Campbell Chapter Reading ch.45

Dr.Ahmad Jaber ALMUJALHEMK.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

Women: 20 to 29 years in 1965 50 to 79 years in 2005

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)

Race & Ethnicity:

• Soucie and colleagues

(1994) (USA) (Men):

• Highest prevalence of

stone disease in

whites, followed by

Hispanics, Asians, and

African-Americans

Mente and colleagues (2007):

Europeans (Caucasians) (reference group)

Relative risk of calcium stones:

I. Arabs (OR 3.8,95% CI 2.7 to 5.2)

II. West Indian (OR 2.5, 95% CI 1.8 to 3.4)

III. West Asian (OR 2.4, 95% CI 1.7 to 3.4)

IV. Latin American (OR 1.7, 95% CI 1.2 to 2.4)

V. East Asian (OR 0.4, 95% CI 0.3 to 0.5)

VI. African (OR 0.7, 95% CI 0.5 to 0.9)

Epidemiology

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

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).

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 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 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-Horsfall mucoprotein inhibits aggregation

(Hess et al, 1991)Uropontin inhibits crystal growth

(Shiraga et al, 1992)Bikunin inhibitor of crystal nucleation & aggregation

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 Citrate,magnesium & pyrophosphate:

20% of the inhibitory activity of whole urine• (Bisaz et al, 1978)

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 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 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 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 Formation Osteopontin (uropontin):

Acidic phosphorylated glycoprotein: 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 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 (Hochstrasser et al, 1984; Atmani et al,1999)

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% nonamino sugars, 5% glucosamine, 10% bound water, 12% organic ash

(Boyce, 1968)

Mucoprotein matrix substance A • (Hess et al, 1996)

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

(Bronner et al, 1999)

Substances that complex calcium: Phosphate, citrate, oxalate,sulfate & fatty acids Reduce the availability of ionic calcium for absorption

(Allen, 1982)

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

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

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 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 Oxalobacter formigenes

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)

PATHOGENESIS OF UPPER URINARY TRACT CALCULI

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

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

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/dL glomerular filtration)

Normal serum calcium values

Hypercalciuria Resorptive Hypercalciuria:

Primary hyperparathyroidism is the cause of nephrolithiasis in about 5% of cases

(Broadus, 1989)

Hypercalcemia & Hypercalciuria Occasionaly Normocalcemia

“Thiazide challenge” Administration of a thiazide diuretic will enhance renal

calcium reabsorption and exacerbate the hypercalcemia

(Coffey et al, 1977)

Sarcoid and Granulomatous Disease

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

Urinary oxalate >40

mg/day

Primary Hyperoxaluria:

Rare autosomal recessive

disorder

Nephrocalcinosis ESRD (@age 15) 50% Death rate 30%

(Cochat et al, 1999)

• Rx: Combined liver-kidney transplant

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): Hyperoxaluria develops at least 6 months after

undergoing Rouxen-Y gastric bypass surgery

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

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

phosphoribosyltransferase deficiency,overactivity of phosphoribosylpyrophosphate

synthetase, & hereditary renal hypouricemia

(Halabe and Sperling, 1994).

HypocitraturiaUrinary 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 acidThiazides Diuretics induce hypokalemia & intracellular acidosis

Renal Tubular AcidosisClinical 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

Magnesium complexes with oxalate and

calcium salts

Low urinary magnesium is a/w decreased

urinary citrate levels

Uric acid 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 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:

solubilities of 300 mg/L, 400 mg/L & 1000 mg/L at pH levels of 5, 7, and 9, respectively

(Dent et al,1955)

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

Xanthine and Dihydroxyadenine Stones

Ammonium Acid Urate Stones

IBD, Laxative abuse, recurrent UTI, Rec UA stones

Matrix Stones

Medication-Related Stones:

Indinavir Stones

Triamterene Stones

Guaifenesin and Ephedrine

Silicate Stones

Anatomic Predisposition to Stones Ureteropelvic Junction Obstruction

Horseshoe Kidneys

Caliceal Diverticula

Medullary Sponge Kidney

Stones in Pregnancy

Thanks for Listening

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