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One of the biggest problems for dialysis patients has been the low production of EPO (erythropoietin) , which is needed to keep their red blood cell levels (hematocrit levels) at a reasonable level.  This has been the reason why most dialysis patients receive a (costly) treatment of EPO, which has been a boon for Amgen and Johnson and Johnson [the two providers of the drug], as well as for the dialysis centers [who were paid separately from their treatment reimbursements to administer same].  (This is no longer the case, see my blog discussion here.)

For a long time, it was thought that the low hematocrit was a result of damage to nephrons (kidney cells) that produce the EPO.  Now, a research group under the direction of Dr. Wanja Bernhardt (University Hospital of Erlangen, Germany) has shown this not to be the case.  Instead, they found that dialysis patients fail to produce EPO due to metabolic changes in the regulation of the production, not in the ability to produce EPO per se, as reported in the Journal of the American Society of Nephrology. As such, a drug, FG-2216 (FibroGen), was able to stimulate the production of EPO in hepatocytes (liver cells) and nephrons (kidney cells) of these patients.

This drug is an inhibitor of prolyl-hydroxylase (an enzyme that responds to hypoxia [low oxygen levels]).  Normally,  hypoxia induced transcription factor prolyl-hydroxylase (HIF prolyl-hydroxylase)  is inhibited (it uses oxygen as a co-substrate), which allows cells to produce EPO in response to these hypoxic conditions; in so doing, red blood cells are produced, which can carry more oxygen within the blood.  FG-2216 is a drug that has been found to inhibit the HIF prolyl-hydroxylase.  The researchers found that FG-2216 works in normal subjects, as well as dialysis patients. More importantly, it worked even with those patients who had NO functioning kidneys and those whose kidneys had been removed surgically. ( The drug stimulated EPO  production in the liver.)  The resulting production was almost as high as those for normal subjects.  Over the 24 hour study period, the increases in EPO levels were 12.7, 14.5, and 30.8 multiples (healthy, anephric, and impaired subjects, respectively).

These studies were effected on 18 subjects (6 healthy, 6 anephric, and 6 impaired function patients) with a single dose (20 mg/kg body weight) of FG-2216 (Phase I studies). Long term safety studies need to be effected, as well as why the HIF prolyl hydroxylase is inhibited in dialysis patients.

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