Our goal is to determine the biochemical basis for widespread but poorly understood derangements of body functions in chronic renal failure. The functions of body proteins are the specific foci of attention, with our studies to date using the abnormal binding by plasma albumin in uremia as a model. We have succeeded in extracting a family of aromatic organic acids from uremic serum, which account for this specific example of uremic toxicity. A crude extract of uremic sera and normal urine contains active compounds which inhibit binding of small ligands by serum and also depress transport of PAH by the isolated perfused kidney. We are using chromatographic techniques to obtain each of these solutes in completely pure form, determining their chemical composition, localizing the specific region of albumin where they interact and defining the transport pathway(s) by which they are normally eliminated by the kidney. In addition to hippuric acid, we have tentatively identified Beta-[m-hydroxyphenyl]-hydracrylic acid as active inhibitors of binding to serum albumin of both endogeous ligands such as tryptophan and drugs which affect two of the main binding loci of albumin (warfarin and diazepam sites). We are developing high pressure liquid chromatographic methods to separate and quantitate these organic acids in serum and will search for other toxic effects they may have in patients with advanced renal failure or patients receiving regular dialysis therapy. Part of the inadequacy of present day dialysis techniques may relate to failure to eliminate such strongly protein-bound toxins which may be of endogenous or dietary origin. New methods of augmenting the efficacy of dialysis, such as solute displacement, could result from clearer knowledge of the chemical basis of uremia. It also may be possible to delay or reduce the frequency of dialysis by identifying and eliminating the sources of these toxins from the diet.
