We continue to be puzzled by the limited benefit or even harm associated with increased dialysis dose in AKI, as seen in the Tolwani, ATN, and RENAL trials. How could these studies fail to show a benefit, when the earlier Ronco, Saudan, and possibly the Bouman trials showed improved long-term survival with prescription of 35-45 ml/kg/hour of therapy? Two general sets of hypotheses suggested themselves. First, is it possible that the newer studies of CVVHDF were somehow different from the earlier studies of CVVH, and in one case, CVVH vs CVVHDF? Using bovine blood and techniques similar to those used to test performance of novel hemofilters, we determined that middle molecule clearance in CRRT is a strong function of membrane area and relatively insensitive to prescribed mode of therapy (PMID 19282753). We went on to measure middle molecule clearance at 20 versus 35 ml/kg/hour CVVHDF and found that there was negligible difference in middle molecule clearance between the two arms (PMID 20016150). This suggests that the treatment arms in early studies differed in both small-molecule and middle molecule clearance, while later studies varied small molecule clearance while inadvertently holding middle molecule clearance constant. We are in the planning stages of a study varying middle molecule clearance while holding small solute clearance constant.
Technology Development for End-Stage Renal Disease
Maintenance dialysis prescriptions have come to target frequent and prolonged therapy. Prolonged dialysis appears to confer significant clinical benefit in cardiac, nutritional, and endocrine health. The existing infrastructure of dialysis clinics cannot expand in capacity to deliver prolonged daily therapy to all patients, and home-based dialysis has only penetrated 0.5% of the US market. The rate limiting factor in uptake of home-based intensive maintenance dialysis appears to be patient concerns about safety of the therapy and burden on family members. Reconfiguring delivery of ESRD care to resemble the AICD model for cardiac rhythm management based on an autonomous implanted device would facilitate adoption of intensive therapies. An implanted device internalizes the blood circuit, minimizing risk of accidental disconnect, and locates infection-prone percutaneous connections on the traditionally nonsterile dialysate side of the circuit. Wearable therapies in development appear to require long-term percutaneous vascular or peritoneal access, with attendant worries regarding infection and accidental disconnection. Hollow-fiber membranes have limited service lifetime and require significant energy to propel fluid – be it blood or dialysate – through the cartridge, precluding use in implanted devices. Therefore, new membranes designed to maximize permeability and selectivity are critical to implementing a fundamentally enabling paradigm shift in ESRD care.