Intrinsic Mechanisms of GFR Regulation

  • Glomerular filtration rate (GFR) is the total volume of ultrafiltrate formed by the collective kidney nephrons per minute;
  • GFR is closely regulated to balance potentially opposing requirements:
    – Excess solutes and water needs to be removed from the blood.
    – The body tissues need nearly constant blood volume and pressure.

Intrinsic mechanisms

  • Physiological responses that are initiated by renal structures to modify the hydrostatic capillary pressures; renal autoregulation.
  • Maintain nearly constant GFR as long as mean arterial pressure is 80-180 mmHg, which allows for consistent kidney functioning despite changes in blood pressure.
  • During daily activities, cardiac output, and, therefore, arterial blood pressure fluctuates—for example, during exercise it increases and during sleep it decreases.
  • At high blood pressures, autoregulation protects the glomerulus from damage, and,
  • At lower blood pressures, it ensures that the kidneys receive sufficient blood flow to filter wastes.
  • If mean arterial pressure drops below 80 mmHg, such as during hemorrhage, extrinsic mechanisms activate (which we discuss in detail, elsewhere).

Myogenic mechanism:

  • Relies on inherent properties of the arterioles, themselves.
  • Arteriole walls comprise smooth muscle, made of vascular smooth muscle cells.
  • When increased renal blood flow exerts increased hydrostatic capillary pressure on the walls, stretch receptors are activated and induce vasoconstriction.
  • This reduces renal blood flow and, therefore, GFR.
  • When renal blood flow is low, the stretch receptors are inactivated, and the arteriole dilates to increase GFR.

Tubuloglomerular feedback mechanism:

  • Relies on interaction between the nephron tubule and glomerulus.
  • As renal blood flow increases, so does hydrostatic capillary pressure, and, therefore, GFR increases.
  • As the GFR increases, so does the concentration of salt in the ultrafiltrate, because high flow rate allows less time for tubular reabsorption.
  • The macula densa of distal tuble senses the high salt concentration in the ultrafiltrate as it passes through the distal tubule;
  • In response, it releases vasoconstrictor chemicals (the specifics of which are disputed).
  • Consequently, the nearby afferent arteriole constricts, which, as we saw earlier:
    Reduces renal blood flow, hydrostatic capillary pressure, and GFR.
  • When renal blood flow decreases, so does the sodium concentration, and eventually the macula densa stops releasing vasoconstrictors, which ultimately allows renal blood flow and GFR to again increase.

Regulation of Glomerular Filtration Rate – Overview

  • Kidneys‘ objective is to maintain homeostatatic balance of blood volume, pressure, and ion concentrations via filtration of the blood, despite fluctuations in blood pressure throughout the day.
  • GFR regulation achieves this balance through both intrinsic and extrinsic mechanisms.
  • GFR is most easily regulated by adjusting the net filtration pressure, which is determined by the hydrostatic and oncotic forces at the filtration membrane.

Intrinsic vs Extrinsic Mechanisms

Intrinsic response

  • Involve intra-renal mechanisms
  • Structures within the kidneys initiate the intrinsic mechanisms
  • Dominate as long as MAP is 80-180 mmHg
  • Goal is to maintain nearly constant GFR over a wide range of mean arterial pressures
  • Includes myogenic and tubuloglomerular feedback, which act primarily on afferent arteriole.

Extrinsic response

  • Involve neural and hormonal mechanisms.
  • Requires transport of neurotransmitters/hormones in bloodstream.
  • Active when MAP is below 80 mmHg.
  • Goal is to maintain blood volume and pressure; regulation of GFR is one facet of this.
  • Sympathetic response acts primarily on afferent arteriole (Norepinephrine)
  • Hormonal response acts primarily on efferent arteriole (Angiotensin II)

Glomerular Filtration Rate – Determinants

GLOMERULAR FILTRATION RATE

  • The volume of ultrafiltrate formed by all of the nephrons of the kidneys per minute;
  • Units = mL/min.
  • Typical healthy GFR is between 110-130 mL/min; it varies based on sex, body composition, age, and other factors.

GFR is directly proportional to:

  • Filtration membrane permeability
  • Surface area available for filtration
  • Net filtration pressure is largely influenced by hydrostatic glomerular capillary pressure (PGC), which is easily adjusted by altering blood flow through the glomerulus.
  • Of the three variables that determine GFR, net filtration pressure is the easiest to manipulate.

Key Relationships:

Baseline:

  • Constant supply of renal blood flows through the afferent arteriole, glomerulus, and efferent arteriole.
  • Constant hydrostatic capillary pressure.
  • Constant GFR.

Afferent Arteriole Constriction:

  • Reduces renal blood flow
  • Reduces hydrostatic capillary pressure
  • Reduces GFR

Afferent Arteriole Dilation:

  • Increases renal blood flow
  • Increases hydrostatic capillary pressure
  • Increases GFR

Efferent Arteriole Mild Constriction:

  • Decreases renal blood flow
  • Increases hydrostatic capillary pressure
  • Increases GFR

Efferent Arteriole Extreme Constriction:

  • Decreases renal blood flow
  • Increases capillary oncotic forces
  • Decreases GFR

Efferent Arteriole Dilation:

  • Increases renal blood flow
  • Decreases hydrostatic capillary pressure
  • Decreases GFR

Clinical Correlations:

  • GFR is clinically measured to evaluate kidney functioning.
  • GFR can be altered by medications that cause vasoconstriction or vasodilation.

Renal Clearance

Renal blood flow

  • Volume of blood that flows through the kidneys per minute (mL/min).
  • Typically 20-25% of total cardiac output.

Renal blood plasma

  • Volume of renal blood plasma that flows through the kidneys per minute (mL/min)
  • Plasma is the aqueous portion of the blood.

Renal clearance

  • Volume of plasma from which a substance is removed in a given amount of time.
  • Indicates whether a substance is filtered, reabsorbed, and/or secreted.
  • It is calculated according to the Fick Principle, which states:
    The amount of substance that enters the kidney is equal to the amount of substance that leaves it.

Blood composition:

  • Approximately 55% renal plasma
    -93% plasma water, which gets filtered across the glomerularcapillaries to create ultra filtrate.
    -7% plasma proteins
  • Approximately 45% blood cells (hematocrit)
  • Renal blood flow = Renal plasma flow divided by (1 minus Hematocrit).
    – Renal blood flow averages 1000-1250 mL/min.
    – Renal plasma flow averages 550-690 mL/min.

Calculating renal clearance:

Clearance of substances varies from 0% to nearly 100%:

  • Renal clearance of albumin, which is a large protein, is 0% because large proteins are excluded from the ultrafiltrate.
  • Renal clearance of glucose, which is freely filtered, is also 0%, because it is completely reabsorbed in the nephron tubule.
  • Renal clearance of para-amniohippuric acid (PAH), which is an organic acid, is nearly 100% because it is both filtered at the renal corpuscle and secreted into the nephron tubule lumen.
    – In other words, nearly all of the PAH that enters the kidney is cleared from the plasma and excreted into the urine.

Clinical use of PAH:

Because it is both filtered and secreted, the clearance of PAH can be used clinically to measure the effective renal plasma flow. Be aware that it does not measure true renal plasma flow because some PAH remains in the blood (approximately 10%).

  • To express this mathematically:
    The clearance of PAH and effective renal plasma flow are equal to:
    – The urine concentration of PAH multiplied by the urine flow rate divided by the plasma concentration of PAH.
  • In other words, we apply the Fick principle to compare the amount of PAH that entered the kidney in the blood plasma with the amount of PAH that was excreted in the urine; we ignored the amount of PAH in the renal vein, because it is almost completely excreted in the urine.
  • Clinical example to understand how renal clearance is used to calculate effective renal plasma flow and renal blood flow.
    – A patient has the following lab results:
    Urine concentration of PAH is 550 mg/100 mL
    Urine flow rate is 1 mL/min
    Plasma concentration of PAH is 1 mg/100 mL
    Hematocrit is 0.45.
    – With these values, we can estimate PAH clearance, and, therefore, renal plasma flow:
    550 mg/100 mL multiplied by 1 ml/min
    Divided by 1 mg/100 mL.
    =
    550 mL/min.
    – Then, return to our equation for renal blood flow, and write that:
    Renal blood flow= 550 mL/min divided by 1-0.45.
    Thus, we have a renal blood flow of 1000 mL/min.

Additional clinical uses of renal clearance:

  • GFR marker is a substance with a clearance equal to GFR; therefore, its clearance can be clinically determined to evaluate GFR and kidney functioning.
  • Two examples of GFR markers:
    Inulin has a clearance exactly equal to GFR because it is filtered, but not reabsorbed or secreted.
    Creatinine has a clearance that is nearly equal to GFR because it is filtered and only minimally secreted.
    – However, since creatinine is an endogenous substance (and inulin is not), it is the preferred GFR marker in most clinical situations.

Micturition: Anatomy and Physiology

OVERVIEW

  • Parasympathetic nervous system ACTIVATES urination.
  • Sympathetic nervous system INHIBITS it.
  • Somatomotor system (volitional control) INHIBITS it.

MAJOR STRUCTURES

The major functional structures of the lower urinary system:

  • Urinary bladder
  • Urethra
  • Detrusor muscle (the bladder wall muscle).
  • Internal urethral sphincter
  • External urethral sphincter

MAJOR FUNCTIONS

Filling phase

During the filling phase:

  • Detrusor relaxes (stretches).
  • Internal sphincter contracts (closes).
  • External sphincter contracts (closes).

Voiding phase

During the micturition (voiding) phase,

  • Detrusor contracts.
  • Internal sphincter relaxes (opens).
  • External sphincter relaxes (opens).

FILLING CIRCUITRY

Sympathetic nervous system

  • The sympathetic preganglionic origins are in the intermediolateral cell column from T10 – L2).
  • The sympathetic fiber system acts on the detrusor muscle and internal urethral sphincter to promote bladder filling: this is an unconscious action.

Somatomotor system

  • Onuf ‘s nucleus (aka nucleus of Onufrowicz) comprises the S2 – S4 motor neurons in the anterior horn of the spinal cord; these motor neurons provide volitional innervation to the pelvis.
  • The somatomotor system acts on the external urethral sphincter to promote bladder filling: this is under volitional control – so you can “hold” your urine.

VOIDING CIRCUITRY

Stretch Receptors

  • Stretch receptors, which are mechanoreceptors in the bladder walls excite the micturition response when there is sufficient bladder wall distention, typically at 400ml of urine.

Parasympathetic nervous system

  • The parasympathetic preganglionic originates in the intermediolateral cell column of S2 – S4.
  • It acts on the detrusor muscle and internal urethral sphincter to promote emptying: this is an unconscious action.

REVIEW

  • Sympathetic fibers inhibit bladder wall contraction and excite internal urethral sphincter constriction, which inhibits urination.
  • Parasympathetic fibers excite bladder wall contraction and inhibit internal urethral sphincter constriction, which activates urination.
  • Somatomotor efferents provide tonic activation of the external urethral sphincter, which inhibits urination.

PONTINE MICTURITION CENTER

  • The pontine micturition center lies in the medial (M) region of the dorsolateral pontine tegmentum and the pontine continence center lies ventro-lateral to it in the lateral (L) region. Barrington first described the pontine micturition center, so it is often referred to as the Barrington nucleus.
  • These regions receive innervation from the brain, including the periaqueductal gray area, frontal lobes, hypothalamus, limbic system, and others; their action on micturition is understood from their general roles in the nervous system.

KEY PATHOLOGIC CONDITIONS

  • Urinary retenion (overdistension of the bladder) occurs from mechanical causes (enlarged prostate) or failure of bladder wall contraction (spinal shock).
  • Stress incontinence involves sudden, unnanticipated micturition, which can occur from a weak external urinary sphincter or an overexcitable bladder (such as from chronic spinal cord injury).

Volume Contraction and Expansion

  • Water moves along osmotic gradients
    — Osmolarity is the concentration of solute particles within a solution (there are intertextual discrepancies regarding osmolarity vs. osmolality).
  • A change in the amount of solute and/or water will cause water to shift between body fluid compartments.
  • Isosmotic = no change in extracellular fluid osmolarity
  • Hyperosmotic = increase in extracellular fluid osmolarity
  • Hyposmotic = decrease in extracellular fluid osmolarity
  • To predict how changes in water volume or solutes affect water distribution, we’ll ask ourselves the following three questions:
    — First, how did the extracellular fluid change? Was water volume or solute concentration changed? Was it an increase or a decrease?
    — Second, does the change produce an increase, decrease, or no change in the osmolarity of the extracellular fluid?
    — Third, if extracellular osmolarity changes, will water shift into or out of the intracellular compartment?

Baseline Distribution

  • About two-thirds of total body water is in the intracellular compartment; this is the water within all the body’s cells.
  • The remaining body water is in the extracellular compartment (1/3).
  • The osmolarity of the extracellular and intracellular compartments is equal, despite differences in specific solute concentrations (this is addressed in detail, elsewhere).
  • Furthermore, recognize that “body water” is not synonymous with “pure” water.

VOLUME CONTRACTION

Isosmotic volume contraction

Occurs when isosmotic fluid is lost from diarrhea.

  • Because the fluid lost in diarrhea has roughly the same osmolarity as that of the ECF, the volume, but not the osmolarity, of extracellular fluid decreases.
  • And, because osmolarity remained stable, there is no water shift from the intracellular compartment, which remains unchanged.

Hyperosmotic volume contraction

Occurs when hyposmotic fluid is lost from the extracellular compartment. For example, imagine an individual running in the desert without drinking water; he will experience excessive sweating without fluid replenishment. Be aware that sweat is hyposmotic, that is, its water:solute ratio is higher than that of the blood.

  • Excessive sweating leads to contraction of the extracellular compartment volume.
  • Because sweat is hyposmotic, its loss from the extracellular compartment will increase the osmolarity of the remaining fluid.
  • Then, because the osmolarity of the extracellular compartment is higher than that of the intracellular compartment, water shifts from the ICF to the ECF.
    — Notice that the water shift only partially compensates for volume contraction.
  • Now, the remaining fluid in the intracellular compartment is also hyperosmotic, because only water, not solutes, moved to the ECF.

Hyposmotic volume contraction

Occurs when hyperosmotic fluid is lost from the ECF in individuals with adrenal insufficiency.
Recall that sodium is a key extracellular solute, and that aldosterone promotes its reabsorption in the distal nephron; thus, aldosterone is essential for maintaining ECF osmolarity.
However, individuals with adrenal insufficiency do not produce adequate aldosterone, so excess salt is excreted in the urine.

  • Extracellular osmolarity decreases due to salt loss.
  • At this point, extracellular osmolarity is lower than intracellular osmolarity.
  • To correct this imbalance, water to shifts from the ECF to the ICF until the osmolarity of the two compartments is reduced to the same level.
  • Intracellular fluid volume is increased by the water shift.

VOLUME EXPANSION

Isosmotic volume expansion

Caused by an infusion of isotonic saline.

  • Extracellular fluid volume increases, but does not change its osmolarity.
  • Because there is no change in extracellular osmolarity, there is no water shift.
  • The volume and osmolarity of the intracellular fluid compartment are unchanged.

Hyperosmotic volume expansion

Caused by the addition of dry solute to the ECF, for example, upon ingestion of salty foods.

  • The addition of solute to the extracellular fluid increases its osmolarity.
  • In response, water shifts from the intracellular compartment until the two compartments have the same osmolarity.
  • Thus, extracellular volume increases, only partially compensating for the increased osmolarity.
  • And, Intracellular volume decreases, leaving the remaining intracellular fluid hyperosmotic.

Hyposomotic volume expansion

Recall that antidiuretic hormone (ADH) promotes water reabsorption in the collecting ducts;
In individuals with Syndrome of Inappropriate Antidiuretic Hormone (SIADH), excessive AHD results in too much water reabsorption.

  • This water is added to both the extracellular and intracellular compartments.
  • And, because water was added, osmolarity decreases in both compartments.

Water Balance

KEY POINTS:

  • The kidneys play a key role in osmoregulation, which maintains the osmolarity of the body’s fluids.
  • Homeostatic osmolarity of blood is approximately 290 milliosomoles/liter.
  • Shifts in blood osmolarity trigger renal mechanisms that alter water reabsorption in urine to return to blood osmolarity to homeostasis.
  • Thus, urine osmolarity reflects these changes.

KEY DEFINITIONS: RELATE URINE OSMOLARITY TO BLOOD OSMOLARITY

  • Isosmotic urine has the same osmolarity as blood.
  • Hyperosmotic urine has higher osmolarity than blood.
  • Hypoosmotic urine has lower osmolarity than blood.

Water Deprivation:

Water deprivation triggers the production of hyperosmotic urine.

  • High solute concentration raises blood osmolarity.
  • Osmoreceptors in hypothalamus are activated.
    – In response, osmoreceptors trigger increased thirst
    – Osmoreceptors also trigger the pituitary gland to release ADH.
  • In the kidney, ADH increases the number of nephron principal cell aquaporins
    – More water is reabsorbed
  • Blood osmolarity returns to homeostasis.
  • Urine volume is reduced; osmolarity is increased.

Clinical Correlations:

  • One of the treatments for bedwetting is to give exogenous ADH (vasopressin) in order to reduce urine volume at night.
  • In the syndrome of inappropriate ADH (SIADH), circulating levels of ADH are abnormally elevated, which increases the amount of water reabsorption and produces hyperosmotic urine; ADH inhibitors can correct this.

Water excess:

Water excess triggers production of hyposmotic urine.

  • High body water content reduces blood osmolarity.
  • Hypothalamic osmoreceptors are not activated, so pituitary gland is not stimulated to release ADH.
  • In absence of ADH, fewer aquaporins in the nephron reabsorb water.
  • Excess water is released in the urine.
  • Blood osmolarity returns to homeostasis.
  • Urine volume is high, its osmolarity is low.

Clinical Correlations:

  • In diabetes insipidus, there is either pathologic failure of ADH release or failure of kidney detection of ADH; as a result, large volumes of dilute urine are produced. DI can be treated with exogenous ADH or other medications

Body Fluid Compartments

Total body water:

  • Water comprises 50-70% of total body weight; the rest comprises solids.
  • Precise volume largely depends on proportion of muscle tissue (which have more water) to adipose tissue (which has less).
  • Body water is distributed between two major compartments:
    – Intracellular compartment = 2/3; this is the water contained within cells, and bound by cell membranes.
    – Extracellular compartment = 1/3; this is the fluid that bathes cells, and is outside of the cell membrane.
    The extracellular fluid is further subdivided:
    – Eighty percent is in the interstitial fluid, which is the fluid that “bathes” the non-blood cells of the body.
    – The remaining twenty percent is in the plasma, which is the fluid that suspends the blood cells; it is bound by capillary walls.

Water shifts compartments in response to osmotic conditions

  • We can think of the body compartments as containers of solution:
    – The solvent is water.
    – Solutes include electrolytes, which are charged particles, and nonelectrolytes, which include mostly organic molecules (such as glucose and lipids).
  • Osmolarity is the concentration of solute particles within a solution (be aware of intertextual variation regarding osmolarity vs. osmolality).
  • In homeostasis, the intracellular osmolarity and extracellular osmolarity are equal.

Key solutes of intracellular fluid:

  • Potassium and magnesium ions.
  • Proteins and organic phosphates (for example, ATP).

Key solutes of extracellular fluid:

  • Sodium, chloride, and bicarbonate ions.
  • Plasma proteins.
  • Because the interstitial fluid is an ultrafiltrate of plasma, it contains no proteins (this is discussed in detail, elsewhere).

Osmotic gradients:

  • Solutes create osmotic gradients, which drive shifts in water between compartments.
    – Shifts between compartments occur in response to changes in the amount of solute and/or water.
    – This can be because of changes in solute amount or water amount.
  • Direction of water shifts:
    – Between the plasma and interstitial fluid of the extracellular fluid.
    – Between interstitial fluid and the intracellular fluid.

Ureters and Urinary Bladder (urothelium)

Kidneys

  • Filter the blood to produce urine;

Ureters

  • Drain the kidneys medially (from the hilum), and descend along the posterior abdominal wall and into the pelvis, where they drain into the urinary bladder

Urinary bladder

  • Stores urine until micturition

URETER HISTOLOGY

Three tunics

  • Adventitia; recall that retroperitoneal organs, including the ureters and urinary bladder, have adventitia as their outer tunic instead of serosa (which comprises visceral peritoneum).
  • Muscularis layer
    • Outer circular, which wraps around the diameter of the ureter
    • Inner longitudinal, which runs the length of the ureter
  • Mucosa
    • Opens to the lumen of the ureter; the mucosal folds unfurl to increase the diameter of the lumen and accommodate urine.
    • Outer layer of lamina propria, which is a thick layer of connective tissues
    • Inner layer of transitional epithelium (aka, urothelium), which is continuous with the linings of the renal pelvis of the kidney and urinary bladder.
    • Transitional epithelium comprises irregularly shaped cells that change shape to accommodate changes in urine volume; thus, we’ll see it also in the urinary bladder.

URINARY BLADDER HISTOLOGY

  • Adventitia is the outermost layer
  • Muscularis comprises the detrusor muscle, a collection of three layers of smooth muscle; the detrusor muscle contracts to expel urine and relaxes during urine storage.
  • Submucosa, comprises connective tissues that support the urinary bladder walls, and,
  • Mucosa, which, like the mucosa of the ureter, comprises folds of lamina propria and transitional epithelia (not shown, here).
    • Mucosal rugae of the internal surface of the urinary bladder facilitate expansion to accommodate urine.
    • Openings of the ureters on the posterior/inferior bladder wall and internal urethral orifice form the trigone, is a smooth, triangularly shaped portion of the bladder wall; its shape and smooth surface act as a funnel to direct urine from the openings of the ureters to the urethra.
    • Epithelium comprises basal cells, intermediate cells, and, in the apical layer, umbrella cells.
      Umbrella cells derive their name from their wide dome shape; because they face the urine, they have tight junctions, a mucin layer, and other features that form a barrier to water and urea.

Clinical correlation

  • Transitional cell carcinoma is the most common type of bladder cancer; high-grade transitional cell carcinoma can spread through the muscular layer and to nearby organs and lymph nodes.

Nephron Loop and Collecting Duct

Key Functions and Features

  • The nephron loop’s function is to produce and maintain a high osmotic gradient in the medullary extracellular fluid
  • The vasa recta, which comprises a looping capillary network, travels in parallel with the nephron loop to effectively participate in the counter-current exchange
  • The collecting duct further concentrates urine and regulates its acidity to maintain systemic acid-base homeostasis

Anatomical Context

Kidney:

  • Renal capsule covers the cortex
  • Medulla comprises the renal pyramids
  • Cortico-medullary junction is where the cortex and medulla meet
    Nephron:
  • Renal corpuscle gives rise to the proximal convoluted tubule
  • PCT turns towards the medulla as the thick descending limb (aka, pars recta of the proximal tubule), then the thin descending limb
  • At bottom of the loop, the thin descending limb becomes the thin ascending limb, then abruptly becomes the thick ascending limb (the thick ascending limb is sometimes called the pars recta of the distal tubule).
  • The thick limb transitions to the distal convoluted tubule, which drains into a collecting duct via a collecting tubule.

Histological structures

Thin segments of the nephron loop

  • A thin layer of interdigitating squamous epithelial cells
  • Intercellular junctions link cells laterally
  • Nuclei are oval to round in shape, and lie near the lumen of the tubule.
  • Sparsely populated with organelles.

Thick ascending limb, aka, the diluting segment,

  • Has features that reflect active transport via the sodium-potassium pump.
  • Low cuboidal cells with interdigitating basolateral processes; these processes create an extensive intercellular matrix.
  • Nuclei and the abundant mitochondria support the energetic needs of the sodium-potassium pump.
  • Thick ascending limb has few, if any, short stubby microvilli; as in the thin limbs, there is no brush border.

Collecting duct

  • Comprises bulging columnar cells that enclose a large diameter.
  • Abundant organelles and basal infoldings
  • Distinct lateral borders are connected via intercellular junctions
  • Two types of collecting duct cells: principal and intercalated
    — Intercalated cells are darker-staining because they have more organelles and basal infoldings than do principal cells
    — Intercalated cells may also have numerous stubby microvilli (but not enough to constitute a brush border).

Tips to identify these structures in a histological sample

  • First, identify a portion of thick limb by its low columnar/cuboidal cells and roundish nuclei.
  • Next, identify portions of the thin limbs by their characteristic squamous epithelium.
  • Compare this to a portion of the vasa recta, which is also thin-walled; the two can be distinguished by the presence of red blood cells in the vasa recta.
  • Lastly, identify the tall bulging cells of a collecting duct; notice the wide diameter and dark-staining organelles.