Degradation of low molecular weight uremic solutes by oral delivery of encapsulated enzymes.
An alginate microcapsule was developed that contains three enzymes (urease, uricase, and creatininase) capable of effectively degrading urea, uric acid, and creatinine, which are elevated to pathologic levels in patients with kidney failure. The capsules were evaluated in vitro and in vivo in a rodent model and evidenced considerable potential as a possible adjunctive therapy in the treatment of ESRD. In vitro, 5 mL of the capsules incorporating a quantity of enzymes in the mg range effectively degraded all the uric acid, 97% of the urea, and 70% of the creatinine within 24 hours in a 100 mL test solution simulating the concentration of these solutes in uremic plasma. Enzyme degradation of urea followed Michaelis-Menten kinetics, and the Lineweaver-Burk plots for both encapsulated enzymes and unencapsulated control animals were superimposable, indicating that mass transfer through the capsules was not rate limiting in the degradation process. A chemically induced acute renal failure model in the rat was used to evaluate the ability of encapsulated enzymes, along with an oral sorbent (ion exchange resin), to degrade uremic toxins in vivo. Encapsulated enzyme therapy decreased the severity of azotemia by as much as 70%. Preliminary scale up calculations indicated that oral delivery to humans would involve a practical and manageable quantity of enzymes. This is the first study using a combination of enzymes in a single delivery vehicle to degrade multiple uremic toxins.
O'Loughlin
Jill A
JA
Center for Biomedical Engineering, Brown University, Providence, Rhode Island, USA.
Bruder
Jan M
JM
Lysaght
Michael J
MJ
D058186:Acute Kidney Injury; D000284:Administration, Oral; D000464:Alginates / Q000737:chemistry; D000818:Animals; D002214:Capsules; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004800:Enzymes, Immobilized / Q000737:chemistry; D020100:Hydrogels; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000628:therapy*; D007700:Kinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014503:Urate Oxidase / Q000737:chemistry; D014508:Urea / Q000378:metabolism; D014512:Ureohydrolases / Q000737:chemistry; D014527:Uric Acid / Q000378:metabolism
D000464:Alginates; D002214:Capsules; D004800:Enzymes, Immobilized; D020100:Hydrogels; D014527:Uric Acid; D014508:Urea; D003404:Creatinine; D014503:Urate Oxidase; D014512:Ureohydrolases; C019944:creatinase