October 1, 1999

Can Bacteria Be Trained to Do the Kidney's Work?

In industrialized countries, peritoneal- and hemo-dialysis sustain the lives of more than a quarter of a million patients whose kidneys don't work effectively (renal insufficiency). The cost of this therapy, however, exceeds health care budgets in all developing countries. The majority living in poorer nations have no chance of effective treatment should their kidneys fail. Even in richer countries, concerned about rising health care costs, it may one day be difficult for everyone who needs it to receive dialysis. But there is hope. Two cutting-edge bionic approaches offer the possibility of a low-cost way of substituting for failing kidney function (uremia). For all those who cannot afford expensive dialysis to keep them alive, there is urgency in the quest for this alternative, minimal cost therapy.

The Bowel as a Substitute Kidney
One possibility involves construction of a bioartificial kidney in which filtering and secreting kidney functions are performed by culture-grown cells implanted in a hollow fiber or mesh matrix. In the other approach, trained bacteria will break down nitrogenous wastes within the gut. These treatments are still in the experimental stages but show promise.

Historical Background
More than two thousand years ago, Hippocrates, the ancient Greek physician, vaguely described oral treatment for kidney disorders. Use of bowel elimination as a means of managing kidney disease is recorded in Dioscorides' Materia Medica in 40 B.C. in which terra sigillata, a sacred earth found on the Greek island of Lemnos, is advocated for multiple disorders including diseases of the kidney. By 100 A.D., Pliny prescribed this esteemed medicine as an oral sorbent against complaints of the spleen and kidneys, copious menstruation, poisons and wounds caused by serpents. Though terra sigillata is forgotten, other oral sorbents including charcoal, oxidized starch, locust bean gum (a mannose polymer derived from seeds of the ceratonia siliqua tree) and microcrystalline carbon with an oxygen complex surface oxide have each been reported in this century as beneficial in the uremic syndrome by promoting nitrogenous waste extraction.

Oral Sorbents
In 1976, W.J. Kolff, a distinguished researcher, pioneered the investigation of the usefulness of oral sorbents in uremia, exploring the effect of charcoal ingestion on nitrogenous waste serum levels. He found that creatinine, uric acid and other nitrogenous human wastes can easily be removed with charcoal, although perhaps the charcoal removes too much. He also found that phosphates can easily be removed with aluminum preparations.

The real problem is the waste product, urea. Twenty grams of urea must be removed from a person's bloodstream every day in order to maintain the best possible metabolic balance. Scientists realized that limiting dietary protein might help minimize the nitrogenous waste burden, a step now incorporated in the management of kidney failure. By using various polymers as capsules (microencapsulation) around particles of activated charcoal, the amount of charcoal needed to remove 400 mg of creatinine is reduced from 190 g to approximately 50g.

Recently, AST-120, an oral sorbent synthesized in Japan, comprised of particles of porous carbon has attracted attention. Clinical trials (thus far limited to Japan) of AST-120, administered to 27 patients with renal insufficiency, prolonged the interval between hemodialysis treatments from a mean of 5.0 months in controls to a mean of 14.3 months, giving the patients an extra nine months free from dialysis.

Diarrhea Therapy
It has been observed that during cholera diarrhea, the blood urea level decreased. As a result, the idea that induced diarrhea might have value in nitrogen extraction is being explored.12,13 Especially noteworthy is the low cost of components of the diarrhea regimen, which would today be about $5.00 per treatment as compared with $130 for a typical hemodialysis and $140 for a day of peritoneal dialysis.

Chinese uremic patients in Taipei, treated for up to two years with thrice weekly induced diarrhea lasting 3-7 hrs, had symptomatic improvement with good tolerance of the regimen. Because no objective, controlled, randomized prospective studies of diarrhea therapy have been reported, though the concept is appealing, proof of efficacy is lacking.

Bacterial Enzyme Nitrogen Recycling
Farmers depend on nitrogen recycling chemical reactions when they feed urea and cellulose wastes to cattle who, within the rumen, convert urea to essential amino acids using cellulose as an energy source. Dairy cows live for six generations, calve and produce normal milk on a protein-free diet. Rumen microbial enzymes "learn" to utilize urea and ammonium salts as sole sources of nitrogen permitting protein synthesis.

Dr. K. Setala, a Professor of Pathology at the University of Helsinki, Finland, who recognized the potential of transposing ruminant reactions to humans and devised a unique treatment of uremia using the patient's gastrointestinal tract. From cultured soil bacteria, Setala extracted enzymes which were then introduced into the uremic patient's gut to recycle nitrogenous substances. Treated patients showed greatly reduced nitrogen waste products in their blood and lowered high blood pressure. To date, however, confirmation of Setala's reports has not been published.

Is a bowel-for-kidney therapy a real hope?
With yeast cells now the prime source of human insulin and cultured Chinese hamster ovary cells routinely manufacturing genetically-engineered hormone products, it is not unlikely that one day we will see trained bacteria substitute for kidney, liver and most endocrine functions.
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