In vivo and in vitro degradation of urea and uric acid by encapsulated genetically modified microorganisms.
This study was undertaken to characterize the capacity of a combination of genetically modified bacteria to lower elevated levels of urea and uric acid and thus to serve as a potential adjunct to maintenance dialysis in patients with chronic renal failure. Two strains of genetically modified bacteria expressing enzymes, urease to degrade urea and uricase to degrade uric acid, were identified, combined, and dispersed in 600-microm alginate microcapsules suitable for oral administration. In 24 h in vitro experiments, 5 mL of these capsules completely cleared 95% of the urea and >99% of the uric acid from 100 mL of a challenge solution formulated to the concentration of these solutes in a presenting hemodialysis patient. The process of urea degradation was found to be intracellular and each bacterial strain was specific for its substrate. Solute degradation in vivo was evaluated with a chemically induced model of acute renal failure, using Sprague-Dawley rats. Orally administered capsules were found to remain in the gastrointestinal tract for at least 6 h. The severity of azotemia and hyperuricaemia after chemical induction of acute renal failure was reduced by 64 and 31%, respectively, on administration of the capsules. Reduction of urea concentration (but not uric acid concentration) in vivo required coadministration of an ion-exchange resin to adsorb ammonia. Oral delivery of a combination of genetically modified microorganisms should be further explored in chronic renal failure models as a useful adjunct to dialysis or to immunosorption for the treatment of uremia.
O'Loughlin
Jill A
JA
Center for Biomedical Engineering, Brown University, Providence, Rhode Island 02912, USA.
Bruder
Jan M
JM
Lysaght
Michael J
MJ
D058186:Acute Kidney Injury / Q000628:therapy*; D000818:Animals; D001673:Biodegradation, Environmental; D018929:Cell Culture Techniques / Q000379:methods*; D003131:Combined Modality Therapy / Q000379:methods; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D030781:Organisms, Genetically Modified / Q000378:metabolism*; D051381:Rats; D006435:Renal Dialysis / Q000379:methods; D016896:Treatment Outcome; D014508:Urea / Q000378:metabolism*; D014527:Uric Acid / Q000378:metabolism*
D014527:Uric Acid; D014508:Urea