Urine Crystals (Crystalluria)

Sample

1. Freshly voided urine is the best sample.
2. Refrigerate or if you keep at room temperature that will increase the formation of the crystals.

Precautions:

1. pH is very important to note.
2. Take the history of the medications, will save time and energy.
3. Refrigeration will precipitate out many crystals, because of the change in the solubility of various crystals.
4. Urine kept at room temperature leads to precipitation or dissolve the crystals.
5. The radiographic dye can make crystals in dehydrated patients.
6. Ampicillin and sulfonamides also give rise to crystal formation, this happens in dehydrated patients.

Pathophysiology

1. Definition:
   1. There may be well-defined crystals or amorphous material in the urine sediment.
   2. These appear as geometrical formed structures or amorphous materials.
2. The presence of crystals in the urine is called Crystalluria.
3. When urine left at room temperature or refrigerated then urine becomes cloudy because of the precipitation of crystals or amorphous material.
4. Importance of the Crystals in the urine:
   1. These crystals are important in the case of kidney stones.
   2. Renal damage caused by the crystals.
   3. In liver diseases.
   4. Inborn error of metabolism.
   5. Some of the crystals indicate some metabolic disorders like cystinuria or a sulfa drug.
5. The stone formation may be without crystals in the urine or crystalluria may be without stone formation.
6. Crystals are seen mostly in concentrated urine.
7. Crystals are divided into :
   1. Normal  or abnormal
   2. In alkaline or acidic urine.
   3. Crystals found due to medication.
8. Crystals found in acidic urine have a pH of <6.5 and in alkaline urine pH is >7.0.
9. Reporting of the crystalluria:
   1. Rare/HPF.
   2. FeW/HPF.
   3. Moderate/HPF.
   4. Many/HPF.
10. Mechanism of the formation of crystals:
    1. Kidneys are the main site for the excretion of the waste product of metabolism which is needed by the body.
       1. Urea from the metabolism of the amino acid.
       2. Creatinine from the muscles.
       3. Uric acid from the nucleic acid.
       4. The hemoglobin end product is bilirubin.
       5. Hormones are excreted as hormone metabolites.
       6. kidneys also excrete the toxins, and other foreign substances produced by the body or ingested, such as pesticides, drugs, and food additives.
    2. Crystals formed by the crystalization of urine solutes.
    3. The solutes are:
       1. Inorganic salts.
       2. Organic compounds.
       3. Medications by drug use.
    4. Precipitation is dependent upon:
       1. Temperature.
       2. pH.
       3. Solute concentration.
          1. As the concentration of solutes increases, their ability to remain solution decreases and result in crystal formation.
    5. Solute precipitate more readily at low temperatures.
       1. 1. So if you keep the urine at room temperature or refrigerate, then crystals are abundant.
    6. Organic and iatrogenic compounds crystalize more easily in the acid urine.
    7. Inorganic salts are less soluble in neutral or alkaline pH.
       1. The exception is calcium oxalate which precipitates in both acidic and alkaline medium.
    8. The Slower crystalization leads to larger crystal formation but the basic structure remains the same.
    9. Reversal of the pH will dissolve the crystals.
    10. Amorphous urates crystals formed in the refrigerated sample, if you warm the urine these will disappear.
    11. Amorphous phosphate crystals need acetic acid to dissolve. But practically this is not done because the acetic acid will distort the RBCs.
11. Helping point in Reporting of the crystals:
    1. Always note the pH of the urine which will help to identify the crystals.
    2. All abnormal crystals are found in acidic urine.
    3. Polarized microscopy also helps to identify the crystals.
12. Characteristics of crystals:
    
    1. Most of the urate crystals are yellow to reddish-brown.
    2. Amorphous urates appear yellow-brown granules. these are in clumps and look like the granular cast.
    3. If urine refrigerated then the amorphous urates crystals precipitate and give pink sediment.
    4. Amorphous urates crystals appear in the urine with low pH >5.5 and uric acid crystals appear when pH is lower.

Various types of crystals in acid urine:

1. Acidic- urine crystals are:
   1. Uric acid.
   2. Amorphous urates.
   3. Sodium urates.
   4. Cystine (these are rarely found).
   5. Cholesterol crystal (these are rarely found).
   6. Tyrosine (these are rarely found).
   7. Leucine (these are rarely found).
   8. Bilirubin.
2. Uric acid:
   1. Serum uric acid is raised in 40 to 50% of the patients.
   2. These are seen in a variety of shapes like four-sided flat plates, wedge-shaped, and rosettes.
   3. These are usually yellow-brown in color.
   4. But maybe colorless and six-sided shapes like cystine crystals.
   5. these are birefringent in polarized light.
   6. These are common in patients with leukemia getting chemotherapy.
   7. Sometimes these are seen in gout.
      

      Uric acid crystals

3. Acid urates and sodium urates:
   1. These are like amorphous urates and seen in less acidic urine.
   2. These are seen along with amorphous urates and have little clinical significance.
   3. Sodium urates crystals are needle-shaped and are seen in the synovial fluid during the attack of gout and also appear in the urine.
4. Amorphous urates:
   1. These are yellow-brown granules.
   2. These may appear in clumps resembling granular cast.
   3. These crystals are found in acidic urine with pH>5.5.
      

      Urine amorphous urates

5. Calcium oxalate:
   1. More common in acid urine, but may be seen in neutral or even in alkaline urine.
   2. The most common is dihydrate, which is a colorless, octahedral envelope shape or two pyramids joined together at their bases.
   3. Monohydrate crystals are oval or dumble-shaped.
   4. In polarized light both are birefringent.
   5. The finding of clumps of calcium oxalate crystals indicates renal stone formation.
   6. These are commonly seen when taking foods like tomato, asparagus, and ascorbic acid.
   7. Monohydrate crystals are seen in ethylene glycol  (antifreeze) poisoning.
      

      Urine calcium oxalate crystals

Crystals in the acidic urine :

Name of crystals	pH	Effect of heating  (solubility)	Shape	Color
Sodium urate	acidic (<acidic)	soluble at 60 C	amorphous	Colorless to yellow, Amorphous, or large granules
Uric acid	acidic <5.5	alkali-soluble	rhombic, four-sided flat plates	yellow-brown
Amorphous urates	acidic >5.5	alkali and heat	amorphous or sand-like	Microscopically  yellow-brown and occurs in clumps
Sodium urates	Acidic
Calcium oxalate	acidic or alkaline	dilute HCL	enveloped shaped, dumbbell-shaped	The colorless octahedral envelope or two pyramids joined at the base.
Cystine	acidic	Dilute  HCl acid	hexagonal	Colorless
Cholesterol	acidic	Chloroform	rectangular, notched plates	Colorless
Tyrosine	acid/neutral	Alkali or heat	needles shape form clumps or rosettes	Colorless to yellow, needles
Leucine	acidic /neutral	Hot alkali or alcohol	spheres with a concentric circle or  radial striations	yellow-brown
Bilirubin	acid	Acetic acid, HCL, ether or chloroform	clumped  needles or granular	yellow color
Sulphonamide	acid/neutral	Acetone	Rosette form, needle,	colorless to yellow-brown
Ampicillin	acid/neutral		in needles form	colorless
Radiographic dye	acid	10% NaOH	like cholesterol	colorless

Various types of crystal in alkaline urine:

1. Alkaline urine crystals are:
   1. Calcium phosphate.
   2. Amorphous phosphates.
   3. Calcium carbonate.
   4. Ammonium biurate.
   5. Tripple phosphate.
2. Amorphous phosphate:
   1. These are granular in shape like amorphous urates.
   2. If refrigerated then these produce white precipitate which does not dissolve on warming.
   3. These are differentiated from the urates by color and the pH of the urine.
      

      Urine Amorphous phosphates

3. Tripple phosphate (Ammonium magnesium phosphate):
   1. These are seen in alkaline urine.
   2. These are colorless, prism-shaped, resembling the coffin lid.
   3. Under polarized lights are birefringent.
   4. These have no clinical significance.
      

      Urine tripple phosphate

4. Calcium phosphate:
   1. These are colorless, flat rectangular plates.
   2. Or thin prism and often in rosette forms.
   3. Rosette forms need to be differentiated from the sulphonamides crystals.
   4. These crystals dissolve in dilute acetic acid while sulphonamides crystals will not.
   5. These have no clinical significance.
5. Calcium carbonate:
   1. These are small. colorless, with a dumbbell or spherical shapes.
   2. These may occur in clumps and resemble amorphous material.
   3. If you add acetic acid, then there is gas formation.
   4. In polarized light are birefringent and this differentiates from the bacteria.
   5. Thes crystal has no clinical significance.
6. Ammonium biurates:
   1. These have characteristic yellow-brown colors.
   2. These are usually described as thorny apples, because of the spicule-covered spheres.
   3. These dissolve at 60 °C.
   4. If you add glacial acetic acid, then these will change into uric acid.
      

      Urine ammonium biurates crystals

Crystals in alkaline urine :

Name of crystals	pH	Effect of heat	Color and shape
Amorphous phosphates	Alkaline	Remain insoluble	Granular
Triple phosphates	Alkaline		Colorless and prism-shaped like a coffin lid
Calcium phosphate	Alkaline	Remain insoluble	Colorless, flat rectangular plates or thin prisms often in rosettes
Calcium Carbonate	Alkaline		Small, colorless with a dumbbell  or spherical shape, may occur in clumps and resemble amorphous material
Ammonium biurate	Alkaline	Dissolve at 60 °C	Yellow-brown color, thorny apples

The solubility of crystals:

Crystals	Color	pH	Soluble in
Calcium oxalate	Colorless	Acid/neutral	Dilute  HCl acid
Uric acid	Yellow-brown	Acid	Alkali
Amorphous urates	Brick dust or yellow-brown	Acid	Alkali and when heated
Tripple phosphate	Colorless	Alkaline	Dilute acidic acid
Amorphous phosphate	White-colorless	Alkaline/neutral	Dilute acid acid
Calcium phosphate	Colorless	Alkaline/neutral	Dilute acidic acid
Calcium carbonate	Colorless	Alkaline	Acetic acid
Ammonium biurate	Yellow-brown	Alkaline	Acetic acid with heat

Abnormal crystals:

1. 1. Metabolic origin:
      1. Tyrosine.
      2. Cystine.
      3. Cholesterol.
      4. Leucine.
      5. Bilirubin.
      6. Hemosiderin.
   2. Drugs origin:
      1. Sulfonamides.
      2. Radiographic contrast media.
      3. Ampicillin.

Cystine crystals:

1. 1. These are seen in the inborn error metabolic disorder when the cystine is not absorbed by the renal tubules (cystinuria).
   2. There is a tendency to form renal calculi.
   3. These are colorless, hexagonal plates and may be thick or thin.
   4. In the presence of ammonia, there is the disintegration of these crystals.
   5. Cysteine stones are seen in 1 to 2% of the cases.
   6. Cyanide-nitroprusside test needed to confirm the cystine crystals.
      

      Urine Cystine crystals

Cholesterol crystals:

1. 1. These are not seen unless the urine is refrigerated.
   2. These have a characteristic appearance resembling the rectangular plates with a notch in one or more corners.
   3. These are seen disorders producing lipiduria in nephrotic syndrome, along with fatty acids and oval fat bodies.
   4. In polarized light, these are birefringent.
      

      Urine Cholesterol crystals

Sulfonamide crystals:

1. 1. There are a variety of crystal shapes and colors.
   2. Shapes variable like needles, whetstone, rhombic, wheat, and rosette with color ranging colorless to yellow-brown,
   3. The history of the patient will help you to diagnose these crystals.
   4. Diazo reaction can confirm these crystals.

Tyrosine crystal:

1. 1. These are fine colorless to yellow needles like structure which form clumps or rosettes.
   2. These may be seen in inherited disorders of amino acid metabolism.

Leucine crystals:

1. 1. These are seen because of the defect in the amino acid, leucine.
   2. These are yellow-brown spheres that will show concentric circles and radial striations.
   3. These are also called wagon wheels.
   4. These are soluble in hot alcohol and alkali.
   5. These are less frequent than the tyrosine crystals.
   6. These are accompanied by tyrosine crystals.

Bilirubin Crystals:

1. 1. Bilirubin crystals are present in liver diseases where there is an increased amount of the bilirubin excreted in the urine.
   2. These crystals are clumped needles or granules with the characteristic color of the bilirubin as yellow.
   3. Chemicals reaction for the bilirubin is positive.

Significance of crystals:

1. Calcium oxalate crystals in clumps indicate renal stone formation.
   1. Calcium oxalate crystals are abundant in food with high oxalic acid like tomatoes, asparagus, and ascorbic acid.
2. Monohydrate oxalate crystals are seen in ethylene glycol poisoning (antifreeze material).

Normal urine picture:

Physical features	Chemical features	Microscopic findings
Color = Pale yellow or amber Appearance = Clear to slightly hazy pH = 4.5 to 8.0 Specific gravity = 1.015 to 1.025	Blood = Negative Glucose = Negative Ketones= Negative Protein = Negative Bilirubin = Negative Urobilinogen = Negative (±) Leucocyte esterase = Negative Nitrite for bacteria = Negative	RBCs = Rare or Negative WBC = Rare or Negative Epithelial cells = Few Cast = Negative (Occasional hyaline) Crystal = Negative (Depends upon the pH of the urine) Bacteria = Negative

Contamination and artifacts:

There are few contaminants that interfere with the microscopy of the sediments like:

1. Starch.
2. Fibers including diaper fibers.
3. Oil droplets.
4. Air bubbles.
5. Pollin grains.
6. Fecal contamination.
7. Glass fragments.

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