HYPEROXALURIA

1
HYPEROXALURIA
Presented By Alim Janmohamed (alim.janmohamed_at_ut
oronto.ca) Joshua Garcha (joshua.garcha_at_utoronto.c
a) Navtej Gill (navtej.gill_at_utoronto.ca) Parag
Shah (parag.shah_at_utoronto.ca)
2
WHAT IS HYPEROXALURIA?

• Defined as excessive urinary oxalate
• Oxalate is the salt form of oxalic acid and is a
  natural end product of metabolism in the body
• Commonly presents with kidney stones
• More common in men because of diet

3
OXALATE

• Produced in plants leaves, nuts, fruit, and bark
• Oxalate rich foods potatoes, broccoli, wheat and
  bran
• Daily in take usually 80-120mg daily but can vary
  from 30-350mg in some diets

4
OXALATE

• Absorbed via colon
• Can combine withto form organic salts
• Na ? Soluble
• K ? Soluble
• Ca ? INSOLUBLE!
• Both Ca and oxalate are secreted via kidney
  into the urine for excretion from the body
• BUT, can combine with Ca ? calcium-oxalate
  crystals ? kidney stone

5
BIOCHEMISTRY OF ENDOGENOUS OXALATE

• Metabolic end product of glycolate metabolism in
  the liver

6
BIOCHEMISTRY OF ENDOGENOUS OXALATE

• supersaturation of urine with oxalate
• these crystals can grow and cause renal tubular
  injury, which is necessary for the right
  crystal-cell interaction to cause crystal growth,
  and aggregation
• this interaction involves renal tubular
  apoptosis, necrosis, inflammation and even the
  production of ROS (reactive oxygen species)
• somewhat of a vicious cycle the renal damage
  promotes stone formation

7
TYPES OF HYPEROXALURIA

• Type I Hyperoxaluria
• Most common type
• Genetically inherited recessive trait
  (polymorphic alleles major and minor - minor has
  P11L and I340M amino acid substitutions )
• Causes deficiency in activity of AGT
• Results in blockage of the glyoxylic acid to
  glycine pathway (which increases oxalate levels!)
• Type II Hyperoxaluria
• Less common than type I
• Due to a deficiency in D-glyceric dehydrogenase
• Results in the overconversion of glyoxylate to
  oxalate
• Enteric Hyperoxaluria
• Due to g.i. problem ? e.g. chronic diarrhea
• Lack of calcium ? none left to bind oxalate in
  the intestinal tract ? additional oxalate is
  absorbed and then excreted in the urinary tract
• Idiopathic or Mild Hyperoxaluria
• Due to dietary excess of high-oxalate food
  sources
• Or to increased endogenous oxalate production

8
SIGNS AND SYMPTOMS

• Typical first sign is kidney stones
• Severe or sudden abdominal or flank pain
• Blood in the urine
• Urge to urinate often
• Pain when urinating
• Fever and chills
• Untreated will lead to kidney failure
• A decrease in or no urine output
• General ill feeling, tiredness, and marked
  fatigue
• Nausea, vomiting
• Anemia
• Young children may fail to develop and grow
  normally

9
DIAGNOSIS

• Blood and urine tests
• X-ray, Ultrasound, CT Scan
• Biopsy of liver or kidney tissue
• Echocardiogram look for deposits in heart
• Family screening if known history
• DNA testing is possible for definitive diagnosis
  of Type I and II and for prenatal diagnosis
• But is not widely used

10
NON-PHARMACOLOGICAL TREATMENT

• High Fluid Intake
• Increase the amount of water and other fluids,
  this keeps the kidneys flushed to prevent the
  buildup of oxalate and prevents kidney stones

11
NON-PHARMACOLOGICAL TREATMENT

• Dietary Modifications
• Limit oxalate in diet (fruits, beats, nuts,
  spinach, potatoes, broccoli, chocolate, bran) ,
  if hyperoxaluria is enteric also limit fat in
  diet
• Food products from animal
• Have minimal oxalate
• content

12
DRUG THERAPY

• Pyridoxine (vitamin B6)
• Decreases the production of oxalate by enhancing
  the conversion of glyoxylate to glycine
  (decreasing the substrate)
• Orthophosphate
• With pyridoxine for treatment of primary
  hyperoxaluria.
• Increases urinary pyrophosphate which complexes
  with calcium ? decrease in urinary calcium,
• Contraindicated in renal failure
• Magnesium Hydroxide
• Complexes with oxalate in GI ? reducing level
  free oxalate and urinary calcium
• In combination with pyridoxine ? higher
  reductions in urinary oxalate

13
TREATMENT OF HYPEROXALURIA

• Kidney/Liver Transplantation
• If disease progresses, pt. can get (end stage
  renal failure)
• pt. is temporarily put on dialysis to remove
  excess fluids and wastes from the body, until a
  transplant can be performed
• Transplants are most often in patients with Type
  I primary hyperoxaluria who do not respond to
  vitamin B6

14
COMPARISON OF THERAPIES

• Common Therapies Aim to reduce amount of free
  oxalate or calcium in the blood
• Enteric Hyperoxaluria somewhat different
• Calcium supplementation
• calcium binds to free intestinal oxalate
• calcium citrate - citrate natural inhibitor of
  calcium oxalate urinary crystallization.
• Cholestyramine
• Non absorbable resin that binds bile salts, fatty
  acids, and intestinal oxalate.

15
SUMMARY

• Hyperoxaluria excess urinary oxalate leading to
  the formation of kidney stones via insoluble
  crystal formation with Ca
• Oxalate found in plants, nuts, fruits, potatoes,
  broccoli, wheat
• Endogenous sources metabolic end product of
  glycolate and amino acid metabolism in the liver
• Type I most common, genetically inherited
  recessive trait ? deficiency in alanine
  glyoxylate aminotransferase (Vit. B6 dependent
  process) ? build up of glyoxylate ? OXALATE!
• Acute kidney stones, pain, hematouria ? Chronic
  renal failure
• Non Drug Treatment Diet modification, high fluid
  intake, transplant
• Drug Treatment commonly B6 that increases
  metabolism of glyoxalate or drugs that bind free
  oxalate or calcium
• Diagnosis examine tissue and fluid samples for
  excess oxalate also radio-imaging

16
QUESTIONS?
17
REFERENCES

• Mayo Foundation for Medical Education and
  Research . Primary Hyperoxaluria.2008. Access on
  February 24th, 2008. http//ndc.mayo.edu/mayo/rese
  arch/nephrology/hyperoxaluria.cfm
• The Oxalosis and Hyperoxaluria Foundation . About
  the Disease. 2008. Access on February 24th, 2008.
  http//www.ohf.org/about_disease.html
• Shekarriz, Bijan. Hyperoxaluria. American
  Urological Association. Accessed via
  WebMD.http//www.emedicine.com/MED/topic3027.htm
• Tsujihata, M. Mechanism of calcium oxalate renal
  stone formation and renal
• tubular cell injury. International Journal of
  Urology (2008) 15, 115120 (Accessed 2008 Feb.
  21). Available from UofT E-resources
• Murray MS, Holmes RP, Lowther WT. Active Site and
  Loop 4 Movements within Human Glycolate Oxidase
  Implications
• for Substrate Specificity and Drug Design.
  Biochemistry 2008, 47, 2439-2449. (Accessed 2008
  Feb 21). Available from UofT E-resources
• Cellini B, Bertoldi M, Montioli R, Paiardini A,
  and Borri Voltattorni C. Human wild-type
  alanineglyoxylate aminotransferase and its
  naturally
• occurring G82E variant functional properties and
  physiological implications. Biochem. J. (2007)
  408, 3950 (Printed in Great Britain)
  doi10.1042/BJ20070637. (Accessed 2008 Feb 21).
  Available from UofT E-resources
• Horton HR, Moran LA, Scrimgeour KG, Perry MD,
  Rawn JD. Principles of Biochemistry. 4th ed.
  Pearson Prentice Hall (NJ) 2006. p. 408-409, 820.