Kidney Stones

Description

Alternative Names

Causes

Kidney stones develop as a result of a complicated interaction of biologic events that are most likely triggered by genetic susceptibility coupled with dietary factors. The process is not completely known.

General Biologic Events Leading to Kidney Stones

The key process in the development of kidney stones is supersaturation.

• This process involves salts that are carried in urine. Such salts may include calcium oxalate, uric acid, cystine, or xanthine.
• These salts can become extremely concentrated under certain circumstances: if the volume of urine is significantly reduced; or if abnormally high amounts of crystal-forming salts are present.
• When concentration levels reach the point at which the salts no longer dissolve, they precipitate out and form crystals.

Different factors may be involved in either reducing urine volume or increasing the levels of the salts.

Deficiencies in Protective Factors. Normally, urine contains protective factors that include magnesium, citrate, pyrophosphate, and various proteins and enzymes. These compounds may protect against stone formation in various ways:

• Allowing salt in the urine to be at higher-than-normal concentrations without forming crystals.
• Preventing crystal formation.
• Coating the crystals and preventing them for adhering to the tube surface.

Deficiencies in these protective substances, therefore, cause stones.

Changes in the Acidity of the Urine. Changes in the balance of acid to alkaline in the urine can affect stone precipitation.

• Uric acid and cystine stones thrive in acidic urine.
• Calcium phosphate and struvite stones thrive in alkaline.

Factors that Bind Crystals to the Kidney Tubules. Researchers are studying the cells lining the kidney tubules in order to understand how and why early crystals bind to the tubes long enough to form stones. Under investigation are elevated levels of substances that either cause crystals to adhere to the tubes or deficiencies in those that prevent them from sticking.

Causes of Calcium Stones

In general, calcium stones form when there are imbalances of components in the urine that either promote or inhibit formation of the stone. Often, the cause of calcium stones is not known, a condition called idiopathic nephrolithiasis. Increasingly, research suggests that abnormalities in metabolism (i.e., digestion and intestinal absorption of calcium or oxalate) are responsible for nearly all stones. Genetic factors may play a role in about half of these cases. A number of medical conditions and drugs can also affect digestion and intestinal absorption.

Excess Calcium in the Urine (Hypercalciuria). About 70% of calcium-containing stones are caused by hypercalciuria, in which there is too much calcium in the urine. A number of conditions may produce hypercalciuria. Many are due to genetic factors, but most cases are idiopathic, or due to unknown causes. The following are mechanisms that can lead to hypercalciuria and calcium stones:

• Overly efficient intestinal absorption of calcium. In many cases, the source of calcium overload in urine is the intestine, not the kidney. In most of these conditions, genetic factors conspire to increase calcium absorption in the intestine. Researchers are investigating a number of suspects, including a possible defective gene that regulates calcitriol, a form of vitamin D, which, in excess levels, may increase intestinal absorption of calcium. (This is the situation in which restricting calcium in the diet can help prevent stones.)
• Excessive chloride. Chloride has a negative charge and calcium a positive one, so they are often used by the body to balance each other. Excess chloride, then, may lead to excess calcium. A gene known as CLCN5, which regulates chloride in the urine, is defective in many patients with calcium stones.
• Renal calcium leak. This is a condition in which the filtering processes in the kidney fail, causing an increase of calcium in the urine.
• Excessive sodium. Calcium absorption in the kidney tubules follows the absorption of sodium and water. High urinary levels of sodium then result in increased levels of calcium. Defects in the kidney tubules transport system can cause imbalances in sodium and phosphate that result in elevated calcium in the urine. A high salt diet can also produce this effect.

Excess Oxalate in the Urine (Hyperoxaluria). Oxalate, also called oxalic acid combines with calcium to form calcium oxalate, which is the most common stone-forming compound. Excessive oxalate in the urine (hyperoxaluria) is responsible for about 30% of calcium stones and is a more common cause of stones than too much calcium in the urine.

Hyperoxaluria is defined as either primary or secondary.

• Primary hyperoxaluria is an inherited disorder in which excess oxalate in the urine is the primary problem.
• Secondary hyperoxaluria is caused by specific conditions that result in excess urinary oxalate.

Secondary hyperoxaluria is usually caused by excessive intake of dietary oxalates (found in a number of common vegetables, fruits, and grains) or by abnormalities in the metabolism of oxalates. Such defects may be due to various factors, such as the following:

• Deficiencies of pyridoxine (vitamin B6). Severe vitamin B6 deficiencies (usually due to genetic disorders) can result in overproduction of oxalic acid.
• Deficiencies in Oxalobacter formigene. Deficiency in an intestinal bacterium called Oxalobacter formigenes is now a suspect in some cases. This bacterium degrades oxalate and low levels in the intestine increase the risk for oxalate absorption and stone formation.
• Short bowel syndrome. Short bowel syndrome, which may result from surgery in the small intestine, is marked by the inability of the intestines to absorb fat and nutrients properly (malabsorption). In such cases, calcium may bind to unabsorbed fat instead of to oxalates. This leaves excess oxalate, which is absorbed by the intestine and excreted into the kidney.
• Hormones. Some studies have suggested that androgens (male hormones) are associated with a higher risk for the formation of calcium oxalate crystals while estrogens (female hormones) are linked to a lower risk. Estrogen may help prevent the formation of calcium stones by keeping urine alkaline and raising protective citrate levels.

Excessive Calcium in the Bloodstream (Hypercalcemia). Hypercalcemia generally occurs when bones break down and release too much calcium into the bloodstream. This is a process called resorption, which can occur because of the following:

• Hyperparathyroidism. Overactive parathyroid glands cause about 5% of calcium stones. And people with this disorder have at least a 20% chance of developing kidney stones. Women are more likely to have this disorder than men.
• Immobilization.
• Renal tubular acidosis, a disorder that causes acid and alkaline imbalance. It not only increases calcium levels in the bloodstream, it also reduces citrate levels.

High Levels of Uric Acid (Hyperuricosuria). High levels of uric acid in urine are referred to as hyperuricosuria and occur in between 15% to 20% of people (mostly men) with calcium oxalate stones. (Hyperuricosuria is not related to the acidity of the urine itself.) In such cases, urate (the salt formed from uric acid) creates a crystal nidus (the nucleus of a crystal), around which calcium oxalate crystals form and grow. Such stones tend to be severe and recurrent and appear to be strongly related to a high intake of protein. (Hyperuricosuria also plays a major role in some uric acid stones.)

Low Urine Levels of Citrate (Hypocitraturia). Citrate is the primary agent for removal of excess calcium. It also inhibits the process that turns calcium crystals into stone. Low levels in the urine, known as hypocitraturia, are a significant risk factor for calcium stones. In addition, hypocitraturia also increases the risk for uric acid stones. This condition most likely contributes to about a third of all kidney stones.

Many conditions can reduce citrate levels, but often the causes of hypocitraturia severe enough to cause stones are unknown. Some causes include the following:

• Renal tubular acidosis. This disorder results in abnormalities in the acid and alkaline balance in the body's fluids, which causes a reduction of citrate in the urine. To make matters worse, the disorder also causes bone resorption and increases calcium levels in the blood.
• Potassium or magnesium deficiency.
• Urinary tract infection.
• Kidney failure.
• Chronic diarrhea.

Low Levels of Other Stone-Inhibiting Compounds. In addition to citrate, other substances in urine also prevent calcium from precipitating out or forming calcium stones. Some of these include nephrocalcin-A and uropontin (molecules known as glycoproteins), glycosaminoglycan, magnesium, and pyrophosphate.

Nanobacteria Infection. An interesting focus of investigation is the discovery of extremely tiny infectious agents, termed nanobacteria. (Although their name implies bacteria, it is not even clear if these are living things.) Nanobacteria are able to pass from the blood into urine and coat themselves with mineral deposits that resemble the composition of kidney stones. Cells infected with these agents develop mineral deposits both on the inside and outside. Researchers hypothesize that nanobacteria may form the cores of the kidney stones in many people.

Causes of Uric Acid Stones

Uric acid stones are formed from crystals made from purine, a nitrogen end product of dietary protein. There are usually three conditions observed in patients with uric stones:

• Urine is persistently acidic so that even normal amounts of uric acid can precipitate and form stones. Persistently acid urine is the most important cause of uric acid stones.
• Patients produce lower than normal amounts of urine.
• Patients have high amount of uric acid in the urine (hyperuricosuria). This is less often a cause of uric acid than acidic or low volume of urine. Hyperuricosuria may be due to a high intake in protein, can be an inherited condition, or is associated with high levels of uric acid in the blood (hyperuricemia). Note: this condition is also common in calcium stones. Therefore, a combination of calcium and uric acid stones may be present in patients with hyperuricosuria.

A number of conditions may contribute to or cause uric acid stones:

• Gout. Uric acid and other kidney stones are present in 10% to 25% of patients with primary gout, a prevalence more than 1,000 times that of the general population.
• Possibly kidney abnormalities that reduces ammonia productions, particularly in people with diabetes or insulin resistance.
• Genetic factors.
• Hypocitraturia.
• Diets overly rich in animal proteins.
• Certain medications (chemotherapy agents, diuretics, and salicylates).
• Binge drinking.
• Fasting.
• Lead toxicity.
• Blood diseases (leukemia, certain uncommon anemias, multiple myeloma, and lymphomas).
• Chronic diarrhea.

Causes of Struvite Stones

Struvite stones are almost always caused by urinary tract infections due to bacteria that secrete certain enzymes. These enzymes, in turn, raise urine concentrations of the ammonia that composes the crystals forming struvite stones. The stone-promoting bacteria are usually Proteus, but may also include Pseudomonas, Klebsiella, Providencia, Serratia, and staphylococci. Women are twice as likely to have struvite stones than men.

Causes of Other Stones

Other stones, including cystine and xanthine stones, are usually due to genetic abnormalities.

Causes of Cystine Stones. Cystine stones develop from genetic defects that cause abnormal transport of amino acids in the kidney and gastrointestinal system leading to a build-up of cystine, one of these amino acids. Researchers have identified two genes responsible for this condition: SLC3A1 and CLC7A9.

Causes of Xanthine Stones. In some cases, xanthine stones may develop in patients being treated with allopurinol for gout.