MEDICINE FOR ALL

Total plasma volume filters into the renal tubules about every 22 minutes, so all plasma  would be drained  away as urine in less than 30 minutes were it not for the fact that most of the tubule contents are quickly reclaimed  and returned to the blood. This reclamation process, called tubular reabsorption, is a selective transepithelial process that begins as soon as the filtrate enters the proximal tubules. To reach the blood, reabsorbed substances follow either  either the transcellular or paracellular route. In the transcelullar route, transported transported substances move through the luminal membrane, the cytosol, and the basolateral membrane of the tubule cell and then the endothelium of the peritubular capillaries.  Movement of substances in the paracellular route between the tubule cells is limited because these cells are connected by tight junctions. In the proximal nephrons, however, these tight junctions are “leaky” and allow some important ions (Ca^2+, Mg^2+, K⁺, and some Na⁺) through the paracellular route.

Given healthy  kidneys, virtually all organic nutrients  such as glucose and amino acids are completely reabsorbed to maintain or restore  normal plasma concentrations. On the other hand, the reabsorbtion of water and many ions  is continuosly regulated and adjusted in response to hormonal signals. Depending of the substances transported, the reabsortion process  may be passive (no ATP required) or active (at least one of its steps is driven by ATP directly or indirectly)

Other factors affecting Glomerular filtration rate

Renal cells produce a battery of chemicals, many of which act as paracrines (local signaling molecules) :

• Prostaglandin E2  (PGE2) : The vasodilatory paracrine PGE2, counteracts vasoconstriction by norepinephrine  and angiotensin II within the kidney. The adaptive value of these opposing actions is to prevent renal damage while responding to body demands to increase peripheral resistance

• Intrarenal angiotensin II : Although we usually think of angiotensin II as hormone, the kidney makes its own, locally acting angiotensin II that reinforces the effects of hormonal angiotensin II, It also dampens the resulting renal vasoconstriction by causing PGE2 release.

• Adenosine : Adenosine can be released as such or produced extracellularly from ATP released by macula densa cells. Although it functions as avasodilator systemically, adenosine constricts the renal vasculature

Abnormally low urine output (less than 50 ml/day), called anuria, may indicate that glomerular blood pressure is too low to cause filtration. However, renal failure and anuria can result from situations in which the nephrons cease to functions for a variety of other reason, including acute nephritis, transfusion reactions and crush injuries.

EXTRINSIC CONTROLS (NEURAL AND HORMONAL MECHANISM)

The purpose of the  extrinsic controls regulating the glomerular filtration rate is to maintain systemic blood pressure – sometimes to the detriment of the kidneys.

• Symphatetic nervous system controls

Neural renal controls serve the needs of the body as a whole. When the volume of the extracellular fluid is normal and the sympathetic nervous system is at rest , the renal blood vessels are dilated and renal autoregulation mechanisms prevail. However, during extreme stress or emergency when it is necessary to shunt blood to vital organs, neural controls may overcome renal autoregulatory mechanisms.

Norepinephrine released by symphatetic nerve fibers  (and epinephrine released by the adrenal medulla) acts on alpha-adrenergic receptors on vascular smooth muscle, strongly constricting afferent arterioles, thereby inhibiting filtrate formation. This, in turn, indirectly trips the renin-angiotensin mechanism by stimulating the macula densa cells. The sympathetic nervous system also directly stimulates the granular cells to release renin.

• RENIN-ANGIOTENSIN MECHANISM

The renin-angiotensin mechanism is triggered when various stimuli cause the granular cells to release  the hormone renin. Renin acts enzymatically on angiotensinogen, a plasma globulin made by the liver, converting it  to angiotensin I. This, in turn, is converted to angiotensin II by angiotensin converting enzyme (ACE) associated with the capillary endothelium in various body tissues, particularly the lungs.

Angiotensin II acts in five ways to stabilize systemic blood pressure and extracellular  fluid volume. (1) As a potent vasoconstrictor , angiotensin II activates smooth muscle of arterioles throughout the body, raising mean arterial blood pressure. (2) Angiotensin II stimulates reabsorption of sodium, both directly by acting on renal tubules and indirectly by triggering the release of aldosterone from the adrenal cortex. Because water follows sodium osmotically, blood volume and blood pressure rise. (3) Angiotensin II stimulates the hypothalamus to release anti diuretic hormone and activates the hypothalamic thirst center, both of which increase blood volume. (4) Angiotensin II also increases fluid reabsorption by decreasing peritubular capillary hydrostatic pressure. This pressure drop occurs because the efferent arterioles constrict, and the downstream drop in hydrostatic pressure allows more fluid to move back into the peritubullar capillary bed. (5) Angiotensin II targets the glomerular mesangial cells, causing them to contract and reduce the glomerulus filtration rate by decreasing the total surface area of glomerular capillaries available for filtration.

While this seems daunting list at first, it will help that all of the effects of angiotensin II are aimed at restoring blood volume and blood pressure. Of angiotensin II’s many effects, the first two are the most important.

Several factors acting independently or collectively can trigger renin release:

1. Reduced stretch of the granular cells. A drop in mean systemic blood pressure below 80 mmHg (as might be due to hemorrhage, dehydration, etc) reduces the stretch of the granular cells and stimulates them to release more renin
2. Stimulation of the granular cells by input from activated macula densa cells. When macula densa  cells sense low NaCl concentration (slowly moving filtrate), they signal the granular cells to release renin. This signal may decrease release of ATP (also thought to be the tubuloglomerular feedback messenger), increased release  of the prostaglandin PGE2, or both
3. Direct stimulation of granular cells via β1-adrenergic receptors by renal symphatetic nerves.

Regulation of glomerular filtration

Glomerular filtration rate is regulated by both intrinsic and extrinsic controls. These two types of controls serve two different (and sometimes opposing) needs. The kidneys need a relatively constant glomerular filtration rate in order to do their job and maintain extracellular homeostasis. On the other hand,the body as the whole needs a constant blood pressure, and therefore a constant blood volume.

Intrinsic controls (renal autoregulation) act locally within the kidney to maintain glomerular filtration rate, while extrinsic controls by the nervous and endocrine systems maintain blood pressure. In extreme changes of blood pressure  (mean arterial pressure less than 80 or greater than 180 mmHg), extrinsic control take precedence over intrinsic controls.

INTRINSIC CONTROLS  (RENAL AUTOREGULATION)

By adjusting its own resistance to blood flow, a process called renal autoregulation, the kidney can maintain a nearly constant glomerular filtration rate despite fluctuations in systemic arterial pressure. Renal autoregulation entails two types of controls :

• Myogenic mechanism

The myogenic mechanism reflects the tendency of vascular smooth muscle to contract when stretched. Increasing systemic blood pressure causes the afferent arterioles to constrict, which restricts blood flow into the glomerulus and prevents glomerular blood pressure from rising to damaging levels. Declining systemic blood pressure causes dilatation of afferent arterioles and raises glomerular hydrostatic pressure. Both responses  help maintain a normal glomerular filtration rates.

• Tubuloglomerular feedback mechanism

Autoregulation by the flow-dependent tubuloglomerular feedback mechanism is “directed” by  the macula densa cells of the juxtaglomerular apparatus. These cells, located in the walls of the ascending limb of Henle’s loop, respond to filtrate NaCl concentration (which varies  directly with filtrate flow rate). When glomerular filtration rate  increases, there is insufficient time for reabsorption and the concentration of NaCl in the filtrate remains high. This causes the macula densa cells to release a vasoconstrictor chemical (probably ATP) that causes intense constriction of the afferent arteriole. This constriction hinders blood flow into the glomerulus, which decreases the net filtration pressure and glomerulus filtration rate, allowing more time for filtrate processing (NaCl reabsorption),

On the other hand, when macula densa cells are exposed to slowly flowing filtrate with its low NaCl concentration, ATP release is inhibited, causing vasodilatation  of the afferent  arterioles. This allows more blood to flow  into the glomerulus, thus increasing net filtration presure and glomerulus filtration rate.

Autoregulatory mechanism maintain a relatively constant glomerulus filtration rate over an arterial pressure range from about 80 to 180 mmHg. Consequently, our normal day to day activity (such as exercise, sleep or changes in posture) do not cause large changes in water and solute excretion. However,  the intrinsic controls cannot handle extremely low systemic blood pressure, such as might result from serious hemorrhage (hypovolemic shock). Once the mean arterial pressure drops below 80 mmHg, autoregulation ceases.

Glomerular filtration

Glomerular filtration is a passive process in which hydrostatic pressure forces fluids and solutes through a membrane. The glomeruli can be viewed as simple mechanical filters because filtrate formation does not consume metabolic energy.

The glomerulus is a much more efficient filter than other capillary beds. One reason is that its filtration membrane has a large surface area and is thousands  of times more permeable to water and solutes. Furthermore, glomerular blood pressure is much higher than that in other capillary beds (approximately 55 mmHg as opposed to 18 mmHg or less), resulting in  a much higher net filtration pressure.  As a result of these differences, the kidneys produce about 180 L of filtrate daily, in contrast to the 2 to 4 L formed daily by all other capillary beds of the body combined.

Molecules smaller than 3 nm in diameter such as water, glucose. amino acids, and nitrogenous wastes pass freely from the blood into thr glomerular capsule. As a result, these substancesusually show similar concentration in the blood and the glomerular filtrate. Larger molecules pass with greater difficulty, and those larger than 5 nm are generally barred from entering the tubule. Keeping the plasma proteins in the capillaries maintains the colloid osmotic (oncotic) pressure of the glomerular blood, preventing the loss of all its water to the renal tubules. The presence of proteins or blood cells in the urine usually indicates a problem with the filtration membrane.

Net filtration pressure

The net filtration pressure, responsible for filtrate formation, involves forces acting at the glomerular bed. Glomerular hydrostatic pressure, which is essentially glomerular blood pressure, is the chief force pushing water and solutes out of the blood and across the filtration membrane. Although theoretically the colloid osmotic pressure in the capsular space of the glomerular capsule “pulls” the filtrate into the tubule, this pressure is essentially zero because virtually no proteins enter the capsule.

Glomerular filtration rate

The glomerular filtration rate is the volume of filtrate formed each minute by the combined activity of all 2 million glomeruli of the kidneys. Factors governing filtration rate at the capillary beds are :

• Total surface area available for filtration
• Filtration membrane permeability
• Net filtration pressure

In adults the normal glomerular filtration rate in both kidneys is 120-125 ml/min. Because glomerular capillaries are exceptionally permeable and have a huge surface area (collectively equal to the surface area of the skin), huge amounts of filtrate can be produced even with the usual modest net filtration pressure.  The opposite side of this “coin” is that a drop in glomerular pressure of only 18% stops filtration altogether.

The glomerular filtration rate is directly proportional to the net filtration pressure, so any change in any of the pressures acting at the filtration membrane changes both the net filtration pressure and the glomerular filtration rate. In the absence of regulation, an increase in arterial (and glomerular) blood pressure in the kidneys increases the glomerular filtration rate.

Urine formation and the adjustment of blood composition involve three major processes: glomerular filtration by the glomeruli, tubular reabsorption and tubular secretion in the renal tubules. In addition, the collecting ducts work in concert with the nephrons to make concentrated or dilute urine.

How do the kidneys “clean” the blood? Conceptually, it’s really very simple.  The kidneys “dump” (by glomerular filtration)  (1) cell- and protein-free blood into a separate “container” (the renal tubules and collecting ducts). From this container, the kidneys reclaimed (by tubular reabsorption) (2) everything that the body need to keep. This is almost everything-all of the glucose and amino acid, and some 99% of the water, salt and other components. Anything that is not reabsorbed becomes urine.  In addition, some things are selectively added to the container (by tubular secretion) (3)Fine-tuning the bodys chemical balance,

The volume of blood proceed by the kidneys each day is enormous. Of the approximately 1200 ml of blood that passes through the glomeruli each minute, some 650 ml is plasma, and about one-fifth of this (120-125 ml) is forced into the renal tubules. This is equivalent to filtering out your entire plasma volume more than 60 times each day. Considering the magnitude of their task, it is not surprising that the kidneys (which account for only 1% of body weight) consume 20-25% of all oxygen used by the body at rest.

Filtrate and urine are quite different. Filtrate contains everything found in blood plasma except proteins. Urine contains mostly metabolic wastes and unneeded substances. The kidneys process about 180 L of blood-derived fluid daily. Of this amount, less than 1% (1,5L) typically leaves the body as urine, the rest returns to the circulation.