doc. Nephrolithiasis

1. By
Ala'a Fadhel Hassan
5th stage, pharmacy department
Hospital training
Supervised by
Dr.Ali

2. NEPHROLITHIASIS
It is a commondisease that is estimatedto produce medical
costs of$2.1 billionper year in the United States. Nephrolithiasis
specifically refers to calculi in the kidneys, but this article
discusses bothrenal calculi (see the first image below) and
ureteral calculi (ureterolithiasis;see the secondimage below).
Ureteral calculi almost always originate inthe kidneys, although
they may continue to growonce they lodge in the ureter.
Small renal calculus that would likely
respondto extracorporeal shockwave
lithotripsy.
Distal ureteral stone observed
througha small, rigidureteroscope
prior to ballistic lithotripsy and
extraction.The small caliber and
excellent optics of today's endoscopes
greatly facilitate minimally invasive
treatment of urinary stones.
Urinary tract stone disease has been a part of the human
conditionfor millennia; in fact, bladder and kidney stones have
even been found in Egyptian mummies.Some ofthe earliest
recordedmedical texts and figures depict the treatment of
urinary tract stone disease.
Acute renal colic is probably the most excruciatingly painful
event a personcan endure. Striking without warning, the pain is
often describedas being worse than childbirth,broken bones,
gunshot wounds, burns, or surgery.Renal colic affects
approximately 1.2 millionpeople each year and accounts for
approximately 1% of all hospital admissions.

3. Most active emergency departments (EDs) manage patients with
acute renal colic every day, depending on the hospital’s patient
population. Initial management consists ofproper diagnosis,
prompt initial treatment,and appropriate consultations,but
concurrently efforts shouldbe directedtowards patient
education, including initial preventive therapy measures.
Although nephrolithiasis is not a commoncause ofrenal failure,
certainproblems,such as preexisting azotemiaand solitary
functional kidneys, clearly present a higher riskof additional
renal damage.Other high-riskfactors include diabetes, struvite
and/or staghorncalculi, and various hereditary diseases suchas
primary hyperoxaluria,Dent disease, cystinuria,and polycystic
kidney disease. Spinal cord injuries and similar functional or
anatomical urological anomalies also predispose patients with
kidney stones to an increasedrisk ofrenal failure.
Recurrent obstruction,especially whenassociatedwith
infection and tubular epithelial or renal interstitial cell damage
from microcrystals,may activate the fibrogenic cascade,which
is mainly responsible for the actual loss offunctional renal
parenchyma. (1)
Pathophysiology (2)
 Stone formationis inhibited by Citrate
 Women have muchhigher levels of citrate than men
 Low citrate levels are related to most stone forms
Types of Stones (2)
 Calcium Nephrolithiasis (75%)
1. Calcium oxalate (70%)
2. Calcium Phosphate (5-10%)
 Uric Acid Nephrolithiasis (10-15%)
 Struvite (15-20%)
 Cystine (1%)
 Drug-Induced (1%)
Indinavir &Triamteren

4. EPIDEMIOLOGY AND NATURAL HISTORY
Incidence (3)
● 12% lifetime incidence
● Sex: male predominance
● Race: relatively rare in African Americans
● Geographic: “stone belts,” developed
countries
Associated Features and Risk Factors (3)
● Obesity and hypertension
● Diet:
_ Highanimal proteinintake
_ Low fluid intake
_ Low calcium intake
_ Highsalt intake
● Hot climate or occupation
● Family history
● Medications
Recurrence (3)
● Up to 50% at 5 years, 80% lifetime
(untreated)
CLINICAL FEATURES
Renal Colic (2)
 Severe Abdominal Painof sudden onset
 Unilateral flank pain
 Lower Abdominal Pain
 Associatedsymptoms
 Nausea and Vomiting
Symptoms related to stone location (2)
 Kidney (Vague flank pain &Hematuria)
 Proximal Ureter (Flankpain , Upper Abdominal Pain&
Renal colic)

5.  Mid-Ureter (Flank pain ,Anterior Abdominal Pain &Renal
colic)
 Distal ureter (Ureteropelvic junction)
1. Dysuria
2. Urinary frequency
3. Anterior Abdominal Pain
4. Flank pain
5. Renal colic
Radiological Assessment (3)
● Relative diagnostic sensitivity ofdifferent
modalities:
_ Computedtomography,near 100%
_ Abdominal plain film, 60% to 65%
_ Ultrasound,10% to 25%
● Specific applications:
_ Computedtomography in acute renal
colic
_ Renal ultrasound in pregnancy
_ Abdominal plain film to determine if
stone is radiopaque and thus likely not
uric acid
StaghornStones
● Definition: extend from one calyx to another
● Struvite, cystine,uric acid
● Associatedwith urinary tract infection, renal
failure, not stone passage
Differential Diagnosis (2)
 Acute onset of symptoms
1. Urinary Tract Infection
2. Acute Prostatitis
3. Musculoskeletal spasm
4. Acute Constipation or other acute bowel disorder
 Chronic intermittent or insidious onset ofsymptoms
5. Bowel disease
6. Interstitial Cystitis
7. Inguinal Hernia

6. 8. Testicular mass
9. Urothelial or Renal Mass & Benign prostatitic
hyperplasia
MEDICAL MANAGEMENT OF ACUTE STONE
EVENTS
Most stones are smaller than 5 mm and readily pass without
interventions such as lithotripsy,ureteroscopy,or percutaneous
nephrolithotomy.
Even if the stone is as large as 1 cm,I would let the patient try to
pass it spontaneously if it is in the distal ureter,and I would
allowup to 4 weeks for this to happen.
For most patients,pain management is paramount. Randomized
controlledtrials suggest that parenteral nonsteroidal anti-
inflammatory drugs (NSAIDs) are as effective as narcotics for
controlling the pain ofrenal colic.Diclofenac (Voltaren) has been
used in several studies.
To hasten stone passage,some recommendinducing high urine
flow withoral intake ofat least 2 to 3 L of fluids per 24 hours to
ensure a urine output of at least 2 L per day.
Drugs may also help the stone to pass. A recent study in 210
patients withureteral stones averaging 6 mm in diameter
showedthat tamsulosin(Flomax) increasedthe likelihoodof
spontaneous stone passage.A meta-analysis of693 patients in
nine randomized trials concludedthat alpha-blockers and
calcium channel blockers increasedthe likelihoodof stone
passage comparedwith no treatment.in a randomized, double-
blind study in 86 patients with unilateral ureteral stones,
reporteda higher rate of stone passage in patients treatedwith
methylprednisolone (Medrol) 16mg/day plus nifedipine
(Procardia) 40mg/day than in those given methylprednisolone
alone. (4)
PREVENTING RECURRENT STONES: PRINCIPLES AND
SPECIFICS (4)
Urinary stone disease recurs in 30% to 50% of patients within 5
years.

7. In preventing recurrent stones,some principles apply to all
patients and some are specific to the type of stone the patient
had.
Stones form when the urine is supersaturated
Nephrolithiasis occurs whenthe concentrationof stone-forming
salts such as calcium oxalate, calcium phosphate, or uric acid is
high. When the concentrationis high enough to allow crystals to
form or preformedcrystals to grow,the urine is saidto be
supersaturated.
Several factors are the major determinants ofwhether the urine
is supersaturatedby different salts:
 Calcium oxalate—lowurine volume and high
concentrations ofcalcium and oxalate
 Calcium phosphate—ahigh urine calcium concentration
and alkaline urine
 Uric acid—acidic urine
 Cystine—ahigh urinary cystine concentrationand acidic
urine.
Increasing daily fluid intake
Since the urinary concentrationof stone-forming salts is
strongly affectedby the daily urine volume,it follows that
increasing daily fluid intake is important in preventing
recurrent stone disease.
In one study, 199 patients with a first calcium stone were
randomizedto a program ofhigh oral fluid intake or no
intervention. Five years later,12 (12%) ofthe 99 patients in the
high-fluid intake group had had a secondstone, comparedwith
27 (27%) in the untreated group(P = .008). Of interest,the
baseline 24-hour urine volumes were significantly lower in
patients withstones than in 101 normal controls (P= .001),
suggesting that habitual low daily fluid intake is a riskfactor for
calcium stone disease.
PREVENTING CALCIUM STONES (4)
Most stones are composedof calcium oxalate or calcium
phosphate. Calcium stone disease occurs most often in the 3rd to
5th decades of life.
Naturally occurring inhibitors ofcalcium crystal formationin
the urine include citrate,nephrocalcin, uropontin, and
magnesium.Of these, only citrate and magnesium levels are
routinely measured;low levels of citrate are treatedas a cause
of calcium stone disease. It follows that the risk ofcalcium

8. nephrolithiasis is the result of the interplay between the
supersaturatedstate and the level of urinary inhibitors.
Hypercalciuriaandcalcium oxalate stones
Calcium oxalate stones begin as crystals that form on the surface
of the renal papillae over collections ofsuburothelial calcium
phosphate particles calledRandall plaque. The driving force for
calcium oxalate overgrowthonplaque is calcium oxalate
supersaturation,which is strongly linked to high urinary
calcium excretion.The fractionof papillary surface coveredby
plaque in patients with idiopathic calcium oxalate stones
correlates directly withthe urine calcium level and inversely
with urine volume and pH.
Most patients with calcium oxalate stones have hypercalciuria
(defined as 24-hour urinary calcium excretion> 300 mg in men,
> 250 mg in women, or > 4 mg/kg in men or women).
Hypercalciuriacanbe idiopathic
Hypercalciuriacanoccur in primary hyperparathyroidism,
sarcoidosis,vitaminDexcess,corticosteroidtreatment,renal
tubular acidosis,hyperthyroidism,andmalignant neoplasms.If
none of these conditions is present, elevatedurinary calcium
excretionis consideredidiopathic.
Some patients with idiopathic hypercalciuriahave a strong
family history of hypercalciuriaand, likely, a genetic basis for
the disease.This conditionhas been categorizedby the
presumedsite of the primary abnormality:
Absorptive hypercalciuria. Most patients with idiopathic
hypercalciuriaabsorbtoo much calcium from the intestine.In
many of them, 1,25 dihydroxyvitaminD levels are slightly high
and serum phosphorous levels are slightly low;the hypothesis is
that they produce more 1,25 dihydroxyvitaminD or are more
sensitive to it. However,Breslauet al showed that not all
patients withidiopathic hypercalciuriahave absorptive
hypercalciuriamediatedby 1,25 dihydroxyvitaminD, which
suggests that the intestinal hyperabsorptionof calcium has
other mechanisms.
Resorptive hypercalciuria occurs ifincreasedbone turnover
leads to urinary loss ofbone calcium.
Renal leak is due to a primary defect in renal tubular transport
that causes loss ofcalcium into the urine and a secondary
increase in intestinal calcium absorptionor mobilizationfrom
bone.

9. This categorizationis basedon measuring fasting and 24-hour
urine calcium,urinary calcium responses to a low-calcium diet,
and responses to an oral calcium load. However,these studies
are difficult to do and have been shownto have minimal clinical
value.
To reduce calcium in the urine, limit sodium,give thiazides
Idiopathic hypercalciuriais worsenedby a diet high in
sodium and animal protein. Thiazide diuretics lower urinary
calcium excretionand promote mineral retention. Therefore,
treatment of idiopathic hypercalciuriaconsists ofhigh fluid
intake, dietary sodium restriction,and thiazide diuretics.
Calcium restrictionis not advised
For several reasons,a calcium-restricteddiet is not advised for
patients withidiopathic hypercalciuria Dietary calcium
restrictioncanput the patient into negative calcium balance.
Further, it is thought that with less calcium to bind to dietary
oxalate,more unbound oxalate can be absorbedin the colonand
eventually excretedin the urine. This increase in urinary
oxalate can be to the point ofsupersaturation,even though
urinary calcium levels remainunchanged.This, in turn,
increases the likelihoodofstone formation.
Several studies showedthat a higher intake of dietary calcium is
actually associatedwith fewer calcium stone events in both men
and women.
Further, a study in 120 Italian patients with hypercalciuric
calcium oxalate stones concluded that a diet that is normal in
calcium,low in sodium,and lowin animal protein was
associatedwitha lower frequency of calcium stones than a low-
calcium diet. Although both diets were associatedwitha
reductionin urinary calcium concentrations,urinary oxalate
excretionrose in those on a low-calcium diet and fell in those on
a normal-calcium diet. The reductionin urinary oxalate
excretionin patients on a normal-calcium diet was attributed to
intestinal binding ofdietary oxalate by dietary calcium, thus
lessening the amount offree oxalate available for absorption.
Although calcium oxalate excretionfell in both groups,it fell
more in those on a normal calcium intake. Comparedwith those
on a low-calcium diet, the patients on the normal-calcium,low-
sodium,low-proteindiet had a 50% lower riskof stones at 5
years.

10. Hyperparathyroidism
Primary hyperparathyroidism cancause hypercalciuriaand
nephrolithiasis.In one series, 56 (4.9%) of 1,132 consecutive
patients withnephrolithiasis had a confirmeddiagnosis of
hyperparathyroidism.Parathyroidectomy prevented
subsequent stone disease in 48 patients.
However,only 17% to 24% of patients with primary
hyperparathyroidism have urinary stones composedof calcium
oxalate or calcium phosphate. In many studies, it was difficult to
determine why a minority of these patients develop stones,but
two studies shed some light on this.
Parks et al found that, comparedwith nephrolithiasis patients
with idiopathic hypercalciuria,those with primary
hyperparathyroidism have elevatedserum calcium levels (but
usually < 11.5 mg/dL),greater degrees of hypercalciuria(352
mg/day vs 252 mg/day, P < .001), and lower serum phosphate
levels (2.45 vs 3.10 mg/dL, P < .001).
Odvina et al found, in a study of 131 patients withproven
primary hyperparathyroidism,that 78 had nephrolithiasis and
53 did not. Those with stones excretedmore calcium (343
mg/day) than those without stones (273mg/day),had a higher
urinary saturationofcalcium oxalate and brushite,and excreted
twice as much calcium following a 1-g oral calcium load.
These studies suggest that in patients with primary
hyperparathyroidism,the riskof forming stones is relatedto the
degree of hypercalciuria,and in particular to the increased
intestinal absorptionof dietary calcium.
Renal tubular acidosis
Features of distal renal tubular acidosis are systemic metabolic
acidosis,alkaline urine, hypokalemia,hypercalciuria,
hypocitraturia,and nephrolithiasis.The chronic metabolic
acidosis results inloss of bone calcium,contributes to
hypercalciuria,and is responsible for the hypocitraturia. Stone
formationis the result of excessive urinary calcium excretion,
the deficiency ofthe urinary crystal inhibitor citrate,and
persistently alkaline urine.
Treatment with sodium bicarbonate or potassium citrate
corrects the metabolic acidosis,reduces the loss of calcium from
bone, corrects hypokalemia,and increases urinary citrate.
Too much uric acidin the urine
Elevatedurinary uric acid excretion(> 800 mg/day in men, >
750 mg/day in women) is associatedwith formationof calcium

11. oxalate stones and, in conjunctionwith low urine pH, withuric
acid stones.An increase in dissolveduric acid salts induces
heterogeneous calcium oxalate nucleation. In one randomized
clinical trial, giving allopurinol (Zyloprim) loweredurinary uric
acid excretionand was associatedwitha lower rate of calcium
stone disease.
Too much oxalate in the urine
The 95th percentile for urinary oxalate excretionis 45 mg/day
in women and 55 mg/day in men. Hyperoxaluriaincreases
calcium oxalate supersaturationand contributes to calcium
stone formation.
Normally,90% of dietary oxalate binds to dietary calcium in the
small intestine and passes into the stool as calcium oxalate;10%
of dietary oxalate remains free and is absorbedin the colon and
subsequently excretedin the urine.
Hyperoxaluriamay simply be a result of high dietary oxalate
intake. However,increasedenteric absorptionofdietary oxalate
can occur in those on a low-calcium diet (in which less calcium is
available to bind to dietary oxalate, as describedabove) and
may partially explain why a low-calcium diet has been
associatedwithincreasedfrequency of calcium stone disease.
Patients with enteric malabsorptionoffat (eg, due to
inflammatory bowel disease or intestinal bypass surgery for
obesity) may also develop hyperoxaluria.This occurs because
the excess enteric fat binds dietary calcium and allows free
oxalate to be more readily absorbedin the colon.
Rarely,hyperoxaluriais caused by one of several recessively
inherited disorders ofoxalate metabolism.
The growing number of people with obesity has resultedin an
upsurge in gastric bypass surgery.Althoughthe current
procedures do not pose the same metabolic risks as were noted
in the 1970s when a different type of bypass was performed,the
incidence of kidney stones does appear to be higher after these
procedures.A recent analysis of 1,436 patients undergoing
Roux-en-Y gastric bypass surgery found that 60 of them
developed calcium stones afterward.Of these, 31 who
underwent metabolic studies were found to have higher oxalate
and lower citrate levels at 12 months offollow-up.
Not enough citrate,a stone inhibitor
Hypocitraturiais defined as a daily urine citrate excretionless
than 500 mg in women and 434 mg in men. As already

12. mentioned, citrate plays an important role in inhibiting calcium
crystal formationand preventing stone formation.
Urinary citrate excretionis mainly determinedby tubular
reabsorption,which is increasedby acid loads and decreasedby
alkali loads.Low urine citrate levels are often seen in conditions
that cause chronic metabolic acidosis,suchas inflammatory
bowel disease, intestinal malabsorption,and renal tubular
acidosis—all ofwhichare associatedwithincreased occurrence
of nephrolithiasis.However,in most nephrolithiasis patients
with hypocitraturia,the cause is not apparent, and the
mechanism of the hypocitraturiacannot be determined.
In recent years, high-protein, low-carbohydrate diets have
become popular for weight reduction, but they also have
metabolic effects that increase the riskof stones.45 The
metabolism ofa diet high in animal proteinproduces more
hydrogenions that are buffered by bone, releasing calcium from
bone and increasing urinary calcium excretion.These diets also
cause intracellular acidosis,resulting in decreasedurinary
excretionof citrate.As a result of these effects, the stone-
forming propensity of the urine is increased.
STRUVITE STONES MUST BE REMOVED (4)
Struvite stones are the result of chronic upper urinary infection
with urease-producing bacteria
(Proteus sp, Haemophilussp,Klebsiella sp, and Ureaplasma
urealyticum).The hydrolysis ofureayields ammonium and
hydroxyl ions and a persistently alkaline urine, and this
scenario promotes the formationofstones composedof
magnesium ammonium phosphate, ie, struvite.
Struvite stones,which are oftenbranched (“staghorn” stones),
occur more often in womenand in patients who have chronic
urinary obstructionor aneurologic disorder that impairs
normal emptying of the bladder.
Treatment requires eradicating the infection withantibiotics
and removing the bacteria-laden stones by one ofseveral
interventional techniques. Acetohydroxamic acidinhibits
urease and has been used to treat struvite stone disease,but it
has frequent and serious adverse effects.
URIC ACID STONES FORM IN VERY ACIDIC URINE (4)

13. Uric acid stones occur especially in patients with unusually low
urine pH and hyperuricosuria.In some patients,this very low
urine pH is the result of a defect in renal ammoniasecretion,
which results in less buffering ofsecretedhydrogen ions.
The tendency to form uric acid stones is reportedto be
increasing in obese people with the metabolic syndrome.Some
studies have shown that the defect in ammoniaproductionby
the kidney may be the result of insulin resistance.
Urate stones are radiolucent but can be seen on
ultrasonography and helical CT. On helical CT, they can be
distinguishedfrom calcium stones by their lower density.51
Since uric acid is much more soluble in an alkaline solution,
both preventionand treatment shouldconsist of alkalinization
of urine to a pH of more than 6.0 with oral sodium bicarbonate
or citrate solutionand hydration.This treatment may actually
dissolve uric acid stones.If hyperuricemiaor hyperuricosuriais
present, allopurinol can be prescribed.
CYSTINE STONES ALSO FORM IN ACIDIC URINE (4)
Cystine stone disease occurs inpeople who have inherited an
autosomally recessive gastrointestinal andrenal tubular
transport disorder offour amino acids, ie, cystine, ornithine,
arginine, and lysine. Of these, cystine is the most insoluble in
normally acidic urine and thus precipitates into stones.The
onset is at a younger age than in calcium stone disease; the
stones are radio-opaque.
Treatment consists of:
 Hydration,to achieve daily urine volumes of 3 to 3.5 L
 Alkalinizationof the urine to a pH higher than 6.5 with
potassium alkali (potassium citrate) or sodium
bicarbonate
 Reductionof proteinand sodium intake to reduce cystine
excretion.
If these measures fail, D-penicillamine (Depen), tiopronin
(Thiola),or captopril (Capoten) can be given to convert the
cystine to a more soluble disulfide cysteine-drug complex.
Captopril has only a modest effect at best and is usually given
with another disulfide-complexing drug; it also has the
disadvantage of producing hypotension.Adverse effects of D-
penicillamine and tiopronininclude abdominal pain, loss of
taste, fever,proteinuria, and, in rare cases,nephrotic syndrome.

14. WORKUP AND MANAGEMENT OF NEPHROLITHIASIS (4)
The diagnostic evaluationof a first stone includes a routine
chemistry panel (electrolytes,creatinine,calcium),urinalysis,
parathyroidhormone measurement,and helical CTwithout
contrast.Stone analysis should always be done whenever stone
material is available.
Anyone under age 20 with an initial stone deserves amore
extensive evaluation, including screening for renal tubular
acidosis,cystinuria,and hyperoxaluria.A more extensive
workup is also warranted in patients with a history of chronic
diarrhea, sarcoidosis,or aconditionassociatedwith renal
tubular acidosis (eg,Sjögrensyndrome),inpatients with a
family history of kidney stones,in patients with high-protein
weight-loss diets,and in those undergoing gastric bypass
surgery for obesity.In these high-riskpatients, the evaluation
should include 24-hour urine studies to measure calcium,
oxalate,citrate, uric acid, creatinine, sodium, and volume.
Other diagnostic clues are often helpful in the decision to do a
more comprehensive evaluation.
 Nephrocalcinosis onroentgenography suggests
hyperparathyroidism,medullary sponge kidney, or renal
tubular acidosis.
 Hypercalcemiathat develops after treatment of
hypercalciuriawitha thiazide diuretic suggests latent
hyperparathyroidism.
 A history of recurrent urinary tract infections or of
anatomic abnormalities inthe urinary tract should lead to
an evaluation for struvite stone disease.
 Uric acid stones shouldbe suspectedin a patient with
metabolic syndrome or a history ofgout and are usually
accompaniedby a urine pH lower than 5.5.
 A urinalysis showing cystine crystals always indicates
cystinuria,which should be confirmedby 24-hour urine
cystine determination.
 A family history ofrenal stones is more commonin
idiopathic hypercalciuria,cystinuria, primary
hyperoxaluria,and renal tubular acidosis.
References

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Author: J Stuart Wolf Jr, MD, FACS; Chief Editor:Bradley Fields
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http://www.medescape.net
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(3) ORECURRICULUM IN NEPHROLOGY
Nephrolithiasis
Alan G. Wasserstein,MD From the University ofPennsylvania
School ofMedicine,
Medicine/Renal Electrolyte,Renal Division,Hospital ofthe
University ofPennsylvania, Philadelphia, PA.
ReceivedJuly 19, 2004; accepted in revisedform October
6, 2004.
(4) Clevelandclinic journal of medicin
Nephrolithiasis: Treatment, causes, and prevention
PHILLIP M.HALL, MD
http://www.ccjm.org/