Urine Formation

Created by Musango07/04/11

The kidney converts blood plasma to urine in three stages

1. Glomerular filtration
2. Tubular reabsorption and secretion
3. Water conservation 

 Glomerular Filtration

•As fluid travels through the nephron, its composition changes, thus its name

–Glomerular filtrate- fluid in the capsular space that is similar to blood plasma except that it has almost no protein

–Tubular fluid- fluid from the PCT through the DCT

•Differs from the glomerular filtrate in that substances are removed and added by the tubule cells

–Urine- fluid that enters the collecting ducts

• Components of Filtration

Filtration membrane- the barrier through which the fluid must pass to enter the capsular space. Consist of:

-          The fenestrated endothelium of the capillary-  the honeycombed structure of the capillary endothelium, containing large pores that allow various substances to pass through (not blood cells or large proteins)

-          The basement membrane- Its structure is like a kitchen sponge. While blood plasma is 7% protein, the glomerular filtrate is only 0.03% protein.  It has traces of albumin and smaller polypeptides, including some hormones.

-          Filtration slits- octopi like structure of the podocytes. Each arm has numerous little extensions called pedicles (foot processes) that wrap around the capillaries and interdigitate with each other. Pedicles have a negatively charged filtration slits; this restricts anions like albumins from being filtered.

–Water, electrolytes, glucose, fatty acids, nitrogenous wastes, and vitamins are filtered.

–Some substances that are of low molecular weights are retained in the blood plasma because they are bound to plasma proteins e.g. Calcium, iron, thyroid hormone and plasma fatty acids. The small fraction of the above that are unbound will pass through

•About 20% of the plasma that passes through the kidney gets filtered into the nephron

•Filtration  takes place in the glomerulus

•It is driven by the hydrostatic pressure of the blood (osmosis (oncotic pressure) opposes filtration, but the hydrostatic pressure is larger)

•Water and small molecules are filtered; blood cells and large molecules (most proteins) do not pass through the filter 

•  Kidney trauma and infections can damage the filtration membrane and allow albumin or blood cells to filter through

1. Proteinuria (albuminuria)- the presence of protein in the urine

1. Hematuria- the presence of blood in the urine

•Strenuous exercise can temporarily cause proteinuria or hematuria

–Strenuous exercise greatly reduces perfusion of the kidney causing glomerular damage due to prolonged hypoxia.

1. Albuminuria

•More than the normal amount of albumin in the urine. Albumin is the predominant protein in human blood and it is the key to the regulation of the osmotic pressure of blood.

•It is normal to have some albumin in urine. But too much albumin indicates that protein is leaking through the kidney.

•Albuminuria can mean many things. For example, albuminuria may be a sign of significant kidney disease or it may simply be a sequel of vigorous exercise. Albuminuria is a form of proteinuria.

1. Hematuria

•is a sign that something is causing bleeding in the genitourinary tract

•There are two types of hematuria,

–Microscopic- the amount of blood in the urine is so small that it can be seen only under a microscope.

–Gross (or macroscopic) - the urine is pink, red, or dark brown and may contain small blood clots.

1. Joggers hematuria

results from repeated jarring of the bladder during jogging or long-distance running.

•Reddish urine that is not caused by blood in the urine is called pseudohematuria. It may be caused by some drugs and some types of food. Find out from BNF

• Filtration Pressure

•Glomerular filtration follows the same principles that govern filtration in other blood capillaries but with some  significant differences in the magnitude of forces involved

–The blood hydrostatic pressure is much higher, about 60mm Hg compared with 10-15 mm Hg in most other capillaries

–Results from the fact that the afferent arteriole is substantially larger (than those in other parts of the body) than the efferent arteriole, giving the glomerulus a large inlet and small outlet.

– The osmotic pressure (Oncotic) which opposes the hydrostatic pressure is comparatively lower.

1. Nephrosclerosis 

High blood pressure in the glomeruli makes the kidneys especially vulnerable to hypertension, which can rupture glomerular capillaries and lead to scarring of the kidney (Nephrosclerosis) and atherosclerosis of renal blood vessels, leading to renal failure

Glomerular Filtration Rate (GFR)

Is the amount of filtrate formed per minute by the two kidneys combined. GFR depends upon;

–Permeability of the filtration barrier

–Surface area of the filtration barrier

GFR measurement 

It a way of measuring kidney function. It is not measured directly. We use a marker substance, which is neither reabsorbed nor secreted by the kidney. The reasoning is: the amount of the substance excreted per minute should be equal to the amount filtered.

Two substances are used to measure GFR:

1. Inulin: a polysaccharide which is not metabolized by the body or reabsorbed from the urine. Inulin is not found in the body and must be injected. This substance gives the most accurate results and is used for research purposes.
2. Creatinine: a breakdown product from creatine phosphate, which is naturally found in the blood. Not quite as accurate as Inulin (about 10% is reabsorbed), but often used in medicine, since no injection is required.

Using Inulin in Measuring GFR

-          Is only filtered by the kidney; it is neither reabsorbed nor secreteted

-          Since no Inulin is reabsorbed from or secreted into the tubule, the amount filtered into the tubule at the glomerulus must equal the amount appearing in the urine

-          P X GFR = U X V ; where,

P = plasma concentration of Inulin, in mg/mL

GFR = glomerular filtration rate of plasma, in mL/min

U = urine concentration of Inulin, in mg/mL

V = rate of urine production, in mL/min

Solving the equation for GFR will give:

GFR = (U X V)/P

The normal value of GFR is 125ml/min

Renal Clearance

the volume of blood plasma from which a particular waste is completely removed in 1 minute.

Clearance= (U*V)/P

The clearance of Inulin= GFR and is taken as the standard, because it's neither secreted nor reabsorbed.

-          If a substance has a clearance greater than Inulin, then it must have been secreted into the tubular fluid by the nephron epithelium.

-          If it's lower, then either it was not filtered at the glomerulus or it must have been reabsorbed from the tubular fluid.

Regulation of Glomerular Filtration

GFR must be finely controlled:

If it is too high,

–Fluid flows through the renal tubules too rapidly for them to reabsorb the usual amount of water and solutes

–Urine output rises and creates a threat of dehydration and electrolyte depletion           

If it is too low

–Fluid flows sluggishly through the tubules and they reabsorb wastes that should be eliminated and azotemia may occur. GFR is adjusted by three homeostatic mechanisms:

1. Renal autoregulation- can even be observed in denervated kidneys e.g. transplanted kidneys!
2. Sympathetic control
3. Hormonal control

Renal Autoregulation

•The ability of the Nephrons to adjust their own blood flow and GFR without external (nervous or hormonal) control.

•Allows stable fluid and electrolyte balance in spite of alterations in mean arterial pressure.

•Therefore, a primary role of the renal autoregulatory mechanism is to regulate intrarenal haemodynamics and intrarenal pressures to levels that maintain an optimal balance with tubular metabolic functions.

•There are two mechanisms of autoregulation

• Myogenic mechanism

• Tubular glomerular feedback (TGF)

Myogenic Mechanism

Keeping mind that filtration pressure is a matter of blood pressure (or glomerular capillary pressure); Blood pressure changes are sensed through stretch receptors and respond accordingly through relaxation or constriction.

–afferent arteriolar vasoconstriction would serve to protect the glomerulus from uncontrolled systemic hypertension,

–while afferent arteriolar vasodilatation would allow for greater blood flow into the glomerulus in times of hypotension

The autoregulatory system accomplishes this by maintaining the glomerular capillary pressure around 60-70 mm Hg

Tubular glomerular Feedback

•The Juxtaglomerular apparatus (JGA) is made up of specialized cells in the wall of the afferent arteriole and granular cells in the wall of the distal tubule (the macula densa).

•This area is innervated by adrenergic fibers and the granular cells carry renin in intracellular granules

•The principle function of the JGA is adapting the GFR to early distal tubule fluid characteristics by modulating renin synthesis and release: this is known as the Tubular glomerular feedback (TGF) loop.  

•Afferent arteriolar caliber is principally controlled by TGF

•Besides altered sodium concentration at the macula densa of the distal tubule, release of renin can also be induced by changes in the blood flow patterns of the afferent arteriole, or by adrenergic stimulation.

Renin-Angiotensin Mechanism

•When blood pressure drops, the sympathetic nerves stimulate the JGA cells to secrete renin

•Renin acts on angiotensinogen to create angiotensin.

•Angiotensin is converted to angiotensin II by the action of angiotensin-converting enzyme (ACE) from the lungs and kidneys. Angiotensin II has multiple effects.

Renin-Angiotensin Mechanism

•Stimulates widespread vasoconstriction which raises the Mean Arterial Pressure throughout the body

•Constricts both the afferent and efferent arterioles (more prominent here because of greater concentration of Angiotensin II receptors) which reduces GFR and water loss

•Stimulates the secretion of antidiuretic hormone which promotes water reabsorption

•Stimulates the adrenal cortex to secrete Aldosterone, which in turn promotes sodium and water retention

•Stimulates the sense of thirst and encourages water intake

In summary, renal vascular resistance controlled by

•Intrinsic mechanisms

–Stretch receptors in wall of afferent and efferent arterioles

•Extrinsic mechanisms

–Hormones – renin-angiotensin II axis. Angiotensin II acts to increase efferent arteriolar tone

–Sympathetic innervation- in strenuous exercise or acute conditions such as circulatory shock. Norepinephrine directly increases afferent arteriolar tone causing a reduction in GFR and urine production, while redirecting blood from the kidneys to the heart, brain, and skeletal muscles.

Note: Angiotensin II release is dependent on renin release which results from

–blood flow changes in the afferent arteriole

–adrenergic stimulation

–solute changes at the macula densa 

Note: The normal GFR can only be maintained within systemic arterial pressures of 90-200 mmHg.

Circumstances under which GFR does not remain constant

1. Major heamorrhage- a large increase in sympathetic activity causes greater constriction of the afferent arterioles more than the efferent thus reducing GFR
2. Liver disease and malnutrition- reduces the plasma oncotic pressure considerably thus increasing GFR.

Assignment:

1. Define the terms; oliguria, polyuria, edema.
2. Describe the Pathophysiology of Glomerular nephritis.