Renal Physiology

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RUBRIC.docx
Baylis-RenalHemodynamicsI.pdf
Baylis-RenalHemodynamicsIV.pdf
Baylis-RenalHemodynamicsII.pdf
Baylis-RenalHemodynamicsIII.pdf

RUBRIC.docx

In this task you must be guided by the PDF attachment in order to answer the following questions:

There are four parts to this set. Please type your answers in the text

box below, using no more than 250 words for the whole set.

About 60% of the fluid filtered into the nephron is reabsorbed back into

the circulation by the time the tubular fluid enters the loop of Henle.

1) How does the osmolality of tubular fluid in Bowman's capsule

compare with the osmolality of tubular fluid at the beginning of the

descending thin limb of the loop of Henle?

2) If inulin had been injected into the organism and time had been

allowed for equilibration, how would the concentration of inulin in

Bowman's capsule compare with the concentration of inulin at the

beginning of the descending thin limb of the loop of Henle?

3) If the protein content of the blood were to double, what would be the

effect on glomerular filtration? What would be the immediate effects and long term effects?

4) In muscle capillaries, plasma oncotic pressure is constant all along

the length of the capillary, but in the glomerulus, the plasma oncotic

pressure increases along the length of the capillary. What causes the

capillaries in these two tissues to differ in this way?

NOTE: DO NOT USE THE ANSWERS BELOW THIS AD AS POSSIBLE ARGUMENTS.

1- The osmolality of the tubular fluid in Bowman's capsule is lower than the osmolality of the tubular fluid at the beginning of the descending thin limb of the loop of Henle. This is due to the reabsorption of water and other substances from the glomerular filtrate, as it travels through the tubules of the nephron. The osmolality continues to decrease as the fluid travels through the loop of Henle.

2- The concentration of inulin in the tubular fluid is affected by both reabsorption and secretion, as well as by the concentration of inulin in the blood. So, the concentration of inulin in Bowman's capsule and in the beginning of the descending thin limb of the loop of Henle will depend on the balance of these processes.

So, by the time the tubular fluid reaches the beginning of the descending thin limb of the loop of Henle, the concentration of inulin in Bowman's capsule would be essentially the same as it was when it was initially filtered at the glomerulus. This behavior of inulin makes it a valuable substance for measuring the glomerular filtration rate (GFR) because it is not subject to reabsorption or secretion within the nephron.

3- if the protein content of the blood were to double, this would cause an increase in glomerular filtration, at least in the short term. This is because the increased protein concentration in the blood would cause an increase in the osmotic pressure of the blood, which would lead to an increase in the filtration pressure in the glomerulus. In the long term, however, the increased filtration rate would lead to damage to the glomerular filtration barrier, which could eventually lead to decreased filtration and even kidney failure.

4- The difference in the plasma oncotic pressure between muscle capillaries and glomerular capillaries is the presence or absence of a basement membrane. In muscle capillaries, the plasma oncotic pressure is constant because there is a basement membrane present, which prevents fluid from passing from the capillary into the interstitial fluid. However, in the glomerulus, there is no basement membrane, so fluid can pass freely from the capillary into the tubule, which leads to an increase in the plasma oncotic pressure along the length of the capillary.

Baylis-RenalHemodynamicsI.pdf

All contents are copyrighted. No unauthorized distribution allowed.

Renal Hemodynamics I

Chris Baylis, PhD

Learning Objectives: To learn and understand:

• How the unique vascular anatomy of the renal resistance vessels creates a hydrostatic pressure gradient throughout the renal blood vessels, and importantly, a relatively high glomerular blood pressure, required for glomerular filtration.

• How the structure of the glomerular capillary (GC) wall provides an effective filter which keeps the large circulating molecules (plasma proteins) from leaving the capillary during filtration of water and small solutes.

• How the GC wall provides both size selective and electrostatic restriction to the large, anionic plasma proteins at multiple locations.

RENAL BLOOD FLOW (RBF).

Functions

1.Glomerular filtration and tubular absorption/secretion. 2. In addition, RBF regulates:

erythropoietin release; control of renin-angiotensin system water balance, countercurrent exchange.

TYPICAL VALUES 70KG ADULT

Weight (both kidneys) = ~400g Total renal blood flow, RBF = ~1.2 L/min (~25% of cardiac output) Total renal plasma flow, RPF = ~600 ml/min (hct ~50%) Glomerular filtration rate, GFR = ~120 ml/min (~173L/day)

Plasma volume ~ 3L

Determinants of RBF Flow = pressure gradient along vessel / resistance to flow.

Resistance mainly determined by vessel radius. Renal blood vessels are complex.

100

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HIDDEN SLIDE The aorta and the renal, segmental, interlobar and arcuate arteries

are conduit vessels with low resistance, so there is only a small blood pressure drop as blood flows through these vessels.

Resistance vessels in series cause progressive drops in blood pressure as blood flows through the renal vasculature.

The interlobular (cortical radial) artery is the first resistance vessel, then the afferent arteriole and BP falls ~ 55 mmHg by the glomerulus.

There is a minimal fall in BP along the glomerulus (2-3 mmHg) then a substantial fall along the efferent arteriole. The BP arriving in the peritubular capillaries is ~ 20 mmHg.

Resistance vessels before and after the glomerulus (pre- and post- glomerular resistances or afferent and efferent resistances, RA and RE) control rate of plasma flow and the blood pressure within the renal circulation.

Basic Renal Processes.

1). Filtration of plasma.

Modification of filtrate by; 2). Secretion from the peritubular blood into the tubule and 3). Reabsorption of valuable solutes and water.

This leads to excretion of waste, excess water and excess solutes.

GLOMERULAR FILTRATION Glomerular filtrate:

Aqueous portion of plasma, forced, under pressure, across the glomerular capillary wall.

Glomerular filtrate is an “ultrafiltrate” of plasma

ie. water, low MW substances; electroytes, urea, small peptides.

Large proteins and blood cells are EXCLUDED

ie. The glomerulus is a filter or sieve.

The glomerulus as a sieve

Fractional clearance of large molecules (not reabsorbed or secreted) gives an index of restriction to filtration. FC 1.0 = no restriction.

Compare a large substance with freely filtered INULIN.

(NOTE: This is in contrast to the fractional clearance of small substances which gives index of tubular handling).

Large molecules (MW>7,000; effective radius > 1.8 nm) are not freely filtered.

HIDDEN SLIDE Dextrans are filtered depending on size and charge and then

remain in the tubule (no reabsorption or secretion) so FC dextran measures glomerular restriction.

The glomerular capillary (GC) wall behaves as if it has size selective pores and is negatively charged.

The neutral dextran sieving curve measures size selectivity. The greater restriction to equivalent sized anionic dextran

and facilitation of cationic dextran, demonstrates the additional charge restriction.

Filtration of circulating macromolecules (proteins) determined by: SIZE and CHARGE.

Proteins are also globular which makes it harder to pass through a given sized pore.

GFR is ~ 120 ml/min and plasma protein concentration is ~ 7g/ 100ml. So ~8.4 g protein pass through the glomerulus each min, or ~ 12Kg protein / day!!!! We estimate that only ~ 2g/ day cross the glomerulus. Where is the filter?

Hidden slide. There are many filters within the glomerular capillary wall:

At the endothelium: The endothelial cells are covered with negative charges (polyanionic glycoproteins). There is recent evidence of a glomerular endothelial glyco-calyx over the fenestrae; a “sticky” meshwork of glycosaminoglycans and proteoglycans that forms a physical barrier to large molecules.

The glomerular basement membrane, GBM is a gel which contains fixed negative charges (glycosaminoglycans). Also, meshwork of structural proteins (collagens etc) that support the gel and provide “pores”, restricting passage of large molecules.

The final barrier is the podocyte slit pore and its diaphragm. This consists of several specialized proteins including nephrin, podocin, Neph1 and 2, FAT1 and 2

The epithelial slot pore and diaphragm are composed of several specialized proteins.

Mutations in these proteins lead to loss of podocyte organization and proteinuria. Eg: A nephrin mutation causing congenital nephrotic syndrome (heavy proteinuria >3.5g/d) of the Finnish type.

Normal urine contains very little protein

The normal GC wall restricts >99.9% of the proteins that flow through the GC, so only ~2g of protein/24h is filtered.

In the normal urine there is <150mg/24h which means that most (>99%) of the filtered protein is normally reabsorbed. This occurs in the proximal tubule where proteins are taken up and degraded within the cell to amino acids which are then returned to the circulation via the peritubular capillaries.

Hemodynamic consequence of heavy proteinuria

When excess protein appears in the urine this often indicates kidney disease. When protein excretion is very heavy (>~3.5 g/24h) the plasma protein level falls and this disturbs capillary fluid balance thoughout the circulation, leading to widespread edema (fluid accumulation in the interstitium).

Proteinuria can also occur due to failure of proximal tubular reabsorption or urological causes (Eg. Bladder infection).

Summary of key concepts • The complex renal resistance vessels create a blood

pressure gradient throughout the kidney, with a high GC blood pressure (~55 mmHg).

• The normal GC wall provides an effective barrier to the passage of circulating proteins into the tubule.

• The restriction to proteins occurs at the GC endothelium (negative charge and size/ glycocalyx), GBM (negative charge and size/ collagen scaffold) and the podocyte slit pore diaphragm (mainly size / due to complex protein assembly).

• Normal urine contains very little protein (<150 mg/24h) since most protein that is filtered (~2g/day) is “reabsorbed” in the proximal tubule. Proteinuria often (but not always) indicates glomerular disease.

Baylis-RenalHemodynamicsIV.pdf

All contents are copyrighted. No unauthorized distribution allowed.

Renal Hemodynamics IV

Chris Baylis, PhD

Learning Objectives: To learn and understand:

• The mechanisms of renal autoregulation • How events at the glomerulus control

peritubular capillary reabsorption. • The relationship between renal

metabolism and renal oxygen extraction • Clinical assessment of RBF • How renal hemodynamics are deranged in

kidney disease.

PHYSIOLOGIC SITUATIONS IN WHICH RENAL HEMODYNAMICS ARE ALTERED

Volume depletion/overload

Volume depletion: Renal vasoconstriction; decreased RPF and GFR; suppression of vasodilatory systems; activation of vasoconstrictors, ANG II and SNS

(reverse occurs in volume expansion)

GENERALLY GFR STAYS FAIRLY CONSTANT IN HEALTHY, "VOLUME REPLETE" ADULTS.

EXCEPTIONS: High Dietary protein Vasodilation of both afferent and efferent resistance; increased RPF and GFR. Pregnancy Vasodilation of both afferent and efferent resistance; increased RPF and GFR. Exercise Vasoconstriction of afferent and efferent resistance; decreased RPF and GFR.

Renal Hemodynamics can change dramatically in disease.

Maintaining a constant GFR as BP changes RENAL AUTOREGULATION

Renal perfusion pressure (RPP) (mm Hg)

0 40 80 120 160 200 240

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Autoregulatory range

Afferent glomerulus efferent arteriole PGC arteriole

BP No change in RPF

HIDDEN SLIDE Renal Autoregulation means constant renal blood

flow (and RPF) over a range of systemic blood pressure (BP) (remember BP is changing constantly).

RPF= pressure drop (BP - renal vein P) renal vascular resistance

Constancy of RPF during changes in BP must involve parallel changes in renal resistance. Only the afferent arteriole (RA) participates.

An increase in BP (RPP) leads to constriction of RA, resulting in ~ constant RPF and PGC. This leads to excellent autoregulation of GFR.

2 MECHANISMS OF RENAL AUTOREGULATION

1. Myogenic (immediate, msec) general autoregulatory mechanism.

2. Tubuloglomerular feedback (delayed,sec to min) specific to kidney

HIDDEN SLIDE Occurs at juxtaglomerular apparatus, JGA. Signal : rate of delivery of fluid to the macula

densa Feedback response to change resistance in the

afferent arteriole.  BP  Transient   flow and PGC  SNGFR  distal delivery of fluid  signal at macula densa  vasoconstriction of afferent arteriole  restoration of flow and PGC.

NOTE 1: Autoregulation means constant RPF and GFR during a change in BP. Hormones/drugs/nerve traffic can act directly on kidney vasculature and alter RPF, GFR.

NOTE 2: Autoregulation of PGC is very important for long term kidney health.

Events at the glomerulus determine the reabsorptive pressure in the peritubular capillaries

As glomerular filtrate is formed:

1). Protein concentration increases in glomerular blood ( GC).

2). Postglomerular blood flow decreases (because some volume is filtered out of the glomerular blood).

The peritubular capillaries need to reabsorb most of the filtrate.

Pressure profile through the renal microcirculation

P 

P  

P

FILTRATION NO FLUID FLUX REABSORPTION

Glomerular capillary efferent arteriole peritubular capillaries

HIDDEN SLIDE The PGC is ~ 55mmHg and P is ~ 40 mmHg at the

beginning and ~38 mmHg at the end of the glomerulus. As water leaves by filtration, plasma protein concentration and therefore  increases.

When blood leaves the glomerulus it enters RE. There is no fluid movement across the wall of RE so  stays high. RE is a resistance vessel so blood pressure must fall significantly during forward flow of blood.

Therefore, when blood enters the peritubular capillaries (PTC) it has a low hydrostatic pressure (P, ~20mmHg) and a high colloid osmotic pressure (, ~ 40 mmHg) which creates a net reabsorbtive pressure.

Other Functions Peritubular blood flow supports tubular secretion of organic anions

and cations, drugs. Sensing the circulating red cell mass in control of erythropoietin

release, which is synthesized by interstitial cells of the renal cortex

RBF supplies oxygen for metabolism. Renal O2 uptake regulated according to energy requirement.

Main energy requiring process is active sodium reabsorption in the tubules.

RBF, GFR and sodium reabsorption usually change in proportion to each other. Therefore, when RBF increases, sodium reabsorption increases and O2 utilization increases so that the O2 extraction across the kidney stays constant.

Clinical Measurement of Renal Perfusion

Quantitative methods to measure RPF (CPAH), used for research.

Quantitative assessment of renal perfusion is not necessary for most renal patients.

Commonly used clinical measures are semi- quantitative doppler ultrasonography imaging methods (contrast).

Renal Blood Flow Values

Renal perfusion ~ 20-25% of the cardiac output.

~4 mL/min/g kidney tissue weight 4 times more than blood flow rate to

exercising muscle RPF > men vs women, irrespective of size

increases with size increases with maturation decreases with aging, after ~40 in men.

Renal Hemodynamics in Kidney Disease

ACUTE KIDNEY INJURY (AKI) An abrupt loss of kidney function due to compromised

hemodynamics. Sometimes due to severe systemic hypotension, to below the

autoregulatory range. Sometimes due to intense renal vasoconstriction. Always reductions in RPF and GFR in AKI.

Afferent glomerulus efferent arteriole  PGC arteriole

Chronic Kidney Disease (CKD) Chronic kidney disease can develop from many causes. Irrespective of the cause, renal disease tends to be progressive. When GFR falls, control of body fluid and composition is deranged. When patients reach end stage kidney disease (ESKD) they require dialysis or a renal transplant to survive.

There are several primary causes of CKD (eg. diabetes 1 and 2); hypertension; immune and autoimmune diseases, etc. The renal hemodynamic pattern as each disease evolves often includes increases in PGC.

200

150

100

Glomerular filtration rate (GFR)

(ml / min)

0 25 50 75 100 125 0

Plasma creatinine concentration

(Pcr) (mg / dl)

Blood urea nitrogen

(BUN) (mg / dl)

Many potential Mechanisms of Progressive Glomerular Injury

Hemodynamic Glomerular capillary Hypertension

Preferential efferent arteriolar vasoconstriction lead to increased glomerular blood pressure. This directly damages the glomerular capillary.

Inappropriate activation of intrarenal ANGII raises PGC. Also promotes expansion of mesangium and vascular smooth muscle cells; fibrosis and oxidative stress. Angiotensin converting enzyme (ACE) inhibitors slow down progression of diabetic renal disease. They lower BP. They give superior renal protection over other antihypertensive treatments. Brenner et al.

Summary of key concepts. • Renal autoregulation, achieved by the myogenic response

and tubuloglomerular feedback (TGF) maintain constant GFR over a wide range of BP, by control of RA.

• Filtration of fluid at the glomerulus leads to high colloid osmotic and low blood pressure in the peritubular capillaries, which favor reabsorption.

• When RBF increases, renal oxygen utilization increases (due increased tubular reabsorption of sodium). Although absolute oxygen uptake is increased, the oxygen extraction (A-V difference) remains fairly constant.

• In AKI, falls in RPF and PGC lead to falls in GFR, either due to large falls in systemic BP or to increased RA.

• In CKD, increased PGC often contributes to progression of the disease. Elevated intrarenal ANGII activity contributes to the pathogenesis.