1. New Insight of Stone Pathogenesis SOETOJO 1

2. Introduction In US (2000), urinary stones insidens 116 for 100000 population 10% men and 5% women will got urinary stone disease at their life Lifetime chance 12% Incidence doubled since 1970s due to obesity 50% recurrence risk 2nd most income for Urologist Carol Peckham, Urologist Compensation Report, 2014 2

3. Knowing the etiology Knowing pathogenesisKnowing modifiable risk factor Continuing evaluation ReccuranceRate 3

4. Etiology Multi factorial disease Sex  Male vs Female ‘genetics’ Geography Sedentary and ‘life style’ Abnormality in urinary tract  congenital vs acquired 4

5. New Insight of Stone Pathogenesis PHYSIOCHEMICAL ASPECTS OF URINARY STONE FORMATIONVASCULAR DISEASE ASSOCIATIONS WITH UROLITHIASISOBESITY, DIABETES, AND URINARY STONE DISEASEDYSLIPIDEMIA AND URINARY STONE DISEASETHE METABOLIC SYNDROME AND UNIFICATION OF THE METABOLIC LINKS TO URINARY STONE DISEASEHEAVY METALS AND URINARY STONE DISEASEGENETIC LINKS TO URINARY STONE DISEASE Herman Singh Bagga, MD, Thomas Chi, MD, Joe Miller, MD, and Marshall L. Stoller, MD. New Insights Into the Pathogenesis of Renal Calculi. Urol Clin North Am. 2013 February ; 40(1): 1–12. 5

6. Physiochemical Aspects of Urinary Stone Formation  Urolithiasis is the physiochemical formation of urinary stones.  As the glomerular filtrate  the urine concentrated with stone- forming salts  supersaturated  crystals  An estimated transit time at nephron of 5 to 7 minutes  did not allow sufficient time for free particles to aggregate  Occlude in tubular lumen  site of stone formation  Some adhesion to tubular epithelial cells as fixed particles  crystal growth and subsequent stone formation.  Intraluminal deposits, mostly within the distal nephron, could serve as sites of stone formation. Stoller, ML.; Meng, MV. Urinary stone disease. Totowa (NJ): Humana Press; 2007. Finlayson B, Reid F. The expectation of free and fixed particles in urinary stone disease. Invest Urol. 1978; 15:442–448. Kok DJ, Khan SR. Calcium oxalate nephrolithiasis, a free or fixed particle disease. Kidney Int. 1994; 46:847–854. 6

7. Histopathologic evidence of plugs of mineral deposits in distal nephron in brushite stones, hyperparathyroidism, cystinuria, distal renal tubular acidosis, Patients with a history of intestinal surgery, including bypass surgery for obesity, small bowel resection, and ileostomy creation Evan AP, Unwin RJ, Williams JC Jr. Renal stone disease: a commentary on the nature and significance of Randall’s plaque. Nephron Physiol. 2010; 119:49–53. Coe FL, Evan AP, Lingeman JE, et al. Plaque and deposits in nine human stone diseases. Urol Res.2010; 38:239–247. 7

8. Vascular Disease Associations with Urolithiasis The association between nephrolithiasis-subclinical atherosclerosis  Coronary Adult Risk Development in Young Adults (CARDIA) cohort study  a significant association kidney stones and carotid artery atherosclerosis  odds ratio [OR], 1.6. Patients with a history of nephrolithiasis have an increased relative risk (RR) of MI (RR, 1.78) and angina (RR, 1.63). Nephrolithiasis has been associated with a 31% increased risk of myocardial infarction (MI) Eisner BH, Cooperberg MR, Kahn AJ, et al. Nephrolithiasis and the risk of heart disease in older women. J Urol. 2009; 181:517–518. Reiner AP, Kahn A, Eisner BH, et al. Kidney stones and subclinical atherosclerosis in young adults: the CARDIA study. J Urol. 2011; 185:920–925. 8

9. Vascular Disease Associations with Urolithiasis (Hypertension) Hypertensive people  increased parathyroid gland activity, urinary cyclic AMP, and intestinal calcium absorption. Increased levels of urinary uric acid and decreased levels of urinary citrate Cappuccio and colleagues  RR of 1.96 for the development of kidney stones in hypertensive men compared with normotensive men at 8 years. Borghi and colleagues  OR of 5.5 hypertension to the formation of a kidney stone at 5 years of follow-up. This risk seemed particularly pronounced for individuals who were overweight. Madore and colleagues  a cohort of more than 50,000 men,  an association between nephrolithiasis and risk of hypertension (OR, 1.31), men who had both disorders, 79.5% experienced the occurrence of nephrolithiasis before or concomitant to their diagnosis of hypertension Cappuccio FP, Siani A, Barba G, et al. A prospective study of hypertension and the incidence of kidney stones in men. J Hypertens. 1999; 17:1017–1022. Borghi L, Meschi T, Guerra A, et al. Essential arterial hypertension and stone disease. Kidney Int. 1999; 55:2397–2406. Madore F, Stampfer MJ, Rimm EB, et al. Nephrolithiasis and risk of hypertension. Am J Hypertens. 1998; 11:46–53. 9

10. Obesity, Diabetes, and Urinary Stone Disease Taylor and colleagues, in an analysis of 3 large prospective cohorts of nearly 250,000 individuals RR of incident kidney stone  weighing more than 100 kg, compared with those weighing less than 68.2 kg  was 1.44 in men, 1.89 in older women,1.92 in younger women. sing a BMI cutoff of 30, the RRs were 1.33, 1.90, and 2.09, respectively. Taylor and Curhan In nonobese patients (BMI <30), an increasing BMI lent itself to a higher risk of urolithiasis. Most significant in women, BMI of 23 to 24.9 had a 25% increased incidence of stones compared a BMI of 21 to 22.9. BMI of 27.5 to 29.9 had a 65% to 75% increased incidence. Similar results were seen in men, a BMI of 25 to 29.9 had a 15% to 25% increase in stone incidence compared BMI of 21 to 22.9. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005; 293:455–462. Taylor EN, Curhan GC. Body size and 24-hour urine composition. Am J Kidney Dis. 2006; 48:905–915. 10

11. Obesity, Diabetes, and Urinary Stone Disease Urinary composition in the obese population seems to contain higher levels of substances known to precipitate urinary stones compared with the nonobese population (oxalat, calcium, uric acid, phosphate, sodium, sulfate, and cysteine) Ekeruo WO, Tan YH, Young MD, et al. Metabolic risk factors and the impact of medical therapy on the management of nephrolithiasis in obese patients. J Urol. 2004; 172:159–163. Powell CR, Stoller ML, Schwartz BF, et al. Impact of body weight on urinary electrolytes in urinary stone formers. Urology. 2000; 55:825–830. 11

12. Obesity, Diabetes, and Urinary Stone Disease Decreased function of interstitial cells and neural tissue within the urothelial tissue of diabetic rabbits  affect ureteral peristalsis and promote urinary stone formation by virtue of urinary stasis. Insulin resistance has been noted to impair renal ammoniagenesis,  acidic urine  promotes reabsorption of uric acid in the proximal tubule  hyper-uricemia  uric acid urolithiasis Hyperglycemia  increased urinary calcium and oxalate excretion These metabolic changes may explain the consistent association seen between diabetes and urinary stone disease. Chung SD, Chen YK, Lin HC. Increased risk of diabetes in patients with urinary calculi: a 5-year followup study. J Urol. 2011; 186:1888–1893. Daudon M, Traxer O, Conort P, et al. Type 2 diabetes increases the risk for uric acid stones. J Am Soc Nephrol. 2006; 17:2026–2033. Canda AE. Re: Increased risk of diabetes in patients with urinary calculi: a 5-year followup study: S.-D. Chung, Y.-K. Chen and H.-C. Lin J Urol 2011; 186: 1888–1893. J Urol. 2012; 187:2279–2280. 12

13. Dyslipidemia and Urinary Stone Disease 600 endourologic stone  >30% of characterized as dyslipidemic (defined by the use of a cholesterol- lowering medication). 70% had calcium oxalate stones 15% had uric acid stones. Kadlec reported total cholesterol levels in stone former > total cholesterol in normal people, association noted for calcium oxalate and uric acid stone formers. Inci and colleagues found that Kadlec AO, Greco K, Fridirici ZC, et al. Metabolic syndrome and urinary stone composition: what factors matter most? Urology. 2012; 80(4):805–810. Inci M, Demirtas A, Sarli B, et al. Association between body mass index, lipid profiles, and types of urinary stones. Ren Fail. 2012; 34(9):1140–1143. 13

14. Dyslipidemia and Urinary Stone Disease Tsujihata reported atorvastatin to stone-forming rats significantly lowered crystalline deposits on kidney anti-inflammatory and antioxidative effects of the drug were responsible, through preventing renal tubular cell injury from oxalate and subsequently inhibiting renal crystal retention. Tsujihata M, Momohara C, Yoshioka I, et al. Atorvastatin inhibits renal crystal retention in a rat stone forming model. J Urol. 2008; 180:2212–2217. Tsujihata M, Yoshioka I, Tsujimura A, et al. Why does atorvastatin inhibit renal crystal retention? Urol Res. 2011; 39:379–383. 14

15. The Metabolic Syndrome and Unification of The Metabolic Links To Urinary Stone Disease link the components of the metabolic syndrome with urinary stone disease Systemic malfunction of inflammation and tissue damage as an underlying mechanism Vascular theory Prevalence of kidney stones increased with the number of traits, from 3% with 0 traits to 9.8% with 5 traits. The presence of 2 or more traits significantly increased the odds of stone disease, and 4 or more traits was associated with an approximate 2- fold increase. West and colleagues West B, Luke A, Durazo-Arvizu RA, et al. Metabolic syndrome and self-reported history of kidney stones: the National Health and Nutrition Examination Survey (NHANES III) 1988–1994. Am J Kidney Dis. 2008; 51:741–747. Jeong IG, Kang T, Bang JK, et al. Association between metabolic syndrome and the presence of kidney stones in a screened population. Am J Kidney Dis. 2011; 58:383–388. 15

16. The Metabolic Syndrome and Unification of The Metabolic Links To Urinary Stone Disease Rendina and colleagues 2-fold increase in the risk of stone disease for patients with metabolic syndrome. the only syndrome trait independently associated  hypertension with an OR of 2.1 for men and 4.9 for women. hypertension + other trait of metabolic syndrome further increased the risk of urolithiasis, n OR of 2.2 compared with with hypertension alone. Rendina D, Mossetti G, De Filippo G, et al. Association between metabolic syndrome and nephrolithiasis in an inpatient population in southern Italy: role of gender, hypertension and abdominal obesity. Nephrol Dial Transplant. 2009; 24:900–906. 16

17. Heavy Metals and Urinary Stone Disease Calcium based stone  predominant nidus from calcium hydroxyapatite A recent study has found that other heavy metal compounds may act comparably. Strontium is a heavy metal same metabolic process as calcium  intestinal absorption and renal filtration has been observed to substitute for calcium during the process of bio-mineralization in bone studies, incorporating into hydroxyapatite in bones through replacing a proportion of the calcium ions. Hypercalciuric stone formers were noted to have increased strontium absorption compared with normocalciuric Using synchrotron radiation imaging on human stone samples  80% of strontium in these stones as strontium apatite and 20% as strontium carbonate strontium hydroxyapatite can be a nidus for calcium-based stone formation  potentially valuable marker to study calcium-based stone pathogenesis. Vezzoli G, Baragetti I, Zerbi S, et al. Strontium absorption and excretion in normocalciuric subjects: relation to calcium metabolism. Clin Chem. 1998; 44(3):586–590. Blaschko SD, Miller J, Chi T, et al. Micro-composition of human urinary calculi using advanced imaging techniques. J Urol. 2012 17

18. Genetic Links to Urinary Stone Disease Genetic links to urolithiasis have been long established in certain heritable disorders primary hyperoxaluria and the AGXT gene cystinuria and the SLC3A1 and SLC7A9 genes xanthinuria and the XDH gene. calcium-sensing receptor (CASR) protein inhibits calcium absorption in the ascending limb in response to increased interstitial calcium Polymorphisms of the osteopontine (OPN) gene  urinary crystallization inhibitor  calcium urolithaisis vitamin D receptor (VDR), and the claudin family of genes (particularly CLDN14) polymorphisms  increase calciuria Etc... 18

19. Genetic Links to Urinary Stone Disease calcium-based and other urinary stone disease  not singgle but result from many genetic polymorphisms  increased individual susceptibility to stone formation. The identification of a limited set of common genetic defects that contribute to a large proportion of stone disease remains elusive, most likely because of the contributions of diet, obesity, and other environmental factors in the pathogenesis of urinary stone disease. Vezzoli G, Terranegra A, Arcidiacono T, et al. Genetics and calcium nephrolithiasis. Kidney Int. 2010; 80:587–593. 19

20. Knowing the etiology Knowing pathogenesisKnowing modifiable risk factor Continuing evaluation ReccuranceRate Take home massage 20

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