| | Dialysis Dosing in Critically Ill Patients With Acute Kidney InjuryCommentary on Palevsky PM, Zhang JH, O'Connor TZ, et al: VA/NIH Acute Renal Failure Trial Network: Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury. N Engl J Med 359:7-20, 2008. Maintenance dialysis on the whole is non-physiological and can be justified only because of the finiteness of its alternative. While industry appears to be faring well, research-minded professionals are beginning to recognize that we face a distinct danger that hemodialysis may become institutionalized. Satisfied with what we have wrought in this field, we will pile small improvements on top of other minor advances in dialysis technology. Ultimately the technology of [renal failure] therapy will become entrapped in its own net for failure to break out in new directions.1 Dr Benjamin Burton, Director, Artificial Kidney–Chronic Uremia Program, National Institute of Diabetes and Digestive and Kidney Diseases, 1976 Since Ben Burton's articulated concern over 3 decades ago, the prevalence of in-hospital acute renal failure, or acute kidney injury (AKI), has strikingly increased with modest, if any, improvement in mortality rate, persisting at greater than 50% in the intensive care unit (ICU) setting.2 The development of hemodialysis to treat acute and chronic renal failure transformed a uniformly fatal clinical disorder into a treatable disease.3 The substitution of the small-solute clearance function of the kidney with dialytic techniques prevented death from renal failure by accomplishing the removal of metabolic waste products and excess fluid volume, and the maintenance of electrolyte balance. Over the years, improvements in hemodialysis techniques have been evaluated in attempts to reduce the morbidity and mortality of patients with AKI. Improved biocompatible hemodialysis membranes, high-flux membranes for improved convective clearance function, and continuous renal clearance substitution therapies have been implemented clinically to improve renal failure therapy. Nearly 200 clinical studies have been published in peer-reviewed journals addressing these advances in dialysis technology, with inconsistent and, hence, inconclusive results.4 Two treatment variables uniformly considered important in determining the outcomes of patients with AKI have yet to be evaluated in a manner to guide best practice. These variables are dose of dialysis and size of molecules cleared by dialysis. In its issue of July 3, 2008, the New England Journal of Medicine published an article by Palevsky et al designed as a definitive study to assess dialysis dose on the clinical outcomes of patients with AKI.5 This landmark work, entitled “Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury,” was the product of members of the Veterans Administration/National Institutes of Health Acute Renal Failure Trial Network (ATN) Study. What Does this Important Study Show?  This study was designed as a multicenter, randomized trial in critically ill AKI patients with 1 or more additional organ failures or sepsis. The patients were randomized into 2 treatment groups: intensive and less-intensive dialysis therapy. Patients were allowed to transition from 1 dialysis modality to another as long as the dose intensity was adhered to. Hemodynamically stable patients received intermittent hemodialysis (IHD); hemodynamically unstable patients underwent continuous venovenous hemodiafiltration (CVVHDF) or sustained low-efficiency dialysis (SLED). Initiation of dialysis volume replacement and adjunctive medical care was determined at the clinical site based upon current practice standards. The intensive group received IHD or SLED of Kt/Vurea targeting 1.2 to 1.4 per session with a frequency of 6 times a week, or CVVHDF with combined dialysis and filtration rates (that is, a total effluent rate) of 35 mL per kilogram of body weight per hour. The less-intensive group received IHD or SLED targeting the same Kt/Vurea dose, 1.2 to 1.4 per session, but with a frequency of 3 times a week, or CVVHDF with total effluent rate of 20 mL/kg/h. The primary end point was 60-day all-cause mortality rate. The study was targeted for a patient enrollment of 1,164 to achieve a 10% difference in mortality rate with a statistical power of 90% with a 2-sided significance level of 0.05. The treatment regimen of IHD and SLED in both groups achieved targeted dosing with Kt/Vurea of 1.2 to 1.4 per session. IHD in the intensive group resulted in substantially lower pre- and postdialysis serum urea nitrogen (SUN) levels compared to the less-intensive group (45 ± 25 and 16 ± 12 mg/dL v 70 ± 33 and 25 ± 15 mg/dL). Delivered total effluent rate of CVVHDF in the intensive group was 35.8 ± 6.4 mL/kg/h as compared with 22.0 ± 6.1 mL/kg/h in the less-intensive group. Unfortunately, the rate of death at 60 days was 53.6% in the intensive group and 51.5% in the less-intensive group (P = 0.47). Recovery of renal function and rate of nonrenal organ failure were also similar between the 2 groups. Of note, more episodes of hypotension, hypophosphatemia, and hypokalemia occurred in the intensive group. The study concluded that increasing the small-solute clearance of renal dialysis in critically ill patients with AKI over current adequate dialysis dosing schedules had no effect on clinical outcome in this disease process. Similar to the Hemodialysis (HEMO) Study, which assessed the dose of dialysis in patients with end-stage renal disease on long-term hemodialysis, more intense dialysis than current guidelines for dialysis adequacy did not result in improved outcomes.6 How Does this Study Compare to Other Studies? This report currently should be viewed as the definitive study defining dialysis dosing in critically ill patients with AKI. The multicenter, randomized approach with adequate patient enrollment targets to define a statistically valid result is the gold standard of clinical trial design. Another ongoing study similar to this investigation, called the Randomized Evaluation of Normal Versus Augmented Level of Renal Replacement Therapy in ICU (RENAL) study, will also be completed this year by an experienced group of clinical investigators in Australia and New Zealand.7 Comparisons of these 2 studies will, hopefully, determine best practice. Of the large number of previously published clinical studies in this area, several are selected for comment here to demonstrate important issues relevant to this study. A recent single-center, nonrandomized study involving 160 patients with AKI requiring dialytic care demonstrated an improved mortality rate (14 days after discontinuing hemodialysis) with daily IHD compared to “conventional” (alternate-day) IHD, 28% versus 46%, respectively (P = 0.01). Review of the data suggests that the conventional treatment group was inadequately dosed for dialysis with time-averaged SUN levels of 104 mg/dL. In contrast, the less-intensive dialysis group in the ATN study averaged pre- and postdialysis SUN levels of 70 and 25 mg/dL, respectively. Thus, this study suggests a dialysis dose target, as suggested in the ATN study, should be 1.2 to 1.4 Kt/Vurea in order to assure optimal clinical outcome.8 Two additional studies compared high-dose CVVHDF in these types of patients with combined hemofiltration and dialysate flow approaching the dialysis dose of the intensive group of the ATN study, which averaged 35.8 mL/kg/h. Both studies were single-center, randomized trials aimed at detecting a statistically valid difference of 20% mortality between groups. One study achieved an improved survival outcome in the higher–dialysis dose group comparing total effluent rate of 25 mL/kg/h versus 18 mL/kg/h,9 whereas the other study did not find the difference comparing 30 mL/kg/h versus 35 mL/kg/h.10 Two additional unblinded, single- or two-center studies examined the mortality outcomes of critically ill patients with AKI with the use of high-volume continuous venovenous hemofiltration (CVVH; >35 mL/kg/h) to increase convective clearance of middle molecules. Once again, one study revealed no difference comparing 48 mL/kg/h versus approximately 19 to 20 mL/kg/h,11 whereas the other demonstrated a significant survival benefit when ultrafiltration was increased from 20 to 35 mL/kg/h. In the latter study, however, no further benefit was observed with an increase to 45 mL/kg/h.12 Of note, the technical difficulty of maintaining filter patency and increased cost of delivering these high rates of hemofiltration, especially with postdilution infusion of replacement fluid, makes this approach difficult to justify unless the clinical evidence is more conclusive. The last 4 studies demonstrate the difficulty of interpreting and determining practice guidelines with single-center unblinded studies. What Should Clinicians and Researchers Do? The ATN study is the largest randomized, multicenter trial to date to determine dialysis dosing in critically ill patients with AKI. The size and design of the study with adequate statistical power provides generalizable information for a nephrologist/intensivist to base clinical practice on these results. The data clearly demonstrate that the outcome of patients with AKI is improved neither by increasing frequency of IHD or SLED, as long as Kt/Vurea exceeds 1.1 to 1.2, nor by increasing total filtration/effluent rate of CVVH/CVVHDF. It is possible that suboptimal dosing of CVVH/CVVHDF, for example, less than 20 mL/kg/h based on published literature, has a negative impact on outcome of severe AKI. However, survival benefit of continuous renal clearance substitution therapy or high rates of convective clearance over 35 mL/kg/h were not tested. Perhaps the ongoing RENAL trial, which focuses on continuous renal replacement therapy, will provide perspective on these important points.7 In the meantime, an intensivist/nephrologist should target a small-solute clearance that is not in or below the suboptimal ranges suggested in the previous studies with either hemodialysis or CVVHDF techniques. The disappointing results of the ATN study suggest that improvements in renal small-solute clearance substitution therapy will have minimal impact on clinical outcomes. Research in new directions and technologies is imperative for the renal community to escape from its current “entrapment” by conventional renal substitution therapy.1 Current research endeavors have been predominantly nephrocentric in their focus. Major efforts are ongoing to identify biomarkers in order to diagnose AKI earlier and more accurately so that preventive measures to minimize renal injury may change patient outcome.13 The use of stem cells to enhance the rate of recovery from AKI is also being investigated by multiple groups,14 anticipating that earlier renal recovery may lessen the morbid and mortal consequence of AKI. Although these directions of inquiry may ultimately prove useful as adjunct approaches, a more promising direction is to better understand and interrupt the pathophysiological processes that are activated in AKI, resulting in distant multi-organ dysfunction and eventually death. During the maintenance phase of AKI, while hemodialysis/hemofiltration techniques are being utilized, the patient dies from multi-organ failure while in exquisite electrolyte and fluid balance. Technologies directed to disrupting multi-organ dysfunction may well be the next major improvement to enhance the clinical outcome of these critically ill patients. Our group has focused on 2 major areas of evaluation. The first is the recognition that current renal substitution therapy only provides the small-solute clearance function of the kidney but not the metabolic and endocrine functions of the kidney. Similar to the clinical evidence that kidney transplantation markedly prolongs survival and improves health related quality of life compared to dialysis,15 the replacement of renal parenchymal cell functions in AKI may change the natural history of this disorder. A tissue engineering approach utilizing an extracorporeal renal tubule cell assist device in series to a hemofilter has had early clinical success.16 A second approach is the recognition that AKI results in a profound inflammatory response state resulting in microvascular dysfunction in distant organs.17, 18 The kidney as an important immunomodulatory organ needs further investigation. In this regard, leukocyte activation plays a central role in these acute inflammatory states.19 Disruption of the activation process of circulating leukocytes may limit microvascular damage and multi-organ dysfunction. Our group has recently developed a synthetic membrane embedded in an extracorporeal device to bind and inhibit circulating leukocytes. This device improves septic shock survival times in preclinical animal models and improves the survival outcome of ICU patients with multi-organ failure in a small exploratory, randomized, double-blinded, multicenter trial.20, 21 Creative new approaches need to be developed and evaluated to advance AKI therapies from enhancing renal clearance function to providing more complete renal replacement therapy. The future will provide numerous opportunities to develop life-saving technologies only if our discipline breaks out of the current institutionalized dialysis technology into new innovative approaches for intensive renal care. Acknowledgements Dr Song's funding institution is the Department of Internal Medicine, Center for Advanced Medical Education by BK-21 Project, Inha University School of Medicine, Incheon, Korea. Financial Disclosure: Dr Humes is founder and shareholder of Nephrion, Inc, and Innovative BioTherapies, Inc, biotechnology spin-out companies of the University of Michigan. References 1. 1Burton B. Overview of end stage renal disease. J Dial. 1976;1:1–23. MEDLINE 2. 2Lameire N, Van Biesen W, Vanholder R. The rise of prevalence and the fall of mortality of patients with acute renal failure: what the analysis of two databases does and does not tell us. J Am Soc Nephrol. 2006;17:923–925. MEDLINE |
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5. 5Palevsky PM, Zhang JH, O'Connor TZ, et al. VA/NIH Acute Renal Failure Trial Network: Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359:7–20.
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12. 12Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomized trial. Lancet. 2000;356:26–30. Abstract | Full Text |
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13. 13Waikar S, Liu K, Chertow G. Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol. 2008;3:844–861. 14. 14Imai E, Iwatani H. The continuing story of renal repair with stem cells. J Am Soc Nephrol. 2007;18:2423–2428.
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15. 15Wolfe RA. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341:1725–1730. MEDLINE |
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16. 16Tumlin J, Wali R, Williams W, et al. Efficacy and safety of renal tubule cell therapy for acute renal failure. J Am Soc Nephrol. 2008;19:1034–1040.
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17. 17Simmons EM, Himmelfarb J, Sezer MT, et al. Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int. 2004;65:1357–1365. MEDLINE |
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18. 18Okusa MD. The inflammatory cascade in acute ischemic renal failure. Nephron. 2002;90:133–138. 19. 19Maroszynska I, Fiedor P. Leukocytes and endothelium interaction as rate limiting step in the inflammatory response and a key factor in the ischemia-reperfusion injury. Ann Transplant. 2000;5:5–11. MEDLINE 20. 20Ding F, Song JH, Lou L, et al: A novel selective cytopheretic inhibitory device (SCD) inhibits circulating leukocyte activation and ameliorates multiorgan dysfunction in a porcine model of septic shock. J Am Soc Nephrol (abstr) (in press) 21. 21Humes HD, Dillon J, Tolwani A, et al: A novel selective cytopheretic inhibitory device (SCD) improves mortality in ICU patients with acute kidney injury (AKI) and multiorgan failure (MOF) in a phase II clinical study. J Am Soc Nephrol (abstr) (in press) a University of Michigan School of Medicine, Ann Arbor, Michigan b Fudan University, Huashan Hospital, Shanghai, China c Inha University School of Medicine, Incheon, Korea  Address correspondence to H. David Humes, MD, Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, 4520 MSRB I, SPC 5651, 1150 W Medical Center Dr, Ann Arbor, MI 48109
PII: S0272-6386(08)01236-5 doi:10.1053/j.ajkd.2008.07.033 © 2008 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved. | |
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