Kidney and GFR Flashcards
(42 cards)
1
Q
Glomerular Filtrate and Urine
A
Glomerular filtrate and urine have different composition–> get this through tubular reabsorption and tubular secretion
- filtrate formed in the nephron: glomerular filtrate
2
Q
Glomerulus
A
- Glomerular capillaries have an endothelium that is fenestrated
- Podocytes are epithelial cells covering the glomerular capillaries
- Filtration membrane (basement membrane) lies in between the podocytes and the capillary endothelium
- Mesangium is a supporting tissue consisting of mesangial cells and matrix
3
Q
The Filter Components of Glomerular Filtration
A
- Three layers that act as a filter
1. Single layer of endothelial cells lining the glomerular capillaries (containing fenestrations): this restricts the passage of blood cells
2. Glomerular basement membrane: lies between the endothelium and the visceral layer of the capsule (NEGATIVELY CHARGED) - main filtration barrier
- negatively charged, repels - charged things (such as proteins!)
3. single layer of the epithelial cells (called podocytes) lining Bowman’s capsule: phagocytose macromolecules and resitricts passage of medium sized proteins
FILTRATE WITHIN THE BOWMANS CAPSULE IS ESSENTIALLY PROTEIN FREE
-contains all the substances present in plasma in approximately the same concentration (freely filtering ions, etc.)
exceptions: some low molecular weight substances that are bound to proteins (e.g. plasma fatty acids, plasma calcium)
4
Q
Molecular Weight cut off for glomerular capillaries
A
- Molecular size is the main determinant of whether a substance will be filtered or retained within capillaries
- MW cut-off: 70,000 Da
- freely permeable to molecules: <7000 Da
5
Q
Charge and Filtration
A
- cations are more readily filtered than anions for the same molecular radius
- Serum albumin has a radius of about 3.5 nm (69000Da) but its negative charge prevents filtration
- Albumin has a slightly larger shape and is negatively charged, VERY little gets through (as it is a main plasma protein)
- DON’T WANT TO SEE PROTEIN IN URINE
- In many disease processes, the negative charge on the filtration barrier is lost so that proteins are more readily filtered –> Proteinuria
6
Q
Forces behind Glomerular filtration
A
- Capillary filtration is determined by opposing forces
- Hydrostatic Pressure difference across the capillary wall favours filtration
- protein concentration across the capillary wall which determines oncotic pressure opposes filtration
- mostly have hydrostatic pressure, but sometimes a bit of pressure going back into blood due to charge of water
7
Q
GFR
Glomerular Filtration Rate
A
volume of fluid filtered from glomeruli into Bowman’s space per unit time (oftern per minute)
-SO important to have the kidneys in homeostasis, needs to be tightly controlled
Affected by:
- Hydrostatic BP within glomerular capillaries is the main determinant of GFR
- Actions of mesangial cells (irregular shaped stellate cells lying between the glomerular capillaries: equivalent to vascular smooth muscle)
- Control of renal blood flow
8
Q
Mesangial Cells
A
- capable of contraction in response to:
- angiotensin II (ang II): increases mesangial cell contraction
- anitdiuretic hormone (ADH)
- noradrenaline (NA) -sympathetic innervation
- mesangial cell contraction will reduce flow to glomerular capillaries and in turn reduce GFR
- intraglomerular mesangial cells- have some phagocytotic activity
- extraglomerular mesangial cells (Lacis cells): found at vascular pole and are part of the JGA
9
Q
Renal Blood Flow
A
- pressure in the renal artery is approximately equal to systemic BP
- most vascular resistance in the kidneys derives from changing the diameter of the arterioles and small arteries (Control flow into the tubules and glomerulus)
- interlobular arteries (smallest)
- afferent arterioles
- efferent arterioles
-
resistance controlled by
i) sympathetic nervous system
ii) hormones
iii) local mechanisms (e.g. autoregulation)
Renal Blood Flow (Q) = Afferent- Efferent arteriolar pressure (delta P)/Resistance (R)
Controlling resistance is really key to how much blood flow you are getting
10
Q
Hormones causing vasocontriction and changes in GFR
A
- angiotensin II
- noradrenaline
- adrenaline
- Depends on how you want to affect GFR
- Large amount of vasoconstricters and constrict efferent and afferent, send BP back to central system
11
Q
Renin angiotensin system (RAS)
A
- Ang II preferentially constricts efferent arterioles
- Really on efferent in terms of GFR
- low concentrations of Ang II cause constriction of the efferent arteriole maintaining glomerular hydrostatic pressure and GFR when renal perfusion pressure falls below normal
- High concentrations of ang II cause constriction of both efferent and afferent arterioles
12
Q
Vasodilators of Efferent and Afferent arterioles
A
- hormones that cause vasodilation (thus increase renal blood flow and GFR)
1. Prostaglandins (PG’s):
2. PGE2
3. prostacyclin (PGI2) - work on the afferent in particular
- Ang II stimulates the synthesis of renal PG’s, PGE2 and PGI2
- This local production of PG’s counteracts the vasoconstrictive effect of ang II
- Example of negative feedback to fine tune the response
13
Q
Autoregulatory Hormones of the Kidney
A
- Prostaglandins
- Resin
- Regulation is completely intrinsic
- -different to others as it is INTRINSIC to the kidneys, doesn’t rely on other regulation from NS
- Autoregulation is virtually absent below 70mmHg (normally operates between 80-180 mmHg) - ** IMPORTANT TO KNOW- if you drop below this, autoregulation will not occur properly
14
Q
Myogenic Hypothesis
(autoregulation theory)
A
- When arterial pressure increases the renal afferent arteriole is stretched
- Pressure stretches it, and causes response from stretch sensors and causes constriction to return flow to normal
- Vascular smooth muscle responds by contracting and thus increasing resistance (increase of vascular tone)
15
Q
Tubuloglomerular feedback
(autoregulation theory)
A
- Alteration of tubular flow (or a factor in the filtrate) is sensed by the macula densa of JGA and produces a local signal that alters GFR
- Increase GFR, increase filtration coming through –> sensed by macula densa in vascular pole (prostaglandins are then produced locally)
16
Q
Clearance
A
- volume of plasma from which a substance is completely removed by the kidney in a given amount of time (usually a minute)
- clearnace for urea in humans is 65ml/min
- that means that the kidney removes all of the urea from 65ml of plasma in one minute
17
Q
Renal Plasma Flow
A
- In humans every minute approximately 625 ml of plasma goes into the kidney
- This is renal plasma flow
- Some of the fluid leaves the kidney in the plasma while some of it leaves the kidney as urine
- To end up in urine, it is either:
- filtered at the glomerulus and then not reabsorbed
- or the substance is not filtered but is secreted by the peritubular capillaries into the tubules
- In either instance, the substance ends up in the collecting duct and is excreted into urine
18
Q
GFR value and clearance
A
- Of the 625 ml/min (afferent arteriole) of plasma that goes to the glomerulus, 125ml/min are filtered into Bowman’s Capsule forming the filtrate (this is the glomerular filtration rate GFR)
- The remaining 500 ml/min remain in the blood and enter the peritubular capillaries (efferent arteriole)
- Of the 125 ml/min filtered, almost all of the water in this fluid is reabsorbed and put back into the blood (about 120ml is reabsorbed)
19
Q
Inulin
A
- Only the plasma that is filtered is cleared of inulin
- The clearance of inulin is therefore equal to the amount of plasma filtered in a minute
- same as GFR: 125 ml/min
- therefore clearance of inulin is equal to GFR
- freely filtered, not reabsorbed, and not secreted
- Measurement of the clearance of inulin allows one to determine the GFR and whether the kidneys are filtering properly
- Can measure appearance in urine or disappearance in circulation
20
Q
Clearance Equation
A
- The clearance also represents the volume of plasma that hypothetically would be returned to the circulation completely free of N
- Clearance of substance N= (concentration of N in urine) x (urine flow rate)/ concentration of N in plasma
Cn= (Un) x V/(Pn)
- this can be used to calculate the renal clearance for any substance
- BUT, only when the substance used is freely filtered and neither reabsorbed nor secreted will the renal clearance be a measure of GFR
21
Q
Glucose
A
- like inulin, glucose is freely filtered
- but, no glucose usually appears in urine as glucose is completely reabsorbed as it passes through the tubules
- no glucose is excreted in urine, therefore the clearance value is 0. Completely reabsorbed into circulation even though it is freely filtered
- clearance of glucose is therefore 0 ml/min
- this would be true for any substance that is completely reabsorbed
22
Q
Para amino hippuric acid (PAH)
A
- PAH is freely filtered, not reabsorbed and is completely secreted by the kidney
- Thus all the PAH entering the kidney ends up in the urine:
- the PAH that is filtered
- and that which is not filtered
-ALL SECRETED
- this means that all the PAH entering the kidneys would be cleared
- Since the renal plasma flow is 625 ml/min in a normal kidney, the clearance of PAH must be 625 ml/min
- PAH clearance is equal to renal plasma flow
- Can be used to be compare adequate flow in the kidneys
23
Q
Creatinine Clearance
A
- Creatinine is the breakdown product of creatinine phosphate found in muscle
- Creatinine is usually at a steady state concentration in the blood and it is freely filtered by the glomerulus (some active secretion in very small amounts): overestimates GFR by 10-20%
- Unlike precise GFR measurements involving constant infusions of inulin, as creatinine is already at a steady state in the blood, measuring the creatinine clearance is much more cumbersome
- As an endogenous substance it does have limitations, as it can be altered (heavy exercise)
- Blood urea nitrogen and serum creatinine also give an indication of renal (kidney) health
24
Q
Active Reabsorption
A
-
Gradient Time maximum: the magnitude of the gradient varies inversely with rate of flow of tubular fluid (e.g. Sodium)
- i.e. the slower the flow the bigger the gradient, the more reabsorption or secretion you get - Those with a Transport Maximum (Tm): Anything with a Tm has a carrier process and can get SATURATED and a maximum is reached when all carriers are occupied
- if a substance is in excess of the Tm, the excess cannot be reabsorbed and will be excreted in urine
* Case of proximal convoluted tubule if there is too much glucose : diabetes
25
Transport-limited transport mechanisms
* **Tm for reabsorption:** glucose and many other monosaccharides, many aa's, uric acid, phosphate, and sulphate ions
* **Tm for secretion**: penicillin, certain diuretics, salicylate, para-amino-hippuric acid (PAH) and thiamine (vitamin B1)
26
Glucose filtering in the kidney and Tm
Glucose is freely filtered so the more you increase the more it gets filtered, but it all gets reabsorbed until it reaches transporter limit (SATURATION) --\> hits a plateau. Everything above the green line is then EXCRETED. Cant be reabsorbed so it goes into urine
**Tm is about 375 mg/min**
**-and will start to be excreted above the threshold of 180 to 200 mg/dL**
--\> see in diabetes mellitus
27
How does the kidney vary water and electrolyte excretion?
* by altering
- glomerular filtration
- tubular reabsorption
- tubular secretion
28
renal sodium regulation
* Being of **low molecular weight** sodium (Na+) is freely filtered at the glomerulus
* Like water, most of the sodium that is filtered is reabsorbed (99.4%) during passage through the nephron
* **Most renal energy is utilised in accomplishing this reabsorption**
* most of the E in the kidney is used to compensate reabsorption
* **The bulk of water and sodium reabsorbtion: 67% occurs in the proximal convoluted tubule**
* Howerver the major controls of reabsorption are exerted on the collecting ducts
29
Sodium reabsorption and basolateral membrane
* Sodium reabsorption is a prmary active process dependent on **N****a/K-ATPase pumps**in the**basolateral membranes** of tubular epithelial cells and occurs in all four major tubular segments
1. proximal tubule
2. loop of Henle
3. distal convoluted tubule
4. collecting duct
* Key pump that is vital to sodium reabsorption, what kidney is spending its energy to do
* Sodium reabsorbtion back into circulation is dependent on this pump!
* **The major regulator of tubular sodium reabsorption is aldosterone**
30
Control of Aldosterone Synthesis
* The major regulator of tubular sodium reabsorption is the steroid hormone aldosterone
* Aldosterone stimulates sodium reabsorption in the late distal convoluted tubule and collecting ducts by stimulating the production of proteins involved in Na-K regulation
* Aldosterone is secreted by the zona glomerulosa cells of the adrenal cortex
* ALdosterone binds to MR (mineralocorticoid receptor) and there is a signal that goes to the nucleus to say we need more Na+/K-ATPase pumps
* result is more sodium being pumped (through ENaC) than K+ excreted (through ROMK)
31
Renin-Angiotensin-aldosterone system
* Macula densa recognizes NaCl (solutes) and then the kidney produces renin
* Angiotensinogen is circulated in the blood constantly
* Renin is an enzyme that turns angiotensinogen to Ang I
- and then get Ang I converted to Ang II in lungs
- Ang II causes release from Aldosterone release from Z. glomerulosa and causes a rise in EFL and Na retention
32
ANP
| (Atrial natuurietic peptide)
* **ANP (also know as ANF) promotes sodium excretion**
* Atrial naturietic peptide is secreted from cells in the cardiac atria in response to atrial stretch due to plasma volume
* Vasodilator
* Decreases aldosterone release
* Decreases renin release
* Reduces ENaC (sodium pump)
* Increase GFR
* Increased sodium loss
33
Renal Water Regulation
* Major control is via **ADH (Antidiuretic Hormone)** mediated control of **water reabsorbtion** in the _collecting ducts_
* Its effects are on the collecting duct, cannot reabsorb water into the collecting duct without ADH
* ADH secretion is controlled by:
- **hypothalamic osmoreceptors** (small change in plasma osmolarity leads large change in ADH release)
- **atrial volume receptors:** (\>5% decrease in ECFV increases ADH release)
34
ADH
* **ADH is essential for life**
* ADH causes the insertion of water permeable channels into the late DCT and collecting duct of the nephron
* Without these channels, the duct remains impermeable to water, which cannot thereforebe reabsorbed
* The result is loss of copious hypo-osmotic urine, dehydration and loss of associated salts. Hence poor salt/water balance
* Plasma osmolarity will rise above normal levels
* ADH is released from the posterior pituitary after recieving signals from the hypothalamic receptors in the supraoptic nuclei (SON) and paraventricular nuclei (PVN)
* ADH will then go to the kidney collecting duct and input aquaporin 2 (this is all in response to increased plasma osmolality)
* By the time you encounter thirst, a lot of ADH has been released
* Binds to the ADH receptor and signals a cAMP cascade that tell storage vesicles containing aquaporins to fuse to the collecting duct basolateral membrane and reabsorb water
35
Vasopressor Actions of ADH
* ADH has vasopressor actions
* it constricts arterioles, which increases peripheral vascular resistance and raises arterial BP (mediated through the V1a receptor)
* These in particular become important in conditions of severe haemorrhage
* ADH secretion is depressed by alcohol!
36
Diabetes Insipidus and ADH
* **Diabetes Insipidus (DI)** is a condition characterized by **excessive thirst** and **excretion of large amounts of severely dilute urine** (reduction of fluid intake having no effect)
* _Central diabetes insipidus_ involves a deficiency of ADH from posterior pituitary
* _Nephrogenic Diabetes Insipidus_ is due to an insensitivity of the kidneys nephrons to ADH
* Treatment of central diabetes insipidus is by admin. of ADH-like analogue: DDAVP
37
Renal Potassium Regulation
* Potassium like water and sodium is freely filtered at the glomerulus
* Potassium also undergoes both **reabsorption and secretion**
* Secretion of potassium occurs in the collecting duct in return for the absorption of sodium (principle cells) --\> **basolateral NaK-ATPases** maintain the high intracellular concentration of K+ in tubular epithelial cells and this allows K+ to pass through specific potassium channels into the tubular fluid
* **Changes in plasma [K+] _directly_ affects aldosterone secretion (a difference to Na+)**
* If there is too high of plasma K+ then aldosterone will increase the excretion of potassium rather than just sodium reabsorb.
38
Transport Processes: Proximal Convoluted Tubule
* 65-70% of filtered Na+ and water is reabsorbed in this segment
* Na+ is reabsorbed by:
1. active transport
2. coupled transport to: glucose (symport) and aa's
3. passive diffusion
4. Na+ -H+ exchange (antiport) **\* acid base lectures**
* ****filtered bicarbonate reabsorbed from lumen
* chloride and potassium ions are passively absorbed
* **All revolves around sodium K ATPase pump**
39
Transport Processes: descending Loop of Henle
* Na+ and Cl- are **NOT** reabsorbed
* this region of the loop of Henle is impermeable to electrolytes
* Segment is freely permeable to H2O
* Na+ and Cl- are concentrated in the lumen
40
Trasnport Processes within thick ascending loop of Henle
* 25% of filtered Na+ is reabsorbed in this segment
- this segment is impermeable to water
- Na+, K+ and Cl- are coupled and actively transported out of the lumen (symport)
- Ca2+ and Mg2+ are passively reabsorbed (paracellular route)
--\> Loop diuretics, think about electrochemical gradient created
-luminal fluid is hypotonic as it leaves this segment
41
Transport processes within the Distal Convoluted Tubule
* At this point, have reabsorbed most of the Na and water concentration
* 4% of filtered Na+ is reabsorbed in this segment (remainder)
* Cl- is transported with Na+ (symport)
* Ca2+ reabsorbtion --\> role of parathyroid hormone during calcium imbalance
* the tubule epithelium is impermeable to water- leads to further dilution of tubular urine
42
Transport Processes within the late distal tubule and collecting ducts
* 4% of filtered Na+ is actively reabsorbed in this segment
* K+ and H+ are actively secreted
* an increase in Na+ load reaching this segment tends to increase K+ and H+ secretions as Na+ is reabsorbed
* aldosterone acts on this segment to increase Na+ absorbtion and K+ excretion
* **water is reabsorbed only if ADH is present**
* sodium and water conservation through aldosterone and ADH (vasopressin) are independent but often linked!
