Chapter 18 - Urinary System: Renal Function

Functions of Urinary System
     The primary functions of the kidney are:
1. Regulation of plasma ionic composition including sodium, potassium, calcium, magnesium, chloride, bicarbonate and phosphates
2. Regulation of plasma volume
3. Regulation of plasma osmolarity
4. Regulation of plasma hydrogen ion concentration
5. Removal of metabolic waste products and foreign substances
     By regulating the plasma composition the kidneys ultimately control the volume and composition of all the body's fluids. Secondary kidney functions include:
6. Secretion of hormones and enzymes:
a. Erythropoietin -stimulates erythrocyte production
b. Renin - enzyme that converts angiotensinogen into angiotensin I
7. Activation of Vitamin D3
8. Gluconeogenesis during periods of need
Anatomy of Urinary System
     Review the anatomy.
Basic Renal Exchange Processes
   Three basic exchange processes of the renal nephrons are:
1. Glomerular Filtration
2. Reabsorption
3. Secretion
  Glomerular Filtration
      Filtration is driven by Starling forces (hydrostatic and osmotic pressure gradients). The filtrate resembles plasma except in lacking proteins present in plasma. The glomerular filtrate passes three barriers to enter Bowman's capsule.
1. Capillary endothelial cell layer - These cells have fenestrations or pores that increase the movement of fluid through the cells by bulk flow. 
2. Epithelial cell layer of Bowman's capsule -  These cells are called podocytes because they have foot processes that interdigitate and form slit pores.
3. Basement membrane - The basement membrane is sandwiched between the previous two layers and acts as the primary barrier to the filtration of proteins.  
     Together these three layers form the glomerular membrane or filtration barrier. This membrane allows the bulk flow of protein-free fluid from the blood into the lumen of Bowman's capsule.
  Glomerular Filtration Pressure:
     The glomerular filtration pressure is the same thing as the net filtration rate and is due to the same Starling forces:
1. Glomerular Capillary Hydrostatic Pressure
   This pressure is approximately 60 mm Hg. The higher hydrostatic pressure is due to the high resistance of the efferent arteriole.
2. Bowman's Capsule Oncotic Pressure
   Normally this pressure is negligible because very little protein leaves the capillaries and enters the capsule. If we assume that the Bowman's capsule oncotic pressure is equal to 0 mm Hg, the pressure favoring filtration is 60 mm Hg. 
3. Bowman's Capsule Hydrostatic Pressure
   This pressure opposes filtration and is typically about 15 mm Hg. This pressure is less than the capillary hydrostatic pressure and filtration is favored.
4. Glomerular Oncotic Pressure
   The pressure is due to the presence of proteins in the capillaries. The oncotic pressure is about 29 mm Hg and opposes filtration.
The net pressure opposing filtration at the renal corpuscle under normal conditions is:
15 mm Hg + 29 mm Hg = 44 mm Hg


  Glomerular Filtration Rate
     The net filtration pressure is:
      Glomerular Filtration Pressure =
(PGC + pBC) -

(PBC + pGC)

60 mm Hg + 0 mm Hg - (15 mm Hg + 29 mm Hg) = 16 mm Hg
     Glomerular filtration rate is the volume of plasma filtered per unit time and is approximately 125 ml/min which over the course of a day means that 180 liters is filtered. This means that a volume of fluid equal to the total plasma volume is filtered through the glomerulus every 22 minutes.
   Filtration fraction is equal to the glomerular filtration rate divided by the renal plasma flow rate:
Filtration Fraction = GFR
Renal Plasma Flow
125 ml/min = 0.20 = 20%
625 ml/min
  Filtered Load
     The quantity of a particular solute that is filtered per unit time is know as the filtered load. If the solute in question moves across the glomerular membrane without restriction it is said to be freely filterable. Then the filtered load is equal to the glomerular filtration rate times the solute's plasma concentration (Px). For example, for glucose, whose normal concentration is 100 mg/dL = 1 mg/ml, the filtered load under normal conditions is:
125 ml/min x 1 mg/ml = 125 mg/min
  Regulation of Glomerular Filtration Rate
     Less than 1% of the filtered plasma is excreted from the body. Hence, 99% is reabsorbed. Changes in the GFR can have a large impact on how much must be reabsorbed and GFR needs to be closely regulated.
   Intrinsic Control of GFR 
     The GFR will change with MAP. Increases in MAP would cause an increase in GFR and vice versa. The kidneys maintain the GFR within a narrow range by three intrinsic mechanisms:
1. Myogenic Regulation
   When MAP increases the pressure in the afferent arteriole rises and stretches the smooth muscle of the afferent arteriole. This causes the reflex contraction of the muscle. The vasoconstriction of the afferent arteriole causes the pressure in the glomerular capillaries to decrease. A fall in MAP has the opposite effect. 
2. Tubuloglomerular Feedback
   Changes in GFR cause a change in tubular fluid flow. This change in the flow is detected by the specialized cells of the macula densa. Cells of the macula densa secrete paracrines that affect the contraction of the muscles of the afferent arteriole. An increase in GFR increases tubular flow and this causes the afferent arteriole to constrict and reduce the flow.
3. Mesangial Cells
   The mesangial cells are modified smooth muscle cells that surround the glomerular capillaries. When blood pressure increases this causes the mesangial cells to stretch and in response these cells contract and decrease the surface area of the capillaries available for filtration.
  Extrinsic Control of Glomerular Filtration
     The intrinsic control of GFR works only over a limited range of MAP (80 - 180 mm Hg). Outside of this range intrinsic controls are not enough to maintain a constant GFR and it either rises or falls. A fall of MAP causes increased sympathetic nervous activity which causes  the afferent and efferent arterioles to contract. The increase in resistance contributes to an increase in MAP. It also decreases urine output which helps to conserve water and maintain blood volume.
     Reabsorption is the movement of filtered solutes and water from the lumen of the tubule back into the plasma.
  Solute Reabsorption
     Solutes must pass across two barriers to be reabsorbed: the tubule epithelium and the capillary endothelium. Please note in the figure above the tight junctions between epithelial cells, the apical membrane with microvilli and the basolateral membrane.
     Substances that are actively transported require the expenditure of energy. This active transport can take place by two different mechanisms:
1. Active transporters can be present in the basolateral membrane with carrier proteins present in the apical membrane allowing facilitated diffusion or:
2. Active transporters can be present in the apical membrane with carrier proteins located on the basolateral membrane.
     Water reabsorption occurs by osmosis. Active transport of substances from the tubule into the plasma causes the osmolarity of the plasma to increase and that of the tubule to decrease. This creates a concentration gradient for water and the water flows to the region of greater osmolarity in the plasma.
     Some substances are passively reabsorbed by diffusion. For passive reabsorption to occur the substance must have a higher concentration in the tubular fluid than in the plasma and the substance must be permeant through the plasma membranes. An example of this is urea.
  Transport Maximum
     When solute concentration is so high that all carrier proteins and pumps are occupied, the transport maximum for that solute is reached. When the plasma concentration of the solute rises to the point that the filtrate concentration exceeds the transport maximum, some of the solute starts to appear in the urine as "spillover" and at this point the renal threshold is said to have been reached.
   Glucose Reabsorption and Renal Threshold
     Glucose is actively transported across the apical membrane by sodium-linked active transport. A carrier protein moves it across the basolateral membrane into the peritubular fluid from where it can diffuse into the plasma.
     The transport maximum (Tm) for glucose reabsorption is 375 mg/min. Normal plasma glucose is 80-100 mg/dL GFR is 1.25 dL/min. The filtered load of glucose is:
1.25 dL/min X 100 mg/dL = 125 mg/min
Since 125 mg/min << 375 mg /min all the glucose is reabsorbed.
   The renal threshold for glucose is
GFR X Renal Threshold = Transport Maximum
1.25 dL/min X Renal Threshold = 375 mg/min
Renal Threshold = 375 mg/min = 300 mg/dL
1.25 dL/min
    The true renal threshold for glucose is 160-180 mg/dL. The filtered load of glucose is approximately 225 mg/min. The reason for the difference between the theoretical and actual values is that some glucose molecules in the filtrate avoid the carrier molecules even though they are not 100% saturated.
     In tubular secretion molecules move from the plasma into the renal tubules to become part of the filtrate. Secretion involves the same mechanisms as reabsorption except in reverse. Substances secreted include potassium, H ions, waste products such as choline and creatinine and foreign substances such as penicillin.
Regional Specializations of the Renal Tubules
     Regions of the renal tubules differ in the substances transported and in the mechanisms of transport
  Nonregulated Reabsorption in the Proximal Tubule
   About 70% of the sodium and water that is filtered, is reabsorbed in the proximal tubule. Some solutes, such as glucose, is 100% reabsorbed. Because such a large proportion of solutes and water is reabsorbed in the proximal tubule in a nonregulated manner, it is called the mass absorber. 
   Three features of the proximal tubule facilitate mass absorption:
1. The apical membrane has many microvilli that increase the surface area for transport. 
2. The cells possess a large number of mitochondria to supply the ATP necessary for active transport. 
3. The tight junctions between epithelia are permeable to small solutes and water which enables diffusion by paracellular transport. 
  Regulated Reabsorption and Secretion in the Distal Tubule and Collecting Duct
     The distal tubule and collecting duct are designed so that both reabsorption and secretion can be regulated. Differences between these regions and the proximal tubules include:
1. Fewer microvilli are present on the apical membrane.
2. Epithelial cells have fewer mitochondria.
3. Tight junctions are less permeable. 
     The regulation is achieved by the presence of receptors to various hormones that effect change in the absorption and secretion of various solutes and water. Also, water reabsorption is separated from solute reabsorption in various regions. 
  Water Conservation in the Loop of Henle
     The loop of Henle of juxtamedullary nephrons is designed to create an osmotic gradient in the medulla so that the osmotic pressure increases from the boundary between the cortex and the medulla to the renal papilla. In combination with the regulatory features of the collecting ducts this osmotic gradient enables the kidneys to conserve water. 
     Excretion is the elimination of solute and water from the body as urine:
amount excreted = amount filtered + amount secreted - amount reabsorbed
  Excretion Rate
    The figure below schematically shows all four processes filtration, reabsorption, secretion and excretion. Refer to this figure for a sample calculation.
    If the filtered load of a solute is calculated and compared to the solute excreted per minute, the net effect of renal processing can be determined by two simple rules:
1. If the amount of solute excreted is less than the filtered load then net reabsorption of the solute occurred.
2. If the amount of solute excreted is greater than the filtered load then net secretion of the solute occurred.
     Clearance  is a way of measuring excretion rates. It is imaginary because it is a measure of the volume of plasma from which a substance is completely removed.
Clearance = Excretion Rate/Plasma Concentration
However, portions of plasma are never completely cleared of a solute as this "virtual" measure suggests.
     Clearance is useful for describing how the kidneys are handling one substance compared to another. The relative clearance of solutes indicates how excretion affects the plasma concentration of one solute compared to another. For example, if the kidneys excreted potassium and sodium at the same rate, the excretion rates would be identical. However, this would be misleading because potassium plasma concentration is much lower than sodium and the kidneys would be removing potassium from the plasma at a much greater rate than sodium. 
  Clinical Uses of Clearance
     Three values are used to express clearance:
Ux= Concentration of substance in urine
Px= Concentration of substance in plasma
V = Urine flow rate
Excretion Rate = Ux x V
Clearance = Ux x V
For example, clearance for sodium can be calculated as follows:
= 450 ml/60 min = 7.5 ml/min
UNa  = 15 mM/L
PNa  = 145 mM/L
ClearanceNa = 15 mM/L x 7.5 ml/min = 0.78 ml/min
145 mM/L
  Estimates of Glomerular Filtration Rate
     A substance can be used to calculate the glomerular filtration rate if it is neither absorbed or secreted. A substance like this is inulin. The excretion rate of inulin is equal to the filtered load or
Excretion rate = GFR x Pinulin
GFR = Excretion Rateinulin/Pinulin = Clearance
     A natural substance in the body that can be used to estimate the GFR is creatinine. Creatinine is freely filtered, not reabsorbed and only slightly secreted. It slightly overestimates GFR but its clearance can be used as a suitable clinical estimate of GFR.
  Determining the Fates of Solutes in Renal Tubules
     Two rules apply:
1. If the clearance of a substance is greater than the GFR then net secretion occurred in the renal tubules.
2. If the clearance of a substance is less than the GFR then net reabsorption occurred.
     Glucose is an example of a substance that is completely reabsorbed and the clearance of glucose is zero.
     Para-aminohippuric acid (PAH) is freely filtered, is not reabsorbed and is secreted completely into the tubules. The clearance of PAH is equal to the renal plasma flow. If the hematocrit is known this can be converted to the renal blood flow.
     Urine is stored in the bladder until it is expelled in a process called micturition. The smooth muscle in the wall of the bladder is called the detrusor muscle. The smooth muscle at the neck of the bladder forms the internal urethral sphincter. The flow of urine is also controlled by the skeletal muscle of the pelvic floor called the external urethral sphincter.
     Urine is delivered to the bladder on a continual basis. The internal and external urethral sphincters are contracted so urine does not leave the bladder and the volume increases. Relaxed detrusor muscles accommodate this expansion. However, as expansion of the bladder continues stretch receptors in the wall of the bladder become activated and trigger the micturition reflex. 
     Nervous control to the bladder is as follows:
1. Parasympathetic neurons innervate the detrusor muscle.
2. Sympathetic neurons innervate the internal urethral sphincter.
3. Somatic motor neurons innervate the external urethral sphincter.
     Increased activity of stretch receptors activate parasympathetic neurons that cause contractions of the detrusor muscle. This increases the pressure of urine within the bladder. The stretch receptors also inhibits sympathetic neurons innervating the internal urethral sphincter and the somatic motor neurons innervating the external urethral sphincter. This allows the bladder to empty.
     The micturition reflex is overridden by voluntary control. Descending pathways from the cerebral cortex  can inhibit parasympathetic neurons and stimulate motor neurons that excite the external urethral sphincter and thus inhibit the micturition reflex.