This document provides an overview of urinary lithiasis (kidney stone disease) including its epidemiology, etiology, pathogenesis, and classification. Some key points: - Kidney stone disease prevalence has been increasing globally due to westernization and is most common in middle-aged adults. - Stones form when urine becomes supersaturated, allowing crystals to nucleate and grow. Inhibitors normally prevent this but may be insufficient in stone formers. - Calcium stones are most common and result from hypercalciuria in many cases. Other stone types include uric acid, struvite, and cystine stones. - Multiple dietary, medical, and genetic factors influence stone risk by affecting urine

1. Urinary lithiasis : Epidemiology,
Etiology & Pathogenesis

2. Introduction
• Although stone disease is one of the most
common afflictions of modern society, it has
been described since antiquity.
• With Westernization of global culture,
however, the site of stone formation has
migrated from the lower to the upper urinary
tract
• And the disease once limited to men is
increasingly gender blind.

3. History
 First known stone:
– 6.5 cm bladder stone consisted of
Calcium Phosphate and Uric acid.
– Carbon-dated 4800 B.C., it was
found in 1901 in a child’s mummy
at a grave site in El Amrah, Upper
Egypt.
– Preserved in Royal Museum in
London until destroyed by
bombardment in 1941.
Calcium Oxalate Monohydrate
(Mummy Stone – 800 AD)
herringlab.com

4. Stone surgery: Vedic times in
India:
• First record of stone surgery
• Described varieties of stones, and signs
and symptoms
• Detailed anatomy and extraction of
urinary bladder stones and operative
complications
• Wine was used as an anesthetic Sushruta (1500 BCE) Statue in
Haridwar
Sushruta Samhita (सुश्रुतसंहिता) is a surgery textbook
written in 800 BCE,
describes 300 surgical procedure, 120 surgical
instruments, and 8 types of surgery.
http://en.wikipedia.org/wiki/Sushurata

5. Epidemiology
• The lifetime prevalence of kidney stone disease is
estimated at 1% to 15%, varying according to age,
gender, race, and geographic location.
• 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 stone disease has
been increasing over time around the world

6. Gender
> >
>

7. Race/Ethinicity
70%
63%
44%

8. • The kidney stone disease is common in most
of the countries & rare in some countries like
in green land & japan
• The gender distribution of stone disease varies
according to race.
• Male-to-female ratio among whites of 2.3 and
among African-Americans of 0.65.

9. Age
• Stone occurrence is relatively uncommon
before age 20 but peaks in incidence 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

10. Geography
• 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.
• High stone prevalence included the United States,
the British Isles, Scandinavian and Mediterranean
countries, northern India and Pakistan, northern
Australia, Central Europe, portions of the Malay
peninsula, and China

11. Climate

13. By the year 2050

14. Occupation

15. • Those exposed to high temperatures exhibited
1. lower urine volumes and pH,
2. higher uric acid levels
3. higher urine specific gravity
• leading to higher urinary saturation of uric
acid

17. Obesity, Diabetes, and Metabolic
Syndrome
>

18. • The constellation of visceral obesity along with
hyperlipidemia, hypertriglyceridemia,
hyperglycemia, and/or hypertension, known as
metabolic syndrome, has also been linked to an
increased risk for kidney stones.
• While the association between obesity, diabetes,
and metabolic syndrome has been explored in
the epidemiologic literature, the exact
pathophysiologic mechanism responsible for this
association has yet to be completely defined

19. • Subjects with higher BMI excreted more
urinary oxalate, uric acid, sodium, and
phosphorus than those with lower BMI.
Furthermore,urinary supersaturation of uric
acid increased with BMI.

20. Cardiovascular Disease
• Increased dietary intake of
substances associated with
both hypertension and
stone disease, including
calcium, sodium, and
potassium.
• Observed higher urinary
calcium, uric acid, and
oxalate and supersaturation
of calcium oxalate in men
and women with
hypertension compared to
normotensive individuals.

21. Water

22. PHYSICOCHEMISTRY AND
PATHOGENESIS
• 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.

23. Stone Formation
Urine saturation
Supersaturation
Crystal nucleation
Aggregation
Retention and growth

24. • A solution containing ions or molecules of a
sparingly soluble salt is described by the
concentration product, which is a mathematic
expression of the product of the
concentrations of the pure chemical
components (ions or molecules) of the salt.

25. • 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.

26. • 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).

27. unstable
metastable
undersaturated

28. Pathogenesis: Saturation
Reference
• Think of the urine as a solution containing calcium and oxalate
ions
• The [Ca2+]*[C2O4
2-] = solubility product
• The lower the solubility product, the more undersaturated the
urine (or solution) is
• Now imagine that you add more Ca2+ or oxalate2- to your
solution
No crystals in solution because we have
a low solubility product

29. Pathogenesis: Saturation (cont’d)
Reference
• The solubility product increases as the ion
concentrations increase
• But, crystals do not form de novo
• Crystals that existed previously would
grow, but no new crystals would be formed
• The solution you have created is
metastable
• These are solutions that have
increased solubility products such that
pre-existing crystals/surfaces can
facilitate further crystal growth, but the
solution itself does not have a high
enough solubility product to produce
native crystals
A metastable solution
+ a pre-existing
surface or crystal
A precipitated solution

30. Pathogenesis: Saturation (cont’d)
Reference
• If you continue to add ions to
the solution, you will traverse the
metastable range and reach the
upper limit of metastability
• ULM: the solubility
product beyond which de
novo crystallization can
occur
• Studies show that stone
formers have a higher solubility
product than non-stone formers
• Stone formers are more
likely to have urine at the
ULM or greater
Y-axis: SP for
Calcium Oxalate

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 citrate, while increased calcium, oxalate,
phosphate, and uric acid all increase calcium oxalate
supersaturation.
• Once the concentration product of calcium oxalate exceeds
the solubility product, crystallization can potentially occur.
• However, in the presence of urinary inhibitors and other
substances, calcium oxalate precipitation occurs only when
supersaturation exceeds solubility by 7 to 11 times.

32. • 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.

33. Pathogenesis: Nucleation
• Metastable solutions form crystals by heterogeneous nucleation
• Homogeneous nucleation: the spontaneous formation of
crystals
•Heterogeneous nucleation: the process of forming crystals
onto pre-existing surfaces
•Since the normal urine sample is a metastable solution, it is
easier for heterogeneous nucleation to occur
• Randall plaque helps facilitate heterogeneous nucleation
• the plaque can be found in the interstitium, at the level of the
papilla
• When it expands into the urinary space, it facilitates
heterogeneous nucleation by acting as a pre-existing surface
Reference

35. Pathogenesis: Nucleation (cont’d)
• Some studies suggest that crystals cannot form in the lumen without an
anchor
• It is thought that the transit time through the nephron and urothelial
space is too short for crystals to form without an anchor point
• one such anchor point would be the Randall plaque
• this is known as the Fixed Particle Theory
• However, not all stone formers have a Randall plaque
• in these cases, it is theorized that the epithelial cells adhere to or
uptake the crystal to form an anchor point for nucleation and growth
Reference

36. • Evan and colleagues (2003) presented an
alternative view of the pathogenesis of stone
formation on the basis of extensive analysis of
papillary plaques derived from biopsies obtained
during percutaneous nephrolithotomy in
idiopathic calcium oxalate stone formers.
• They localized the origin of the plaque to the
basement membrane of the thin limbs of the
loops of Henle and demonstrated that the plaque
subsequently extends through the medullary
interstitium to a subepithelial location

37. • Once the plaque erodes through the urothelium,
it is thought to constitute a stable, anchored
surface on which calcium oxalate crystals can
nucleate and grow as attached stones.
• The origin of the crystals that initiate the plaque
at the basement membrane of the thin loop of
Henle is unclear; however, they do not appear to
come from the renal tubular cells or lumen.

38. • One intriguing but unproven hypothesis for
the origin of the calcium phosphate particles
described earlier involves nanobacteria, or
calcifying nanoparticles (CNPs), which are
self-propagating entities that precipitate
calcium apatite on their exterior membrane
but for which to date no genomic material has
been identified

39. Inhibitors of Crystal Formation
• 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
• 1) Inorganic pyrophosphate was found to be
responsible for 25% to 50% of the inhibitory
activity of whole urine against calcium
phosphate crystallization.

40. 2) Citrate
• It acts as an inhibitor of calcium oxalate and
calcium phosphate stone formation by a variety
of actions.
• First, it complexes with calcium, thereby reducing
the availability of ionic calcium to interact with
oxalate or phosphate.
• Second, it directly inhibits the spontaneous
precipitation of calcium oxalate and prevents the
agglomeration of calcium oxalate crystals.
• Lastly, citrate prevents heterogeneous nucleation
of calcium oxalate by monosodium urate

41. • 3) The inhibitory activity of magnesium is
derived from its complexation with oxalate,
which reduces ionic oxalate concentration and
calcium oxalate supersaturation.
• It also reduces the contact time between
calcium and oxalate molecules in vitro, an
effect that showed synergism with citrate and
was negated by the presence of uric acid

42. • 4)Polyanion macromolecules, including
glycosaminoglycans, acid
mucopolysaccharides, and RNA, have been
shown to inhibit crystal nucleation and growth
by bonding with surface calcium ions.
• The most prominent glycosaminoglycan in
human urine is chondroitin sulfate

43. • 5) Two urinary glycoproteins, nephrocalcin and Tamm-
Horsfall glycoprotein, 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.
• Tamm-Horsfall protein 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.

44. • 6) 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.

45. • 7)Urinary prothrombin fragment 1 (F1) is a
crystal matrix protein named for its
resemblance to the F1 degradation product of
prothrombin.
• It is associated with a reduction in crystal
aggregation and deposition.

46. • 8)Lastly, inter-α-trypsin is a glycoprotein
synthesized in the liver that is composed of
three polypeptides (two heavy chains and one
light chain), of which bikunin comprises the
light chain.
• Bikunin is a strong inhibitor of calcium oxalate
crystallization, aggregation, and growth.

47. Mineral metabolism

48. Calcium metabolism

50. Phosphorous
• Total amount of phosphate in the body is 500 to 800g.
• Though it is present in every cell of the body, 85% to
90% of body’s phosphate is found in the bones and
teeth.
• Normal plasma level of phosphate is 4 mg/dL.
• It is absorbed from GI tract into blood.
• It is also resorbed from bone. From blood it is
distributed to various parts of the body.
• While passing through the kidney, large quantity of
phosphate is excreted through urine

52. Magnesium
• Magnesium is absorbed from the intestine by
passive diffusion or active transport, although
passive diffusion accounts for most of the net
magnesium absorption.
• Magnesium is absorbed in both the large and
small intestine, with the majority absorbed
from the distal small intestine.
• Hormonal regulation of magnesium is
primarily through vitamin D.

53. Oxalate
• Although 30% to 40% of ingested calcium is absorbed
from the intestine, only 6% to 14% of ingested oxalate
is absorbed.
• Oxalate transport occurs via both transcellular and
paracellular pathways.
• The transport protein responsible for oxalate secretion
has been suspected to belong to the SLC26 family of
solute-linked carrier (SLC) anion exchangers.
• A putative anion exchange transporter, SLC26A6, that
is expressed in the apical membrane of small intestinal
and perhaps colonic epithelial cells has been
implicated in intestinal oxalate transport

54. • A number of other factors can influence oxalate
absorption, including the presence of oxalate-binding
cations such as calcium or magnesium and oxalate-
degrading bacteria.
• Coingestion of calcium- and oxalate-containing foods
leads to formation of calcium oxalate complexes, which
limits the availability of free oxalate ion for absorption.
• Oxalate-degrading bacteria, notably Oxalobacter
formigenes, use oxalate as an energy source and
consequently reduce intestinal oxalate absorption.

55. Classification of nephrolithiasis

56. Calcium Stones
• Hypercalciuria is the most common
abnormality identified in calcium stone
formers.
• Criteria defining hypercalciuria are variable,
but the strictest definition classifies
hypercalciuria as greater than 200 mg of
urinary calcium/day after adherence to a 400-
mg calcium, 100-mg sodium diet for 1 week

57. • Others defined hypercalciuria as excretion of
greater than 4 mg/kg/day or greater than 7
mmol/day in men and 6 mmol/day in women.
• However, arguably a threshold level of
calcium that separates hypercalciuria from
normocalciuria is artificial, and urinary calcium
demonstrates a spectrum of effects over its
range by which higher or lower calcium levels
are associated with a greater or lesser effect

58. • Pak and colleagues divided hypercalciuria into
three distinct subtypes on the basis of unique
pathophysiologic abnormalities:
1. absorptive hypercalciuria due to
increasedintestinal absorption of calcium,
2. renal hypercalciuria due to primary renal leak
of calcium, and
3. resorptive hypercalciuria due to increased
bone demineralization.

59. Calcium Stones
Hypercalciuria - Absorptive
• Urine calcium exceeds 250 mg/day in females,
300 mg/day in males
• Most common cause of hypercalciuria
• familial, 50% of 1st degree relatives, M=F
• Patients have a higher incidence of reduced
bone mineral density
• Caoxalate & Ca++phosphate stones

60. Absorptive Hypercalciuria
• Type I (Diet Independent)
– High urinary calcium despite diet
• Type II (Diet dependent)
– Responds to calcium restriction
• Type III (phosphate leak)
– Low serum phosphate with increased Vit D and increased GI
absorption
• Sarcoidosis
– Increased Vit D-->increased GI absorption

61. • Gene product of cytochrome P450 (CYP) 27B1
(CYP27B1), which is present in a variety of tissues.
• The mitochondrial enzyme 1,25(OH)2D-24-hydroxylase
(CYP24A1), which is present in the intestine and kidney,
inactivates both major vitamin D metabolites,
25(OH)D3 and 1,25(OH)2D3.
• Bi-allelic mutations in CYP24A1 have been shown to
reduce activity of the enzyme, resulting in elevated
levels of 1,25(OH)2D3, particularly in individuals taking
large amounts of vitamin D

62. Calcium Stones
Hypercalciuria - Absorptive
 Calcium Absorption
 Serum calcium
 PTH Urinary Calcium

63. Renal hypercalciuria
• High fasting urinary calcium levels (>0.11 mg/dL
glomerular filtration) with normal serum calcium
values are characteristic of renal hypercalciuria.
• The actual cause of renal calcium leak is not known.
• Dent disease (X-linked recessive nephrolithiasis) is
linked to defects in chloride channel-5 (ClC-5), which is
located in the proximal renal tubule, the thick
ascending limb of the loop of Henle, and the α-type
intercalated cells of the collecting ducts.
• Dent disease is characterized by hypercalciuria,
proteinuria, nephrolithiasis, nephrocalcinosis, and
progressive renal failure

64. Hypercalciuria
Renal Leak
Urinary Calcium
PTH
GI Absorption
Bone Resoprtion
Plasma Calcium

65. Resorptive hypercalciuria
• Resorptive hypercalciuria is an infrequent
abnormality most commonly associated with
primary hyperparathyroidism.
• 5% of cases
• Excessive PTH secretion from a parathyroid
adenoma leads to excessive bone resorption and
increased renal synthesis of 1,25(OH)2D3, which
in turn enhances intestinal absorption of calcium.
• The net effect is elevated serum and urine
calcium levels and reduced serum phosphorus
levels.

66. Hypercalciuria
Resorptive (PTH)
PTH
Urinary Ca
Bone Resorption GI Absorption
Plasma Ca

67. Hypercalciuria
Intestinal
Absorption
Fasting
Urinary Ca
PTH
High
High
High
High
High
High
High
Low-nl
High
Normal
Low-nl
HighSerum Ca
ResorptiveRenalAbsorptive

68. Sarcoid and Granulomatous Disease.
• Additional, rare causes of resorptive
hypercalciuria include hypercalcemia of
malignancy, sarcoidosis, thyrotoxicosis, and
vitamin D toxicity.
• Many granulomatous diseases, including
tuberculosis, sarcoidosis, histoplasmosis, leprosy,
and silicosis, have been reported to produce
hypercalcemia.
• Among these, sarcoidosis is most commonly
associated with urolithiasis.

69. • The hypercalcemia in sarcoidosis is due to the
production of 1,25(OH)2D3 from 1α-
hydroxylase present in macrophages of the
sarcoid granuloma, causing increased
intestinal absorption of calcium,
hypercalcemia, and hypercalciuria.

70. Malignancy-Associated Hypercalcemia.
• Lung and breast cancers account for about
60% of malignancy-associated hypercalcemia,
• renal cell (10% to 15%),
• head and neck (10%), and
• hematologic cancers such as lymphoma and
myeloma (10%) account for the rest.

71. • Although direct mechanical destruction of
bone constitutes one cause of hypercalcemia,
many tumors secrete humoral factors,
including PTHrP, transforming growth factor-α,
and cytokines such as interleukin-1 and tumor
necrosis factor, which activate osteoclasts and
result in bone lysis and hypercalcemia.

72. Glucocorticoid-Induced
Hypercalcemia.
• Glucocorticoids promote bone resorption and
reduce bone formation, ultimately leading to
osteopenia with chronic use (Manelli and
Giustina, 2000).
• Additionally, they stimulate release of PTH

73. Calcium oxalate monohydrate

74. Calcium oxalate dihydrate

75. Calcium phosphate brushite

76. Hyperoxaluria
• Hyperoxaluria, defined as urinary oxalate
greater than 40 mg/day, leads to increased
urinary saturation of calcium oxalate and
subsequent promotion of calcium oxalate
stones.
1. Primary ( rare genetic disease)
2. Enteric
3. Dietary
4. Idiopathic Hyperoxaluria.

77. Primary Hyperoxaluria
• Inherited disorder of glyoxylate metabolism
• Type I: Alanine-glyoxylate aminotransferase (1 in
120,000 births)
• Median age at presentation 5 yrs
• Oxalate deposition occurs in bones
• Screen all patients with stones for hyperoxaluria
• Type II
• D-glycerate dehydrogenase
• ESRD less common

79. Primary Hyperoxaluria
• ESRD
• 50% of patients by age 15 and 80% by age 30
• Therapy
• High urinary flow
• Pyridoxine supplements
• Liver/Kidney Transplant

80. • A third type of primary hyperoxaluria has
recently been recognized.
• Primary hyperoxaluria type 3 (PH3) is caused
by a defective mitochondrial enzyme, 4-
hydroxy-2-oxoglutarate aldolase (HOGA),
which is thought to play a role in
hydroxyproline metabolism

81. Enteric Hyperoxaluria
• Due to malabsorption
• Associated with chronic diarrhea or short
bowel syndrome
• Normally, calcium binds to intestinal oxalate
reducing its absorption
• Overindulgence in oxalate-rich foods such as
nuts, chocolate, brewed tea, spinach,
potatoes, beets, and rhubarb can result in
hyperoxaluria in otherwise normal
individuals.

82. Calcium
Calcium
Oxalates
Calcium
Soaps
Oxalic
Acid
Fatty
Acids
NORMAL
A A
B B
S S
O O
R R
P P
T T
I I
O O
N N
Calcium Stones
Enteric Hyperoxaluria

83. Calcium Stones
Enteric Hyperoxaluria
Calcium
Calcium
Oxalates
Calcium
Soaps
Oxalic
Acid
Fatty
Acids
ENTERIC HYPEROXALURIA
A A
B B
S S
O O
R R
P P
T T
I I
O O
N N

84. Enteric Hyperoxaluria
Bowel Disorder
Fat malabsorption
Excess fats bind
to intestinal Ca
Insufficient
calcium to bind
oxalate
Unbound oxalate

85. Idiopathic Hyperoxaluria.
• Several studies have suggested that mild
hyperoxaluria is as important a factor as
hypercalciuria in the pathogenesis of
idiopathic calcium oxalate stones.

86. Hyperuricosuria
• Hyperuricosuria is defined as urinary uric acid exceeding
600 mg/day.
• Up to 10% of calcium stone formers have high urinary uric
acid levels as an isolated abnormality, but it is found in
combination with other metabolic abnormalities in up to
40% of calcium stone formers
• Predisposes to the formation of calcium-containing calculi
because sodium urate can produce malabsorption of
macromolecular inhibitors
• can serve as a nidus for the heterogeneous growth of
calcium oxalate crystals
• Therapy involves potassium citrate supplementation,
allopurinol, or both

87. Hypocitraturia
• Hypocitraturia is an important and correctable
abnormality associated that occurs alone
(10%) or with other abnormalities (50%)
• More common in females
• May be idiopathic or secondary
• Acidosis reduces urinary citrate by  tubular
reabsorption

88. Hypocitraturia
• Associated with distal RTA, metabolic acidosis
of diarrhea, & consumption of a diet rich in
meat
• Tend to form calcium oxalate stones (except
Type I RTA)
• Rx:  dietary protein, alkali (K citrate or K
bicarbonate), avoid sodium bicarbonate

89. Renal Tubular Acidosis
• RTA is a clinical syndrome characterized by
metabolic acidosis resulting from defects in renal
tubular hydrogen ion secretion or bicarbonate
reabsorption.
• There are three types of RTA: 1, 2, and 4.
• Type 1 (distal) RTA is of particular significance to
urologists not only because it is the most
common form of RTA but also because it is the
form of RTA most frequently associated with
stone formation, which occurs in up to 70% of
affected individuals

90. Type 1 (Distal) Renal Tubular Acidosis
• Comprises a syndrome of abnormal collecting
duct function characterized by inability to
acidify the urine in the presence of systemic
acidosis.
• The classic findings include hypokalemic,
hyperchloremic, non–anion gap metabolic
acidosis along with nephrolithiasis,
nephrocalcinosis, and elevated urine pH
(>6.0).

93. Type 2 (Proximal) Renal Tubular
Acidosis.
• Proximal RTA is characterized by a defect in
HCO3− reabsorption associated with initial high
urine pH that normalizes as plasma HCO3−
decreases and the amount of filtered HCO3− falls
• As the filtered HCO3− load declines with
progressive metabolic acidosis.
• Nephrolithiasis is uncommon in this disorder
owing to relatively normal urinary citrate
excretion

94. Type 4 (Distal) Renal Tubular Acidosis
• Associated with chronic renal damage, usually
seen in patients with interstitial renal disease
and diabetic nephropathy.
• The protection against renal stone formation
in these patients may be attributed to reduced
renal excretion of stone-forming substances
such as calcium and uric acid owing to
impaired renal function.

95. Hypomagnesiuria
• Magnesium complexes with oxalate and
calcium salts, and therefore low magnesium
levels result in reduced inhibitory activity.
• Low urinary magnesium is also associated
with decreased urinary citrate levels, which
may further contribute to stone formation.

96. Uric Acid Stones

97. Uric Acid Stones
• Main determinants of uric acid stone
formation
– Urinary pH < 5.5,  urine volume
Hyperuricosuria
• Genetic overproduction
• Myeloproliferative disorders
• High purine diet
• Drugs

99. Pathogenesis of Low Urine pH
• Although the pathogenesis of low urine pH in
idiopathic uric acid stone formers is not known
with certainty and may be multifactorial, several
potential mechanisms have been proposed.
• First observed that normouricosuric individuals
with pure uric acid stones were more likely to
have diabetes mellitus or to demonstrate glucose
intolerance than normal individuals or those with
mixed uric acid–calcium oxalate or pure calcium
oxalate stones.

100. • Further investigation revealed that the uric
acid stone formers excreted less acid into the
urine as ammonium and proportionately more
titratable acid and less citrate in order to
maintain normal overall acid-base balance.
• This apparent impairment in ammonium
excretion in uric acid stone formers has been
putatively linked to an insulin-resistant state.

102. Hyperuricosuria
• Hyperuricosuria is defined as urinary uric acid
exceeding 600 mg/day.
• Hyperuricosuria predisposes to uric acid stone
formation by causing supersaturation of the
urine with respect to sparingly soluble
undissociated uric acid.

103. Low Urinary Volume
• All conditions that contribute to low urinary
volume increase the risk of uric acid
supersaturation.

104. Cystine Stones

105. Cystine Stones
• Inherited autosomal recessive disorder (or
rarely autosomal dominant with incomplete
penetrance) characterized by a defect in
intestinal and renal tubular transport of
dibasic amino acids, resulting in excessive
urinary excretion of cystine.

106. Cystine Stones
• Cystine is soluble in the urine to a level of only
24 - 48 mg/dl
• In affected patients, the excretion is 480 -
3500 mg/day
• Nephrolithiasis usually occurs by the 4th
decade

107. Cystine Stones
• Hexagonal, radiopaque, greenish-yellow
• Often present as staghorn calculi or multiple bilateral
stones
• Two genes involved in the disease have been
identified: SLC3A1 (Pras et al, 1994), which resides on
the short arm of chromosome 2 and codes for a 663–
amino acid heavy subunit (rBAT) of the cystine
transporter, and SLC7A9 (Feliubadaló et al, 1999),
which is located on the long arm of chromosome 19
and codes for a 487–amino acid light subunit (b°,+AT)
of the cystine transporter

108. Infected Stones/Struvite

109. Struvite Stones - Magnesium
Ammonium Phosphate
• More common in women than men
• Most common cause of staghorn calculi
• Grow rapidly, may lead to severe
pyelonephritis or urosepsis and renal failure
• Light brown or off white
• Gnarled and laminated on X-ray

110. Struvite Stones
Infection Stones
• Caused in part by infections by organisms with
urease ( Proteus, Klebsiella, Pseudomonas,
and Serratia)
• Hydrolysis of urea yields ammonia & hydroxyl
ions, consumes H+ & thusurine pH
•  urine pH increases saturation of struvite

111. Urea
(NH2)2-CO
2NH3 + CO2
NH4OHMgNH4(OH)2
MgNH4PO46H2O
+ Urease
+ H2O
+ Mg2+ (found in
urine normally)
+ PO4
3- (found in
urine normally)
Struvite

113. Miscellaneous stones

114. Xanthine stones
• Xanthine stones comprise a rare stone type that
is often confused with uric acid stones because
both are radiolucent.
• They form as a result of an inherited disorder in
the catabolic enzyme xanthine dehydrogenase
(XDH) or xanthine oxidase, which catalyzes the
conversion of xanthine to uric acid.
• Because xanthine is poorly soluble in urine, the
high levels of xanthine that accumulate in XDH
deficiency lead to xanthine stones

115. Ammonium Acid Urate Stones
• Ammonium acid urate stones represent less
than 1% of all stones
• Conditions associated with ammonium acid
urate crystallization include laxative abuse,
recurrent urinary tract infection, recurrent uric
acid stone formation, and inflammatory bowel
disease.

116. Matrix Stones
• They are typically radiolucent and may be
mistaken for tumor or uric acid stones depending
on the imaging study obtained.
• Pure matrix stones may contain upwards of 65%
protein where as the matrix component of
calcium based stones comprises only 2.5% of the
dry weight of the stone.
• The composition of matrix stones was
approximately two-thirds mucoprotein and one-
third mucopolysaccharide by weight.

117. Medication-Related Stones
• Drug-induced stones form either directly as a
result of precipitation and crystallization of a drug
or its metabolite or indirectly by altering the
urinary environment, making it favorable for
metabolic stone formation.
• They are of two types –
1. Medications That Directly Promote Stone
Formation
2. Medications That Indirectly Promote Stone
Formation.

118. Indinavir sulfate
• It is a protease inhibitor that has been shown
to be effective in increasing CD4+ cell counts
and decreasing HIV-RNA titers in patients
infected with human immunodeficiency virus
(HIV) or who have acquired immunodeficiency
syndrome
• Incidence of 4% to 13%
• Mechanism- high urinary excretionand poor
solubility of the drug at physiologic urinary pH

119. Triametrene
• It is a potassium-sparing diuretic commonly
used for the treatment of hypertension
• It is an uncommon stone composition,
accounting for only 0.4% of 50,000 calculi in
one report, with only one third of the stones
composed largely or entirely of triamterene

120. Guaifenesin and Ephedrine.
• Consumption of large quantities of
guaifenesin and ephedrine can lead to stones
composed of their metabolites

121. Silicate Stones.
• Silicate stones are extremely rare and have
been associated with consumption of large
amounts of silicate-containing antacids such
as magnesium trisilicate

122. Medications That Indirectly Promote
Stone Formation
• Other medications indirectly promote stone
formation by increasing urinary stone risk factors
• Corticosteroids, vitamin D, and phosphatebinding
antacids can induce hypercalciuria
• Thiazides cause intracellular acidosis and
subsequent hypocitraturia
• Carbonic anhydrase inhibitors such as
acetazolamide block resorption of sodium
bicarbonate at multiple segments in the nephron,
thereby inducing a metabolic acidosis and leading
to urinary alkalinization

123. • Laxative abuse has also been associated with stone
formation because persistent diarrhea increases the
risk of ammonium acid urate stones.
• Patients abusing laxatives excrete large amounts of
ammonia in the urine to eliminate excess acid,
resulting in low urine pH.
• In the setting of low urine volume resulting from
dehydration and low urinary sodium from laxative use,
the urine of these patients can be highly
supersaturated with respect to ammonium urate

125. Anatomic Predisposition to Stones
• Patients with anatomic anomalies associated with
urinary obstruction and/or stasis have been noted to
have a high incidence of associated stones.
• It has long been debated whether the predisposition to
stone disease is a result of urinary stasis and delayed
transit time through the nephron, leading to higher
likelihood of crystal formation and retention, or if these
patients form stones as a result of the same or unique
metabolic abnormalities associated with stone
formation.

126. Ureteropelvic Junction Obstruction
• The incidence of renal calculi in patients with
ureteropelvic junction obstruction (UPJO) is nearly 20%
• However, Husmann and colleagues (1995) provided
several lines of evidence to suggest that patients with
UPJO and concurrent renal calculi carry the same
metabolic risks as other stone formers in the general
population.
• Thus correction of the UPJO did not prevent recurrent
stones in most patients, further emphasizing the role
of underlying metabolic abnormalities in the etiology
of renal calculi in patients with UPJO.

127. Horseshoe Kidneys
• Occur with a prevalence of 0.25% but have an
associated rate of renal calculi of 20%.
• Because of the high insertion of the ureter
into the renal pelvis, there is a relative
impairment of renal drainage, predisposing to
UPJO.
• Therefore the risk of stone formation has been
attributed to urinary stasis rather than to
metabolic derangements.

128. Caliceal Diverticula
• Caliceal diverticula are associated with stones in
up to 40% of patients.
• Stones formed in caliceal diverticula are mainly
composed of calcium oxalate monohydrate, but
they can also contain struvite– carbonate apatite
owing to an infectious component.
• Calyceal diverticular calculi arise from a
combination of metabolic abnormalities and
urinary stasis

129. Medullary Sponge Kidney
• Recurrent infection and
urinary stasis within the
ectatic tubules
• Renal tubular defects,
including hypercalciuria,
• Impaired renal
concentrating ability, and
• defective urinary
acidification are likely
contributing factors

130. Stones in Pregnancy
• Symptomatic stones
during pregnancy occur at
a rate of 1 in 3000 (Butler
et al, 2000) pregnant
women.
• The majority of
symptomatic stones occur
in the second and third
trimesters of pregnancy,
heralded by symptoms of
flank pain or hematuria

131. • The diagnosis can be difficult in this patient
population; up to 28% of women are
misdiagnosed with appendicitis, diverticulitis,
or placental abruption.
• Hydronephrosis may be in part due to the
effects of progesterone, compression of the
ureters by the gravid uterus is at least a
contributory, if not the primary, factor.

132. • 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
• Hypercalciuria is further enhanced by placental
production of 1,25(OH)2D3, which increases intestinal
calcium absorption and secondarily suppresses PTH.
• Despite increases in a number of stone-inducing
analytes, pregnant women have been shown to excrete
increased amounts of inhibitors such as citrate,
magnesium, and glycoproteins

133. Thank you