Renal Page 11 to 21

• The kidneys receive 25% of the cardiac output, which is among the highest of all organ systems
• For a person with a cardiac output of 5 L/min, renal blood flow (RBF) is 1.25 L/min or 1800 L/day
• High rates of RBF help the kidneys maintain the volume and composition of body fluids

Regulation of Renal Blood Flow

• RBF (Q) is directly proportional to the pressure gradient (ΔP) between the renal artery and vein
• RBF is inversely proportional to the resistance (R) of the renal vasculature.
• Resistance is mainly provided by arterioles
• The kidney is unusual because it has two sets of arterioles: afferent and efferent
• Changing arteriolar resistance is the major mechanism for changing blood flow
• This is accomplished by changing afferent arteriolar resistance and/or efferent arteriolar resistance

Sympathetic Nervous System and Catecholamines

• Afferent and efferent arterioles are innervated by sympathetic nerve fibers
• Sympathetic nerve fibers produce vasoconstriction by activating α1 receptors
• Afferent arterioles have more α1 receptors
• Increased sympathetic nerve activity causes a decrease in both RBF and GFR
• During hemorrhage, blood loss decreases arterial pressure, which increases sympathetic outflow
• Activation of renal α1 receptors causes vasoconstriction of afferent arterioles
• Vasoconstriction leads to decreased RBF and GFR
• The cardiovascular system tries to raise arterial pressure, reducing blood flow to the kidneys

Angiotensin II

• Angiotensin II constricts both afferent and efferent arterioles
• Angiotensin II increases resistance, and decreases blood flow
• Efferent arterioles are more sensitive to angiotensin II than afferent arterioles, affecting GFR
• Low levels of angiotensin II increase GFR by preferentially constricting efferent arterioles
• High levels of angiotensin II decrease GFR by constricting both afferent and efferent arterioles
• In hemorrhage, decreased arterial pressure activates the renin-angiotensin-aldosterone system
• High levels of angiotensin II, with increased sympathetic nerve activity constrict afferent and efferent arterioles, decreasing RBF and GFR

Atrial Natriuretic Peptide (ANP)

• ANP and related substances like brain natriuretic peptide (BNP) dilate afferent arterioles
• ANP constricts efferent arterioles
• ANP's dilatory effect on afferent arterioles is greater than its constrictor effect on efferent arterioles
• ANP causes an overall decrease in renal vascular resistance
• ANP leads to an increase in RBF
• ANP increases GFR

Prostaglandins

• Prostaglandins (e.g., prostaglandin E2 and prostaglandin I2) are produced locally in the kidneys
• Prostaglandins cause vasodilation of both afferent and efferent arterioles
• Stimuli that activate the sympathetic nervous system and increase angiotensin II levels in hemorrhage also activate local renal prostaglandin production
• The vasodilatory effects of prostaglandins are protective for RBF as they attenuate vasoconstriction
• Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis
• NSAIDs interfere with the protective effects of prostaglandins on renal function following a hemorrhage and can cause a reduction in RBF
• Unopposed vasoconstriction can cause a profound reduction in RBF, resulting in renal failure

Dopamine

• Dopamine, a precursor of norepinephrine
• Dopamine dilates cerebral, cardiac, splanchnic, and renal arterioles
• Dopamine constricts skeletal muscle and cutaneous arterioles
• Low dosage of dopamine can be administered during hemorrhage
• Dopamine has a protective (vasodilatory) effect on blood flow in critical organs including the kidneys

Nitric Oxide

• Nitric oxide is synthesized by renal endothelial cells from L-arginine
• Nitric oxide dilates renal arterioles
• Nitric oxide protects against the vasoconstrictor effects of the sympathetic nervous system

Autoregulation of Renal Blood Flow

• Renal blood flow (RBF) is autoregulated over a wide range of mean arterial pressures (80 to 200 mm Hg)
• RBF remains constant unless renal arterial pressure decreases to less than 80 mm Hg
• Constancy of blood flow is maintained by varying the resistance of the arterioles.
• As renal arterial pressure increases or decreases, renal resistance increases or decreases proportionately
• Resistance is controlled primarily at the level of the afferent arteriole, rather than the efferent arteriole
• Autoregulation is intrinsic to the kidney
• The autonomic nervous system is not involved, as a denervated kidney autoregulates

Myogenic Hypothesis

• Increased arterial pressure stretches blood vessels, causing reflex contraction of smooth muscle
• Stretch-induced contraction involves the opening of stretch-activated calcium (Ca2+) channels in smooth muscle cells
• More calcium entering vascular smooth muscle cells leads to more tension in the blood vessel wall
• Increases in renal arterial pressure stretch the walls of the afferent arterioles, causing them to contract
• Afferent arteriolar contraction leads to increased afferent arteriolar resistance
• Resistance balances the increase in arterial pressure, and RBF is kept constant

Tubuloglomerular Feedback

• When renal arterial pressure increases, both RBF and GFR increase
• Increased GFR results in increased delivery of solute and water to the macula densa region of the early distal tubule
• Macula densa responds to the increased delivered load by secreting a vasoactive substance that constricts afferent arterioles via a paracrine mechanism
• Local vasoconstriction of afferent arterioles reduces RBF and GFR back to normal
• Increased GFR leads to increased delivery of fluid and solutes downstream to the macula densa
• Na+ and Cl- are transported into macula densa cells by the Na+-2Cl-K+ cotransporter
• Increased intracellular Cl- concentration depolarizes the basolateral membrane of macula densa cells
• Depolarization opens Ca2+ channels and causes increased intracellular Ca2+ concentration
• Increased intracellular Ca2+ releases adenosine from macula densa cells
• Adenosine acts locally, by a paracrine mechanism, to cause vasoconstriction of nearby afferent arterioles
• Vasoconstriction causes a decrease in RBF and GFR back to normal
• Factors like volume expansion, atrial natriuretic peptide, and a high-protein diet alter the sensitivity of tubuloglomerular feedback
• A high-protein diet increases GFR by increasing Na+ and Cl- reabsorption, decreasing delivery to the macula densa

Measuring Renal Plasma Flow and Renal Blood Flow

• Renal plasma flow (RPF) can be estimated from the clearance of an organic acid, para-aminohippuric acid (PAH)
• Renal blood flow (RBF) is calculated from the RPF and the hematocrit

Fick Principle

• The amount of a substance entering an organ equals the amount of the substance leaving the organ
• The substance is neither synthesized nor degraded by the organ
• For the kidney, the amount of a substance entering the kidney via the renal artery equals the amount of the substance leaving the kidney via the renal vein plus the amount excreted in the urine

Simplifications for Measuring Effective RPF

• Infusion of PAH, sampling urine, and sampling blood from the renal artery and renal vein are necessary to measure real RPF
• Because it is difficult to get blood samples from the renal blood vessels in humans, simplifications can be used to measure effective RPF
• Effective RPF approximates real RPF to within 10%
• [RV]PAH is assumed to be zero because most of the PAH entering the kidney via the renal artery is excreted in the urine by the combined processes of filtration and secretion
• [RA] PAH equals the PAH concentration in any peripheral vein, which can be easily sampled

Measuring Effective Renal Plasma Flow

• Equals the clearance of PAH
• Underestimates true RPF by about 10%
• Effective RPF underestimates true RPF because [RV] PAH is not zero because a tiny fraction of the RPF serves kidney tissue that is not involved in filtration and secretion of PAH
• PAH contained in that blood is returned to the renal vein

Measuring Renal Blood Flow

• Renal blood flow (RBF) is calculated from renal plasma flow (RPF) and the hematocrit (Hct)
• RBF is the RPF divided by 1 minus the hematocrit, where hematocrit is the fraction of blood volume that is occupied by red blood cells.

Glomerular Filtration

• Glomerular filtration is the first step in the formation of urine
• Blood is filtered into Bowman's space
• The filtered fluid (ultrafiltrate) is similar to interstitial fluid and contains water and small solutes of blood, but not proteins and blood cells
• Characteristics of the glomerular capillary wall and the glomerular filtrate determine both the rate of glomerular filtration.

Layers of the Glomerular Capillary

• Starting with the capillary lumen and moving toward Bowman's space:

• Endothelial Cell Layer:

  • Has pores 70 to 100 nanometers (nm) in diameter
  • Allows fluid, dissolved solutes, and plasma proteins
  • Doesn't allow blood cells

• Basement Membrane:

  • Has three layers: the lamina rara interna, lamina densa, and lamina rara externa
  • Multilayered, doesn't allow filtration of plasma proteins

• Epithelial Cell Layer:

  • Specialized cells called podocytes attached to the basement membrane by foot processes
  • Filtration slits are 25 to 60 nm in diameter, bridged by thin diaphragms
  • The epithelial layer also inhibits filtration

Negative Charge on the Glomerular Capillary Barrier

• Negatively charged glycoproteins are present on the endothelium, basement membrane layers, podocytes, and filtration slits
• Positively charged solutes are attracted and easily filtered
• Negatively charged solutes are repelled and difficult to filter
• Important for large solutes such as plasma proteins, which have a net negative charge at physiologic pH.
• The negative charge helps prevent their filtration
• Certain glomerular diseases remove the negative charges, resulting in increased protein filtration and proteinuria

Starling Forces Across Glomerular Capillaries

• Starling pressures drive fluid movement across the glomerular capillary wall
• Two hydrostatic pressures and two oncotic pressures
• The oncotic pressure of Bowman's space is considered to be zero because filtration of protein is negligible

Starling Equation

• Fluid movement across the glomerular capillary wall is glomerular filtration
• It is described by the Starling pressures, with the assumption that the oncotic pressure of Bowman's space is zero

Starling Equation Parameters

• Kf or filtration coefficient, is the water permeability or hydraulic conductance of the glomerular capillary wall
• High Kf results in a larger volume of fluid being filtered; GFR is 180 L/day
• Kf for glomerular capillaries is more than 100-fold that for systemic capillaries
• PGC or hydrostatic pressure, is a force favoring filtration
• PGC is relatively high (45 mm Hg) compared to systemic capillaries
• In systemic capillaries, hydrostatic pressure falls along the length of the capillary; glomerular capillaries remain constant
• PBS or hydrostatic pressure in Bowman's space, is a force opposing filtration
• Hydrostatic pressure in Bowman's space measures 10mm Hg
• The origin of this pressure is fluid present in the lumen of the nephron.
• πGC or oncotic pressure in glomerular capillaries, is another force opposing filtration
• Determined by the protein concentration of glomerular capillary blood
• Does not remain constant along the capillary length, but progressively increases as fluid is filtered out
• πGC increases to the point where net ultrafiltration pressure becomes zero and glomerular filtration stops (filtration equilibrium)
• GFR is the product of Kf and the net ultrafiltration pressure
• The greater the net pressure, the higher the rate of glomerular filtration