Handling of Organic Substances

Describe the role of the kidney in the handling of glucose, nitrogenous products and drugs

Broadly speaking, the kidney:

• Reabsorbs important substances
• Filters and secretes waste products

Methods of Reabsorption

Reabsorption from tubule to blood can occur via two mechanisms:

• Transcellular reabsorption
  Substance is absorbed into tubular epithelium and then secreted into blood. This is typically achieved by symporters, which rely on the low intracellular sodium concentration to move substances out of the tubule against their concentration gradient.
• Paracellular reabsorption
  Substance passes through the matrix of tight junctions between epithelial cells.

Rate Limitation

There are functional upper limits on the rate of reabsorption of substances from the tubule. There are two limits:

• Tubular Maximum (T_max) Limited
  Saturation of transporters occur, so a further increase in solute concentration does not increase the rate of substance reabsorption.

  The maximum solute concentration for a T_max system is a function of the transporter.

• Gradient Limited
  Leaks in the tight junctions will result in solute moving from the interstitium back into the tubule if the tubular concentration falls too low.

  The maximum solute concentration for a gradient limited system is related to the permeability of the tight junctions.

Glucose

Glucose is:

• Freely filtered at the glomerulus
• Completely reabsorbed via the transcellular route in the proximal convoluted tubule under normal circumstances
• Actively transported via the SGLUT (Sodium-dependent Glucose symporter) transmembrane protein
  • Secondary active transport (down the established Sodium gradient)
  • There are two subtypes of the SGLUT protein:
    • Low-affinity, high-capacity
      Rapidly reabsorbs glucose, but is ineffective when glucose concentration is low. It is located early in the PCT, and reabsorbs ~90% of filtered glucose.
    • High-affinity, low-capacity
      Slowly reabsorbs glucose, but remains effective even when glucose concentration is low. It is located late in the PCT, where glucose concentration is lower (having already been reabsorbed by the high-capacity transporter), and reabsorbs ~10% of filtered glucose.

• As GFR increases, glucose filtration and therefore glucose absorption increase
• As glucose is co-transported with Na⁺, absorption of Na⁺ and H₂O also increase
• This phenomenon is known as glomerulo-tubular balance

• Glucose reabsorption is a T_max system, and is overwhelmed when filtered glucose exceeds 300mg.min^-1 or 16mmol.min^-1
  • This typically occurs when plasma (and therefore filtered) glucose concentrations exceed 12mmol.L^-1

Consequences of Glycosuria

Glycosuria occurs when filtered glucose exceeds the capacity of the PCT to reabsorb it, and causes:

• Increased urine volume
  • Glucose acts as an osmotic diuretic by:
    • Reducing Na⁺ reabsorption in the PCT
      As some glucose is not absorbed, the sodium that would normally be reabsorbed with (tubuloglomerular balance) is remaining in the tubule.
    • Reducing water and salt reabsorption in the Loop of Henle
      Due to high tubular flow rates.
      • Impairs the formation of the medullary concentration gradient, limiting concentrating capacity
  • Stimulates ADH release
• Electrolyte derangements
  • Hypokalaemia due to:
    • Reduced K⁺ reabsorption due to high tubular flow rates
    • Aldosterone release due to hypovolaemia, increasing Na⁺ reabsorption and K⁺ secretion
  • ADH release in response to hypovolaemia
• Loss of substrate for ATP generation
• Increase risk of urinary infections

Nitrogenous Products

• Amino acids are reabsorbed by amino-acid transporters
  These are not (entirely) selective, and reabsorb several structurally similar amino acids.
  • These shared pathways create competition for binding sites between amino acids
  • Excess of one substance will lead to both excretion of this substance in urine, as well as inappropriate excretion of related substances

• Larger proteins (such as albumin) are in fact filtered at the glomerulus (though in very small amounts)
  Reuptake occurs in several stages:
  • Endocytosis at the luminal membrane
    This is an energy-dependent process, requiring protein to bind to membrane receptors.
  • Degradation of protein into individual amino acids
  • Reuptake across the basolateral membrane

• Smaller proteins and peptides (e.g. insulin, angiotensin II) are completely filtered
  • Catabolism occurs in the tubular lumen by membrane-surface peptidases
  • Amino acids are reabsorbed by standard amino-acid transporters

Urea

Urea is a small, water soluble molecule produced in the liver from ammonia as a method for eliminating nitrogenous waste.

Urea excretion is complex, as it has an important role in the counter current multiplier. This means that in the short term (hours to days) elimination may not match production, although over weeks they will be equal. Urea is:

• Freely filtered
• ~50% of filtered load is reabsorbed in the PCT by solvent drag (with water reabsorption)
  Urea concentration is slightly increased as more water is reabsorbed than urea.
• The urea reabsorbed in the PCT is then secreted into the Loop of Henle via UT uniporters
  • Luminal concentration of urea is much higher in the ascending limb due to the absorption of water
• ~50% is reabsorbed (again) in the medullary collecting ducts
  Here, urine becomes so concentrated that luminal concentration of urea exceeds medullary concentration.
  • Overall, 50% of filtered load is excreted

pH Dependent Drug Reabsorption

• Many substances, such as drugs, are weak acids or bases
• Reabsorption of these substances is pH dependent
  • Weak acids are proportionally more ionised at a pH above their pKa
  • Weak bases are proportionally more ionised at a pH below their pKa
  • Unionised substances are lipid soluble, and able to diffuse into tubular cells down concentration gradients
  • Ionised substances are trapped within the lumen

References

1. Eaton DC, Pooler JP. Vander's Renal Physiology. 6th Ed (Revised). McGraw-Hill Education - Europe. 2004.