Pathogenesis of Urolithiasis

1. PATHOGENESIS OF
UROLITHIASIS
Topic Presentation by
Dr. Muhammad Z. Z. Khan
R4 Urology, JPMC

2. INTRODUCTION
Urinary stones are polycrystalline aggregates composed of varying
amounts of crystalloid and organic matrix.
Stages of Stone Formation:
Supersaturation
Nucleation
Crystallization
Aggregation
Matrix Formation
Stone

3. SUPERSATURATION
Supersaturation depends on:
Urinary pH
Ionic Strength
Complexation
Solute Concentration

4. • Urinary pH
Urinary constituents may change
dramatically during different physiologic
states from a relatively acidic urine in a first
morning void to an alkaline tide noted after
meals.
Urinary pH affects the solubility of ions.
At low pH, even a modest amount of total
urinary uric acid will exceed its solubility. At
high pH, even massive hyperuricosuria is
well tolerated.
Periods of intermittent supersaturation of
urine with various substances can occur as
a consequence of dehydration and
following meals.

5. • Ionic Strength
Ionic strength is determined primarily by the relative concentration of
monovalent ions.
As the ionic strength increases, the activity coefficient decreases. The activity
coefficient reflects the availability of a particular ion.
• Complexation
It influences the availability of specific ions. For instance, sodium complexes
with oxalate and decreases its free ionic form, while sulfates can complex
with calcium.
Crystal formation is modified by a variety of other substances found in the
urinary tract, including magnesium, citrate, pyrophosphate, and a variety of
trace metals.
These inhibitors may act at the active crystal growth sites or as inhibitors in
solution (as with citrate).

6. • Solute Concentration
The greater the concentration of two ions, the more likely they are to
precipitate. Low ion concentrations result in undersaturation and
increased solubility.
As ion concentrations increase, their activity product reaches a specific
point termed the solubility product (Ksp). Concentrations above this
point are metastable and are capable of initiating crystal growth and
heterogeneous nucleation.

7. Above Ksp, crystals of calcium and oxalate should form, but they do not
because of the presence of inhibitors of crystal formation. However,
above a certain concentration of calcium and oxalate, inhibitors of
crystallization become ineffective and crystals of calcium oxalate start
to form.
As solutions become more concentrated, the activity product
eventually reaches the formation product (Kfp). Supersaturation levels
beyond this point are unstable, and spontaneous homogeneous
nucleation may occur.

8. CRYSTAL COMPONENT
Nucleation, Crystal Growth, Aggregation & Retention
Nucleation initiates the stone process and may be induced by a variety
of substances, including proteinaceous matrix, crystals, foreign bodies,
and other particulate tissues. Heterogeneous nucleation, which
requires less energy and may occur in less saturated urine.
A crystal of one type thereby serves as a nidus for the nucleation of
another type with a similar crystal lattice. This is frequently seen with
uric acid crystals initiating calcium oxalate formation.
The theory of mass precipitation or intranephronic calculosis suggests
that the distal tubules or collecting ducts, or both, become plugged
with crystals, thereby establishing an environment of stasis, ripe for
further stone growth.

9. The nucleation theory suggests that urinary stones originate from
minute crystals or foreign bodies immersed in supersaturated urine.
The crystal inhibitor theory claims that calculi form due to the
absence or low concentration of natural stone inhibitors including
magnesium, citrate, pyrophosphate, and a variety of trace metals.

10. RANDALL’S PLAQUE THEORY
Alexander Randall noted whitish-
yellow precipitations of crystalline
substances occurring on the tips of
renal papillae as submucosal
plaques.
These plaques are associated with
both the vasa recta and the urinary
collecting ducts and grow deep
within the papilla. The tips of the
plaques can be appreciated during
endoscopy of the upper urinary tract.
Endoscopic and Histologic image of
Randall’s Plaque

11. CARR’S HYPOTHESIS
The calculi form in obstructed lymphatics and then rupture into adjacent
fornices of a calyx.
EVAN’S THEORY
They localized the origin of the plaque to the basement membrane of the
thin limbs of the loops of Henle and demonstrated that the plaque
subsequently extends through the medullary interstitium to a subepithelial
location.
Once the plaque erodes through the urothelium, it is thought to constitute a
stable, anchored surface on which calcium oxalate crystals can nucleate and
grow as attached stones.

12. MATRIX COMPONENT
Renal calculi consist of both crystalline and noncrystalline components.
The noncrystalline component is termed matrix, which typically
accounts for about 2.5% of the weight of the stone.
In some cases, matrix comprises the majority of the stone (up to 65%),
usually in association with chronic urinary tract infection.
Chemical analysis reveals a heterogeneous mixture consisting of
approximately 65% protein, 9% nonamino sugars, 5% glucosamine, 10%
bound water, and 12% organic ash.

13. Matrix may serve as a nidus for
crystal aggregation or as a naturally
occurring glue to adhere small crystal
components and thereby hinder
uneventful passage down the urinary
tract.
Alternatively, matrix may have an
inhibitory role in stone formation or
may be an innocent bystander,
playing no active role in stone
formation.
An unusual type, a gelatinous
textured, radiolucent stone
called a matrix calculus

14. INHIBITORS & PROMOTERS OF CRYSTAL FORMATION
INHIBITORS
Inhibits Crystal Growth:
• Citrate – complexes with calcium
• Magnesium – complexes with oxalates
• Pyrophosphate – complexes with
calcium
• Zinc
Inhibits Crystal Aggregation
• Glycosaminoglycans
• Nephrocalcin
• Tamm-Horsfall Protien
• Osteopontin
PROMOTERS
Bacterial Infection
Matrix
Anatomic abnormalities – PUJO, MSK
Prolonged Immobilization
Altered Calcium and Oxalate transport
in renal epithelium
Increased Uric Acid levels –
taking increased purine substances –
promotes crystallization of calcium and
oxalate

15. Inhibitors have been identified that prevent calcium oxalate and calcium phosphate
crystallization, no specific inhibitors are known that affect uric acid crystallization.
Citrate acts as an inhibitor of calcium oxalate and calcium phosphate stone
formation by a variety of actions.
1. It complexes with calcium, thereby reducing the availability of ionic calcium to
interact with oxalate or phosphate.
2. It directly inhibits the spontaneous precipitation of calcium oxalate and
prevents the agglomeration of calcium oxalate crystals. Although it has limited
inhibitory effect on calcium oxalate crystal growth, it has potent activity in
reducing calcium phosphate crystal growth.
3. Citrate prevents heterogeneous nucleation of calcium oxalate by monosodium
urate.

16. Two urinary glycoproteins, Nephrocalcin and Tamm-Horsfall
glycoprotein, are potent inhibitors of calcium oxalate monohydrate
crystal aggregation.
Tamm-Horsfall is the most abundant protein found in the urine and a
potent inhibitor of calcium oxalate monohydrate crystal aggregation,
but not growth.
It is expressed by Renal Epithelial Cells in the Thick ascending Limb on
Henle and the Distal Convoluted tubule as a membrane anchored
protien
In alkaline urine it is a strong inhibitor of calcium oxalate monohydrate
crystal aggregation, while in acidic urine it polymerizes into a
configuration that promotes crystal aggregation.

17. THANK
YOU
Take Care OF Your Kidneys!!!