Glomerular filtration in detail	What is not passed through the filter (1) Proteins (2) Substances bound to proteins - half the plasma calcium, virtually all fatty acids.
Forces of filtration Fig 16-8	A bulk flow process like any flow across capillaries. Favoring filtration: 60 mm Hg capillary pressure. Renal arterioles are bigger than most, so have less resistance than most and higher pressure.  Opposing filtration: (1) 15 mm Hg fluid pressure in Bowman's space, (2) 29 mm Hg osmotic force in plasma due to protein. Net filtration pressure is 16 mm Hg
Glomerular filtration rate	The amount of fluid filtered from the glomeruli into Bowman's space per unit of time.  Renal capillaries are much more permeable than others. The flow rate is 180 L/day (125 ml/min) compared to 4 L/day in the other capillaries. The entire plasma volume is filtered about 60 times a day! Most is reabsorbed!
Filtered load of a substance	GFR x plasma concentration of a substance ie. 180 L/day x 1 g/L = 180 g/day This can be compared to amount excreted to tell whether there is net tubular reabsorption or net secretion.
Tubular reabsorption	Water, sodium and glucose are all virtually reabsorbed. Urea is 44% reabsorbed. Table 16-2. Urea is a nitrogen waste product from protein breakdown. Organic nutrients are not generally excreted with urine, just water and inorganic chemicals are.
Transport maximum (Tm)	In tubular reabsorption, there is often a limit to the amounts of material that can be reabsorbed back into the capillaries per unit time because the membrane proteins that do the transporting become saturated. This limit is usually not exceeded, so most organic molecules can be completely reabsorbed. However, In diabetes mellitus, the glucose load filtered through the glomerulus is so large that Tm is exceeded and some glucose is excreted with the urine. The same can happen with ingesting very large quantities of vitamins.
Reabsorption by diffusion	Some substances are reabsorbed because their concentration in the distal tubule exceeds that in the capillaries, so they diffuse back into the capillaries down their concentration gradient. An example is urea. Many drugs and environmental pollutants are lipid soluble and so can diffuse from the distal tubules into the capillaries. Thus, their excretion is difficult. However, the liver can make some of them polar so that when they pass into the kidney tubules they cannot diffuse back into the capillaries.
Tubular secretion	The second pathway into the tubule. H+ and K+ are the most important solutes secreted in this way. Organic molecules can also be secreted.
Metabolism by the tubules	The tubules can make ammonium to be excreted into the urine. The tubules can also break down peptides into amino acids.
RENAL CLEARANCE Fig 16-10	A renal clearance test helps one determine if the kidney is healthy and functioning properly by measuring the ability of the kidney to eliminate a given substance in a standard time. The renal clearance of a substance is: the volume of plasma from which the substance is completely cleared per unit of time.  The units are: volume (of plasma) per unit time =L/hr Cs = UsV/Ps(mg/hr)/(mg/L) = L/hr where: Cs = clearance of solute S (L/hr) Us = urine concentration of S (mg/L) V = urine volume per unit time (L/hr) Ps = plasma concentration of S (mg/L) Ie. Inulin, a sugar not usually in the body. Give it by IV to make Ps = 4 mg/L. V = 0.1 L (volume of urine in one hour) Us = 300 mg/L (urine concentration of inulin) Cs = 7.5 L/hr inulin clearance This equation works for substances that are not reabsorbed, secreted or metabolized in the tubules. No substances normally present in the blood meet these criteria. Creatinine, a waste product produced by muscle, comes close, so creatinine clearance is often used to estimate the GFR. What is the clearance of glucose? Zero! Us is zero for glucose. If clearance is less than the GFR, that substance must undergo reabsorption, and will be less than inulin clearance.

 

MICTURITION	Urine is stored in the bladder and ejected during urination, termed micturition.
Bladder 16-11	A balloon-like chamber with walls of smooth muscle. The muscle near the exit of the bladder is an internal sphincter muscle. When the wall contracts the sphincter relaxes and vise-versa. There is an external sphincter muscle that is skeletal muscle that can be used to prevent urination.
Autonomic nerve control of urination `	The bladder wall contains stretch receptors that send sensory nerves to the spinal cord that stimulate parasympathetic nerves that go back out to the bladder and stimulate the detrusor muscle to contract and the external sphincter to relax so urination can occur.  The filling of the bladder stimulates the stretch receptors to start this cycle.
Voluntary nerve control of urination	Ascending sensory pathways to the brain tell one the bladder is full. To prevent urination descending pathways from the brain cause contraction of the external sphincter and inhibition of the nerves to the detrusor muscle so it will not contract.

 

REGULATION OF SODIUM, WATER AND POTASSIUM BALANCE
Primary active transport Fig 16-12	The key feature of sodium reabsorption in the kidney. Na,K-ATPase pumps on the capillary side of the tubular epithelial cells pumps sodium out of these cells into the interstitial space. This keeps Na+ concentration low in these cells, so Na+ diffuses out of the lumen into these cells. This is done by carrier mediated transport, so other chemicals also are taken out of the lumen to be reabsorbed back into the capillaries.
Carrier mediated transport Fig 16-13	This does not require energy. Transportation is down concentration gradients. The chemicals carried out of the tubular lumen are different in different parts of the lumen: 1) Proximal tubule: glucose, amino acids carried out. 2) Ascending loop of Henle: chloride, potassium. 3) Distal convoluted tubule: chloride.
Water reabsorption. Fig 16-13	When sodium is moved out of the lumen by active transport, the osmolarity is lowered in the lumen and raised in the interstitial fluid. Water flows out of the lumen by osmosis to equalize the osmolarity. The tubular epithelium varies in water permeability in different parts. In the proximal tubule it is very high. In the collecting ducts water permeability depends on ADH (also called vasopressin) which is secreted by the posterior pituitary. ADH stimulates cAMP and the insertion of channels into the luminal membrane. When ADH kicks in, water is reabsorbed through these channels into the capillaries. Urine output of water is low.With less ADH, urine output is high.  "Diabetes" is Greek for passing through. In those with diabetes insipidus ADH is not produced. Daily urine output can be as high as 25 L. ADH must be administered.  In those with diabetes mellitus, there is osmotic diureses. Glucose is not reabsorbed and much water follows it to maintain osmotic equilibrium.
The countercurrent multiplier system Fig 16-14	This allows for a hyperosmotic urine, that is, urine with a higher osmolarity than plasma. This is a required response when one has little water intake. This response occurs in the collecting ducts of the renal medulla. Here, the interstitial fluid is very hyperosmotic and water flows out of the ducts as a result.  This hyperosmolarity is set up by the countercurrent multiplier system in the loops of Henle. How does this work? It requires energy and active transport. The ascending loop transports Na+ and Cl- into the interstitial fluid. The membrane is relatively impermeable to water, which does not follow the NaCl. The descending limb is quite permeable to water. Water diffuses out of the descending limb into the hyperosmolar interstitial fluid (400 mOsmol/L).This creates a hyperosmolarity in the descending loop (400 mOsmol/L). This hyperosmolar fluid flows into the ascending loop, which again pumps more NaCl into the interstitial fluid, which is at a higher osmolarity than before. The descending loop can build up a high osmolarity this way (Fig. 16-14).  The ascending limb and distal convoluted tubule are dilute. The interstitial fluid is concentrated. In the collecting ducts ADH kicks in. ADH is required create membrane channels to allow water to diffuse out of the cortical and medullary collecting ducts. Water flows out of the dilute ducts into the concentrated interstitial fluid. Water reabsorption occurs all along the medullary collecting ducts. The water enters the medullary capillaries (the vasa recta). The urine leaving the kidneys has the same osmolarity as the 1400 mOsmol/L interstitial fluid.

 

RENAL SODIUM REGULATION	Total body sodium only varies by a few percent despite what can be wide ranges of sodium intake from day to day. The kidney precisely regulates sodium excretion to maintain this balance.
Control of GFR Fig 16-16	The amount of sodium excreted in the urine = sodium filtered - sodium reabsorbed The body can change both processes. This starts with cardiovascular baroreceptors, including the carotid baroreceptors. When the baroreceptors sense an decrease in arterial pressure, (1) reflexes increase MAP and (2) GFR is decreased and sodium reabsorption is increased so plasma volume is not further decreased. When there is an increase in MAP, the reverse occurs. Sodium is the major extracellular solute. When it is increased or decreased, plasma and extracellular fluid volume will do the same.
	When there is a loss of body sodium, as in sweating or diarrhea, the plasma volume and MAP decrease. This reduces GFR so less sodium is filtered into the renal tubules. How is GFR reduced? The afferent arterioles to the kidneys are constricted by a sympathetic nerve reflex response that constricts these arterioles. This lowers glomerular capillary pressure and decreases GFR in the kidneys. When there is an increase in total body sodium, MAP increases and GFR increases, ridding the body of sodium.

 

CONTROL OF SODIUM REABSORPTION	Sodium reabsorption is more important than GFR for long term sodium balance.
Aldosterone and the renin-angiotensin system	Aldosterone is a steroid hormone and is the major factor controlling sodium reabsorption. It is released by the adrenal cortex. (outer portion of the adrenal gland which sits above each kidney). It is released into the blood and its site of action is in the kidney, at the collecting ducts of the renal cortex. It controls reabsorption of 35 grams of sodium a day.  Aldosterone induces protein synthesis at its target cells (like other steroid hormones). The proteins are for sodium transport: channel proteins and parts of the Na,K-ATPase pump. Aldosterone by the same mechanism causes sodium reabsorption from the large intestine and from the ducts of the sweat glands.
How is aldosterone secretion controlled? Fig 16-17	By angiotensin II, a potent stimulator of aldosterone secretion.
How is angiotensin II formed?	By the following process: (1) The liver secretes angiotensinogen, which is always present in the blood.  (2) Renin is released by the kidneys into the blood. renin converts angiotensinogen into angiotensin I (A I).  THIS IS THE RATE LIMITING STEP TO ANGIOTENSIN II (A II) PRODUCTION. (3) A converting enzyme of the walls of capillaries, especially in the lungs, converts A I to A II. (4) A II is circulating in the blood. When it gets back to the liver it stimulates aldosterone secretion into the blood.
How is renin secretion from the kidneys regulated? Figs 16-18	(1) Renal sympathetic nerves: Reduced plasma sodium and plasma volume lowers MAP. These act on baroreceptors that increase sympathetic discharge to the juxtaglomerular cells, stimulating renin release. (2) Juxtaglomerular cells also act as intra-renal baroreceptors. When MAP is down, these baroreceptors sense it and increase renin secretion.  (3) Macula densa in the ascending loops of Henle sense a decreased concentration of NaCl flowing by these cells. This signals increased renin secretion.
Atrial Natriuretic Factor (ANF) Fig 16-19	Although aldosterone is the most important control of sodium reabsorption, other factors contribute. The most important is ANF, which is synthesized and secreted by cells in the right and left atria of the heart. ANF is increased when there is an increased MAP (and thus increased sodium). ANF acts on the kidneys to inhibit sodium reabsorption and on renal blood vessels to increase GFR, increasing sodium excretion.

 

RENAL WATER REGULATION	Water excretion is the difference between the volume of water filtered (the GFR) and the amount reabsorbed.
ADH = vasopressin	ADH is the main determinant of water reabsorption. ADH originates in neurons of the hypothalamus. These neurons terminate in the posterior pituitary where ADH is released into the blood.
What does ADH do?	ADH increases the water permeability of the collecting ducts, so more water is reabsorbed and less is excreted.
What triggers ADH (vasopressin) to be released? Fig 16-20	Baroreceptors decrease their rate of firing when decreased blood volume decreases MAP. This lowered firing rate to the hypothalamus increases ADH secretion.
OSMORECEPTOR CONTROL OF ADH SECRETION Fig 16-21	In the previous examples sodium and water gain or loss followed each other, along with the reflex responses to correct them. When there is water gain or loss without sodium gain or loss there is another way to compensate. When there is water gain or loss without sodium gain or loss, plasma osmolarity changes. Osmoreceptors in the hypothalamus sense this change and control ADH secretion. For example, drinking 2 L of mineral-free water will decrease plasma osmolarity. The osmoreceptors will sense this and inhibit ADH secretion, and hypo-osmotic urine will be excreted.
Other input to ADH-secreting cells	These cells also receive input from many other brain areas, so ADH secretion, and therefore urine volume and concentration, can be altered by pain, fear, drugs. Alcohol inhibits ADH release, therefore urine volume increases.
The response to sweating 16-22	Sweat is hypo-osmotic and it contains mainly water, Na and Cl.  This decreases plasma volume, which lowers GFR and increases plasma aldosterone. This lowers Na excretion. Sweat also increases plasma osmolarity. This increases plasma ADH, which reduces water excretion.

 

THIRST AND SALT APPETITE Fig 16-23

When one is thirsty the drive to drink water is stimulated by a lowered plasma volume and high plasma osmolarity. The osmoreceptors and baroreceptors that control ADH secretion are the identical ones for thirst. The hypothalamus receives input from these receptors to stimulate thirst. Angiotensin II, and a dry mouth and throat also stimulate thirst.

 

POTASSIUM REGULATION	Potassium is the main intracellular ion but only about 2% is extracellular. Extracellular K+ has profound effects on excitable membranes (of nerve and muscle). A high K+ depolarizes membranes, triggering action potentials and then lack of excitation. Low K+ can cause heart arrhythmias. A low K+ hyperpolarizes membranes which can make muscles weak.
Renal regulation of K+ Figs 16-25, 16-26.	K+ can be freely filtered in the glomerulus. Most is reabsorbed in the proximal tubule and loop of Henle. The cortical collecting ducts can secrete K+ which is where K+ excretion is mainly controlled.
In the case of potassium loss as in vomiting or diarrhea.	There is no potassium secretion by the cortical collecting ducts.
Aldosterone