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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

Campbell Chapter Reading ch.45

Dr.Ahmad Jaber ALMUJALHEM

K.U.B. RIII

Academic Day

epidemiology
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
epidemiology1
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)
epidemiology2
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
epidemiology3
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
epidemiology4
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).
epidemiology5
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)
physicochemistry
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
nucleation crystal growth aggregation retention
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

physicochemistry1
PHYSICOCHEMISTRY

Calcifying nanoparticles (CNPs)

  • several lines of evidence support a role of CNPs in stone formation
      • (Kajander et al, 2001)
inhibitors and promoters of crystal formation
Inhibitors and Promoters of Crystal Formation

Citrate,magnesium & pyrophosphate:

  • 20% of the inhibitory activity of whole urine
    • (Bisaz et al, 1978)
inhibitors and promoters of crystal formation1
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)
inhibitors and promoters of crystal formation2
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)
inhibitors and promoters of crystal formation3
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
inhibitors and promoters of crystal formation4
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
inhibitors and promoters of crystal formation5
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)
inhibitors and promoters of crystal formation6
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)
matrix
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)
mineral metabolism
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)
calcium
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
calcium1
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).
phosphorus
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

oxalate
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)
hypercalciuria
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
hypercalciuria1
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
hypercalciuria2
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
hypercalciuria3
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
hypercalciuria4
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:

hyperoxaluria
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
hyperoxaluria1
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
hyperoxaluria2
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

hyperuricosuria
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).
hypocitraturia
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

renal tubular acidosis
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
hypomagnesuria
Hypomagnesuria

Magnesium complexes with oxalate and calcium salts

Low urinary magnesium is a/w decreased urinary citrate levels

ua stone
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)
cystine stones
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)
infection stones
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

miscellaneous stones
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
anatomic predisposition to stones
Anatomic Predisposition to Stones

UreteropelvicJunction Obstruction

Horseshoe Kidneys

CalicealDiverticula

Medullary Sponge Kidney

Stones in Pregnancy

thanks for listening
Thanks for Listening

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