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Campbell Chapter Reading ch.45

Campbell Chapter Reading ch.45 . Dr.Ahmad Jaber ALMUJALHEM K.U.B. RIII Academic Day. Epidemiology . USA: Prevalence of stone disease  10% to 15% (Norlin et al, 1976; Sierakowski et al, 1978; Johnson et al, 1979) Peak incidence: Men: 20 to 49 years in 1965 30 to 69 years in 2005

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Campbell Chapter Reading ch.45

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  1. Campbell Chapter Reading ch.45 Dr.Ahmad Jaber ALMUJALHEM K.U.B. RIII Academic Day

  2. Epidemiology USA: • Prevalence of stone disease  10% to 15% • (Norlin et al, 1976; Sierakowski et al, 1978;Johnson et al, 1979) Peak incidence: • Men: • 20 to 49 years in 1965 • 30 to 69 years in 2005 • Women: • 20 to 29 years in 1965 • 50 to 79 years in 2005

  3. Epidemiology Gender: • Men are affected two to three times more often than women • (Hiatt et al, 1982;Soucie et al, 1994; Pearle et al, 2005) • Stamatelou and colleagues (2003): • Male-to-female ratio of stone disease • 1.75 (between 1976 and 1980) • 1.54 (between 1988 and 1994)

  4. Epidemiology • Mente and colleagues (2007): • Europeans (Caucasians) (reference group) • Relative risk of calcium stones: • Arabs (OR 3.8,95% CI 2.7 to 5.2) • West Indian (OR 2.5, 95% CI 1.8 to 3.4) • West Asian (OR 2.4, 95% CI 1.7 to 3.4) • Latin American (OR 1.7, 95% CI 1.2 to 2.4) • East Asian (OR 0.4, 95% CI 0.3 to 0.5) • African (OR 0.7, 95% CI 0.5 to 0.9) • Race & Ethnicity: • Soucie and colleagues (1994) (USA) (Men): • Highest prevalence of stone disease in whites, followed by Hispanics, Asians, and African-Americans

  5. Epidemiology Age: • Peaks in incidence in the fourth to sixth decades of life • (Marshall et al, 1975; Johnson et al, 1979; Hiatt et al, 1982) Geography: • Higher prevalence of stone disease is found in hot, arid, or dry climates: • Mountains, desert, or tropical areas

  6. Epidemiology Climate: • Chen & colleagues 2008: • Peak incidence of stone-related claims occurred in July through September • Sharp decline in claims in October • Military personnel who developed symptomatic stones after arrival in Kuwait and Iraq: • Mean time interval to stone formation of 93 days • (Evan et al, 2005).

  7. Epidemiology Occupation: • Heat exposure & dehydration constitute occupational risk factors Body Mass Index and Weight: • Prevalence & incident risk of stone disease were directly correlated with weight & BMI in both sexes • (Curhan et al, 1998; Taylor et al, 2005) • Subjects with higher BMI excreted more urinary oxalate, uric acid, sodium & phosphorus Water: • Fluid intake was found to be inversely related to the risk of incident kidney stone formation • (Curhan et al, 1993, 1997)

  8. PHYSICOCHEMISTRY Concentration product: • A solution containing ions or molecules of a sparingly soluble salt Thermodynamic solubility product (Ksp) • Is the point at which the dissolved & crystalline components are in equilibrium for a specific set of conditions Formation product (Kf) • Concentrations of the salt increase further, the point at which it can no longer be held in solution is reached and crystals form Relative saturation ratio (concentration product ratio) • Ratio of the concentration product of the urine • to the solubility product of the specified stone-forming salt

  9. Nucleation & Crystal Growth, Aggregation & Retention Nuclei are the earliest crystal structures that will not dissolve Magnesium & citrate inhibit crystal aggregation Nephrocalcin (acidic glycoprotein) inhibits calcium oxalate nucleation,growth & aggregation • (Nakagawa et al, 1987; Asplin et al,1991) Tamm-Horsfallmucoprotein inhibits aggregation • (Hess et al, 1991) Uropontin inhibits crystal growth • (Shiraga et al, 1992) Bikunin inhibitor of crystal nucleation & aggregation

  10. PHYSICOCHEMISTRY Calcifying nanoparticles (CNPs) • several lines of evidence support a role of CNPs in stone formation • (Kajander et al, 2001)

  11. Inhibitors and Promoters of Crystal Formation Citrate,magnesium & pyrophosphate: • 20% of the inhibitory activity of whole urine • (Bisaz et al, 1978)

  12. Inhibitors and Promoters of Crystal Formation Citrate: • Inhibitor of calcium oxalate & calcium phosphate stone formation • Complexes with calcium  reducing the availability of ionic calcium to interact with oxalate or phosphate • (Meyer et al, 1975; Pak et al, 1982) • Inhibits the spontaneous precipitation of calcium oxalate • (Nicar et al, 1987) • Prevents the agglomeration of calcium oxalate crystals • (Kok et al,1986) • Prevents heterogeneous nucleation of calcium oxalate by monosodium urate • (Pak and Peterson, 1986)

  13. Inhibitors and Promoters of Crystal Formation Magnesium: • Complexation with oxalate  reduces ionic oxalate concentration & calcium oxalate supersaturation • (Meyer et al, 1975) • Reduces the rate of calcium oxalate crystal growth in vitro • (Desmars et al, 1973)

  14. Inhibitors and Promoters of Crystal Formation Urinary glycoproteins: • Nephrocalcin • Tamm-Horsfall glycoprotein • Potent inhibitors of calcium oxalate monohydrate crystal aggregation • (Nakagawa et al,1987) • Nephrocalcin: • Acidic glycoprotein containing predominantly acidic amino acids • Synthesized in the proximal renal tubules & the thick ascending limb

  15. Inhibitors and Promoters of Crystal Formation Tamm-Horsfall protein: • Expressed by renal epithelial cells in the thick ascending limb & the distal convoluted tubule • Membrane-anchored protein • The most abundant protein found in the urine • Potent inhibitor of calcium oxalate monohydrate crystal aggregation, but not growth

  16. Inhibitors and Promoters of Crystal Formation Osteopontin (uropontin): • Acidic phosphorylatedglycoprotein: • Bone matrix • Renal epithelial cells of the ascending limb of the loop of Henle& the distal tubule • Inhibit nucleation, growth & aggregation of calcium oxalate crystals • Reduce binding of crystals to renal epithelial cells in vitro • (Asplin et al, 1998; Wesson et al, 1998)

  17. Inhibitors and Promoters of Crystal Formation Bikunin: • Inter-α-trypsin: • Glycoprotein synthesized in the liver • Composed of three polypeptides • (two heavy chains & one light chain) • Bikuninlight chain • Strong inhibitor of calcium oxalate crystallization, aggregation growth in vitro • (Hochstrasseret al, 1984; Atmani et al,1999)

  18. Matrix Renal calculi: • Crystalline component • Matrix  noncrystalline components • Accounts for about 2.5% of the weight of the stone • (Boyce and Garvey, 1956) Chemical analysis heterogeneous mixture: • 65% protein, 9% nonaminosugars, 5% glucosamine, 10% bound water, 12% organic ash • (Boyce, 1968) • Mucoprotein matrix substance A • (Hess et al, 1996)

  19. MINERAL METABOLISM Calcium: • 30-40% of dietary calcium is absorbed from the intestine • Most being absorbed in the small intestine • Approximately 10% absorbed in the colon • (Bronneret al, 1999) • Substances that complex calcium: • Phosphate, citrate, oxalate,sulfate & fatty acids • Reduce the availability of ionic calcium for absorption • (Allen, 1982)

  20. Calcium Vitamin D, 1,25(OH)2D3: • Most potent stimulator of intestinal calcium absorption Decrease in serum calcium increases secretion of PTH •  Stimulates the enzyme 1α-hydroxylase Calcitriol: • Increasing calcium absorption from the intestine

  21. Calcium PTH: • Increases renal calcium reabsorption • Enhances phosphate excretion • leading to a net increase in serum calcium  suppresses further PTH secretion & synthesis of 1,25(OH)2D3 Calcitriol: • Inhibiting synthesis of PTH: • Through enhanced vitamin D receptor & calcium-sensing receptor expression in the parathyroid glands • (Dusso et al, 2005).

  22. Phosphorus 60% of the phosphate in the diet is absorbed by the intestine 65% of absorbed phosphate is excreted by the kidney • The remainder by the intestine 80% to 90% of the filtered load of phosphate is reabsorbed in the renal tubule 10% to 20% is excreted in the urine

  23. Oxalate 6% to 14% of ingested oxalate is absorbed • (Holmes et al, 1995; Hesse et al, 1999) Oxalate absorption: • Half or more occurring in the small intestine • Half in the colon • (Holmes et al, 1995) Co-ingestion of calcium and oxalate containing foods formation of a calcium oxalate complex • Limits the availability of free oxalate ion for absorption • (Liebman and Chai, 1997; Hess et al, 1998). Oxalate-degrading bacteria Oxalobacterformigenes • Use oxalate as an energy source reduce intestinal oxalate absorption Absorbed oxalate is nearly completely excreted in the urine • (Hodgkinson et al, 1974; Prenan et al, 1982)

  24. PATHOGENESIS OF UPPER URINARY TRACT CALCULI

  25. Hypercalciuria >200 mg of urinary calcium/day • After adherence to a 400-mg calcium, 100-mg sodium diet for 1 week • (Menon, 1986) Parks and Coe (1986): • Excretion of >4 mg/kg/day • >7 mmol/day in men • >6 mmol/day in women

  26. Hypercalciuria Absorptive Hypercalciuria: • Increased urinary calcium excretion (>0.2 mg/mg creatinine) after an oral calcium load • Increased intestinal absorption of calcium, which occurs in approximately 55% of stone formers • (Menon,1986) • Type I: • Urinary calcium remains high despite a low calcium diet • (400 mg dietary calcium daily) • Type II: • Urinary calcium normalizes with a restricted calcium intake

  27. Hypercalciuria Renal Hypercalciuria: • 70% of calcium reabsorption occurs in the proximal tubule • Impaired renal tubular reabsorption of calcium  elevated urinary calcium levels  2ry hyperparathyroidism • (Coe et al, 1973) • High fasting urinary calcium levels • (>0.11 mg/dLglomerular filtration) • Normal serum calcium values

  28. Hypercalciuria ResorptiveHypercalciuria: • Primary hyperparathyroidism is the cause of nephrolithiasis in about 5% of cases • (Broadus, 1989) • Hypercalcemia & Hypercalciuria • Occasionaly Normocalcemia • “Thiazidechallenge” • Administration of a thiazide diuretic will enhance renal calcium reabsorption and exacerbate the hypercalcemia • (Coffey et al, 1977) • Sarcoid and Granulomatous Disease

  29. Hypercalciuria Malignancy-Associated Hypercalcemia: • Lung & breast cancers (60%) • Renal cell (10% to 15%) • Head and neck (10%) • Hematologic cancers (lymphoma & myeloma)(10%) Glucocorticoid-Induced Hypercalcemia:

  30. Hyperoxaluria Urinary oxalate >40 mg/day Primary Hyperoxaluria: • Rare autosomal recessive disorder • Nephrocalcinosis • ESRD (@age 15) 50% • Death rate 30% • (Cochatet al, 1999) • Rx: Combined liver-kidney transplant

  31. Hyperoxaluria Enteric Hyperoxaluria: • A/W chronic diarrheal states • Fat malabsorptionsaponification of fatty acids with divalent cations (calcium & magnesium) • Reducing calcium oxalate complexation • Increasing the pool of available oxalate for reabsorption • (Earnest et al,1975) • Sinha and colleagues (2007): • Hyperoxaluriadevelops at least 6 months after undergoing Rouxen-Y gastric bypass surgery

  32. Hyperoxaluria Dietary Hyperoxaluria: • The contribution of dietary oxalate to urinary oxalate excretion can range from 24% to 42% • (Holmes et al, 2001) • Oxalate-rich foods: • Nuts, chocolate, brewed tea, spinach, broccoli, strawberries & rhubarb Idiopathic Hyperoxaluria

  33. Hyperuricosuria Urinary uric acid exceeding 600 mg/day The most common cause of hyperuricosuria is increased dietary purine intake Diseases: • gout, myeloproliferative & lymphoproliferative disorders, multiple myeloma, secondary polycythemia, pernicious anemia, hemolytic disorders, hemoglobinopathies & thalassemia, complete or partialhypoxanthine-guanine phosphoribosyltransferasedeficiency,overactivityof phosphoribosylpyrophosphatesynthetase, & hereditary renal hypouricemia • (Halabe and Sperling, 1994).

  34. Hypocitraturia Urinary citrate <320 mg/day • (Pak, 1987) <0.6 mmol (men) <1.03 mmol (women) daily • (Menon and Mahle, 1983) Distal renal tubular acidosis (RTA): • Urine pH (>6.8), high serum chloride& low serum bicarbonate and potassium • (Preminger et al, 1985) • (Ammonium Chloride test): • Inability to acidify urine in response to an oral acid Thiazides Diuretics induce hypokalemia& intracellular acidosis

  35. Renal Tubular Acidosis Clinical syndrome characterized by metabolic acidosis resulting from defects in renal tubular: • Hydrogen ion secretion (type 1/ distal) • Bicarbonate reabsorption (type 2/ proximal) Types of RTA: 1, 2& 4 • Type 1 (distal) RTA: • Most common stone composition calcium phosphate • Urine pH >6 • Nephrocalcinosis • Hypocitraturia Secondary RTA: • Obstructive uropathy, pyelonephritis, acute tubular necrosis,hyperparathyroidism & idiopathic hypercalciuria

  36. Hypomagnesuria Magnesium complexes with oxalate and calcium salts Low urinary magnesium is a/w decreased urinary citrate levels

  37. Uric acid stone

  38. UA stone @pH 6.5, concentrations of uric acid exceeding 1200 mg/L remain soluble • (Asplin, 1996) Gouty diathesis (idiopathic low urine pH): • Normal urinary uric acid levels • Acidic urine Hyperuricosuria: • Urinary uric acid >600 mg/day • (Menon, 1986)

  39. Cystine Stones Cystinuria: • Inherited autosomal recessive disorder • Defect in intestinal & renal tubular transport of dibasic amino acids • Resulting in excessive urinary excretion of cystine • (Ng and Streem, 1999, 2001) • High urinary concentrations of lysine, ornithine & arginine • Poor solubility of cystinestone formation • The solubility of cystine is highly pH dependent: • solubilitiesof 300 mg/L, 400 mg/L& 1000 mg/L at pH levels of 5, 7, and 9, respectively • (Dent et al,1955)

  40. Infection Stones Magnesium ammonium phosphate hexahydrate • (MgNH4PO4 •6H2O) May in addition contain calcium phosphate in the form of carbonate apatite • (Ca10[PO4]6 • CO3) Infection with urease-producing bacteria is a prerequisite for the formation of infection stones

  41. Miscellaneous Stones Xanthineand DihydroxyadenineStones Ammonium Acid UrateStones • IBD, Laxative abuse, recurrent UTI, Rec UA stones Matrix Stones Medication-Related Stones: • IndinavirStones • TriamtereneStones • Guaifenesin and Ephedrine • Silicate Stones

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