What is the first step in urine formation?
It is the filtration of large amounts of fluid through glomerular capillaries into Bowman's capsule-almost 180 liters each day
What are glomerular capillaries relatively impermeable to?
To proteins (so the filtered fluid called glomerular filtrate is essentially protein free and devoid of red blood cells)
What are the concentrations of other constituents of glomerulra filtrate?
Including most salts and organi molecules (which are similar to the concentrations in plasma)
What is the GFR determined by?
1) balance of hydrostatic and colloid osmotic forces acting across capillary membrane 2) capillary filtration coefficient (Kf), the product of permeability and filtering surface area of capillaries
Why do the glomerular capillaries have a much higher rate of filtration than most other capillareis?
Because of a high glomerular hydrostatic pressure and a large Kf
What is the GFR in the average adult human?
It is about 125 ml/min or (180 L/day)
What is the fraction of renal plasma flow that is filtered (filtration fraction)?
It averages about 0,2, which means that about 20% of plasma flowing through kidney is filtered through glomerular capillaries
How is the filtration fraction calculated?
Filtration fraction=GFR/Renal plasma flow
Which are the layers of glomerular capillary membrane?
1) endothleium of capillary 2) basement membrane 3) layer of epithelial cells (podocytes) surrounding outer surface of capillary basement membrane (all these layers make together up the filtration barrier)
What is the 1) capillary endothelium perforated by?
Thousands of small holes called fenestrae (which are large), but endothelial cell proteins are richly endowed with negative charges that hinder the passage of plasma proteins
What is surrounding the endothelium of capillary?
A basement membrane, which consists of collagen and proteoglycan fibrillae (basement membrane prevents filtration of plasma proteins because of strong engative electrical charges associated with proteoglycans)
What are podocytes?
They are encircling the outer surface of capillaries. The foot processes are separated by gaps called slit pores through which the glomerular filtrate moves
What do epithelial cells also have?
They have negative charges, providing additional restriction to filtration of plasma proteins
As a summary, what do all layers of glomerular capillary wall provide?
A barrier to filtration of plasma proteins
What happens as the molecular weight of molecule approaches that of albumin?
Filterability rapidl ydecreases, approaching zero
Why is albumin restricted from filtration?
BEcause of its negative charge and electrostatic repulsion exerted by negative charges of glomerular capillary wall proteoglycans
What is minimal change nephropathy?
In certain kidney diseases, the negative charges on basement membrane are lost even before there are noticeabel changes in kidney histology
What does lead to minimal change nephropathy?
It is believed to be related to an immunological response with abnormal T-cell secretion of cytokines that redue anions in the glomerular capillary or podocyte proteins
What does minmial change nephropathy lead to?
As a result of loss of negative charges on basement membranes, some albumin are filtered and appear in the urine
When is minimal change nephropathy most common?
In young children but can also occur in adults, especially in those who have autoimmune disorders
What is GFR determined by?
1) sum of hydrostatic and colloid osmotic forces across glomerular membrane which gives the net filtration pressure and 2) glomerular Kf
Expressed mathematically, the GFR equals what?
It equals the product of Kf and the net filtration pressure (GFR=Kf * Net filtration pressure)
Net filtration pressure represents the sum of what?
Sum of hydrostatic and colloid osmotic forces that either favor or oppose filtration across glomerular capillaries
Which are the forces included in net filtration pressure?1
1) hydrostatic pressure inside glomerular capillaries (glomerular hydrostatic pressure, PG)
Which are the forces included in net filtration pressure?2
2) hydrostatic pressure in Bowman's capsule PB outside the capillaries, which opposes filtration
Which are the forces included in net filtration pressure?3
3) colloid osmotic pressure of glomerular capillary plasma proteins PIG, which opposes filtration
Which are the forces included in net filtration pressure?4
4) colloid osmotic pressure of proteins in Bowman's capsule PIB, which promootes filtration
How can GFR be expressed?
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What are the values of the determinants of GFR?
Forces favoring filtration (mm Hg): Glomerular hydrsotatic pressure 60, Bowman's apsule colloid osmotic pressure 0, Forces opposing filtration: Bowman's capsule hydrostatic pressure 18, and Glomerular capillary colloid osmotic pressure 32
What is the net filtration pressure considering the values that are from the previous card?
Net filtration pressure=60-18-32=+10 mm Hg
What can happen with the determiants of GFR?
They can change markedly under different physiological conditions, whereas others are altered mainly in disease states, as discussed later
What is Kf?
It is a measure of product of hydraulic conductivity and surface area of glomerular capillaries, Kf cannot be measured directly, but it is estimated experimentally by dividng the rate of glomerular filtration by net filtration pressure: Kf=GFR/Net filtration pressure
Because the total GFR for both kidneys is about 125 ml/min and net filtration pressure is 10 mm Hg, the normal Kf is calculated to be what?
About 12,5 ml/min/mm Hg of filtration pressure
What do some diseases do with Kf?
They can lower the Kf by reducing the number of functional glomerular capillaries (thereby reduing the surface area for filtration) or by increasing the thickness of glomerular capillary membrane and reducing its hydraulic conductivity
What do chronic, uncontrolled hypertension and diabetes mellitus do?
It reduces Kf by increasing the thickness of glomerualr capillary basement membrane and eventually by damaging the capillaries so severely that there is loss of capillary function
How is net filtration rpessure (10 mmHg calculated)?
Net filtration pressure=Glomerular hydrostatic pressure 60-Bowman's capsule pressure 18 - Glomerular oncotic pressure 32 mm Hg (so basically it is minus minus minus, and Bowman is in the middle)
What does an increased Bowman's capsule hydrostatic pressure do?
It decreases GFR
What is a reasonable estimate for Bowman's capsule pressure in humans about?
18 mm Hg under normal conditions, and an increase in hydrostati pressure in Bowman's capsule reduces GFR, whereas decreasing the pressure raises GFR
When can Bowman's capsule pressure increase markedly, causing serious reduction of GFR?
In certain pathological states, associated with obstruction of urinary tract (for example precipitation of calcium or of uric acid may elad to stones lodging in urinary tract in ureter, thereby obstructing outflow or urinary tract and raising Bowman's capsule prssure, reducing GFR and causing hydronephrosis
What is hydronephrosis?
Distention and dilation of renal pelvis and calyces, and can damage or even destroy teh kidney unless the obstruction is relieved
What happens as blood passes from afferent arteriole through glomerular capillaries to efferent arterioles?
The plasma protein concentration increases about 20% percent because 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 glomerualr capillareis is 28 mm Hg, this value usually rises to what?
To about 36 mm Hg by the time the blood reaches the efferent end of capillaries (from afferent end)
The average colloid osmotic pressure of glomerular capillary plasma proteins is what?
It is midway between 28 and 36 mm Hg, or about 32 mm Hg
Which are the two factors that influence the glomerular capillary colloid osmotic pressure?
1) arterial plasma colloid osmotic pressure and 2) fraction of plasma filtered by glomerular capillaries (filtration fraction). SO increasing the arterial plasma colloid osmotic rpessure raises the glomerular capillary colloid osmotic pressure, which in turn decreases GFR
What does also raise glomerular colloid osmotic pressure?
By increasing the filtration fraction, it concentrates the plasma proteins and raies glomerualr colloid osmotic pressure (filtration fraction=GFR/renal plasma flow, so filtration fraction can be increased by raising GFR or by reducing renal plasma flow)
With increasing renal blood flow, what happens?
It causes a slower rise in glomerular capillary colloid osmoti crpessure and les inhibitory effect on GFR, so it increases the GFR
What is the glomerular capillary hydrostatic pressure value?
60 mm Hg
Increases in glomerular hydrostatic pressure does what?
It raises the GFR, whereas decreases in glomerular hydrostatic pressure reduce the GFR
Glomerular hydrostatic pressure is determined by what?
By three variables, each of which is under physiological control: 1) arterial pressure 2) afferent arteriolar resistance and 3) efferent arteriolar resistance
What do increased arterial pressure tend to do?
It tends to raise glomerular hydrostati pressure and therefore increase the GFR
Increased resistance of afferent arterioles tends to do what?
It reduces glomerular hydrostatic pressure and decreases the GFR
What does dilation of afferent arteriole sdo?
It increases both glomerular hydrostsatic pressure and GFR
What does efferent arteriolar constriction have for effect on GFR?
It has a biphasic effect on GFR, at moderate levels of constriction there is a slight increase in GFR, but with serere constriction there is a decrease in GFR
To summarize, constriction of afferent arterioles does what?
It causes constriction of afferent arterioles reducing GFR (glomerular filtration rate ml/min)
What is the combined blood flow through both kidneys?
It is about 22% percent of cardiac output
Tell about the fraction of oxygen consumed by kidneys?
It is related to the high rate of active sodium reabsorption by renal tubules, if renal blood flow and GFR are reduced and less sodium is fitlered, less sodium is reabsorbed and less oxygen is consumed, therefore, renal oxygen consumption varies in proportion to renal tubular sodium reabsorption which in turn is related to GFR and rate of sodium filtered
Which are the determinants of renal blood flow?
It is determined by pressure gradient across renal vasculature (difference between renal artery and renal vein hydrostatic pressure), divdied by total renal vascular resistance: (Renal artery pressure-Renal vein pressure)/(Total renal vascular resistance)
What does renal artery pressure equal about?
About systemic arterial pressure and renal vein pressure averages about 3 to 4 mm Hg under most conditions
Total vascular resistance through kidneys is determined by what?
By the sum of resistances in individual vasculature segments, including arteries, arterioles, capillaries and veins
Most of renal vascular resistance resides where?
IN three major segments: interlobular arteries, afferent arterioles and efferent arterioles (resistance of tehe vessels is controlled by sympathetic nervous system, various hormones and local internal renal control mechanisms)
An increase in resistance of any of t he vascular segments (interlobular arteries, afferent arterioles and efferent arterioles) tend to do what?
Tends to reduces renal blood flow, whereas a decrease in vascular resistance increases renal blood flow (just look at the formula, RENAL PRESSURE DIFFERENCE/TOTAL RENAL VASCULAR RESISTANCE)
What is autoregulation?
It is a process where kidneys have effective mechanisms for maintaining renal blood flow and GFR relatively constant over an arterial pressure range between 80 and 170 mm Hg
Which are the determinants of GFR that are most variable and subject to physiological control?
Glomerular hydrostatic pressure and glomerular capillary colloid osmotic pressure (these variables, in turn are influenced by sympathetic nervous system, hormones and autacoids which are vasoactive substances released in kidneys and act locally)
What does a strong sympathetic nervous sytem activation do?
It decreases GFR
What are essentially all blood vessels of kidneys, including afferent and efferent arterioles innervated by?
By sympathetic nerve fibers, so astrong activataion of renal sympathetic nerves constrict the renal arterioles and decrease renal blood flow and GFR, whereas moderate or mild stimulation has little influence on renal blood flow and GFR
What is most important in reducing GFR during severe, acute disturbances lasting for a few minutes to a few hours, such as those leicited by defense reaction brain ischemia or severe hemorrhage?
Renal sympathetic nerves
Which hormones constrict afferent and effernt arteriols, causing reductions in GFR and renal blood flow?
Norepinephrine and epinephrine
What is another vasoconstrictor?
Endothelin, which can be released by damaged vascualr endothelial cells of kidneys, as well as by other issues, which contribute to hemostasis (minmizing blood loss) when a blood vessel is severe
What do nitric oxide and prostaglandins do?
They counteract the vasoconstrictor effects of angiotensin II in the blood vessels
Efferent arterioles however are highly sensitive to angiotensin II, because angiotensin II constricts efferent artioles increaed angiotensin II levels do what?
Increased angiotensin II levels raise glomerular hydrostatic pressure while reducing renal blood flow (angiotensin II formation occurs when there is decreased arterial pressure which tend to decrease GFR), so angiotensin II prevents decreases in glomerular hydrostatic pressure and GFR
What does induced constriction by angiotensin II increase?
It increases tubular reabsorption of sodium and water, which helps restore blood volume and blood pressure
What can angiotensin II effect on GFR be summarized as?
<-> but prevents lower GFR, (it prevents lower GFR when arterial pressure becomes low, because low arterial pressure means lower GFR)
What does nitric oxide production appear to be importanta for?
For maintaining vasodilation of kidneys because it allows kidneys to excrete normal amouts of sodium and water (therefore administration of drugs that inhibit formation of nitric oxide inreases renal vascular resistance and decreases GR and urinary sodium excretion, eventually causing high blood pressure)
What do prostaglandins (PGE2 adnd PGI2) and bradykinin do?
They decrease renal vascular resistance and tend to increase GFR
What effets do prostaglandins and bradykin have?
They may dampen renal vasoconstrictor effects of sympathetic nerves or angiotensin II, especially their effects to constrict the afferent arterioles
WHat effects do prostaglandins have?
By opposing vasoconstriction of afferent arterioles, the prostaglandins may help prevent excessive reductions in GFR and renal blood flow
What does aspirin cause?
Under stressful conditions, such as volume depletion or after surgery, the administration of nonsteroidal antni-inflammatory agents such as aspirin thati nhibit prostaglandin synthesis may cause significant reductions in GFR
Tell about GFR and its effects?
GFR is about 180 L/day and tubular eabsorption is 178,5 L/day leaving 1,5 L/day of fluid to be excreed in urine (in absence of autoregulation a small increase in blood pressure from 100 to 125 mm Hg would cause a 25% percent increase in GFR from about 180 to 225 L/day, if tubular reabsorption remained constant at 178,5 L/day the urine flow would increase to 46,5 L/day
Changes in arterial pressure exert much less of an effect on urine volume for what reasons?
1) renal autoregulation prevents large changes in GFR that would otherwise occur, and 2) there are additional adaptive mechanisms in the renal tubules that cause them to increase their reabsorption rate when GFR rises, a phenomenon referred to as glomerulotubular balance (discussed in chapter 28, so when GFR rise leads to increase in reabsorption rate)
What effects does do changes in arterial pressure have on renal excretion of wataer and sodium?
This si referred to as pressure diuresis or pressure natriuresis, so it is when arterial pressure have significant effects on renal excretion fo water and sodium
Special feedback mechanism (tubuloglomerular feedback mechanism) linking changes in sodium chloride concentration at macula densa with control of renal arteriolar resistance (efferent or affernt) and autoregulation of GFR helps what?
Ensures that a relatively constant delivery of sodium chloride to the distal tubule and helps prevent spurious fluctuations in renal excretion that would otherwise occur
What is acting in tubuloglomerular feedback mechanism?
Two components are acting to control GFR 1) afferent arteriolar feedback mechanism and 2) efferent arteriolar feedback mechanism (and these both mechanisms depend on special anatomical arrangements of the juxtaglomerular complex)
What does the juxtaglomerular complex consist of?
It consists of a macula densa cells in the initial portion of distal tubule and juxtaglomerular cells in walls of afferent and efferent arterioles
What is macula densa?
It is a specialzied group of epithelial cells in distal tubules that come in close contact witwh afferent and effent arterioles containing Golgi apparatus)
What does decreased macula densa sodum chloride cause?
It causes dilation of afferent arterioles and increased renin release
A decreased GFR does what?
It slows the flow rate in loop of Henle, causing increased reabsorption of percentage % of sodium and chloride ions delivered to ascending loop of Henle, thereby reducing the concentration of sodium chloride at macula densa cells, this decrease in sodium chloride concentration initiates a signal from macula densa that has two effects
Which are the two effects of macula densa?
1) it decreases resistance to blood flow in afferent arterioles raising glomerular hydrostatic pressure and returning GFR toward normal AND 2) it increases renin release from juxtaglomerualr cells of afferent and efferent arterioles, which are the major storage sites for renin
What is myogenic mechanism?
It is another mechanism that contributes to maintenance of a relatively constant renal b lood flow and GFR is the ability of individual blood vessels to resist stretching during increased arterial pressure
Explain myogenic mechanism further?
Stretch of vascular wall allows increased movement of calcium ions from extracellular fluid into cells causing them to contract through mechanisms discussed in chapter 8, and this contraction prevents excessive stretch of vessel and at the same time, by raising vascular resistance, helps prevent excessive increases in renal blood flow and GFR when arterial pressure increases
What happens when we ingest protein?
Level of amino acids increases, proximal tubular amino acid reabsorption increases, proximal tubular NaCl reabsorption increases, Macula densa NaCl decreases, Afferent arteriolar resistance decreases, and GFR then increases