GFR

GFR- GFR is determined by

- (1) the balance of hydrostatic and colloid osmotic forces acting across the capillary membrane and

- (2) the capillary filtration coefficient (Kf), the product of the permeability and filtering surface area of the capillaries.

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

- The fraction of the renal plasma flow that is filtered (the filtration fraction) averages about 0.2;

- this means that about 20 per cent of the plasma flowing through the kidney is filtered

- Filtration fraction = GFR/Renal plasma flow

Glomerular Capillary Membrane

Glomerular Capillary Membrane- The capillary endothelium is perforated by

thousands of small holes called fenestrae

- Although the fenestrations are relatively large, endothelial cells are richly endowed with fixed negative charges that obstruct the passage of plasma proteins.

- The basement membrane consists of a meshwork of collagen and proteoglycan fibrillae that have large spaces through which large amounts of water and small solutes can filter.

- The basement membrane effectively prevents filtration of plasma proteins because of strong negative electrical charges associated with the proteoglycans.

Glomerular Capillary Membrane- The final part of the glomerular membrane is a

layer of epithelial cells that line the outer surface of the glomerulus.

- These cells are not continuous but have long foot like processes (podocytes) that encircle the outer surface of the capillaries.

- The foot processes are separated by gaps called slit pores through which the glomerular filtrate moves.

- The epithelial cells also have negative charges, provide additional restriction to filtration of plasma proteins.

Determinants of the GFR- The GFR is determined by - (1) the sum of the hydrostatic and colloid

osmotic forces across the glomerular membrane, which gives the net filtration pressure,

- (2) the glomerular capillary filtration coefficient, Kf.

- GFR = Kf X Net filtration pressure

- The net filtration pressure represents the sum of the hydrostatic and colloid osmotic forces that either favor or oppose filtration across the glomerular capillaries

Determinants of the GFR- (1) hydrostatic pressure inside the glomerular

capillaries (glomerular hydrostatic pressure, PG), which promotes filtration;

- (2) the hydrostatic pressure in Bowman’s capsule (PB) outside the capillaries, which opposes filtration;

- (3) the colloid osmotic pressure of the glomerular capillary plasma proteins (µG), which opposes filtration; and

- (4) the colloid osmotic pressure of the proteins in Bowman’s capsule (µB), which promotes filtration.

Determinants of the GFR- (Under normal conditions, the

concentration of protein in the glomerular filtrate is so low that the colloid osmotic pressure of the Bowman’s capsule fluid is considered to be zero.)

- The GFR can therefore be expressed as

- GFR = Kf X (PG – PB – µG + µB)

Determinants of the GFR- Increased Bowman’s Capsule Hydrostatic

Pressure Decreases GFR

- In certain pathological states associated with obstruction of the urinary tract, Bowman’s capsule pressure can increase markedly - serious reduction of GFR.

- Precipitation of calcium or uric acid may lead to “stones” that lodge in the urinary tract, often in the ureter, thereby obstructing outflow of the urinary tract and raising Bowman’s capsule pressure.

Determinants of the GFR- Increased Glomerular Capillary Colloid Osmotic

Pressure Decreases GFR

- As blood passes from the afferent arteriole through the glomerular capillaries to the efferent arterioles,

- the plasma protein concentration increases about 20 %

- (1) the arterial plasma colloid osmotic pressure and - (2) the fraction of plasma filtered by the glomerular

capillaries (filtration fraction).

- Increasing the arterial plasma colloid osmotic pressure raises the glomerular capillary colloid osmotic pressure - decreases GFR.

Determinants of the GFR- Increased Glomerular Capillary

Colloid Osmotic Pressure Decreases GFR

- Increasing the filtration fraction also concentrates the plasma proteins and raises the glomerular colloid osmotic pressure

- a greater rate of blood flow into the glomerulus tends to increase GFR, and a lower rate of blood flow into the glomerulus tends to decrease GFR.

Determinants of the GFR- Increased Glomerular Capillary

Hydrostatic Pressure Increases GFR

- Increased arterial pressure tends to raise glomerular hydrostatic pressure and so increases GFR.

- Increased resistance of afferent arterioles reduces glomerular hydrostatic pressure and decreases GFR.

- dilation of the afferent arterioles increases both glomerular hydrostatic pressure and GFR

Determinants of the GFR- Increased Glomerular Capillary

Hydrostatic Pressure Increases GFR

- Constriction of the efferent arterioles increases the resistance to outflow from the glomerular capillaries.

- This raises the glomerular hydrostatic pressure, and as long as the increase in efferent resistance does not reduce renal blood flow too much, GFR increases slightly

Determinants of the GFR- Increased Glomerular Capillary Hydrostatic

Pressure Increases GFR

- Efferent arteriolar constriction reduces renal blood flow - the filtration fraction and glomerular colloid osmotic pressure increase

- So, if the constriction of efferent arterioles is severe, the rise in colloid osmotic pressure exceeds the increase in glomerular capillary hydrostatic pressure caused by efferent arteriolar constriction.

- When this occurs, the net force for filtration actually decreases, causing a reduction in GFR.

Determinants of the GFR- Increased Glomerular Capillary

Hydrostatic Pressure Increases GFR

- constriction of afferent arterioles reduces GFR.

- the effect of efferent arteriolar constriction depends on the severity of the constriction;

- moderate efferent constriction raises GFR,

- severe efferent constriction reduces GFR.

Physiologic Control of GFR and RBF- Sympathetic Nervous System

Activation Decreases GFR

- Strong activation of the renal sympathetic nerves can constrict the renal arterioles and decrease renal blood flow and GFR

- Norepinephrine, Epinephrine and Endothelin Constrict Renal Blood Vessels and Decrease GFR

Physiologic Control of GFR and RBF- Angiotensin II Constricts Efferent

Arterioles- raise glomerular hydrostatic pressure while

reducing renal blood flow - helps prevent decreases in glomerular hydrostatic pressure and GFR

- Endothelial-Derived Nitric Oxide Decreases Renal Vascular Resistance and Increases GFR

- Prostaglandins and Bradykinin Tend to Increase GFR

Autoregulation of GFR and RBF- Feedback mechanisms intrinsic to the

kidneys normally keep the renal blood flow and GFR relatively constant, despite marked changes in arterial blood pressure.

- Role of Tubuloglomerular Feedback in Autoregulation of GFR

- Decreased Macula Densa Sodium Chloride Causes Dilation of Afferent Arterioles and Increased Renin Release

Myogenic Autoregulation- the ability of individual blood vessels to resist

stretching during increased arterial pressure.

- Arterioles respond to increased wall tension or wall stretch by contraction of the vascular smooth muscle.

- Stretch of the vascular wall allows increased movement of calcium ions from the ECF into the cells, causing them to contract

- This contraction prevents overdistension of the vessel and raises vascular resistance - prevent excessive increases in RBF and GFR when arterial pressure increases.

Clearance Methods- The rates at which different substances are “cleared”

from the plasma provide a useful way of quantitating the effectiveness with which the kidneys excrete various substances.

- The renal clearance of a substance is the volume of plasma that is completely cleared of the substance by the kidneys per unit time

- renal clearance of a substance is calculated from the urinary excretion rate (U X V) of that substance divided by its plasma concentration (P).

C = U X V / P

Inulin Clearance- If a substance is freely filtered and is not

reabsorbed or secreted by the renal tubules,

- then the rate at which that substance is excreted in the urine is equal to the filtration rate of the substance by the kidneys

- Inulin, a polysaccharide molecule with a molecular weight of about 5200.

- Inulin is not produced in the body, is found in the roots of certain plants and must be administered intravenously to a patient to measure GFR.

Inulin Clearance- (1) if the clearance rate of the substance

equals that of inulin, the substance is only filtered and not reabsorbed or secreted;

- (2) if the clearance rate of a substance is less than inulin clearance, the substance must have been reabsorbed by the nephron tubules; and

- (3) if the clearance rate of a substance is greater than that of inulin, the substance must be secreted by the nephron tubules.

Creatinine Clearance- Creatinine is a by-product of muscle

metabolism and is cleared from the body fluids almost entirely by glomerular filtration.

- Because measurement of creatinine clearance does not require intravenous infusion into the patient, this method is much more widely used than inulin clearance for estimating GFR clinically.

- creatinine clearance is not a perfect marker of GFR because a small amount of it is secreted by the tubules, so that the amount of creatinine excreted slightly exceeds the amount filtered

Creatinine ClearanceGFR = CCreatinine = Ucreatinine X V / Pcreatinine

- If GFR suddenly decreases by 50%, the kidneys will transiently filter and excrete only half as much creatinine,

- causing accumulation of creatinine in the body fluids and raising plasma concentration

- plasma creatinine concentration is inversely proportional to GFR

GLOMERULAR DISEASES- Glomerular diseases include a large and

clinically significant group of renal diseases.

- Glomerulonephritis (GN) is the term used for diseases that primarily involve the renal glomeruli.

- I. Primary glomerulonephritis in which the glomeruli are the predominant site of involvement.

- II. Secondary glomerular diseases include certain systemic and hereditary diseases which secondarily affect the glomeruli.

GLOMERULAR DISEASES- The clinical presentation of

glomerular disease is quite variable but in general four features—proteinuria, hematuria, hypertension and disturbed excretory function

- nephritic and nephrotic syndromes;

- acute and chronic renal failure;- asymptomatic proteinuria and

haematuria

ACUTE NEPHRITIC SYNDROME- This is the acute onset of haematuria, proteinuria,

hypertension, oedema and oliguria following an infective illness about 10 to 20 days earlier.

- 1. The haematuria is generally slight giving the urine smoky appearance and erythrocytes are detectable by microscopy

- 2. The proteinuria is mild (less than 3 gm per 24 hrs) and is usually non-selective (nephritic range proteinuria).

- 3. Hypertension is generally mild.- 4. Oedema in nephritic syndrome is usually mild

and results from sodium and water retention.- 5. Oliguria is variable

NEPHROTIC SYNDROME- it is characterised by findings of massive

proteinuria, hypoalbuminaemia, oedema, hyperlipidaemia, lipiduria, and hypercoagulability.

- 1. Heavy proteinuria (protein loss of more than 3 gm per 24 hrs) is the chief characteristic of nephrotic syndrome (nephrotic range proteinuria).

- A highly-selective proteinuria consists mostly of loss of low molecular weight proteins, while a poorly-selective proteinuria is loss of high molecular weight proteins in the urine.

- In nephrotic syndrome, proteinuria mostly consists of loss of albumin (molecular weight 66,000) in the urine.

NEPHROTIC SYNDROME- 2. Hypoalbuminaemia is produced primarily

consequent to urinary loss of albumin, and partly due to increased renal catabolism and inadequate hepatic synthesis of albumin.

- 3. Oedema in nephrotic syndrome appears due to fall in colloid osmotic pressure resulting from hypoalbuminaemia.

- 4. Hyperlipidaemia - the liver faced with the stress of massive protein synthesis in response to heavy urinary protein loss, also causes increased synthesis of lipoproteins

NEPHROTIC SYNDROME- 5. Lipiduria occurs following

hyperlipidaemia due to excessive leakiness of glomerular filtration barrier.

- 6. Hypercoagulability – - increased urinary loss of antithrombin III, - hyperfibrinogenaemia from increased

synthesis in the liver, - decreased fibrinolysis, - increased platelet aggregation and - altered levels of protein C and S.

Thank You…