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Functions of the kidney

Bioactive (Excretion of bioactive substances e,g hormones and drugs)

Metabolic waste (Excretion of metabolic waste)

Water and electrolytes (Regulation of water and electrolyte balance)
Gluconeogenesis (most in liver, but some in kidneys)

RBC production (erythropoeitin produced in kidneys)

Arterial BP (Regulation of BP)

Vitamin D (Regulation of Vit D production)
Gross anatomy of kidneys
Pg 4
What is the renal corpuscule?
- Consists of the glomerulus and the Bowman's capsule

What is the filtration barrier of the renal corpuscle
- The barrier which all filtered substances must pass through 

1) The fenestrae of the glomerular capillary endothelial layer
- Freely permeable to everything in the blood except RBC and platelets

2) Capillary basement membrane

3) Slit diaphragms between the podocyte foot processes

- This permits filtration of large volumes of fluid from the capillaries into the Bowman's space but restricts filtration of large plasma proteins such as albumin
Draw the renal corpuscle and tubules
FIgure 1-2 Pg 6

Bowman's capsule

Proximal convoluted tubule
Proximal straight tubule
Descending thin limb
Ascending thin limb
Thick ascending limb
Distal convoluted tubule
Connecting tubule
Cortical collecting duct
Medullary collecting duct
Pathway for fluids flowing within a nephron
-Starts in the cortex (Bowman's capsule)
-Descends into the medulla (descending limb)
- Returns to cortex (thick ascending limb)
-Passes into medulla again (Medullary collecting tubule)

- Ends in a renal calyx, which is continuous with the ureter
The urine is not altered after it enters the ..?
Renal calyx
Blood supply to the nephrons (cortex)
- Blood enters each kidney via the renal artery -> interlobar artery -> arcuate artery -> interlobular/cortical radial artery

Arterioles will branch off from the interlobular arteries, leading to the glomerulus (afferent arterioles)

- Afferent arterioles -> glomerulus -> efferent arterioles

- Efferent arterioles will subdivide to becomes the peritubular capillaries 

- These arteries and glomeruli are only found in the cortex, never in the medulla

Difference between vasa recta and peritubular capillaries
peri =around; tubular =tube; recta =parallel

so peritubular capillaries are capillaries that encircle a tube found in the cortex and carry blood away from the kidney

while vasa recta are parallel arteries found in the medulla and function in carrying blood to the kidney
How much of the plasma entering the glomerulus is filtered by the Bowman's capsule?
- 20% of the plasma (and non of the erythrocytes) entering the glomerulus is filtered from the glomerulus into the Bowman's capsule

- 80% will flow on to the next vascular segment
Blood supply to the nephrons (Medulla)
- Medulla receives much less blood than the cortex

- No glomeruli in the medulla

- In contrast to the efferent arterioles of the coretex, those from the juxtamedullary glomeruli do not branch into peritubular capillaries, but descend downward into the outer medulla, where they divide to form the descending vasa recta

- Only the centermost vasa recta supplies capillaries in the inner medulla, so limited blood flows into the papilla

- The capillaries from the inner medulla reform into ascending vasa recta taht run closely to the descending vasa recta; hence in addition to being conduits for blood, the vasa recta also participates in exchange of water and solutes between plasma and interstitium

FIgure 1-6 Page 14

The juxta-glomerular apparatus
- The area of the late thick ascending limb where it comes between the afferent and efferent arterioles at the glomerulus

- Contains 3 types of cells:

1) Juxtaglomerular (JG) cell
- Secrete renin

2) Extraglomerular mesangial cells (EGM)
- Continuous with the glomerular mesangial cells but lie outside the Bowman's capsule

3) Macula densa cells
- Detectors of luminal content of the nephron at the very end of the thick ascending limb
-Contributes to the control of GFR and control of renin secretion
Innervation of the kidneys
- Mainly innervated by sympathetic neurons

- No significant parasympathetic innervation
Definition of filtration
- Process by which water and solutes in the blood leave the vascular system through the filtration barrier and enter Bowman's space

Figuer 1-7 Page 16
Definition of secretion
- Process of moving substances into the tubular lumen from the cytosol of epithelial cells that form the walls of the nephron
Definition of reabsoprtion
- Process of moving substances from the lumen across the epithelial later into the surrounding interstitium

- Usually the reabsorbed substances then move from the interstitium into surrounding blood vessels
Definition of excretion
- Exit of the substance from the body
What are freely-filtered substances?
- Substances that are present in the filtrate at the same concentration as in the plasma

- The glomerular filtrate is very much like bloodplasma; but it contains bery little total protein as they are large 

- Among the freely filtered substances are sodium, potassium, chloride, bicarbonate; glucose and urea, insulin and ADH
Normal GFR in a young, healthy adult male?
- 180 L/day (125 mL/min)
Regulation of renal function
- From neural and hormonal input

- Neural signals originate in the sympathetic celiac plexus. SNS signals exert major control over RBF, GFR and the release of vasoactive substances (renin-angiotensin system)

- Hormonal signals originate in the:
a) Adrenal gland (adrenal cortex secretes aldosterone and cortisol; adrenal medulla secretes adr and noradr; all these hormones, mainly aldosterone, are regulators of sodium and potassium excretion by the kidney)
b) Pituitary gland (ADH: major regulator of water excretion, and via its influence on renal vasculature, sodium excretion as well)
c) Heart (heart secretes hormones and natriuretic peptides that contribute to signalling increased excretion of sodium by the kidneys)
What is the filtration segment
GFR/renal plasma flow
Total RBF determined by?
1) Mean pressure in the renal artery

2) Contractile state of the smooth muscle of the renal arterioles of the cortex

- Change in arteriolar resistance produces the same effect on RBF regardless of whether it occurs in the afferent or efferent arteriole; because these 2 vessels are in series, a change in either one has the same effect in total

- If the 2 resistances both change in the same direction, the effects on RBF is additive; if they change in different directions, they exert opposing effects on RBF
What is the selectivity of the glomerular filtration barrier to filtered slute dependant on?
Molecular size and electrical charge

1) Molecular size

- The filtration barrier poses no hindrance to movement of molecules with molecular weights less than 7,000 Da

- For molecules ranging from 7,000 to 70,000 Da, the amount filtered becomes progressively smaller as the molecule becomes larger

2) Electrical charge

- For any given size, negatively charged macromolecules are filtered less, and positively charged molecules are filtered more than neutralmolecules

- This is because the surfaces of all the components of the filtration barrier (cell coats of the endothelium, the bsaement membrane and cell coats of the podocytes) contain fixed polyanions which repel negatievly charged macromolecules 

- Because almost all plasma proteins bear net negative charges, this adds to the size restriction effect

- But negative charges in the filtration membranes act as a hindrance only to macromolecules and not to mineral ions or low-molecular-weight organic solutes
Factors affecting GFR
GFR = Renal plasma flow x filtration fraction

Renal plasma flow increased by: 
-Increased cardiac output
-Increased renal plasma flow (by afferent arteriole dilation) 
Filtration fraction increased by:
-Increased glomerular pressure (by increasing arterial BP or constricting efferent arteriole)
-Difference in Starling forces between glomerulus and Bowman's capsule 

Afferent arteriole controls glomerular flow, efferent arteriole controls glomerular pressure
Effects of GFR on salt and water excretion
Increased GFR will increase salt and water excretion
GFR and RBF autoregulation
- GFR is strongly influenced by arterial BP. Increased BP will cause increased salt and water excretion (pressure natriuresis). 
- So to protect the glomerular capillaries from hypertensive damage and to preserve a healthy GFR, there is autoregulation of the GFR.

- Within the range of normal MAP (~80-200 mmHg), RBF varies only modestly with changes in arterial BP. This is partly because of the myogenic response (very fast-acting, protects the glomeruli from short-term flucutations in BP) and partly by intrarenal signals.  

- Autoregulation of GFR also involves local production of PG in conditions where stron vasoconstriction might by itself reduce GFR and renal blood flow too much (high sympathetic stimulation and high levels of AT2). Intrarenal (autoregulatory) PG production opposes the actions of AT2 on kidneys (i.e PG causes vasodilation of arterioles and relaxation of mesangial cells). Inncreased local (intrarenal) AT2 assoc. with renin release and increased sympathetic input stimulate the production of PG. THe vasodilatory effect of PG dampens the efefct of AT2 and sympathetic input on renal arterioles and permits a reasonable but reduced blood flow and GFR to continue.

Intra-renal signals:
- Mainly by tubuloglomerular feedback. This is the feedback from the tubules back to the glomerulus (events in tubules cause changes in glomeruli). As the filtration rate in an individual nephron increase/decreases, the amount of sodium that escapes reabsorption in the proximal tubule and the loop of Henle also increases/decreases. More sodium filtered means more sodium remaining in the lumen and more sodium flowing through the thick ascending limb into the distal tubule. The macula densa senses the amount of sodium and chloride in the lumen, causing a change in the secretion of transmitter agents in the interstitial space that affect the filtration in the nearby glomerulus. High levels of sodium flowing past the macula densa causes a decrease in filtration rate, and vice-versa.

- The transmitter agents cause vasoconstriction of the afferent arteriole, thereby reducing the effective filtration coefficient.

- Autoregulation blunts/lowers the RBF and GFR responses to changes in BP, but does not totally prevent these changes
What is definition of general and specific renal clearance
- Both general and specific clearance can be defined as the volume of plasma per unit time from which all of a substance is removed

- General clearance from the whole body is often called the metabolic clearance rate, but clearance specifically done by the kidney is called renal clearance
How to calculate clearance?
C = UV/P
C = clearance

U = urine concentration

V = Urine volume

P = plasma concentration
Relationship between clearance, excretion rate and plasma concentration
Clearance = excretion rate divided by plasma concentration
What is inulin
- A polysaccharide that is freely filtered and neither reabsorbed nor secreted. All that is filtered is excreted. Therefore, the volume of plasma cleared per unit time is the same as the GFR. Inulin is the hallmark for measuring GFR because:

1) Its filterability. It moves into Bowman's space in the same proportion as the volume filtered.

2) It cannot move in either direction by the paracellular route around the tubular epithelium. THe tight junctions are too restrictive.

3) There are no transport mechanisms at the tubular epithelum to takek up inulin.

4) There are no enzymes (amylases) in the tubular lumen to break down inulin.

- So it is freely filtered, and all that is filtered moves through the nephron into the urine.
What is PAH (Para amino hippuric acid)
- It is a small water-soluble organic anion that is freely filtered and also avidly secreted by the proximal tubule epithelium. THe secretion rate is saturable (there is a max rate of PAH secretion into the tubule). But at low plasma concnetrations, about 90% of PAH entering the kidney is removed from the plasma and excreted in the urine. Its clearance, therefore, is nearly as great as the renal plasma flow. 

- PAH clearance is used as a measure of renal plasma flow (effective renal plasma flow; as the value is slightly less than the true renal plasma flow)
Relation between clearance and GFR
- If clearance of a substance equals GFR, there is no net reabsorption or secretion

- If clearance is more than GFR, there is net secretion

- If clearance is less than GFR, there is net reabsorption
What is gold standard to measure GFR
- Gold standard is to measure inulin clearance
How to calculate GFR using tracer (i.e inulin)?
GFR = U x V/P

U = urine conc of tracer

V = Urine volume

P = Arterial plasma concentration of tracer
Practical ways to measure GFR
- Creatinine clearance. Creatinine is an end product of creatine metabolism and is exported into the blood continuously by skeletal muscle. The rate is proportional to skeletal muscle mass. Creatinine is freely filtered and not reabsorbed. A small amount is secreted by the proximal tubule. So, the creatinine appearing in the urine represents the filtered and secreted component. Because of the secreted component, the creatinine clearance is slightly higher than GFR.

- The urine is collected for 24H, and a blood sample is taken during the collection period. BLood and urine are assayed for creatinine concentration, and apply the clearance formula

- For a patient with a very low GFR, the secreted component is relatavely larger fraction of the total amount excretedm so creatinine clearance more severely overestimates GFR in patients with very low GFR.
Measuring GFR from plasma creatinine
- This is d/t the fact that most excreted creatinine gains entry to the tubule by filtration. If ignore the small amount secreted, there is a good correlation between plasma creatinine concentration and GFR.

- Example on page 43 
Why a single plasma creatinine measurement is not accurate
1) Some creatinine is secreted

2) There is no way of knowing exactly what the person's original creatinine was when GFR was normal

3) Creatinine production may not remain completely unchanged

- But a rising plasma creatinine is a red flag that there is a renal problem
Why urea not accurate to measure GFR
- Urea also handled by filtration. But it is a much less accurate indicator for GFR because the range of normal plasma urea concentration varies widely, depending on protein intake and changes in tissue catabolism, and because urea excretion is under partial hormonal regulation.
What are barriers involved in secretion and reabsorption
- Solutes and water must cross 1) tubular epithelium and 2) the vascular endothelium

- In the cortex, the vascular endothelium (peritubular capillaries) is fenestrated. This offers virtually no resistance to the passive movement of water and small solutes. This means:
1) Overall transport is governed by events in the tubular epithelium rather than the vascular endothelium
2) The cortical interstitium has an osmolality and concentration of small solutes close to those in plasma. The interstitial composition changes when plasma composition changes.

- In the medulla, blood flow and transport events are less. Only some of the vasculature is fenestrated, meaning:
1) The overall transport depends on propoerties of both the vascular endothelium and tubular epithelium
2) The medullary interstitium is NOT plasma-like in composition

Ways to cross the tubular epithelium
1) Paracellular route (single step)

- The substance goes around the cells. (through the matrix between cells)

2) Transcellular route (two step process)

- More common

- Across the apical membrane facing the tubular lumen, then across the basolateral membrane facing the interstitium (2 step process)
- Diffusion is the frenzied random movement of free molecules in solution

- Net diffusion occurs across a barrier if there is a driving force (a concentration gradient or a potential gradient) and if the barrier is permeable

- Applies to substances taking the paracellular route around the tubular epithelium, and to some substances taking the transcellualr route through membranes

- Substances that are lipid soluble, such as blood gas or steroids, can diffuse directly through the lipid bilayer
Movement through channels
- Many substances cannot penetrate lipid membranes. To cross a membrane, they mux move through specific intergral membrane proteins (channels and transporters)

- Channels are small pores (proteins with a 'channel' through the interior of the protein) that permit water or specific solutes to diffuse through them i.e sodium/potasisum channels, aquaporin

- CHannels typically flicker open and close, so the permeability of a membrane containing many channels is proportional to the probability of their being open

- Movement through channels is passive (no energy required). The energy to drive the diffusion is inherent in the concentration or electrochemical gradient.

- Channels represent a mechanism for rapidly moving across membranes large amounts of specific substances, which would otherwise diffuse slowly or not at all.

- Many channels can be gated, meaning that the probability that the channel is open is incresae/decreased

- Many channels have phosphorylation sites such that phosphorylation either locks the channel shut or allows it to be gated by othe rmechanisms
Movement through transporters (general)
- Transporters like channels, permit tarnsmembrane flux of a solute that is otherwise impermeable in the lipid bilayer. Channels can move large amounts across the memvbrane in a short period of time, but many transporters have a lower rate of transport because the transported solutes bind much more avidly to the transport protein.
- Permit movement of a single solute species through the membrane.

- Basic difference between a channel and uniporter is that a channel is a tiny hole, whereas a uniporter requires the solute to bind to a site that is alternately available to one side and the other side of the membrane.

- Movement through a nuniporter is called facilitated diffusion. It is driven by concentration gradients.
Symporters and antiporters
- SYmporters and antiporters move 2 or more solutes in the same direction across a membrane (symporter) or in the opposite direction (antiporter).

- All molecular transport requires energy. In case of diffusion through a channel or uniporter, the energy is inherent in the electrochemical gradient for the solute. With symporters and antiporters, at least 1 of the solutes moves down its concentration gradient and provides the energy to move 1 or more of the other solutes up its electrochemical gradient. Movemeny of any solute up its electrochemical gradient is called active transport. In the case of symporters and antiporters that do not hydrolyze ATP, the active transport is called secondary active transport because the energy is provided indirectly from the transport of another solute rather than directly from a chemical reaction.

- Usually sodium is one of the solutes moved to provide energy
Primary active transporters
- These aremembrane proteins that are capable of moving 1 or more solutes up their electrochemical gradients, using the energy obtained from the hydrolysis of ATP. All transporters that move solutes in this manner are ATPasa (their structure is both that of an enzyme that splits ATP and a transporter that has binding sites)

- Among the key primary active transporters in the kidney is the Na-K-ATPase (usually called sodium pump)
Hydrostatic pressure, osmosis and oncotic pressure
- Hydrostatic presure (hydraulic pressure) drives the volume flux of filtration across the endothelial walls of glomerular capillaries.

- As long as solutes are equally permeable as water, they will move along with filtered water or reabsorbed water and have the same concentration in the filtrate as in the plasma. Solutes play a different role when a barrier is less permeable to solutes than to water.

- SOlutes dissolved in water reduce the concentration of water, and therefore, reduce the tendency of water to diffuse out of a solution. Solutions that are highly concentrated with solutes are lower in water concentration. Therefore, when solutions of different solute concentrations are separated by a barrier, water will move from the more silute solution to the more concentrated solution (from where the water is more concentrated to where the water is less concentrated). THis is called osmosis. 

- The ability of solutes to lower the concentratin of water is called osmolality. It is a function of the concentration of solutes and the kind of solutes.

- Osmolality is in units of osmoles per kg of water. Osmolality is same meaning as osmotic pressure.

- 'Water follows the osmoles'

- Osmolality is only effective in driving osmosis when the barrier is less permeable to solutes than to water. In the fenestrated endothelial barriers of glomerular capillaries and peritubular capilalries, most of the solutes are as permeable through the fenestrae as water, and thus do not influence water movement. However, the large plasma proteins are not permeable and influence water movement.
How to calculate osmolality
- Kwnogin the osmolality of a solution is impossible without measuring it

- Can get a rough idea of the osmolality from osmolarity.

- Osmolarity is the sum of the molar concentrations of all solutes without regard to kind.

E.g if a solution contains 140 mEq/L of sodium and 140 mEq/L of chloride, the osmolarity is 140 + 140 = 280 mOsm/L

- Osmolarity and osmolality are within 10%. So for convenience, usually calculate osmolality and call it osmolarity
Transport mechanisms in reabsorption
- Most of the transport in kidney is via reabsorption

- Most of the reabsorption is very nearly isotonic, meaning the water and solutes are reabsorbed in equal proportions. Filtration in the glomerulus is iso-osmotic. Almost all solutes (except large plasma proteins) move from plasma into the filtrate in the same proportion as waterl thus their concentration in the glomerular filtrate is the same as in the plasma. In the proximal tubule, where the majority of reabsorption occurs, the process is virtually iso-osmotic (water and solutes are absorbed in equal proportions). In the later portions of the nephron, reabsorption is generally not iso-osmotic.

- Most of the solute reabsorbed in the proximal tubule consists of sodium and the anions that must accompany sodium to maintain electroneutrality. These solutes are removed from the tubular lumen and put into the interstitium. Thus a large amount of solute is transferred from lumen to interstitium, setting up an osmotic gradient that favours the parallel movement of water. THe proximal tubule epithelium is very permeable to water, and water follows solute from the lumen to the interstitium. The water moves in equal proportions as solute, so that both the fluid removed from the lumen and that remaining behind are essentially iso-osmotic with the original filtrate (same osmolality).

- Tubular hydrostatic presure is several mmHg greater than interstitial hydrostatic pressure, and this gradient also favours reabsorption.

- Once in the interstitium, the solutes and water move from interstitium into the peritubular capillaries and are returned to the systemic circulation. Fortunately the Starling forces across the peritubular capillaries favor reabsorption. The capillary hydraulic pressure in the glomerulus which opposes uptake of interstitial fluids has fallen within the peritubular capillaries, but the plasma oncotic pressure (d/t filtration in the glomerular capillaries) has risen. There is a small but significant interstitial pressure. So the net filtration pressure is now a net absorptive pressure, and net fluid movement is into the peritubular capillaries.

- As blood flows through the peritubular capillaries, there is rapid diffusion of individual molecules back and forth between capillary plasma and cortical interstitial fluid. The total volume of interstitial space is only 4% of the total cortical volume, and the vascular volume is a little higher. Given the very high renal blood flow, the solute concentrations in the interstitial fluid are essentially clamped to those in the blood perfusing the cortex. The cortical interstitium remains quite plasma-like (Minus the proteins).
Transcellular route
- Epithelial transport requires that epithelial cells are polarized. THis polarization can promote net flux of sodium from lumen to interstitium, which is the key in which the transport of virtually every other subsstance depends on. 

- 4 steps:

1) Active extrusion of sodium via Na-K-ATPase from the cell to the interstitium. This creates a low concentration of sodium within the cell so that sodium moves downhill from the lumen to the cell interior via a variety of symporters, antiporters and channels. A key player in the proximal tubule is the sodium-proton antiporter. The consequence of this transcellular sodium movement is the separation of charge (excess Na on the interstitial side), leading to step 2.

2) Movement of anions through anion-specific transculluar and paracellualr pathways to balance the positive charge.

3) The accumulation sodium and anions in the interstitial space produces an osmotic gradient from lumen to interstitium that promotes water movement.

4) The accumulation of salt and water in the interstitium promotes bulk flow of solute and water into the peritubular capillaries driven by Starling forces.

Figure 4-4, Page 58
Paracellular route
- As water follows sodium and its anion across the epithelium, the volume remaining in the lumen decreases. So, any solute that has not been specifically transported via the transcellular route will be more concentrated. If 2/3 of water is removed, a nontransported solute will increase in concentration to 3x its original value. As the luminal concentration rises, this generates a concentration gradient across the tight junctions between the lumen and the interstitium. If the tight junctions are permeable to the substance, the substance will diffuse from the lumen to interstitium.

- Because ions are driven not only by concentration gradient byt also by voltage gradients, the transepithelial voltage plays a role. Early in the proximal tubule, the lumen is slightly negative relative to the interstitium, whereas later, it is slightly positive. This voltage enhances paracellular anion reabsorption early, and reduces it later. 

- Can account for most paracellular reabsorption purely on the basis of the rise in luminal concentration that occurs when water is reabsorbed. 

- One substance that does nto get reabsorbed by the paracellular route is glucose. First, it is transported by the transcellular route. Second, the tight junctions are not permeable to saccharides. Thus, it cannot diffuse no matter how large the concentration gradient is.
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