Urolithiasis refers to kidney stone formation. The lifetime prevalence of kidney stones is 1-15%, with peak prevalence occurring in adults aged 60-69 years old. Males are more affected than females. Risk factors include age, gender, geography, climate, occupation, obesity, and medical conditions like diabetes. Stone formation occurs through a process where urine becomes supersaturated, crystals nucleate, aggregate, and are retained in the kidneys. The balance between substances that promote or inhibit crystallization and stone growth determine whether stones will form.

1. Urolithiasis
Epidemiology
&
Pathogenesis
Presenter:
Rojan Adhikari
FCPS II Urology Resident
SDNTC

3. History
• First known stone: – 6.5 cm bladder stone
consisted of Calcium Phosphate and Uric
acid.
• Carbon-dated 4800 B.C., it was found in
1901 in a child’s mummy at a grave site in
El Amrah, Upper Egypt. Calcium Oxalate Monohydrate
(Mummy Stone)

4. Sushruta Samhita
• Stone surgery was done in Vedic
times and this the first record of
stone surgery
• Described varieties of stones, and
signs and symptoms
Sushruta Samhita (सुश्रुतसंहिता) 800 BCE

5. Epidemiology of calculi
• Life time prevalence: 1%-15% 1
• Around the world prevalence rates varies ranging from 7% to 13% in
North America, 5% to 9% in Europe, and 1% to 5% in Asia 1
• Prevalence of stone disease overall was 7.4% (5.8% in women and
9.0% in men), with an overall peak prevalence of 19.4% in 60- to 69-
year-old adults 2
(1. Sorokin et al., 2017)
(2. Huang et al., 2013)

6. Gender
• males > women , 2.43 : 1 1, 2
1. Pearle et al., 2005
2. Walker et al. (2013)

7. •Race/Ethnicity
• Prevalence by Race is highest among white males>
Hispanics> Asians> African-Americans
Soucie et al. (1994)

8. Age
• uncommon < 20 years old 1
• peak incidence: 4th to 6th decade oflife 2
• In women, bimodal distribution of stone disease occurs
• 2nd peak occurs on the 5 - 6th decade corresponding to the
onset of menopause 3 1. Bonzo and Tasian, 2017)
2. Lieske et al. (2006)
3. Nordin et al., 1999

9. Geography
• Higher prevalence of stone disease is found in hot, arid,
or dry climates such as the mountains, desert, or
tropical areas.

11. Climate
• Seasonal variation in stone disease is likely related to
temperature by way of fluid losses from perspiration
& sunlight induced increases in vitamin D
• Those exposed to high temperatures exhibited
1. lower urine volumes and pH,
2. higher uric acid levels
3. higher urine specific gravity
leading to higher urinary saturation of uric acid

12. Occupation
Occupational risk factors:
• heat exposure
• Dehydration
Occupations associated with increase risk:
• cooks
• engineering personnel
• steel workers
• farmers
Occupations that limit bathroom access, such as taxi
drivers and operating room personnel, have been
shown to have an increased risk of stones
(Linder et al., 2013; Mass et al., 2014)

13. Obesity, Diabetes, and Metabolic Syndrome
• Higher BMI leads to excretion of urinary oxalate,
uric acid, sodium, and phosphorus than those with
lower BMI 1
• obesity and calcium oxalate stone-- due to
increased excretion of promoters of stone
formation 2
• obesity and uric acid stone formation is primarily
influenced by urinary pH. 2
1. Taylor and Curhan, 2006
2. Negri et al., 2007

14. Robertson et al. (1980)

15. Water
• water intake is inversely related to
kidney stone formation 1
• geographical differences on incidence
of stone disease have been associated
to the difference in the mineral &
electrolyte content of water
1. Curhan et al., 1993, 1997

16. Hypertension
• Increased dietary intake of substances associated with both
hypertension and stone disease, including calcium, sodium, and
potassium.
• Observed higher urinary calcium, uric acid, and oxalate and
supersaturation of calcium oxalate in men and women with
hypertension compared to normotensive individuals. 1
• Dyslipidemia has been associated with alterations in urine chemistry
that can predispose to kidney stone formation 2
1. Borghi et al. (1999)
2. Torricelli et al., 2014

17. Pathophysiology
• stone formation is a cascade of events that occurs as the glomerular filtrate
traverses the nephron
Campbell and Walsh Urology 121h edition

18. State of Saturation
• A solution containing ions or molecules of a sparingly soluble salt is described
by the concentration product, which is a mathematic expression of the
product of the concentrations of the pure chemical components (ions or
molecules) of the salt.
• The concentration product at the point of saturation is called the
thermodynamic solubility product (Ksp), which is the point at which the
dissolved and crystalline components are in equilibrium for a specific set of
conditions.
Campbell and Walsh Urology 121h edition

19. • 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.
• As concentrations of the salt increase further, the point at which it
can no longer be held in solution is reached and crystals form.
• The concentration product at this point is called the formation
product (Kf).
Campbell and Walsh Urology 121h edition

20. undersaturation
Campbell and Walsh Urology 121h edition
metastable
unstable

21. Nucleation and Crystal Growth, Aggregation,
and Retention
• In normal human urine, the concentration of calcium oxalate is four
times higher than its solubility in water.
• Once the concentration product of calcium oxalate exceeds the
solubility product, crystallization can potentially occur.
• However, in the presence of urinary inhibitors and other substances,
calcium oxalate precipitation occurs only when supersaturation
exceeds solubility by 7 to 11 times.
Campbell and Walsh Urology 121h edition

22. • Within the timeframe of transit of urine through the nephron,
estimated at 5 to 7 minutes, crystals cannot grow to reach a size
sufficient to occlude the tubular lumen.
• However, if enough nuclei form and grow, aggregation of the crystals
will form larger particles within minutes that can occlude the tubular
lumen.
• Inhibitors can prevent the process of crystal growth or aggregation.
Campbell and Walsh Urology 121h edition

23. Pathogenesis: Nucleation
 Homogeneous nucleation: the spontaneous formation of crystals
 Heterogeneous nucleation: the process of forming crystals into pre-
existing surfaces
• Metastable solutions form crystals by heterogeneous nucleation
• Since the normal urine sample is a metastable solution, it is easier for
heterogeneous nucleation to occur
Campbell and Walsh Urology 121h edition

24. Pathogenesis: Nucleation
Randall plaque helps facilitate heterogeneous nucleation
• the plaque can be found in the interstitium, at the level of the papilla
• When it expands into the urinary space, it facilitates heterogeneous
nucleation by acting as a pre-existing surface
Khan et al., 2012

25. Some studies suggest that crystals cannot form in the lumen without an
anchor
• It is thought that the transit time through the nephron and urothelial
space is too short for crystals to form without an anchor point
• one such anchor point would be the Randall plaque, this is known as
the Fixed Particle Theory . However, not all stone formers have a
Randall plaque
• In these cases, it is theorized that the epithelial cells adhere to or
uptake the crystal to form an anchor point for nucleation and growth
Campbell and Walsh Urology 121h edition

26. • Evan and colleagues presented an alternative view of the pathogenesis of
stone formation on the basis of extensive analysis of papillary plaques
derived from biopsies obtained during percutaneous nephrolithotomy in
idiopathic calcium oxalate stone formers.
• 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
Evan et al., 2003, 2005

27. `
• 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.
• The origin of the crystals that initiate the plaque at the
basement membrane of the thin loop of Henle is unclear;
however, they do not appear to come from the renal tubular
cells or lumen.

28. • Another intriguing but unproven hypothesis for the origin of
the calcium phosphate crystal involves
• calcifying nanoparticles (CNPs), aka nanobacteria,
• which have been implicated in other types of pathologic
calcifications such as atherosclerotic plaques
Shiekh et al., 2009

29. Inhibitors Promoters
Inorganic pyrophosphate Calcium
Citrate Oxalate
inhibitory activity of magnesium Urate
Polyanion macromolecules, including
glycosaminoglycans,
mucopolysaccharides
Cystine
Two urinary glycoproteins, nephrocalcin
and Tamm- Horsfall glycoprotein
Low urinary pH
Urinary prothrombin fragment 1 (F1) Low urine volume and flow
inter-α-trypsin Bacterial products

30. In Conclusion
• Life time prevalence of urolithiasis : 1%-15%
• Man affected more than women
• Gender, age, ethnicity, geography, climate, occupation,
Obesity, Diabetes, and Metabolic Syndrome, water are the
etiological factors

31. • Urine saturation --- Supersaturation --- Crystal nucleation ---
Aggreation --- Retension and growth
• Stone formation is a play between solubility product and ion
formation product in urine
• Promoters of stone formation facilitate stone formation whilst
inhibitors prevent it.

32. Thank you