Embodiments of the invention pertain to cartridges, systems and methods for performing hemodialysis and related extracorporeal blood treatment modalities and therapies, in which blood flows in the inter fiber space and dialysate flows in the lumens of hollow fibers. Appropriate connectors and fitting orientations may be provided. There may be provided orbital distributors, fanning of fibers, and features to promote uniformity of fiber spacing in the fiber bundle. Orbital distributors may contain contoured surfaces, flow redirectors, non-uniform-conductance flow elements, through-wall distributors, and other features. There may be subdivision of the fiber bundle into two groups of fibers with separate control fluid to each group. Appropriate systems may be provided for various therapies. Flow past the fibers may be parallel, transverse or other configuration. These various features may enable long-term application to all dialysis and ultrafiltration related therapies, and also to other therapies and to applications including implantables, portables and wearables.