In this post, Dr. Paul Palevsky (PP) discusses his recent review in American Journal of Kidney Diseases on dosing renal replacement therapy (RRT) in patients with acute kidney injury with Dr. Matthew Sparks, eAJKD web advisory board member.
eAJKD: How is RRT dosed in patients with acute kidney injury (AKI) and sepsis?
PP: There is really no evidence that we need to dose RRT in patients with AKI and sepsis any differently than for other patients with AKI. In the prespecified subgroup analyses in both the ATN study and the RENAL study, there were similar results in patients with and without sepsis.
eAJKD: What would be the benefits of a higher dose of RRT in patients with sepsis?
PP: The theoretical benefit, as proposed by Dr. Ronco, was the removal of inflammatory cytokines. However, studies looking at cytokine removal in patients with sepsis have not shown a benefit.
eAJKD: Can you point out some of the theoretical risks associated with higher dose RRT?
PP: I think the biggest issue relates to medication dosing, particularly antibiotics, with a significant risk of under-dosing due additional extracorporeal clearances. Unfortunately, this was not assessed during either the ATN or RENAL studies. Other problems include electrolyte depletion – particularly hypokalemia and hypophosphatemia – and micronutrient depletion. In the intensive therapy arm of the ATN study, we observed more patients experienced intradialytic hypotension while on IHD, although this may have been related to exposure since the rate of hypotension normalized to treatment frequency was similar in the two arms. We did not see any adverse outcomes attributable to these episodes of hypotension, however the analysis is complicated by the fact that patients who survived had greater exposure (i.e., more IHD treatments) and therefore more hypotensive episodes.
eAJKD: What are some other trials currently underway looking at this question?
PP: The IVOIRE study is the only study of very high dose of therapy that I am aware of and this study was stopped early. Results of this study, which compared CVVH at 35 ml/kg/hr to 70 ml/kg/hr, have not been released, but the fact the study was terminated is not encouraging. There are some other novel approaches that might be more promising for patients with sepsis, such as coupled plasmafiltration and heme-adsorption, and the use of Polyumixin adsorption to remove endotoxin, but these are not really dialytic techniques for the management of AKI, but specific therapies directed at sepsis instead.
eAJKD: Can you comment on volume management in patients with AKI requiring RRT? Are there any trials looking at this?
PP: The studies done to date have all looked at dose in terms of small solute – essentially urea – clearance. Volume management is another important element of RRT, both in terms of when to start and how to manage therapy once treatment is started. Although studies have shown that severity of volume overload is strongly associated with mortality risk, it has not been demonstrated that different strategies to volume management using RRT impact survival or other outcomes. Although the ARDSNet FACTT study showed a benefit to a conservative fluid strategy, it should be remembered that the study protocol applied when patients were not in shock and were off all vasopressors. The problem that we encounter clinically is the dilemma of fluid removal in a patient who has massive total body fluid overload but is still on high-dose vasopressors. To my knowledge, no one has demonstrated that aggressive volume removal in this setting is associated with improved survival. This needs to be rigorously evaluated in a clinical trial.
eAJKD: What is the take home message of your recent paper?
PP: The current data does not support more intensive RRT in patients with AKI results in better outcomes. That does not imply that appropriate dosing of therapy is not important. I think the literature demonstrates that under-dosing is associated with increased complications and higher mortality. While we don’t know the true floor for the delivered dose of therapy, CRRT delivered with an effluent flow of 20 mL/kg/hour appears to be sufficient. It is critical, however, to ensure that this dose is actually delivered, recognizing that in the ATN and RENAL studies, the time on treatment my have been greater than what is commonly achieved in clinical practice. Institutions need to have quality improvement processes in place to ensure that the prescribed dose of therapy is actually delivered. Similarly, when intermittent hemodialysis is used, a 3x/week or every-other day schedule is adequate, so long as the delivered Kt/V is at least 1.2-1.3 or the URR is at least 0.7. I suspect that in most centers pre- and post-dialysis BUNs are not routinely measured so the delivered dose of therapy is not known. We need to do better. It is also very important to recognize that the dialysis prescription needs to be individualized to the patient, and more intensive therapy will be required for hypercatabolic patients and more frequent treatments may be required for volume management issues.