Ganong Chapter 37: Renal Function and Micturition

What makes up the nephron?

Renal tubule + glomerulus

Is the diameter of the afferent or efferent arteriole larger?

Afferent arteriole

What are the layers that separate blood from glomerular filtrate?

Capillary endothelium

Specialized epithelium of the capsule

Structure of the Glomerular Capillary Endothelium

Fenestrated

Pores 70-90 nm in diameter

Completely surrounded by glomerular basement membrane and podocytes

• Podocytes have pseudopodia that interdigitate to form filtration slits along the capillary wall

Glomerular Basement Membrane

Basal lamina

Does not contain visible gaps or pores

Functionally permits the free passage of neutral substances up to 4 nm in diameter and almost totally excludes those with diameters greater than 8 nm

Mesangial Cells

Located between the basal lamina and endothelium

Contractile and play a role in regulation of glomerular filtration

Secrete the extracellular matrix, take up immune complexes, and are involved in the progression of glomerular disease

Structure of the Proximal Convoluted Tubule

Wall made up of a single layer of cells that interdigitate with one another and are united by apical tight junctions

Between the cells are extensions of the extracellular space called the lateral intercellular spaces

Luminal edges of the cells have a striated brush border

Structure of the Loop of Henle

Descending portion of the loop and proximal portion of the ascending limb made up of thin, permeable cells

The thick portion of the ascending limb is made up of thick cells containing many mitochondria

Cortical nephrons have short loops of Henle

Juxtamedullary nephrons have long loops extended down into the medullary pyramids

What makes up the juxtaglomerular apparatus?

Macula densa

Neighboring lacis cells

Renin-secreting granular cells in the afferent arteriole

Structure of the Distal Convoluted Tubule

Starts at the macula densa

Epithelium is lower than that of the proximal tubule

No distinct brush border

Structure of the Collecting Ducts

Pass through the renal cortex and medulla to empty into the pelvis of the kidney at the apexes of the medullary pyramids

Epithelium is made up of principal cells (P cells) and intercalated cells (I cells)

Principal Cells (P cells)

Relatively tall

Have few organelles

Involved in Na+ reabsorption and vasopressin-stimulated water reabsorption

Intercalated Cells (I cells)

Present in smaller numbers

Also found in the distal tubules

Have more microvilli, cytoplasmic vessels, and mitochondria

Concerned with acid secretion and HCO3- transport

Renal Medullary Interstitial Cells (RMICs)

Specialized fibroblast-like cells

Major site of COX-2 and prostaglandin synthase (PGES) expression

What is the major prostanoid synthesized in the kidney?

PGE2

Function of PGE2

Important paracrine regulator of salt and water homeostasis

Where is PGE2 secreted from?

Renal medullary interstitial cells (RMICs)

Macula densa

Cells in the collecting ducts

Where are PGI2 and other prostaglandins secreted from?

The arterioles and glomeruli

What are afferent arterioles branches of?

Interlobular arteries

What do efferent arterioles become?

Peritubular capillaries before draining into interlobular veins

What are the only capillaries in the body that drain into arterioles?

Glomerular capillaries

Where do efferent arterioles from the juxtamedullary glomeruli drain into?

Efferent arterioles from the juxtamedullary glomeruli drain into a peritubular network and into vessels that form hairpin loops (vasa recta)

• Descending vasa recta have a nonfenestrated endothelium that contains a facilitated transporter for urea

• Ascending vasa recta have a fenestrated endothelium

How much blood is in the renal capillaries at any given time?

30-40 mL

Renal Circulation

Where do the renal lymphatics drain?

Via the thoracic duct

Renal Capsule

Limits swelling if the kidney becomes edematous and renal interstitial pressure rises which decreases GFR and enhances and prolongs anuria in AKI

What do renal nerves contain?

Many postganglionic sympathetic efferent fibers and a few afferent fibers

Cholinergic Innervation of the Kidney

Via the vagus nerve

Sympathetic Preganglionic Innervation of the Kidney

Comes primarily from the lower thoracic and upper lumbar segments of the spinal cord

Where are cell bodies of the post ganglionic neurons of the kidney located?

In the sympathetic ganglion chain, in the superior mesenteric ganglion, and along the renal artery

Where are sympathetic fibers distributed in the kidney?

Afferent and efferent arterioles

Proximal and distal tubules

Juxtaglomerular apparatus

What is the innervation of the thick ascending loop of Henle?

Dense nonadrenergic innervation

Where do renal nociceptive afferents enter the spinal cord?

In the thoracic and upper lumbar dorsal roots

Renorenal Reflex

An increase in ureteral pressure in one kidney leads to a decrease in efferent nerve activity to the contralateral kidney which permits and increase in its excretion of Na+ and water

How much blood per minute do the kidneys receive in a resting adult?

1.2-1.3 L of blood per minute or just under 25% of the cardiac output

Determining Renal Blood Flow with the Fick Principle

By measuring the amount of a given substance taken up per unit of time and dividing this value by the arteriovenous difference for the substance across the kidney

Renal Plasma Flow (RPF)

Equals the amount of a substance excreted per unit of time divided by the renal arteriovenous difference as long as the amount in the red cells is unaltered during passage through the kidney

• Any excreted substance can be used if its concentration in arterial and renal venous plasma can be measured and if it is not metabolized, stored, or produced by the kidney and does not itself affect blood flow

Measuring RPF using PAH

• RPF can be measured by infusing p-aminohippuric acid (PAH) and determining its urine and plasma concentrations

  • PAH is filtered by the glomeruli and secreted by the tubular cells so its extraction ratio is high

    • When PAH is infused at low doses, 90% of the PAH in arterial blood is removed in a single circulation through the kidney

  • Can calculate RPF by dividing the amount of PAH in the urine by the plasma PAH level, ignoring the level in renal venous blood

    • Peripheral venous plasma PAH concentration is essential identical to that in the arterial plasma reaching the kidney

    • Value obtained called the effective renal plasma flow (ERPF) to indicate that the level in renal venous plasma was not measured

Extraction Ratio

Arterial concentration minus renal venous concentration divided by arterial concentration

Effective renal plasma flow (ERPF)/extraction ratio = actual RPF

Calculating Renal Blood Flow Using the Hematocrit

What is the glomerular capillary pressure when mean systemic arterial pressure is 100 mmHg?

Around 45 mmHg

What is the pressure drop across the glomerulus?

The pressure drop across the glomerulus is only 1-3 mmHg but a further drop occurs in the efferent arteriole so that the pressure in the peritubular capillaries is about 8 mmHg

What is the pressure in the renal vein?

About 4 mmHg

What % of systemic arterial pressure is glomerular capillary pressure?

About 40% of systemic arterial pressure

Action of Norepinephrine on Renal Blood Flow

Constricts renal vessels

Greatest effect of injected norepinephrine on interlobular arteries and afferent arterioles

Action of Dopamine on Renal Blood Flow

Causes renal vasodilation and natriuresis

Effect of Angiotensin II on Renal Blood Flow

Exerts a constrictor effect on both the afferent and efferent arterioles

Effect of Prostaglandins on Renal Blood Flow

Increase blood flow in the renal cortex and decrease blood flow in the renal medulla

Effect of Acetylcholine on Renal Blood Flow

Renal vasodilation

What effect does a high protein diet have on renal blood flow?

High protein diet raises glomerular capillary pressure and increases renal blood flow

What does stimulation of the renal nerves result in?

Increases renal secretion by direct action of released norepinpehrine on B1-adrenergic receptors on the juxtaglomerular cells and it increases Na+ reabsorption, probably by a direct action of norepinephrine on renal tubular cells

What is order of responses seen as renal nerves are stimulated to increasing extents?

First response is an increase in the sensitivity of the granular cells in the juxtaglomerular apparatus

Followed by renin secretion

Then increased Na+ reabsorption

Last, renal vasoconstriction with decreased glomerular filtration and renal blood flow

What occurs following strong stimulation of the sympathetic noradrenergic nerves to the kidneys?

Causes a marked decrease in renal blood flow which is mediated by a1-adrenergic receptors and to a lesser extent by postsynaptic a2-adrenergic receptors

What is the response of renal blood flow when systemic blood pressure falls?

The vasoconstrictor response produced by decreased discharge in the baroreceptor nerves includes renal vasoconstriction

Autoregulation of Renal Blood Flow

• When the kidney is perfused at moderate pressures (90-220 mmHg in the dog), the renal vascular resistance varies with the pressure so renal blood flow is relatively constant

• Prevented by administration of drugs that paralyze vascular smooth muscle

• At low perfusion pressures, angiotensin II appears to play a role by constricting the efferent arterioles, maintaining the GFR

Renal Cortical Blood Flow

Renal cortical blood flow is relatively great and little oxygen is extracted from the blood

What is the rate of renal cortical blood flow?

5 ml/g of kidney tissue/min

What is the PO2 of the renal cortex?

About 50 mmHg

Renal Medullary Blood Flow

Maintenance of the osmotic gradient in the medulla requires a relatively low blood flow

Metabolic work is being done, particularly to reabsorb Na+ in the thick ascending limb of Henle, so relatively large amounts of O2 are extracted from the blood in the medulla

What is the rate of blood flow in the renal medulla?

About 2.5 ml/g/min in the outer medulla

About 0.6 ml/g/min in the inner medulla

What is PO2 in the renal medulla?

About 15 mmHg, making the medulla vulnerable to hypoxia if flow is reduced further

Glomerular Filtration Rate (GFR)

The amount of plasma ultrafiltrate formed each minute

What is equine GFR?

~2-2.1 mL/kg/min

How is GFR measured?

Can be measured in experimental animals and humans by measuring the plasma level of a substance and the amount of that substance that is excreted

• Substance to be used must be freely filtered through the glomeruli and neither secreted or reabsorbed by the tubules

  • Also must be nontoxic and not metabolized by the body

• Inulin is used in humans and most animals

Renal Plasma Clearance

Volume of plasma from which a substance is completely removed by the kidney in a given amount of time (usually minutes)

GFR Equation

• GFR = concentration of X in urine (U_x) x urine flow per unit of time (V)/arterial plasma level of X (P_x) = clearance of X (CX)

Clearance of Creatinine (C_Cr)

Can also be used to determine GFR, but some creatinine is secreted by the tubules so clearance of creatinine will be slightly higher than inulin

• More common is the use of P_Cr values as an index of renal function

What % of renal filtrate is normally reabsorbed?

99% or more

Factors that Govern Filtration Across the Glomerular Capillaries

Size of the capillary bed

Permeability of the capillaries

Hydrostatic and osmotic pressure gradients across the capillary wall

GFR Equation for Each Nephron

• K_f = glomerular ultrafiltration coefficient

  • Product of the glomerular capillary wall hydraulic conductivity (i.e. its permeability) and the effective filtration surface area

• P_GC - mean hydrostatic pressure in the glomerular capillaries

• P_T - mean hydrostatic pressure in the tubule (Bowman's space)

• pi_GC - oncotic pressure of the plasma in the glomerular capillaries

• pi_T - oncotic pressure of the filtrate in the tubule (Bowman's space)

How many times more permeable are glomerular capillaries than skeletal muscle capillaries?

About 50 times more

What types of substances are freely filtered through the glomerulus?

Neutral substances with effective molecular diameters of less than 4 nm

What type of substances are not filtered through the glomerulus at all?

Neutral substances with diameters of more than 8 nm

What is the rate of filtration in the glomerulus for substances between 4 and 8 nm in diameter?

Filtration is inversely proportional to diameter

How does filtration of anionic substances 4 nm in diameter relate to neutral substances of the same size?

Filtration of anionic substances 4 nm in diameter is less than half that of neutral substances of the same size

What is the filtration of cationic substances compared to neutral substances?

Filtration of cationic substances is greater than that of neutral substances

Where does most of the protein in the urine come from?

Most of the protein in the urine is not filtered but comes from shed tubular cells

What can alter the glomerular ultrafiltration coefficient (K_f)?

K_f can be altered by the mesangial cells, with contraction of these cells producing a decrease in K_f that is largely due to a reduction in the area available for filtration

Agents that Cause Contraction of Mesangial Cells

Endothelins

Angiotensin II

Vasopressin

Norepinephrine

Platelet-activating factor

Platelet-derived growth factor

Thromboxane A2

PGF2

Leukotrienes C4 and D4

Histamine

Agents that Cause Mesangial Cell Relaxation

ANP

Dopamine

PGE2

cAMP

Why is pressure in the glomerular capillaries higher than in other capillary beds?

The afferent arterioles are short, straight branches of the interlobular arteries and the efferent arterioles have a relatively high resistance

What opposes renal capillary hydrostatic pressure?

Capillary hydrostatic pressure is opposed by the hydrostatic pressure in Bowman’s capsule and the oncotic pressure gradient across the glomerular capillaries

• The oncotic pressure of Bowman’s capsule is normally negligible so the oncotic pressure gradient is essentially equal to the oncotic pressure of the plasma proteins

Net Filtration Pressure (P_UF) of the Glomerular Capillaries

Net filtration pressure is 15 mmH at the afferent end of the glomerular capillaries, but it falls to zero (filtration equilibrium is reached) proximal to the efferent end of the glomerular capillaries

• This is because fluid leaves the plasma and the oncotic pressure rises as blood passes through the glomerular capillaries

A decrease in the rate of rise of the delta curve produced by an increase in RPF would increase filtration because it would increase the distance along the capillary in which filtration was taking palce

What limits exchange across glomerular capillaries?

Exchange across the glomerular capillaries is flow-limited rather than diffusion-limited

Factors that Affect the GFR

Changes in renal blood flow

Changes in glomerular capillary hydrostatic pressure

Changes in systemic blood pressure

Afferent or efferent arteriolar constriction

Changes in hydrostatic pressure in Bowman’s capsule

Ureteral obstruction

Edema of kidney inside tight renal capsule

Change in concentration of plasma proteins: dehydration, hypoproteinemia, etc (minor factors)

Changes in K_f

Changes in glomerular capillary permeability

Changes in effective filtration surface area

Filtration Fraction

Ratio of GFR to RPF

• Normally 0.16-0.20

GFR varies less than RPF

When there is a fall in systemic blood pressure, the GFR falls less than the RPF because of efferent arteriolar constriction and the filtration fraction rises

Tubular Function

• The amount of any substance (X) that is filtered is the product of the GFR and the plasma level of the substance (C_InP_x)

• The tubular cells may add more of the substance to the filtrate (tubular secretion), may remove some or all of the substance from the filtrate (tubular reabsorption), or may do both

• The amount of the substance excreted per unit of (U_xV) time equals the amount filtered plus the net amount transferred by the tubules

  • Amount filtered by the tubules represented by T_x

• Clearance of the substance equals the GFR if there is no net tubular secretion or reabsorption, exceeds the GFR if there is net tubular secretion, and is less than the GFR if there is net tubular reabsorption

Mechanisms of Tubular Reabsorption and Secretion

• Small proteins and some peptide hormones are reabsorbed in the proximal tubules by endocytosis

• Other substances are secreted or reabsorbed in the tubules by passive diffusion between cells and through cells by facilitated diffusion down chemical or electrical gradients or active transport against the gradients

• The tubular epithelium is a leaky epithelium

  • Tight junctions between cells permit passage of some water and electrolytes - paracellular pathway

Transport Maximum (T_m)

Maximal rate that renal active transport systems can transport a particular solute

• The amount of a particular solute transported is proportional to the amount present up to the T_m for the solute, but at higher concentrations, the transport mechanism is saturated and there is no appreciable increment in the amount transported

What % of sodium is reabsorbed in the proximal tubule?

60%

What % of sodium is reabsorbed in the thick ascending limb?

30%

What % of sodium is reabsorbed in the distal convoluted tubule?

7%

What % of sodium is reabsorbed in the collecting duct?

3%

Function of the Na/glucose CT in the Proximal Tubule

Na+ uptake, glucose uptake

Function of the Na+/P_i CT in the Proximal Tubule

Na+ uptake, P_i uptake

Function of the Na+/Amino Acid CT in the Proximal Tubule

Na+ uptake, amino acid uptake

Function of the Na/Lactate CT in the Proximal Tubule

Na+ uptake, lactate uptake

Function of the Na/H Exchanger in the Proximal Tubule

Na+ uptake, H+ extrusion

Function of the Cl/Base Exchanger in the Proximal Tubule

Cl- uptake, HCO3- reabsorption

Function of the Na-K-2Cl CT in the Thick Ascending Limb

Na+ uptake, Cl- uptake, K+ uptake