This disclosure relates to medical fluid pumping systems and related devices and methods. In some aspects, a medical fluid pumping system includes a medical fluid pumping machine including a piston head that can be linearly displaced and a medical fluid cassette that can be secured to the medical fluid pumping machine. The medical fluid cassette includes a fastening member attached to a region of a flexible membrane overlying a fluid pump chamber, and the piston head is configured to be mechanically connected to the fastening member of the cassette.