GLOMERULAR FILTRATION RATE & RENAL ВLOOD FLOW REGULATION

STRUCTURE AND PROPERTIES

OF THE FILTRATION BARRIER The filtration barrier of the glomerular capillaries consists of three major elements:– the first of these is the endothelial cells that

line the inside of the glomerular capillary;– the second is the basement membrane of the

capillary itself;– the third is the epithelial cells containing

podocytes or foot process projections that lie on the outside of the capillary in the urinary space of Bowman’s capsule.

STRUCTURE AND PROPERTIESOF THE FILTRATION BARRIER

The glomerular filtration barrier is about 1000 times more porous than other capillaries. It excludes cells and behaves as a molecular sieve restricting solute filtration based on molecular size, shape and charge.

ENDOTHELIUM • The nuclei of the endothelial cells

are usually found in an area of the basement membrane that is attached to the messangium.

• The remainder of each cell is distributed around the inner wall of the glomerular capillary.

• The endothelial cell cytoplasm becomes quite thin and contains 70 nm pores called fenestrae.

• Thin single membranes of a protein-polysaccharide film cover these fenestrae. These are highly permeable, and do not pose a significant barrier to the movement of even large molecules but do exclude passage of cellular elements of the blood.

BASEMENT MEMBRANE • The basement membrane of the

glomerular capillary consists of three layers (these layers do not contain pores).

• In the middle of the basement membrane is a dense inner layer called the lamina densa.

• The lamina densa separates two thinner layers, the lamina rara interna, nearest the capillary lumen, and the lamina rara externa nearest the urinary space.

• The lamina densa is made of type IV collagen which selectively filters molecules between the fibers based on size.

• The lamina rara layers contain heparin sulfate, a polyanionic molecule (act as a charge barrier to large negatively charged molecules such as proteins).

EPITHELIUM: CELL TYPES Two types of epithelial cells are found within the urinary space of Bowman’s capsule.

• The first of these are the parietal epithelial cells that line the inside of Bowman’s capsule. These cells are not part of the filtration barrier.

• The second type of epithelial cells are the visceral epithelial cells or podocytes, which rest on the basement membrane of the glomerular capillary and which are the largest of the cells in the glomerulus.Extending from the main cell body of the podocytes are primary processes from which pedicels or foot processes extend and actually contact the lamina rara externa of the basement membrane. Additional pedicels also arise from secondary and tertiary processes.

EPITHELIUM: FILTRATION SLITS • The distance between pedicels in

the normal glomerulus is approximately 25 nm. This region is referred to as a slit pore or filtration slit.

• A thin membrane covers the area of the slit pore, but does not offer much resistance to filtered substances. This membrane is similar to the membrane seen across the pores in the fenestrated glomerular endothelial cells.

• Pedicels from one cell are seen on many different capillary basement membranes. The adjacent pedicels from any one podocyte alternate with the pedicels arising from other podocytes.

COMPOSITION OF GLOMERULAR FILTRATE

• The glomerular filtration barrier allows fluid to be filtered at a high rate while remaining nearly impermeable to cells and larger molecules. Up to molecular weights of about 7000 daltons molecules are freely filtered across the barrier. As molecular weight increases, filterability decreases progressively.

• Plasma albumin is very poorly filtered. The resultant glomerular filtrate is very close to plasma in composition of small solutes, while being nearly devoid of protein.

• Because the contribution of protein to total plasma osmolarity is quite small and that of the filtrate even less, the filtrate is essentially isosmotic with the plasma from which it is derived.

GLOMERULAR FILTRATION RATE

• The glomerular filtration rate (GFR) is defined as the volume of plasma filtered by all the glomeruli in a given period of time.

• The GFR determines the volume of fluid, both water and solutes, available to the nephron to act on in performing its major function of regulation of water and electrolyte balance.

• In the normal adult male, the GFR is equal to about 125 ml/minute. In the normal adult female the GFR is 10% less.

• At this GFR, about 180 L of fluid are filtered in 24 hours. Urine output, however, is only about 1 to 2 L per day. From these values it may be assumed that about 99% of the glomerular filtrate is reabsorbed by the renal tubules.

FORCES DRIVING THE GLOMERULAR FILTRATION RATE

The forces that contribute to filtration across the glomerular capillary wall are essentially the same as those affecting movement across the other capillaries in the body and are as follows:

• KF = filtration coefficient which is a product of the glomerular capillary permeability and the glomerular capillary surface area;

• PGC = mean capillary hydraulic pressure;• PT = mean tubule hydraulic pressure;• OGC = oncotic (protein osmotic) pressure in the plasma in the glomerular

capillaries;• OT = oncotic pressure of the glomerular filtrate in the renal tubules

(because filtrate protein concentration is very low PT is low and plays a minimal role).

Measurement of GFR by Creatinine Clearance

• Creatinine is an endogenous inert end product of creatine metabolism and is derived mainly from the large mass of muscle tissue. As long as muscle mass remains constant it is produced at a constant rate and its concentration in plasma is essentially constant.

• Creatinine is excreted almost exclusively by the kidney and the primary mechanism by which it enters the tubule is glomerular filtration. It is not reabsorbed by the tubule but does undergo tubular secretion by a rate limited mechanism. Because it is secreted as well as filtered the creatinine clearance overestimates the GFR.

Measurement of GFR by Creatinine Clearance

• In clinical practice it is convenient to use the creatinine clearance as an estimator of GFR since it does not require intravenous infusion of an exogenous substance like inulin. Usually it is measured as a 24 hour clearance. Under these conditions bladder catheterization to ensure complete emptying of the bladder is not usually required as is the case for short term urine collections required in performing inulin clearances.

• Blood samples are collected for measurement of plasma creatinine concentration and the patient is provided with an appropriate container and preservative and instructed to collect all urine excreted over the next 24 hours. The urine volume and creatinine concentration is measured and the clearance is calculated.

PLASMA CREATININE CONCENTRATION AS AN ESTIMATOR OF GFR

• In clinical practice measuring plasma creatinine concentration is a useful screening method for assessing glomerular function.

• The plasma creatinine concentration (Pcr) is constant as long as the production rate equals the excretion rate. This relationship is described by the equation:Pcr x GFR = Creatinine production rate = Ucr x V

• When GFR decreases Pcr will increase until Pcr x GFR again equals the creatinine production rate. Thus if GFR decreases by 50% Pcr will increase twofold; if GFR decreases by 75% Pcr will increase fourfold and so on.

FILTRATION FRACTIONThe filtration fraction (FF) is defined as the ratio of the GFR to the RPF. Under normal conditions this represents about 20% of the plasma volume passing through the kidneys or approximately 180 L /day (is calculated as the ratio of C inulin to C PAH). The average adult produces a urine volume of 1 to 2 L in the same period. This means that greater than 99% of the filtrate must be reabsorbed by the tubules. The FF plays a role in determining tubular reabsorptive efficiency, particularly in the proximal tubule. As FF increases the protein concentration in the plasma entering the peritubular capillaries also increases.

Effect of Glomerular Capillary Hydraulic Pressure on GFR

• Changes in glomerular capillary hydraulic pressure due to changes in systemic blood pressure or renal arteriolar resistance (afferent or efferent) will alter GFR. An increase in glomerular capillary hydraulic pressure will increase GFR. Conversely a decrease in capillary pressure will cause a decrease in GFR.

• An increase of the hydraulic pressure within Bowman’s capsule, due to conditions such as kidney edema or ureteral obstruction, will oppose filtration and will decrease GFR.

Effect of Glomerular Capillary Oncotic Pressure on GFR

GFR can be affected by conditions that alter plasma protein concentration. Changes in plasma protein concentration cause changes in the plasma colloid osmotic, or oncotic, pressure. Glomerular capillary oncotic pressure acts in opposition to glomerular capillary hydraulic pressure. The net filtration pressure which drives GFR is determined primarily by the difference between these two parameters. At any given glomerular capillary hydraulic pressure an increase in plasma oncotic pressure will decrease the net filtration pressure causing a fall in GFR. Conversely a decrease in plasma oncotic pressure will increase the net filtration pressure causing a rise in GFR.

Effect of Glomerular Capillary Oncotic Pressure on GFR

• Hypoproteinemia, resulting in a decrease in plasma oncotic pressure, may result from malnutrition or from impaired protein production due to hepatic disease or gastrointestinal protein loss.

• Conditions causing dehydration will produce an increase in plasma protein concentration due to the loss of water from the ECF. The rise in plasma oncotic pressure decreases net glomerular capillary filtration pressure and contributes to reduction of GFR.

CHARACTERISTICS OF RENAL BLOOD FLOW

• The blood flow through both kidneys of the average adult male equals slightly more than 20% of the total cardiac output, or approximately 1200 ml/minute.

• Approximately 600 ml/min of this is the renal plasma flow containing water and solutes which are subject to glomerular filtration and tubular transport processes.

• Approximately 20% of the renal plasma flow, about 120 ml/min, undergoes glomerular filtration.

• The 480 ml/min of renal plasma flow that escapes filtration continues, along with the blood cells, through the efferent arteriole and perfuses the peritubular capillary bed.

DISTRIBUTION OF RENAL BLOOD FLOW

• The renal blood flow is not uniformly distributed throughout the kidney. The renal cortical tissue containing the glomeruli and the proximal and distal convoluted tubules receives 90% of the total RBF. The remaining 10% of the RBF is distributed to the renal medulla via the vasa recta to perfuse the loops of Henle and the collecting ducts.

• The medulla may be further divided into the outer medulla receiving 8% and the inner medulla receiving 2% of the RBF.

• Medullary blood flow is slower than cortical flow. These have functional significance relating to the role of the cortex in regulation of solute content and composition of the extracellular fluid and the role of the medulla in urinary concentration in the conservation of water and urinary dilution in the excretion of excess water.

RENAL PERFUSION PRESSURE AND VASCULAR RESISTANCE

• Renal blood flow, like blood flow through any organ, is defined by the pressure difference between the arterial and venous ends of the vascular bed, and by the vascular resistance of that bed.

• The equation relating pressure difference (DP), resistance (R), and flow (Q) is given in the figure and is the same for any organ.

RENAL PERFUSION PRESSURE AND VASCULAR RESISTANCE

• The distinguishing feature of the renal circulation is the presence of two arteriolar resistance sites in series across the glomerular capillary bed. The mean perfusion pressure in the renal artery is about 100 mm Hg.

• Perfusion pressure across the entire kidney drops from 100 mm Hg in the renal artery to about 8 mm Hg in the renal vein.

• The major contributions to this decrease are a 40 mm Hg decrease across the afferent arteriole and a 42 mm Hg decrease across the efferent arteriole as the blood enters and leaves the renal glomerulus.

MEASURING RENAL BLOOD FLOW: FICK PRINCIPLE

The amount of a substance taken up, utilized, or excreted unchanged by the kidney or any other organ, (or the whole body for that matter), per unit time is equal to the difference between the arterial and venous levels of that substance multiplied by the organ blood flow. Stated differently, it is possible to calculate renal plasma flow by measuring the amount of a given substance excreted (used) by the kidney, and dividing this value by the plasma arteriovenous concentration difference of this substance.

AUTOREGULATION OF RENAL BLOOD FLOW

The kidney, like many other organs, exhibits autoregulation of blood flow over a fairly broad range of arterial pressures. Autoregulation is defined as the ability of an organ to maintain blood flow relatively constant over a wide range of changes in perfusion pressure. For flow (Q) to remain relatively unchanged over a pressure range requires that, as pressure varies (DP), changes in vascular resistance must also occur according to the relationship demonstrated in the figure.

PRESSURE RANGE OF AUTOREGULATION

• Renal blood flow is autoregulated in the perfusion pressure range between 80 - 180 mm Hg.

• The glomerular filtration rate (GFR) remains relatively unchanged over the same range in pressure. An important determinant of GFR is the hydraulic pressure (blood pressure) in the glomerular capillaries which is determined by the renal afferent and efferent arteriolar resistances.

• From a functional point of view autoregulation of GFR is most important since significant changes in GFR could have profound effects on fluid and electrolyte balance of the body.

SITE OF AUTOREGULATION

• An increase in afferent vascular resistance tends to reduce glomerular capillary hydraulic pressure and would decrease GFR while a decrease in afferent vascular resistance tends to increase glomerular hydraulic capillary pressure and would increase GFR. This is because the glomerular capillaries are downstream from the resistance change.

• An increase in efferent arteriolar resistance increases glomerular capillary hydraulic pressure and would tend to increase GFR while a decrease in efferent arteriolar resistance decreases glomerular capillary pressure and would tend to decrease GFR. In this case the glomerular capillaries are upstream from the resistance change.

SITE OF AUTOREGULATION

• Any change in glomerular capillary pressure causes a change in glomerular filtration pressure and therefore in GFR and the delivery of fluid to the renal tubule. The observation that GFR, and to a lesser extent RPF remains constant over a wide range of mean arterial pressures suggests that autoregulation must occur primarily via resistance changes in the afferent arterioles.

• These observations also suggest that the function being regulated is the GFR. The advantage of maintaining a constant GFR is that significant changes in mean arterial pressure do not result in major changes in salt and water excretion and the adverse effects of volume retention or depletion associated with such changes.

MYOGENIC MECHANISM OF AUTOREGULATION

• The myogenic mechanism is based on the observation that vascular smooth muscle contracts in response to stretch. This phenomenon is observed in a variety of organs in which autoregulation of blood flow occurs.

• As blood vessels increase in size in the kidney in response to a pressure increase, the smooth muscle cells of the afferent arteriolar vasculature contract increasing resistance and minimizing any increase both in renal blood flow and in glomerular filtration pressure.

• Conversely a decrease in renal perfusion pressure results in afferent arteriolar smooth muscle cell relaxation decreasing resistance and minimizing any decrease in renal blood flow and in glomerular filtration pressure.

TUBULOGLOMERULAR FEEDBACK MECHANISM

• The tubuloglomerular feedback mechanism of autoregulation (which involves the JGA) is based on the premise that an increase in renal perfusion pressure causes an increase in GFR.

• This results in increased tubular fluid flow and increased delivery of fluid to the distal nephron.

• The cells of the macula densa sense this increased flow, by detecting changes in tubular sodium chloride concentration and/or transport at this site and respond by increasing their secretion of a vasoconstrictor substance which acts locally to increase afferent arteriolar vascular resistance.

TUBULOGLOMERULAR FEEDBACK MECHANISM

• A decrease in renal perfusion pressure and the associated decrease in GFR results in an opposite sequence of events, a decreased secretion of vasoconstrictor causing a decreased afferent arteriolar resistance and an increase in GFR.

• The action of the vasoconstrictor substance on the afferent arteriolar vascular resistance is responsible for maintaining glomerular filtration pressure and therefore GFR within normal limits.

• There is strong evidence that adenosine is a renal vasoconstrictor which may play a significant role in autoregulation of GFR.

NERVOUS REGULATION OF RBF: SYMPATHETIC NERVOUS SYSTEM

• The renal arteries and arterioles are richly innervated by adrenergic sympathetic fibers.

• Renal sympathetic nerve stimulation increases renal vascular resistance in both afferent and efferent arterioles. This increased resistance, decreases renal blood flow.

• Because the sympathetic activity affects both afferent and efferent resistance, the effect on glomerular hydraulic pressure, and therefore GFR, is not as great as the effect on renal plasma flow.

• In general, sympathetic activity decreases the hydraulic pressure in the glomerular capillaries and reduces GFR, but the reduction in GFR is less than the reduction in renal plasma flow.

• The main effect of sympathetic activity is to increase filtration fraction and enhance tubular reabsorptive capacity.

VASOACTIVE SUBSTANCES

• Many vasoactive substances alter renal vascular resistance and, therefore, renal blood flow.

• Substances considered to be of greatest physiological importance are: antidiuretic hormone, angiotensin II, and the various paracrines, in particular the prostaglandins.

Angiotensin II: Vascular effects

• Angiotensin II is the most potent vasoconstrictor released in the body. It affects most vascular smooth muscle, including both afferent and efferent renal arterioles.

• It increases renal vascular resistance and reduces renal blood flow. In general, renal efferent arterioles are more responsive to angiotensin II than are the afferent arterioles.

• The net effect on renal hemodynamics is to decrease both RBF and GFR. Because the vasoconstrictor effect of angiotensin II is greater on the efferent than on the afferent arteriole the GFR is reduced less than the RBF.

Angiotensin II: Vascular effects

• The release of angiotensin II is controlled by renin which is secreted by the granular cells of the JGA. These cells serve as intrarenal baroreceptors varying their renin secretion rate inversely with changes in intrarenal perfusion pressure.

• Renin secretion is also stimulated by renal sympathetic nerves acting on beta-adrenergic receptors on the granular cells.

Angiotensin II: Mesangial Effects

• The observed decrease in GFR in the presence of angiotensin II is, in part, due to the effect of angiotenin II on renal mesangial cell function.

• Mesangial cells constrict in response to angiotensin II and reduce the Kf by decreasing the glomerular capillary surface area. It is this effect on Kf that accounts for the overall decrease in GFR.

• As a generalization, elevated levels of angiotensin II lead to an increased renal vascular resistance, a decreased Kf, and consequently to a reduction in RBF and GFR.

• Filtration fraction, however, increases because the fall in GFR is less than the fall in RBF.

ANTIDIURETIC HORMONE (ADH)

• At physiological levels the action of ADH is limited to its effect on collecting duct water permeability. However, extremely high doses of ADH, exhibit widespread vasoconstrictor activity, including constriction of the afferent and efferent renal arterioles.

• The importance of ADH in normal daily regulation of vascular resistance and blood pressure is doubtful because of the high doses required to elicit measurable changes in resistance.

ANTIDIURETIC HORMONE (ADH)

• Under pathological conditions, such as hemorrhage and shock, ADH release from the posterior pituitary is sufficient to elevate plasma ADH to levels that cause vasoconstriction.

• At these high levels ADH causes contraction of glomerular mesangial cells and reduces the Kf of the glomerular capillaries.

• In such pathological conditions, therefore, the net effect of ADH is to reduce GFR and renal blood flow.

• Because of its differential effect on afferent and efferent arterioles the decrease in GFR is less than the decrease in RBF and, therefore, ADH can cause an increase in the FF.

PROSTAGLANDINS• Several prostaglandins affect renal vascular resistance.

PGE2 and PGI2 are vasodilators that act primarily on the afferent arterioles.

• The physiological role of these prostaglandins in regulating renal blood flow is not fully understood. These prostaglandins are produced within the kidney and act directly on renal arteriolar smooth muscle.

• Their synthesis and release is stimulated by increased renal sympathetic nerve activity and by increased levels of Angiotensin II and it is thought that they act to modulate the effects of these vasoconstrictors and so reduce the possibility of ischemic damage to the kidney when vasoconstrictor activity is high.

• Other prostaglandins, such as TXA2, also act as vasoconstrictors but no physiological role has been postulated for these agents.

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