Glomerular filtration

Dr Bindu K BHMS,MD(Hom)

The kidneys are the primary means of eliminating waste products of metabolism that are no longer needed by the body. These products include urea (from the metabolism of aminoacids), creatinine (from muscle creatinine) uric acid (from nucleic acids), the end products of haemoglobin breakdown such as bilirubin and metabolites of various hormones. These waste products are to be eliminated from the body as rapidly as they are produced. Kidneys also eliminate most toxins and other foreign substances that are either produced by body or ingested such as pesticides, drugs and food particles.

Renal blood supply-
Renal circulation is unique in that it has two capillary beds; the glomerular and peri-tubular capillaries which are arranged in series and separated by efferent arterioles that help regulate the hydrostatic pressures in both sets of capillaries. High hydrostatic pressure in glomerular capillaries (about 60 mm of Hg) causes rapid fluid filtration, lower hydrostatic pressure in peritubular capillaries (about 13 mm of Hg) permits rapid fluid reabsorption. By adjusting the resistances of afferent and efferent arterioles, kidneys regulate the hydrostatic pressures in both glomerular and peritubular capillaries, thereby changing rate of glomerular filtration or tubular reabsorption in response to body homoeostatic demands.

Urine formation results from glomerular filtration, tubular reabsorption and tubular secretion.

Rates at which different substances are excreted in urine represent the sum of 3 renal processes-
(1) Glomerular filtration
(2) Reabsorption of substances from renal tubules into blood (3)Secretion of substances from blood into renal tubules.

Expressed mathematically:
Urinary excretion rate =Filtration rate –Reabsorption rate+Secretion rate.

Determinants of Glomerular Filtration Rate
GFR is determined by:
(1) Sum of hydrostatic and colloid osmotic forces across the glomerular membrane which gives the net filtration pressure
(2) Glomerular capillary filtration coefficient Kf.

Expressed mathematically GFR=Kf x Net filtration pressure.

Net filtration
pressure is the sum of hydrostatic and colloid osmotic forces that either favour or oppose filtration across the glomerular capillaries.

These forces include:
(1) Hydrostatic pressure inside the glomerular capillaries (Pg) which promotes filtration
(2) Hydrostatic pressure in Bowman’s capsule (Pb) which opposes filtration
(3) Colloid osmotic pressure of glomerular capillary plasma proteins which opposes filtration (Iig)
(4) Colloid osmotic pressure of proteins in Bowman’s capsule (Iib) which promotes filtration.
(Under normal conditions the concentration of proteins in the glomerular filtrate is so low that the colloid osmotic pressure of Bowman’s capsule fluid is considered to be zero.)

Although the normal values for the determinants of GFR have not been measured directly in humans, they have been estimated in animals such as dogs and rats. Based on the results in animals, approximate normal forces favoring and opposing glomerular filtration are as follows.

Forces favoring filtration(mm of Hg)
Glomerular hydrostatic pressure 60
Bowman’s capsule colloid osmotic pressure 0
Forces opposing filtration (mm of Hg)
Glomerular capillary colloid osmotic pressure 32
Bowman’s capsule hydrostatic pressure 18
Net filtration pressure=60-32-18=10 mm of Hg.

GFR can be expressed as Kf (Pg – Pb – Iig – Iib)

Increased glomerular capillary filtration coefficient (Kf) increases GFR.
Kf is a measure of product of hydraulic conductivity and surface area of the glomerular capillaries. Kf can’t be measured directly but estimated experimentally by dividing rate of glomerular filtration by net filtration pressure.

Kf = GFR/Net filtration pressure.

Total GFR for both kidneys is about 125 ml/minute.Net filtration pressure is 10 mm of Hg, so Kf is calculated to be 12.5ml/min/mm of Hg of filtration pressure. When Kf is expressed in 100gms of kidney weight it averages about 4.2ml/min/mm Hg per 100gms of kidney weight, a value about 400 times as high as Kf of most other capillary systems of the body. Average Kf of other tissues in the body is only about 0.01 ml/min/mm of Hg per 100 gms. High Kf for glomerular capillaries contributes to their rapid rate of fluid filtration.

Increased Kf raises GFR and decreased Kf reduces GFR.
Changes in Kf probably don’t provide a primary mechanism for normal day to day regulation of GFR. Some diseases lower Kf by reducing the number of functional glomerular capillaries (reducing surface area for filtration) or by increasing the thickness of glomerular capillary membrane and reducing its hydraulic conductivity. For eg: Chronic uncontrolled hypertension and diabetes mellitus reduce Kf by increasing the thickness of glomerular capillary basement membrane and eventually by damaging capillaries so severely that there is loss of capillary function.

Increased Bowman’s capsule hydrostatic pressure reduces GFR.
Increasing hydrostatic pressure in Bowman’s capsule reduces GFR but decreasing this pressure raises GFR. Changes in Bowman’s capsule normally don’t serve as a primary means for regulating GFR.
In certain pathological states associated with obstruction of urinary tract, Bowman’s capsule pressure can increase markedly causing serious reduction in GFR. For eg: percipitation of calcium or of uric acid may lead to stones that lodge in urinary tract often in the ureter thereby obstructing outflow of urinary tract and raising Bowman’s capsule pressure and this reduces GFR and eventually damage or destroy the kidney unless the obstruction is relieved.

Increased glomerular capillary colloid osmotic pressure decreases GFR.
As blood passes from the afferent arteriole through the glomerular capillaries to efferent arterioles, the plasma protein concentration increases for about 20%.The reason for this is about one fifth of fluid in capillaries filters into Bowman’s capsule thereby concentrating glomerular plasma proteins that are not filtered. Assuming that the normal colloid osmotic pressure of plasma entering the glomerular capillaries is about 28 mm of Hg. This value normally rises to about 36 mm of Hg by the time blood reaches the efferent end of the capillaries. Average colloid osmotic pressure of the glomerular capillary plasma proteins is midway between 28 and 36 mm of Hg or about 32 mm of Hg.

Thus two factors that influence the glomerular capillary colloid osmotic pressure:
(1) Arterial plasma colloid osmotic pressure
(2) Fraction of plasma filtered by glomerular capillaries(filtration fraction).

Increasing arterial plasma colloid osmotic pressure raises the glomerular capillary colloid osmotic pressure reduces GFR.

Increased glomerular capillary hydrostatic pressure increases GFR.
Glomerular capillary hydrostatic pressure estimated to be about 60 mm of Hg under normal conditions. Changes in glomerular hydrostatic pressure serve as a primary means for physiological regulation of GFR. Increase in hydrostatic pressure raise GFR and decrease in Glomerular hydrostatic pressure lowers GFR.

Glomerular hydrostatic pressure is determined by 3 variables each of which is under physiologic control:
(1) Arterial pressure
(2)Afferent arteriolar resistance
(3) Efferent arteriolar resistance.
Increased arterial pressure tends to raised glomerular hydrostatic pressure and so increase GFR. Increased resistance of afferent arterioles reduces glomerular hydrostatic pressure and reduces GFR. Dilation of afferent arterioles increases both glomerular hydrostatic pressure and GFR.
Constriction of efferent arterioles increases resistance to outflow from glomerular capillaries. This raises glomerular hydrostatic pressure and as long as increase in efferent arteriolar resistance does not reduce renal blood flow too much, GFR increases slightly. Efferent arteriolar constriction also reduce renal blood flow, filtration fraction and glomerular colloid osmotic pressure increase as efferent arteriolar resistance increases. If constriction is severe, rise in colloid osmotic pressure exceeds the increase in glomerular capillary hydrostatic pressure caused by efferent arteriolar constriction. When this occurs the net force for filtration decreases reduction in GFR.

Efferent arteriolar constriction has a biphasic effect on GFR. At moderate levels of constriction, slight increase of GFR. But with severe constriction reduction in GFR. Primary cause of eventual decrease in GFR as follows as efferent arteriolar constriction severe and as plasma protein concentration rises there is rapid non-linear increase in colloid osmotic pressure caused by Donnan effect, higher protein concentration more rapidly colloid osmotic pressure rises due to interaction of ions bound to plasma proteins exert osmotic effect.

Physiologic control of Glomerular filtration and renal blood flow
Determinants that are most variable and subject to physiologic control include glomerular hydrostatic pressure and glomerular capillary osmotic pressure. These variables are influenced by sympathetic nervous system, hormones and autacoids (vasoactive substances that are released in kidney and act locally) and other feed back mechanisms that are intrinsic to kidneys.

Sympathetic nervous system activation decreases GFR
Essentially all blood vessels of kidneys are innervated by sympathetic nerve fibers. Strong activation of renal sympathetic nerves constricts renal arterioles and decrease renal blood flow and GFR. Moderate or mild sympathetic stimulation has little influence on renal blood flow and GFR. Reflex activation of it resulting from moderate decrease of pressure at carotid sinus baro-receptors or cardiopulmonary receptors has little influence on renal blood flow and GFR. Baro-receptors adapt within minutes or hours to sustained changes in arterial pressure, so reflex mechanisms have a role in long term control of renal blood flow and GFR. It has a role in reducing GFR.

In severe acute disturbances lasting for few minutes to hours such as those elicited by defense reaction, brain ischaemia or severe haemorrhage.

Hormonal and autacoid control of renal circulation-
(1) Nor-epinephrine, Epinephrine and endothelin constrict blood vessels and reduce GFR.
Hormones that constrict both afferent and efferent arterioles causing reduction in GFR and renal blood flow include nor-epinephrine and epinephrine released from adrenal medulla. In general blood vessels of these hormones parallel activity of sympathetic nervous system. Thus they have no effect in renal haemodynamics except under severe haemorrhage.
Endothelin peptide that is released by damaged vascular endothelial cells of kidneys as well as other tissues. It contributes to haemostasis when a blood vessel is severed which damages the endothelium and releases it. It is increased in certain diseases associated with vascular injury like toxaemia of pregnancy, acute renal failure, chronic uraemia.

(2) Angiotensin II constricts efferent arterioles—
Angiotensin II is a vasoconstrictor which is released during situation of decreased arterial pressure and volume depletion. It constricts efferent arterioles thereby increasing glomerular hydrostatic pressure and increasing GFR and promotes excretion of metabolic waste products. But due to constriction of efferent arterioles, decreased flow through the peritubular capillaries which increases reabsorption of sodium and water.

(3) Endothelial derived Nitric oxide decreases renal vascular resistance and increases GFR—
Basal level of Nitric oxide production appears to be important in preventing excessive vasoconstriction of kidneys and allowing them to excrete normal amounts of sodium and water. Administration of drugs that inhibit formation of Nitric oxide increases renal vascular resistance and reduces GFR and urinary sodium excretion causing high blood pressure. Thus in hypertensive patients, impaired nitric oxide production contribute to renal vasoconstriction and increased blood pressure.

(4) Prostaglandins and Bradykinin tend to Increase GFR.
Opposing vasoconstriction of afferent arterioles they help to prevent excessive reduction of GFR and renal blood flow. Under stressful conditions such as volume depletion or after surgery administration of non-steroidal anti-inflammatory agents inhibit prostaglandin synthesis and cause reduction in GFR.

Autoregulation of GFR and renal blood flow
Feedback mechanisms intrinsic to kidneys normally keep renal blood flow and GFR constant despite marked changes in arterial blood pressure.These function in blood perfused kidneys that have been removed from the body independent of systematic influences. This relative constancy of GFR and renal blood flow is called as autoregulation.

The primary function of blood flow autoregulation in most other tissues besides kidneys is to maintain delivery of oxygen and nutrients to tissues at a normal level and remove waste products of metabolism despite changes in arterial pressure. Major function of autoregulation in kidneys is to maintain a relatively constant GFR and allow precise control of renal excretion of water and solutes.

Importance of GFR autoregulation in preventing extreme changes in renal excretion—
Changes in arterial pressure exerts less effect on urine volume for two reasons—
(1) Renal autoregulation prevents large changes in GFR that would otherwise occur
(2) Additional adaptive mechanisms in renal tubules that allow kidneys to increase reabsorption rate when GFR rises a phenomenon called as glomerulo-tubular balance.

Yet changes in arterial pressure has significant effects on renal excretion of sodium and water referred ta as pressure diuresis or pressure natriuresis and it is crucial in regulation of body fluid volumes and arterial pressure.

Role of Tubuloglomerular feedback in GFR auto-regulation
Tubuloglomerular feedback mechanism has 2 components that act together to control GFR.
(1) Afferent arteriolar feedback mechanism
(2) Efferent arteriolar feedback mechanism.

These depend on special anatomical arrangements of juxtaglomerular complex. It consists of macula densa cells in initial portion of distal tubule and juxtaglomerular cells in the walls of afferent and efferent arterioles. Macula densa is a specialised group of epithelial cells in distal tubules that come in contact with afferent and efferent arterioles. They contain golgi apparatus which are intra cellular secretory organelles directed towards arterioles suggesting that these cells may be secreting a substance towards arterioles.

Increased macula densa sodium chloride causes dilation of afferent arterioles and increased renin release
Reduced GFR slows rate of flow in loop of Henle causing an increased reabsorption of sodium and chloride ions in ascending loop of Henle and reduced concentration of sodium chloride at macula densa cells and it initiates signals from macula densa cells that has 2 effects:

(1) It reduces resistance of afferent arterioleswhich raises glomerular hydrostatic pressure and helps to return GFR to normal.
(2) It increases renin release from juxtaglomerular cells of afferent and efferent arterioles which are storage sites for renin.

Renin released from these cells functions as an enzyme to increase formation of angiotensin I converted to angiotensin II and it constricts efferent arterioles increasing glomerular hydrostatic pressure and returning GFR to normal.

Myogenic autoregulation of renal blood flow and GFR
Ability of individual blood vessels to resist stretching during increased arterial pressure a phenomenon referred to as myogenic mechanism. Individual blood vessels throughout the body respond to increased wall tension or wall stretch by contraction of smooth muscle. Stretch of vascular wall allows increased movement of calcium ions from ECF to cells, causing them to contract. Contractions prevent overdistention of vessels and at the same time by raising vascular resistance prevent excessive increase in renal blood flow and GFR when arterial pressure increases. High protein intake and increased blood glucose also increases renal blood flow and GFR.

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