A number of organic acids including phenols are accumulated in plasma of uremic patients because of reduced renal clearance. Some of them account for uremic problems such as reduced drug binding. Protein-bound organic acids such as hippuric acid, indoxyl sulfate, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), are markedly accumulated in uremic plasma, and produce defective protein binding of drugs. CMPF is tightly bound to serum albumin, and thus cannot be removed by conventional hemodialysis, but continuous ambulatory peritoneal dialysis and protein-leaking hemodialysis can remove CMPF, leading to lower serum levels. Based on the findings that indoxyl sulfate stimulates the progression of chronic renal failure in rats, and that low-protein diet or oral sorbent exert protective effects on the progression of chronic renal failure and reduce the serum and urine levels of indoxyl sulfate, the author proposes a protein metabolite hypothesis that endogenous protein metabolites such as indoxyl sulfate play a significant role in the progression of chronic renal failure.