Renal Stone

Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of crystal to aggregate and form hard masses, or calculi (stones) in the upper urinary tract. Because renal calculi typically form in the kidney, if small enough, they are able to leave the urinary tract via the urine stream. A small calculus may pass without causing symptoms. However, if a stone grows to more than , it can cause blockage of the ureter, resulting in extremely sharp and severe pain (renal colic) in the lower back that often radiates downward to the groin. A calculus may also result in blood in the urine, vomiting (due to severe pain), or painful urination. About half of all people who have had a kidney stone are likely to develop another within ten years.

''Renal'' is Latin for "kidney", while "nephro" is the Greek equivalent. "Lithiasis" (Gr.) and "calculus" (Lat.- pl. calculi) both mean stone.

Most calculi form by a combination of genetics and environmental factors. Risk factors include high urine calcium levels, obesity, certain foods, some medications, calcium supplements, gout, hyperparathyroidism and not drinking enough fluids. Calculi form in the kidney when minerals in urine are at high concentration. The diagnosis is usually based on symptoms, urine testing, and medical imaging. Blood tests may also be useful. Calculi are typically classified by their location: nephrolithiasis (in the kidney), ureterolithiasis (in the ureter), cystolithiasis (in the bladder), or by what they are made of (calcium oxalate, uric acid, struvite, cystine).

In those who have had renal calculi, drinking fluids, especially water,
is a way to prevent them. Drinking fluids such that more than two liters of urine are produced per day is recommended. If fluid intake alone is not effective to prevent renal calculi, the medications thiazide diuretic, citrate, or allopurinol may be suggested. Soft drinks containing phosphoric acid (typically colas) should be avoided. When a calculus causes no symptoms, no treatment is needed. For those with symptoms, pain control is usually the first measure, using medications such as nonsteroidal anti-inflammatory drugs or opioids. Larger calculi may be helped to pass with the medication tamsulosin or may require procedures such as extracorporeal shock wave lithotripsy, ureteroscopy, or percutaneous nephrolithotomy.

Renal calculi have affected humans throughout history with a description of surgery to remove them dating from as early as 600 BC in ancient India by Sushruta. Between 1% and 15% of people globally are affected by renal calculi at some point in their lives. In 2015, 22.1 million cases occurred, resulting in about 16,100 deaths. They have become more common in the Western world since the 1970s. Generally, more men are affected than women. The prevalence and incidence of the disease rises worldwide and continues to be challenging for patients, physicians, and healthcare systems alike. In this context, epidemiological studies are striving to elucidate the worldwide changes in the patterns and the burden of the disease and identify modifiable risk factors that contribute to the development of renal calculi.

Signs and symptoms

The hallmark of a stone that obstructs the ureter or renal pelvis is excruciating, intermittent pain that radiates from the flank to the groin or to the inner thigh. This is due to the transfer of referred pain signals from the lower thoracic splanchnic nerves to the lumbar splanchnic nerves as the stone passes down from the kidney or proximal ureter to the distal ureter. This pain, known as renal colic, is often described as one of the strongest pain sensations known. Renal colic caused by kidney stones is commonly accompanied by urinary urgency, restlessness, hematuria, sweating, nausea, and vomiting. It typically comes in waves lasting 20 to 60 minutes caused by peristaltic contractions of the ureter as it attempts to expel the stone.

The embryological link between the urinary tract, the genital system, and the gastrointestinal tract is the basis of the radiation of pain to the gonads, as well as the nausea and vomiting that are also common in urolithiasis. Postrenal azotemia and hydronephrosis can be observed following the obstruction of urine flow through one or both ureters.

Pain in the lower-left quadrant can sometimes be confused with diverticulitis because the sigmoid colon overlaps the ureter, and the exact location of the pain may be difficult to isolate due to the proximity of these two structures.

Risk factors

Dehydration from low fluid intake is a factor in stone formation. Individuals living in warm climates are at higher risk due to increased fluid loss. Obesity, immobility, and sedentary lifestyles are other leading risk factors.

High dietary intake of animal protein, sodium, sugars including honey, refined sugars, fructose and high fructose corn syrup, and excessive consumption of fruit juices may increase the risk of kidney stone formation due to increased uric acid excretion and elevated urinary oxalate levels (whereas tea, coffee, wine and beer may decrease the risk).

Kidney stones can result from an underlying metabolic condition, such as distal renal tubular acidosis, Dent's disease, hyperparathyroidism, primary hyperoxaluria, or medullary sponge kidney. 3–20% of people who form kidney stones have medullary sponge kidney.

Kidney stones are more common in people with Crohn's disease; Crohn's disease is associated with hyperoxaluria and malabsorption of magnesium.

A person with recurrent kidney stones may be screened for such disorders. This is typically done with a 24-hour urine collection. The urine is analyzed for features that promote stone formation.

Calcium oxalate

Calcium is one component of the most common type of human kidney stones, calcium oxalate. Some studies suggest that people who take calcium or vitamin D as a dietary supplement have a higher risk of developing kidney stones. In the United States, kidney stone formation was used as an indicator of excess calcium intake by the Reference Daily Intake committee for calcium in adults.

In the early 1990s, a study conducted for the Women's Health Initiative in the US found that postmenopausal women who consumed 1000 mg of supplemental calcium and 400 international units of vitamin D per day for seven years had a 17% higher risk of developing kidney stones than subjects taking a placebo. The Nurses' Health Study also showed an association between supplemental calcium intake and kidney stone formation.

Unlike supplemental calcium, high intakes of dietary calcium do not appear to cause kidney stones and may actually protect against their development. This is perhaps related to the role of calcium in binding ingested oxalate in the gastrointestinal tract. As the amount of calcium intake decreases, the amount of oxalate available for absorption into the bloodstream increases; this oxalate is then excreted in greater amounts into the urine by the kidneys. In the urine, oxalate is a very strong promoter of calcium oxalate precipitation—about 15 times stronger than calcium.

A 2004 study found that diets low in calcium are associated with a higher overall risk for kidney stone formation. For most individuals, other risk factors for kidney stones, such as high intakes of dietary oxalates and low fluid intake, play a greater role than calcium intake.

Other electrolytes

Calcium is not the only electrolyte that influences the formation of kidney stones. For example, by increasing urinary calcium excretion, high dietary sodium may increase the risk of stone formation.

Drinking fluoridated tap water may increase the risk of kidney stone formation by a similar mechanism, though further epidemiologic studies are warranted to determine whether fluoride in drinking water is associated with an increased incidence of kidney stones. High dietary intake of potassium appears to reduce the risk of stone formation because potassium promotes the urinary excretion of citrate, an inhibitor of calcium crystal formation.

Kidney stones are more likely to develop, and to grow larger, if a person has low dietary magnesium. Magnesium inhibits stone formation.

Animal protein

Diets in Western nations typically contain a large proportion of animal protein. Eating animal protein creates an acid load that increases urinary excretion of calcium and uric acid and reduced citrate. Urinary excretion of excess sulfurous amino acids (e.g., cysteine and methionine), uric acid, and other acidic metabolites from animal protein acidifies the urine, which promotes the formation of kidney stones. Low urinary-citrate excretion is also commonly found in those with a high dietary intake of animal protein, whereas vegetarians tend to have higher levels of citrate excretion. Low urinary citrate, too, promotes stone formation.

Vitamins

The evidence linking vitamin C supplements with an increased rate of kidney stones is inconclusive. The excess dietary intake of vitamin C might increase the risk of calcium-oxalate stone formation. The link between vitamin D intake and kidney stones is also tenuous.

Excessive vitamin D supplementation may increase the risk of stone formation by increasing the intestinal absorption of calcium; correction of a deficiency does not.

Pathophysiology

Supersaturation of urine

Kidney stones are primarily composed of calcium salts, with the most common being calcium oxalate (70-80%), followed by calcium phosphate and uric acid. When urine contains high concentrations of these ions, they can form crystals and eventually stones.

The formation of kidney stones occurs in three main phases:
# nucleation (initial crystal formation)
# growth (expansion of single crystals)
# aggregation (clumping together of multiple crystals)

When the urine becomes supersaturated (when the urine solvent contains more solutes than it can hold in solution) with one or more calculogenic (crystal-forming) substances, initial seed crystals may form through the process of nucleation. Heterogeneous nucleation (where there is a solid surface present on which a crystal can grow) proceeds more rapidly than homogeneous nucleation (where a crystal must grow in a liquid medium with no such surface), because it requires less energy. Adhering to cells on the surface of a renal papilla, a seed crystal can grow and aggregate into an organized mass. Depending on the chemical composition of the crystal, the stone-forming process may proceed more rapidly when the urine pH is unusually high or low.

Supersaturation of the urine with respect to a calculogenic compound is pH-dependent. For example, at a pH of 7.0, the solubility of uric acid in urine is 158 mg/100 mL. Reducing the pH to 5.0 decreases the solubility of uric acid to less than 8 mg/100 mL. The formation of uric-acid stones requires a combination of hyperuricosuria (high urine uric-acid levels) and low urine pH; hyperuricosuria alone is not associated with uric-acid stone formation if the urine pH is alkaline. Supersaturation of the urine is a necessary, but not a sufficient, condition for the development of any urinary calculus. Supersaturation is likely the underlying cause of uric acid and cystine stones, but calcium-based stones (especially calcium oxalate stones) may have a more complex cause.

Randall's plaque

While supersaturation of urine may lead to crystalluria, it does not necessarily promote the formation of a kidney stone because the particle may not reach the sufficient size needed for renal attachment. On the other hand, Randall's plaques, which were first identified by Alexander Randall in 1937, are calcium phosphate deposits that form in the papillary interstitium and are thought to be the nidus required for stone development. In addition to Randall's plugs, which form in the Duct of Bellini, these structures can generate reactive oxygen species that further enhance stone formation.

Pathogenic bacteria

Some bacteria have roles in promoting stone formation. Specifically, urease-positive bacteria, such as ''Proteus mirabilis'' can produce the enzyme urease, which converts urea to ammonia and carbon dioxide. This increases the urinary pH and promotes struvite stone formation. Additionally, non-urease producing bacteria can provide bacterial components that promote calcium oxalate crystallization, though this mechanism is poorly understood.

Inhibitors of stone formation

Normal urine contains chelating agents, such as citrate, that inhibit the nucleation, growth, and aggregation of calcium-containing crystals. Other endogenous inhibitors include calgranulin (an S-100 calcium-binding protein), Tamm–Horsfall protein, glycosaminoglycans, uropontin (a form of osteopontin), nephrocalcin (an acidic glycoprotein), prothrombin F1 peptide, and bikunin (uronic acid-rich protein). The biochemical mechanisms of action of these substances have not yet been thoroughly elucidated. However, when these substances fall below their normal proportions, stones can form from an aggregation of crystals.

Sufficient dietary intake of magnesium and citrate inhibits the formation of calcium oxalate and calcium phosphate stones; in addition, magnesium and citrate operate synergistically to inhibit kidney stones. The efficacy of magnesium in subduing stone formation and growth is dose-dependent.

Hypocitraturia

Hypocitraturia or low urinary-citrate excretion (variably defined as less than 320 mg/day) can be a contributing cause of kidney stones in up to 2/3 of cases. The protective role of citrate is linked to several mechanisms; citrate reduces urinary supersaturation of calcium salts by forming soluble complexes with calcium ions and by inhibiting crystal growth and aggregation. Therapy with potassium citrate is commonly prescribed in clinical practice to increase urinary citrate and to reduce stone formation rates. Alkali citrate is also used to increase urine citrate levels. It can be prescribed or found over-the-counter in pill, liquid or powder form.

Diagnosis

Diagnosis of kidney stones is made on the basis of information obtained from the history, physical examination, urinalysis, and radiographic studies. Clinical diagnosis is usually made on the basis of the location and severity of the pain, which is typically colicky in nature (comes and goes in spasmodic waves). Pain in the back occurs when calculi produce an obstruction in the kidney. Physical examination may reveal fever and tenderness at the costovertebral angle on the affected side.

Imaging studies

Calcium-containing stones are relatively radiodense (opaque to X-rays), and they can often be detected by a traditional radiography of the abdomen that includes the kidneys, ureters, and bladder (KUB film). KUB radiography, although useful in monitoring size of stone or passage of stone in stone formers, might not be useful in the acute setting due to low sensitivity. Some 60% of all renal stones are radiopaque. In general, calcium phosphate stones have the greatest density, followed by calcium oxalate and magnesium ammonium phosphate stones. Cystine calculi are only faintly radiodense, while uric acid stones are usually entirely radiolucent.

In people with a history of stones, those who are less than 50 years of age and are presenting with the symptoms of stones without any concerning signs do not require helical CT scan imaging. A computed tomography (CT) scan is also not typically recommended in children.

Otherwise a noncontrast helical CT scan with sections is the diagnostic method to use to detect kidney stones and confirm the diagnosis of kidney stone disease. Near all stones are detectable on CT scans with the exception of those composed of certain drug residues in the urine, such as from indinavir.

Where a CT scan is unavailable, an intravenous pyelogram may be performed to help confirm the diagnosis of urolithiasis. This involves intravenous injection of a contrast agent followed by a KUB film. Uroliths present in the kidneys, ureters, or bladder may be better defined by the use of this contrast agent. Stones can also be detected by a retrograde pyelogram, where a similar contrast agent is injected directly into the distal ostium of the ureter (where the ureter terminates as it enters the bladder).

Renal ultrasonography can sometimes be useful, because it gives details about the presence of hydronephrosis, suggesting that the stone is blocking the outflow of urine. Radiolucent stones, which do not appear on KUB, may show up on ultrasound imaging studies. Other advantages of renal ultrasonography include its low cost and absence of radiation exposure. Ultrasound imaging is useful for detecting stones in situations where X-rays or CT scans are discouraged, such as in children or pregnant women. Despite these advantages, renal ultrasonography in 2009 was not considered a substitute for noncontrast helical CT scan in the initial diagnostic evaluation of urolithiasis. The main reason for this is that, compared with CT, renal ultrasonography more often fails to detect small stones (especially ureteral stones) and other serious disorders that could be causing the symptoms.

On the contrary, a 2014 study suggested that ultrasonography should be used as the initial diagnostic imaging test, with further imaging studies be performed at the discretion of the physician on the basis of clinical judgment, and using ultrasonography rather than CT as an initial diagnostic test results in less radiation exposure and equally good outcome.

File:Kidney stones abdominal X-ray.jpg, Bilateral kidney stones can be seen on this KUB radiograph. There are phleboliths in the pelvis, which can be misinterpreted as bladder stones.
File:3mmstone.png, Axial CT scan of abdomen without contrast, showing a 3-mm stone (marked by an arrow) in the left proximal ureter
File:Ultrasonography of renal stone located at the pyeloureteric junction.jpg, Renal ultrasonograph of a stone located at the pyeloureteric junction with accompanying hydronephrosis.
File:CT measurement of kidney stone in soft tissue and bone window.jpg, Measurement of a 5.6 mm large kidney stone in soft tissue versus skeletal CT window.

Laboratory examination

Laboratory investigations typically carried out include:
* microscopic examination of the urine, which may show red blood cells, bacteria, leukocytes, urinary casts, and crystals;
* urine culture to identify any infecting organisms present in the urinary tract and sensitivity to determine the susceptibility of these organisms to specific antibiotics;
* complete blood count, looking for neutrophilia (increased neutrophil granulocyte count) suggestive of bacterial infection, as seen in the setting of struvite stones;
* renal function tests to look for abnormally high blood calcium levels (hypercalcemia);
* 24 hour urine collection to measure total daily urinary volume, magnesium, sodium, uric acid, calcium, citrate, oxalate, and phosphate;
* collection of stones (by urinating through a StoneScreen kidney stone collection cup or a simple tea strainer) is useful. Chemical analysis of collected stones can establish their composition, which in turn can help to guide future preventive and therapeutic management.

Composition

Calcium-containing stones

By far, the most common type of kidney stones worldwide contains calcium. For example, calcium-containing stones represent about 80% of all cases in the United States; these typically contain calcium oxalate either alone or in combination with calcium phosphate in the form of apatite or brushite of oxalate crystals in the urine, such as primary hyperoxaluria, are associated with the development of calcium oxalate stones. The formation of calcium phosphate stones is associated with conditions such as hyperparathyroidism and renal tubular acidosis.

Oxaluria is increased in patients with certain gastrointestinal disorders including inflammatory bowel disease such as Crohn's disease or in patients who have undergone resection of the small bowel or small-bowel bypass procedures. Oxaluria is also increased in patients who consume increased amounts of oxalate (found in vegetables and nuts). Primary hyperoxaluria is a rare autosomal recessive condition that usually presents in childhood.

Calcium oxalate crystals can come in two varieties. Calcium oxalate monohydrate can appear as 'dumbbells' or as long ovals that resemble the individual posts in a picket fence. Calcium oxalate dihydrate have a tetragonal "envelope" appearance.

Struvite stones

About 10–15% of urinary calculi are composed of struvite (hexa-hydrated ammonium magnesium phosphate, NH₄MgPO₄·6H₂O). Struvite stones (also known as "infection stones," urease, or triple-phosphate stones) form most often in the presence of infection by urea-splitting bacteria. Using the enzyme urease, these organisms metabolize urea into ammonia and carbon dioxide. This alkalinizes the urine, resulting in favorable conditions for the formation of struvite stones. ''Proteus mirabilis'', ''Proteus vulgaris'', and ''Morganella morganii'' are the most common organisms isolated; less common organisms include ''Ureaplasma urealyticum'' and some species of '' Providencia'', ''Klebsiella'', ''Serratia'', and ''Enterobacter''. These infection stones are commonly observed in people who have factors that predispose them to urinary tract infections, such as those with spinal cord injury and other forms of neurogenic bladder, ileal conduit urinary diversion, vesicoureteral reflux, and obstructive uropathies. They are also commonly seen in people with underlying metabolic disorders, such as idiopathic hypercalciuria, hyperparathyroidism, and gout. Infection stones can grow rapidly, forming large calyceal staghorn (antler-shaped) calculi requiring invasive surgery such as percutaneous nephrolithotomy for definitive treatment.

Struvite stones (triple-phosphate/magnesium ammonium phosphate) have a 'coffin lid' morphology by microscopy.

Uric acid stones

About 5–10% of all stones are formed from uric acid. People with certain metabolic abnormalities, including obesity, may produce uric acid stones. They also may form in association with conditions that cause hyperuricosuria (an excessive amount of uric acid in the urine) with or without hyperuricemia (an excessive amount of uric acid in the serum). They may also form in association with disorders of acid/base metabolism where the urine is excessively acidic (low pH), resulting in precipitation of uric acid crystals. A diagnosis of uric acid urolithiasis is supported by the presence of a radiolucent stone in the face of persistent urine acidity, in conjunction with the finding of uric acid crystals in fresh urine samples.

As noted above (section on calcium oxalate stones), people with inflammatory bowel disease (Crohn's disease, ulcerative colitis) tend to have hyperoxaluria and form oxalate stones. They also have a tendency to form urate stones. Urate stones are especially common after colon resection.

Uric acid stones appear as pleomorphic crystals, usually diamond-shaped. They may also look like squares or rods which are polarizable.

Other types

People with certain rare inborn errors of metabolism have a propensity to accumulate crystal-forming substances in their urine. For example, those with cystinuria, cystinosis, and Fanconi syndrome may form stones composed of cystine. Cystine stone formation can be treated with urine alkalinization and dietary protein restriction. People affected by xanthinuria often produce stones composed of xanthine. People affected by adenine phosphoribosyltransferase deficiency may produce 2,8-dihydroxyadenine stones, alkaptonurics produce homogentisic acid stones, and iminoglycinurics produce stones of glycine, proline, and hydroxyproline. Urolithiasis has also been noted to occur in the setting of therapeutic drug use, with crystals of drug forming within the renal tract in some people currently being treated with agents such as indinavir, sulfadiazine, and triamterene.

Location

Urolithiasis refers to stones originating anywhere in the urinary system, including the kidneys and bladder. Nephrolithiasis refers to the presence of such stones in the kidneys. Calyceal calculi are aggregations in either the minor or major calyx, parts of the kidney that pass urine into the ureter (the tube connecting the kidneys to the urinary bladder). The condition is called ureterolithiasis when a calculus is located in the ureter. Stones may also form or pass into the bladder, a condition referred to as bladder stones.

Size

Stones less than in diameter pass spontaneously in up to 98% of cases, while those measuring in diameter pass spontaneously in less than 53% of cases.

Stones that are large enough to fill out the renal calyces are called ''staghorn stones'' and are composed of struvite in a vast majority of cases, which forms only in the presence of urease-forming bacteria. Other forms that can possibly grow to become staghorn stones are those composed of cystine, calcium oxalate monohydrate, and uric acid.

Prevention

Preventative measures depend on the type of stones. In those with calcium stones, drinking plenty of fluids, thiazide diuretics and citrate are effective as is allopurinol in those with high uric acid levels in urine.

Dietary measures

Specific therapy should be tailored to the type of stones involved. Diet can have an effect on the development of kidney stones. Preventive strategies include some combination of dietary modifications and medications with the goal of reducing the excretory load of calculogenic compounds on the kidneys. Dietary recommendations to minimize the formation of kidney stones include:
* increasing total fluid intake to achieve more than two liters per day of urine output;
* limiting cola, including sugar-sweetened soft drinks; to less than one liter per week.
* limiting animal protein intake to no more than two meals daily (an association between animal protein and recurrence of kidney stones has been shown in men);
* increasing citrate, including from lemon and lime juice; citric acid in its natural form, such as from citrus fruits, "prevents small stones from becoming 'problem stones' by coating them and preventing other material from attaching and building onto the stones"; citrate inhibits the formation of kidney stones on all phasesnucleation, growth and aggregationby raising the limit at which oxalate remain stable, slowing oxalate crystal growth, and notably, reducing crystal aggregation within the kidney tubules;
* increase alkaline load by consuming more fruits and vegetables (because uric acid crystals form in acidic environment);
* reducing sodium intake is associated with a reduction in urine calcium excretion.

Maintenance of dilute urine by means of vigorous fluid therapy is beneficial in all forms of kidney stones, so increasing urine volume is a key principle for the prevention of kidney stones. Fluid intake should be sufficient to maintain a urine output of at least per day. A high fluid intake may reduce the likelihood of kidney stone recurrence or may increase the time between stone development without unwanted effects.

Calcium binds with available oxalate in the gastrointestinal tract, thereby preventing its absorption into the bloodstream. Reducing oxalate absorption decreases kidney stone risk in susceptible people. Because of this, some doctors recommend increasing dairy intake so that its calcium content will serve as an oxalate binder. Taking calcium citrate tablets during or after meals containing high oxalate foods may be useful if dietary calcium cannot be increased by other means as in those with lactose intolerance. The preferred calcium supplement for people at risk of stone formation is calcium citrate, as opposed to calcium carbonate, because it helps to increase urinary citrate excretion.

Aside from vigorous oral hydration and eating more dietary calcium, other prevention strategies include avoidance of higher doses of supplemental (since ascorbate is metabolized to oxalate) and restriction of oxalate-rich foods such as leaf vegetables, rhubarb, soy products and chocolate. However, no randomized, controlled trial of oxalate restriction has been performed to test the hypothesis that oxalate restriction reduces stone formation. Some evidence indicates magnesium intake decreases the risk of symptomatic kidney stones.

Urine alkalinization

The mainstay for medical management of uric acid stones is alkalinization (increasing the pH) of the urine. Uric acid stones are among the few types amenable to dissolution therapy, referred to as chemolysis. Chemolysis is usually achieved through the use of oral medications, although in some cases, intravenous agents or even instillation of certain irrigating agents directly onto the stone can be performed, using antegrade nephrostomy or retrograde ureteral catheters. Acetazolamide is a medication that alkalinizes the urine. In addition to acetazolamide or as an alternative, certain dietary supplements are available that produce a similar alkalinization of the urine. These include alkali citrate, sodium bicarbonate, potassium citrate, magnesium citrate, and bicitrate