Urolithiasis

UROLITHIASIS
A. R. Morton and J.W.L. Wilson
1.?INTRODUCTION
?1.1?Historical Aspects
?-a disease described in antiquity by the many observers
?-mentioned in Oath of Hippocrates; itinerant lithotomists caused significant trauma, morbidity and high
mortality rate in patients who were willing to have these major procedures without any anaesthetic or
analgesia because of the severity of their symptoms
?-over last 150 years, pattern of stone disease has changed in industrialized societies from lower urinary
tract calculi (bladder stones) to upper tract calculi (renal and ureteric calculi of calcium oxalate)
?-lower tract urate calculi still a problem in the third world, particularly in children, where malnutrition
common and diets based on grains
?1.2?Epidemiology
?-upper urinary tract calculi common in North America and industrialized societies with high expenditure on
food and dependence on animal protein
?- geographic variations common, e.g.: stone belt in South-East USA; incidence of renal calculi decreases
from east to west in Canada
?-lower urinary tract (bladder) calculi seen in Canada only as a secondary problem due to outlet obstruction
(e.g. prostatic obstruction in men) or in presence of chronic infection or foreign bodies e.g.: indwelling
catheters
?-upper tract stones more common in men than women
?-60 year old male in USA has 8-10% chance of having a stone at some time in his life
?-urolithiasis is a recurrent problem; once an individual has had a stone, he/she has 35-50% chance of
having recurrent stone at some time later in life
?-incidence of stone disease varies throughout the world and may be positively correlated to age, race,
heredity, geography, local water supply, climate, hygiene, occupation, diet although data often conflicting
1.3?Physical-chemical Risk Factors for Recurrent Urolithiasis
??1) low urine volume
??2) elevated urinary excretion/ concentration of oxalate
??3) elevated urinary excretion/ concentration of calcium
??4) elevated urinary excretion/ concentration of uric acid
??5) decrease excretion of inhibitors of stone growth
??6) increase in urinary pH
?-most important risk factor is urine volume; if urine volume is doubled, the risk of forming further stones is
reduced be a factor of 4
?-a decrease in inhibitor excretion may increase risk of stone formation; inhibitors are ions, poly-anions,
http://meds.queensu.ca/medicine/urology/education/lectures/urolithiasis_2001.html etc., which are normally present in urine which inhibit the growth of stones or the nucleation of renal calculi:
some examples are pyrophosphate, citrate, some glycosaminoglycans, and some specialized glycoproteins -
nephrocalcin, osteopontin.
2.?THE PHYSICAL CHEMISTRY OF UROLITHIASIS
?2.1?Crystalline Composition of Renal Calculi
?-most common type of stone found is calcium oxalate either as monohydrate or dihydrate crystal form;
about 60% calculi are pure calcium oxalate
?-mixed calcium oxalate-calcium phosphate; about 10%
?-pure calcium phosphate 9%
?-struvite (infection stones of magnesium ammonium phosphate, also called triple phosphate stones) 5-10%
?-uric acid stones 5 - 10% ( variable depending on diet)
?-miscellaneous stones 1-5% (cystine, rare metabolites, drugs etc.)
?-analysis of stone to determine composition is critical aspect of management of patients with renal stones
?-stones also contain approximately 2.5% organic material called stone matrix, the function of which has not
been fully determined
?2.2?States of Saturation-Formation of Renal Calculi
?-calculi will not grow in an undersaturated urine, however most of the time most people excrete urine that
is supersaturated for calcium phosphate, calcium oxalate, and uric acid, so that there is "energy" for
precipitation of crystals and further growth of these crystals
?-saturation state may be affected by:
?1) ionic strength-(increase in ionic strength decreases supersaturation) 2) complexation-(e.g. citrate forms
soluble complexes with calcium which decreases the supersaturation of calcium containing crystals, calcium
oxalate and calcium phosphate) 3) pH - (particularly for uric acid as an increase in pH will increase the
solubility of uric acid)
?-nucleation must occur before crystals will grow; in the urinary tract the heterogeneous nucleation typical
since there is cellular debris and cell surfaces on which nucleation will occur
?-once nucleation occurs there must be retention of the micro-crystal long enough for a stone to grow, and
this may occur by adherence of the crystal on the distal tubule cell in or by adherence to the renal papilla
(Randall's plaque).
2.3?Natural Inhibitors of Stone Formation
?-crystal formation is a complex process involving nucleation, aggregation of micro-crystals, disaggregation,
crystal growth and dissolution so stone formation occurs as a multi-step process which may be modified by
inhibitors of crystal growth and aggregation, or by promoters of crystal growth or by complexors of the
various ions in solution in urine
3?THE PATHOPHYSIOLOGY OF UROLITHIASIS
?3.1?Renal Handling of Calcium, Phosphate, Oxalate and Urate.
??3.1.1 Calcium
?The glomeruli of the kidneys filter about 1% (10 g) of the total body calcium each day. Only the
http://meds.queensu.ca/medicine/urology/education/lectures/urolithiasis_2001.html ultrafilterable calcium crosses the glomerular basement membrane. The ultrafilterable calcium is the free or
ionized calcium (47%) plus a small amount (6%) which is complexed to phosphates and citrates. Of the
filtered calcium, 98% is reabsorbed by the renal tubules. The proximal tubules are responsible for 65%, the
ascending loop of Henle for 20-25% and the distal tubules for 10%. The calcium in the tubular fluid is nearly
all ionized.
?The hormonal control of calcium reabsorption is exerted in the distal tubules. Here, both parathyroid
hormone (PTH) and 1,25-dihydroxyvitamin D (1,25-(OH)2D3) act to promote calcium reabsorption.
???3.1.1.1?Idiopathic hypercalciuria.
?From the point of view of urolithiasis, conditions increasing the urinary calcium throughput will increase
the likelihood of crystal formation. Despite what is known about renal calcium handling, the idiopathic form
of hypercalciuria is the most common. It occurs in about 50% of calcium oxalate stone formers. Two main
mechanisms have been proposed. The first is absorptive hypercalciuria. This condition appears to be
familial behaving in a Mendelian dominant fashion. The serum calcium is normal, and the suspected
mechanism is enhanced gastrointestinal calcium absorption. It is currently believed that this is due to
excessive 1,25-(OH)2D3 levels. The second mechanism is renal hypercalciuria. In this condition, a proximal
tubular calcium leak is believed to be present. Thus in renal hypercalciuria, fasting urinary calcium excretion
is elevated, whereas it is normal in absorptive hypercalciuria.
???3.1.1.2?Primary hyperparathyroidism.
?This causes hypercalciuria in about 5% of calcium stone formers. The disorder of often very subtle and
requires frequent estimations of serum ionized calcium and of simultaneous PTH levels to make the
diagnosis.
???3.1.1.3?Renal tubular acidosis.
?Patients with RTA are frequently hypercalciuric. These disorders will be described below.
???3.1.1.4?Rare causes of hypercalciuria.
?This includes diseases such as sarcoidosis and vitamin D intoxication.
??3.1.2?Phosphate
?The vast majority of the phosphate in plasma is in the ultrafilterable form. The tubular resorption of
phosphate is, again, mostly handled by the proximal tubules where 80% is reabsorbed. There is very little
phosphate handling in the loop of Henle.
?The fine control of phosphate handling is under the control of the distal tubules. This is influenced by PTH
and, possibly 1,25-(OH)2D3. Another factor important in serum phosphate balance are the extracellular fluid
volume. An increased ECF volume will enhance renal phosphate excretion and lead to phosphate depletion if
intake is poor.
?From the point of view of renal stone disease, urinary phosphate excretion is of little importance except
when urine pH is abnormally elevated, leading to the possibility of struvite (magnesium ammonium
phosphate) stone formation.
??3.1.3?Oxalate
?Oxalate is an end product of several metabolic pathways including ascorbate, serine/glycine and
hydroxyproline catabolism. Oxalate is not metabolised further by the body, so that renal excretion is the sole
route of elimination. It is freely filtered by the glomerulus and, since the clearance of oxalate exceeds
creatinine clearance, it is likely that there is net tubular secretion of oxalate. Changes in oxalate excretion
are the most important factors which may predispose to recurrence of stones, but oxalate metabolism is the
most adjust by diet or medication alterations.
http://meds.queensu.ca/medicine/urology/education/lectures/urolithiasis_2001.html ???3.1.3.1?Primary hyperoxaluria
?The is the term for two distinct autosomal recessive disorders of glycine/serine metabolism which result in
the over production of oxalate. From the point of view of nephrolithiasis, the most important in this group is
type I primary hyperoxaluria. The defect appears to be in the enzyme a-ketoglutarate:glyoxlyate carboligase
which is deficient in many tissues, most critically the liver. This results in a build up of glyoxylate which is
oxidised to oxalate. The resulting increased oxalate levels must be excreted by the kidneys. Since calcium
oxalate is very insoluble, the excess oxalate excretion may result in frequent calcium oxalate stones at a
very young age and usually results in chronic renal failure due to deposition of calcium oxalate in the renal
tubules.
???3.1.3.2?Enteric hyperoxaluria
?Any chronic malabsorption syndrome with fat malabsorption may result in increased absorption of dietary
oxalate and resultant increased urinary excretion of oxalate and formation of calcium oxalate calculi. The
mechanism of increased oxalate absorption is complex, and involves calcium malabsorption, and
saponification with malabsorbed fat, freeing oxalate for intestinal uptake, as well as the malabsorbed bile
salts increasing colonic permeability to oxalate.
?Dietary hyperoxaluria occurs in people who eat large amounts of nuts, peppers, chocolate rhubarb and
spinach. Large doses of vitamin C can cause spurious hyperoxaluria since the assays for oxalate result in
the breakdown of excreted urinary Vitamin C to oxalate.
???3.1.3.3?Toxic hyperoxaluria
?Ingestion of ethylene glycol (anti-freeze) results in massive tubular precipitation of calcium oxalate crystals
and is a rare cause of renal failure.
??3.1.4?Uric Acid (urate)
?Urate is the end product of purine oxidation. About two thirds is excreted by the kidneys, and one third by
the gastrointestinal tract where it undergoes bacterial degradation. Approximately 98% of the filtered urate is
reabsorbed by the proximal tubules. The majority of the urate which appears in the urine (80%) is present as
a result of distal tubular excretion. Much of this excretion process is by "back-leak" of urate from the
tubular interstitial space through the distal tubules.
?Urate is always present in the tubular fluid in a supersaturated state. The liability to precipitation is greatest
when the urine is most acidic. The solubility of uric acid/urate is 0.5 mmol/l at pH 5, 1.3 mmol/l at pH 6 and
9.4 mmol/l at pH 7.
???3.1.4.1?Mixed uric acid: urate stones
?From the point of view of renal stone disease the greatest danger for urate precipitation occurs when the
concentrations of sodium and urate are greatest. These conditions arise in the renal medulla when
concentrated urine is being formed. The urine pH in patients who form mixed urate stones is nearly always
below 6. About 12% of calcium stone formers will have mixed stones.
???3.1.4.2?Pure uric acid stones
?These are rare, occurring in about 5% of stone formers. These patients typically have very acid urine (pH 5)
and thus are more susceptible to crystal formation. These stones are frequently found in patients with gout
and other familial disorders.
???3.1.4.3?Hyperuricosuria
?About 25% of calcium stone formers excrete increased amounts of urate in the urine. It is thought that, in
these individuals, the precipitation of calcium or sodium urate may enhance calcium oxalate crystal
propagation.
http://meds.queensu.ca/medicine/urology/education/lectures/urolithiasis_2001.html ?These patients often have high purine intakes (meats), but may have one of the rarer syndromes of urate
overproduction.
3.2?Urinary Acidification and Alkalinization
?3.2.1?Acidification
?The urinary acidification mechanism is highly adapted in order to excrete the approximately 70 mmol/day
of hydrogen ions produced by normal metabolism. This is a major undertaking, considering that the serum
hydrogen ion concentration is kept in the nmolar range. Several inherited and acquired renal conditions (the
Renal Tubular Acidoses) give rise to defects in hydrogen ion excretion. The majority (including proximal
(type II) renal tubular acidosis and those associated other systemic diseases such as primary biliary
cirrhosis, Sjogren's Syndrome, or toxins such as Amphotericin B, lithium etc. are not associated with
nephrolithiasis.
??3.2.1.1?Distal renal tubular acidosis (Type I).
?The hereditary or idiopathic, sporadic distal RTA is associated with nephrocalcinosis and renal calculi. The
stones formed are for the most part calcium phosphate in nature. They appear to be related to the presence
of hypercalciuria, alkaline urine pH and hypocitraturia.
?The mechanism of the hyercalciuria is related to increased bone mineral wastage. The bone buffers are
constantly being used up to defend the body against the chronic metabolic acidosis. In addition to the
calcium leakage from bone, phosphate also leaks out. Thus the urinary calcium-phosphate product is
elevated. Because of the tubular bicarbonate wasting, the urine pH is abnormally alkaline, thus enhancing
the tendency for calcium phosphate precipitation. Urinary citrate levels are low due to enhanced
mitochondrial citrate metabolism in the face of the metabolic acidosis.
?3.2.2?Alkalinization
?The urinary mechanism for bicarbonate excretion is incompletely understood. The majority of the acid-
base functions of the kidney are aimed at hydrogen ion excretion. As the serum bicarbonate concentration
rises (in the absence of extracellular fluid volume contraction), increasing quantities of bicarbonate are
delivered to the distal nephron, due to a failure of proximal tubular resorption. The maintenance of
metabolic alkalosis is dependent on a continued supply of base in the presence of extra cellular volume
contraction.
?3.2.2.1?Struvite Stones
?Abnormal urinary alkalinization can occur in the presence of organisms which metabolise urea (commonly
proteus, but also pseudomonas, staph., candida, but not E. coli). The urea is split to ammonia, which is
hydrolyzed to ammonium hydroxide, raising urine pH to 8 to 9, at which pH struvite (magnesium ammonium
phosphate) precipitates. The bacteria persist in the stone as long as there are any residual fragments
present. Struvite stone disease has been called "stone cancer" since total eradication of all stone material is
necessary to prevent recurrence of stone. The stones tend to be very large (staghorn), and frequently result
in renal damage, but patients may be relatively symptom free until the stone occupies entire collecting
system.
3.3?Formation of Rare Stones
?3.3.1 Inborn Errors of Metabolism
?A number of uncommon inborn errors of metabolism increase the propensity of the body to form stones.
The hyperoxalurias have been mentioned briefly already. Furthermore, a small number of patients have
abnormal activity of the enzymes involved in uric acid synthesis. Examples include increased activity of
phosphoribosyl-pyrophosphate synthetase and decreased activity of hypoxanthine-guanine phosphoribosyl
transferase.
http://meds.queensu.ca/medicine/urology/education/lectures/urolithiasis_2001.html ?3.3.1.1?Cystinuria
?This condition is an inborn error of metabolism characterized by increased urinary excretion of cystine,
ornithine, lysine, arginine (COLA), due to a defect in renal tubular reabsorption of these amino acids. The
disease is of clinical significance only because cystine is relatively insoluble (1 mmol/l) and will precipitate
in concentrated urine, otherwise this would be a biochemical curiosity only. The stones tend to be large
when present and are partially radiolucent and are a recurrent problem, beginning early in life.
? The treatment is based on increasing fluid intake so that urine becomes more dilute and able to keep
cystine in solution. This requires an intake of about 3 - 6 litres of fluid per day. Cystine is more soluble at
alkaline pH (>7.4), so urinary alkalinization is also important. D-penicillamine forms soluble complexes with
cystine but its toxicity (anemia, thrombocytopenia, hepatic dysfunction, nephrotic syndrome etc.) limits its
usefulness. a-mercaptopropionylglycine (a-MPG) and captopril have also been used.
3.3.2?Curiosities
?Some drugs (triamterene, some of the older sulphas) can be metabolized to insoluble compounds which
can precipitate in urine.
?The carbonic anhydrase inhibitor, acetazolamide, used in patients with glaucoma and some neurological
disorders, causes a combined Type 1 and Type 2 RTA which may result in nephrolithiasis.
4.?CLINICAL SYNDROMES OF UROLITHIASIS
4.1?Acute Ureteric Colic
?Acute ureteric (renal) colic is a most painful clinical syndrome. Its identification and appropriate
management bring relief and satisfaction to patients and their families.
?4.1.1?Presentation
?Ureteric colic is an agonizing pain which originates in the loin and radiates to the groin. It begins suddenly
without warning and rapidly becomes excruciating. It is frequently accompanied by vomiting and sweating.
Strangury (the passage a small amount of (bloody) urine after straining) is common. Haematuria is
frequently present. The colic must be distinguished from appendicitis, acute pelvic inflammatory disease,
inflammatory bowel disease, ectopic pregnancy etc. Once experienced, the pain is never forgotten and
patients who have experienced renal colic are very good at diagnosing subsequent recurrences. The pain
will require narcotics for relief; supplementation with NSAID by suppository will increase efficacy.
?4.1.2?Investigation
?Documentation of the calculus with radiological studies is required. An IVP usually necessary to identify
the stone, the site of obstruction and degree of obstruction to urine drainage. Ultrasound is not usually
sensitive for small ureteric calculi since the ureter is an "invisible" area on ultrasound and hydronephosis
may not occur until several hours to days after obstruction by a stone has occurred. Currently in many
centres, the standard of care for diagnosis of a patient presenting with flank pain suspicious for a ureteral
calculus is a spiral CT without contrast - this is very sensitive for diagnosis of the stone and permits
adequate differentiation from other possible diagnoses - e.g. PID, diverticular disease, appendicitis, ovarian
cysts etc.
?4.1.3?Management
?Most stones will pass spontaneously (90% stones less than 5 mm in diameter) so the management of the
acute episode is fluids, analgesics, reassurance, rest and tincture of time.
?The presence of fever or other signs of infection require surgical intervention, the goal being to establish
urinary drainage.
http://meds.queensu.ca/medicine/urology/education/lectures/urolithiasis_2001.html ??4.1.3.1?Indications For Surgical Management
?The indications for surgical intervention include: persistent pain, signs of urinary infection, non-
progression of the calculus and evidence of obstruction to urine drainage without early spontaneous
passage of the stone (calyectasis, hydronephrosis, hydroureter etc.).
??4.1.3.2?Forms of Available Surgical Therapy
?Until 10 years ago all stones required open surgery (pyelolithotmy, ureterolithotomy) but these are not
necessary now with newer less invasive surgical techniques.
?Percutaneous nephrostolithotomy removes stone through tract established through flank with radiological
guidance, larger stones can be fragmented with ultrasonic, electrohydraulic or laser probes.
?Extracorporeal Shock Wave Lithotripsy (ESWL) uses focused shock waves transmitted through body
tissues to fragment stones which then can be passed spontaneously down ureter and out from bladder. This
technique obviates need for surgery; anaesthetics are not needed.
?Ureteric stones can be approached from below using fine calibre ureteroscopes and lithotripsy, either
electrohydraulic, pneumatic percussion or laser, to fragment calculi which can be manipulated out using
various instruments (stone baskets) or allowed to pass spontaneously.
4.2? Solitary & Recurrent Stone Formation
?Since the recommended approach to these clinical situations is similar, they will be discussed together.
Longitudinal studies have shown that the incidence of recurrence after the appearance of a single renal
stone is 50% at 5 years and over 60% at 9 years.
?4.2.1?Renal Calculi - Presentation
?Stones located in the renal pelvis and calyces usually are not associated with severe pain although there
may be a dull ache localized to the flank. The first symptoms however may begin dramatically, with ureteric
colic, when the stone moves from the renal pelvis into the ureter. Calculi may be found as an incidental
finding on an abdominal radiograph or ultrasound examination performed for some other purpose. In
addition, patients with stones may present with (relatively) painless passage of "grit" or "gravel" in the
urine.
?4.2.2?Investigation
?Laboratory determination of the composition of the stone is the cornerstone of rational investigation and
management. Renal function should be assessed and presence of urinary tract infection determined. It is
worth remembering that only about 5% of stone formers will have a readily diagnosable condition.
??4.2.2.1?History
?In the search for an aetiology for stones, the history should focus on dietary intake of calcium, meats and
oxalate rich products. Fluid intake is also very important. A drug history (vitamin D, acetazolamide,
triamterene, steroids) and family history (cystinuria, RTA, idiopathic hypercalciuria) are mandatory. A
previous history of abdominal surgery may be relevant.
??4.2.2.2?Laboratory Studies
?The identification of stone type will determine further investigations (e.g. cystine stones, urate stones).
Since majority of stones will be calcium oxalate or mixed calcium oxalate / calcium phosphate stones,
investigation will frequently proceed along the following lines. In general, laboratory investigations are only
necessary when possible findings would indicate an alteration in therapy - either surgical or medical
therapy. Since medical therapy is not indicated in all stone formers, extensive investigations should not be
done in all patients.
?Serum electrolytes, bicarbonate, urate and creatinine, ionized calcium and phosphorus. The presence of an
http://meds.queensu.ca/medicine/urology/education/lectures/urolithiasis_2001.html elevated ionized calcium mandates a search for primary hyperparathyroidism. Repeated measurements of
urine pH. The presence of a low serum bicarbonate (< 16 mmol/l) and an elevated fasting urine pH (> 5.4)
suggests distal renal tubular acidosis. Hyperuricaemia should lead to a search for hyperuricosuria and low
urine pH. A 24-hour urine collection for creatinine clearance and volume is very useful. Urinary excretion of
calcium, urate, oxalate and citrate may be measured. Absorptive and renal hypercalciurias can be
differentiated on the basis of fasting urinary calcium excretion.
??4.2.3?Medical Management
?The general principles of treatment for renal stones disease are simple. Maximal hydration should be
achieved, and a recommended fluid intake of 3l/day is reasonable. This permits excretion of at least 2 l/day
of dilute urine. Dietary restriction of oxalate, urate and sodium is probably of more benefit than dietary
restriction of calcium. An excessive intake of calcium is to be avoided however restriction of calcium
containing food is not required. In fact severe restriction of dietary calcium may increase the risk of
recurrent renal calculi. Urinary infection should be eradicated.
???4.2.3.1?Urinary Alkalinization
?The solubility of many crystals is affected significantly by urinary pH. Alkalinization (pH > 6.5) of the urine
with potassium citrate or sodium / potassium bicarbonate is useful in the treatment of nephrolithiasis and
nephrocalcinosis associated with RTA, urate stone disease and cystinuria. Unfortunately, a urine pH > 7.5 is
difficult to achieve and sustain.
???4.2.3.2?Thiazide Diuretics
?Thiazide diuretics have been shown to useful in reducing recurrence of stones in patients with
hypercalciuria. These agents actively stimulate distal tubular resorption of calcium. In addition by reducing
proximal tubular "wastage" of calcium, the calcium throughput is decreased. Thus these agents are useful
for recurrent calcium oxalate stone formers. Used in the long term, thiazides may result in a small decrease
in oxalate excretion.
???4.2.3.3?Allopurinol
?Allopurinol inhibits the final 2 steps in the synthesis of uric acid and thus greatly diminishes urinary urate
concentrations. This agent may also be useful in some recurrent calcium stone formers where a urate nidus
is occasionally present.
???4.2.3.4?Binders
?The use of cholestyramine or calcium carbonate, which bind oxalate in the gut has been suggested for
patients who excrete large amounts of oxalate. In addition sodium cellulose phosphate (a calcium binder)
has been used in cases of absorptive hypercalciuria.
???4.2.3.5?Citrate
?Increasingly citrate preparations are being used for the prevention of recurrent calcium oxalate stones. The
increase citrate results in a reduced excretion of calcium, and an increased excretion of the inhibitor and
complexor - citrate. Many citrate preparations are now available and in general the drug is well tolerated -
although it needs to be taken three or four times a day which has an impact on patient compliance.
References
1) Kidney Stones - Medical and Surgical Management ed.: Coe, Favus, Pak, Parks, Preminger Lippincott-
Raven 1996
2) Urinary Stones - Diagnosis, Treatment and Prevention of Recurrence
Hesse, Tiselius, Jahnen Karger 1997
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