Lecture #10: Physiology: Transport of Urea, Glucose and Organic Solutes

Where is filtered glucose normally reabsorbed?

Essentially all filtered glucose is reabsorbed transcellularly in the proximal tubule, so healthy individuals normally excrete virtually no glucose in the urine.

What is the normal fasting plasma glucose concentration given in the lecture?

Approximately 4–5 mM, or 70–100 mg/dL.

Is glucose freely filtered at the glomerulus?

Yes. Glucose is freely filtered and is then normally completely reabsorbed in the proximal tubule.

What transporter reabsorbs most glucose in the early proximal tubule?

SGLT2 in the PCT S1 segment; it is a high-capacity, low-affinity Na⁺-glucose cotransporter responsible for approximately 90% of glucose reabsorption.

What transporter retrieves the remaining glucose in the late proximal tubule?

SGLT1 in the PST S3 segment; it is a low-capacity, high-affinity Na⁺-glucose cotransporter.

What is the Na⁺:glucose stoichiometry of SGLT1?

SGLT1 transports 2 Na⁺ for every 1 glucose molecule, allowing it to generate a larger glucose gradient across the apical membrane.

How does glucose leave proximal tubular cells across the basolateral membrane?

Through GLUT1 and GLUT2 transporters by Na⁺-independent facilitated diffusion.

How do SGLT transporters differ from GLUT transporters?

SGLTs are apical Na⁺-glucose cotransporters that use the Na⁺ gradient, whereas GLUT1/GLUT2 are basolateral Na⁺-independent facilitated-diffusion transporters.

What is the significance of SGLT2 inhibitors?

They act as "glucuretics" by decreasing proximal glucose reabsorption and increasing urinary glucose excretion; the lecture notes their use in type 2 diabetes mellitus and congestive heart failure.

What is the renal threshold for glucose?

Approximately 200 mg/dL, or about 11 mM; above this plasma concentration, glucose begins to appear in the urine.

Why is glucose normally absent from urine?

Normal plasma glucose is well below the renal threshold, allowing essentially all filtered glucose to be reabsorbed.

What is the transport maximum (Tm) for glucose?

The maximum rate at which the proximal tubule can reabsorb glucose, approximately 400 mg/min in the lecture; it occurs when SGLT transporters become saturated.

What happens when filtered glucose exceeds its transport maximum?

Additional filtered glucose cannot be reabsorbed, remains in the tubular lumen, and is excreted as glucosuria.

What is "splay" on the glucose titration curve?

The gradual rather than abrupt approach to glucose Tm caused by anatomical and kinetic differences among individual nephrons.

Why can glucosuria begin before the theoretical glucose Tm is reached?

Different nephrons have different filtered loads and SGLT transporter densities, so some nephrons reach their reabsorptive limit earlier than others, producing splay.

What is urea?

A 60-Da, highly polar, water-soluble end product of protein and amino-acid metabolism that provides a major route for nitrogen waste excretion.

What is the normal plasma urea concentration?

Approximately 2.5–6 mM.

What is the normal BUN range given in the lecture?

Approximately 7–18 mg/dL.

Is urea freely filtered?

Yes. Urea is freely filtered and subsequently undergoes both tubular reabsorption and secretion.

What fraction of filtered urea is normally excreted?

Approximately 50% of the filtered urea load is ultimately excreted under normal urine flow and hydration conditions.

How is urea handled in the proximal tubule?

Approximately 50% of filtered urea is reabsorbed paracellularly by diffusion and solvent drag accompanying water reabsorption.

What happens to urea in the thin limbs of Henle?

An amount roughly equal to the urea previously reabsorbed is secreted transcellularly back into the thin descending and ascending limbs.

How is urea secreted into the thin limbs?

By facilitated diffusion through urea transporters of the SLC14 transporter family, including UT-A2.

How is urea handled in the medullary collecting duct?

Approximately 50% of luminal urea is reabsorbed transcellularly through urea transporters such as UT-A1 and UT-A3.

How does urine flow affect urea excretion?

Low urine flow increases water and urea reabsorption and may reduce urea excretion to about 15% of the filtered load; high urine flow decreases reabsorption and can increase excretion to as much as about 70%.

Why can progressive renal disease increase BUN?

Decreased GFR often produces lower urine flow and increased urea retention, raising plasma BUN.

How are amino acids handled by the kidney?

Amino acids are freely filtered, but more than 98% are retrieved transcellularly by the proximal tubule because they are important nutrients.

How do amino acids enter proximal tubular cells?

Through multiple apical Solute Carrier family transporters driven by Na⁺ or H⁺ gradients and through amino-acid exchangers.

How do amino acids leave proximal tubular cells?

They exit across the basolateral membrane through amino-acid exchangers, some of which are Na⁺ dependent.

Why is Na⁺-dependent amino-acid uptake important in the late proximal tubule?

In the S3 segment luminal amino-acid concentration is low, so Na⁺-dependent transport helps recover the remaining amino acids.

What is SLC38A3's role in amino-acid handling?

It contributes to basolateral transfer of amino acids important for proximal tubular cellular nutrition and metabolism.

What are oligopeptides?

Short chains of approximately 2–20 amino-acid residues that can have specialized signaling, immune, and endocrine functions.

How much filtered oligopeptide is reabsorbed by the proximal tubule?

Approximately 99%; nephron segments beyond the proximal tubule contribute little to oligopeptide transport.

How are many filtered oligopeptides reabsorbed?

Brush-border peptidases first hydrolyze them into individual amino acids, which can then be transported into proximal tubular cells.

Which brush-border enzymes participate in oligopeptide digestion?

Examples include γ-glutamyltransferase, aminopeptidases, endopeptidases, and dipeptidases.

How are small oligopeptides resistant to brush-border digestion absorbed?

Peptides of roughly 2–5 amino acids can enter proximal tubular cells through H⁺-coupled PepT1 and PepT2 transporters.

How do PepT1 and PepT2 differ?

PepT1 is low-affinity, high-capacity and located mainly in PCT S1–S2; PepT2 is high-affinity, low-capacity and located mainly in PST S3.

What happens to oligopeptides after they enter proximal tubular cells?

They are hydrolyzed by intracellular cytosolic peptidases into amino acids.

How much filtered albumin is reabsorbed by renal tubules?

Approximately 96–99% of the small amount of albumin that crosses the glomerular filtration barrier is reabsorbed.

Why can proximal tubular injury cause proteinuria without glomerular injury?

The proximal tubule normally retrieves filtered albumin, low-molecular-weight proteins, and polypeptides; impaired tubular reabsorption allows these proteins to remain in urine.

How are filtered proteins reabsorbed by proximal tubular cells?

Primarily by receptor-mediated endocytosis: apical receptor binding → coated-vesicle internalization → endosome formation → lysosomal delivery and digestion.

What happens to proteins after lysosomal digestion in proximal tubular cells?

Low-molecular-weight digestion products are transported across the basolateral membrane into the peritubular circulation.

Are most filtered proteins returned intact to the blood?

No. Hardly any are reabsorbed intact; most are digested within lysosomes, although a small subset can undergo transcytosis.

What is urate?

A monovalent anion and the end product of purine catabolism; normal plasma concentration is approximately 3–7 mg/dL.

How is urate handled by the proximal tubule?

Urate is filtered, reabsorbed, and secreted in the proximal tubule, with reabsorption being quantitatively more important.

Which transporters mediate transcellular urate reabsorption?

Apical URAT1, OAT4, and OAT10 mediate uptake, while basolateral URATv1 mediates exit toward the blood.

Which transporters mediate urate secretion?

Basolateral OAT1 and OAT3 move urate into proximal tubular cells, while apical NPT1/NPT4, MRP4, and BCRP move it into the tubular lumen.

How does extracellular volume depletion affect urate?

Volume depletion enhances proximal Na⁺ and water reabsorption, increasing paracellular urate reabsorption, decreasing urate excretion, and increasing plasma urate.

What is the significance of the renal organic acid/anionic secretory system?

It allows proximal tubular secretion and elimination of numerous endogenous metabolites and exogenous substances, including many drugs and toxins.

Why is PAH useful in renal physiology?

PAH is freely filtered and strongly secreted by the proximal tubule, so at low plasma concentrations most PAH entering the kidney is removed in one pass; PAH clearance can therefore estimate effective renal plasma flow.

What is the renal organic base/cation secretory system?

A proximal straight tubule S3 system that secretes a wide range of endogenous and exogenous organic cations, including neurotransmitters, creatinine, morphine, quinine, atropine, amiloride, and triamterene.

How are organic cations secreted across proximal tubular cells?

Organic cations enter across the basolateral membrane primarily through OCT2, driven by the inside-negative membrane potential, then exit apically through MATE1, MATE2-K, and MDR1 using the H⁺ gradient.