Renal physiology

Dr Raghuveer Choudhary

Chief Functions of Renal System

1.Regulation of water & electrolyte balance 2.Regulation of acid & base balance 3.Excretion of waste products of protein metabolism, e.g., Urea from protein breakdown Uric acid from nucleic acid breakdown Creatinine from muscle creatine breakdown End products of hemoglobin breakdown 4.Excretion of foreign chemicals, e.g., drugs, food additives, pesticides, etc. 5.Endocrine function: erythropoietin, renin, 1,25-dihydoxy-vitamin D.

Physiological anatomy of the Kidney

General organization of the urinary system and the kidney
Kidney: paired organs,about

fist sized, 150 g,

outside peritoneum against the back.

FUNCTIONAL ANATOMY OF KIDNEYS & URINARY TRACT

The kidneys lie high on the posterior abdominal wall below the diaphragm & on either side of the vertebral column. In adults each kidney is the size of a clenched fist & weighs ~150 g. Urine produced by the kidneys is delivered to the urinary bladder by 2 ureters. The bladder continuously accumulates urine and periodically empties its contents via urethra under the control of an external urethral sphincter a process known as micturition.
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FUNCTIONAL ANATOMY: kidney

Each kidney is formed of 2 distinct parts: An outer cortex An inner medulla.

The nephron is the functional

unit of the kidney. Each kidney contains ~ 1 million nephrons. The nephron is composed of 2 main components: A. The renal corpuscle B. The renal tubule

The Nephron

Nephron
the basic functional unit of kidney 1 million nephrons in each kidney The kidney cannot regenerate new nephrons.

glomerulus

renal corpuscle
Bowman capsule proximal tubule thick segment of descending limb Loop of Henle thin segment of descending limb thin segment of ascending limb thick segment of ascending limb

Nephron

renal tubule

distal tubule

THE NEPHRON
A. Renal Corpuscle: (Site of filtration of blood)
1. The Glomerulus: - It is present in the cortex. - Each glomerulus is formed of a tuft of capillaries that are invaginated into the Bowmans capsule. - Blood enters the capillaries through the afferent arteriole and leaves through the slightly narrower efferent arteriole. - Glomerular capillaries are unique in that they are interposed between 2 arterioles. This arrangement serves to maintain a high hydrostatic pressure in the 12 capillaries, which is necessary for filtration.

THE NEPHRON
A. Renal Corpuscle:
2. The Bowmans Capsule:
It is the proximal expanded portion of the renal tubule forming a double-walled cup

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THE NEPHRON
B. Renal Tubule:
1. Proximal convoluted tubule (PCT) 2. Loop of Henle: It is further subdivided into: Thin descending limb Thin ascending limb Thick ascending limb 3. Distal convoluted tubule (DCT) - Many DCTs open into a collecting duct (CD). CDs pass from the cortex (cortical CD) to the medulla (medullary CD) and finally drain urine into the renal pelvis. - PCT & DCT are present in the cortex, while the descending limb of loop of Henle dips into the medulla, forming a hairpin turn & then returns back to the cortex.
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THE NEPHRON
Juxtaglomerular Apparatus:
Each DCT passes between the afferent & efferent arterioles of its own nephron. At this point there is a patch of cells with crowded nuclei in the wall of the DCT called the macula densa. They sense the concentration of NaCl in this portion of the tubule. The wall of the afferent arteriole opposite the macula densa contains specialized cells known as the juxtaglomerular cells (JG cells). They secrete renin. Together, the macula densa & JG cells are called the juxtaglomerular apparatus (JGA).
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Lecis/mesan gial cells

Juxta Glomerular Cells

The Juxtaglomerular Apparatus

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1. Renin-Angiotensin System:
Most important mechanism for Na+ retention in order to maintain the blood volume. Any drop of renal blood flow &/or Na+, will stimulate volume receptors found in juxtaglomerular apparatus of the kidneys to secrete Renin which will act on the Angiotensin System leading to production of Angiotensin II.

Renin Angiotensin Vasoconstrictor Mechanism

Main function (i) Control of BP (ii)Regulation of ECF Volume Renin Secreted from JG Cells Stimulus Low BP Function convert ATG to AT-I
ACE

AT-I

AT-II

(in lungs endo cells)

 Renin-Angiotensin System:
renal blood flow &/or Na+ ++ Juxtaglomerular apparatus of kidneys (considered volume receptors) Renin Angiotensinogen Angiotensin I
(Lungs) Converting enzymes

Angiotensin III
(powerful vasoconstrictor)

(powerful vasoconstrictor) Adrenal cortex

Angiotensin II

Aldosterone

Corticosterone

N.B. Aldosterone is the main regulator of Na+ retention.

Functions of Angiotensin-II
Vasoconstriction BP Na+ & Water retention by Kidney BP

Stimulate thirst BV BP

THE NEPHRON
There are 2 types of nephrons in the kidney:
1. Cortical Nephrons: (80% of nephrons) Their glomeruli lie in the outer layers of the cortex. Their tubular system is relatively short. Their loops of Henle penetrate only for a short distance into the outer portion of renal medulla. 2. Juxtamedullary Nephrons: (20% of nephrons) Their glomeruli lie at the boundary between cortex & medulla. They have long loops of Henle, which dip deeply down into the medulla toward the tips of the pyramids. They play a major role in the process of urine concentration.
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Types of nephrons
Items

Cortical nephrons

Juxtamedullary nephrons

% Of total Glomeruli Loop of Henle

85 % Out part of cortex Short i.e. dips to the junction between inner and outer medulla. Peritubular capillaries No Vasa Recta Na reabsorption Present Present

15% Inner part of cortex . Long i.e. dips deeply into the medullary pyramids to the inner medulla Vasa recta and peritubular capillaries Urine concentration Absent Absent

Blood supply

Special function JG apparatus

Autoregulation

Juxtamedullary Nephron

Cortical Nephron

The efferent vessels of juxtamedullary glomeruli form long looped vessels, called vasa recta which is important for urine concentration.

So,why is the loop of Henle useful?

The longer the loop, the more concentrated the filtrate and the medullary IF become Importance: the collecting tubule runs through the hyperosmotic medulla more ability to reabsorb H2O
Desert animals have long nephron Loop More H2O is reabsorbed

Glomerular capillary membrane

1. Three major layers:
(1) capillary endothelium (2) basement membrane (3) epithelium (podocytes) of visceral layer of Bowmans capsule

Glomerular membrane
Capillary endothelium; It has small holes (70-90 nm). It does not act as a barrier against plasma protein filtration. Basement membrane; (BM) filamentous layer attached to glomerular endothelium & podocytes, carry strong-ve charges which prevent the filtration of plasma proteins, but filters large amount of H2O and solutes. Podocytes; Epithelial cells that line the outer surface of the glomeruli. They have numerous foot processes that attach to the BM, forming filtration slits (25 nm wide).

fenestrae (fenestratio

capillary endothelium

epithelium

(1) capillary endothelium

fenestrae(fenestra tion) 70-90nm Not act as a major barrier for plasma proteins

(2) basement membrane

Meshwork of collagen and proteoglycan fibrillae that have spaces( 2-8nm) Filter large amounts of water and small solutes, but effectively prevent filtration of plasma proteins

(3) epithelium (podocytes)

surrounding the outer surface of the capillary basement membrane podocytes :long foot-like processes pedicels slit pores(filtration slits) 25nm Provide some restriction to filtration

epithelium

Renal blood supply

Renal arterysegmental arteries interlobar arteriesarcuate arteries interlobular arteries(radial arteries) afferent arterioles glomerular capillaries characteristics of efferent arterioles renal blood supply: two capillaries beds peritubular capillaries interlobular vein arcuate vein interlobar vein segmental vein renal vein.

Renal artery

interlobar arteries arcuate arteries interlobular arteries

BLOOD VESSELS in the NEPHRONS

Each kidney receives its blood supply from a renal artery, which arises directly from the abdominal aorta. In the kidney, the renal artery progressively subdivides into smaller branches until they form afferent arterioles, which break up into a tuft of capillaries, the glomerulus. Then the capillaries form the efferent arteriole. The efferent arteriole again subdivides to form peritubular capillaries, which surround the various segments of the renal tubules. N.B. There are 2 sets of capillaries & 2 sets of arterioles!! The efferent arterioles of juxtamedullary nephrons form a special type of peritubular capillaries called vasa recta. They are straight & long capillaries that form hairpin loops along side the loops of Henle. They play an important role in the process of urine 45 concentration.

Blood supply of the kidney

-It is a portal circulation i.e. blood flows through 2 sets of capillaries (the glomerular and peritubular capillaries) before it drained by veins. - The renal circulation is the only circulation where there are capillaries which are drained by arterioles (glomerular capillaries drain in efferent arterioles).

two capillaries beds

glomerular capillaries: Higher hydrostatic pressure( about 45 mmHg)
--- in favor of rapid fluid filtration ;

peritubular capillaries: Lower hydrostatic pressure ( about 10 mmHg)

---in favor of rapid fluid reabsorption;

Major Renal Capillaries

Glomerular capillary bed
1. Receives bl from afferent art. 2. High presure bed 45- 55 mmHg

Peritubular capillary bed

Receives bl from efferent art. Low pressure bed 10- 13 mmHg

3.Represents arterial end of cap. 4. allows fluid filtration.

Represents venous end of cap. Allows fluid reabsorption.

Renal Blood Flow and its Regulation

Characteristics of RBF:
1. High blood flow: 1200ml/min: 25% cardiac output 0.4 % of total body weight 300-400ml/100gm/min A high blood flow is necessary for glomerular filtration. 2.Distribution: cortex 90% Vasa recta is 40 mm long outer medulla 9% Low Hydrostatic Pressure inner medulla 1% Increased viscosity

RENAL BLOOD FLOW (RBF)

Renal blood flow is about 20% of the cardiac output This is a very large flow relative to the weight of the kidneys (350 g)

RBF determines GFR RBF also modifies solute and water reabsorption and delivers nutrients to nephron cells.

Renal blood flow is autoregulated between 80 and 180 mm Hg by varying renal vascular resistance (RVR).
i.e. the resistances of the interlobular artery, afferent arteriole and efferent arteriole

4. Physiological control of RBF and GFR

1. Autoregulation of the RBF and GFR
1 RBF is relatively constant when BP fluctuating between 80180 mm Hg even if there are not regulations of nerve and humoral factors. 2 Myogenic mechanism: Tubuloglomerular feedback: 3significance: to maintain a relatively constant GFR to allow of renal excretion of water and solutes under normal conditions.

In every nephron, the macula densa senses changes in GFR by measuring the tubular fluid flow rate. If the tubular fluid flow rate increases, the macula densa signals to the afferent arteriole to contract, thereby reducing GFR and normalizing flow .

 Arterial pressure
(-)

Macula densa feedback mechaniam (-)

glomerular hydrostatic
pressure

GFR Macula densa

NaCl

renin Angiotensin II Efferent arteriolar

resisance

Afferent arteriolar
resisance

Autoregulation of RBF & GFR

Note: Autoregulation is important to prevent large changes in GFR that would greatly affect urinary output.

EFFECT OF ARTERIAL PRESSURE CHANGES ON GFR, RBF AND URINE OUTPUT

150
RBF or GRF (% of normal) RBF 100

GFR

50

Urine Output

50

100

150

200

Arterial Pressure (mmHg)

Impact of autoregulation
Autoregulation: GFR=180L/day and tubular reabsorption=178.5L/day Results in 1.5L/day in urine Without autoregulation: Small in BP 100 to 125mm Hg, GFR by 25% (180 to 225L/day) If tubular reabsorption constant, urine flow of 46.5 L/day What would happen to plasma volume?

The formation of urine by Kidney

1. 2. glomerular filtration tubular reabsorption 3. tubular secretion Concentration and dilution of urine
Peritubular capillary blood

Urine Formation
Glomerular Filtration substances move from blood to glomerular capsule Tubular Reabsorption substances move from renal tubules into blood of peritubular capillaries glucose, water, urea, proteins, creatine amino, lactic, citric, and uric acids phosphate, sulfate, calcium, potassium, and sodium ions Tubular Secretion substances move from blood of peritubular capillaries into renal tubules drugs and ions

Overall fluid movement in the kidneys

Urinary excretion rate=filtration rate-reabsorption rate + secretion rate

Glomerular filtration
The first step in urine formation when blood flows into the glomerular capillaries, the water bulk flow of proteinfree plasma filtrate into Bowmans capsule through the glomerular membrane

ultrafiltrate
Most substances in the plasma(except protein)are freely filtrated,so that their concentrations in Bowmans capsule are almost the same as in the plasma.

Glomerular filtration

Fluid and small solutes dissolved in the plasma such as glucose, amino acids, Na, K, Cl, HCO3- , other salts, and urea pass through the membrane and become part of the filtrate. The glomerular membrane hold back blood cells, platelets and most plasma proteins. The filtrate is about 20% of the plasma. The volume of fluid filtered per unite time is called the glomerular filtration rate (GFR). The GFR is about 180 L/day (=125 ml/min.).

Glomerular membrane
Capillary endothelium;
It has small holes (70-90 nm). It does not act as a barrier against plasma protein filtration.

Basement membrane; (BM)

filamentous layer attached to glomerular endothelium & podocytes, carry strong-ve charges which prevent the filtration of plasma proteins, but filters large amount of H2O and solutes.

Podocytes;
Epithelial cells that line the outer surface of the glomeruli. They have numerous foot processes that attach to the BM, forming filtration slits (25 nm wide).

Filterability of the Membrane

Filterability is a term used to describe membrane selectivity based on the molecular size and charge Pore size would favor plasma protein (albumin) passage, but negative charge on protein is repelled by the (-) charged basement membrane (proteoglycan filaments & podocytes) Loss of this proteinuria. (-) charge causes

GFR (glomerular filtration rate)

GFR=volume of glomerular filterate formed each minute by all the nephrons in both kidneys
the amount of ultra filtrate formed by two kidneys per minute.

Normal value:125ml/min,180L/day Filtration fraction = GFR / Renal plasma flow Normal value:about 20% (125/660=19%) (about 20% of the plasma flowing through the kidney is filtered by the glomerular capillaries)

Define Filtration fraction It is the fraction of the renal plasma flow (RPF) that becomes glomerular filtrate. the average filtration fraction about 16-20%. It is calculated as (GFR/RPF X100).

Glomerular Filtration Rate (GFR)

In an average man: 125 ml/minute. In women : 10% less. High renal blood flow (20-25% of cardiac output) needed for high GFR. GFR equals about 180 L/day so plasma volume (3L) filtered about 60 times daily, More than 99% of GFR is normally reabsorbed. Normal volume of urine is about 1.5 litre/day.

GFR (glomerular filtration rate)

The GFR is determined by (1)Effective filtration pressure (EFP) and (2)glomerular capillary filtration coefficient(Kf) GFR= Kf EFP

Glomerular filtration rate =Net filtration pressure X Filtration coefficient GFR = EFP (l0) X Kf (12.5) = 125ml/min.

- Kf is determined by 2 factors: 1- The permeability of the capillary bed. 2- The surface area of the capillary bed.

Kf = permeability of membrane X effective filtration surface area (of both kidneys).

Effective filtration pressure,EFP

Represents the sum of the hydrostatic and colloid osmotic forces that either favor or oppose filtration. Forces favoring filtration:
Glomerular hydrostatic pressure(PG) Bowmans capsule colloid osmotic pressure (B)=0

Forces opposing filtration

Bowmans capsule hydrostatic pressure (PB) Glomerular capsule colloid osmotic pressure (G)

Forces affecting filtration

Favoring Filtration
Glomerular hydrostatic pressure 45 mm Hg Bowmans capsule colloid osmotic pressure 0 mm Hg

Opposing Filtration
Glomerular capillary colloid osmotic pressure 25 mm Hg Bowmans capsule hydrostatic pressure 10 mm Hg

Net = +10 mm Hg

FORCES of GFR

45mmHg

25mmHg

1ommHg

45mmHg

1ommHg

25mmHg

Regulation of Filtration
(1) Changes in glomerular hydrostatic pressure.
(1) Diameter of the afferent arterioles. VD of afferent arterioles ++ Hydrostatic pr. in glomerular capillary ++ GFR. VC of afferent arterioles e.g ++ sympathetic activity - Hydrostatic pr. in glomerular capillary (HPGC) -GFR.
(2) Diameter of the efferent arterioles. Moderate VC ++ Hydrostatic pr. in glomerular capillary slight ++ of GFR. (3) Arterial Blood Pressure: Between 70 & 170 mmHg: GFR and RBF are kept relatively constant by autoregulatory mechanisms.

Changes in GFR by constriction or dilation of afferent (AA) or efferent (EA) arterioles

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Constriction of the afferent arteriole reduces both the RBF and theGFR, leaving the filtration fraction unchanged. Efferent arteriole constriction reduces RBF but conserves GFR, causing an increase in the filtration fraction.

Regulation of Filtration
(2) Changes in Bowmans Capsule hydrostatic pressure ++ Hydrostatic pr in Bowmans capsule e.g. stone in ureter -- GFR . (3) Change in glomerular colloidal osmotic pressure Increased Colloidal osmotic pressure in glomerular capillary e.g in dehydration decreased GFR. Decreased Colloidal osmotic pressure in glomerular capillary e.g in hypoproteinemia increased GFR. (4) Functioning kidney mass When the number of functioning nephrons decreases e.g. in renal disease (failure), there is reduction of filtration coefficient (kf) & decrease in GFR (decreasing the filtering surface area).

Determinants of GFR
3. glomerular capillary filtration coefficient(Kf)
Kf is the product of the permeability and filtering surface area of the capillaries.
Kf GFR

Example:
diabetes mellitus thickness of glomerular membrane Kf GFR

Changes in filtering surface area: This is changed by contraction or relaxation of mesangial cells. They are contracted by vasopressin (ADH), adrenaline, angiotensin II, prostaglandin F2 and sympathetic stimulation.
They are relaxed by prostaglandin E2, dopamine, cAMP and ANP. Contraction of mesangial cells decrease surface area available for filtration decrease in Kf & decrease in GFR and vice versa.
Changes in the permeability of glomerular membrane: GFR is directly proportional to the permeability of glomerular membrane e.g. hypoxia, fevers, some renal diseases increases this permeability.

Renal Clearance
Clearance is the virtual volume of plasma from which a substance is completely removed and excreted in to the urine in one minute Or Clearance is a ratio of the amount of substance excreted in urine to the plasma concentration of the substance i.e. Urinary excretion rate/plasma concentration

Arterial Plasma Each Block=100ml

PX=1mg /ml

Urine output=1ml 100mgx

Venous Plasma

In One Minute

Renal clearance
Definition: The renal clearance of a substance is the volume of plasma that is completely cleared of the substance by the kidneys per unit time. the ability of the kidneys to "clear" or remove a specific substance from the blood. Clearance equation: C = U V / P ml/min

Renal Clearance
Clearance and urinary excretion rate (U x V) of a substance are not identical because increasing the plasma concentration of a substance leads to an increased rate of excretion; clearance remains unchaned. Clearance equation: C = U V / P ml/min

 The concept of clearance can be applied for determination of

GFR (Glomerular Filteration Rate) RPF (Renal Plasma Floow) FF (Filtration Fraction)

GFR
Suppose there were a magic substance freely filtered ,neither reabsorbed nor secreted then the amount of the substance excreted per minute would be equal to the amount of substance filtered i.e. P x GFR = U x V GFR= U x V/P =clearance

Inulin clearance; Inulin has the following characteristics:

Freely filtered i.e. plasma conc.= filtrate concentration. not reabsorbed or secreted by renal tubules i.e. amount filtered per min.= amount excreted in urine/min.

Not metabolized.
Not stored in the kidney.

Does not affect filtration rate & its conc. is easily measured.

There is such a substance Inulin

C inulin = 125ml/min=GFR Inuline is freely filtered. Biologically inert & non toxic. Not bound to plasma proteins. Not metabolized to another substance

Substances that are freely filtered but neither reabsorbed nor secreted have renal clearance rate equal to GFR and hence are called glomerular markers.

Inulin Mannitol Sorbitol Sucrose (i.V.) Radioactive Cobalt labeled Vit

B12

51 Cr Labelled EDTA Radio-iodine labeled Hypaque

Renal Blood Flow

RBF can be measured by Ficks Principle. Imagine about the organ(kidney) -Blood conc. Of substance on arterial end. -Blood conc. Of substance on venous end. Amount of substance either added or taken out of body by organ Then Flow= Amount of substance removed per min
Arterial-Venous plasma conc.

Ficks Principle
The amount of substance removed (excreted) by an organ(kidney) per unit time(U x V) is equal to the renal plasma flow multiplied by the arteriovenous difference in plasma concentration.

Flow= Amount of substance removed per min Arterial-Venous plasma conc.

Ficks Priciple
But suppose we had a magic substance that was so completely cleared by the kidney that the venous conc were zero .

Flow= Amount of substance removed per min

Arterial Plasma concentration

So the clearance of such substance would equal RPF

RPF
Para-amino-Hippuric acid is continuously (freely) filtered by the glomeruli & also secreted by the proximal convoluted tubules to such an extent that it is completely removed during its renal circulation. RPF = UPAH x V/PPAH = Clearance PAH

 At low plasma conc. CPAH = 650ml/min = ERPF (10% lower then actual RPF) RBF=RPF x I/I-Hct

Describe how to measure renal blood flow

By PAH clearance The substance used is PAH (paraminohippuric acid)

because

If is freely filtered by the glomerulus.

It is completely secreted from the peritubular capillaries into the tubular lumen in single circulation.
Measurement of the effective renal plasma flow ERPF. The extraction ratio of PAH is 90% i.e. only 90% of PAH in renal arterial blood is removed in a single circulation. This is because only 90% of ARPF go to the nephrons Actual RPF = ERPF.x 100/90. Measurement of the actual (total) renal blood flow RBF Knowing the haematocrite value. RBF = RPF / 1 HV = about 1200 mL/min

Para-aminohippuric acid (PAH) clearance: (Exogenous).

It is freely filterable, almost complete secretion in one single circulation (90%) with no absorption. So, it is used for measurement of RBF. Why?
a- It is not metabolized and not stored nor produced by the kidney. b- It does no affect RBF. c- Its level can be measured easily. d- 90% is removed from the blood in a single circulation.

Substances that are filtered and also secreted by the tubules, but not reabsorbed have the highest renal clearance rate.Such substances are thus entirely exreted by a single passage of blood through kidneys. Clearance of such substances represent the range of blood flow

PAH=650ml/min Diodras

Substances that are freely filtered ,but are partially reabsorbed in the tubules have renal clearance rate less than GFR Urea (partially reabsorbed)
Urea Clearace < 125ml/min

Substances that are freely filtered ,but are completely reabsorbed have lowest clearance rate

Sodium Glucose HCO3 Amino acids Chloride

Filteration Fraction (FF)

Given that GFR is about 125ml/min and RPF is about 650ml/min, only about @19% of the renal plasma flow is actually filtered in to Bowmans space FF is the ratio of GFR to the Renal Plasma Flow or the ratio of inulin clearance to that of Paraaminohippuric acid clearance. FF= GFR/RPF = Cin/C
PAH

RPF = GFR/FF

Creatinine clearance:
Actually GFR is rarely measured clinically by inulin clearance. Rather ,Creatinine,a normal product of muscle metabolism is used Creatinine is not an ideal substance for this purpose since it is not only is filtered but also secreted to a small extent in the human. The error introduced by this secretory component is about 10%

Creatinine clearance:
Fortunately the laboratory methods of measuring plasma creatinine overestimate the true value by about 10%. Consequently the two error cancel & in most clinical studies Ccr provide a reasonable estimate of GFR.

Creatinine clearance:
Finally in most cases the muscle mass does not changes day to day,so the amount of creatinine presented to the kidney for excretion is relatively constant. Pcr x GFR = Rate of production(constant) Given this constancy there are 2 varibles. GFR & Plama creatinine

Creatinine clearance:
So as one variable decrease, the another increases. Pcr x GFR = Rate of
production(constant) Imagine a normal person with the following renal values GFR=100ml/min, Pcr=1mg/dl Now if the kidney fails & GFR decreases to 50ml/min ,Pcr would increase to 2mg/dl. As physician you should note that when plasma creatinine value doubles this means GFR must have fallen to of its normal Value

Estimates of GFR

while creatinine clearance is a good estimate of GFR,

plasma creatinine is often used as a clinical indicator of GFR

Creatinine clearance:
Two groups in which this method should not be used (1) New Born (2) Individuals with wasting diseases (cancer) In both cases one cannot assume a constancy of muscle mass

Creatinine clearance:
-Mode of handling: complete filtration, partial secretion, no reabsorption. So, creatinine clearance is more than GFR = 140 ml/min. -It is an endogenous substance coming from creatine metabolism in skeletal muscles. It is released into blood at relatively constant rate. - It can be used clinically for measuring GFR, it is easier but it is slightly inaccurate.