Urine Formation by the Kidneys: Glomerular Filtration, Renal Blood Flow, and Their Control

Functions of the Kidneys

Excretion of metabolic waste products and foreign chemicals

Regulation of water and electrolyte balances

Regulation of body fluid osmolality and electrolyte concentrations

Regulation of arterial pressure

Regulation of acid-base balance

Secretion, metabolism, and excretion of hormones

Gluconeogenesis

Physiologic Anatomy of the Kidneys

The Nephron Is the Functional Unit of

the Kidney

Each human kidney has approximately 1 million nephrons

Each nephron contains a tubule and a glomerulus

Glomerulus The glomerulus, which is about 200 μm in diameter, is formed by the invagination of a tuft of capillaries into the dilated, blind end of the nephron known as Bowman’s capsule

The capillaries are supplied by an afferent arteriole and drained by the efferent arteriole

The diameter of the afferent arteriole is larger than the efferent arteriole

Glomerular capillary membrane seperates the blood from the glomerular filtrate in Bowman’s capsule

Glomerular Capillary Membrane

It has three (instead of the usual two) major layers:

the endothelium of the capillary

a basement membrane

a layer of epithelial cells (podocytes)

The capillary endothelium is perforated by thousands of small holes (70–90 nm in diameter) called fenestrae

Surrounding the endothelium is the basement membrane, which consists of a meshwork of collagen and proteoglycan fibrillae having negative charges

Podocytes surrounds the outer surface of the capillary basement membrane and have numerous pseudopodia that interdigitate to form filtration slits (25nm) along the capillary wall

Stellate cells called mesangial cells are located between the basal lamina and the endothelium. They are similar to cells called pericytes, which are found in the walls of capillaries elsewhere in the body. The mesangial cells are contractile and play a role in the regulation of glomerular filtration

Functionally, the glomerular membrane permits the free passage of neutral substances up to 4 nm in diameter and almost totally excludes those with diameters greater than 8 nm. However, the charge on molecules as well as their diameters affects their passage into Bowman’s capsule

Albumin (6 nm diameter) is restricted from filtration because of its negative charge and the electrostatic repulsion exerted by negative charges of the glomerular capillary wall proteoglycans

The total area of glomerular capillary endothelium across which filtration occurs in humans is about 0.8 m2

Section through vascular pole, showing capillary loops

Relation of mesangial cells and podocytes to glomerular capillaries

Detail of the way podocytes form filtration slits on the basal lamina, and the relation of the lamina to the

capillary endothelium

Enlargement of the rectangle in C to show the podocyte processes. The fuzzy material on their surfaces is glomerular

polyanion

Tubules Fluid filtered from the glomerular capillaries flows into Bowman’s capsule and then into the proximal tubule, which lies in the cortex of the kidney

From the proximal tubule, fluid flows into the loop of Henle, which dips into the renal medulla.

Each loop of Henle consists of a descending and an ascending limb

The walls of the descending limb and the lower end of the ascending limb are very thin and therefore are called the thin segment of the loop of Henle

After the ascending limb of the loop returns partway back to the cortex, its wall becomes much thicker, and it is referred to as the thick segment of the ascending limb

At the end of the thick ascending limb is a short segment that has in its wall a plaque of specialized epithelial cells, known as the macula densa

The macula, the neighbouring lacis cells , and the renin-secreting granular cells in the afferent arteriole form the juxtaglomerular apparatus

Beyond the macula densa, fluid enters the distal tubule, which lies in the renal cortex. This is followed by the connecting tubule and the cortical collecting tubule, which lead to the cortical collecting duct

The initial parts of 8 to 10 cortical collecting ducts join to form a single larger collecting duct that runs downward into the medulla and becomes the medullary collecting duct

The epithelium of the collecting ducts is made up of principal cells (P cells) and intercalated cells (I cells)

P cells are involved in Na+ reabsorption and vasopressin-stimulated water reabsorption

I cells are concerned with acid secretion and HCO3– transport

The collecting ducts merge to form progressively larger ducts that eventually empty into the renal pelvis through the tips of the renal papillae

The total length of the nephrons, including the collecting ducts, ranges from 45 to 65 mm

Cortical nephrons

• 70-80 %

• glomeruli located in the outer cortex

• short loops of Henle that penetrate only a short distance into the medulla

• the entire tubular system is surrounded by an extensive network of peritubular capillaries

Juxtamedullary nephrons

• 20-30 %

• glomeruli lie deep in the renal cortex near the medulla

• long loops of Henle that dip deeply into the medulla, in some cases all the way to the tips of the renal papilla

• Long efferent arterioles extend from the glomeruli down into the outer medulla and then divide into specialized peritubular capillaries called vasa recta

RENAL CIRCULATION

Peritubular capillaries

Efferent arterioles

Glomerular capillaries

Afferent arterioles

Interlobular arteries

Arcuate arteries

Interlobar arteries

Renal artery

1100 ml/min 20-25% of cardiac output

JG CELLS

• Myoepitheloid cells• Have golgi apparatus, mitochondria, endoplasmic

reticulum• Secrete renin

Features:a) Baro-receptors: sympathetic stimulationb) Volume receptors : stimulated by hypovoluemia

MACULA DENSA• Specialized tubular cells• Prominent nuclei• Cells act as chemoreceptor : stimulated by low sodium

concentration• Not innervated

MESENGIAL CELLS• Contacts with JG and macula densa cells• Contractile, regulates GFR

Urine Formation Results from Glomerular Filtration, Tubular Reabsorption, and Tubular Secretion

Why are large amounts of solutes filtered and then reabsorbed by the kidneys?

Most waste products are poorly reabsorbed by the tubules and, therefore, depend on a high GFR for effective removal from the body

The entire plasma volume is only about 3 liters, whereas the GFR is about 180 L/day, the entire plasma can be filtered and processed about 60 times each day

Glomerular Filtration: The First Step in Urine Formation

Composition of the Glomerular Filtrate

The glomerular capillaries are relatively impermeable to proteins, so the filtered fluid (called the glomerular filtrate) is essentially protein free and devoid of cellular elements, including red blood cells

The concentrations of other constituents of the glomerular filtrate, including most salts and organic molecules, are similar to the concentrations in the plasma

Exceptions to this generalization include a few low molecular-weight substances, such as calcium and fatty acids, that are not freely filtered because they are partially bound to the plasma proteins

Determinants of the GFR

GFR =Kf × Net filtration pressure

Net filtration pressure = (PG − PB− πG + πB)

Where, Kf is the capillary filtration coefficient (the product of the permeability and surface area of the capillaries),

PG is the glomerular hydrostatic pressure,

PB is the hydrostatic pressure in Bowman’s capsule,

πG is the colloid osmotic pressure of the glomerular capillaries,

πB is the colloid osmotic pressure in Bowman’s capsule

Summary of forces causing filtration by the glomerular capillaries. The values shown are estimates for healthy humans

Bowman’s capsule oncotic pressure = 0 mm Hg

Net filtration pressure = 60 + 0 - 18 - 32 = +10 mm Hg

Kf is calculated to be about 12.5 ml/min/mm Hg of filtration pressure

In the average adult human, the GFR is about 125 ml/min, or 180 L/day

(AP=arterial pressure)

(RE=Efferent arteriolar resistance)

(RA=Afferent arteriolar resistance)

Blood flow to the two kidneys is normally about 22 percent of the cardiac output, or 1100 ml/min

The renal circulation is unique in having two capillary beds, the glomerular and peritubular capillaries

High hydrostatic pressure in the glomerular capillaries (about 60 mm Hg) causes rapid fluid filtration, whereas a much lower hydrostatic pressure in the peritubular capillaries (about 13 mm Hg) permits rapid fluid reabsorption

Filtration fraction = GFR/Renal plasma flowfiltration fraction, is normally 0.16–0.20

By adjusting the resistance of the afferent and efferent arterioles, the kidneys can regulate the hydrostatic pressure in both the glomerular and the peritubular capillaries, thereby changing the rate of glomerular filtration, tubular reabsorption, or both in response to body homeostatic demands

Physiologic Control of Glomerular Filtration and Renal Blood Flow

Strong activation of the renal sympathetic nerves can constrict the renal arterioles and decrease renal blood flow and GFR. Moderate or mild sympathetic stimulation has little influence on renal blood flow and GFR

Several hormones and autacoids can influence GFR and renal blood flow, as summarized in following Table

Norepinephrine, epinephrine and endothelin constrict afferent and efferent arterioles,causing reductions in GFR and renal blood flow

Afferent arterioles, appear to be relatively protected from angiotensin II–mediated constriction in most physiologic conditions due to release of vasodilators, especially nitric oxide and prostaglandins. The efferent arterioles, however, are highly sensitive to angiotensin II.

Increased angiotensin II formation usually occurs in circumstances associated with decreased arterial pressure or volume depletion, which tend to decrease GFR. In these circumstances, the increased level of angiotensin II, by constricting efferent arterioles, helps prevent decreases in glomerular hydrostatic pressure and GFR

prostaglandins (PGE2 and PGI2), bradykinin, and endothelial-derived nitric oxide cause vasodilation and increased renal blood flow and GFR

Autoregulation of GFR and Renal Blood Flow

The kidneys have effective mechanisms for maintaining renal blood flow and GFR relatively constant over an arterial pressure range between 80 and 170 mm Hg, a process called autoregulation

MECHANISMS

Tubuloglomerular feedback Myogenic autoregulation of renal blood flow

Tubuloglomerular Feedback and Autoregulation of GFR

Myogenic Autoregulation of Renal Blood Flow and GFR

The myogenic hypothesis states that increased arterial pressure stretches the blood vessels, which causes reflex contraction of smooth muscle in the blood vessel walls and consequently increased resistance to blood flow

ANGIOTENSIN II• Alpha globulin, synthesized in liver• ACE : in lung epithelium• Actions: 1. Most potent vasoconstrictor2. Aldosterone secretion 3. Contraction of mesangial cells : GFR4. Direct action on renal tubular cells : increased

sodium reabsorbtion5. Increase water intake

ERYTHROPOIETIN• Glycoprotein• Acts on stem cells of bone marrow • Secreted from interstitial cells of peritubular

capillaries 85% and perivenous hepatocytes of liver 15%

Q1. Function/s of kidney is/are:

a) Glycogenolysisb) Secretion of thrombopoietinc) Acid-base balanced) Both (b) and (c)

Q2. Average number of nephrons in both kidneys are:

a) 1 millionb) 2 millionc) 4 milliond) none

Q3. Glomerular capillary membrane is formed of:

a) Endothelium of the capillaryb) Basement membrane of the capillaryc) Podocytesd) All of the above

Q4. True about juxtamedullary nephrons is:

a) 70-80%b) Short loop of Henlec) Vasa rectad) All of the above

Q5. Albumin is not filtered because of:

a) Large size/diameterb) Negative charge on basement membranec) Both (a) and (b)d) None

Q6. Juxtaglomerular apparatus is formed of:

a) Lacis cellsb) Juxtaglomerular cellsc) Macula densad) All of the above

Q7. Erythropoietin is secreted by:

a) Juxtaglomerular cellsb) Interstitial cells around peritubular capillariesc) Macula densad) Lacis cells

Q8. Renin is secreted by:

a) Juxtaglomerular cellsb) Interstitial cells around peritubular capillariesc) Macula densad) Lacis cells

Q9. GFR depends on :

a) glomerular hydrostatic pressureb) glomerular colloid osmotic pressurec) hydrostatic pressure in Bowman’s capsuled) All of the above

Q10. net filtration pressure in glomerulus is about:

a) 10 mm Hgb) 18 mm Hgc) 32 mm Hgd) 60 mm Hg

Q11. true about filtration fraction :

a) Filtration fraction = GFR/Renal plasma flowb) Filtration fraction = Renal plasma flow/GFRc) is more than 0.25d) Both (a) and (b)

Q12. isolated constriction of efferent arteriole :

a) Increases renal plasma flowb) Decreases GFRc) No change in filtration fractiond) None of the above

Q13. renal blood flow and GFR remains relatively constant over an arterial pressure range of :

a) 40 – 130 mm Hgb) 60 – 150 mm H gc) 80 – 170 mm Hgd) None of the above

Q14. during decreased arterial pressure, tubuloglomerular feedback in nephrons will cause:

a) Increased renin secretionb) Decreased efferent arteriolar resistancec) Increased afferent arteriolar resistanced) All of the above