STONE DISEASES : Risk, causes and pathogenesis[Autosaved].pptx

STONE DISEASES : Risk, causes and pathogenesis[Autosaved].pptx

1. URINARY STONE DISEASE; RISKS, CAUSES AND PATHOGENESIS PRESENTER; DR. BONIFACE KILANGI SUPERVISOR; PROF. MUHSIN ABOUD

2. Outline Objectives Introduction to Urinary stone diseases Causes of Urinary stones Risk factors for Urinary stones Pathogenesis of Urinary stones Preventive measures for Urinary Stone disease

3. Objectives To understand the risk factors for Urinary stone disease To explain the causes of urinary stone disease To elaborate the mechanisms or pathogenesis behind urinary stone disease To discuss the preventive measures for urinary stone diseases

4. Introduction Renal stones are formed within the kidneys, and this is called nephrolithiasis. Urolithiasis is a condition that occurs when these stones exit the renal pelvis and move into the remainder of the urinary collecting system, which includes the ureters, bladder, and urethra.

5. Upper urinary tract stones occur more commonly in men than women, but there is evidence that the gender gap is narrowing. Whites have highest incidence of upper tract stones compared with Asians, Hispanics, and African-Americans Prevalence of stone diseases, shows geographic variability with the highest prevalence of stone disease in the Southeast.

6. Stone incidence depends on geographical, climatic, ethnic, dietary, and genetic factors. The recurrence risk is basically determined by the disease or disorder causing the stone formation. Accordingly, the prevalence rates for urinary stones vary from 1% to 10% In countries with a high standard of life such as Sweden, Canada or the USA, renal stone prevalence is notably high (> 10%)

7. The lifetime prevalence of kidney stone disease is estimated at 1% to 15%, varying according to; age Gender race geographic location. Around the world prevalence rates vary ranging from 7% to 13% in North America, 5% to 9% in Europe, and 1% to 5% in Asia

8. The rise in kidney stone prevalence is a global phenomenon. Data from five European countries, Japan, and the United States showed that the incidence and prevalence of the stone disease has been increasing over time around the world. The annual incidence of symptomatic stones does not increase significantly, despite significant increases in the incidence of asymptomatic stones in both genders

9. Risk Factors Non-modifiable Risk Factors Gender - Historically, the stone disease affected adult men more commonly than adult women. - However, recent evidence suggests that the difference in incidence between men and women is narrowing. - The NHANES data (2007–2010) revealing a stone prevalence of 10.6% in men and 7.1% in women for a ratio of 1.49, which is only slightly lower than that reported for 1988 to 1994

10. 2. Race and Ethnicity Racial and ethnic differences in the incidence of stone disease have been observed. Among US men, the highest prevalence of stone disease in whites, followed by Hispanics, Asians, and African-Americans, who had prevalence of 70%, 63%, and 44% , respectively. The gender distribution of stone disease varies according to race with a male-to-female ratio among whites of 2.3 and among African-Americans of 0.65.

11. 3. Age -Historically it was relatively uncommon for stones to occur in individuals under age 20. However, over the last few decades stone disease has been increasing at a rate of 5% to 10% annually in the pediatric population. It has been suggested that epidemiologic changes, by which risk factors such as obesity and metabolic syndrome that predispose to kidney stones are more often affecting younger generations, may play a role.

12. In adults, the incidence of kidney stones peaks in the fourth to sixth decades of life. It has been observed that women show a bimodal distribution of stone disease, demonstrating a second peak in incidence in the sixth decade of life corresponding to the onset of menopause and a fall in estrogen levels ( age groups 30 to 39 and 60 to 69 ). Estrogen-treated postmenopausal women had lower urinary calcium and saturation of calcium oxalate than untreated women.

13. 4. Geography The geographic distribution of stone disease tends to roughly follow environmental risk factors; a higher prevalence of stone disease is found in hot, arid, or dry climates such as the mountains, desert, or tropical areas -However, genetic factors and dietary influences may outweigh the effects of geography.

14. 5. Climate -Seasonal variation in stone disease is likely related to temperature by way of fluid losses from perspiration and perhaps by sunlight induced increases in vitamin D. -The highest incidence of stone disease in the summer months with the peak occurring within 1 to 2 months of maximal mean temperatures. A hypothesis for the increased incidence of stones related to temperature is that more people are exposed to urban heat islands as a result of progressive urbanization. -The effects of urban architecture and infrastructure coupled with reduced vegetation result in cities that are warmer than more rural areas .

15. 6. Occupation -Heat exposure and dehydration constitute occupational risk factors for stone disease as well. -Cooks and engineering room personnel, who are exposed to high temperatures, were found to have the highest rates of stone formation. -Individuals with sedentary occupations such as those in managerial or professional positions have been found to carry an increased risk of stone formation.

16. 7. Obesity, Diabetes, and Metabolic Syndrome The prevalence and incident risk of stone disease directly correlated with weight and body mass index (BMI) in both sexes, although the magnitude of the association is greater in women than in men. - In addition to BMI, less physical activity and increased dietary energy intake (more than 2200 kcal/day) are each associated with an increased incident risk of kidney stones.

17. -The constellation of visceral obesity along with hyperlipidemia, hypertriglyceridemia, hyperglycemia, and/or hypertension, known as metabolic syndrome, has been linked to an increased risk for kidney stones. - Stone formers with type 2 diabetes have been shown to have higher urinary oxalate and lower urine pH than nondiabetic stone formers .

18. Evidence linking obesity and insulin resistance with low urine pH and uric acid stones as well as an association between hyperinsulinemia and hypercalciuria ,could account for an increased risk of uric acid and/or calcium stones in obese patients. Overweight (BMI 25–30 kg/m2 ) has also been shown to be associated with lower urine pH and higher urinary sodium, uric acid, and calcium compared with normal weight.

19. Subjects with higher BMI excreted more urinary oxalate, uric acid, sodium, and phosphorus than those with lower BMI. Furthermore, similar to other studies, urinary supersaturation of uric acid increased with BMI. It has been suggested that the association of obesity with calcium oxalate stone formation is primarily due to increased excretion of promoters of stone formation . In contrast, the association of obesity and uric acid stone formation is primarily influenced by urinary pH.

20. 8. Cardiovascular Disease A number of investigators have explored the association between hypertension and kidney stones. Increased dietary intake of substances associated with hypertension and stone disease, including calcium, sodium, and potassium, has been proposed as a possible explanation for this finding. Higher urinary calcium, uric acid, oxalate and supersaturation of calcium oxalate are observed in men and women with hypertension compared with normotensive individuals . Hypertensive stone formers excrete about 25 mg/day more calcium than normotensive stone formers.

21. B. Modifiable Risk Factors  Poor oral fluid intake H igh animal-derived protein intake H igh oxalate intake (found in foods such as beans, beer, berries, coffee, chocolate, some nuts, some teas, soda, spinach, potatoes), H igh salt intake. Low calcium intake increase the risk Consumption of citrate helps to prevent stone

22. Drug-induced urolithiasis eg. Protease inhibitors Urinary tract infection causing infectious stones by Urea spleating organisms

23. Pathophysiology of Urolithiasis Urolithiasis occurs when crystals that the stone is composed of supersaturate the urine due to being present in a high concentration and begin to collect and crystallize within the parenchyma of the kidney, forming the renal calculi

24. The physical process of stone formation comprises a complex cascade of events that occurs as the glomerular filtrate traverses the nephron . 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.

25. Steps for stone formation 1. Supersaturation 2. Nucleation 3. Crystal Growth 4. Aggregation 5. Retention

26. State of Saturation A pure aqueous solution of a salt is considered saturated when it reaches the point at which no further added salt crystals will dissolve . 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. 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 .

27. 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. 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 )

28. The solubility product and the formation product differentiate the three major states of saturation in urine: undersaturated, metastable, and unstable. Below the solubility product, crystals will not form under any circumstances, and dissolution of crystals is theoretically possible. At concentrations above the formation product , the solution is unstable and crystals will form. In the metastable range between the solubility product and the formation product, in which the concentration products of most common stone components reside, spontaneous nucleation or precipitation does not occur despite urine that is supersaturated.

29. In this area modulation of factors controlling stone formation can take place and therapeutic intervention is directed. However, crystal formation can occur in metastable range under certain circumstances-; In parts of the nephron local concentration products may exceed the formation product for long enough time periods to allow nucleation to occur

30. Local areas of obstruction or stasis in the upper urinary tract may prolong urinary transit time and allow crystal formation to occur in metastable urine Microscopic impurities or other constituents in the urine can facilitate the nucleation process by adsorption of the crystal components in a geometric way that resembles the native crystal.

31. 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. Urinary factors favoring stone formation include low volume and low citrate , whereas increased calcium, oxalate, phosphate, and uric acid increase calcium oxalate supersaturation. Once the concentration product of calcium oxalate exceeds the solubility product, crystallization can potentially occur.

32. Homogeneous nucleation is the process by which nuclei form in pure solution. Nuclei are the earliest crystal structures that will not dissolve. Small nuclei are unstable; below a critical size threshold, dissolution of the crystal is favored over crystal growth. If the driving force (supersaturation level) and the stability of the nuclei are favorable and the lag time to nucleation is sufficiently short compared with the transit time of urine through the nephron, the nuclei will persist.

33. Inhibitors, such as citrate , destabilize nuclei, whereas promoters stabilize nuclei by providing a surface with a binding site that accommodates the crystal structure of the nucleus. In urine, crystal nuclei usually form through heterogeneous nucleation by adsorption onto existing -; surfaces of epithelial cells cell debris other crystals.

34. 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 .

35. Crystal nucleation and growth are key factors in the production of all types of kidney stones. Nucleation is when crystals begin to compound together to initiate stone formation. Supersaturation of the urine with organic materials contributing to stone formation is a driving force of this mechanism. There are two theories , free particle vs. fixed particle, that describe the growth and aggregation of crystals.

36. The free particle mechanism states that the crystals will increase in size and aggregate within the urine of the tubules. These aggregates enlarge and block urine outflow from tubular openings, which promotes the formation of smaller stones. T he fixed particle mechanism states that stones formed attached to calcific plaques called Randall plaques. These plaques are rooted deeply within the basement membrane of the loop of Henle. The cause of the initial formation of Randall’s plaque is unknown

37. Because this process of calcium phosphate deposition in association with collagen has been observed in atherosclerotic lesions, some investigators have proposed a vascular origin for Randall plaque formation. Repair of damaged vessel (due to Vascular injury to the vasa recta near the renal papilla) walls could involve an atherosclerotic-like reaction that results in calcification of the endothelial wall, followed by erosion into the papillary interstitium and then into the collecting ducts, where it could serve as a nidus for stone formation.

38. The pathogenesis of stone formation in other calcium stone formers and in non-calcium stone formers may differ from that of typical idiopathic calcium oxalate stone formers. Indeed, Randall plaques are not a universal finding in all types of stone formers. Patients with enteric hyperoxaluria resulting from intestinal bypass for obesity demonstrate no plaque but instead show apatite crystal deposits plugging the inner medullary collecting duct lumens, along with associated epithelial cell damage with interstitial inflammation and fibrosis

39. Brushite stone formers have been found to have pathology intermediate between idiopathic calcium oxalate stone formers and intestinal bypass patients , demonstrating interstitial apatite plaque and apatite plugging of the inner medullary and terminal collecting ducts, along with associated collecting duct injury and interstitial fibrosis The pathogenesis of brushite stones has been postulated to occur by way of crystallization of apatite in the collecting ducts , leading to collecting duct injury, cell death, and enlargement of collecting ducts

40. Unified Theory of formation on plaques and plugs Renal epithelial cells when subjected to oxidative stress induced by excessive urinary excretion of calcium, oxalate, and phosphate and/or decreased production of crystallization inhibitors, de-differentiate into osteoblast-like cells. As a result, calcium phosphate crystals, forming within membrane-bound vesicles, grow and propagate beyond the basement membrane.

41. -When the crystals make contact with collagen and membranous degradation products, they form a plaque that extends through the interstitial causing local inflammation and fibrosis further propagating the plaque. -Finally, with the assistance of matrix metalloproteinases to breach the papillary surface epithelium, the plaque is exposed to urine in the renal pelvis, which facilitates stone growth.

42. With regard to the formation of plugs in the collecting ducts, Khan et al (2015) theorized that the plugs formed by supersaturated tubular fluid and pelvic urine slow movement of urine from the ducts to the renal pelvis, thereby promoting crystal formation and aggregation through retention.

43. Anatomical Abnormalities Predisposing to Stone Ureteropelvic Junction Obstruction Horseshoe Kidneys Medullary Sponge Kidney Caliceal Diverticula

44. Inhibitors and Promoters of Crystal Formation At the concentrations at which most stone-forming salt components (including calcium, oxalate, and phosphate) are present in urine, urine is supersaturated, thereby favoring crystal formation. However, the presence of molecules that raise the level of supersaturation needed to initiate crystal nucleation or reduce the rate of crystal growth or aggregation prevents stone formation from occurring on a routine basis. Although inhibitors have been identified that prevent calcium oxalate and calcium phosphate crystallization, no specific inhibitors are known that affect uric acid crystallization .

45. Citrate acts as an inhibitor of calcium oxalate and calcium phosphate stone formation by a variety of actions-; It complexes with calcium, thereby reducing the availability of ionic calcium to interact with oxalate or phosphate. It directly inhibits the spontaneous precipitation of calcium oxalate and prevents the agglomeration of calcium oxalate crystals. Citrate prevents heterogeneous nucleation of calcium oxalate by monosodium urate

46. The inhibitory activity of magnesium is derived from its complexation with oxalate, which reduces ionic oxalate concentration and calcium oxalate supersaturation. Two urinary glycoproteins, nephrocalcin and Tamm-Horsfall, are potent inhibitors of calcium oxalate monohydrate crystal aggregation 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

47. It has been shown to inhibit nucleation and aggregation of calcium oxalate crystals Nephrocalcin has been identified in four isoforms: Non–stone formers excrete greater quantities of two isoforms associated with the most inhibitory activity Stone formers excrete urine enriched for the two isoforms lacking inhibitory activity . -The isoforms with inhibitory activity were found to contain γ- carboxyglutamic acid residues that were lacking in the isoforms isolated from stone formers.

48. 2. Tamm-Horsfall protein , also known as uromodulin , is expressed by renal epithelial cells in the thick ascending limb and the distal convoluted tubule as a membrane-anchored protein that is released into the urine after cleavage of the anchoring site by phospholipases or proteases. Tamm-Horsfall is the most abundant protein found in the urine and a potent inhibitor of calcium oxalate monohydrate crystal aggregation , but not growth. The role of Tamm-Horsfall protein in stone formation is controversial and may depend on the state of the molecule, which determines whether it functions as an inhibitor or a promoter of crystal formation

49. In alkaline urine it is a strong inhibitor of calcium oxalate monohydrate crystal aggregation. In acidic urine it polymerizes into a configuration that promotes crystal aggregation.

50. Osteopontin , or uropontin , is an acidic phosphorylated glycoprotein expressed in bone matrix and renal epithelial cells of the ascending limb of the loop of Henle and the distal tubule. 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

51. Stones in Pregnancy A number of physiologic changes occur during pregnancy. Physiologic hydronephrosis occurs in up to 90% of pregnant women and persists up to 4 to 6 weeks postpartum. Important physiologic changes in the kidney occur during pregnancy and modulate urinary stone risk factors. Renal blood flow increases, leading to a 30% to 50% rise in glomerular filtration rate, which subsequently increases the filtered loads of calcium, sodium, and uric acid

52. Classification of Urinary Stones

53. Stone size -Stone size is usually given in one or two dimensions, and stratified into those measuring up to 5, 5-10, 10-20, and > 20 mm in largest diameter Stone location - Stones can be classified according to anatomical position: upper, middle, or lower calyx; renal pelvis; upper, middle, or distal ureter; and urinary bladder.

54. Prevention Of Renal Stones.

55. References Campbell and Walsh 12 th Edition EUA guideline on Urolithiasis March 2022 National Library of Medicine ; History, epidemiology and regional diversities of urolithiasis Michelle López1 and Bernd Hoppe corresponding author