Researchers Search for Probiotic Factors To Reduce Risk of Calcium Oxalate Kidney Stones Interview with:

Dr. Hatim A. Hassan Section of Nephrology, Department of Medicine The University of Chicago Chicago, IL 60637

Dr. Hatim A. Hassan

Dr. Hatim A. Hassan MD PhD
Section of Nephrology, Department of Medicine
The University of Chicago
Chicago, IL 60637 What is the background for this study?

Response: Nephrolithiasis is the second most prevalent kidney disease in USA after hypertension, with a rising prevalence and complications including advanced chronic kidney disease (CKD) and end stage renal disease (ESRD). It remains a major source of patient discomfort and disability, lost working days, and health-care expenditure, with an annual economic cost approaching $10 billion. Hyperoxaluria is a major risk factor for kidney stones (KS), and 70-80% of KS are composed of calcium oxalate. Urinary oxalate is an important determinant of supersaturation, and the risk for stone formation is affected by small increases in urine oxalate. Oxalate is a metabolic end product that cannot be further metabolized and is highly toxic. The mammalian intestine plays a crucial role in oxalate homeostasis, by regulating the amount of absorbed dietary oxalate and providing an avenue for enteric oxalate excretion. Anion exchanger SLC26A6 (A6)-mediated intestinal oxalate secretion plays a critical role in preventing hyperoxaluria and calcium oxalate kidney stones (COKS). Inflammatory bowel disease patients have a significantly increased risk of kidney stones due to the associated enteric hyperoxaluria. Obesity is a risk factor for KS and obese stone formers often have mild to moderate hyperoxaluria. Hyperoxaluria is also emerging as a major complication (developing in > 50% of patients) of bariatric surgery for obesity. With the rising prevalence of obesity and increased utilization of bariatric surgery, it is expected that the incidence of hyperoxaluria and related COKS (including the associated cost burden) will continue to increase at a significant rate. Primary hyperoxaluria (PH) is an inherited disease in which there is endogenous oxalate overproduction, which leads to recurrent KS and/or progressive nephrocalcinosis, ESRD, as well as significant hyperoxalemia, systemic oxalosis and premature death. Systemic deposition of calcium oxalate (oxalosis) leads to bone disease, cardiac arrhythmias, cardiomyopathy, skin ulcers, erythropoietin refractory anemia, and digital gangrene. The only treatment known to fully correct the underlying metabolic defect is liver transplantation or combined kidney-liver transplantation once ESRD develops. In addition, significant hyperoxalemia is also seen in ESRD. Cardiovascular diseases are the leading cause of morbidity and mortality in ESRD patients, and a recent report raised the possibility that the ESRD-associated hyperoxalemia might contribute to this increased risk. Lowering serum oxalate might improve cardiovascular outcomes in ESRD patients if these findings are confirmed.

Unfortunately, there is currently no specific therapy that effectively lowers urine and/or plasma oxalate level(s), and the risk of recurrent COKS, nephrocalcinosis, oxalate nephropathy, ESRD, & systemic oxalosis remains substantial in the absence of treatment.

Oxalobacter formigenses (Of) is an anaerobic bacterium and utilizes oxalate as its exclusive energy source.  Of colonization correlates with reduced risk of COKS formation in a number of studies, presumably by reducing intestinal oxalate absorption and urinary oxalate excretion.  In addition to degrading intraluminal dietary oxalate, Of also interacts with colonic epithelium by inducing distal colonic oxalate secretion, leading to reduced urinary excretion via a potential unknown secretagogue. Of colonization of PH1 mice (a mouse model of primary hyperoxaluria type 1) significantly reduced serum and urinary oxalate levels due to induction of colonic oxalate secretion. However, all PH1 mice lost colonization within 18 days when switched from a high oxalate/low calcium diet (1.5% oxalate/0.5% calcium; needed to induce and maintain colonization) to regular mouse chow (0.25% oxalate/1% calcium). In addition, colonization cannot be maintained without reducing dietary calcium which contradicts the current recommendations to increase dietary calcium for preventing recurrent kidney stones. Moreover, it has been suggested from studies in PH patients & PH1 mice that the intraluminal environment in PH is not supportive of sustained Of colonization. Collectively, maintaining Of colonization in the absence of high exogenous oxalate remains problematic (and therefore making use of live Of as a potential therapeutic agent not practical now), underscoring the need for identifying Of-derived bioactive factors exerting effects similar to live Of and thus might have significant potential for clinical application.

Therefore, the goal of this study was to identify the Of-derived bioactive factor(s) inducing colonic oxalate secretion. What are the main findings?

Response: We found that small molecular weight protein(s) and/or peptide(s) secreted by Of in its culture conditioned medium (CM) to significantly stimulate oxalate transport (>2.8-fold) by human intestinal Caco2-BBE cells through mechanisms including PKA activation and increased A6 transport activity. Rectal administration of Of CM significantly reduced (>32.5%) urinary oxalate excretion and stimulated (>42%) distal colonic oxalate secretion in PH1 mice. What should readers take away from your report?

Response: The reduction in urinary oxalate excretion in hyperoxaluric mice treated with Of CM reflects the in vivo retention of biologic activity and the therapeutic potential of these factors. Therefore, the Of-derived secreted bioactive factors have significant potential to serve as novel therapeutic agents for prevention and/or treatment of hyperoxaluria, hyperoxalemia, and related COKS. What recommendations do you have for future research as a result of this study?

Response: Probiotic bacteria have several health benefits; however, the difficulties in determining intestinal bacterial bioavailability and biosafety concerns when administering live probiotics are potential problems facing current probiotics clinical applications. Developing probiotics-derived soluble factors as novel therapeutic agents is an alternative approach that addresses such concerns. The difficulties described above in maintaining Of colonization in the absence of high exogenous dietary oxalate and biosafety concerns with administering live of necessitate the identification of the Of-derived factors. The fact that these factors retain their biological activity in vivo and can effectively reduce urinary oxalate excretion in hyperoxaluric mice indicates their significant potential to serve as novel therapeutic agents for prevention and/or treatment of hyperoxaluria, hyperoxalemia, and related COKS, and therefore provides a compelling reason for the aggressive pursuit of their characterization, which is currently underway. Thank you for your contribution to the community.


Oxalobacter formigenes–Derived Bioactive Factors Stimulate Oxalate Transport by Intestinal Epithelial Cells
Donna Arvans, Yong-Chul Jung, Dionysios Antonopoulos, Jason Koval,Ignacio Granja, Mohamed Bashir, Eltayeb Karrar, Jayanta Roy-Chowdhury,Mark Musch, John Asplin, Eugene Chang, and Hatim Hassan
JASN ASN.2016020132; published ahead of print October 13, 2016,doi:10.1681/ASN.2016020132

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Last Updated on November 1, 2016 by Marie Benz MD FAAD