Renal/Acid-Base

1. Differences between active transport, facilitated diffusion, and diffusion.

Ref: BRS physiology p. 2-4

The fundamentals:

Diffusion – Is the only form of transport that requires no carrier molecule and no energy.

Facilitated diffusion – Similar to diffusion in that molecules flow down an electrochemical gradient and no ATP is consumed. The difference is that carrier proteins mediate the transport (which makes it go faster).

Active transport occurs against an electrochemical gradient (i.e. opposes thermodynamic equilibrium) and requires the hydrolysis of ATP.

Some finer points and clarifications:

- Diffusion equation (simplified form): flux = permeability * area * difference in concentrations.

- An increase in diffusion area, permeability or a large discrepancy between concentrations increases the speed of diffusion

- Permeability is increased by Ý oil/water partition coefficient of solute (i.e. Ý hydrophobicity), ß radius of solute, ß membrane thickness

- Carrier mediated transport can be stereospecific. Transportation efficiency is also be affected by saturation of the transporter and/or competitive inhibition by related solutes.

- Primary active transport requires direct input of metabolic energy, while secondary active transport involves coupled transport of two or more solute (normally including Na⁺). Metabolic energy is indirectly derived from the Na⁺ gradient (which requires ATP to maintain).

- Examples:

- Facilitated diffusion – glucose transport in muscle and adipose cells (impaired in diabetes melitus)

- Primary active transport

- Na⁺,K⁺-ATPase (aka NA⁺-K⁺ pump) – maintains low intracellular Na & high extracellular K. The cardiac glycoside drugs (ouabain and digitalis) inhibit this pump

- Ca²⁺-ATPase pump in sarcoplasmic reticulum

- H⁺,K⁺-ATPase (aka protein pump) in gastric parietal cells. Inhibited by omeprazole

- Secondary active transport

- Contransport: Na⁺-glucose contransport in small intestine, Na⁺- K⁺-2Cl^- cotransport in renal thick ascending limb

- Countertransport: Na⁺-Ca²⁺ exchange and Na⁺-H⁺ exchange

2. Differences between central and nephrogenic diabetes insipidus

Ref: BRS physiology p. 175-180 esp p. 178

The fundamentals:

Diabetes Inspidus – the cause of inappropriately hyposmotic urine (which can lead to plasma hyperosmolarity)

Central DI – occurs when circulating ADH is low

Nephrogenic DI – occurs when ADH is inefective

Some finer points and clarifications:

ADH (anti-diuretic hormone) is normally released from the posterior pituitary when the plasma osmolarity is too high. It increases the water permeability of the late distal tubule and collecting duct. This in turn increases water reabsorption and increases urine osmolarity. If this pathway is ineffective, then less water will be reabsorbed by the kidney which leads to hyposmotic urine. If this isn’t compensated for, the plasma osmolarity will increase.

3. Major transporter in each nephron segment

Ref: STARS physiology p.262

BRS physiology p. 167-179

The fundamentals:

This chart on p.262 of STARS is a good summary

Segment/Cell Type	Major Functions	Cellular Mechanisms	Hormone Actions	Diuretic
Early Proximal Tubule	Isosmotic reabsorption of solute and water	Na⁺-glucose, Na⁺-amino acid, Na⁺-phosphate cotransport Na⁺-H⁺ exchange	PTH inhibits Na⁺-phosphate cotransport Angiotensin II stimulates Na⁺⁺-H⁺ exchange	Osmotic Diuretics Carbonic Anhydrase inhibitors
Late proximal tubule	Isosmotic reabsorption of solute and water	NaCl reabsorption drive by Cl^- gradient		Osmotic Diuretics
Thick ascending limb of Henle’s loop	Reabsorption of NaCl without water Dilution of tubular fluid Single effect of countercurrent multiplication Reabsorption of Ca²⁺ and Mg²⁺ driven by lumen-positive potential	Na⁺-K⁺-2Cl^- cotransport	ADH stimulates Na⁺-K⁺-2Cl^- cotransport	Loop diuretics
Early distal tubule	Reabsorption of NaCl without water Dilution of tubular fluid	Na⁺-Cl^- cotransport	PTH stimulates Ca²⁺ reabsorption	Thiazide diuretics
Late distal tubule and collecting ducts (principal cells)	Reabsorption of NaCl K⁺ secretion Variable water reabsorption	Na⁺ channels K⁺ channels Water channels	Aldosterone stimulates Na⁺ reabsorption Aldosterone stimulates K⁺ reabsorption ADH stimulates water reabsorption	K⁺-sparing diuretics
Late distal tubule and collecting ducts (alpha-intercalated cells)	Reabsorption of K⁺ Secretion of H⁺	H⁺-K⁺ ATPase H⁺ ATPase	Aldosterone stimulates H⁺ secretion

Some finer points and clarifications:

- Glomerulotubular balance - The proximal tubule isosmotically reabsorbs 2/3 of the filtered sodium and water.

- Carbonic anhydrase inhibitors (ex: acetazolamide) act by inhibiting reabsorption of HCO₃^- which is directly linked to Na⁺-H⁺ exchange

- Loop diuretics ex: furosemide, ethacrynic acid, bumetanide

- Thick ascending limb of the loop of Henle is impermeable to water and is thus known as the diluting segment (The early distal tubule is also impermeable to water = cortical diluting segment)

- K⁺-sparing diuretics ex: spironolactone, triamterene, amiloride. These are used in combo with other diuretics to offset K⁺ losses.

- Causes of increased distal K⁺ secretion: high K⁺ diet, hyperaldosteronism, alkalosis, thiazide diuretics, loop diuretics, luminal anions

- The corticopapillary osmotic gradient and countercurrent multiplication in the loop of Henle are essential for the production of concentrated urine

- Urea regulation –Reabsorption from the inner medullary collecting ducts contributes to urea recycling and development of the corticopapillary osmotic gradient

- Phosphate regulation – Parathyroid hormone (PTH) inhibits phosphate reabsorption in the proximal tubule by activating adenylate cyclase à cAMP à inhibition of Na⁺-phosphate cotransport

- Loop diuretics à Ý urinary Ca²⁺ excretion (because calcium and sodium absorption are linked in the loop of Henle). So loop diuretics can be used to treat hypercalcemia (if volume is replaced).

- PTH & thiazide diuretics Ý Ca²⁺ reabsorption. Thiazide diuretics are used in the treatment of hypercalciuria.

- In the thick ascending limb Mg²⁺ and Mg²⁺ compete for reabsorption. Thus, hypercalcemia à increased Mg²⁺ excretion (and vice versa).

4. Clearance calculation

Ref: BRS physiology p. 158-160

The fundamentals:

Clearance = the volume of a plasma cleared of a substance per unit time

Clearance Equation: C = U*V/P

- C = Clearance (ml/min or ml/24 hr)

- U = Urine concentration (mg/ml)

- V = Urine volume/time (ml/min)

- P = Plasma concentration (mg/ml)

Some finer points and clarifications:

- Note that if urine concentraion of a solute = plasma concentration, then the clearance is simply the urine volume/time.

- PAH clearance = RPF – Paraaminohippuric acid (PAH) if essentially completely removed from the blood that flows through the kidney. Thus the clearance of PAH is a good estimate of the renal plasma flow (RPF).

- RBF calculation – The renal blood flow (RBF) = RPF / (1-Hematocrit). Note that (1-Hematocrit) = fraction of blood occupied by plasma. So this equation is really just saying that the renal plasma flow = renal blood flow * the % of blood occupied by plasma.

- Inulin clearance = GFR – The glomerular filtration rate is the amount of blood that crosses the glomerular capillaries. Inulin is freely filtered in the kidney, but it is not reabsorbed or secreted by the renal tubules. Thus inulin’s clearance is a good estimate of GFR.

5. Effects of afferent and efferent arteriolar constriction on GFR & RPF

Ref: BRS physiology p. 162-163

The fundamentals:

Constriction of afferent arterioles decreases GFR and RPF

Constriction of efferent arterioles increases GFR and decreases RPF

Some finer points and clarifications:

- Path of blood flow: renal artery à afferent arteriole à glomerular capillary à efferent arteriole à preitubular capillary.

- Constriction of an arteriole increases its resistance which results in less flow. This is why constriction of afferent or efferent arterioles result in decreased RPF

- Constriction of effferent arterioles means that there will be a bigger pressure drop across the efferent arterioles. Thus the pressure at the glomerular capillaries will increase. This is why efferent arteriole constriction à increased GFR.

- Conversely afferent arteriole cosntriction à Ý pressure drop across afferent arteriole à ß pressure at glomerular capillary à ß GFR