Abstract. Clinical hemodialysis systems achieve high single pass extraction of small solutes that are not bound to plasma proteins. But they clear protein-bound solutes much less effectively. This study examines the extent to which clearance of a protein-bound test solute is improved by increasing the dialyzer mass transfer area coefficient (K o A) and the dialysate flow rate (Q d Protein-bound solutes are poorly cleared during conventional hemodialysis (1-4). Accumulation of such solutes may contribute to residual uremic disorders when levels for dialytic clearance of urea and other small, unbound solutes are considered "adequate" (3-5). The dialytic clearance of an unbound solute is determined by the blood flow rate, Q b , the dialyzer mass transfer area coefficient, K o A, for that solute, and the dialysate flow rate, Q d (6). In conventional practice, K o A and Q d are set to achieve values for urea clearance close to Q b . Further increases in K o A and Q d cannot significantly increase urea clearance and are therefore generally not contemplated.The study presented here examined whether the clearance of protein-bound solutes could, by contrast, be improved by increasing K o A and Q d relative to the plasma flow rate, Q p . In vitro dialysis experiments measured the clearance of phenol red, a small solute strongly bound to albumin, from artificial plasma. As expected, the clearance of phenol red was much lower than the clearances of the unbound solutes, urea and creatinine. Phenol red clearance could, however, be increased by increasing both K o A and Q d . We developed a mathematical model to predict the clearance of a protein-bound solute from Q p , Q d , K o A, the albumin concentration, and the association constant, K A , that describes the strength of solute binding to albumin. Mathematical modeling accurately predicted the pattern of measured results and showed further that clearance values for tightly protein-bound solutes can be made to approach Q p by significantly increasing K o A and Q d . Materials and Methods Clearance Measurements during In Vitro DialysisModel Dialysis System. Clearances of phenol red, urea, and creatinine were measured during dialysis in vitro. Fluid representing a patient's plasma was placed in a continuously stirred 4.5 L reservoir and dialyzed with a Fresenius D machine (Fresenius, Gurnee, IL). The reservoir and dialysate fluids were prepared to have identical free electrolyte concentrations, which approximated Na 140 mEq/L, K 4.0 mEq/L, HCO 3 24 mEq/L, Mg 2.0 mEq/L, Ca 2.5 mEq/L, and PO 4 4.0 mg/dl. Fluid preparation comprised addition of small amounts of KCl, MgCl 2 , and CaCl 2 to Fresenius 6615 acid concentrate and NaH 2 PO 4 to 1.0 M NaHCO 3 concentrate solutions. These solutions were then mixed and appropriately diluted by the dialysis machine. Addition of reagent phenol red, urea, and creatinine to the reservoir provided concentrations of approximately 3.0 mg/dl, 120 mg/dl, and 12.0 mg/dl, respectively, at the beginning of each dialysis run. Dialysis experiments en...