GAINESVILLE, Fla.---Cystic fibrosis patients who lack a beneficial intestinal bacterium have a greatly increased likelihood of developing a condition that can lead to kidney stones, and extensive use of antibiotics may be to blame, University of Florida researchers reported today (9/26) in the scientific journal The Lancet.
The study is one of the first to directly link an absence of the organism, known as Oxalobacter formigenes, to the formation of the painful crystals. Previously, many researchers believed cystic fibrosis patients developed kidney stones in connection with intestinal malabsorption problems.
Cystic fibrosis, one of the most common genetic diseases among Caucasians, afflicts approximately 1 in 3,200 people born each year in the United States. The so-called "thief of breath" slowly destroys patients' lungs through recurrent infections and often affects other vital organs. While kidney function is not greatly altered in these patients, kidney stones are an increasingly common complication as the life expectancy of these patients increases. In addition, nine out of 10 eventually are found to have a hardening of the kidneys from a build-up of calcium and oxalate. Oxalate is a byproduct of digestion.
"Our study in fact shows that cystic fibrosis patients, in general, have a very, very low frequency of colonization with this intestinal bacteria," said Ammon Peck, a professor of pathology at UF's College of Medicine. UF researchers collaborated with scientists from Alachua, Fla.-based Ixion Biotechnology Inc., Northwestern University, the University of Bonn and two German hospitals.
Of the 43 cystic fibrosis patients UF researchers studied, 19 produced too much oxalate, and all 19 lacked the bacterium, Peck said. In contrast, the few patients who were colonized - even with low levels of the organism - had normal oxalate levels. The study participants, all residing in Germany and ranging in age from 3 to 39, had cystic fibrosis and showed no signs of an intestinal malabsorption problem. Their results were compared with findings from 21 healthy volunteers ages 4 to 44.
O. formigenes appears to break down calcium oxalate before it can form crystals that evolve into kidney stones, he said. Oxalate is found in high concentrations in many foods, including asparagus, tea, broccoli, peanut butter, spinach and chocolate.
When oxalate levels are kept low, it is easier for the body to excrete the substance through the kidneys. But if there is more oxalate than can be dissolved in the urine, the crystals settle out and form stones.
Peck and colleagues suspect prolonged antibiotic use and other high-dose drug regimens may preclude natural colonization with the organism, or may irreversibly destroy the colonies. Most infants naturally acquire the bacterium from their environment between the ages of 9 months to 1 year, and by 6 to 8 years of age almost all healthy children are colonized.
Researchers reviewed study participants' medical records and discovered that among the patients, 29 different antibiotic regimens had been used, and many patients were likely to be on other medications as well. Only one patient had not been treated with antibiotics - the only person who tested strongly positive for O. formigenes.
"When we investigated the potential reasons for the loss of the bacterium, we already had some evidence that this bacterium is very sensitive to antibiotic treatment, so an analysis of these patients in terms of their antibiotic treatment was performed," Peck said. "It appears that ceftazidime and trimethroprim-sulfmethoxazole, two broad-spectrum antibiotics often used against a variety of bacteria, are highly toxic to this bacterium, as well. We were able to show that all the patients who had taken either ceftazidime or trimethroprim-sulfmethoxazole lacked Oxalobacter.
"What these findings tell us is that the presence of this bacterium may be very beneficial, but because of the use of antibiotic treatment, often because of overprescription, we can alter our normal intestinal bacterial flora," he said. "If we extrapolate these results, then a lot of children are placed on antibiotics for very minor things and may lose their normal flora, for example Oxalobacter formigenes, possibly placing them at higher risk for having complications later on."
The study is fascinating because researchers are finding similar data with patients who are suffering from kidney stone formation as a primary disease, Peck said.
Kidney stones, one of the most common disorders of the urinary tract, have plagued mankind throughout time. Reference is made to those "laboring under the stone" in the Hippocratic oath, and scientists have even detected evidence of kidney stones in an Egyptian mummy more than 7,000 years old. Today, kidney stones afflict 5 to 10 percent of the population worldwide. Each year, nearly 1 million Americans suffer from painful kidney stone episodes.
"Many patients are wondering why they are developing stones and most physicians cannot say much about why certain patients form stones," Peck said. "If physicians know certain individuals do not have O. formigenes, patients can be informed that they are probably at increased risk for the development of multiple stones."
Armed with the information, physicians can advise their patients about appropriate intervention tactics, such as a low-oxalate diet.
Meanwhile, research efforts are ongoing. UF researchers recently received a $1 million grant from the National Institutes of Health to study aspects concerning colonization with O. formigenes and whether kidney stones can be prevented in laboratory rats by replenishing the bacterium.
Another UF and Ixion Biotechnology study has shown that daily enzyme treatment may prevent kidney stone formation. Researchers have found that giving laboratory animals a pill containing proteins that Oxalobacter uses to degrade oxalate with meals successfully lowers oxalate levels and eliminates crystals in the urine.
"The subject is really kind of new and in its early phase," Peck said. "A lot of questions need to be asked and answered."
By Melanie Fridl Ross
(For more information contact Melanie Ross, Health Science Center Office of Public Information 352/690-7051 or e-mail: ufcardiac@aol.com )
Journal
The Lancet