A hemofiltration system or method removes unwanted molecules from a flow of blood using cascaded first and second hemofilters. Filtration of the blood in first hemofilter raises hemoconcentration of unwanted protein-bound molecules. Combination of a substitution fluid with outflow from the first hemofilter creates a concentration differential between bound and unbound molecules that frees unwanted molecules from protein bonds. Filtration of the combined fluids in a second hemofilter removes the unwanted free molecules. A second substitution fluid may be added to the twice filtered blood fluid for return to a patient. Removal of inflammatory mediators, apoptotic mediators, and certain electrolytes may be effected, and the removal may be optimized by controlling fluid flows and transmembrane pressures.
