Glomerular Apparatus and Filtration - Anatomy & Physiology

Glomerular Filtration

The role of the renal corpuscle is to selectively filter the blood by allowing small molecules through but preventing plasma proteins from leaving the blood. This filtration occurs extracellulary and is done by what is know as the glomerular filtration barrier. This structure is made up of three layers:

Fenestrated capillary endothelium
Glomerular basement membrane
Podocytes

Fenestrated Capillary Endothelium

There are small gaps called fenestrae in the cytoplasm of the capillary endothelium.
They account for approxamately 10% of the surface area of the cells
They allow water and non-cellular components of the blood to pass through
They act mainly as a barrier to the cells of the blood

Glomerular Basement Membrane

Also known as the basal lamina
This is the main barrier to proteins
- Restricts all but the smallest plasma proteins from passing through
Made up of a protein mesh in a gelatinous matrix
- Composed of collagen and other matrix proteins
Prevents filtration of compounds >7,000 Da
Lower permeability to anions compared to cations. This allows for further selective filtration

Podocytes

The cells of the visceral layer of the Bowmans capsule posses finger like foot processes called pedicels. These wrap around the outer layer of the basal lamina. Filtration occurs through small gaps between pedicels called slit diaphragms. This is the final barrier against proteins

Factors Which Determine Selective Filtration

Hydrostatic pressure in the capillaries causes filtration but as the filtrate is basically protein free there is no real protein osmotic pressure in the Bowmans capsule. This means the filtration is almost entirely powered by the hydrostatic pressure in the capillaries.
Molecular size - molecules with a radius of 4nm or more aren't filtered, whilst those with a radius less than 2nm are filtered without restriction. Thus the filtration barrier is selectively permeable.
Electrical charge
- The barrier has a net negative charge thanks to cells in the membrane having a negatively charged surface and a basal lamina with negatively charged glycoproteins.
- Therefore negatively charged molecules are filtered less than positive or neutral ones
- Proteins are negatively charged this and their size prevents their filtration
Protein binding
- Drugs, ions or small molecules which are bound to protein are not filtered
Molecular configuration
- Round molecules fit less easily than ellipsoid ones
Rigidity
- The higher the rigidity of a molecule the less easily it is filtered

Composition of Filtrate

Normal filtrate is basically protein free.
However small amounts of albumin do make it across the membrane. These are completely reabsorbed in the proximal tubules
Small molecules with a molecular weight <7,000 Da are filtered without restriction these include:
- Water
- Sodium, chloride, creatinine, urea, uric acid and phosphate are filtered in isotonic levels (same concentration as plasma)
Larger molecules with a molecular weight >7,000 Da such as myoglobin (17,000 Da) are filtered less
Movement of larger molecules is restricted
- Plasma proteins with molecular weights up to 70,000 Da are heavily restricted from passing through the glomerulus
Charged molecules over 70,000 Da are not filtered at all
The threshold for neutral molecules is 100,000 Da

Substance	MW (Da)	Ratio Filtrate/Plasma
Glucose	180	1
Myoglobin	17,000	0.75
Haemoglobin	68,000	0.03
Albumin	69,000	<0.01

Glomerular Filtration Rate

The glomerular filtration rate or GFR is the amount of fluid filtered from the capillaries into the Bowmans capsule per unit time. The GFR can be expressed as the following formula:

GFR = K_f x net filtration pressure

K_f = the filtration coefficent

K_f can furthermore be expressed by the following formula

K_f = membrane permeability x filtration area

The GFR is practically proportional to metabolic body mass. Therefore the bigger the animal the greater the GFR. This obviously makes sense.

Regulation of the GFR

The following formula helps us to understand GFR and how various factors affect it. Whilst reading this article you may find it useful to refer back to it:

 Q = (PA - PE) ÷ R

 Q = Flow, PA = Pressure in afferent arteriole, PE = Pressure in efferent arteriole, R = Resistance

There are two major forces opposing GFR. These are the hydrostatic pressure in the Bowmans space and the plasma protein osmotic pressure. These are not under physiological control. The filtration coefficient is also beyond the realms of physiological control. On the other hand the hydrostatic pressure in the capillaries and the renal blood flow are under physiological regulation and adjust filtration according to the bodies needs.

Regulation of Renal Blood Flow and Capillary Hydrostatic Pressure

These two factors are determined by the arterial blood pressure coupled with the contraction of both the afferent and efferent arterioles. The total resistance of the afferent and efferent arterioles, which is determined by the contraction of them, determines the renal blood flow and any particular arterial pressure. Therefore it is important that they change with arterial pressure in order to maintain a steady renal blood flow.

Constriction of the Afferent and Efferent Arterioles

Normally the afferent arteriole is of larger diameter than the efferent. This means there is high resistance as the blood is forced from a wider vessel to a narrower one and this promotes filtration. If the arterial blood pressure remains constant then contracting either vessel reduces blood flow as it increases resistance. However contracting either has opposite effects on the filtration pressure. If you contract the afferent arteriole there will be less of a pressure difference between the afferent and efferent arteriole so there will be reduced filtration pressure. However if you constrict the efferent arteriole you are increasing the pressure difference between the two and filtration pressure increase.

Overall the constriction of the afferent arteriole decreases both blood flow and filtration pressure where as constricting the efferent arteriole decreases blood flow but increases filtration pressure. _{(Both of these statements are assuming a constant blood pressure)}. The fact that both can be altered allows independent regulation of both GFR and blood flow.

Physiological Regulators of GFR

The main systems which regulate renal blood flow and GFR are:

Autoregulation

Angiotensin 2

Sympathetic Nervous System.

Nitrous Oxide and Prostaglandins

Pressure in the Peritubular Capillaries

The peritubular capillaries have a lower hydrostatic pressure and a higher protein osmotic pressure than the rest of the capillaries in the body. This is largely thanks to the fact that the blood within them has had a substantial quantity of its plasma removed by the Glomerulus. Resulting in a low concentration of solutes but a high concentration of protein. These pressures however are not constant and changes in them affect reabsorption. They have the biggest effect in the proximal tubule thanks to the relatively weaker tight junctions which allow water and ions to pass paracellulary.

The Effects of Changing Pressure

If hydrostatic pressure is elevated and protein osmotic pressure reduced then water leaves the Interstium and enters the tubular lumen thus increasing water loss. These pressure changes are characteristic of a situation where the animal drinks a large amount of water in a short period of time.

If the situation is reversed it results in a decreased urinary output and is often caused by a fall in blood pressure associated with a reduction in ECF.

Renal Clearance

Renal clearance is the ability of the kidney to remove a compound from the blood. It is intimately linked to the glomerular filtration rate, tubular reabsorption and secretion. Renal clearance is just part of the total body clearance of a compound. Other methods of clearance include; biliary, pulmonary and salivary excretion. To look at the renal clearance you need to know the amount of plasma that must have been filtered to produce that much of the substance in the urine per given unit of time. This is given by the following formula:

 Clearance = (Urine Concentration of a Substance x Urine Volume per unit time) / Plasma Concentration of the Substance

Renal Clearance and GFR

For the clearance to represent the GFR the substance looked at must be filtered freely and from that point on as it travels through the nephron its concentration must not be altered. Therefore it must not be secreted or reabsorbed.

Determination of GFR from Renal Clearance

Inulin, Creatinine or Urea can be used.

Inulin

Inulin is injected into the plasma. It is freely filtered by the glomerulus and therefore its rate of excretion is directly proportional to the rate of filtration of water and solutes.

Creatinine

Creatinine is also freely filtered by the glomerulus so it represents a close approximation to GFR. You can measure endogenous creatinine. It's production from muscle is constant. In renal failure its secretion is reduced and it is secreted into the gut. You can also measure it by infusing exogenous creatinine. It is difficult as urine collection needs to be carried out over time and blood samples need to be taken.

Urea

The idea behind this is that you measure factors which would normally be excreted. The same idea is behind the measurement of endogenous creatinine. However this is not ideal as it is altered by non-renal factors and they only change when the renal failure is very advanced as there is a large functional reserve in the kidneys. Urea is also not idea in horses and ruminants as it is used by the digestive micro flora to make microbial protein.