Renal physiology II

Renal Physiology II.

V. Functional properties of nephron (continued)

C. tubular transport mechanisms

1. Is a particular substance absorbed from, or secreted into, the nephron beyond Bowman's capsule? Concept of clearance:

a. Clearance of filterable substance X is the volume flow of plasma, in a period of time, that would be completely cleared of X to supply the amount of X that appears in urine in the same period of time.

b. expressed as: C_X = (U_X · V) / P_X (C = clearance, U = urine concentration, P = plasma concentration, V = urine flow, vol/time)

c. A synthetic carbohydrate, inulin, is freely filtered from glomerulus (so filtrate concentration = P_inulin) and is neither reabsorbed nor secreted along the nephron,

i. so, when inulin is infused into blood to a constant P_inulin, all filtered inulin -- no more, no less -- leaves in the urine

ii. and C_inulin = GFR (glomerular filtration rate), about 120 ml/min; i.e., P_inulin · GFR = U_inulin · V
(think: low conc. x high flow = high conc. x low flow)

d. If C_X is less than GFR, then some of X must be reabsorbed.

e. If C_X is greater than GFR, then some X must be secreted along nephron.

2. Na⁺-coupled glucose uptake from filtrate in proximal tubule

a. Na⁺-glucose co-transporter, driven by electrochemical gradient of Na⁺, brings glucose into cells.

b. Electrochemical gradient of Na⁺ maintained by Na/K-ATPase and leak of K⁺.

c. Glucose leaves cells, into extracellular fluid, via another glucose carrier (independent of Na⁺) -- and then into peritubular capillaries -- down glucose concentration gradients.

d. Many other nutrient molecules, such as amino acids, are reabsorbed by similar mechanisms.

e. Normally, virtually all glucose is reabsorbed (and C_glucose = 0). But, in untreated diabetes mellitus, impaired glucose metabolism (low insulin production or faulty insulin receptors) causes plasma glucose to rise from normal 0.8 - 1.0 mg/ml to more than 3 mg/ml, at which point filtered rate of glucose exceeds maximum rate of glucose reabsorption by proximal tubule and glucose appears in urine, holding extra water in filtrate by osmosis and increasing urine volume. (Beyond proximal tubule, there are no more glucose transporters. As salts continue to be reabsorbed, trapped glucose becomes a major solute remaining in urine.)

3. Bicarbonate is ~90% reabsorbed in conjunction with H⁺ secretion (% that is reabsorbed varies with body's need to adjust pH of body fluids).

a. Na/H-exchanger, driven by electrochemical gradient of Na⁺, moves H⁺ into tubular lumen, Na⁺ from lumen into cell.

b. H⁺ reacts with HCO₃^- in lumen --> H₂CO₃ --> H₂O + CO₂

c. CO₂ diffuses into cells, reacts with H₂O --> H⁺ + HCO₃^-

d. HCO₃^- diffuses from cell toward capillary.

e. H⁺ in lumen is buffered by some anions, like phosphate: HPO₄²- + H⁺ -> H₂PO₄^-, so more acid can be secreted than suggested by the 1000-fold higher free H⁺ concentration that can be reached in urine (pH 4.4 vs. pH 7.4).

4. K⁺ is reabsorbed in proximal tubule, secreted in distal tubule; balance between two processes depends partly on K⁺ level in body, but secretion is also linked to Na⁺ reabsorption in distal tubule.

5. Hypertonic NaCl reabsorption from thick ascending limb of Henle's loop and distal tubule

a. Na⁺ is actively pumped out of these segments; Cl^- follows passively.

b. Water permeability of these segments is low. Some water is absorbed along with solutes, but not enough for isotonic reabsorption.

c. Remaining filtrate becomes hypotonic in these segments of nephron.

6. Some substances are actively secreted by proximal tubule, e.g., by "organic anion" transporters that secrete penicillin, among many molecules; clearance > GFR. But, in terms of total particles transported, reabsorption overwhelms secretion.

7. Some ammonia (NH₃) is secreted by nephron, from deamination of amino acids within tubular cells; adds to acid-carrying capacity of urine.

a. NH₃, small and uncharged, diffuses through cell membrane into lumen,

b. then reacts with H⁺ to form ammonium ion, NH₄⁺, which can't diffuse back through membrane, "trapping" both ammonia and H⁺ in lumen.

8. In collecting duct, water is preferentially reabsorbed through water channels inserted into luminal membranes. These membranes otherwise have very low water permeability.

a. Insertion of water channels is under hormonal control, described later.

b. Movement of water is toward a higher osmolarity maintained in the medullary tissue space, also described later.

VI. Intrinsic, neural, and hormonal controls

A. Renal autoregulation: without any external input, kidney is capable of adjusting constriction of afferent and efferent arterioles to maintain a fairly constant GFR in spite of variations in body's blood pressure.

B. Neural inputs (sympathetic nerves of autonomic nervous system) can adjust renal blood flow to accommodate changing needs of other body tissues.

C. Hormonal controls:

1. antidiuretic hormone (ADH, also called vasopressin)

a. made in hypothalamus, secreted by posterior pituitary

b. ADH increases when osmoreceptors (in hypothalamus) sense increase in osmolarity of blood (mainly due to increase in Na⁺ concentration).

c. stimulates cells lining collecting ducts to insert water channels in their luminal membranes to increase water permeability of duct -- water taken up into high osmolarity of kidney medulla.

d. defect of ADH synthesis causes diabetes insipidus:

i. abnormally low water reabsorption from collecting ducts

ii. Urine volume is very high, several liters per day (but contains no glucose).

iii. Synthetic ADH is available for injection to treat condition.

e. Ethanol (beverage alcohol) slightly inhibits secretion of ADH, increasing urine volume (but effect is much less extreme than diabetes insipidus).

2. renin - angiotensin - aldosterone system

a. renin produced by kidney, released in response to lower blood pressure or to lower NaCl in filtrate

b. renin converts angiotensinogen (plasma protein made by liver) to angiotensin I (peptide)

c. angiotensin I is converted, by angiotensin converting enzyme, to angiotensin II

d. angiotensin II has multiple effects (to elevate blood pressure and increase Na⁺ retention):

i. vasoconstriction

ii. stimulates adrenal cortex to secrete aldosterone

iii. stimulates hypothalamus to secrete more ADH

iv. stimulates sensation of thirst (also through hypothalamus)

e. aldosterone (steroid hormone), from adrenal cortex, acts in nuclei of distal tubule cells to increase production of Na/K-ATPase, increasing Na⁺ reabsorption and supporting maintenance of body fluid volume through retention of NaCl.

3. atrial natriuretic peptide: from right atrial cells of heart

a. secreted in response to increased stretching of stretch receptors in right atrium due to increased blood volume, usually resulting from increased Na⁺ intake or retention

b. decreases Na⁺ reabsorption by distal tubules, increasing excretion of salt and water

VII. Renal concentrating mechanism: increasing concentrations of NaCl and urea in interstitial fluid, from outer to inner medulla

A. mechanism for building NaCl gradient:

1. Na⁺ is actively pumped out of thick ascending limb of Henle's loop; Cl^- follows.

2. Water permeability of ascending limb is low, so osmolarity of surrounding interstitial fluid increases.

3. Water permeability of descending limb of Henle's loop is high, so filtrate entering from proximal tubule loses water to equilibrate with interstitial fluid.

4. Filtrate with increasing osmolarity moves down through loop, then has more NaCl pumped out as it reaches thick ascending limb.

5. Continued pumping of Na⁺ and flow of filtrate result in NaCl gradient, from 300 mOsmolar in cortex up to ~700 mOsmolar in middle and inner medulla. (Study Fig. 12.14 in textbook)

B. mechanism for building urea gradient in inner medulla (not in textbook):

1. Loops of Henle that extend into inner medulla have high urea permeability in thin portions, and there is high urea permeability in deeper reaches of collecting ducts.

2. Thick ascending limb, distal tubule, and outer portion of collecting duct have low urea permeability. As NaCl is pumped out of these portions, followed by some water, urea becomes concentrated in the remaining filtrate.

3. Urea at high concentration in collecting duct can then escape when it encounters high urea permeability of inner collecting duct, building up urea concentration in inner medullary interstitial fluid.

4. Some of this urea can then pass into thin portion of Henle's loop, to be further concentrated by another trip through segments with active Na⁺ pumping and low urea permeability.

5. Continuation of this concentrating cycle builds steep urea gradient in inner medulla, reaching up to ~700 mOsmolar urea deepest in the medulla.

C. Combined gradient:

1. NaCl gradient is in outer medulla; urea gradient in inner medulla is added to NaCl (constant at ~700 mOsm in inner medulla) for maximum total osmolarity of ~1400 mOsm deepest in medulla.

2. Note that both NaCl and urea gradients are dependent on:

a. active NaCl transport

b. different permeabilities in different portions of nephron

c. continuous flow of filtrate through nephron

3. Total gradient allows water to be osmotically drawn from collecting duct filtrate into medullary space, concentrating urine up to ~4.6 times osmolarity of body water.

D. removal of reabsorbed water from medulla; maintenance of gradient:

1. Water moving from collecting ducts into medullary space would tend to dilute osmotic gradient.

2. Water is carried away toward renal veins by capillaries that follow a U-shaped path in and out of medulla, leaving osmotic gradient intact.

a. Blood in these vessels equilibrates with higher osmolarity as it moves into medulla.

b. This blood picks up water reabsorbed from collecting ducts, then re-equilibrates with lower osmolarities as it flows back toward cortex and is almost back to 300 mOsm as it leaves medulla.

c. Thus, there is only minimal "wash-out" of high osmolarity from medulla, easily counteracted by gradient-building mechanisms described above.

VIII. Plasma urea level as an indicator of renal failure

A. Urea is produced at a fairly constant rate; in the long run, its excretion in urine (U_urea · V) must match its rate of production.

B. Although there is some absorption and secretion of urea along nephron, filtered urea (P_urea · GFR) is principal determinant of how much urea gets excreted.

C. If GFR drops drastically, as in renal failure, urea excretion initially drops too, but urea production remains constant.

D. Therefore, plasma concentration of urea must then increase until P_urea · GFR (i.e., higher conc. x lower flow) is again high enough to make U_urea · V equal to the rate of urea production.

E. Thus, greatly elevated P_urea, which is easily determined by standard blood testing, suggests developing renal failure.