The document discusses the etiopathogenesis of urolithiasis or kidney stone formation. It covers topics like epidemiology, risk factors related to gender, age, geography, occupation and diet. It then describes the pathophysiological processes involved - supersaturation of urine, crystal nucleation, growth and aggregation. It discusses theories around crystal fixation and Randall's plaques. Various inhibitors that prevent stone formation are also outlined. The role of the non-crystalline matrix component of stones is briefly mentioned.

1. ETIOPATHOGENESIS OF
UROLITHIASIS
Dept of Urology
Govt RoyapettahHospital and KilpaukMedicalCollege
Chennai

2. Moderators:
Professors:
 Prof. Dr. G. Sivasankar, M.S., M.Ch.,
 Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
 Dr. J. Sivabalan, M.S., M.Ch.,
 Dr. R. Bhargavi, M.S., M.Ch.,
 Dr. S. Raju, M.S., M.Ch.,
 Dr. K. Muthurathinam, M.S., M.Ch.,
 Dr. D.Tamilselvan, M.S., M.Ch.,
 Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC,Chennai. 2

3. Epidemiology
 Site – migrated from lower to upper urinary
tract
 Gender gap narrowing
 Rise in incidence – rise in the detection of
asymptomaticcalculithrough increased
radiographic imaging
 The incidence of symptomatic stones did not
increase significantly
3
Dept of Urology, GRH and KMC,Chennai.

4. Gender & Age
 Uncommon before 20 years
 Peak – 4th to 6th decade
 Women – bimodaldistribution
 30-39years & 60-69 years
 Second peak corresponding to the onset of
menopause
 Estrogen influence
 Protective against stone formation
 Enhanced renal calcium absorption & reduced
bone resorption
4
Dept of Urology, GRH and KMC,Chennai.

5. GEOGRAPHY
 Geography - hot, arid, dry climates
 Climate & Seasonal variation
 Summer (July to September)
 High temperature & Sunlight induced increase in
vitamin D
 Peak occuring within 1 to 2 months of maximal
mean temperature.
 Temperature dependence – primarily attributed to
effect on men likely due to differential sunlight
exposure, occupation, and hydration status.
5
Dept of Urology, GRH and KMC,Chennai.

6. Occupation
 Risk factors - Heat exposure & Dehydration
 Occupation – Cooks, Engineering room personnel,
Steel workers, Glass plant workers
 Exposure to higher temperature Higher incidence
of low urine volume, low pH, higher uric acid levels,
higher urine specific gravity and hypocitraturia 
higher urinary saturation of uric acid. (High incidence
of uric acid stones)
 Sedentary occupations – increased risk reflective of
more indulgent diet and lifestyle
6
Dept of Urology, GRH and KMC,Chennai.

7. Diet & Metabolic association
 Decreased risk
 High fluid intake
 Low protein intake
 Increased risk
 Obesity
 Metabolic syndrome (hyperlipidemia,
hypertriglyceridemia,hyperglycemia, and/or
hypertension)
 Type 2 Diabetes mellitus – higher urinary oxalate
and lower urine pH
7
Dept of Urology, GRH and KMC,Chennai.

8.  Exact pathophysiologicmechanism – not completely
elucidated.
 Most probably – Metabolic state of Insulin resistance
 Higher BMI
 Excreted more urinary oxalate, uric acid, sodiumand
phosphorous.
 Urinary supersaturationof uric acid inreased with BMI
 Association of obesity & calcium oxalate - primarily
due to increased excretion of promoters of stone
formation.
 Association of obesity & Uric acid – primarily
influenced by urinary pH
8
Dept of Urology, GRH and KMC,Chennai.

9. Pathogenesis
Supersaturation of urine with
stone forming salts
Crystal / nuclei formation
Anchoring of crystals and
aggregation
Stone formation
9
Dept of Urology, GRH and KMC,Chennai.

10. State of Saturation
 Saturated solution
 Pure aqueous solution when it reaches the point at
which no further added salt crystals will dissolve
 Solubility Product
 Concentration product at the point of saturation
 The point at which dissolved and crystalline
components are in equilibrium for a specific set of
conditions.
 Formation product
 As the concentration product increase, the point at
which the solution can be no longer be held in solution
and crystals form
10
Dept of Urology, GRH and KMC,Chennai.

11. States Of Saturation In
Urine
 Undersaturated
 Below the solubility product – crystal will not form
 Metastable
 Between the solubility product & formation product
 Spontaneous nucleation or precipitation does not
occur despite urine is supersaturated
 It is in this area modulation of factors controlling stone
formation can take place and therapeutic intervention
is directed
 Unstable
 At concentrations above formation product – crystals
will form
11
Dept of Urology, GRH and KMC,Chennai.

12. States of Saturation
12
Dept of Urology, GRH and KMC,Chennai.

13. Nucleation & Crystal Growth,
Aggregation & Retention
13
Dept of Urology, GRH and KMC,Chennai.

14. Crystal Nucleation
 Homogenous Nucleation
 Nuclei form in pure solution
 Heterogenous Nucleation
 Nuclei formation by adsorption onto existing
surfaces of epithelial cells, cell debris or other
crystals
14
Dept of Urology, GRH and KMC,Chennai.

15.  Within the timeframe of transit of urine
throughthe nephron, estimated at 5 to 7
minutes, crystal cannot grow to reach a size
sufficient to occludethe tubularlumen
 In the presence of urinary inhibitors , calcium
oxalate precipitation occursonly when
supersaturation exceed solubility by 7 to 11
times
15
Dept of Urology, GRH and KMC,Chennai.

16. Stone growth Theories
 Free particle growth theory
 Recent studies – free crystalline particles can be
formed that are large enough to be retained during
normal transit time through the kidney
 Findings based on recalculation using current nephron
dimensions, supersaturation and crystal growth rates
 Fixed particle growth theory
 Anchoring site to which crystals bind  prolongs the
time the crystals are exposed to supersaturated urine
 crystal aggregation & growth
16
Dept of Urology, GRH and KMC,Chennai.

17. Crystal Fixation
 Oxalate induced injury to renal tubular epithelial
cells mediated by reactive oxygen species–
adherence of calcium oxalate crystals
 Role of antioxidants
 Neutralises cytotoxicity & allow retention of renal cell
integrity (N-acetyl cysteine)
 Lower levels of serum antioxidants (α-carotene, β-
carotene, β-cryptoxanthin) – increased risk
 Oxidative stress implicated in – diabetes, metabolic
syndrome, coronary heart disease
 Gender disparity – differential antioxidant production
associated with testosterone and estradiol
 Increase testosterone  increased oxidative stress &
stones
 Increased estradiol  suppressed both
17
Dept of Urology, GRH and KMC,Chennai.

18.  Crystal bind preferentially to regenerating /
redifferentiatingrenal tubularcells
 Mediated by – luminal membrane molecules
 Hyaluronic acid
 Osteopontin
 Annexin II
 Nucleolin related protein
18
Dept of Urology, GRH and KMC,Chennai.

19. Randall Plaques
 Randall (1937) first observed areas of damage
associated with subepithelial plaques on the
renal papillae
 Initiating event – vascular injury to the vasa
recta near the renal papilla
 Repair of damaged vessel wall 
atheroscleroticlike reaction  calcification of
endothelial wall  erosion into papillary
interstitiumand then into collectingducts 
serves as nidus for stone formation
19
Dept of Urology, GRH and KMC,Chennai.

20. Structure
 Crystal component – calciumapatite
 Deposits consisted of individual laminated
particles with mineral and organic layers
 All crystals were coated with organic material
 Osteopontin was identified on the outer
surface of the crystal at the junction of
overlying organic molecularlayer.
20
Dept of Urology, GRH and KMC,Chennai.

21. Crystal growth
 High concentrations of calcium oxalate induces local
inflammation that triggers phenotypic diiferentiation of
tubular epithelial cells into mesenchymal cells with
osteogenic activity
 Bone osteoid proteins – osteopontin & osteocalcin found in
the plaques
 The volume of papillary surface covered by plaque was
shown to correlate negatively with urine volume and
positively with hypercalciuria
 Growth on plaque is the primary mechanism of stone
growth
21
Dept of Urology, GRH and KMC,Chennai.

22. Calcifying Nanoparticle
(CNPs)
 Self propagating particles that precipitate
calciumapatite on their exterior membrane
 Have been detected in blood, blood
products,renal stones as well as in pathologic
calcifications
 Promote rapid precipitationof calcium
phosphate from bloodunder physiologically
unfavorableconditions
22
Dept of Urology, GRH and KMC,Chennai.

23.  Enteric hyperoxaluria
 No plaque
 Apatite crystal deposits plugging inner medullary collecting
duct lumens, along with associated epithelialcell damage
with interstitial inflammationand fibrosis
 Brushite stone formers
 Intermediate pathology
 Interstitial apatite plaque and apatite crystal plugging of
inner medullary and terminal collecting ducts along with
associatedcollecting duct injury and interstitial fibrosis.
 Distal RTA
 Extensive renal calcifications
 Papillary changes – minimal to papillae pitted and
contained calcium phosphate plugs protruding from dilated
collecting ducts with extensive surrounding fibrosis
 Randall plaques were rarely encountered
23
Dept of Urology, GRH and KMC,Chennai.

24.  Cystinuria
 Plugging of terminal collecting ducts of Bellini
with masses of cystine crystals; apatite deposits
were also identified in the inner medullary
collecting ducts and in the thin ascending limbs of
the loops of Henle
 Primary hyperparathyroidism
 Similar to brushite stone formers with interstitial
deposits of plaque and associated stone
overgrowth traditionally seen with idiopathic
calcium oxalate stone formers.
24
Dept of Urology, GRH and KMC,Chennai.

25. Inhibitors
 Molecules that raise the level of
supersaturation needed to initiate crystal
nucleationor reduce the rate of crystal
growth or aggregation & prevent stone
formation from occurringon a routine basis.
 No specific inhibitors for uric acid
crystallisation
25
Dept of Urology, GRH and KMC,Chennai.

26. Inhibitors
 Inorganic Pyrophosphate
 Citrate, magnesium
 Polyanion macromolecules – glycosaminoglycans,
acid mucopolysaccharides, RNA
 Urinary glycoproteins – Nephrocalcin,Tamm-
Horsfall protein
 Osteopontin / Uropontin
 Urinary porthrombin fragment 1 (UF1)
 Bikunin of inter-α-trypsin
26
Dept of Urology, GRH and KMC,Chennai.

27. Citrate
 Reduces the availability of ionic calciumto
interact with oxalate or phosphate
 Inhibits the spontaneous precipitation of
calciumoxalate
 Prevents crystal aggregation
 Prevents heterogenous nucleationof calcium
oxalate by monosodiumurate
27
Dept of Urology, GRH and KMC,Chennai.

28. Magnesium
 It form complexationwith oxalate  reduces
ionic oxalate concentration and calcium
oxalate supersaturation
 Reduces the contact time between calcium
and oxalate moleculesin vitro
 Pyrophosphate,citrate, magnesium – inhibit
crystal growth
 High concentration of magnesium &
pyrophosphate– inhibit aggregation
28
Dept of Urology, GRH and KMC,Chennai.

29. Polyanion macromolecules
 Bonds with surface calciumions and inhibits
crystal nucleation and growth
 Most prominent glycosaminoglycanin
human urine – chondroitinsulfate
 Heparin sulfate interacts most strongly with
calciumoxalate monohydratecrystals
29
Dept of Urology, GRH and KMC,Chennai.

30. Nephrocalcin
 Acidic glycoprotein containing predominantly acidic
amino acids that is synthesized in the proximal renal
tubules and thick ascending limb
 Inhibits growth , nucleation and aggregation
 Four isoforms
 Non stone formers – excrete greater quantities of 2
isoforms with most inhibitory activity
 Isoforms with inhibitory activity were found to
contain γ-carboxyglutamic acid residues that were
lacking in the isoforms of stone formers
30
Dept of Urology, GRH and KMC,Chennai.

31. Tamm Horsfall protein
 Expressed by renal epithelial cells in the thick
ascending limb and the distal convoluted tubule
as a membrane anchored protein
 Released into the urine after cleavage of the
anchoring site by phopholipases or proteases.
 Potent inhibitor of calcium oxalate monohydrate
crystal aggregation, but not growth.
 Function varies
 Alkaline urine – inhibitor
 Acidic urine – polymerizes into a configuration that
promotes crystal aggregation.
31
Dept of Urology, GRH and KMC,Chennai.

32. Osteopontin or Uropontin
 Acidic phosphorylatedglycoprotein
 Expressed in bone matrix and renal epithelial
cells of the ascending limb of loop of Henle
and the distal tubule.
 Inhibit nucleation,growth, and aggregation
of calcium oxalate crystals, as well as to
reduce binding of crystals to renal epithelial
cells in vitro
 May work in conjunction with constitutively
expressedTamm-Horsfallprotein
32
Dept of Urology, GRH and KMC,Chennai.

33. Urinary Prothrombin Fragment 1
(F1)
 Crystal matrix protein
 Named for its resemblance to the F1
degradation productof prothrombin
 Inhibits crystal aggregation and deposition
33
Dept of Urology, GRH and KMC,Chennai.

34. Bikunin
 Comprises the light chain of inter-α-trypsin, a
glycoproteinsynthesized in liver
 Inhibitor of calcium oxalatecrystallisation,
aggregation and growth
34
Dept of Urology, GRH and KMC,Chennai.

35. MATRIX
 The noncrystalline component of renal calculi
 Accounts for about 2.5% of the weight of the
stone.
 In some, matrix comprises the majority – usually
in association with chronic UTIs
 Heterogenous mixture
 Protein – 65%
 Non amino sugars – 9%
 Glucosamine – 5%
 Bound water – 10%
 Organic ash – 12%
35
Dept of Urology, GRH and KMC,Chennai.

36.  Proteins –Tamm-Horsfall, neprhocalcin, renal
lithostathine, albumin, glycosaminoglycans,
mucoprotein matrix substance A
 Substance A is immunologically unique and
present in the matrix component of all stone
formers
 Inflammatory proteins – immunoglobulins,
defensin-3, clusterin, complement C3a,
kininogen and fibrinogen; comprises the
predominant protein in calcium oxalate and
phosphate stones
 Exact role of matrix yet to be elucidatied.
36
Dept of Urology, GRH and KMC,Chennai.

37. Summary
 Urine must be supersaturated for stones to
form
 Supersaturationalone is insufficientowing to
the presence of urinary inhibitors
 Nucleation in stone formation is
heterogenous
 Subepithelial plaques serve as an anchor on
which calcium oxalate aggregate and stone
growth occurs
 Noncrystalline component is matrix
37
Dept of Urology, GRH and KMC,Chennai.

38. 38
Dept of Urology, GRH and KMC,Chennai.