Lisette Ramos-Voigt November 25, Kidney Stone Formation. substances found in the urine (Leslie & Swierzewski, 1998). There are various types of

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1 Lisette Ramos-Voigt November 25, 2008 Kidney Stone Formation Kidney stones are hard solid pieces of material that form in the kidneys out of substances found in the urine (Leslie & Swierzewski, 1998). There are various types of kidneys stones based on their content. The most common type is rich in calcium. The calcium comes from the excess in our diet not used by the bones and muscles. The calcium is usually expelled by the kidneys with the rest of the urine. However, in some cases people keep the calcium within the kidneys instead of releasing it. The calcium joins other waste products and the combination is called calcium oxalate (Leslie & Swierzewski, 1998). Other types of kidney stone include struvite stone. These stones usually form after a urinary tract infection, and are made up of magnesium and the waste product ammonia. Uric acid stones may form when the urine is too acidic. This acidity may be caused by the consumption of large amounts of meat. Cystine stones are the rarest type of the kidney stones. Cystine is a compound found in nerves, muscles and other tissues, which can build up in the urine. This particular disease runs in families (Leslie & Swierzewski, 1998). Nanobacteria are extremely small, Gram negative, cytotoxic, atypical bacteria, belonging to the Proteobacteria group (Ciftcioglu, et al., 1999). These bacteria are about 1/20 the size of most of the other bacteria belonging to this group. They were recently discovered in fetal bovine serum, in commercial cell culture serum, and in human blood. The uniqueness of these bacteria includes the formation of a needle-shaped calcium

2 apatite cell wall which encloses the organism (Travis, 1998). IR spectroscopy has revealed that the mineral is actually carbonate apatite. They have been found to be implicated in the precipitation of calcium in the urinary system (Kajander & Ciftcioglu, 1998). Using scanning electron microscopy (SEM) nanobacteria and kidney stone units were compared. It was found that the nanobacteria units were very resistant to the demineralization process using 1 N HCl. Demineralized kidney stones were screened using a double staining method and were found to have apatite units resembling in morphology those of the nanobacteria (Ciftcioglu, et al., 1999). Further analysis detected an antigen released by the nanobacteria confirming their presence in all kidney stones. However, in struvite stones, the appearance of other common bacteria, besides nanobacteria, were found in large numbers. The nanobacteria form extracellular calcifications and thus are the initial center or nucleus (nidi) on which metabolic kidney stones are built up at a rate dependent on the supersaturation of urine (Kajander, et al., 2001). These nanobacteria begin by attaching, invading and damaging the urinary epithelial tissue of the collecting tubules as they gather the minerals within the urine and form the calcium phosphate centers found in the stones (Kajander, et al., 2002). A calcium phosphate nidi is always formed and may subsequently become coated with calcium oxalate, struvite, cystine and biofilms (Kajander & Ciftcioglu, 1998).

3 Some scientists propose that the formation of kidney stones is a nanobacterial disease similar to Helicobacter pylori infections where ulcers are formed, and that dietary factors influence their progression (Ciftcioglu, et al., 1999). Kidney stones formed of the mineral struvite are produced mainly by bacteria that produce an enzyme called urease (Travis, 1998). The urease makes the urine more alkaline, enabling mineral precipitation to occur more readily, encouraging kidney stone formation (Parsek & Singh, 2003). Struvite kidney stones occur in the setting of urinary tract infections. The stones are produced by the interplay between the infecting bacteria and the minerals found dissolved in the urine resulting in a biofilm (Parsek & Singh, 2003). Infectious kidney stones or struvite stones cause disease by obstructing urine flow and by producing inflammation and recurrent infections that can lead to kidney failure (Parsek & Singh). The pathogenic nature of the bacteria forming kidney stones is enhanced by their ability to form communities encased in extracellular material (Musk & Hergenrother, 2006). Because the kidney stones are a biofilm disease, they are extremely resistant to treatment and relapses of urinary tract infections occur. The only cure is to remove the kidney stones surgically. Studies have been performed to identify the bacteria that could, because of their production of urease, form large encrustation amounts of calcium and magnesium salts and be the cause of struvite kidney stones. To test the bacteria a model of a catheterised urinary bladder was used with artificial urine (Stickler, et al., 1998). The medium was adjusted to a slightly acid ph level. Urease-positive bacteria such as Morganella

4 morganii, Klebsiella pneumoniae, and Pseudomonas aeruginosa did not raise the urinary ph and did not form any crystalline biofilms. However, Proteus mirabilis, Proteus vulgaris, and Providencia rettgeri did produce an alkaline environment and extensive encrustration of the catheter used (Stickler, et al.). Although some models of kidney stone formation may led to the idea that the urine needs to be alkaline, carbonate apatite can be produced by nanobacteria at ph levels of 7.4. The formation of the kidney stones by nanobacteria can occur at environments like those of tissue fluids and glomerular filtrate normal in our body. The subsequent addition of minerals by other bacteria producing alkaline phosphate or urease does enhance the biomineralization of other compounds. Ways to reduce or inhibit encrustration of catheters by Proteus mirabilis has been attempted using hydrogel or silver coatings with no success (Morris, Stickler & Winters, 2003). Other methods used, which have been partially successful, include the use of chemicals that cause interference with the quorum sensing used by the bacteria to communicate (Musk & Hergenrother, 2006). Recently, however, at the University of Colorado a new non-toxic peptide based biofilm inhibitor has been developed, which has successfully prevented the colonization of Pseudomonas aeruginosa in stainless steel and non-metal surfaces. The peptide may be an antimicrobial in nature and could possibly prevent the colonization of a wide variety of organisms (Poticha, 2007). Researchers Milton Allison and Albert Baetz from the National Animal Disease Center in Ames, Iowa have helped lay the groundwork for medical research that may offer relief for some individuals suffering from certain types of kidney stones. They have

5 studied a bacterium known as Oxalobacter formigenes, found in the digestive tracts of cattle, sheep, and humans, which can break down oxalates and consume it as its source for energy (Cooke, 1995). Together with Peter Maloney, a microbiologist at John Hopkins University in Baltimore, they have been able to isolate two oxalate-busting enzymes from the bacterium. Their finding could be further developed and used in patients prone to kidney stones, due to their large oxalate content diets, for protection. Why do scientists believe that nanobacteria may induce calcification and stone formation in vivo? Because They are in human blood Can be transported from the blood to the urine as living organisms Antigens are found in kidney stones. Can infect phagocytotic cells resulting in intracellular and extracellular calcifications

6 References: Ciftcioglu, N., Bjorklund, M., Kuorikoski, K., Bergstrom, K. & Kajander, E. (1999, November). Nanobacteria: An infectious cause for kidney stone formation. Kidney Infections. 56(5) p Cooke, L. (1995, October). Bacteria break kidney stone-oxalate link. Agricultural Research. Retrieved November 25, 2008, from Kajander, E., Ciftcioglu, N., Aho, K. & Garcia-Cuerpo, E. (2003). Characteristics of nanobacteria and their possible role in stone formation. Urology. 31 p Kajander, E., Ciftcioglu, N., Miller-Hjelle, M. & Hjelle, J. (2001, May). Nanobacteria: Controversial pathogens in nephrolithiasis and polycystic kidney disease. Current Opinion in Nephrology and Hypertension. 10(3) p Kajander, E. & Ciftcioglu, N. (1998, July). Nanobacteria: An alternative mechanism for pathogenic inra-and extracellular calcification and stone formation. Proc. National Academy of Science. 95(14) p Retrieved November 24, 2008, from Leslie, S. & Swierzewski, S. (Reviewing Authors) (1998, June 10). Kidney stones. Healthcommunities.com, Inc. Urology Channel. Retrieved November 24, 2008, from Morris, N., Stickler, D. & Winters, C. (2003, October 29). Which indwelling urethral catheters resist encrustation by Proteus mirabilis biofilms? Brtish Journal of Urology. 80(1) p Retrieved November 23, 2008, from / Musk, D. & Hergenrother, P. (1994). Chemical countermeasures for the control of bacterial biofilms: Effective compounds and promising targets. Current Medicinal Chemistry. 13(18) p Retrieved November 24, 2008, from Parsek M. & Singh, P. (2003, January 1). Bacterial biofilms: An emerging link to disease pathogenesis. Annual Review of Microbiology. Retrieved November 23, 2008, from Poticha, D. (2007). Non-toxic peptide-based biofilm inhibitor. Technology Transfer Office,University of Colorado. Retrieved November 24, 2008, from pdf

7 Stickler, D., Morris, N., Moreno, M-C., Sabbuba, N. (1998). Studies on the formation of crystalline bacterial biofilms on urethral catheters. European Journal of Clinical Microbial Infectious Diseases. 17 p Travis, J. (1998, August 1). The bacteria in the stone: Extra-tiny microorganisms may lead to kidney stones and other diseases. Science News. Retrieved November 25, 2008, from