Renal Physiology

I. Introduction

A. Structure of the Nephron
1. glomerulus
2. afferent and efferent arterioles
3. Bowmanís capsule
4. Proximal tubule
5. Loop of Henle
a. descending limb
b. ascending limb
6. Distal tubule
7. Collecting tubule
8. Juxtaglomerular apparatus
a. cells located in the area where the afferent and efferent arterioles are crossed by the tubule

B. Circulatory system
1. peritubule capillaries
a. intimately associated with the tubule to allow for exchange during secretion and reabsorption
2. vasa recta
a. blood vessels which form a hairpin loop near the Loop of Henle

C. General Processes of the Kidney
1. Filtration
a. diffusion of water and solutes across the glomerular capillaries into Bowmanís capsule
2. Secretion
a. transfer of substances from the peritubular capillaries into the tubule
b. generally occurs with substances the body wants to eliminate
3. Reabsorption
a. transfer of substances from the tubule into the plasma of the peritubular capillaries
b. generally occurs with substances the body wants to conserve

II. Filtration A. Substances which are generally filtered
1. Water
2. Salts
3. Glucose
4. Other small solutes

B. Not filtered
1. Proteins
2. Cells

C. Forces Affecting Filtration
1. Glomerular capillary pressure (Pgc)
a. increased Pgc causes increased filtration
b. physiologically the most important regulator of filtration
c. changes are usually induced by changing arterial blood pressure
2. Plasma colloid osmotic pressure
a. since protein is not filtered it creates osmotic pressure drawing water back from Bowmanís capsule into the glomerular capillaries
b. increased colloid osmotic pressure decreases (opposes) filtration
3. Hydrostatic pressure in Bowmanís capsule
a. increased hydrostatic pressure decreases filtration
e.g. if there is some obstruction in the tubule causing increased pressure in the tubule, the rate of filtration will decrease
4. Filtration coefficient
a. depends on permeability characteristics of the glomerular capillary membrane and the amount of surface area available

D. Autoregulation of glomerular capillary pressure (and thus GFR)
1. mechanisms by which GFR is maintained at a fairly constant rate even when arterial blood pressure increases
a. autoregulatory range occurs between 80-180 mm Hg
2. autoregulation involves vasoconstriction and vasodilatation of the afferent arteriole
a. constriction yields decreased Pgc
b. Dilation yields increased Pgc
3. Mechanisms of autoregulation
a. myogenic-increased pressure causes increased stretch of arteriolar smooth muscle which causes vasoconstriction
b. tubuloglomerular feedback
-JG apparatus contains cells which detect changes in fluid flow rate
-JG cells release renin which ultimately causes Angio II release and vasoconstriction
-JG cells also release local vasoconstrictors

E. Neural control of GFR
1. sympathetic input to afferent arterioles causes vasoconstriction, and thus decreased GFR
a. sympathetic nervous system would be turned on following a significant decrease in arterial pressure
-after sever hemorrhage, there would be decreased arterial blood pressure, triggering sympathetic nervous system, causing vasoconstriction, lowering GFR, and thus decreasing loss of plasma volume by excretion of water
-hemorrhage also affects other parameters associated with kidney function as discussed later

III. Reabsorption A. Mechanisms
1. Passive (by diffusion or carrier-mediated transport)
2. Active
3. Secondary active transport
a. Movement of substance itself is passive, following gradient
b. Initial gradient is established by active transport of another substance
e.g. glucose and amino acids are reabsorbed by secondary active transport.
The Na+/K+ ATPase pump pumps Na+ out of kidney tubule epithelial cells. Therefore, the cell has a low concentration of Na+ compared to tubule fluid. This establishes a gradient for Na+. Co-transport protein carriers for Na+/glucose or Na+/amino acid are located in the cell membrane adjacent to the tubule lumen. The 2 molecules (Na+ and glucose or amino acid) will bind to the carrier protein and ìride downî the concentration gradient for sodium (this part is passive).

B. Proximal tubule--the majority of salts and water are reabsorbed here
1. Sodium
a. Na+ enters the tubular epithelium by passive diffusion and is then pumped out into the ECF by the Na+/K+ ATPase pump where it can then diffuse into the peritubular capillaries
b. Na+ reabsorption is not hormonally regulated in the proximal tubule
2. Chloride--follows Na+ down an electrical gradient
3. Glucose and amino acids
a. by secondary active transport as described above
b. glucose transport maximum is reached when glucose/Na+ carriers are saturated
-normally all filtered glucose is reabsorbed
-in diabetes mellitus, the amount of glucose in plasma and thus in filtered fluid exceeds the transport maximum and leads to excretion of glucose
-glucose remaining in the tubular fluid results in osmotic diuresis
4. Water
a. occurs by osmosis initiated by transport of sodium
b. enhanced by increased plasma colloid osmotic pressure
-because protein is not filtered at the glomerular capillaries, there is a high colloid osmotic pressure of plasma in the peritubular capillaries, which helps in water reabsorption
c. water reabsorption is not hormonally regulated in the proximal tubule
5. Urea
a. occurs only at the end of the proximal tubule
b. passive diffusion
6. Other electrolytes
a. phosphate-regulated by parathyroid hormone (PTH decreases reabsorption)
b. calcium-stimulated by PTH
c. potassium
-reabsorbed in the proximal tubule and secreted in the distal tubule. Secretion generally exceeds reabsorption

C. Distal Tubule
1. Sodium
a. regulated by aldosterone (stimulates reabsorption) and atrial natriuretic peptide (decreases reabsorption)
2. Water
3. Chloride

D. Collecting Duct
1. Water and urea (when ADH present)

E. Loop of Henle
-see below in discussion of production of urine of varying concentrations

F. Regulation of reabsorption
1. Sodium reabsorption by aldosterone in distal tubule
a. Decreased ECF volume, blood pressure or Na+ concentration will trigger JG cells
b. JG cells release renin
c. Renin stimulates conversion of angiotensinogen to angiotensin I
d. Angiotensin I is converted to Angiotensin II by ACE (angiotensin converting enzyme) in the lungs
e. Angio II acts on adrenal cortex to stimulate aldosterone release
f. Aldosterone then acts to increase sodium reabsorption
g. Other effects of Angio II include: vasoconstrictive effects, stimulation of thirst
h. Use of ACE inhibitors

2. Water & urea reabsorption by ADH in distal tubule and collecting ducts
a. Increased ECF osmolarity (or >30% drop in blood pressure) stimulates release of ADH (vasopressin) from the posterior pituitary
b. ADH acts on distal and collecting ducts to increase water permeability (without ADH these portions of the nephron are impermeable to water)
c. ADH also increases permeability to urea

IV. Secretion A. Proximal tubule
1. Hydrogen ion secretion (H+)
a. controlled by the acid-base balance of the body
e.g. decreased blood pH results in increased H+ secretion
2. Organic ions
a. hormones
b. drugs
c. toxins

B. Distal Tubule
1. hydrogen ion
2. Potassium ion (K+)
a. controlled by aldosterone (which acts to increase K+ secretion here)
aldosterone release from the adrenal cortex is stimulated either by Angio II (which is an indirect measure of Na+ status) or by increased plasma K+

C. Collecting Duct
1. H+

V. Production of Urine of Varying Concentrations

A. Vertical osmotic gradient in medulla
1. Depends on following characteristics of the loop of Henle:
a. the descending limb is permeable to water but has no active transport system for sodium
b. the ascending limb is impermeable to water but has many Na-K pumps
c. net result is a gradient with very high osmotic concentration in the deepest portion of the medulla
d. also results in production of a hypotonic urine flowing into the distal tubule
B. Water reabsorption in distal tubule and collecting duct
1. Depends on ADH, which acts on distal and collecting duct to increase permeability to water.
2. Without ADH:
a. hypotonic urine enters distal tubule
b. Distal tubule and collecting tubule are impermeable to water
c. urine is excreted as a hypotonic solution
3. With ADH:
a. hypotonic urine enters distal tubule
b. distal tubule and collecting tubule are permeable to water
c. As urine passes in these ducts through the regions of the medulla with increasingly hypertonic concentration gradient, more and more water is lost from the urine by osmosis
d. excretion of hypertonic urine
C. Role of urea
1. ADH increases permeability of distal and collecting ducts to urea
2. As urea leaves the urine, it ìpullsî water with it by osmosis
3. Effect of low protein diet on ability to concentrate urine

VI. Acid-Base Balance A. Summary
The two main systems of the body which regulate acid-base balance are the kidneys and the lungs. The role of the lungs is to regulate acidity by regulating the amount of CO2 which is ìblown offî. The kidneys act by regulating bicarbonate ion and H+ ion secretion.
B. The definition of ph is:
pH= log [H+]
C. The amount of acidity [H+] in the plasma is reflected by the status of the lungs [pCO2] and the kidneys [HCO3-] and can be expressed:
pH = 6.1 + log [HCO3-] / [pCO2]
It is clear from the equation that increased pCO2 leads to a decrease in pH (increased acidity) and increased bicarbonate leads to an increase in pH (alkaline).
D. Lungs:
1. Hypoventilation leads to an increase in pCO2 and therefore respiratory acidosis.
2. Hyperventilation leads to respiratory alkalosis.
E. Kidney acts by:
1. Secreting H+
2. ìReabsorbingî bicarbonate in the proximal tubule (indirectly)
a. HCO3- combines with H+ to form carbonic acid which then is catalyzed by carbonic anhydrase to split into CO2 and H2O (both of which freely diffuse into the peritubular capillaries). This indirect method of reabsorbing bicarbonate is necessary because bicarb itself cannot diffuse.
3. Metabolic acidosis and alkalosis are characterized by changes in HCO3-.
a. Metabolic acidosis examples:
-diabetic ketoacidosis
-buildup of lactic acid
-severe diarrhea (loss of bicarb from G.I.)
b. Metabolic alkalosis examples:
-vomiting (loss of H+ from stomach)
-overingestion of alkaline drugs such as bicarb for indigestion