A hemodialysis system includes (i) a plurality of pump rollers: (ii) a fluid heater, the pump rollers and the heater positioned and arranged to accept a horizontally loaded dialysate cassette: (iii) a dialyzer; (iv) a sorbent cartridge; and (v) wherein the dialysate cassette includes first and second tubes for horizontal interaction with the pump rollers and a third tube for horizontal interaction with the heater, the cassette in fluid communication with the sorbent cartridge.