Urolithiasis epidemology and pathogenesis

urolithiasis

1. U r o lithiasis Epidemiology & Pathogenesis Presenter: Rojan Adhikari FCPS II Urology Resident SDNTC

2. 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)

3. 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

4. E pidemiology of calculi Life time prevalence: 1%- 1 5% 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)

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

6. Race/Ethnicity P revalence by Race is highest among white males> Hispanics> Asians> African-Americans Soucie et al. (1994)

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

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

9. Climate S easonal 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

10. Occupation O ccupational risk factors: heat exposure D ehydration O ccupations 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)

11. 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

12. Robertson et al. (1980)

13. 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

14. 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

15. Pathophysiology stone formation is a cascade of events that occurs as the glomerular filtrate traverses the nephron Campbell and Walsh Urology 12 1h edition

16. 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 12 1h edition

17. 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 12 1h edition

18. undersaturation Campbell and Walsh Urology 12 1h edition metastable unstable

19. 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 12 1h edition

20.  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 12 1h edition

21. 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 12 1h edition

22. 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

23. 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 12 1h edition

24. 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

25. ` 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.

26. 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

27. 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

28. 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

29. 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.

30. Thank you