1. Renal Handling of
Glucose/Proteins/Organic acids&
Uric acid
Renal Physiology
Wisit Cheungpasitporn
Feb 14th 2014/ Valentine day

2. Overview
• Glucose
• Amino acids
• Proteins
• Organic acids
• Cations
• Anions
• Uric acid

3. Glucose Handling by Kidneys
• Glucose is freely filtered
• At normal plasma concentrations it is entirely reabsorbed
• Reabsorption occurs by secondary active transport at the
apical membrane via sodium-glucose cotransporter SGLT
(facilitated by the Na/K ATPase pump on the basolateral
membrane)
Sodium-Glucose-Linked
Transporter (SGLT)
• Glucose exits the basolateral membrane though facilitated
diffusion via GLUT 1 and 2

4. Glucose Reabsorption from the Proximal Tubule
Glucose is freely filtered and nearly 100% reabsorbed.
There is normally no glucose excreted in urine.
Glucose is reabsorbed via the transcellular route.
1. Basolateral Active Na Transport
2. Apical Glucose Transport
 energy from Na gradient
 secondary active transport
 glucose is moved up gradient
by Na-glucose symporter
SGLT
GLUT
3. Basolateral Glucose Transport
 facilitated diffusion
 glucose is moved down its
gradient by a uniporter
4. Glucose moves into capillary
 simple bulk flow
This is
TM process. transport maximum

5. Glucose Absorption in PT
GLUcose Transporters 1 and 2
(GLUT1 and GLUT2)
SodiumGlucoseLinked
Transporter
(SGLT)

6. Secondary active transport:
Glucose
With normal GFR, the threshold of plasma glucose for glycosuria
to occur is about 11 mmol, or 200 mg/dL.

7. Brenner and Rector, 9th edition
©2011 MFMER | slide-10

8. Fanconi’s
syndrome
There are now 18 known genes of the GLUT family, of which 14 have known gene
products
Brenner and Rector, 9th edition
©2011 MFMER | slide-12

9. Peptide Reabsorption from the Proximal Tubule
Small Peptides are freely filtered and essentially none are excreted in urine.
Peptides are reabsorbed via the transcellular route.
What about the general renal mantra that “proteins are not filtered”?
• Main blood proteins are albumin (60%), globulin (35%) & fibrinogen (4%)
….these are not normally filtered (i.e. 99% of plasma protein is not filtered)
• But….blood contains small amounts of other proteins like angiotensin, insulin, etc.
• These “other” proteins are filtered (because they are very small)
• Amino acids (AA’s) are also filtered and reabsorbed (via transcellular route by
AA-Na-symport)
Peptide Reabsorption
• Occurs in proximal tubule
• Some peptides bind to the apical membrane and later internalized by endocytosis.
These will eventually be degraded into AA’s inside the cell.
• Other peptides are degraded to AA’s by peptidases (tethered to apical membrane).
The AA’s are then transported into cells as any filtered AA.
There is normally almost no protein in urine.
Protein in the urine is sign of serious renal dysfunction or disease.

10. Amino Acids (AA)
• Amount of free AA in the plasma total 2.5 mmol
• Proximal tubule is the principal site of AA reabsorption
• There is a physiologically important influx of many AA from
blood into cells across the basolateral membrane
• There is also tubular AA metabolism
• All cells of the renal nephron express an array of distinct amino
acid transporters that play some role in the metabolic needs of
the cells

11. Reabsorption of Amino Acids
• Normally totally reabsorbed.
• Apical amino acid transport is typically active by a sodium-dependent cotransporter (secondary active transport), though some amino acids are
reabsorbed via Na-independent facilitated diffusion.
• On the basolateral membrane most amino acids exit the cell by facilitated
diffusion.
• In some cases, due to similar molecular structures, the amino acids may
exhibit competitive inhibition of transport.
• Amino acid transport kinetics are similar to glucose, in that they exhibit a
transport maximum and may saturate if plasma levels are too high.

12. AA Transport
• AAs enter the cell by cotransport with Na & are returned to the
circulation by facilitated diffusion across the basolateral membrane
• There are several different Na-dependent AA carriers, each of which
recognizes different groups of AA
• Na-independent transporters for neutral AA (leucine, isoleucine, &
phenylalanine) & for cystine and other dibasic AA (ornithine, arginine,
and lysine)
• Mutation in gene SCL3A1 (codes for a protein that mediates Naindependent transport of cystine & dibasic acids in PT & small intestine)
results in cystinuria
• ↓ reabsorption of cystine
cystine stones (cystine is poorly soluble in urine)
• Na-dependent transporters that allow AAs (glycine and glutamine) to
enter the cell at both membranes
• Entry of glutamine may play a role in acid-base balance (it is the primary
source of ammonium production in PT)

13. AA Transport in Nephron
Glutamate
Lysine
Proline

15. Oligopeptides
• An H+-driven cotransporter takes up
oligopeptides across the apical membrane,
whereas endocytosis takes up proteins and
other large organic molecules

17. Pinocytosis
• Endocytosis: Filtered proteins adsorbed to sites
on luminal membranes that are internalized to
form endosomes. Fusion with lysosomes forms
endolysosomes in which digestion of proteins
occurs

19. ©2011 MFMER | slide-36

20. Nature Reviews Molecular Cell Biology 3, 258-268
©2011 MFMER | slide-37

21. ©2011 MFMER | slide-38

22. Rhabdomyolysis
• Myoglobin is freely filtered by glomeruli. Heme
and heme proteins, degradative products of
myoglobin, can cause AKI by inducing
vasoconstriction, direct renal tubular toxicity,
and intratubular obstruction through binding to
Tamm-Horsfall protein to form myoglobin casts.
©2011 MFMER | slide-39

23. • Heme and heme proteins enter renal tubular
cells through cell-surface megalincubulin
receptors.19 They are oxidized to ferric and
ferryl forms, triggering isoprostane generation
and lipid peroxidation (redox cycling), leading to
regional vasoconstriction/tissue ischemia and
oxidization of cellular components.
©2011 MFMER | slide-40

24. Secretion of Organic Anions & Cations
Organic anions and cations may (or may not) be filtered.
Those that are bound to large blood proteins will not be filtered.
Secretion of these anions/cations is transcellular and occurs in proximal tubule.
Many secreted anions & cations occur
naturally in body.
Others are exogenous substances.
The General Secretion Process
•
•
•
•
Occurs in proximal tubule,
Active transport across basolateral membrane
facilitated diffusion or Na-X-antiport across apical
The transporters here are generally not very specific
(one may recognize several related substances)
• Secretion usually a TM limited process
Some Notable Examples:
• Urate…end product of purine catabolism
(too much
gout)
• Creatinine…used routinely to access GFR
• PAH…used to access RPF
• Penicillin…its secretion is why a dose regimen is
required. You need to keep it above its TM to
keep a working dose in the plasma.

25. Organic Cations
©2011 MFMER | slide-43

26. Organic Acid: Cations
• Possess a net positive charge at physiologic pH
• Structurally diverse array of primary, secondary, tertiary, or
quaternary amines
• Kidneys role is to clear the plasma of these OC
• Proximal tubule as the principal site of renal secretion of
OC
• Type I OCs are relatively small (generally <400 Da)
monovalent compounds
• antihistamines, muscle relaxants, antiarrhythmics, and β blockers
• Type II OCs are usually bulkier (generally >500 Da) and
frequently polyvalent
• Vecuronium
• Secreted mainly into the bile

27. Transport of OC
multidrug-resistant
transporter 1
multidrug and toxin
extrusion transporters
hydrophobic
Diffusion down
electrical gradient
Apical exchanger
novel organic
cation transporters
Maintained
by the pump

28. ©2011 MFMER | slide-46

29. Competition Between OC Secretion
Procainamide
Cimetidine
N-acetyl
Procainamide
No cimetidine

30. Proximal organic cation secretion
cimetidine, trimethoprim, and quinidine
©2011 MFMER | slide-50

31. Organic Acid: Anion
• Organic compound that bears a net negative
charge at the pH of the fluid in which the
compound resides
• Can either be secreted or reabsorbed
• Three transport family
• NaDC family (apical and basolateral)
• Reclaim filtered solute – involved in uptake of citrate
(NaDC1)
• OAT family (apical and basolateral)
• OATP family (basolateral)

32. ©2011 MFMER | slide-54

33. Organic Anion: Citrate
• Chelator for UCa & a urinary base
• Final amount of citrate excreted in urine
depends on reabsorption in PT which
depends on pH
• Acid loading increases citrate absorption:
• (1) Low luminal pH titrates citrate3− to
citrate2− (preferred for transport)
• (2) Low pH acutely stimulates NaDC1
activity
• (3) Intracellular acidosis increases
expression & insertion of NaDC1 into the
apical membrane
• (4) Intracellular acidosis stimulates
enzymes that metabolize citrate in the
cytoplasm and mitochondria

34. Organic Acid Anion Transporters
OAT1; PAH and
alpha-ketoglutarate
OAT3; large
organic anions,
such as drugs
and steroid
hormones

35. Organic Anion: Uric Acid
• Uric acid is formed from metabolism of purine
nucleotides.
• The reaction is shifted to the right at the normal
arterial pH of 7.40.
• Normal humans have serum urate concentrations
approaching the theoretical limit of solubility of
urate in serum (6.8 mg/dL).

36. Organic Anion: Uric Acid
• Normal adult males have a total body urate pool
that averages approximately 1200 mg, nearly
twice that of adult females.
• Produced in Liver from the degradation of
dietary and endogenously synthesized purine
compounds.
• Uric acid is not typically ingested, although
dietary intake provides a significant source of
urate precursors.
©2011 MFMER | slide-62

37. Organic Anion: Uric Acid
• Urate production involves the breakdown of the
purine mononucleotides, guanylic acid, inosinic
acid, and adenylic acid, ultimately into the
purine bases, guanine and hypoxanthine.
©2011 MFMER | slide-63

38. ©2011 MFMER | slide-64

39. ©2011 MFMER | slide-65

40. Organic Anion: Uric Acid
• Human tissues have a very limited ability to
metabolize urate.
• Eliminated by the gut and the kidney to maintain
homeostasis.
• The entry of urate into the intestine is mediated
at least in part by the high-capacity urate efflux
transporter, Abcg2, ATP-binding cassette subfamily G member 2.
• Intestinal tract bacteria degrade uric acid. This
process (intestinal uricolysis) is responsible for
approximately one-third of total urate disposal.
©2011 MFMER | slide-66

41. Organic Anion: Uric Acid
• Urinary uric acid excretion accounts for the
remaining two-thirds of the daily uric acid
disposal.
©2011 MFMER | slide-67

42. Organic Anion: Uric Acid
• Renal handling of uric acid poorly understood
• Quadruple-tandem model of filtration-reabsorptionsecretion-reabsorption
• Filtration of all the uric acid in capillary plasma entering the glomerulus
• Reabsorption in PCT of about 98 to 100% of filtered uric acid
• Subsequent secretion of uric acid into the lumen of the distal portion of the
proximal tubule
• Further reabsorption in the distal tubule
• The net urinary excretion of uric acid is 6 to 12% of the
amount filtered
• The pka of uric acid is 5.75
• Above 5.75, uric acid exists mainly as urate ion (more soluble than
uric acid)
• Below 5.75, uric acid is the predominant form

43. Renal handling of uric acid
• The major reabsorptive transporters of urate in
the renal tubule are URAT1 (urate/organic
anion exchanger, product of the SLC22A12
gene) and GLUT9 (SLC2A), electrogenic
hexose transporter.
• Polymorphisms of several renal urate
transporters impart an increased risk for
hyperuricemia and gout.
©2011 MFMER | slide-69

44. URAT1 transporter
• Highly urate-specific and distinct organic anion
exchanger and is encoded by SLC22A12, a
gene residing on chromosome 11q13.
• URAT1 is localized to the luminal membrane of
proximal renal tubular epithelial cells.
• Not present on distal tubular cells or confirmed
to be elsewhere in the body in humans.
©2011 MFMER | slide-70

46. Effects of URAT1, GLUT9, and ABCG2 on urate anion disposition
by the renal proximal tubule epithelial cell and inhibitory effects of
the uricosurics probenecid and benzbromarone on renal urate
reabsorption by inhibition of both URAT1 and GLUT9 .
Terkeltaub Arthritis Research & Therapy 2009
©2011 MFMER | slide-73

47. ©2011 MFMER | slide-74

48. Renal handling of uric acid
• Decreased efficiency of renal uric acid excretion
is responsible for about 85 to 90 percent of
primary or secondary hyperuricemia.
• This results from a reduced efficiency of urate
excretion that obligates a higher serum urate
concentration in order to achieve the necessary
rate of urinary uric acid excretion.
©2011 MFMER | slide-77

49. Renal handling of uric acid
• The remaining 10 - 15 % of patients with
hyperuricemia overexcrete uric acid in the daily
urine
• This reflects inherited defects in regulation of
purine nucleotide synthesis, disordered
adenosine triphosphate (ATP) metabolism, or
disorders resulting in increased rates of cell
turnover.
©2011 MFMER | slide-78

50. ©2011 MFMER | slide-79

51. ORGANIC SOLUTES
• The nonionic diffusion of neutral weak acids
and bases promotes their transport across
tubules and explains why their excretion is pH
dependent

53. Questions & Discussion