Course : PG Pathshala-Biophysics

Paper 13 : Physiological Biophysics

Module 14 : Glomerular Filtration Rate and Renal Hemodynamics

Principal Investigator: Dr. Moganty R. Rajeswari, Professor

AIIMS, New Delhi

Co-Principal Investigator: Dr. T. P. Singh, Professor

AIIMS, New Delhi

Paper Coordinator:

Dr. K. K. Deepak, Prof. & HOD, Physiology

AIIMS, New Delhi

Content Writer: Dr. Prashant Tayade, Assistant professor

AIIMS, New Delhi

Content Reviewer: Dr. Renuka Sharma, Professor

VMMC & SJH, New Delhi

Specific Learning Objectives

Be able to explain components of glomerulus and their function. Be able to draw vascular arrangement around the nephron. Be able to define glomerular filtration rate and state its normal value. Know what the filtration fraction is and its normal value. Be able to enumerate the components of filtration barrier in glomerulus Know what are the determinants of glomerular filtration rate and state normal values of various forces. Should know the significance of Filtration coefficient and its value Be able to describe various factors affecting each of the starling forces. Know the Normal values of the renal blood flow and plasma blood flow. Be able state the effect of changing blood pressure on renal blood flow, glomerular filtration rate. Be able to explain the meaning of autoregulation of renal blood flow. Be able to describe the various mechanism of autoregulation. Be able to name the components of juxtaglomerular apparatus.

Introduction:

As discussed in the previous chapter Nephron is the functional unit of the kidney that carries

out important processes of urine formation such as glomerular filtration, tubular reabsorption

and secretion.

But to perform such functions especially the glomerular filtration is where we need the role of

renal blood flow in the kidney.

To understand this we need to understand the blood supply to kidney as shown in the figure

1.

Renal Blood supply

The two kidneys receive about 22% of the cardiac output that is 1100ml/min. The arterial

supply is by renal artery which enters the kidney through hilum and undergoes branching

sequentially, the interlobar arteries arcuate arteries , interlobular arteries and then the

afferent arterioles that leads to glomerular capillaries enclosed inside bowman’s capsule of

nephron perform the function of filtration of large amount of fluid and solutes except the

plasma proteins. The interlobular arteries go straight to the cortex giving branches and there

is no anastomosis between the branches.

After this distal to the glomerulus, the capillaries coalesce to continue as efferent arteriole,

which leads to form peritubular capillaries that surrounds renal tubules.

Note: There are arteriolar ends on either side of glomerular capillaries not venules as in

other capillaries.

The uniqueness of the renal circulation is that it provides two capillaries, the glomerular

capillaries which has afferent and efferent arterioles on either sides. The narrow lumen of

efferent arterioles builds up a high hydrostatic pressure of 45 mm Hg inside the Glomerular

capillaries that is essential for function of Glomerular filtration.

And the peritubular capillaries after narrow lumen efferent arteriole has low hydrostatic

pressure of about 13 mm Hg carry the second essential function of tubular reabsorption. And

both glomerular capillaries and the peritubular capillaries are arranged in series so that

filtration and reabsorption takes place simultaneously.

By adjusting the the resistance of the afferent and the efferent arteriolar diameters the

glomerular filtration and tubular reabsorption is modified in to fulfil the homeostatic demands

of the body.

The peritubular capillaries empty into the venous system sequentially to form interlobular

vein, arcuate vein, interlobar vein and renal vein which leaves the kidney adjacent to renal

artery and ureter.

As the essential function performed is filtration , so the prime focus has to be glomerular

microcirculation

Glomerular microcirculation

Then glomerular microcirculation is kept in check by the afferent and the efferent arterioles

which has peculiar vessel histology

Afferent arteriole

The afferent arteriole lose their internal elastic layer and smooth muscle cell layer prior to entering the glomerular tuft. Also the smooth muscle cells are replaced by granular cells (renin producing cells) that are in close contact with the extraglomerular mesangium lying close to the distal convoluted tubule essential part of Juxta-glomerular apparatus.

Efferent arteriole

The diameter of the efferent arteriole within the tuft is significantly less than that of the afferent arteriole.

This difference in diameters of the afferent and efferent arterioles creates a high hydrostatic force in glomerulus favouring Filtration.

Post-glomerular

In parallel with the two types of nephrons discussed earlier that is the large in numbers

cortical nephron and 20 -30% juxtamedullary nephrons, the vascular supply also differ in the

two nephrons shown in the figure2.

For cortical nephrons there are extensive network of peritubular capillaries surrounding

entire tubules.

While for juxta-medullary nephron the the long efferent arteriole extend downward from

cortex to outer medulla and divide into specialised peritubular capillaries that extend down

side by side to the long loop of henle. These capillaries which has a very slow blood flow are

called as Vasa recta.

Role of microcirculation Cortical: water and electrolytes reabsorption by dense low hydrostatic pressure peritubular capillary network surrounding proximal tubule segments of superficial nephrons Medulla: process of concentration of urine by vasa recta mediated maintenance of the medullary interstitial hyperosmolarity generated by loop of henle. Which will be discussed in subsequent chapters.

Glomerular Filtration

It is the first step in the formation of the urine, where the water soluble component of blood is filtered out of the glomerular capillaries into the Bowman’s space. The capillaries are relatively impermeable to proteins and cellular elements like RBC’s. while rest all compositions are almost same as the plasma such that the osmolarity of the filtrate is the

same as that of plasma. Calcium and fatty acids are bound to plasma proteins hence cannot be filtered.

Filtration Fraction is the percentage volume of the plasma that is filtered through the glomerular capillaries. In Human the filtration fraction is about 20% and for rat is about 40%. The Filterability of the solutes through the glomerular capillaries depends on certain factors.

1. Filterability of solute is inversely proportion to size Solutes < 2 nm can pass easily While solutes > 5 nm cannot pass 2. Negative charged solutes are less easily filtered

For example albumin is not filtered even though size is 3.6 nm which is less than 5nm. Hence it is necessary to know what is exactly is the Filtration barrier consist of tallow such

precise filtration called as the Ultrafiltration

Filtration Barrier (shown in figure3) consist of the Physical barrier created by Endothelium,

Basement membrane and Podocytes as we go from capillary end to the bowman’s capsule.

And the percentage of resistance to filtration offered by each layer is Endothelium = 2 % ,

Basement membrane = 48% and Podocytes = 50 %.

The capillary endothelium shows small fenestrae of 100nm size which ensure high filtration

rate. also the endothelium is richly has fixed negative charge that repells plasma proteins.

Outer to endothelium layer is the basement membrane layer consisting of collagen and

proteoglycans fibrillae that allows small solutes and water in large proportions . The

basement membrane has strong negative electrical charges due to proteoglycans leading to

strong repulsion to negatively charged proteins and hence effective prevention of plasma

protein filtration.

And the last and outermost layer is formed by cells having foot like processes called as

podocytes. The foot processes are separated by the gaps called as slit pores has effective

pore size of 5 nm. These are also negatively charged and does not allow plasma proteins to

pass.

In the negative charges on the basement membrane is lost then the low molecular weight

proteins such as albumin are filtered and appear in urine. Tjis condition is called as

proteinuria or albuminuria. And loss of negative charge without any change in kidney

histology is called as the Minimal change nephropathy.

Determinants of Glomerular filtration

The GFR Glomerular filtration rate is determined by the sum of the starling forces on either

sides of the glomerular membrane and the filtration coefficient of the capillary membranes,

as occur in the capillaries elsewhere.

The starling forces are Hydrostatic force and colloidal osmotic force at glomerular capillary

and hydrostatic force and the colloidal osmotic force at bowman’s space as shown in fig.4

The force that favour the filtration are Glomerular capillary hydrostatic pressure (PGC

) of 45

mmHg and colloidal osmotic pressure at Bowman’s capsule (πT).

Note that the as proteins are normally not filtered into the bowman’s space the colloidal

osmotic pressure at bowman’s space (πT) is zero.

The forces that oppose the filtration are Bowman’s capsule hydrostatic pressure (PT) of 10

mmHg and glomerular capillary colloidal osmotic pressure of pressure (πGC

) which increases

as we go from afferent to efferent end.

The sum of these forces gives us the Net filtration pressure across the glomerular

membrane the values of each is given below fig.5 at both afferent end of capillaries and

towards the efferent end of capillaries. The net direction of pressure is from capillaries to the

bowman’s space at afferent end and efferent end it comes down to zero. The reason is that

the plasma proteins are not able to cross the capillaries hence proteins are accumulated as

going towards the efferent end which leads to increased osmotic pressure towards efferent

PGC

= Pressure in capillary

PT

= Pressure in Tubule

πGC

= oncotic pressure in capillary

πT = oncotic pressure in tubule

end resisting the hydrostatic pressure more distally and the resultant Net filtration pressure

becomes zero. The Net filtration pressure is considered to be 10 mmHg.

Net Filtration pressure PUF

Filtration coefficient Kf

The Filtration coefficient is the product of hydraulic conductivity (ease of passage of solutes)

and surface area provided for filtration.

That is; Kf = Hydraulic conductivity × Surface area

Hence the determinants of GFR is given as;

GFR = Kf × Net Filtration Pressure

So Kf is ratio of GFR and Net filtration pressure.

The GFR of both the kidneys is given by 125 ml/min; and Net filtration pressure is taken as

10 mmHg. Hence Kf is 125 divided by 10 = 12.5 ml /min/mmHg of filtration pressure.

If expressed in per 100 gm tissue Kf is 4.2ml/min/mmHg which is 400 times than the Kf of

other capillaries existent in the body.

This high filtration coefficient Kf signify the requirement of high fluid filtration rate at

glomerulus in the kidneys. While the other capillaries of body Kf is require for exchange of

nutrient supply and metabolites in the tissues.

Factors affecting the determinants each

Factors affecting Hydrostatic pressure at Glomerulus

The Hydrostatic pressure at the glomerulus is affected directly by the

1. Systemic blood pressure

2. Contraction and relaxation of afferent and efferent arterioles

That is increasing and decreasing the resistance of afferent and efferent arterioles. Fig 6 and 7 shows the effect of increasing Afferent arteriolar resistance and efferent arteriolar resistance respectively on renal blood flow and GFR. As the afferent arteriolar resistance increases then both the Renal blood flow and GFR decreases.

And as the efferent arteriolar resistance increases then renal blood flow is certainly decreased. But the GFR is increases initially and decreases later. The reason for this Biphasic response is due to plasma proteins are unable to filtered go on accumulating causing increased colloidal osmotic pressure offering resistance to the Net hydrostatic pressure decreasing the GFR as the resistance is increased. To summarize

Vasoconstriction Pressure Flow

Afferent arteriole Decrease Decrease

Efferent arteriole Increase Decrease

Factors affecting Oncotic pressure at Glomerulus

Fig 6 and 7

So the colloidal osmotic pressure is affected by

1. Concentration of proteins 2. Filtration fraction (FF)

Factors affecting Hydrostatic pressure at Bowman’s capsule

The hydrostatic pressure at bowman’s capsule is very less normally to resist that of

glomerular capillary. But in certain conditions there in increased back flow from below can

raise the hydrostatic pressure. For example urinary obstruction caused by stones, tumors

pressing on ureter or edema of renal capsule.

Factors affecting Filtration coefficient Kf

Physiological = Dynamic changes in the mesangial cell contractility. Mesangial contractions lead to decreased surface area of the glomerular capillaries. And hence the filtration coefficient reduces. Pathological = Disorders of glomerular filtration barrier function. For example Diabetic nephropathy, chronic renal failure. Uncontrolled Diabetes mellitus can affect the Kf of the kidneys by slowly decreasing the Kf

by increasing thickness of glomerular capillary basement membrane reducing the hydraulic

conductivity and simultaneously reducing the surface area of the capillaries also

So in sum total out of the total cardiac output

Renal parameters Total

Renal blood flow (ml/min) ~ 1,200 (20%)

Renal plasma flow (ml/min) ~ 670

Glomerular filtration rate(ml/min) ~ 130

Table-1

Of which Cortical flow = 85 – 90% and Medullary flow = 10 – 15%.

It is essential to note that during shock, medullary flow is preserved at the cost of cortical

flow.

Renal blood flow exceeds the metabolic demands for its function to be done. Thus, regulation of the Renal blood flow is more for 1. Glomerular filtration of fluid 2. Peritubular and Vasa-recta reabsorption of fluids Regulation of GFR and Renal blood flow

The most fluctuating parameter that can affect renal system is the systemic blood pressure, with increased blood pressure will raise glomerular hydrostatic pressure which might damage glomerular capillary basement membrane. Hence there has to be maintenance of relative constancy of renal blood flow and glomerular capillary pressure despite changes in systemic blood pressure. As shown in graph below, as there is increased SBP, both renal blood flow and GFR increased initially and reach to a plateau after which the systemic BP does not affect GFR and RBF. This dampening of effect of BP requires autoregulatory mechanisms that are presented by kidney.

Figure 8

Dampening of effect of pressure on urine outflow

1. Autoregulation of blood flow 2. T

ubulo-glomerular feedback

Table-2 Autoregulatory mechanisms

Myogenic Tubulo-glomerular feedback

Operate at the level of whole kidney

Operates the level of the individual nephron

High frequency response

(quick changes in BP)

Low frequency response

(slow changes in GFR)

Intrinsic myogenic mechanism: as the blood pressure in preglomerular vessels increased

there is stretching of vessel wall leading to constriction of preglomerular vessel wall. This is

fast response and acts on both kidneys at one point of time. Details given in table-2 above.

Tubulo-glomerular feedback

This autoregulatory modulation of glomerular filtration rate is in response to fluid composition (Na-CL) at the distal convoluted tubule is called tubule-glomerular feedback. For understanding we must know the anatomical arrangement of macula densa cells, extraglomerular mesangial cells, vascular smooth muscle cells, and renin-secreting cells of the afferent arteriole. since the all essential cells are in close approximation to glomerulus, this arrangement is known as the juxtaglomerular apparatus (JGA). Shown in figure 9.

3 – 10 seconds 20 – 60 seconds

Mainly Preglomerular Both preglomerular and post-glomerular

Mainly for Juxta medullary nephrons

Juxta-glomerular apparatus

Diagram of renal corpuscle structure: A – Renal corpuscle B – Proximal tubule C – Distal

convoluted tubule D – Juxtaglomerular apparatus 1. Basement membrane 2. Bowman's

capsule – parietal layer 3. Bowman's capsule – visceral layer 3a. Pedicels (Foot processes

from podocytes) 3b. Podocyte 4. Bowman's space 5a. Intraglomerular Mesangium cell 5b.

Extraglomerular Mesangium cell 6. Granular cells 7. Macula densa 8. smooth muscle 9.

Afferent arteriole 10. Glomerulus Capillaries 11. Efferent arteriole

As the blood pressure increases causes increase in GFR leading to more NaCl delivery at

Macula densa cells of Distal convoluted tubule causes afferent arteriolar vessel constriction

causing decrease in GFR decreasing NaCl delivery at Distal tubule. Since tubular Nacl

sensing changes GFR its called tubule-glomerular feedback.

Macula densa cells sensing of Nacl causes adenosine mediated ca influx in smooth muscle

cell of afferent arteriole and leads to constriction. Also it decreases renin release from

granular cells of juxta-glomerular apparatus, further decreasing blood pressure due to

decrease in RAAS (Renin Angiotensin Aldosterone mechanism).

The summarize look the flow chart below;

Physiological control

Change in GFR

Change in quantum of NaCl delivery

to Macula Densa

Sensing of NaCl load

Activation of JG apparatus

Beside these mechanisms there are certain other influence on GFR that need to be known as mentioned below;

1. Strong Sympathetic activation decreases GFR. Renal cortical shut down in crisis situation.

Hormonal and Autocoids –

1. Norepinephrin, epinephrine and Endothelin Constricts Renal Blood vessels 2. Angiotensin II prevents decrease in hydrostatic pressure and Increases peritubular

reabsorption. 3. Endothelial Derived Nitric Oxide decrease afferent and efferent arteriolar resistance

and increase GFR. 4. Prostaglandin E2 and PGI2, bradykinin are Vasodilators increase GFR. 5. NSAID’s not be given in Postsurgical, volume depleted and Renal failure patients.as

NSAIDS are Prostaglandin inhibitors will cause afferent vasoconstriction decreasing GFR and further deteriorating patients condition.

Summary:

To summarize we beginned this topic with understanding renal blood flow first and renal

vasculature along cortical and juxta-medullary nephron. In this we have seen that the cortical

nephron serve the function of tubular reabsorption and juxta-medullary nephron serve

function of making the medullary interstitium hyperosmolar with the help of vasa recta

causing concentration of urine. Then we discussed the starlings forces determining GFR and

the factors affecting them. To maintain urine output kidneys autoregulate GFR and Renal

blood flow by altering resistance of afferent and efferent arterioles. Constriction of efferent

arterioles causes increased GFR and urine output and vice versa. In autoregulation we have

discussed intrinsic myogenic mechanism which is generalised and tubule-glomerular

feedback along with the understanding of Juxta-glomerular apparatus.