Physicochemistry of renal stones

1. Mohammad Ihmeidan , PGY2
Upper Urinary Tract Stones
Physicochemistry

2. In General
 Urinary stones are the third most common
problem of the urinary tract, exceeded only
by urinary tract infections and pathologic
conditions of the prostate.

3.  With Westernization of global culture, the site of
stone formation has migrated from the lower to the
upper urinary tract and the disease once limited to
men is increasingly gender blind

4. Pathophysiology of stone formation
 The formation of renal stones is a complex process;
depends on the interaction of several factors:
-Urinary concentration of stone forming ions
-Urinary pH
-Urinary flow rate
-The balance between promoter and inhibitory
factors of crystallisation, (e.g., citrate, magnesium, pyrophosphate)
-Anatomic factors that encourage urinary stasis
(e.g., developmental anomalies, foreign bodies)

5. Steps of Stone formation
 There are some steps that are required:
 A) Crystallization
 B) Crystal Growth
 C) Aggregation
(multiple crystals combining together; believed
to take place in the tubules or collecting system)
 D) Adherence of Crystals to Epithelium
(must anchor in order not to be washed out of
the urine long enough to aggregate)

6.  State of Saturation:
 As we mentioned before ,the physical process of stone
formation is a complex cascade of events.
 It begins with urine that becomes supersaturated with
respect to stone-forming salts, such that dissolved ions or
molecules precipitate out of solution and form crystals or
nuclei. Once formed, crystals may flow out with the urine
or become retained in the kidney at anchoring sites that
promote growth and aggregation, ultimately leading to
stone formation.

7.  the concentration product, which is a
mathematical expression of the product of the
concentrations of the pure chemical components
(ions or molecules) of the salt.
 A pure aqueous solution of a salt is considered
saturated when it reaches the point at which no
further added salt crystals will dissolve.

8.  the thermodynamic solubility product, Ksp, is the point
at which the dissolved and crystalline components are
in equilibrium for a specific set of conditions.
 At this point, addition of further crystals to the
saturated solution will cause the crystals to precipitate
unless the conditions of the solution, such as pH or
temperature, are changed.

9.  In urine, despite concentration products of stone-
forming salt components, such as calcium oxalate,
that exceed the solubility product, crystallization
does not necessarily occur because of the presence of
inhibitors and other molecules .
 In this state of saturation, urine is considered to be
metastable with respect to the salt.

10.  As concentrations of the salt increase further, the
point at which it can no longer be held in solution is
reached and crystals form. this point is called the
formation product, Kf.
 Ksp and Kf differentiate the three major states of
saturation in urine: undersaturated, metastable, and
unstable.

11.  Below the solubility product, crystals will not form under any circumstances.
 above the formation product, the solution is unstable and crystals will form.
 In metastable range, in which the concentration products of most
common stone components reside, spontaneous nucleation or
precipitation does not occur despite urine that is supersaturated. in this
area that modulation of factors controlling stone formation can take
place and therapeutic intervention is directed.

13.  Nuclei are the earliest crystal structure that will not
dissolve.
 Homogenous nucleation - process of nuclei
formation in pure solution
 Heterogenous nucleation - nuclei form on
existing surfaces - eg epithelial cells, cell debris,
urinary casts, crystals - Lower concentration needed
 Most of CaOx is heterogenous

14. Randallplaque
• Randall (1937) first observed areas of damage associated with
subepithelial plaqueson the renalpapillae.
• Randall'splaquesaresoft tissuecalcifications found in the deep
renalmedullaskirting the surfaceof the epithelium of the papilla.
• Act asnucleating elementsfor renal calculi orstones.
• Crystalcomponent of plaque wasdetermined to becalciumapatite
(Evan, 2003.)

15. In the photo the Randall plaque can be clearly seen asthe white part at the top of
the renal papilla. Copyright: X.Carpentier et al.,2010.

17. the origin of the plaque is now thought to be 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.

18. Among idiopathic calcium oxalate stone formers, the volume of papillary
surface
covered by plaque was shown to correlate negatively with urine
volume and positively with hypercalciuria (Kuo et al, 2003a,
2003b) and the number of stones formed (Kim et al, 2005a), providing
further corroborating clinical evidence for this sequence of
events. Furthermore, Matlaga and colleagues (2006) observed that
in approximately half of a studied cohort of calcium oxalate stone
formers the stones were observed to be attached to the renal papillae,
suggesting that formation of attached stones is an early step
in the process of stone formation.

19. PHYSICOCHEMISTRY
 Inhibitors:.
 Whole urine, when added to a solution of calcium
phosphate, raises the supersaturation level required to
initiate calcium phosphate crystallization.
 Citrate, Magnesium, and pyrophosphate together were
account for 20% of the inhibitory activity of whole urine,
with citrate comprising the most important factor of the
three.
no specific inhibitors are known that affect uric acid
crystallization.

20. PHYSICOCHEMISTRY
 Citrate
acts as an inhibitor of calcium oxalate and calcium
phosphate stone formation by a variety of actions:
1- it complexes with calcium, reducing the
availability of ionic calcium to interact with oxalate
or phosphate

21. PHYSICOCHEMISTRY
2- It directly inhibits the spontaneous precipitation of calcium
oxalate and prevents the agglomeration of calcium oxalate
crystals.
it has limited inhibitory effect on calcium oxalate crystal growth ,
more potent activity in reducing calcium phosphate growth.
3- citrate prevents heterogeneous nucleation of calcium oxalate
by monosodium urate .

22. PHYSICOCHEMISTRY
Magnesium:.
Its complexe with oxalate, which reduces ionic oxalate
concentration and calcium oxalate supersaturation. In
addition, magnesium reduces the rate of calcium oxalate
crystal growth in vitro.
Inorganic pyrophosphate:.
responsible for 25% to 50% of the inhibitory activity of
whole urine against calcium phosphate crystallization.

23. PHYSICOCHEMISTRY
 Two urinary glycoproteins, nephrocalcin and Tamm-
Horsfall glycoprotein, are potent inhibitors of calcium
oxalate monohydrate crystal aggregation .
1-Nephrocalcin is an acidic glycoprotein containing
predominantly acidic amino acids that is synthesized in
the proximal renal tubules and the thick ascending limb.
In simple solution, nephrocalcin strongly inhibits the
growth of calcium oxalate monohydrate crystals .

24. PHYSICOCHEMISTRY
2. Tamm-Horsfall glycoprotein:
. syn - thick ascending limb & distal tubule
. inhibits aggregation CaOx- most potent
. Under specific condition, THP can promote
aggregation (high ionic strength, high calcium and
low pH)
. Citrate can increase THP and its inhibitory effect

25. PHYSICOCHEMISTRY
 3. Osteopontin (uropontin):
o Osteopontin has been shown to inhibit nucleation,
growth, and aggregation of calcium oxalate crystals
as well as to reduce binding of crystals to renal
epithelial cells in vitro

26. PHYSICOCHEMISTRY
Matrix:
o Renal calculi consist of both crystalline and
noncrystalline components.
o The noncrystalline component is termed
matrix, which typically accounts for about
2.5% of the weight of the stone In some
cases reached up to 65%.

27. PHYSICOCHEMISTRY
 chemical analysis reveals a heterogeneous mixture
consisting of 65% protein, 9% non-amino sugars, 5%
glucosamine, 10% bound water, and 12% organic ash .
 Non–urease-producing bacteria such as E. coli may play
a role in stone formation by increasing the production of
urinary matrix substances, thereby increasing crystal
adherence to the renal epithelium.

28. Key Points: Physicochemistry
 Urine must be supersaturated for stones to form.
 Supersaturation alone is not sufficient for crystallization to occur in
urine, owing to the presence of urinary inhibitors.
 Nephrocalcin, uropontin, and Tamm-Horsfall protein are important
inhibitors of crystal nucleation, growth, or aggregation.
 Urinary calcium and oxalate are equal contributors to urinary
saturation of calcium oxalate.
 Common calcium stones may originate from subepithelial plaques
composed of calcium apatite that serve as an anchor on which calcium
oxalate stones can grow.

29. THANK YOU