Regulation of Renal Blood Flow

Angiotensin II and autoregulation of GFR

As the renal perfusion pressure is diminished (due for example to antihypertensive therapy), the kidney is *initially able to maintain both blood flow and glomerular filtration via the phenomenon of autoregulation* -The first part of the autoregulatory response is decreased afferent (precapillary) arteriolar tone, thereby allowing more of the systemic pressure to be transmitted to the glomerulus. -Afferent DILATION is mediated both by tubuloglomerular feedback and by a direct myogenic response. -With more marked REDUCTIONS in renal perfusion pressure, renin release is stimulated -The ensuing INCREASE in angiotensin II production maintains both intraglomerular pressure and the GFR via a *preferential increase in resistance at the EFFERENT arteriole.* -The net effect is that the GFR and renal blood flow do not begin to fall until these autoregulatory changes in arteriolar resistance are maximized.

Sodium Balance

For a healthy individual to remain in sodium balance *dietary input must be matched to sodium excretion.* -Dietary intake of sodium is highly variable, in this figure of 120mmoles/day is assumed. -5-10 mmoles is not absorbed by the gut and is lost in the feces. -A small fraction of absorbed sodium is lost in sweat (10-15 mmoles/day). -This leaves about 100 mmoles/day that must be excreted by the kidneys. -Remember that the BULK of the sodium in the body is *found in the ECF and is FREELY filtered by the kidneys.* -The filtered load for sodium in this example is 25,500 moles/day. >Of the 25,400 moles/day is reabsorbed.

Quantification of Glomerular Filtration Rate Based on Hydrostatic Properties

Glomerular Filtration Rate *(GFR): GFR = Kf X PUF Where: -Kf = filtration coefficient: reflects hydraulic permeability and total surface area, which reflects nephron number and size. -PUF= Net filtration pressure calculated from Starling Forces ---- This is not a formula you will be expected to apply. -You should be aware that when thinking about factors influencing GFR you must consider the hydraulic permeability and total surface area, in addition to the Starling forces which generate the net filtration pressure.

Adenosine is the Paracrine Factor Released by the Macula Densa

*Adenosine* release from the macula densa causes *vasoconstriction of the afferent arteriole via the A1 Adenosine receptor* and *vasodilatation of the efferent arteriole via the A2 Adenosine receptor.* -NET decrease in glomeruli capillary hydrostatic pressure

Control of Renal Blood Flow: BP (Intrinsic)

*Intrinsic*: -Prostaglandins (several) produced locally in the kidney cause vasodilation of the afferent and efferent arterioles (protective of RBF). -Autoregulation: Acts primarily on the *afferent arteriole* 1. Myogenic response: increased arterial pressure stretches walls of afferent arteriole, leads to activation of stretch-activated Ca2+ channels in smooth muscle, increasing contraction. >Stretch activated: Stretch activation of calcium channels causing VASOCONSTRICTION 2. Tubuloglomerular feedback

Control of Renal Blood Flow: BP (Drugs)

*The nonsteroidal anti-inflammatory drugs (NSAIDS)* are commonly used for fever and pain control. -Most of these drugs are nonselective inhibitors of COX1 and COX2. -They invariably *decrease renal blood flow and glomerular filtration rate*, particularly in patients with preexisting renal disease. -They exert their renal hemodynamic effect primarily via DECREASED renal synthesis of PGE2 (which normally dilates the afferent arteriole). -Overdose of these agents can produce *acute and severe reductions in blood flow.* -In addition, these agents blunt the effects of most antihypertensive drugs, because they promote renal sodium retention (via inhibition of PGE2 synthesis).

The group of cells that detect changes in Cl- concentration in the distal convoluted tubule are labeled:

-- G: Macula Densa!

Remember that in the PCT...

-2/3 of salts and water are reabsorbed -Essentially all of the glucose and amino acids are reabsorbed -*Reabsorption is isoosmotic*: >The osmolality of the tubular fluid remains ~300 milli-osmoles/kg from the beginning to the end of the proximal tubule *Glomerulotubular balance* allows this constant proportion to be reabsorbed in the face of varying tubular flow rates

Renal Blood Flow (RBF)

-Equal to about 25% of cardiac output (~1.25 L/min). -Major RESISTANCES of the renal vasculature occur in the afferent arterioles, efferent arterioles, and interlobular arteries. -Changes in resistances can dramatically alter RBF but... >GFR remains constant over a wide range of RBF due to *autoregulation*

Glomerulotubular Balance

-The kidney is challenged with *reabsorbing most of the filtered water and non-waste solutes* while *regulating the urinary volume and osmolality* to maintain body fluid compartment homeostasis. >A significant portion of this task is accomplished through the process of glomerulotubular balance. >*Glomerulotubular balance* refers to the variable proportion of glomerular filtrate that is reabsorbed isoosmotically in the proximal convoluted tubule. >*Starling forces* acting between the tubular fluid and *plasma in the peritubular capillaries* determines the net reabsorption of fluid. -If a fixed quantity of fluid is reabsorbed each day (178 L of 180 L filtered) then an increase in GFR to 185 should result in the excretion of 7 L of urine. >However, this is undesirable since urine losses of this magnitude could produce life-threatening volume depletion. >Hence, the proximal tubule reabsorption varies to compensate for changes in glomerular ultrafiltration. >Specifically, the proximal tubule reabsorbs a constant FRACTION, rather than absolute volume, of the glomerular filtrate.

A 74 yo retired construction worker is being evaluated for chronic kidney disease secondary to hypertension. The patient's GFR is 50 ml/min and his plasma Na+ concentration of 150mEq/L. What is the filtered load of sodium?

1. 7.5 mEq/min 2. 7.5 ml/min 3. 75 mEq/min 4. 75 ml/min 5. 750 mEq/min 6. 750 ml/min 7. 7500 mEq/min 8. 7500 ml/min ---- 50 X Na conc by plasma

An pharmaceutical investigator infuses a low dose of a putative agonist for angiotensin II into a patient and records changes occurring in the kidney. If the new drug is an effective Ang II agonist the expected action is most likely:

1. Decreased HPGC 2. Increased GFR 3. Increased RPF 4. Mesangial cells relax --- 2

Mechanism of Iso-osmotic Reabsorption in the Proximal Tubule - Glomerulotubular Balance

1. Na+ and solutes enter via previously described mechanisms 2. Na+ pumped out via basolateral membranes using the Na+/K+ ATPase and other transporters. 3. As Na+ pumped out of cells into intercellular space water FOLLOWS from the lumen 4. Lateral intercellular space is an important route for solute and water (Iso-osmotic with fluid in lumen). 5. Starling forces in peritubular capillaries act on fluid in intercellular space. 6. Remember oncotic pressure (πc) in peritubular capillaries is elevated.

A patient with a blood pressure of 170/110 mm Hg, plasma ADH, Na+ and creatinine concentration all within normal ranges and an elevated plasma renin concentration, would be expected to have which of the following conditions?

A) Acute glomerulonephritis B) An excessive daily intake of NaCl C) Primary hyperaldosteronism D) Renonvascular hypertension E) SIADH ---- Renovascular hypertension is a condition of high blood pressure resulting from stenosis of a renal artery. This would result in elevated renin release for the kidney receiving reduced blood flow.

In a patient with renovascular hypertension secondary to an atherosclerotic plaque in the left renal artery, Na+ excretion by the right kidney will most likely be stimulated by which of the following factors...

A) a fall in plasma aldosterone B) increased GFR in the right kidney C) increased sympathetic nervous system activity D) increased plasma Na+ concentration E) angiotensin II acting on the right kidney proximal tubules --- In an effort to increase blood flow to the left kidney renin release is stimulated which through RAAS system activation systemically increases peripheral vascular resistance and in the glomerulus constricts the efferent arteriole to a greater extent than the afferent arteriole. Consequently, GFR in the right kidney will increase (b).

Role of Angiotensin II in Autoregulation

Blue control and red antagonist (decrease GFR) -Effect of reducing renal artery pressure (from a baseline value of about 125 mmHg) on glomerular filtration rate (GFR), expressed as a percentage of control values in dogs fed a normal sodium diet. -The blue squares represent control animals in which both GFR was maintained until the pressure was markedly reduced. -The red circles represent animals given an intrarenal infusion of an *angiotensin II antagonist* >Autoregulation of GFR was LESS well-regulated. -Although not shown, autoregulation also applies to GFR when the renal artery pressure is initially raised and to renal blood flow, which is NOT IMPAIRED by inhibiting the activity of angiotensin II.

Role of Mesangial Cells in GFR Regulation

In the diagram in the center you'll observe the purple mesangial cells. -Contractile elements in these cells are sensitive to paracrine, endocrine, and neural factors. -When mesangial cells contract some glomerular capillaries CLOSE which *DECREASES the surface area* for filtration, Kf decreases and GFR decreases. -High concentrations of angiotensin II are required to stimulate mesangial cell contraction. -Factors that cause mesangial cells to RELAX initiate exactly the opposite sequence of events. ---- PDGF - platelet derived growth factor

Renal Autoregulation

Plot of mean arterial blood pressure vs. renal blood flow rate illustrates a critical feature of renal function. -Note that over a range of mean arterial blood pressures from 80 to 180 mm Hg the renal blood flow rate is held *relatively constant at ~ 1.2 L/min.* -At low mean arterial blood pressures the afferent arteriole is FULLY dilated. -Autoregulation of flow is mainly accomplished increasing VASOCONSTRICTION of the AFFERENT arteriole as mean arterial blood pressure increases.

Relationship of Single Nephron GFR to Macula Densa Perfusion Rate

Relationship of single nephron glomerular filtration rate (GFR) to distal nephron (macula densa) perfusion rate in dogs. -As the perfusion rate increases (via insertion of a micropipette into the late proximal tubule), there is a progressive reduction in GFR to a minimum of about one-half the basal level. -Flow increases then filtration will decrease

Atrial natriuretic peptide (ANP) is believed to cause dilatation of the afferent arteriole and contraction of the efferent arteriole. An increase in the plasma concentration of ANP would be expected to have which of the following combination of effects on the kidney (Hydrostatic pressure GC and GFR: Increase, decrease, or no change).

Relaxation of the afferent and efferent arterioles is going to result in an increase in the hydrostatic pressure in the glomerular capillaries and an increase in the glomerular filtration rate as the dilitation of the larger diameter afferent arteriole has a greater net effect on hydrostatic pressure.

Regulation of Sodium Excretion

Sodium excretion is highly regulated. -There are hormonally regulated processes favoring either retention or excretion. Favoring Sodium Retention: -Angiotensin II -Aldosterone -Hemodynamics -Sympathetics Favoring Sodium Excretion (Natriuresis): -Atrial Natriuretic Peptide (ANP) -DECREASED protein Osmotic Pressure

Control of Renal Blood Flow: BP (Extrinsic)

Sympathetic stimulation constricts afferent and efferent arterioles -*Greatest effect on afferent arterioles* -Angiotensin II constricts afferent and efferent arterioles >*The efferent arterioles are more sensitive to Angiotensin II*

Effects of ECF Volume Expansion and Contraction on Iso-osmotic Reabsorption

This figure illustrates how isoosmotic reabsorption is altered by volume expansion or contraction. -As a result of infusion (or ingestion) of isotonic saline there is a dilution of the plasma proteins. >This dilution results in a DECREASE in the colloid osmotic pressure in the peritubular capillaries which DECREASE the driving force for fluid reabsorption. -Alternately, if a patient has had diarrhea or has been vomiting there would be a *isoosmotic loss* of fluid which would effectively concentrate plasma proteins, increasing the oncotic pressure favoring fluid reabsorption.

Tubuloglomerular Feedback Mechanism (Pathway)

The tubuloglomerular feedback mechanism monitors flow within the nephron indirectly as a surrogate of renal blood flow. -Much of the solutes, water, and sodium are REABSORBED *isoosmotically in the PCT.* -The tubular fluid exiting the Loop of Henle has an osmolarity of approximately 100 mOsmoles/L with the primary cation and anion being sodium and chloride. -Cells in the *macula densa* are capable of detecting the chloride concentration in the tubular fluid. -As arterial blood pressure increases, GFR increases which increases the delivery of NaCl to the macula densa causing the *release of a vasocontrictor (adenosine) that acts on the afferent arteriole.* >Vasoconstriction of the afferent arteriole DECREASES glomerular blood flow and the glomerular capillary pressure. -A major function of autoregulation and TGF is to PREVENT excessive salt and water losses. -To understand this concept, it is important to appreciate the differences in function between the proximal and distal segments of the nephron. -The bulk of the filtrate (about 90 percent) is *reabsorbed in the proximal tubule and loop of Henle*, with the final qualitative changes in urinary excretion (such as hydrogen and potassium secretion and maximum sodium and water reabsorption) being made in the distal nephron, particularly in the *collecting tubules* -The collecting tubules, however, have a relatively LIMITED total reabsorptive capacity. -Thus, the ability of the macula densa to decrease the GFR when distal delivery is enhanced prevents distal reabsorptive capacity from being overwhelmed, which could lead to potentially life-threatening losses of sodium and water. >Viewed in this light, it may be that it is macula densa flow itself, not the GFR, that is being maintained by autoregulation and TGF.

Tubuloglomerular Feedback Mechanism (Diagram)

This figure diagrammatically illustrates how an increase in GFR is detected by the macula densa which releases a paracrine factor to stimulate afferent arteriole vasoconstriction.

Sodium Handling in the Nephron

This figure illustrate the regions of the nephron where sodium reabsorption occurs. -The 3% of sodium reabsorption that occurs in the collecting duct is *hormonally regulated*. >This regulation is essential for maintain sodium balance.

Renal Changes Occurring during ECF Volume Expansion (Flow Diagram)

This flow diagram illustrates the processes contribution to fluid uptake by the peritubular capillaries during volume expansion. -During volume expansion there is a *DECREASE in the resistance* of the EFFERENT arteriole which significantly increase renal plasma flow (RPF) and the hydrostatic pressure entering the peritubular capillaries. -The decrease in resistance in the efferent arteriole also favors an increase in GFR. -Remember that *filtration fraction is GFR divided by RPF*. -Since RPF increases to a greater extent than GFR the *filtration fraction drops.* -If the filtration fraction drops the oncotic pressure entering the peritubular capillaries will also drop.

Tubuloglomerular Feedback Mechanism

Tubuloglomerular feedback is possible because of the unique anatomy of the nephron. -Specialized cells of the distal convoluted tubule form the *macula densa*. >These cells detect *sodium chloride concentration* in the tubular fluid as a surrogate for tubular flow rate. -The close proximity of the macula densa to the afferent and efferent arterioles allows the release of *paracrine factors to affect the tone of the arteriole smooth muscle*. -Also shown is sympathetic innervation of the granular cells (JG cells). >Sympathetic input stimulates renin release.

Regulation of GFR

Vasoconstriction or vasodilation of the afferent or efferent arterioles will have very different effects on the hydrostatic pressure in the glomerular capillary and, as a consequence, on GFR. -Constriction of the afferent arteriole or dilation of the efferent arteriole decreases HPGC and GFR. -Dilation of the afferent arteriole or constriction of the efferent arteriole increases HPGC and GFR. -Several the more important neural, hormonal, and paracrine factors affecting vascular tone at the afferent and/or efferent arterioles are listed.