Renal Ch2 - Glomerular Physiology

Sympathetic Discharge is Stimulated by...

" - Drop in BP - Central Mechanisms (Stress, fright, pain)"

Low Dose Angiotensen II Summary

"Constrict Efferent>afferent arteriole Increase Pgc Increase GFR"

Effects of *High Doses* of Angiotensin II on GFR

"High doses (Circulating levels) *constricts both efferent and afferent* arterioles, in addition to *mesangial cells* --> *GFR Decreased* Local production of *PG's help counterbalance* the vasoconstricitive effects of ATII and the sympathetic nervous system by *dilating the afferent arteriole* to protect RBF. - Note: autoregulation of afferent arteriole also attempts to maintain RBF"

Glomerular Capillary Endothelium (GEN)

*Fenestrated* vascular endothelium - Comprised of a thin, single layer of flattened endothelial cells with gaps or fenestrae within them, each with a diameter of about 100 nm

Tuboglomerular Feedback (TGF)

*High luminal Cl- level* is sensed by the macula densa (threatening excess volume loss or excess nephron work to reabsorb NaCl in AKI) --> *Nephrons can markedly decrease the GFR for protective mechanisms*. 1.) *NKCC* (next card) on macular densa cells senses high luminal Cl and.. 2.) Signals via *Adenosine* to smooth muscle cells in the *afferent arteriole* which 3.) *Contract and decrease Pgc* Note: angiotensin II augments TGF whereas ACE inhibitors and angiotensin receptor blockers inhibit TGF.

Other determinants of GFR

*Hydraulic permeability* - Pore size / number - GBM characteristics *Surface area* - Number of glomeruli - Size of glomeruli capillary network *Kf* is 50-100x greater in the kidney than muscle! - Single nephron GFR = Kf(ΔP - Δπ) [This equations is not for clinical practice, its just a construct to help you understand the factors at play in glomerular filtration!!!!]

*Kf* in the kidney vs muscle

*Kf* is 50-100x greater in the kidney than muscle! KNOW THIS!!!!

Juxtaglomerular Apparatus (JGA)

*Macula Densa and Granular Cells - at the junction of the loop of Henle and distal convoluted tubule courses between the afferent and efferent arterioles of its parent glomerulus *Important in the control of glomerular filtration and the regulation of systemic blood volume and pressure*

Filtration Coefficient (Kf)

*The product of hydraulic permeability and surface area* - GFR is directly proportional to the net filtration pressure (NFP) (Δp-Δπ) and the Kf. Thus: Single nephron GFR (SNGFR) = Kf (Δp-Δπ) Or SNGFR = Kf ([PGC - PBS]- [πGC - πGC])

In a state of High RPF

*less fluid removed* --> *small increase in πgc* --> *filtration continues* along the full length of the glomerular capillary *increasing overall GFR*

In a state of Low RPF

*more fluid is removed* from the glomerular capillary --> *significant rise in πgc* --> *halts glomerular filtration* before the end of the glomerular capillary (*filtration equilibrium*)

Hydrostatic Pressure in Bowman's Capsule (Pbs)

*~15 mm Hg* Not physiologically regulated but provides the *driving pressure for flow of fluid down the nephron*

PGE2

...

Normal Serum Creatinine

0.8-1.2 mg/dl

Slide 21

0:48:45

Angiotensen II: Water Balance

1.) *ADH*: AII stimulates ADH secretion (important for water conservation) 2.) *Thirst*: AII is a potent *dipsogenic peptide* (stimulates drinking). Thirst helps to correct volume defecit after blood loss.

Angiotensen II: Na+ Balance

1.) *Aldosterone*: AII stimulates Aldosterone secretion, important for Na reabsorption and maintenance of blood volume 2.) *Na Reabsorption*: AII directly stimulates NA+ Reabsorption in the proximal tubule (important for volume regulation)

Control of Renin

1.) *Intrarenal Baroreceptors* - Granular cells sense stretch in afferent arteriole, fall in systemic blood pressure decreases stretch and increases renin secretion 2.) *Macula Densa* - Feedback from the tubules signal to granular cells in response to low tubular delivery of Cl-, PgE2 --> Renin secretion 3.) *Renal Sympathetic Nerves* - Vascular baroreceptors sense decreased BP and increase vascular tone and stimulate renin release

Glomerular Filtration Barrier

1.) Glomerular Capillary Endothelium (GEN) 2.) Glomerular Basement Membrane 3.) Visceral Epithelium (Podocytes)

Forces Mediating Renal Autoregulation

1.) Myogenic Reflex 2.) Tubulo-golmerular Feedback (TGF) 3.) Neurohormonal Factors (RAAS)

Determinants of Single Nephron GFR

1.) Starling Forces (net filtration pressure (Δp-Δπ)) 2.) Hydraulic Permeability 3.) Surface Area

Functions of the JGA

1.) Tuboglomerular Feedback (TGF) 2.) Renin Response

Actions of Angiotensen II

1.) Vasoconstriction 2.) Na+ Balance - Aldosterone and Na+-Reabsorption 3.) Water Balance - ADH and Thirst 4.) Effects on GFR (differ at low vs high doses of Angiotensen)

Normal GFR

125mL/min

What % of renal blood flow is filtered?

55% of renal blood flow is Renal PLASMA flow 20% of plasma volume is filtered

Normal Cardiac Output

6L/min - 20% of that (1200mL/min) goes to kidneys

Macula Densa

A small plaque formed by thickening of the epithelial cells the tubular wall at the junction of the loop of Henle and distal convoluted tubule - *senses the composition of tubular fluid*

Glomerulus

A tuft of capillary loops attached to the mesangium enclosed in a pouch like extension of the renal tubule known as Bowman's capsule. The glomerular capillary is unique in that it has an arteriole at both ends.

Glomerular Blood Flow

Afferent arteriole enters the glomerulus --> divides into 2-5 primary capillary branches -->each gives rise to a small capillary network (*glomerular lobule*) --> converge to form the efferent arteriole --> leaves the glomerulus and goes on to supply the remaining nephron

Afferent Arteriole Vasoconstrictors

Angiotensin II Endothelin I SNS (Norepi) Adenosine Others

Angiotensen II: Vasoconstriction

Angiotensin II is a powerful vasoconstrictor of arterioles throughout the body, *increasing peripheral resistance and BP* In kidneys, the *afferent and esp EFFERENT arterioles, are constricted, reducing RBF*. - Note efferent arteriolar vasoconstriction increases PGC, and therefore, *GFR is reduced less than RBF*. GFR is thus supported during times of hypotension Angio = blood vessels, Tensen = tension, Angio-tensen = tense/constrict blood vessels

Angiotensin II Effect on TGF

Augments TGF

Loop diuretics such as Furosemide

Block the NKCC and directly lead to *increased renin production*. (They also block the protective tubuloglomerular feedback TGF in acute renal failure)

Bowman's Capsule in relation to the Glomerulus

Bowman's capsule is not in contact with the glomerular capillaries and is not part of the filtration barrier. It is lined with a simple flattened epithelium (parietal epithelial cell).

Starling Forces Across the Glomerular Capillary (Values)

Chart

Glomerular Capillary

Consist of a tube of endothelial cells, supported by the glomerular basement membrane with podocytes on the outer surface. - Glomerular filtration occurs across capillary wall into Bowman's space - Filtration of larger molecules (e.g. albumin) restricted by capillary wall (*filtration barrier*)

Angiotensinogen

Converted by Renin to Angiotensin I

Angiotensin Converting Enzyme (ACE)

Converts Angiotensin I to Angiotensin II

Oncotic Pressure Glomerular Capillary (πgc) Regulation of GFR

Depends on the oncotic pressure of arterial blood. At the very start of the glomerular capillary, before any filtration has occurred πgc = arterial plasma oncotic pressure - Factors that affect the oncotic pressure of arterial blood similarly affect πgc (e.g. Volume contraction increases arterial and glomerular oncotic pressure and reduces GFR)

Osmosis

Describes the movement of water from area of low solute concentration to area of high solute concentration

Mild Hypotension

During episodes of mild hypotension, PGs dilate the afferent arteriole, and angiotensin II vasoconstricts the efferent arteriole partly maintaining GFR. In the setting of impaired renal perfusion, these protective mechanisms may be blocked by NSAID or ACE inhibitors leading to a marked drop in GFR & acute renal failure.

Non Freely Filtered Molecules

Filtration barrier is relatively impermeable to large molecules such as plasma proteins. - *Proteins with a molecular weight of >70,000 are Totally Excluded* - Some smaller proteins are normally filtered but the protein concentration of glomerular fluid is only 0.02% of that of plasma. - If *small molecules are bound to proteins*, they too will be excluded (e.g. 40% of plasma Ca2+ is protein-bound and [Ca2+] of filtrate is only 60% of [Ca2+] in plasma). - Cells are totally excluded

Factors Regulating Glomerular Filtration Rate

GFR is physiologically regulated and can change in disease. Factors that may change GFR include: 1.) Glomerular Capillary Pressure (Pgc) 2.) Hydraulic Pressure of Bowman's Capsule (Pbc) 3.) Oncotic Pressure Glomerular Capillary (πgc) 4.) Filtration Coefficient (Kf)

Intrarenal Baroreceptors

Granular Cells of the JGA are stretch receptors (baroreceptors) that monitor the high pressures of renal arteries. Fall in BP in afferent arteriole reduces stretch an stimulates renin secretion

Angiotensin II: Graded Level of Effect on the Kidney

High vs Low Dose (Pic)

Sympathetic Nervous System: Autoregulation Override

Hypotension --> activation of *sympathetic nerves* to the kidney (and to splanchnic circulation and skin) causes *vasoconstriction* --> *diverts blood* from kidney to more essential organs (heart and brain) --> *Reduces GFR and minimizes loss of salt and water* In these circumstances, autoregulation is overridden by systemic control mechanisms.

Tuboglomerular Feedback

Increased arterial pressure transmitted to Pgc leads to increased delivery of Cl- to Macula Densa --> constriction of *afferent arteriole*

ACE Inhibitor an Angiotensin Receptor Blockers Effect on TGF

Inhibit TGF

How does the kidney regulate volume?

Juxtaglomerular(JG) Apparatus 1.) Tubuloglomerular feedback 2.) Renin response

Filtration Coefficient (Kf) Regulation of GFR

Kf is controlled physiologically by nerves and hormones. *Contraction of mesangial cells reduces the surface area for exchange, reduces Kf and reduces GFR* Hydraulic permeability also affected by - diseases that cause *thickening of the filtration barrier* or - a *reduction in the surface area by destroying capillaries* - or also *alter charge*

Effects of *Low Doses* of Angiotensin II on GFR

Low doses (Locally) *constricts efferent* arteriole more than the afferent. Thus despite a drop in RBF, GFR can be maintained by increased Pgc. (Results in *increased Filtration Fraction*)

Renin Response

Low luminal NaCl is sensed (e.g. volume depletion) --> increased renin production. Again, the luminal Cl- level is sensed by the NKCC on macula densa cells which signal to the renin producing granular cells via prostaglandin E2 (PGE2).

Renin Response

Low luminal NaCl is sensed (e.g. volume depletion) --> leads to increased renin production. Luminal Cl- level is sensed by the *NKCC* on macula densa cells which release PGE2 which stimulates the granular cells to release renin .

Freely Filtered Molecules

MW <7.000 - water - electrolytes and other small solutes - amino acids - glucose *If a substance is freely filtered: [substance] in Plasma = [Substance] in Tubular Fluid of Bowman's Space*

Macula Dena Control of Renin Secretion

Macula Densa monitors delivery of NaCl to the *distal nephron*. Hypotension --> decreased NaCl delivery --> Macula Densa detects decrease and releases PGE2 that stimulates renin release from the granular cells

Hydraulic Permeability

Magnitude of GFR is largely due to the *high hydraulic permeability of glomerular capillaries*. - Normally, GFR is ~180 L/day (125 ml/min). All of the other capillaries in the body filter only ~4 L/day combined. Glomerular Kf is 50-100x greater than UF coefficient in muscle capillaries. This huge flux in the kidney is driven by a net filtration pressure of only 10 - 24 mm Hg.

Hydrostatic pressure in the glomerular capillary Pgc

Main force driving filtration Physiologically regulated by changing the resistance of the afferent arteriole and efferent arteriole ~*60 mm Hg @ Afferent end* of the glomerular capillaries (markedly higher than other capillary beds) - declines minimally to *~58 mm Hg @ Efferent end* Note: this decline is less than the fall in hydrostatic pressure for other capillary beds because of the resistance vessel (the efferent arteriole) at the end of the glomerular capillaries.

Oncotic Pressure of Plasma in the Glomerular Capillary (πgc)

Main force opposing filtration - *~ 21 mm Hg at the afferent end of the capillaries* - Increases to *~33 mm Hg at the efferent end* because protein-free fluid is removed from the capillaries by filtration (i.e. protein concentration of glomerular capillary plasma increases).

Angiotensin II

Major regulator of GFR Predominantly controled by secretion of renin from granular cells on the afferent arteriole 1.) *Renin* degrades *Angiotensinogen* in the blood (made in liver) to *Angiotensen I* (10aa peptide) 2.) *ACE clips 2 aa's* to form 8aa peptide *Angiotensen II* = Biologically active form of Angiotensin

Normal Clearance (Creatinine)

Men: 120mL/min +/-25 Women: 95mL/min +/-20

Changes in Starling Forces Along the Glomerular Capillary

Net Filtration Pressure drops 24 --> 10 II = π

High Dose Angiotensen II Summary

Occurs in Catastrophic states (e.g. shock) when top priority is to maintain bloodflow to the vital organs Maintain BP: - Potent Systemic Vasoconstrictor - Stimulate Aldosterone Secretion - Increase Thirst - Constrict Efferent AND Afferent Arteriole *Decreased Pgc Decreased GFR*

Hydraulic Pressure of Bowman's Capsule (Pbc) Regulation of GFR

PBC is not controlled physiologically but can *increase if the flow of fluid is blocked* e.g. by a stone in the ureter. *Increased Pbc will reduce NFP and GFR*

Glomerular Capillary Pressure (Pgc) Regulation of GFR

PGC is regulated by nerves and hormones and is thus the *most closely controlled determinant of GFR* Depends on pressure in the renal artery (PRA), afferent arteriole resistance (Ra) and efferent arteriole resistance (Re)

Visceral Epithelium (Podocytes)

Podocytes project tentacle-like *foot processes* onto the basement membrane supporting the capillary loop. Between the foot processes lie the *filtration slits* which are covered by *slit diaphragms*

Transmembrane Pressure

Pressure across the glomerular filtration barrier (transmembrane pressure) can drive filtration in the glomerulus

Afferent Arteriole Vasodilators

Prostoglandins (PGE2) NO Histamine Bradykinin Ach Glucocorticoids Insulin, Insulin-Like Growth Factor (ILGF) Calcitonin Gene Related Peptide cAMP Relaxin (in pregnancy)

Renal Plasma Flow (RPF) and GFR

RPF is the *most important determinant of GFR* - *Determines rate at which πgc* (oncotic pressure in the glomerular capillaries), which opposes glomerular filtration *increases along its length* - Has less effect on PGC due to autoregulation Normally, πgc increases as proteins become concentrated due to the filtration of protein-free fluid (from 21 to 33mmHg along glomerular capillary)

Role of Renin

Renin converts Angiotensinogen to Angiotensin I, which ACE converts to *Angiotensin II*, which causes *Vasoconstriction*, increasing systemic BP

Neurohormonal Factors

Renin-Angiotensin System - Angiotensin II (RAAS)

Single nephron GFR [Starling's Equation]

Single nephron GFR = Kf(ΔP - Δπ)

Granular Cells

Specialized smooth muscle cells in the wall of the afferent arteriole that secrete the enzyme *renin*

Starling Forces

Starling forces govern the movement of fluids across any capillary bed 2 forces *favor* filtration from glomerular to Bowman's Space: 1.) Hydrostatic Pressure in the Glomerular Capillary (Pgc) 2.) Oncotic Pressure of fluid in Bowman's Capsule (πbs) = 0! (no proteins) 2 forces *oppose* filtration: 1.) Hydrostatic Pressure in Bowman's Capsule (Pbs) 2.) Oncotic Pressure of Plasma in the Glomerular Capillary (πgc)

Sympathetic Vasoconstritor Nerves

Supply afferent and efferent arterioles; at rest, the sympathetic tone to the kidney is low. A *fall in BP* Reflexively stimulates *sympathetic discharge* through *baroreceptors* in the aortic arch, carotid sinus, heart, and veins. Sympathetic nerves release *Norepi* --> acts on *a1* receptors on arteriolar muscle to cause *vasoconstriction* - Epi from adrenal gland has same effect

Surface Area

Surface area for exchange is *directly proportional* to GFR. The area is large due to the convoluted nature of the glomerular capillaries that are in contact with Bowman's capsule. - Number of glomeruli - Size of glomeruli capillary network

Prostaglandins

Sympathetic stimulation and angiotensin II induce synthesis of prostaglandins (PGE2 and PGI2) by kidney. Powerful vasodilators, esp of afferent arteriole, where they *dampen the renal vasoconstrictor and mesangial cell effects of sympathetic nerves and angiotensin II*

Tuboglomerular Feedback (TGF) and Acute Kidney Injury (AKI)

TGF decrease of Pgc is a major cause of the *decreased GFR* in acute kidney injury secondary to acute tubular necrosis (ATN) where it is likely a protective mechanism.

Renal Autoregulation

The ability of the nephron to maintain RBF and GFR fairly steady over a range of systolic pressures from 90 to 200mmHg. - Mediated primarily by *changes in the resistance* of the *Afferent arteriole* - Permits adequate excretion of water and solute at different blood pressures - Note that this protective process is impaired at extremes of blood pressure and during AKI

Oncotic Pressure of fluid in Bowman's Capsule (πbs)

The glomerular filtrate is essentially protein free, so *πBS ~ 0 mmHg*

Slit Diaphragm

Thin layer beteen podocyte feet composed of *nephrin* and other proteins Limits filtration of larger molecules - critical for filtration of macromolecules

TGF: Volume Depletion

Too *little* Salt (NaCl) and Water in body --> Decreased BP --> Decreased RBF --> Decreased GFR --> Decreased Cl- excretion/decreased Cl- in glomerular filtrate (luminal Cl-) --> low Cl- sensed by macula densa --> Macula densa releases *Prostoglandin PGE2* --> PGE2 causes *afferent arteriole dilation* to maintain GFR - PGE2 can also stimulate *Renin Release from Granular Cells* (Renin increases BP)

TGF: Volume Excess

Too *much* Salt and Water in body --> Increased BP --> Increased RBF --> Increased GFR --> Increased Cl- excretion/increased Cl- in glomerular filtrate (luminal Cl-) --> Cl- sensed by macula densa --> *macula densa cells swell* --> Macula densa releases *Adenosine* --> Adenosine causes *afferent arteriole constriction* --> Decreased GFR

Kidneys Regulate Fluid Balance

Too much salt and water in your body: - Turn up the GFR and pee it out! Too little salt and water in your body - Hold on to all the salt and water to maintain blood pressure and organ perfusion!

Na:K:2Cl Co-Transporter (NKCC)

Transporter on Macula Densa Cells that senses high luminal Cl and signals via adenosine to smooth muscle cells in the afferent arteriole which contract and decrease Pgc

NSAIDs and PGs

Using NSAIDs to block PG's causes both AII and Sympathetic System to constrict both afferent and efferent arterioles (as well as mesangial cells!), leading to a dramatic drop in both RBF and GFR --> Acute Kidney Injury

Glomerulotubular Balance

Variations in GFR are compensated by *increased or decreased reabsorption in the tubules (mostly proximal) to produce same amount of urine* - a separate phenomenon from TGF (e.g. ↓ in GFR from 125mls/min to 60 mls/min still leads to ~2L urine / day)

Renal Sympathetic Nerves

Vascular baroreceptors sense a drop in arterial pressure and increase *Sympathetic Tone* to kidney --> *stimulates renin release by granular cells* also causes *afferent arteriolar constriction* which enhances ""1 and 2 above"" (Baroreceptors and Macular Densa control of Renin Secretion)

Myogenic Reflex

Very rapid, also observed in other vascular beds 1.) Increase in perfusion pressure stretches muscle in the afferent arterioles 2.) Smooth muscle contracts in response to stretch - Probably bc Ca2+ channels open in the PM, resulting in influx of Ca 3.) Arterioles Constrict, increasing resistance

Glomerular Basement Membrane

a negatively charged mesh of type IV collagen, glycoproteins and mucopolysaccharides, which is secreted by the podocyte and endothelial cell

COX2 inhibitors (i.e. NSAID's)

block PGE2 and inhibit renin production.

Oncotic Pressure (π)

osmotic pressure exerted by colloids (proteins), esp albumin, in a blood vessel's plasma that usually tends to *pull water into the circulatory system*. - Water flows by osmosis to regions of high oncotic pressure. - It is the opposing force to capillary filtration pressure and Interstitial Colloidal Osmotic Pressure.