The Use of Antibiotics and Risk of Kidney Stones

Shivam Joshi; David S. Goldfarb

Disclosures

Curr Opin Nephrol Hypertens. 2019;28(4):311-315. 

In This Article

The Microbiome

A potential mechanism possibly explaining the association between antibiotic exposure and nephrolithiasis is the effect of the intestinal microbiome, the community of microorganisms hosted by the human bowel, on urine chemistry. The complexity of the microbiome cannot be understated; it is home to 500–1000 bacterial species, many with symbiotic relationships that affect the health of their human host. In total, the intestinal microbiome has approximately 150 times more genes than the human genome.[3]

Studies of the gut microbiome of patients with and without kidney stones have shown differences in the patients' microbiome.[4] For example, in a study of 23 kidney stone patients and 6 nonstone forming controls, the Prevotella genus was one of the most abundant bacteria in those without kidney stones and the Bacteroides genus was most abundant in those with kidney stones. As the metabolic effects of these differences in the microbiota on urine chemistry or other risk factors for kidney stones are not known, there is currently no clear hypothesis about the potential causality of these observations.

Oxalobacter Formigenes

Studies of the effects of intestinal microbiota on many disease states and chronic conditions are often unable to identify the specific organisms responsible. The metabolic consequences of colonization with various organisms is not yet understood. Even the molecules mediating many of the proposed effects of the microbiome have not been determined. The situation is different in the case of kidney stone disease. In this case, microbiome studies have particularly focused on the effects of bacterial constituents on the metabolism of oxalate. The importance of this metabolite is clear since nearly 80% of kidney stones are composed of calcium oxalate.[5] In addition, studies have shown that certain gut bacteria, like Oxalobacter, Bifidobacterium, Escherichia coli, Lactobacillus, and Eubacterium, can degrade oxalate, and presumably reduce intestinal oxalate absorption, and thereby reduce oxalate levels in the urine.[6–9] Exposure to antibiotics can reduce levels of these bacteria in the intestine, thereby increasing levels of urinary oxalate and the risk of calcium oxalate stones. An effect of antibiotics to increase calcium oxalate kidney stone risk could then be the result of alterations in the gut microbiome. Of the oxalate-degrading bacteria, Oxalobacter formigenes is the most efficient at degrading oxalate and the best studied. A figure summarizing oxalate metabolism and the potential effects of the microbiota and O. formigenes appears in another article in this issue.[10]

Oxalobacter formigenes is a Gram-negative, obligate anerobic bacterium that requires oxalate uptake for a source of carbon and for the generation of ATP.[11] Colonization rates of the bacterium vary from undetectable levels to 107 per gram of feces. The levels of the bacterium in fecal samples are also affected by the presence of dietary oxalate, which is its only required substrate.[12] Abundance of O. formigenes can increase by about 10-fold with a 10-fold increase in dietary oxalate, and decrease with increasing oral calcium intake by the host, which binds oxalate and renders it unavailable for uptake by the bacteria.

Consumption of oxalate by O. formigenes is thought to reduce the amount of intestinal oxalate available for absorption and excretion in the urine. In addition, the bacterium appears to be able to stimulate intestinal secretion of oxalate, which may ultimately reduce urinary oxalate levels.[13] This appears to occur via production of an as-yet unidentified secretagogue that stimulates the intestinal chloride–oxalate exchanger SLC26A6 present in the apical or luminal intestinal epithelium.[14]

Colonization of the human intestine with O. formigenes has been associated with fewer stones. A case–control study of 247 patients with recurrent calcium oxalate stones and 259 controls without nephrolithiasis matched for age, sex, and region, found a strong inverse association between colonization with O. formigenes and recurrent calcium oxalate stones.[7] Those colonized with the bacterium had a 70% reduction in risk of becoming a recurrent calcium oxalate stone former. Among controls, those who consumed more oxalate had an increased prevalence of O. formigenes whereas the opposite was seen with antibiotic use. However, median urine oxalate excretion was not different between those colonized with O. formigenes and those who were not.

The lack of difference in urinary oxalate excretion could be related to dietary differences. Another study of 37 calcium oxalate stone formers showed no differences in urinary oxalate excretion between those colonized and not colonized with O. formigenes while on a self-selected diet.[15] However, when participants consumed a controlled, standardized diet, urinary oxalate concentrations were lower in those colonized with O. formigenes compared with those who were not. Further, those colonized with O. formigenes were associated with a significant lower number of stone episodes compared with those who were not colonized with the bacterium.

The Effect of Antibiotics on Oxalobacter Formigenes

In adults from USA, colonization rates vary from 38 to 62% of individuals.[16,17] A recent study analyzing the abundance and stability of O. formigenes in 242 healthy young adults in the United States using data from fecal samples from the Human Microbiome Project revealed that whole-genomic shotgun sequencing had the best sensitivity in detecting the bacterium.[17] In this dataset, 29 of 94 participants (31%) tested positive for O. formigenes, a value which may have been reduced by prior antibiotic exposure. Globally, higher rates are seen in populations with less antibiotic use.[18,19]

It is not surprising that antibiotics would reduce the prevalence of O. formigenes. Amerindians, for example, have higher rates of O. formigenes colonization, which is attributed to less antibiotic availability in this population.[20] Amerindians of the Yanomami-Sanema, Yekwana ethnic groups in Venezuela, and the Hadza in Tanzania all had higher rates of detection of O. formigenes than adults from the USA.[20,21] Another example is the children of Ukraine, who have limited access to antibiotics, and have universal colonization at age 3–4 years, which declines with time.[22]

Patients with cystic fibrosis are known to have higher rates of kidney stones and antibiotic exposure. In one study, 71% of patients without cystic fibrosis were colonized by O. formigenes, whereas only 16% of patients with cystic fibrosis were colonized.[23] Those patients who had both cystic fibrosis and O. formigenes colonization demonstrated normal urinary oxalate excretion, whereas 53% of patients not colonized by the bacterium had hyperoxaluria. However, these data were not collected prospectively or longitudinally and could have represented associations of disease severity with antibiotic use, rather than a causal phenomenon. Patients with cystic fibrosis have additional reasons related to their phenotype, and possibly to their genotype, that could represent kidney stone risk factors.[24]

The only longitudinal data to examine the effects of antibiotic exposure on O. formigenes in humans comes from a study in which we selected patients who were found to have intestinal colonization, after undergoing upper endoscopy for indications independent of the study. The persistence of O. formigenescolonization was compared between those who were treated with antibiotics for Helicobacter pylori and those who did not have it, and therefore did not receive antibiotics. Patients receiving antibiotics in the 2 years prior to the study were excluded. All patients underwent stool sampling at baseline and 1 and 6 months afterwards, with detection of O. formigenes by PCR. Those treated with antibiotics (predominantly amoxicillin and clarithromycin; metronidazole, tetracycline, and bismuth; or metronidazole and clarithromycin) had a substantially reduced colonization of O. formigenes at 1 and 6 months: from 100 to 36.8%. Of those who did not receive antibiotics, 91.7% remained colonized. We did not have 24 h urine oxalate excretion or dietary information to determine if the loss of O. formigenescolonization was associated with a greater risk of higher urinary oxalate excretion or the development of stones, but the study was suggestive that these developments were plausible.

The lasting effects are consistent with other reports of reductions in gut bacteria persisting months after antibiotic exposure.[25]

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