Testing the homocysteine hypothesis in end-stage renal disease: Problems and a possible solution

The homocysteine hypothesis states that circulating homocysteine is a vascular toxin in concentrations that occur in the general population and in renal failure. This hypothesis is currently being tested in the Kidney and End State Renal Disease Study (HOST), but data have emerged since the HOST began that suggest its results will be inconclusive. The crucial treatment component in the HOST is folic acid, but its effect is likely to be lost because the American food supply is now fortified with folic acid. A second concern is that the very high doses of folic acid and pyridoxine being used in the HOST may confound the results. Finally, confounding due to ‘reverse epidemiology’ was not considered when the HOST was designed. Parenteral vitamin B12 is a highly promising therapy for homocysteine reduction in end-stage renal disease that merits careful investigation. Clinical trials using it to test the homocysteine hypothesis will avoid the problems inherent in the HOST.