Physiology Note - HICS Initiative

 
Dr Shilpa Sarathy

Consultant in Critical Care

Sindhu Hospital, Hyderabad

                                                GLOMERULAR FILTRATION 

 Introduction

Glomerular Filtration Rate (GFR) represents the volume of plasma filtered by all functioning nephrons per minute and is the single best indicator of kidney function. Understanding the physiology behind GFR is fundamental for interpreting renal disease, critical illness, fluid balance, and drug dosing.

 

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 concentration of other constituents of the glomerular filtrate are like the concentrations in the plasma.

Exceptions to this include a few low molecular weight substances such as calcium and fatty acids that are partially bound to plasma proteins which therefore are not freely filtered.

 

In the average adult human, the GFR is about 125ml/min or 180L/day. About 20% of the renal plasma flowing through the kidneys is filtered through the glomerular capillaries.

Filtration Fraction is calculated as:

FF = GFR / Renal plasma flow

Important contributors to the Glomerular filtration Rate are:

1. Glomerular capillary Membrane

2. Unique pressure dynamics within the glomeruli

 

Glomerular Capillary Membrane: ( Figure 1a and 1b)

Glomerular capillary membrane consists of three layers:

1) Endothelial cell layer of the capillary

2) Basement membrane

3) Epithelial cells (podocytes) surrounding outer surface of the capillary basement membrane.

  

Figure 1a The Glomerulus                                    Figure 1b The Glomerular- Capillary Membrane

                

The capillary endothelium is perforated by numerous small holes called fenestrae (fig2). The endothelial cell proteins are also richly endowed with negative charges that hinder the passage of plasma proteins.

                                                    Figure 2 : The capillary endothelium

The Basement membrane greatly hinders filtration of plasma proteins because of strong negatively charged proteoglycans. Podocytes that line the outer surface of the glomerulus have long foot like processes called pedicles which are separated by gaps called slit pores through which glomerular filtrate moves. These epithelial cells also have negative charge providing additional restriction to filtration of plasma proteins. ( Fig 3)

                                     Figure 3: The podocytes and their relation to Glycocalyx

Factors affecting filterability of solutes: ( Fig 4)

1.     Size: As the molecular weight of the molecules approaches that of albumin, the filterability rapidly decreases approaching zero.

2.     Charge: Positively charged molecules are filtered more rapidly than negatively charged molecules due to the electrostatic repulsion exerted by negative charges of the glomerular capillary wall proteoglycans.

 

    

    

                                        Fig 4: Determinants of filterability of solutes

 

Determinants of Glomerular Filtration Rate: ( Figures 5 and 6)

1)     Starling Forces (Main determinants)

GFR depends on:

 

i)               Glomerular capillary hydrostatic pressure (P_GC)

Ø  It is estimated to be around 60mm Hg.

Ø  Favors filtration

 

P_GC is determined by three variables:

Ø  Arterial pressure: Increased arterial pressure raises glomerular hydrostatic pressure however renal autoregulatory mechanisms maintain a relatively constant glomerular pressure as arterial pressure fluctuates.

Ø  Afferent arteriolar resistance: Increase of arteriolar pressure reduces P_GC and decrease of pressure increases it.

Ø  Efferent arteriolar resistance: Constriction of efferent arterioles increases glomerular hydrostatic pressure and thus increases GFR.

However severe constriction reduces renal blood flow, increases glomerular colloid osmotic pressure and thereby reducing GFR.

Thus, the effect is biphasic.

 Figure 5: Impact of Arteriolar Resistance on GFR

                  Figure 6: Relationship between GFR Renal Blood Flow and Arteriolar Resistance

ii)             Bowman’s space hydrostatic pressure (P_BS)           

 

Ø  Estimated to be about 18 mm hg under normal conditions.

Ø  Opposes filtration: Increased bowman’s capsule hydrostatic pressure reduces GFR whereas decreasing this pressure increases GFR.

Ø  Increased in obstruction of urinary tract (eg: stones, BPH).

           (iii)   Glomerular capillary colloid osmotic pressure            

            (πGC)

Ø  Average colloid osmotic pressure is about 32 mm Hg.

Ø  Opposes filtration

Ø   Factors influencing the glomerular capillary colloid osmotic pressure are

a)     The arterial plasma colloid osmotic pressure   Increase in the plasma oncotic pressure raises the πGC which in turn reduces the GFR

b)    Filtration Fraction: Increasing the filtration fraction concentrates the plasma proteins and raises the πGC which reduces the GFR.

 

iv)            Bowman’s space oncotic pressure (πBS)

Ø  Colloid osmotic pressure of the proteins in bowman’s capsule which promotes filtration.

Ø  Normally negligible (filtrate protein-free).

 

 

2)    Glomerular capillary Filtration co-efficient

 

K_f is a measure of the hydraulic conductivity and the surface area of the glomerular capillaries.

It cannot be measured directly but estimated by dividing GFR by net filtration pressure.

 

K_f = GFR/ Net filtration pressure

 

When expressed per 100gm of kidney weight, it averages about 4.2 ml/min per mm Hg.

 

It can be reduced in diseases where there is increased capillary membrane thickness reducing its hydraulic conductivity or decrease in the number of functional glomerular capillaries.

   Eg:- chronic hypertension

        - obesity / diabetes mellitus

        - glomerulonephritis

 

 

Net filtration pressure

Net filtration pressure represents the sum of the hydrostatic and colloid osmotic forces that favour or oppose filtration across the glomerular capillaries. ( Figure 7)

    

                                         Figure 7: Net Filtration Pressure

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

 

GFR = K_f × ( P_g - P_b - π_{g +} π_b)

 

Renal blood flow

Combined blood flow to both the kidneys is about 1100ml/min or about 22% of the cardiac output.

High blood flows to the kidneys are to supply enough plasma for the high rates of glomerular filtration.

Oxygen and nutrients delivered to kidneys also greatly exceeds their metabolic needs. A large fraction of renal oxygen consumption is related to renal tubular sodium reabsorption.

Factors which affect the renal blood flow also control the GFR.

 

Determinants of renal blood flow

 

RBF =    P / R

    P = difference between renal artery pressure and renal vein pressure

R = total renal vascular resistance

= Ra + Re + Rv

= sum of all resistances in kidney vasculature (afferent arterioles, efferent arterioles and the veins)

 

Regulation of renal blood flow and glomerular filtration:

 

1)    Neural regulation

 

The afferent and efferent arterioles are richly innervated by sympathetic nerve fibres. Strong activation of the renal sympathetic nerves can constrict the renal arterioles and decrease renal blood flow and GFR. Mild or moderate mild sympathetic stimulation however has little influence on renal blood flow and GFR.

 

2)    Hormonal regulation

 

i)               Norepinephrine and epinephrine – with strong activation of the sympathetic nervous system both hormones cause reduction in GFR by constricting afferent and efferent arterioles.

ii)             Endothelin – It is a peptide hormone released by the damaged endothelial cells (severed blood vessel) of the glomerular capillaries causing vasoconstriction and decreased GFR.

iii)           Angiotensin II (AT II) – It is a circulating hormone and a locally produced autocoid. Preferentially constricts efferent arterioles and raises the glomerular hydrostatic pressure and thus the GFR. Released with decreased arterial pressure or volume depletion helps prevent decrease of GFR.

ACE inhibitors → efferent dilation → ↓GFR

iv)            Prostaglandins and nitric oxide – Prevent the vasoconstrictor effect of AT II on afferent arterioles by vasodilatation thereby increase blood flow and maintain GFR.

NSAIDs block PG → afferent constriction → ↓GFR, risk AKI

 

3)     Autoregulation of renal blood flow and GFR

 

Kidney maintains stable GFR over MAP 80–180 mmHg due to feedback mechanisms intrinsic to the kidneys.

1)  Myogenic mechanisms: The myogenic mechanism relies   on inherent properties of the arterioles, themselves. ( Figure 8)

Ø  When increased renal blood flow exerts increased hydrostatic capillary pressure on the walls, stretch receptors are activated and induce vasoconstriction.

Ø  This reduces renal blood flow and, therefore, GFR.

Ø  When renal blood flow is low, the stretch receptors are inactivated, and the arteriole dilates to increase GFR.

Ø  This mechanism is more important in protecting the kidney from hypertension induced injury.

 

                            

 

                 Figure 8: The Myogenic Mechanism

 

 

 

4)     Tubuloglomerular feedback mechanism:

This mechanism links the changes in the sodium chloride concentration at the macula densa with the control of renal arteriolar resistance and autoregulation of GFR.

This helps in maintaining a constant delivery of sodium chloride to the distal tubules.

The tubuloglomerular feedback mechanism has two components that act together to control the GFR.

Ø  An afferent arteriolar feedback mechanism

Ø  An efferent arteriolar feedback mechanism

These mechanisms depend on special anatomical arrangement of the juxtaglomerular complex.

 

The juxtaglomerular complex consists of macula densa cells which are specialized group of epithelial cells in the distal tubules that comes in close contact with the afferent and efferent arterioles and the juxtaglomerular cells in the walls of the afferent and efferent arterioles. ( Figure 9)

                                                            Figure 9 : The Juxta Glomerular Apparatus 

Decrease in the sodium chloride concentration initiates a signal from the macula densa that has two effects:

Ø  It decreases resistance to blood flow in the afferent arterioles, which raises glomerular hydrostatic pressure and helps return GFR towards normal. ( Figure 10)

Ø  It increases renin release from the juxtaglomerular cells of the afferent and efferent arterioles which gets converted into AT II that constricts the efferent arterioles increasing glomerular hydrostatic pressure and helping GFR return to normal.

 

    

                                        Figure 10: Autoregulation of GFR

Pathophysiological Influences on GFR

Multiple conditions directly or indirectly alter GFR:

Ø  Hypovolemia, haemorrhage, shock      strong sympathetic and angiotensin II activation      decreased GFR.

Ø  Obstruction (stones, tumours, BPH)      increases Pb reduces GFR.

Ø  Sepsis      vasodilation + microcirculatory dysfunction variable effects on GFR.

Ø  Diabetes mellitus      initially increased GFR due to afferent dilation, later decline due to Kf reduction.

Ø  Heart failure     low perfusion     decreased GFR despite fluid overload.