Download PRESENTATION NAME

Nephrolithiasis
.
• The human skeleton is composed primarily of
apatite — Ca10 (PO4) 6 (OH) 2 — and is, by far,
the largest repository of calcium in the body.
•
Growth and pregnancy necessitate substantial
absorption of dietary calcium.
• Once
skeletal
formation
is
complete,
nonpregnant humans must excrete any absorbed
calcium in the urine;
• Absorption is not precisely regulated, and it
increases
with
egardless of need.
additional
dietary
intake,
• The ions that are most often complexed
with calcium in kidney stones, oxalate
and phosphate, are, respectively, an
end product of metabolism and another
principal component of bone whose
absorption is also poorly regulated.
• The need to conserve water by terrestrial
humans often results in excretion of these
unneeded ions (calcium, oxalate, and phosphate)
in relatively small volumes of urine.
• Ion excretion in scant urine leads to a substantial
supersaturation
Nephrolithiasis,
although
rarely
causing kidney failure or lifethreatening illness, is responsible
for substantial morbidity.
• With a lifetime risk of 7% to 13%,
results
not
only
in
significant
morbidity but also in substantial
economic costs, both directly from
medical
treatment
and
indirectly
through time lost from work.
• The yearly total economic cost of
kidney stones has been estimated to
approach $5.3 billion in the United
States alone.
• Stones are composed of crystals, often of several different
types, in a protein matrix. The majority (>80%) of crystals are
composed of calcium complexed with oxalate and or
phosphate
•
uric acid, magnesium ammonium phosphate (struvite), or
cystine, alone or in combination.
Epidemiology
Kidney
stones
are
common
in
industrialized nations, with an annual
incidence of 0.5% to 1.9% and a lifetime
incident rate of approximately 13% in
men and approximately 7% in women.
• In the Middle East, the lifetime prevalence of stone disease has been
reported to be up to 25%.
• In addition to age and gender, race, geography, and body mass
index (BMI) are risk factors for kidney stones.
• Non- Hispanic white people have more kidney stones than do nonHispanic black people and Mexican Americans at all ages The
prevalence of stones among Hispanics and Asian men was
intermediate between those of white and black people.
• increases from north to south and from west to east.
• This regional difference is thought to be linked to
the greater sunlight exposure in southern and
easternareas, which leads to an increase in
insensible losses through sweating, resulting in more
concentrated urine.
• Sun exposure enhances vitamin D production, which
leads to an increase in 25-hydroxy vitamin D;
• However this should not increase intestinal calcium
absorption and subsequent urine calcium excretion.
• A smaller urine volume does increase urine
supersaturation with regard to the calciumcontaining solid phases
• Obese men and women have a higher risk of
kidney stones than do people of normal weight.
• Individuals weighing more than (100 kg) have a
significantly greater chance of forming a kidney
stone than those weighing less than 150 pounds (68
kg).
• A BMI higher than 30, in comparison with a BMI
between 21 and 22.9, is also associated with an
increased risk of stone formation, as is a weight
gain of 35 pounds (16 kg) after young adulthood
and an increased waist circumference.
• mostly uric acid stones.
.
• Nephrolithiasis has been associated with chronic
kidney disease (CKD) but is rarely the cause of
endstage kidney disease.
• Even mild CKD is associated with significant
adverse cardiovascular events.
•
If appropriate therapy can result in a decrease in
recurrent stone formation and, ideally, a reduction
in the associated CKD, then stone prevention may
have a significant overall health benefit in addition
to controlling the pain and immediate consequences
of renal colic.
.
Human Genetics
• Specific monogenic causes of kidney stones such as
distal
renal
tubular acidosis
(RTA),
primary
hyperoxaluria, and cystinuria are covered in the
relevant sections. .
• correlative, rather than causative, relationships.
Familial Aggregation
•
detailed description of kindreds of so-called stone
formers.
• Found kidney stones among significantly higher numbers
of parents and siblings of the stone formers than among
relatives of controls demonstrate a threefold-to-fourfold
relative risk of kidney stones in people who have an
affected family member. Many studies have indicated that
20% to 40% of stone formers have positive family
histories of stones;
• Familial aggregation transcends geographic regions and
ethnicity.
• For example, a study from Thailand showed a risk ratio
of 3.2 for calcium stones.
Inheritance Pattern
• [An autosomal dominant trait].
• Because stone disease does not manifest until midlife
and asymptomatic stones are not uncommon,
pedigrees should be drawn with caution.
• The most acceptable notion is that nephrolithiasis is
a
complex
trait
with
polygenic
contribution
(determined by many genes), loci heterogeneity
(stones formers with different genetic backgrounds
are
affected
penetrance
by
different
(positive
genes),
genotype
but
incomplete
negative
phenotype), and extensive phenocopy (nongenetic
causes of the same phenotype).
Twin Studies
• For the discordant twin pairs, the sparing effect in the
unaffected twin may be attributed partly to dietary
factors.
• Genes along the vitamin D axis, Despite the positive
associations, no definitive biologic relationship between
the vitamin D axis and the genetic basis of kidney stones.
• The CaSR gene contains missense single-nucleotide
polymorphisms in the intracellular carboxy-terminal
domain.
• calcium channel TRPPV6
• The data supporting genetic influence in nephrolithiasis
is strong, with up to a 50% contribution to the
phenotype.
• Nephrolithiasis as a phenotype is a complex trait with
polygenic influence, loci heterogeneity, and incomplete
penetrance and is strongly amenable to environmental
modification.
Pathogenesis
• Consider a flask of water containing an ample amount of
calcium oxalate crystals, which is well mixed and at a stable
temperature.
• A solubility product with lower free ion activity would cause
the
crystals
to
dissolve;
such
a
solution is
called
undersaturated.
• A solubility product with higher free ion activity would cause
the crystals to grow.
[Formation product upper limit of metastability (ULM). At]
Factors Influencing Saturation
• Renal
excretion
phosphate,
and
of
calcium,
water
are
oxalate,
primary
determinants of saturation.
• Hypercalciuria, oxaluria, hypocitraturia,
unduly
alkaline
urine,
and
chronic
dehydration all seem to increase the risk of
calcium stone formation, but their presence
alone does not ensure that stones will form.
• APR is an estimate of the degree of
saturation.
• A ratio higher than 1 connotes lower than
1, undersaturation.
Observed Urine Saturation
• Urine from stone formers is more supersaturated
than urine from people who do not form stones.
• Stone formers — even those who are hypercalciuric,
have no detectable metabolic disorder (idiopathic),
or are hyperparathyroid — had higher average
values of urine saturation than.
• This fact is visible: added crystals grow in urine
from most normal persons.
• Urine supersaturation with brushite is more
variable, being highly dependent on urine pH
and calcium.
Limits of Metastability
• Urine APR indicates whether preexistent
crystal, once formed, will grow or shrink while
suspended in urine;
• However,
the
APR
gives
incomplete
information about the ability of that urine to
produce new crystals
Nucleation
•
•
•
•
•
Homogeneous nucleation, the spontaneous formation of new crystal nuclei in a
supersaturated solution, is uncommon.
particles of dust or debris in solution, irregularities on the surface of the
container, or other crystals furnish a surface on which crystal nuclei begin to
form at a lower APR than is required for homogeneous nucleation.
The free energy change needed to create new nuclei is greater than that needed to
enlarge preformed nuclei.
The very existence of the metastable zone reflects this greater change; thus, any
surface that can serve as a substrate on which ions in solution can organize may
act as a heterogeneous nucleus, abridge the costly process of creating a de novo
solid phase, and lower the apparent ULM.
epitaxis,
Crystal Growth and Aggregation
• Once present, crystal nuclei will grow if suspended
in urine with an APR higher than 1.
• In metastable solutions, at 37° C, growth rates of
calcium oxalate and the stone-forming calcium
phosphate crystal are rapid; appreciable changes
in macroscopic dimensions occur over hours to
days.
• Growth rate increases
with the extent of
.
oversaturation and tends be most rapid
in urine with the highest values of APR.
• increase particle size, which results in a
crystal that can lodge in the urinary
tract.
• The urine of stone formers contains
larger crystal aggregates than does
urine from people who do not form
stones.
Cell-Crystal Interactions
•
•
•
•
•
crystals cannot grow or aggregate fast enough to anchor in the urinary tract during
the normal transit time through the nephron.
Therefore, to grow large enough to be of clinical significance, crystals must anchor
to the renal tubule epithelium or urothelium:
This is the fixed particle theory..
The adherence and uptake of crystals appear to be crystal-specific: greater for
calcium oxalate than calcium phosphate.
.
.
• The crystals bind to anionic sites on the cell
membrane in a stereospecific manner.
• Cells may even act as nucleating sites for crystal
formation.
• The binding of crystals to the cells can be inhibited
by a variety of anionic compounds normally found in
urine, which may be part of the normal defense
against kidney stones.
The End