therefore PGC is the only force that favors filtration. The hydrostatic pressure in Bowman’s space (\(P_\mathrm{BS}\)) and the oncotic pressure in the glomerular capillary (\(\pi_\mathrm{BS}\)) oppose filtration.

A net ultrafiltration pressure (\(P_\mathrm{UF}\)) of 17 mm Hg exists at the afferent end of the glomerulus, whereas at the efferent end, it is 8 mm Hg (where \(P_\mathrm{UF}\) = \(P_\mathrm{GC}\) – \(P_\mathrm{BS}\) – \(\pi_\mathrm{GC}\)).

Two additional points concerning Starling forces and this pressure change are important. First, \(P_\mathrm{GC}\) decreases slightly along the length of the capillary because of the resistance to flow. Second, \(\pi_\mathrm{GC}\) increases along the length of the glomerular capillary.

Because water is filtered and protein is retained in the glomerular capillary, the protein concentration in the capillary rises, and \(\pi_\mathrm{GC}\) increases.

The GFR is proportional to the sum of the Starling forces that exist across the capillaries [(\(P_\mathrm{GC}\) – \(P_\mathrm{BS}\)) – σ(\(\pi_\mathrm{GC}\) – \(\pi_\mathrm{BS}\))] multiplied by the ultrafiltration coefficient (\(K_f\)).

That is: GFR = \(K_f\left[\left(P_{G C}-P_{B S}\right)-\sigma\left(\pi_{G C}-\pi_{B S}\right)\right]\) (eq 10)

∴ \(K_f\) is the product of the intrinsic permeability of the glomerular capillary and the glomerular surface area available for filtration.

The rate of glomerular filtration is considerably greater in glomerular capillaries than in systemic capillaries, mainly because \(K_f\) is approximately 100 times greater in glomerular capillaries.

Furthermore, the PGC is approximately twice as great as the hydrostatic pressure in systemic capillaries.

The GFR can be altered by changing \(K_f\) or by changing any of the Starling forces.

In healthy persons, the GFR is regulated by alterations in the \(P_\mathrm{GC}\) that are mediated mainly by changes in afferent or efferent arteriolar resistance. \(P_\mathrm{GC}\) is affected in three ways:

1. Changes In Afferent Arteriolar Resistance: a decrease in resistance increases the \(P_\mathrm{GC}\) and GFR, whereas an increase in resistance decreases the \(P_\mathrm{GC}\) and GFR.
2. Changes In Efferent Arteriolar Resistance: a decrease in resistance reduces the \(P_\mathrm{GC}\) and GFR, whereas an increase in resistance elevates the \(P_\mathrm{GC}\) and GFR.
3. Changes In Renal Artery Pressure: an increase in blood pressure transiently increases the \(P_\mathrm{GC}\) (which enhances the GFR), whereas a decrease in blood pressure transiently decreases the PGC (which reduces the GFR).

Renal Blood Flow

Blood flow (~1.25 L/min) through the kidneys serves several important functions. This blood flow:

1. Indirectly determines the GFR
2. Modifies the rate of solute and water reabsorption by the proximal tubule
3. Participates in the concentration and dilution of urine
4. Delivers oxygen, nutrients, and hormones to the cells of the nephron and returns carbon dioxide and reabsorbed fluid and solutes to the general circulation
5. Delivers substrates for excretion in the urine

Blood flow through any organ may be represented by the following equation: \(\mathrm{Q}=\frac{\Delta \mathrm{P}}{\mathrm{R}}\) (eq 11)

where Q is blood flow, AP is mean arterial pressure minus venous pressure for that organ, and R is resistance to flow through that organ.

Accordingly, RBF is equal to the pressure difference between the renal artery and the renal vein divided by the renal vascular resistance:

RBF = \(\frac{\text { Aortic pressure }- \text { Renal venous pressure }}{\text { Renal vascular resistance }}\) (eq 12)

The interlobular artery, afferent arteriole, and effer¬ent arteriole are the major resistance vessels in the kid¬neys and determine renal vascular resistance.

Like most other organs, the kidneys regulate their blood flow by adjusting the vascular resistance in response to changes in arterial pressure.

These adjustments are so precise that blood flow remains relatively constant as arterial blood pressure fluctuates between 90 and 180 mm Hg. The GFR also is regulated over the same range of arterial pressures.

The phenomenon whereby RBF and GFR are maintained at a relatively constant level, namely autoregulation, is achieved by changes in vascular resistance, mainly through the afferent arterioles of the kidneys.

Because both the GFR and RBF are regulated over the same range of pressures and because RBF is an important determinant of GFR, it is not surprising that the same mechanisms regulate both flows.

Two mechanisms are responsible for the autoregulation of RBF and GFR: one mechanism that responds to changes in arterial pressure and another that responds to changes in the sodium chloride (NaCl) concentration of tubular fluid.

• Both mechanisms regulate the tone of the afferent arteriole. The pressure-sensitive mechanism, the so-called myogenic mechanism, is related to an intrinsic property of vascular smooth muscle: the tendency to contract when it is stretched.
• Accordingly, when the arterial pressure rises and the renal afferent arteriole is stretched, the smooth muscle contracts.
• Because the increase in the resistance of the arteriole offsets the increase in pressure, RBF and therefore GFR remain constant (i.e., RBF is constant if ΔP/R is kept constant.
• The second mechanism responsible for the auto-regulation of GFR and RBF is the NaCl concentration-dependent mechanism known as tubuloglomerular feedback.

• This mechanism involves a feedback loop in which the NaCl concentration of tubular fluid is sensed by the macula densa of the juxtaglomerular apparatus and converted into a signal or signals that affect afferent arteriolar resistance and thus the GFR.
• When the GFR increases and causes the NaCl concentration of tubular fluid at the macula densa to rise, more NaCl enters macula densa cells. This process leads to an increase in the formation and release of adenosine triphosphate (ATP) and adenosine, a metabolite of ATP, by macula densa cells, which causes vasoconstriction of the afferent arteriole.

Vasoconstriction of the afferent arteriole returns the GFR to normal levels. In contrast, when the GFR and NaCl concentration of tubule fluid decrease, less NaCl enters macula densa cells and the production and release of ATP and adenosine decline.

The decrease in ATP and adenosine causes vasodilation of the afferent arteriole, which returns the GFR to normal. Nitric oxide (NO), a vasodilator produced by the macula densa, attenuates tubuloglomerular feedback, whereas angiotensin II enhances tubuloglomerular feedback.

Thus the macula densa may release both vasoconstrictors (for example, ATP and adenosine) and a vasodilator (for example, NO), which oppose each other’s action at the level of the afferent arteriole. Production and release of vasoconstrictors and vasodilators ensure exquisite control over tubuloglomerular feedback.

Illustrates the role of the macula densa in controlling the secretion of renin by the granular cells of the afferent arteriole. This aspect of the JGA function is considered.

Because animals engage in many activities that can change arterial blood pressure (for example, changes in posture, mild to moderate exercise, and sleep), mechanisms that maintain RBF and GFR at relatively constant
levels despite changes in arterial pressure are highly desirable.

If the GFR and RBF were to rise or fall suddenly in proportion to changes in blood pressure, urinary excretion of fluid and solute also would change suddenly.

Such changes in water and solute excretion without comparable changes in intake would alter the fluid and electrolyte balance.

Accordingly, autoregulation of the GFR and RBF provides an effective means for uncoupling renal function from arterial pressure, and it ensures that fluid and solute excretion remains constant when the extracellular fluid volume is normal.

Three Points Concerning Autoregulation Should Be Noted:

1. Autoregulation is absent when arterial pressure is less than 90 mm Hg.
2. Autoregulation is not perfect; RBF and GFR do change slightly as the arterial blood pressure varies.
3. Despite autoregulation, RBF and GFR can be changed by certain hormones and by changes in sympathetic nerve activity.

Tubuloglomerular feedback is absent in mice that do not express the adenosine receptor A1. This finding underscores the importance of adenosine signaling in tubuloglomerular feedback.

Studies have shown that when GFR increases and causes NaCl concentration of tubular fluid at the macula densa to rise, more NaCl enters cells through the \(\mathrm{Na}^{+}-\mathrm{K}^{+}-\)\(2 \mathrm{Cl}^{-}\) cotransporter (NKCC2) located in the apical plasma membrane.

Increased intracellular [NaCl] in turn stimulates the release of adenosine triphosphate (ATP) through ATP-conducting ion channels located in the basolateral membrane of macula densa cells. In addition, adenosine production is enhanced.

Adenosine binds to A1 receptors and ATP binds to P2X receptors located on the plasma membrane of smooth muscle cells in the afferent arteriole.

Both hormones increase intracellular \(\left[\mathrm{Ca}^{++}\right]\), which causes vasoconstriction of the afferent artery and therefore a decrease in GFR. Although adenosine is a vasodilator in most other vascular beds, it constricts the afferent arteriole in the kidney.

Regulation Of Renal Blood Flow And Glomerular Filtration Rate

Several factors and hormones affect GFR and RBF. As discussed, the myogenic mechanism and tubuloglomerular feedback play key roles in maintaining GFR and RBF at a constant level when the extracellular fluid volume is normal.

In addition, sympathetic nerves and angiotensin II play major roles in regulating GFR and RBF.

Although they are quantitatively less important than sympathetic nerves and angiotensin II, prostaglandins, NO, endothelin, bradykinin, ATP, and adenosine also affect RBF and show how changes in afferent and efferent arteriolar resistance, mediated by changes in the hormones listed in Table, modulate the GFR and RBF.

Sympathetic Nerves

• The afferent and efferent arterioles are innervated by sympathetic neurons; however, the sympathetic tone is minimal when the volume of extracellular fluid is normal.
• Sympathetic nerves release norepinephrine and dopamine, and circulating epinephrine (which is a catecholamine like norepinephrine and dopamine) is secreted by the adrenal medulla.
• Norepinephrine and epinephrine cause vasoconstriction by binding to α₁-adrenoceptors, which are located mainly on the afferent arterioles. Activation of adrenoceptors decreases GFR and RBF.
• Dehydration or strong emotional stimuli, such as fear and pain, activate sympathetic nerves and reduce GFR and RBF.
• Renalase, a catecholamine-metabolizing hormone produced by kidneys, facilitates the degradation of catecholamines.

Angiotensin II

Angiotensin II is produced systemically and locally within the kidneys. It constricts the afferent and efferent arterioles and decreases the RBF and GFR.

How norepinephrine, epinephrine, and angiotensin II act together to decrease the RBF and GFR and thereby increase blood pressure and extracellular fluid (ECF) volume, as would occur, for example, with hemorrhage.

Prostaglandins

Prostaglandins do not play a major role in regulating RBF in healthy, resting people.

However, during pathophysiologic conditions such as hemorrhage, prostaglandins (PGI₂, PGE₁, and PGE₂) are produced locally within the kidneys, and they increase RBF without changing the GFR.

Prostaglandins increase RBF by dampening the vasoconstrictor effects of sympathetic nerves and angiotensin II.

• This effect is important because it prevents severe and potentially harmful vasoconstriction and renal ischemia. Prostaglandin synthesis is stimulated by dehydration and stress (for example, surgery and anesthesia), angiotensin II, and sympathetic nerves.
• Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, inhibit the synthesis of prostaglandins.
• Thus administration of these drugs during renal ischemia and hemorrhagic shock is contraindicated because, by blocking the production of prostaglandins, they decrease RBF and increase renal ischemia.
• Prostaglandins play an increasingly important role in maintaining RBF and GFR as people age. Accordingly, NSAIDs can significantly reduce RBF and GFR in the elderly.
• Persons with renal artery stenosis (narrowing of the artery lumen) caused by atherosclerosis, for example, can have an elevated systemic arterial blood pressure mediated by stimulation of the renin-angiotensin system.
• Pressure in the renal artery proximal to the stenosis is increased, but pressure distal to the stenosis is normal or reduced. Autoregulation is important in maintaining RBF, hydrostatic pressure in the glomerular capillary (\(P_{G C}\)), and GFR in the presence of this stenosis.
• The administration of drugs to lower the systemic blood pressure also lowers the pressure distal to the stenosis; accordingly, the RBF, \(P_{G C}\), and GFR decrease.
• Hemorrhage decreases arterial blood pressure and therefore activates the sympathetic nerves to the kidneys by the baroreceptor reflex.
• Norepinephrine causes intense vasoconstriction of the afferent and efferent arterioles and thereby decreases GFR and RBF.

The rise in sympathetic activity also increases the release of epinephrine and renin (renin in turn generates angiotensin II), which causes further vasoconstriction and a fall in RBF.

The rise in the vascular resistance of the kidneys and other vascular beds increases the total peripheral resistance.

The resulting tendency for blood pressure to increase (Blood pressure = Cardiac output x Total peripheral resistance) offsets the tendency of blood pressure to decrease in response to hemorrhage.

Hence this system works to preserve the arterial pressure at the expense of maintaining a normal GFR and RBF.

Nitric Oxide

• NO, an endothelium-derived relaxing factor, is an important vasodilator under basal conditions, and it counteracts the vasoconstriction produced by angiotensin II and catecholamines.
• When blood flow increases, a greater shear force acts on the endothelial cells in the arterioles and increases the production of NO.
• In addition, a number of vasoactive hormones, including acetylcholine, histamine, bradykinin, and ATP, cause the release of NO from endothelial cells. Increased production of NO causes dilation of the afferent and efferent arterioles in the kidneys.
• Whereas increased levels of NO decrease the total peripheral resistance, inhibition of NO production increases the total peripheral resistance.

Endothelin

Endothelin is a potent vasoconstrictor secreted by endothelial cells of the renal vessels, mesangial cells, and tubular epithelial cells in response to angiotensin II, bradykinin, epinephrine, and endothelial shear stress.

Endothelin causes profound vasoconstriction of the afferent and efferent arterioles and decreases the GFR and RBF.

• Although this potent vasoconstrictor may not influence the GFR and RBF in resting subjects, endothelin production is elevated in a number of glomerular disease states (for example, renal disease associated with diabetes mellitus).
• Abnormal production of nitric oxide (NO) is observed in persons with diabetes mellitus and hypertension. Excess renal NO production in persons with diabetes may be responsible for glomerular hyperfiltration (i.e., increased GFR) and damage of the glomerulus, which are problems characteristic of this disease.
• Elevated NO levels increase the glomerular capillary hydrostatic pres¬sure as a result of a decrease in the resistance of the afferent arteriole. The ensuing hyperfiltration is thought to cause glomerular damage.
• The normal response to an increase in dietary salt intake includes the stimulation of renal NO production, which prevents an increase in blood pressure.
• In some persons, however, NO production may not increase appropriately in response to an elevation in salt intake, and blood pressure rises.

Bradykinin

Kallikrein is a proteolytic enzyme produced in the kidneys. Kallikrein cleaves circulating kininogen to bradykinin, which is a vasodilator that acts by stimulating the release of NO and prostaglandins. Bradykinin increases the GFR and RBF.

Adenosine

Adenosine is produced within the kidneys and causes vasoconstriction of the afferent arteriole, thereby reducing the GFR and RBF. As previously mentioned, adenosine plays a role in tubuloglomerular feedback.

Natriuretic Peptides

Secretion of atrial natriuretic peptide (ANP) by the cardiac atria and brain natriuretic peptide (BNP) from the cardiac ventricle increases when the ECF volume is expanded.

Both ANP and BNP dilate the afferent arteriole and constrict the efferent arteriole. Therefore ANP and BNP produce a modest increase in the GFR with little change in RBF.

Adenosine Triphosphate

Cells release ATP into the renal interstitial fluid. ATP has dual effects on the GFR and RBF.

Under some conditions, ATP constricts the afferent arteriole, reduces RBF and GFR, and may play a role in tubuloglomerular feedback. In contrast, ATP may stimulate NO production and increase the GFR and RBF.

Glucocorticoids

Administration of therapeutic doses of glucocorticoids increases the GFR and RBF.

Histamine

The local release of histamine modulates RBF in the resting state and during inflammation and injury. Histamine decreases the resistance of the afferent and efferent arterioles and thereby increases RBF without elevating the GFR.

Dopamine

• The vasodilator dopamine is produced by the proximal tubule. Dopamine has several actions within the kidney, such as increasing RBF and inhibiting renin secretion.
• Finally, as illustrated, vascular endothelial cells play an important role in regulating the resistance of the renal afferent and efferent arterioles by producing a number of paracrine hormones, including NO, prostacyclin (PGI₂), endothelin, and angiotensin II.
• These hormones regulate the contraction or relaxation of vascular smooth muscle cells in afferent and efferent arterioles and mesangial cells.
• Shear stress, acetylcholine, histamine, bradykinin, and ATP stimulate the production of NO, which increases the GFR and RBF. Angiotensin-converting enzyme, located on the surface of endothelial cells lining the afferent arteriole and glomerular capillaries, converts angiotensin I to angiotensin II, which decreases the GFR and RBF.
• Angiotensin II also is produced locally in the granular cells in the afferent arteriole and proximal tubular cells. PGI₂ and PGE₂ secretion by endothelial cells, stimulated by sympathetic nerve activity and angiotensin II, increases the GFR and RBF.

Finally, the release of endothelin from endothelial cells decreases the GFR and RBF.

Angiotensin-converting enzyme (ACE) degrades and thereby inactivates bradykinin. It also converts angiotensin I, an inactive hormone, to angiotensin II, an active hormone.

Thus ACE increases angiotensin II levels and decreases bradykinin levels. Drugs called ACE inhibitors (for example, enalapril and captopril), reduce systemic blood pressure in patients with hypertension, decrease angiotensin II levels, and elevate bradykinin levels.

Both effects lower systemic vascular resistance, reduce blood pressure, and decrease renal vascular resistance, thereby increasing GFR and RBF.

Angiotensin II receptor antagonists (for example, losartan) also are used to treat high blood pressure. As their name suggests, they block the binding of angiotensin II to the angiotensin II receptor (AT1).

These antagonists block the vasoconstrictor effects of angiotensin II on the afferent arteriole; thus they increase GFR and RBF. In contrast to ACE inhibitors, AT1 antagonists do not inhibit kinin metabolism (for example, bradykinin).