Continuous Renal Replacement Therapy

Continuous renal replacement therapy (CRRT) is commonly used to provide renal support for critically ill patients with acute kidney injury, particularly patients who are hemodynamically unstable. A variety of techniques that differ in their mode of solute clearance may be used, including continuous venovenous hemofiltration with predominantly convective solute clearance, continuous venovenous hemodialysis with predominantly diffusive solute clearance, and continuous venovenous hemodiafiltration, which combines both dialysis and hemofiltration. The present article compares CRRT with other modalities of renal support and reviews indications for initiation of renal replacement therapy, as well as dosing and technical aspects in the management of CRRT. Continuous renal replacement therapy (CRRT) is commonly used to provide renal support for critically ill patients with acute kidney injury, particularly patients who are hemodynamically unstable. A variety of techniques that differ in their mode of solute clearance may be used, including continuous venovenous hemofiltration with predominantly convective solute clearance, continuous venovenous hemodialysis with predominantly diffusive solute clearance, and continuous venovenous hemodiafiltration, which combines both dialysis and hemofiltration. The present article compares CRRT with other modalities of renal support and reviews indications for initiation of renal replacement therapy, as well as dosing and technical aspects in the management of CRRT. Acute kidney injury (AKI) is a common complication in critically ill patients and is associated with substantial morbidity and risk of death. Approximately 5% to 10% of patients with AKI require renal replacement therapy (RRT) during their ICU stay,1Tolwani A. Continuous renal-replacement therapy for acute kidney injury.N Engl J Med. 2012; 367: 2505-2514Crossref PubMed Scopus (137) Google Scholar with mortality rates of 30% to 70%.2Liu K.D. Himmelfarb J. Paganini E. et al.Timing of initiation of dialysis in critically ill patients with acute kidney injury.Clin J Am Soc Nephrol. 2006; 1: 915-919Crossref PubMed Scopus (262) Google Scholar, 3Saudan P. Niederberger M. De Seigneux S. et al.Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure.Kidney Int. 2006; 70: 1312-1317Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar, 4Uchino S. Kellum J.A. Bellomo R. et al.Acute renal failure in critically ill patients: a multinational, multicenter study.JAMA. 2005; 294: 813-818Crossref PubMed Scopus (3162) Google Scholar Over the past 2 decades, the incidence of RRT-requiring AKI has increased by approximately 10% per year.5Hsu R.K. McCulloch C.E. Dudley R.A. Lo L.J. Hsu C.Y. Temporal changes in incidence of dialysis-requiring AKI.J Am Soc Nephrol. 2013; 24: 37-42Crossref PubMed Scopus (367) Google Scholar Risk factors for RRT-requiring AKI include older age, male sex, African-American race, higher severity of illness, sepsis, decompensated heart failure, cardiac surgery, liver failure, and use of mechanical ventilation. While once considered an extraordinary measure, the ability to provide RRT, even in the setting of marked hemodynamic instability, has become routine. However, substantial uncertainty remains regarding many of the fundamental aspects of RRT management, including the optimal timing of initiation and discontinuation, as well as the selection of modality.6Macedo E. Mehta R.L. Continuous dialysis therapies: core curriculum 2016.Am J Kidney Dis. 2016; 68: 645-657Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar The present article provides an overview of key issues in the management of RRT in the critically ill patient, focused primarily on the use of continuous renal replacement therapy (CRRT). Multiple modalities of renal support may be used in the management of the critically ill patient with kidney failure. These include CRRT, conventional intermittent hemodialysis (IHD), and the prolonged intermittent renal replacement therapies (PIRRTs), which are a hybrid of CRRT and IHD. All of these use relatively similar extracorporeal blood circuits and differ primarily with regard to duration of therapy and, consequently, the rapidity of net ultrafiltration and solute clearance. In addition, dialytic therapies rely predominantly on diffusive solute clearance, whereas solute removal during hemofiltration occurs by convection. IHD provides rapid solute clearance and ultrafiltration during relatively brief (3- to 5-h) treatments; the continuous therapies provide more gradual fluid removal and solute clearance over prolonged treatment times (optimally, 24 h per day but often interrupted due to system clotting or diagnostic or therapeutic procedures).1Tolwani A. Continuous renal-replacement therapy for acute kidney injury.N Engl J Med. 2012; 367: 2505-2514Crossref PubMed Scopus (137) Google Scholar The multiple forms of PIRRT are characterized by treatments that are generally between 8 and 16 h in duration, with slower rates of solute clearance and ultrafiltration than IHD but more rapid than CRRT. PIRRT is most commonly provided by using equipment similar to that for IHD but with lower blood and dialysate flow rates. It can also be performed by using equipment designed for CRRT but with augmented dialysate and/or ultrafiltration rates to achieve similar delivered therapy over a shorter duration.7Marshall M.R. Ma T. Galler D. Rankin A.P.N. Williams A.B. Sustained low-efficiency daily diafiltration (SLEDD-f) for critically ill patients requiring renal replacement therapy: towards an adequate therapy.Nephrol Dial Transplant. 2004; 19: 877-884Crossref PubMed Scopus (137) Google Scholar Peritoneal dialysis provides an effective alternative to the extracorporeal modalities of RRT,8Burdmann E.A. Chakravarthi R. Peritoneal dialysis in acute kidney injury: lessons learned and applied.Semin Dial. 2011; 24: 149-156Crossref PubMed Scopus (26) Google Scholar but a detailed discussion of this method is beyond the scope of this review. Although CRRT and PIRRT are most commonly used in hemodynamically unstable patients, there is marked variation in practice. Some centers use CRRT (or PIRRT) in all ICU patients with renal failure regardless of hemodynamic status, whereas others use IHD, albeit with adjustments in prescription, even in vasopressor-dependent patients. Although the benefit of a slow, continuous modality of renal support in hemodynamically unstable patients may seem self-evident, randomized trials have failed to show differences with regard to either mortality or recovery of kidney function comparing CRRT with either IHD9Mehta R.L. McDonald B. Gabbai F.B. et al.A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure.Kidney Int. 2001; 60: 1154-1163Abstract Full Text Full Text PDF PubMed Scopus (536) Google Scholar, 10Augustine J.J. Sandy D. Seifert T.H. Paganini E.P. A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF.Am J Kidney Dis. 2004; 44: 1000-1007Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 11Uehlinger D.E. Jakob S.M. 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Hemofiltration compared to hemodialysis for acute kidney injury: systematic review and meta-analysis.Critical Care. 2012; 16: R146Crossref PubMed Scopus (86) Google Scholar or PIRRT.18Zhang L. Yang J. Eastwood G.M. Zhu G. Tanaka A. Bellomo R. Extended daily dialysis versus continuous renal replacement therapy for acute kidney injury: a meta-analysis.Am J Kidney Dis. 2015; 66: 322-330Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 19Kielstein J.T. Kretschmer U. Ernst T. et al.Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: a randomized controlled study.Am J Kidney Dis. 2004; 43: 342-349Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 20Schwenger V. Weigand M.A. Hoffmann O. et al.Sustained low efficiency dialysis using a single-pass batch system in acute kidney injury—a randomized interventional trial: the REnal Replacement Therapy Study in Intensive Care Unit PatiEnts.Crit Care. 2012; 16: R140Crossref PubMed Scopus (81) Google Scholar It must be recognized, however, that to provide IHD in hemodynamically unstable patients, the standard prescription may require modification, such as prolongation of treatment time to allow for more gradual ultrafiltration, use of higher dialysate sodium concentrations, and reduced dialysate temperatures.12Vinsonneau C. Camus C. Combes A. et al.Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial.Lancet. 2006; 368: 379-385Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar Although the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for AKI recommends the use of CRRT for patients who are hemodynamically unstable,21Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO Clinical Practice Guideline for Acute Kidney Injury.Kidney Int. 2012; 2012: 1-138Google Scholar the strength of this recommendation is low. Observational data, however, do suggest that CRRT is more effective in achieving net negative fluid balance than IHD.22Bouchard J. Soroko S.B. Chertow G.M. et al.Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.Kidney Int. 2009; 76: 422-427Abstract Full Text Full Text PDF PubMed Scopus (778) Google Scholar In addition, in patients with fulminant hepatic failure or brain injury with increased intracranial pressure, CRRT is associated with better maintenance of cerebral perfusion than IHD.23Davenport A. Continuous renal replacement therapies in patients with liver disease.Semin Dial. 2009; 22: 169-172Crossref PubMed Scopus (42) Google Scholar, 24Davenport A. Continuous renal replacement therapies in patients with acute neurological injury.Semin Dial. 2009; 22: 165-168Crossref PubMed Scopus (37) Google Scholar, 25Lin C.M. Lin J.W. Tsai J.T. et al.Intracranial pressure fluctuation during hemodialysis in renal failure patients with intracranial hemorrhage.Acta Neurochir Suppl. 2008; 101: 141-144Crossref PubMed Scopus (41) Google Scholar, 26Ronco C. Bellomo R. Brendolan A. Pinna V. La Greca G. Brain density changes during renal replacement in critically ill patients with acute renal failure. Continuous hemofiltration versus intermittent hemodialysis.J Nephrol. 1999; 12: 173-178PubMed Google Scholar While initially developed as an arteriovenous therapy, most CRRT is now performed using pump-driven venovenous extracorporeal circuits. Although this introduces additional degrees of complexity, including pressure monitors and air detectors, the pump-driven venovenous circuit provides higher and more consistent blood flows and eliminates the hazards associated with prolonged arterial cannulation with a large-bore catheter. Multiple techniques for delivering CRRT have been developed. When used solely for volume management, the treatment is known as slow continuous ultrafiltration. More commonly, when provided as continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), or continuous venovenous hemodiafiltration (CVVHDF), CRRT provides both solute clearance and volume removal, with the differences between these modalities related to the mechanisms for solute clearance (Fig 1). In CVVH, a high rate of ultrafiltration across the semi-permeable hemofilter membrane is created by a hydrostatic gradient, and solute transport occurs by convection (Fig 2A ). Solutes are entrained in the bulk flow of water across the membrane, a process often referred to as “solvent drag.”1Tolwani A. Continuous renal-replacement therapy for acute kidney injury.N Engl J Med. 2012; 367: 2505-2514Crossref PubMed Scopus (137) Google Scholar, 27Tolwani A.J. Campbell R.C. Stofan B.S. Lai K.R. Oster R.A. Wille K.M. Standard versus high-dose CVVHDF for ICU-related acute renal failure.J Am Soc Nephrol. 2008; 19: 1233-1238Crossref PubMed Scopus (224) Google Scholar High ultrafiltration rates are needed to achieve sufficient solute clearance, and the ultrafiltrate volume beyond what is required to achieve desired net fluid removal is replaced with balanced IV crystalloid solutions. These replacement solutions may be infused into the extracorporeal circuit either prior to or following the hemofilter. Because the high ultrafiltration rate hemoconcentrates the blood as it passes through the hemofilter fibers, the risk of sludging and fiber occlusion is increased. Prefilter infusion of replacement fluid dilutes the blood entering the hemofilter, mitigating this hemoconcentration. However, prefilter administration of replacement fluid dilutes the solute content of the blood, reducing effective solute clearance at a fixed ultrafiltration rate. Postfilter infusion has no such effects. In CVVHD, dialysate is perfused across the external surface of the dialysis membrane, and solutes exit from blood to dialysate by diffusion down their concentration gradient (Fig 2B). Ultrafiltration rates are relatively low compared with those in CVVH, permitting net negative fluid balance without the need for IV replacement fluids. Although commonly considered as a purely diffusive therapy, unmeasured bidirectional filtration into the dialysate compartment and back-filtration from dialysate to blood (driven by variation in the hemodynamic pressure gradient over the length of the hemodialysis fibers) result in significant convective solute transport. CVVHDF is a hybrid, combining the dialysate flow of CVVHD with the high ultrafiltration rates and use of replacement fluids of CVVH. The various mechanisms of solute clearance provided by CVVH and CVVHD result in different profiles of solute removal with each modality. Diffusion provides efficient clearance of low-molecular-weight solutes (< 500-1,500 Daltons); however, diffusive clearance declines rapidly as solute molecular weight increases. In contrast, solute movement in convection is limited primarily by the size of the pores in the hemofilter membrane. Clearances of lower and higher molecular weight solutes are similar, until the solute molecular radius approaches the size of the membrane pores.27Tolwani A.J. Campbell R.C. Stofan B.S. Lai K.R. Oster R.A. Wille K.M. Standard versus high-dose CVVHDF for ICU-related acute renal failure.J Am Soc Nephrol. 2008; 19: 1233-1238Crossref PubMed Scopus (224) Google Scholar Thus, at equivalent effluent flow rates, CVVH provides higher clearances than CVVHD for solutes in the range of 1,000 to 20,000 Daltons, or even higher if high cutoff membranes with larger pores are used. Although it has been suggested that the augmented clearance of higher molecular weight solutes (eg, pro-inflammatory cytokines) provided by CVVH might be beneficial, this has not been borne out in clinical practice.17Friedrich J.O. Wald R. Bagshaw S.M. Burns K.E.A. Adhikari N.K. Hemofiltration compared to hemodialysis for acute kidney injury: systematic review and meta-analysis.Critical Care. 2012; 16: R146Crossref PubMed Scopus (86) Google Scholar, 28Payen D. Mateo J. Cavaillon J.M. et al.Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis: a randomized controlled trial.Crit Care Med. 2009; 37: 803-810Crossref PubMed Scopus (245) Google Scholar, 29Joannes-Boyau O. Honore P.M. Perez P. et al.High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial.Intensive Care Med. 2013; 39: 1535-1546Crossref PubMed Scopus (273) Google Scholar Independent of diffusion and convection, adsorption of solutes in the CRRT circuit, subject to saturation of membrane binding sites, may also contribute to overall solute clearance.6Macedo E. Mehta R.L. Continuous dialysis therapies: core curriculum 2016.Am J Kidney Dis. 2016; 68: 645-657Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Thus, choice of CRRT modality (CVVH, CVVHD, or CVVHDF) is primarily a function of provider preference rather than patient characteristics or objective outcome data. The indications for initiation of CRRT generally correspond to overall indications for RRT (Table 1), including volume overload, severe metabolic acidosis and electrolyte disturbances, and overt uremic symptoms. Although these indications are well ensconced, they are subject to wide interpretation and should be considered as only semi-objective. In addition, in many patients, RRT is initiated in the setting of persistent or progressive AKI in the absence of these criteria.Table 1Indications for Initiation of Continuous Renal Replacement TherapyVolume overloadMetabolic acidosisElectrolyte abnormalities Hyperkalemia Hyponatremia HyperphosphatemiaUremia Encephalopathy PericarditisPersistent/progressive acute kidney injury Open table in a new tab Volume overload in AKI occurs due to the disruption of the kidney’s ability to maintain fluid balance in the face of administration of IV fluids, blood products, and/or other medications required for resuscitation and supportive treatment of a critically ill patient and may develop even in patients who are not oliguric or anuric.1Tolwani A. Continuous renal-replacement therapy for acute kidney injury.N Engl J Med. 2012; 367: 2505-2514Crossref PubMed Scopus (137) Google Scholar There are no prospective data establishing specific thresholds for RRT initiation. RRT is generally indicated when volume overload compromises organ function and is refractory to diuretic agents. Although observational data in both pediatric and adult populations show a strong association between severity of volume overload at initiation of RRT and mortality risk, causality has not been established.22Bouchard J. Soroko S.B. Chertow G.M. et al.Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.Kidney Int. 2009; 76: 422-427Abstract Full Text Full Text PDF PubMed Scopus (778) Google Scholar, 30Sutherland S.M. Zappitelli M. Alexander S.R. et al.Fluid overload and mortality in children receiving continuous renal replacement therapy: the prospective pediatric continuous renal replacement therapy registry.Am J Kidney Dis. 2010; 55: 316-325Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar, 31Vaara S.T. Korhonen A.M. Kaukonen K.M. et al.Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study.Crit Care. 2012; 16: R197Crossref PubMed Scopus (269) Google Scholar A complex interplay exists between underlying severity of illness, development of volume overload and mortality, and there is an absence of prospective data showing that initiation of extracorporeal ultrafiltration at a specific threshold of volume overload reduces mortality. Progressive metabolic acidosis is an inevitable consequence of kidney failure, developing due to impaired renal acid excretion.32Yessayan L. Yee J. Frinak S. Szamosfalvi B. Continuous renal replacement therapy for the management of acid-base and electrolyte imbalances in acute kidney injury.Adv Chronic Kidney Dis. 2016; 23: 203-210Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar In patients in whom severe acidosis is refractory to medical management, such as the volume overloaded patient who cannot tolerate alkali administration, either intermittent or continuous RRT is effective.32Yessayan L. Yee J. Frinak S. Szamosfalvi B. Continuous renal replacement therapy for the management of acid-base and electrolyte imbalances in acute kidney injury.Adv Chronic Kidney Dis. 2016; 23: 203-210Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 33Finkel K.W. Podoll A.S. Complications of continuous renal replacement therapy.Seminars in Dialysis. 2009; 22: 155-159Crossref PubMed Scopus (63) Google Scholar, 34Cerda J. Tolwani A.J. Warnock D.G. Critical care nephrology: management of acid-base disorders with CRRT.Kidney Int. 2012; 82: 9-18Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Commonly suggested thresholds for initiation of RRT include a pH < 7.1 to 7.2 or serum bicarbonate level < 12 to 15 mmol/L. Earlier initiation of RRT may be necessary in patients with acute lung injury receiving lung-protective ventilation, as severe acidemia can result from the combination of metabolic and respiratory acidosis. Although RRT augments lactate clearance, there is scant evidence that initiation of RRT to augment lactate clearance alters clinical outcomes in patients with lactic acidosis not associated with drug toxicity (eg, metformin). Multiple electrolyte abnormalities are associated with AKI. Severe hyperkalemia is the most life-threatening and requires prompt treatment to prevent cardiotoxicity and arrhythmias. Initiation of RRT is indicated when hyperkalemia is refractory to medical therapy or recurs following the initial treatment. Although rigid thresholds based on level of serum potassium cannot be provided, RRT solely for the management of hyperkalemia is rarely appropriate when the potassium level is < 6 mmol/L. Conversely, RRT is generally appropriate in patients in whom the potassium level remains > 6.5 mmol/L despite medical management. Although IHD provides more rapid correction of hyperkalemia and is the preferred modality in this setting, CRRT provides effective, albeit slower, control of the plasma potassium concentration.35Kellum J.A. Murugan R. Nadim M.K. Indications, timing, and patient selection.in: Kellum J.A. Bellomo R. Ronco C. Continuous Renal Replacement Therapy. Oxford University Press, New York2016: 48-56Crossref Google Scholar Other electrolyte abnormalities, such as severe hyponatremia or hypernatremia and severe hyperphosphatemia, may accompany AKI and should be a factor in the decision to initiate RRT. In patients with severe hyponatremia in the setting of AKI, CRRT may permit the slower and more controlled correction of sodium concentration needed to prevent the neurologic sequelae of osmotic demyelination, compared with IHD.32Yessayan L. Yee J. Frinak S. Szamosfalvi B. Continuous renal replacement therapy for the management of acid-base and electrolyte imbalances in acute kidney injury.Adv Chronic Kidney Dis. 2016; 23: 203-210Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar The use of RRT for the management of overt uremic symptoms, such as encephalopathy and pericarditis, is well established. Although these are relatively late complications of AKI, other manifestations of uremia, such as platelet dysfunction, impaired nutrition, increased susceptibility to infection and sepsis, heart failure, and pulmonary edema, may be difficult to distinguish from other etiologies in the critically ill patient with multiple organ dysfunction.36Meyer T.W. Hostetter T.H. Uremia.N Engl J Med. 2007; 357: 1316-1325Crossref PubMed Scopus (383) Google Scholar It is far more common, when specific indications are not present for RRT, to be initiated prophylactically in response to persistent or progressive azotemia prior to the development of overt uremic manifestations. The appropriate timing for such initiation remains a topic of debate and is discussed below. A variety of toxins and drugs, such as toxic alcohols, lithium, salicylate, valproic acid, and metformin, are dialyzable, and the timely use of RRT in cases of poisoning and drug intoxications with these agents may be able to avert serious complications. The ability of RRT to remove a particular drug or toxin from the circulation is a function of its size, volume of distribution, and protein binding. Thus, RRT is effective for the removal of smaller, nonprotein-bound molecules with a volume of distribution < 1 L/kg body weight.37Mueller B.A. Pasko D.A. Sowinski K.M. Higher renal replacement therapy dose delivery influences on drug therapy.Artif Organs. 2003; 27: 808-814Crossref PubMed Scopus (62) Google Scholar However, because the goal in the treatment of intoxications and overdoses is the rapid clearance of the offending agent, IHD is generally preferred over CRRT in this setting, even in patients who are hemodynamically unstable.38Ghannoum M. Nolin T.D. Lavergne V. Hoffman R.S. EXTRIP WorkgroupBlood purification in toxicology: nephrology's ugly duckling.Adv Chronic Kidney Dis. 2011; 18: 160-166Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 39Patel N. Bayliss G.P. Developments in extracorporeal therapy for the poisoned patient.Adv Drug Deliv Rev. 2015; 90: 3-11Crossref PubMed Scopus (16) Google Scholar The role of RRT in the management of hyperammonemia is uncertain. Based on molecular weight, ammonia is readily cleared by both diffusion and convection. As with the treatment of poisoning and intoxication, IHD will provide more rapid reduction in blood ammonia levels. However, in small case series, high-dose CRRT has been shown to be efficacious for the acute management of severe hyperammonemia (> 400 μmol/L) in infants with inborn errors of metabolism.40Spinale J.M. Laskin B.L. Sondheimer N. Swartz S.J. Goldstein S.L. High-dose continuous renal replacement therapy for neonatal hyperammonemia.Pediatr Nephrol. 2013; 28: 983-986Crossref PubMed Scopus (46) Google Scholar, 41Hanudel M. Avasare S. Tsai E. Yadin O. Zaritsky J. A biphasic dialytic strategy for the treatment of neonatal hyperammonemia.Pediatr Nephrol. 2014; 29: 315-320Crossref PubMed Scopus (17) Google Scholar The role of CRRT in adults with hyperammonemia complicating liver failure is less certain. CRRT is associated with reductions in plasma ammonia levels.42Slack A.J. Auzinger G. Willars C. et al.Ammonia clearance with haemofiltration in adults with liver disease.Liver Int. 2014; 34: 42-48Crossref PubMed Scopus (103) Google Scholar, 43Cardoso FS, Gottfried M, Tujios S, Olson JC, Karvellas CJ, US Acute Live Failure Study Group. Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure [published online ahead of print August 31, 2017]. Hepatology. https://doi.org/10.1002/hep.29488.Google Scholar In a retrospective analysis of registry data, CRRT was associated with improved 21-day transplant-free survival among patients with acute liver failure compared with IHD or no RRT.43Cardoso FS, Gottfried M, Tujios S, Olson JC, Karvellas CJ, US Acute Live Failure Study Group. Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure [published online ahead of print August 31, 2017]. Hepatology. https://doi.org/10.1002/hep.29488.Google Scholar However, these data are not sufficient to establish causality, and there are no prospective studies that have specifically evaluated the use of CRRT for the management of hyperammonemia in liver disease. In the absence of specific indications, the optimal timing for initiation of RRT in AKI is uncertain. Earlier initiation of AKI allows for optimization of volume status, early correction of acid-base and electrolyte disturbances, and control of azotemia prior to the development of the major metabolic disturbances that serve as objective indications. However, these potential benefits of early initiation need to be balanced with the risks and burdens associated with RRT, including vascular access (eg, hemorrhage, thrombosis, vascular injury, infection), intradialytic hypotension, and resource utilization as well as with the potential concern that RRT may impair subsequent recovery of kidney function.44Wald R. Adhikari N.K.J. Smith O.M. et al.Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury.Kidney Int. 2015; 88: 897-904Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar Furthermore, it is often uncertain whether an individual patient will have persistent AKI or rapid reco