SPECIAL FEATURE
Acute Kidney Failure and Renal Replacement Therapy in the ICU: A Review
By Betty T. Tran MD, MSc
Assistant Professor of Medicine, Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago
Dr. Tran reports no financial relationships relevant to this field of study.
Acute renal failure (ARF) necessitating renal replacement therapy (RRT) is a common complication in the ICU, and one associated with high mortality and demand on clinical resources. In an effort to recognize injury to the kidney that may not result in "failure" but also has significant clinical implications, the term "acute kidney injury" (AKI) is increasingly preferred by the nephrology and ICU communities.1 This special feature aims to review the definition and scope of this complication in the ICU and discuss available RRT strategies in terms of the advantages/disadvantages of various modes, dose, and timing.
DEFINITION
There are three commonly encountered definitions for AKI. First, in 2004, the Acute Dialysis Quality Initiative (ADQI) published a consensus definition and classification scheme for AKI in the hopes of standardizing studies aimed at its prevention and treatment. Second, the RIFLE criteria defined AKI as an increase in serum creatinine (SCr) of ≥ 50% developing over ≤ 7 days, or a decrease by ≥ 25% in glomerular filtration rate (GFR), or urine output < 0.5 mg/kg/hour for ≥ 6 hours. The RIFLE acronym summarizes the categories of Risk, Injury, Failure, Loss, and End-stage disease, based on degree of SCr, GFR, and urine output changes (see Table 1).2
Table 1. RIFLE vs AKIN and KDIGO Classification for Acute Kidney Injury |
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Category |
Serum Creatinine (SCr) Criteria |
Urine Output Criteria |
RIFLE |
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Risk |
Increase in SCr ≥ 1.5x baseline, |
< 0.5 mL/kg/h for ≥ 6 hours |
Injury |
Increase in SCr ≥ 2.0x baseline, |
< 0.5 mL/kg/h for ≥ 12 hours |
Failure |
Increase in SCr ≥ 3.0x baseline, |
< 0.3 mL/kg/h for ≥ 24 hours, |
AKIN/KDIGO |
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Stage 1 |
Increase in SCr ≥ 0.3 mg/dL (26.2 μmol/L), or increase to ≥ 150-199% (1.5-1.9-fold) from baseline |
< 0.5 mL/kg/h for ≥ 6 hours |
Stage 2 |
Increase in SCr to 200-299% |
< 0.5 mL/kg/h for ≥ 12 hours |
Stage 3 |
Increase in SCr to ≥ 300% |
< 0.3 mL/kg/h for ≥ 24 hours, |
Adapted from Bagshaw SM, et al.5 (AKI = Acute Kidney Injury; for other definitions see text.) |
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Finally, because even small rises in creatinine of as little as 0.3-0.4 mg/dL were subsequently found to be associated with a 70% increase in mortality risk (95% confidence interval [CI], 1.2-2.6),3 the RIFLE criteria were later refined by the international Acute Kidney Injury Network (AKIN) in an effort to increase sensitivity in AKI diagnosis and its earlier detection. The AKIN criteria are similar to RIFLE in terms of SCr change and urine output definitions, but discarded the GFR criteria given absence of readily available methods to measure GFR (see Table 1). AKIN also modified the definition of AKI to be an abrupt (within 48 hours) change, and emphasized that the criteria should only be applied after volume status had been optimized and urinary tract obstruction excluded if using the urine output criteria.
The Kidney Disease/Improving Global Outcomes (KDIGO) clinical practice guidelines for AKI retained all the AKIN definitions and staging criteria but also included the original ≥ 50% increase in SCr within 7 days criterion from RIFLE (see Table 1).4 When applied in practice, there were no significant differences in the incidence or outcomes of AKI by using the AKIN as opposed to the RIFLE criteria,5 and both classification schemes in addition to KDIGO are recognized by multiple medical societies and used in clinical studies.
EPIDEMIOLOGY AND OUTCOMES
In a large, international cohort of 29,269 critically ill patients in 23 countries, the BEST (Beginning and Ending Supportive Therapy for the Kidney) study reported a period prevalence for ARF of 5.7% (range, 1.4-25.9%).6 Septic shock was the most common contributing factor and was seen in 47.5% of all patients with ARF. Hospital mortality for patients with ARF was 60.3% (95% CI, 58.0-62.6%), with 52% of patients dying in the ICU setting.6 The investigators used a simpler definition of ARF in an effort to identify patients who would likely trigger initiation of RRT in the ICU: 1) urine output < 200 mL in 12 hours, and/or 2) blood urea nitrogen level > 84 mg/dL (> 30 mmol/L). Although other studies have used different definitions of ARF, their estimates of prevalence and ICU/hospital mortality are quite similar.7-9 Risk factors for AKI are well established but are often broad and immutable such that they do not provide opportunities for many preventive trials; these include age, sepsis, cardiac surgery, intravenous contrast, diabetes, rhabdomyolysis, pre-existing renal disease, hypovolemia, and shock.1
In general, the more severe the kidney injury, the higher the short- and long-term mortality risk associated with it. In 5383 ICU patients at a single center, patients with AKI in RIFLE class R, I, and F had hospital mortality rates of 8.8%, 11.4%, and 26.3%, respectively, compared to 5.5% for patients without AKI.10 In a larger study using AKIN criteria with a 2-year follow-up, patients with AKIN 1, AKIN 2, and AKIN 3 stages had increasing 60-day as well as 2-year mortality risks at 1.19, 1.17, and 1.53, respectively (P < 0.001 for all) compared to patients with no AKI.11 Additional studies have also reported decreased survival even at 5 and 10 years in patients with mild AKI (KDIGO stage 1) compared to no AKI.12
Although AKI is a significant risk factor for death in multivariable analyses, it is important to remember that these associations do not necessarily imply a cause and effect relationship. Although it is theoretically possible that renal dysfunction can lead to severe pathophysiologic derangements such as volume overload, acid-base problems, alterations in innate immunity, increased risk for infection, and an overall pro-inflammatory state, it is possible that AKI is simply a surrogate marker for increased morbidity and mortality in the ICU.10
METHODS AND MODES FOR RRT
The most common and contrasted methods for RRT are intermittent hemodialysis (IHD) and continuous venovenous hemofiltration (CVVH). Hemodialysis is based on diffusion, whereby the presence of a concentration gradient drives solutes across a semi-permeable membrane between blood and the dialysate. High dialysate flow rates are required (~500 mL/min). IHD is highly effective at removing small molecules, which allows for intermittent treatments and is advantageous in many acute, potentially life-threatening conditions such as hyperkalemia, rhabdomyolysis, tumor lysis syndrome, and certain poisonings. Other advantages of IHD include low cost and the possibility of performing it without anticoagulation. However, given the rapid reduction in plasma osmolality that causes extracellular water to move into cells and rapid fluid removal, it may not be well tolerated in patients who are hypotensive.
Hemofiltration, on the other hand, relies on convection, whereby positive hydrostatic pressure (rather than a concentration gradient) drives both water and solutes across a semi-permeable membrane from blood to filtrate. Both small and middle-sized molecules are cleared, and the volume of the filtrate has to be continuously substituted by replacement fluids. In contrast to IHD, hemofiltration is delivered continuously for 18-24 hours/day at slower rates (1-3 L/hour), although it can be used intermittently if higher ultrafiltration rates are applied. Its theoretical advantages, however, include more hemodynamic stability allowing for more adequate fluid removal and better recovery of renal function, as well as clearance of mid-size molecules such as cytokines.13 On the other hand, it requires continuous anticoagulation and involves continuous exposure to an extracorporeal circuit that may lead to nutrient depletion, sub-therapeutic levels of antibiotics, and infection.13
Numerous studies, including randomized trials, comparing intermittent to continuous RRT have failed to find consistent results showing one mode is superior to another in terms of clinically important outcomes such as survival rates and renal recovery.14,15 However, given the inherent advantages and disadvantages of each mode, there is significant heterogeneity in the ICU populations that received each type of RRT, which make comparisons difficult. RRT modes, therefore, may not be interchangeable in individual patients and should be selected based on actual clinical conditions. Hybrid techniques employing aspects of both IHD and CVVH have been used, including slow, low-efficiency daily dialysis (SLEDD), which combines the theoretical advantages of both IHD and CRRT (see Table 2).16 Major outcome trials comparing these hybrid techniques to more traditional approaches in large populations are currently lacking.
Table 2. Common Modes of Renal Replacement Therapy |
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RRT Modality |
Transport Principle |
Characteristics |
IHD |
Diffusion |
"Classic" hemodialysis |
SLEDD |
Diffusion |
Uses IHD machine; slower blood and dialysate flows than IHD; longer RRT times; more hemodynamic stability |
CVVHD |
Diffusion |
Continuous hemodialysis at slower dialysate flow rates |
CVVH |
Convection |
"Classic" hemofiltration |
SCUF |
Convection |
No solute removal; good for large volume removal; no dialysate or replacement fluids needed |
AVVH |
Convection |
Higher flow rates than CVVH (350-400 mL/min); shorter RRT times; no anticoagulation needed |
CVVHDF |
Convection and diffusion |
Continuous hemofiltration combined with diffusive dialysis at low flow rates; effective small and middle molecule solute clearance; both dialysate and replacement fluids required |
RRT = Renal Replacement Therapy; IHD = intermittent hemodialysis; SLEDD = slow low-efficiency daily dialysis; CVVHD = continuous venovenous hemodialysis; CVVH = continuous venovenous hemofiltration; SCUF = slow continuous ultrafiltration; AVVH = accelerated venovenous hemofiltration; CVVHDF = continuous venovenous hemodiafiltration. Adapted from John S, Eckardt KU.16 |
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DOSE OF RRT
Quantification of urea removal is commonly used in evaluating RRT efficiency and comparing dialysis dosing. For IHD, this is the Kt/Vd measurement (K: dialyzer clearance of urea, t: duration of dialysis, Vd: urea distribution volume), whereas for hemofiltration, it is equal to the rate of ultrafiltration.
Prior to 2008, randomized controlled trials investigating the effect of RRT dose on mortality and renal function recovery reported mixed results, with some trials suggesting a survival benefit with more intense RRT. The largest, best-designed trials looking at the optimal intensity of RRT among critically ill patients have since found no benefit with higher intensity compared to less intensive regimens. The Acute Renal Failure Trial Network randomized 1124 patients with ARF to either a high intensity (IHD or slow, low-efficiency dialysis six times/week or CVVH at 35 mL/kg/hour, depending on hemodynamics) or less intensive strategy (IHD or slow, low-efficiency dialysis three times/week or CVVH at 20 mL/kg/hour); each IHD or slow, low-efficiency dialysis session provided a dose (Kt/Vd) of 1.2-1.4 per session.17 Sixty-day mortality was similar between the two groups (53.6% high intensity group vs 51.5% less intensive group, odds ratio [OR], 1.09; P = 0.47) with no significant difference in rate of renal recovery.17
Similarly, the Randomized Evaluation of Normal versus Augmented Level (RENAL) Replacement Therapy Study, which enrolled 1508 patients from Australia and New Zealand who were critically ill and receiving CVVH to a higher intensity (40 mL/kg/hour) vs lower intensity (25 mL/kg/hour) regimen, found no difference in 90-day mortality (44.7% in both groups; OR, 1.00; P = 0.99) or rates of renal recovery.18 Based on these studies and prior knowledge that inadequate dialysis has been associated with higher mortality rates in chronic renal failure,4 we can conclude that: 1) RRT doses are important, 2) at least 3.6 Kt/Vd for IHD or SLEDD and 20 mL/kg/h are likely adequate for most critically ill patients requiring RRT for ARF, and 3) increases beyond an adequate level of intensity provide no additional benefit.1
INDICATIONS AND TIMING OF RRT
Although the absolute indications for RRT in critically ill patients are often agreed on (metabolic acidosis, hyperkalemia, and/or hypervolemia that do not respond to medical therapy), the optimal timing ("early" vs "late") to initiate RRT remains unanswered. In general, studies have shown no significant survival benefit or improved chance of renal recovery with earlier commencement of RRT relative to onset of AKI.19,20 However, the risk of death does appear to rise in a graded fashion with progressive delay of RRT, suggesting that further studies are warranted in assessing the role of RRT timing in AKI.20,21 At the other end of the spectrum, "prophylactic" RRT in the absence of renal injury has been ineffective in studies in patients with trauma and septic shock in terms of improving the risk or severity of organ dysfunction.16
CONCLUSION
AKI contributes substantially to the morbidity and mortality of critically ill patients. RRT can provide renal support via a variety of modes, all of which have advantages and disadvantages depending on the individual clinical scenario. Although we have learned that adequate RRT dosing is necessary, many questions remain with regard to the optimal dosing and timing of RRT initiation. As no one mode has been shown to have a survival advantage over another, collaboration between the nephrologist and intensivist is vital to develop a RRT strategy that is appropriate and in keeping with the patient’s medical treatment plan.
REFERENCES
- Brochard L, et al. An Official ATS/ERS/ESICM/SCCM/SRLF statement: Prevention and management of acute renal failure in the ICU patient. Am J Respir Crit Care Med 2010;181:1128-1155.
- Bellomo R, et al. Acute renal failure — definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204-R212.
- Chertow GM, et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365-3370.
- Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int 2012;2(Suppl):1-138.
- Bagshaw SM, et al. A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008;23:1569-1574.
- Uchino S, et al. Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA 2005;294:813-818.
- Brivet FG, et al. Acute renal failure in intensive care units —causes, outcome, and prognostic factors of hospital mortality: A prospective, multicenter study. French Study Group on Acute Renal Failure. Crit Care Med 1996;24:192-198.
- Schaefer JH, et al. Outcome prediction of acute renal failure in medical intensive care. Intensive Care Med 1991;17:19-24.
- Ali T, et al. Incidence and outcomes in acute kidney injury: A comprehensive population-based study. J Am Soc Nephrol 2007;18:1292-1298.
- Hoste EA, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: A cohort analysis. Crit Care 2006;10:R73.
- Fuchs L, et al. Severity of acute kidney injury and two-year outcomes in critically ill patients. Chest 2013;144:866-875.
- Linder A, et al. Small acute increases in serum creatinine are associated with decreased long term survival in the critically ill. Am J Respir Crit Care Med 2014;Mar 6. [Epub ahead of print.]
- Vanholder R, et al. Pro/con debate: Continuous versus intermittent dialysis for acute kidney injury: A never-ending story yet approaching the finish? Crit Care 2011;15:204.
- Bagshaw SM, et al. Continuous versus intermittent renal replacement therapy for critically ill patients with acute kidney injury: A meta-analysis. Crit Care Med 2008;36:610-617.
- Pannu N, et al. Renal replacement therapy in patients with acute renal failure. JAMA 2008;299:793-805.
- John S, Eckardt KU. Renal replacement strategies in the ICU. Chest 2007;132:1379-1388.
- The 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.
- The RENAL Replacement Therapy Study Investigators. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med 2009;361:1627-1638.
- Bouman CSC, et al. Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure. Crit Care Med 2002;30:2205-2211.
- Jun M, et al. Timing of renal replacement therapy and patient outcomes in the Randomized Evaluation of Normal Versus Augmented Level of Replacement Therapy Study. Crit Care Med 2014; Apr 8. [Epub ahead of print.]
- Liu KD, et al. Timing of initiation of dialysis in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2006;1:915-919.
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