WHAT CAUSES KIDNEY STONES?

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

Often, the cause of calcium stones is not known, a condition called idiopathic nephrolithiasis. In general, calcium stones form when there are imbalances of components in the urine that either promote or inhibit formation of the stone. Genetic factors may play a role in 45% of calcium-stone cases.

Excess Calcium in the Urine (Hypercalciuria). Hypercalciuria, in which there is too much calcium in the urine, is responsible for about 70% of calcium-combining stones. A number of conditions may produce hypercalciuria. Many are due to genetic factors, but most causes are unknown. Here are some theories and actual causes:

• Overly efficient intestinal absorption of calcium. In more than half of cases, the source of excess calcium overload in urine is from the intestine, not the kidney. In most cases, a combination of genetic factors conspires to increase calcium absorption. 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.
• 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 results 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.
• Certain cancers and sarcoidosis (a chronic disorder marked by small lumps on organs) can cause excess calcium.
• Many drugs, including thyroid hormones and loop diuretics (drugs that increase urination), can increase calcium concentration in urine. Stones are an uncommon side effect of these medications, however.

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. A number of conditions can contribute to hyperoxaluria:

• Primary hyperoxaluria (type I or type II). This is an inherited disorder associated with kidney stones.
• Deficiencies of pyridoxine (vitamin B6). Severe vitamin B6 deficiencies (usually due to genetic disorders) can result in overproduction of oxalic acid.
• Short bowel syndrome. Short bowel syndrome is the result of surgery in the small intestine that results in malabsorption. This disorder is the inability of the intestines to absorb fat and nutrients. 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. People with Crohn's disease, intestinal infections, and children with structural abnormalities in the small intestine are at risk for these procedures and short bowel syndrome.
• Dietary oxalates. Whether eating foods rich in oxalates or taking too much vitamin C plays any major role in hyperoxaluria is unproven. One Swiss study suggests that certain people may be hypersensitive to meat protein, rendering them susceptible to mild hyperoxaluria. [For foods containing oxalates, see How Can Kidney Stones Be Prevented?, below.]
• Hormones. One 1999 animal study suggested that male hormones may account for the greater risk for kidney stones in men. Androgens (male hormones) were associated with a higher risk for calcium oxalate crystals formation while estrogens (female hormones) decreased it. This finding is consistent with others, suggesting that estrogen may protect against the formation of calcium stones by keeping urine alkaline and raising citrate levels. Whether hormone replacement actually prevents stones in older women is not yet determined, however.

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 are the causes of about 5% of calcium stones. And people with this disorder have at least a 20% chance of kidney stones. Women are more likely to have this disorder than men are.
• Immobilization.
• Renal tubular acidosis, disorder that causes acid and alkaline imbalance. It not only increases calcium in the blood stream, it also reduces citrate levels [ see below ].

Low Urine Levels of Citrate (Hypocitraturia) and Other Stone-Inhibiting Compounds. Citrate is the primary agent for removal of excess calcium. Low levels in the urine, known as hypocitraturia, are a significant risk factor for calcium (and also uric acid) stones. Many conditions can reduce citrate levels, but often the causes of hypocitraturia severe enough to cause stones are unknown:

• 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.

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 bacteria, termed nanobacteria, which are able to pass from the blood into urine. Such bacteria coat themselves with mineral deposits that resemble the composition of kidney stones. Cells infected with the bacteria develop mineral deposits both on the inside and outside. Researchers hypothesize that such bacteria may provide the core kidney stones in many people.

Causes of Uric Acid Stones

Excessive Amounts of Uric Acid (Hyperuricuria). Uric acid stones most often form out of high concentrations of uric acid crystals (hyperuricuria). Such crystals are made from purine, a nitrogen end product of dietary protein. They are not related to the acidity of the urine itself, although in the majority of uric acid stones, the urine is so persistently acidic that even normal amounts of uric acid can precipitate and form stones. (About 10% to 20% of cases of uric acid stones are found in urine with normal pH values.) A number of conditions contribute to hyperuricuria:

• Genetic factors.
• Diets overly rich in animal proteins.
• Gout.
• Certain medications (chemotherapy agents, diuretics, and salicylates).
• Binge drinking.
• Fasting.
• Lead toxicity.
• Blood diseases (leukemia, certain uncommon anemias, multiple myeloma, and lymphomas).
• Chronic diarrhea.

Note: Hyperuricuria may also play a role in some calcium oxalate stones. In this case, 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.

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 are.

Causes of Other Stones

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

Causes of Cystine Stones. Cystine stones are found in patients with an inherited disorder that causes abnormal transport in the kidney and gastrointestinal system of the amino acids cystine, ornithine, lysine, and arginine.

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

Q. What causes kidney stones?
Dr. Green: The exact causes of kidney stone formation are not completely known; however, most credible sources believe that stones are the result of mineral supersaturation and crystallization in the urine.  Heredity, environment, age, sex, urinary infection, diet, and metabolic diseases are probably involved in stone formation.  The primary known causes are: 1) inadequate urinary drainage, 2) dehydration and lack of sufficient fluid ingestion, 3) foreign bodies in the urinary tract, 4) diet with excess oxalates, calcium, and vitamin abnormalities, e.g., Vitamin A deficiencies, Vitamin D excess, 5) urinary infections, 6) metabolic diseases, e.g., hyperparathyroidism, cystinuria, gout, intestinal dysfunction, and 7) use of certain medications, e.g., diuretics, that increase levels of uric acid.