Nephrology Hypertension

Role of Acute Dialysis (CRRT, SLED, Intermittent hemodialysis, other)

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Does this patient have acute kidney injury requiring renal replacement therapy?

What are the indications for renal replacement therapy in patients with acute kidney injury?

In the absence of effective pharmacologic therapies, the care of the patient with acute kidney injury (AKI) is limited to supportive management, with the use of renal replacement therapy (RRT) assuming a major role. The optimal timing to initiate RRT in AKI is not defined and no consensus exists on the precise cutoff values for initiation. As a result, practice patterns vary widely. In most instances, clinicians initiate RRT to prevent uremia and immediate death from the adverse complications of renal failure.

These conventional life-threatening indications for initiating RRT in AKI include:

  • Volume overload unresponsive to diuretic therapy

  • Hyperkalemia refractory to medical management

  • Metabolic acidosis refractory to medical management

  • Uremia with symptoms of encephalopathy, pericarditis, or uremic bleeding

  • Intoxication with a drug that can be removed by dialysis

Unfortunately, beyond this indication-based approach, there is limited evidence to guide clinicians on when to initiate RRT in critically ill patients with AKI. Although several meta-analyses of both randomized controlled trials and cohort studies have suggested that “early” initiation of RRT for AKI (based on a lower urea or creatinine level) is associated with better patient survival, these studies have significant design limitations and need to be confirmed with adequately powered randomized trials. In current practice the decision to start RRT is often based on the broader clinical context of the patient and includes general severity of illness, number of failed non-renal organs, presence of oliguria and fluid overload, and whether the patient is recovering or deteriorating. In patients with AKI and severe multi-organ dysfunction, RRT may be of benefit when started early to maintain metabolic and volume homeostasis and to prevent further deterioration and development of overt symptoms and signs of renal failure. A definitive answer to this important clinical issue will require data from prospective randomized controlled trials. Several such trials have initiated enrollment of patients (IDEAL-ICU, NCT01682590; AKIKI, NCT01932190; STARRT-AKI, NCT02568722, and ELAIN, DRKS00004367). Until these trials are complete, evidence-based recommendations on the optimal timing for RRT is unavailable.

What tests to perform?

N/A

How should patients with acute kidney injury requiring renal replacement therapy be managed??

What are the different modalities of renal replacement therapy available for acute kidney injury?

Once a decision is made that a patient needs RRT, a modality needs to be selected. RRTs are classified by the predominant transport process used to remove solutes and toxins. Most forms of RRT rely on the principle of allowing water and solute transport through a semipermeable membrane with discard of the waste products. Ultrafiltration is the process by which water is transported by a transmembrane pressure gradient across a semipermeable membrane. Diffusion and convection are the two processes by which solutes are transported across the membrane. Diffusion occurs by movement of solutes from an area of higher solute concentration to an area of lower concentration across a semipermeable membrane.

With extracorporeal dialytic techniques, the concentration gradient is maximized and maintained throughout the length of the membrane by running the dialysate (an electrolyte solution usually containing sodium, bicarbonate, chloride, magnesium, and calcium) countercurrent to the blood flow. Small-molecular-weight solutes, such as urea, are cleared efficiently by diffusion, but larger molecular-weight solutes are not. Convection occurs when the transmembrane pressure gradient drives plasma water across a semipermeable membrane as in ultrafiltration but then ‘‘drags’’ with the water both small-molecular-weight (blood urea nitrogen, creatinine, potassium) and large-molecular-weight (inulin, b2-microglobulin, tumor necrosis factor, vitamin B12) solutes. Membrane pore diameter limits the size of the large solutes that can pass.

The available RRT modalities use ultrafiltration for fluid removal and either diffusion, convection, or a combination of diffusion and convection to achieve solute clearance. Options for RRT therapy for AKI include intermittent hemodialysis (IHD), peritoneal dialysis (PD), various forms of continuous renal replacement therapy (CRRT), and newer “hybrid” therapies known as prolonged intermittent renal replacement therapy (PIRRT) or sustained low-efficiency dialysis (SLED).

Intermittent hemodialysis (HD)

Traditionally, nephrologists have managed AKI with IHD, empirically delivered 3 to 6 times a week, 3 to 4 hours per session, with a blood flow rate of over 250 mL/min and a dialysate flow rate of 500 to 800 mL/min. In IHD, solute clearance occurs mainly by diffusion, whereas volume is removed by ultrafiltration. Decisions regarding dialysis duration and frequency are based on patient metabolic control, volume status, and presence of any hemodynamic instability. Advantages of IHD include rapid solute and volume removal. This results in rapid correction of electrolyte disturbances, such as hyperkalemia, and rapid removal of drugs or other substances in fatal intoxications in a matter of hours. IHD also has a decreased need for anticoagulation as compared with other types of RRT because of the faster blood flow rate and shorter duration of therapy

The main disadvantage of IHD is the risk of systemic hypotension caused by rapid electrolyte and fluid removal. Sodium modeling, cooling the dialysate, increasing the dialysate calcium concentration, and intermittent ultrafiltration may be used to improve hemodynamic stability during IHD. Rapid solute removal from the intravascular space can cause cerebral edema and increased intracranial pressure, limiting this therapy in patients with head trauma or hepatic encephalopathy.

Peritoneal dialysis (PD)

In PD, the peritoneum is used as a semi-permeable membrane for diffusive removal of solutes. A dialysate solution with a high concentration of glucose is administered into the peritoneal cavity through a catheter where it dwells for a prescribed period of time, allowing solutes to diffuse from blood in the capillaries into the dialysate. The saturated dialysate is then drained and discarded, and fresh dialysate reintroduced. High concentrations of dextrose are used in the dialysate to create an osmotic gradient for ultrafiltration. Advantages of PD include technical simplicity, hemodynamic stability, and lack of need for anticoagulation or vascular access.

However, the use of PD is limited by practical considerations.

Acute PD requires the surgical insertion of a peritoneal dialysis catheter, which can be complicated by catheter leakage and malfunction. Furthermore, PD may compromise patient respiratory status due to increased abdominal pressure from instilled dialysate, cause hyperglycemia, and provide insufficient solute clearance in hypercatabolic patients. PD is contraindicated in post-operative patients who need abdominal surgery or surgical drains. PD is a less effective modality in certain clinical situations like patients with poisoning, hypercatabolic states, and pulmonary edema. There is also limited data concerning the effect on mortality of PD versus other renal replacement therapies in patients with AKI. However, PD remains an acceptable alternative to IHD and CRRT especially in low and middle income countries where access to technology is difficult.

Continuous renal replacement therapy (CRRT)

CRRT has become the preferred modality for managing hemodynamically unstable patients with AKI. The different CRRT modalities can use diffusion, convection, or a combination of both for solute clearance. Unlike IHD, CRRT is performed continuously (24 hours per a day) with a typical blood flow of 100 to 300 mL/min and a dialysate flow of 17 to 40 mL/min if a diffusive CRRT modality is used. It is performed most commonly through a venovenous vascular access. The most commonly applied modalities of CRRT are continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF). In CVVH, solute clearance occurs by convection. No dialysate is used. The rate at which ultrafiltration occurs is the major determinant of convective clearance. Intravenous ‘‘replacement fluid’’ is provided to replace the excess volume that is being removed and replenish desired solutes.

In CVVHD, solute removal occurs by diffusion. Unlike IHD, the dialysate flow rate is slower than the blood flow rate, allowing small solutes to equilibrate completely between the blood and dialysate. As a result, the dialysate flow rate approximates urea and creatinine clearance. Ultrafiltration is used for volume control. CVVHDF combines the convective solute removal of CVVH and the diffusive solute removal of CVVHD. As in CVVH, the high ultrafiltration rates used to provide convective clearance require the administration of intravenous replacement fluids. Despite increased clearance of middle molecular weight molecules with convective techniques, no study has shown that CVVH or CVVHDF improves patient survival when compared to CVVHD. Since there is insufficient data to recommend one type of CRRT modality over another, the choice of CRRT modality should be based on clinician preference and expertise.

The advantages of CRRT include hemodynamic tolerance caused by slower ultrafiltration and solute removal. The gradual continuous volume removal makes control of volume status easier and allows administration of medications and nutrition with less concern for volume overload. Because it is a continuous modality, there is less fluctuation of solute concentrations over time and better control of azotemia, electrolytes, and acid-base status. It does not raise intracranial pressure like IHD. The main disadvantages of CRRT include access and filter clotting and the consequent need for anticoagulation. Another disadvantage of CRRT is increased cost and demands on ICU nurse time compared with IHD.

Prolonged Intermittent Renal Replacement Therapy (PIRRT)

Hybrid therapies are also known as PIRRT, sustained low-efficiency dialysis (SLED), and extended daily dialysis (EDD). These therapies use conventional hemodialysis machines with lower blood-pump speeds and dialysate flow rates to provide solute and fluid removal slower than IHD but faster than conventional CRRT.

Typically, they use low blood-pump speeds of 200 mL/min and low dialysate flow rates of 300 mL/min for 6 to 12 hours daily. PIRRT combines the advantages of CRRT and IHD. They allow for improved hemodynamic stability through gradual solute and volume removal as in CRRT. At the same time, they are able to provide high solute clearances as in IHD and remove the need for expensive CRRT machines, costly customized solutions, and trained staff. Because they can be done intermittently based on the needs of the patient, they also avoid the interruption of therapy for various diagnostic and therapeutic procedures that may be required in such patients.

Which modality of renal replacement therapy should be employed?

There is a continuous debate regarding which modality for critically ill patients with AKI should be selected, and modality choice is affected by the geographical location of patients with AKI; this was illustrated by the BEST Kidney study, a study that included 1738 patients in 54 intensive care units (ICUs) on five continents. CRRT was the most common choice of initial RRT treatment (80%). IHD was commonly restricted to ICUs in North and South America, where it was used as initial therapy in 30–40% of patients, while, by contrast, CRRT was used first in 100% of ICUs in Australia.

Decisions for modality selection are hampered by lack of evidence for improved outcomes with specific modalities. Modality comparisons have failed to demonstrate any survival advantage for continuous versus intermittent therapies. Three recent multicenter randomized controlled trials have found similar results. In the first one of these studies, investigators randomized 360 patients with AKI to alternate day IHD or CVVHDF. The rate of survival at 60-days did not differ between the groups (32% in the IHD group versus 33% in the CVVHDF group [95 % CI 8.8 – 11.1]). In the second study, Lins et al. analyzed 316 patients with AKI who were stratified according to severity of disease and randomized into two different treatment options: IHD or CVVH. Intention to treat analysis revealed a mortality of 62.5% in IHD group compared to 58.1% in the CRRT group (p = 0.430). No difference between IHD and CRRT was observed in the duration of ICU or hospital stay.

Among survivors, renal recovery at hospital discharge was comparable between both groups (35% versus 29%). In the third study (CONVINT trial), Schefold et al. randomized 252 critically ill patients at a single center in Germany to CVVH or daily IHD. Mortality 14 days after discontinuation of RRT was 39.5% in the IHD group as compared with 43.9% in the CVVH group (p=0.5). There was no difference in 14-day-, 30-day, and all-cause in-hospital mortality between the two groups (all p > 0.5). Similarly, there was no difference in renal recovery.

Three recent meta-analyses reached similar conclusions that the type of RRT does not have a major impact on survival or renal recovery. However, the validity of the data from the studies is dubious on account of issues related to study design, such as exclusion of patients with hemodynamic instability, improper randomization, differences in baseline characteristics between arms, and high crossover rates between modalities.

Despite the evidence pointing toward no difference in terms of survival and renal recovery between CRRT and IHD, some important advantages and disadvantages of CRRT and IHD that may influence decision of modality selection have to be considered:

  1. Use of IHD has been associated with progressively positive fluid balance whereas CRRT permits a better management of volume overload patients with AKI and also allows adequate volume of nutrition without compromising fluid balance.

  2. Removal of fluid in order to get a neutral fluid balance with IHD short sessions can precipitate intra-dialytic hypotension, which is an important contributing factor for an increased risk of recurrent kidney injury and non-recovery of renal function.

  3. Observational studies suggest initial treatment with CRRT may be associated with higher rates of renal recovery.

  4. IHD has some advantages over CRRT, among which include practicality and flexibility of application, limitation of expenses, and fewer bleeding complications.

  5. The hybrid modalities, sustained low efficiency daily dialysis (SLED) and extended daily dialysis (EDD), can provide adequate solute control (as IHD does) and require less intensive monitoring and time in comparison to CRRT.

It is now recognized that more than one therapy can be utilized for managing patients with AKI. Transitions in therapy are common and reflect the changing needs of patients during their hospital course. For instance, patients in the ICU may initially start on CRRT when they are hemodynamically unstable, transition to SLED/EDD when they improve, and leave the ICU receiving IHD.

Given the current state of knowledge, we recommend utilizing the modality that will best support patients’ needs should be utilized. Each modality has a role in the management of patients with AKI and should be tailored for each patient based on the dynamic need.

What dose of dialysis should be delivered and how should dialysis dose be assessed?

Dose of dialysis

Since the year 2000, multiple studies in intermittent and in continuous therapies have suggested that higher doses of renal replacement therapy are associated with improved outcomes. However, two recent large, multicenter, randomized control trials, the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) study and the Randomized Evaluation of Normal versus Augmented level Renal Replacement Therapy (RENAL) trial, do not support the hypothesis that a higher dose of RRT will improve outcomes.

For IHD, the ATN study demonstrated no need to provide treatments more than 3x/week as long as a target of Kt/Vurea of 1.2 – 1.4 per treatment is achieved. For CRRT, both the ATN and RENAL studies demonstrated no benefit in survival when increasing the “delivered” dose of CRRT beyond 19 – 22 mL/kg/h. Nevertheless, one important aspect which needs to be considered, is that the ATN study and RENAL trial did not measure actual solute removal, and that measured effluent volume normalized for effective treatment time significantly overestimates delivered dose of small solutes in CRRT.

To achieve the prescribed dialysis dose, effluent-rate-based dose should be increased by 20% to 25% to account for decreases in treatment time and reduced filter efficacy during CRRT.

It appears that the relationship between dose administered by RRT and survival has two regions: a dosage-dependent region where increases in intensity of dose are associated with improved survival and a dosage-independent region where after a threshold is reached; further increment on the intensity dose is not associated with better outcomes. The ATN and RENAL studies, rather than implying that dose is not important in the treatment of critically ill patients with AKI, suggest that dose should be measured.

The influence on solute clearance of some operational characteristics of CRRT, such as clotting, use of pre-dilution versus post-dilution replacement fluids, convective versus diffusive modalities, and concentration polarization of the filter, affect delivering a prescribed dose; that is why simply prescribing a target dose and adjusting for treatment interruptions is insufficient as to representing actual solute clearance.

Filter function should be monitored continuously using effluent urea nitrogen to blood urea nitrogen ratios (FUN/BUN ratio).

Dose assessment

Originally, dose quantification was restricted to the measurement of blood urea nitrogen (BUN) and creatinine levels.

Intermittent hemodialysis (IHD)

  1. Normalized urea clearance (Kt/Vurea) and the number of treatments per week have been employed for dose assessment when IHD is employed. Some assumptions needed for calculating Kt/Vurea in chronic dialysis cannot be applied in patients with AKI:

  2. Kt/Vurea is unsuitable for quantifying IHD regimens that vary in frequency because cumulative Kt/Vurea does not change proportionally to cumulative solute removal.

  3. Kt/Vurea is a measure of dialyzer performance, and does not reflect patient dialysis.

  4. Multiplying a single treatment Kt/Vurea by the number of treatments per week will overestimate the contribution of intermittent therapy.

Continuous renal replacement therapies (CRRT)

In CRRT, dose is usually assessed in terms of effluent volume per kilogram of body weight per unit of time (mL/kg/hr). However, total effluent volume overestimates the actual delivered dose of dialysis in CRRT; that is why the sieving coefficient (small solute ultrafiltrate to blood ratio) should be continuously monitored at least daily. Delivered dose should be equal to: total effluent volume x (effluent urea nitrogen / blood urea nitrogen).

Assessing dose across different types of RRT

Modality transitions add another complexity in quantifying dose, since the operational characteristics of each modality (IHD, SLED and CRRT) have a different influence on dose measurements. There are several methods for quantifying different RRT in a manner that makes dose expressions comparable.

  1. Standard Kt/V (StdKt/V) is among them, it is calculated using urea mass removal rate extrapolated from urea generation rate (G), which requires the patient to be in steady state, a condition rarely found in AKI patients.

  2. Solute removal index (SRI) is another dose expression that could be used to compare different modalities of RRT, which uses dialysate-side measurements for its calculation.

  3. Equivalent renal urea clearance (EKR), which appears to be a better alternative for dose quantification across different modalities; since it is calculated using time average urea concentrations (TAC) as opposed to peak urea concentrations. It is also expressed in mL/min which can be easily correlated with some parameters like residual renal function and actual solute removal. EKR has a limitation, it assumes that G is equal to the urea removal rate, an assumption that cannot be made during hypercatabolic states like AKI.

Other dose parameters

  • Dose quantification and expression in AKI patients should not only be limited to the assessment of small solute clearance.

  • Fluid balance is a critical component of the care of critically ill patients with AKI and one of the main goals of any RRT should be achieving it.

  • Overall fluid balance depends on the amount of fluid intake, which is countered by the amount removed by urine output and ultrafiltration.

  • When balance is not achieved, fluid accumulation and fluid overload develop and contribute to increase mortality and non-renal recovery in critically ill patients with AKI.

  • Measuring fluid accumulation should become part of the process of quantifying dialysis dose; and a practical way to express this variable was proposed by Goldstein et al; the authors used the following formula to quantify cumulative fluid balance in relation to body weight: [Σ daily (Fluid intake (L) – total output (L))/body weight (Kg)] × 100.

  • Fluid overload could then be defined and expressed as a percentage of fluid accumulation >10% over baseline weight at hospital admission as was shown by Bouchard et al; in this observational study patients with fluid overload experienced significantly higher mortality within 60 days of enrollment. Among dialyzed patients, survivors had significantly lower fluid accumulation when dialysis was initiated compared to non-survivors after adjustments for dialysis modality and severity score. In non-dialyzed patients, survivors had significantly less fluid accumulation at the peak of their serum creatinine. Other observational studies have since then reported similar findings.

When can renal replacement therapy be discontinued?

RRT is continued until the patient manifests evidence of recovery of kidney function, ultrafiltration goal is met or correction of metabolic abnormality occurs. Renal recovery ensues in the setting of increasing urine output. Further assessment of renal recovery can be obtained by measurement of a timed urine collection for creatinine clearance (CrCl). Although the specific threshold of CrCl needed to allow discontinuation of RRT is not known, observational studies have suggested a minimum CrCl of 15 to 20 ml/min is adequate.

What happens to patients with acute kidney disease requiring renal replacement therapies?

What is the prognosis for patients with acute kidney injury who require renal replacement therapies?

Despite improvement in the management of critically ill patients and developments made in renal replacement techniques, the mortality of patients with AKI in the ICU continues to be high as has been shown in recent studies.

In a prospective cohort study, Aldawood et al. analyzed data from 664 critically-ill patients with AKI requiring CRRT. Hospital and ICU mortality rates were 80% and 64% respectively. Multivariate analysis showed that mechanical ventilation requirement was independently associated with an increased mortality risk.

  • In another population-based cohort study, Yasuda et al. analyzed data from 242 AKI patients treated with RRT. Of these 242 patients, 73.6% were treated with CRRT, 24.4% with IHD, and 0.8% with extracorporeal ultrafiltration method. The in-hospital mortality rate was 47.1%. Mortality rates were worse in septic patients with increasing numbers of failing organs, and with decreasing urinary output.

  • In a different population, Park et al. showed that seventy-two (77%) of the 94 critically ill patients with hematologic malignancies and AKI who received RRT died after a median time of 4 days (IQR, 2-20 days) after the initiation of RRT. In a multiple logistic regression analysis, ICU mortality was independently associated with modified SOFA score (odds ratio, 1.83 per modified SOFA score increase; 95% confidence interval, 1.38-2.42) at the initiation of RRT.

  • In a retrospective single center study, Lines et al. described the outcomes of 821 patients with AKI who received RRT during ICU stay. The authors reported ICU and hospital mortality rates of 55% and 66% respectively. Being older (OR 1.02 [1.01-1.03]), having a lower pH (OR 0.07 [0.02-0.27]) or lower hemoglobin levels (OR 0.82 [0.74-0.91]) at the time of admission were predictive of mortality.

In conclusion mortality of critically ill patients with AKI that require RRT continuous to be high, and it seems to be similar across different geographical regions.

How to utilize team care?

The success of CRRT depends upon the presence of a multidisciplinary team. The ideal team should be comprised of a:

  1. Nephrologist

  2. Critical care nurse

  3. Dialysis nurse

  4. Clinical pharmacist

  5. Dietician and

  6. Both the primary ICU and consulting physicians.

Implementing CRRT in an ICU is a somewhat difficult issue. Involvement of both the ICU and nephrology teams is another key to success especially when different modes and higher effluent rates are used.

A nursing group devoted to the ongoing implementation and education of the ICU team is very useful in order to attain the goals that have been set. It may indeed require an on-call medical emergency CRRT team as expertise in this field is really a key issue to success. An example of the important roles of diverse team members in the care of patients treated with CRRT is when tasks are assigned to different members of this team; in this context the dialysis nurses assist with machine and circuit preparation, connection, and treatment initiation, and then let the ICU nurses continue management. The ICU nurse may then seek assistance for ‘‘troubleshooting’’ and circuit disconnection as needed.

Clinical pharmacists may enhance the intensive monitoring and individualization of drug therapy through the knowledge and application of pharmacodynamics and pharmacokinetic principles, which are required in the management of AKI patients treated with RRT. Clinical pharmacists’ participation is also important in identifying particular drug interactions in order to prescribe rationally.

Are there clinical practice guidelines to inform decision making?

Kidney Disease Improving Global Outcome (KDIGO) guidelines on AKI have been published; these guidelines provide needed evidence-based clinical practice guidelines for the diagnosis, evaluation, classification, prevention, and management of AKI. Specific recommendations about renal replacement management of AKI, including type of therapy, dose, initiation, discontinuation, anticoagulants, and vascular access, will be covered. In principle these guidelines build on the conceptual framework outlined above to make decisions for initiating and stopping RRT. The key is to standardize the approach and permit personalization for individual patients.

Other considerations

Other considerations of the RRT prescription include vascular access, membrane, fluids, and anticoagulation.

What is the evidence?

Timing of renal replacement therapy in AKI patients

Seabra, VF, Balk, EM, Liangos, O, Sosa, MA, Cendoroglo, M, Jaber, BL. "Timing of renal replacement therapy initiation in acute renal failure: a meta-analysis". Am J Kidney Dis. vol. 52. 2008. pp. 272-84.

Macedo, E, Mehta, RL. "Early vs late start of dialysis: it's all about timing". Crit Care. vol. 14. 2010. pp. 112-113.

Macedo, E, Mehta, RL. "When should renal replacement therapy be initiated for acute kidney injury?". Semin Dial. vol. 24. 2011. pp. 132-137.

Smith, OM, Wald, R, Adhikari, NK, Pope, K, Weir, MA, Bagshaw, SM. "Canadian Critical Care Trials Group: Standard versus accelerated initiation of renal replacement therapy in acute kidney injury (STARRT-AKI): study protocol for a randomized controlled trial". Trials. vol. 14. 2013. pp. 320.

(The optimal timing of RRT in ICU patients with AKI is unknown. Most studies addressing appropriate timing of RRT for AKI have been observational. The investigators of this trial recently completed a multi-center randomized controlled pilot trial that confirmed the feasibility of performing a larger randomized trial on RRT timing in AKI ICU patients. Patient recruitment and follow-up, as well as patient safety, were successfully demonstrated during the pilot phase. The principal trial is now underway and recruiting patients. The information from this trial, among other ongoing randomized controlled trials, will hopefully provide evidence-based guidelines on RRT initiation for ICU patients with AKI.)

Barbar, SD, Binquet, C, Monchi, M, Bruyère, R, Quenot, JP. "Impact on mortality of the timing of renal replacement therapy in patients with severe acute kidney injury in septic shock: the IDEAL-ICU study (initiation of dialysis early versus delayed in the intensive care unit): study protocol for a randomized controlled trial". Trials. vol. 15. 2014. pp. 270.

(The optimal timing of RRT in ICU patients with AKI is unknown. Most studies addressing appropriate timing of RRT for AKI have been observational. The purpose of this multicenter, randomized controlled trial is to investigate whether early initiation of RRT (within 12 hours after a diagnosis of AKI at the "failure" stage according to the RIFLE Criteria), will reduce 90-day mortality as compared to deferred initiation of RRT (48 to 60 hours after diagnosis), in ICU patients with septic shock who develop AKI. The information from this trial, among other ongoing randomized controlled trials, will hopefully provide evidence-based guidelines on RRT initiation for ICU patients with AKI.)

Gaudry, S, Hajage, D, Schortgen, F. "Comparison of two strategies for initiating renal replacement therapy in the intensive care unit: study protocol for a randomized controlled trial (AKIKI)". Trials. vol. 16. 2015. pp. 170.

(The optimal timing of RRT in ICU patients with AKI is unknown. Most studies addressing appropriate timing of RRT for AKI have been observational. The investigators are in the process of conducting a multicenter prospective randomized open-label trial to compare two initiation strategies in ICU patients (mechanically ventilated and/or receiving catecholamine infusion) with severe AKI defined as RIFLE-F classification. Recruitment is complete. The information from this trial, among other ongoing randomized controlled trials, will hopefully provide evidence-based guidelines on RRT initiation for ICU patients with AKI.)

Zarbock, A, Gerß, J, Van Aken, H, Boanta, A, Kellum, JA, Meersch, M. "Early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury (The ELAIN-Trial): study protocol for a randomized controlled trial". Trials. vol. 17. 2016. pp. 148.

(The optimal timing of RRT in ICU patients with AKI is unknown. Most studies addressing appropriate timing of RRT for AKI have been observational. The purpose of this randomized controlled trial is to investigate the effect of early initiation of RRT (initiated at stage 2 of the AKIN classification) compared to late initiation of RRT at stage 3 of the AKIN classification and/or if absolute indications for RRT are present. The primary outcome parameter is the 90-day mortality from all causes. Recruitment is complete. The information from this trial, among other ongoing randomized controlled trials, will hopefully provide evidence-based guidelines on RRT initiation for ICU patients with AKI.)

RRT modalities for AKI patients and which modality should be chosen

Bagshaw, SM, Berthiaume, LR, Delaney, A, Bellomo, R. "Continuous versus intermittent renal replacement therapy for critically ill patients with acute kidney injury: a meta analysis". Crit Care Med. vol. 36. 2008. pp. 610-7.

Lins, RL, Elseviers, MM, Van der Niepen, P, Hoste, E, Malbrain, ML, Damas, P, Devriendt, J. "Intermittent versus contnuos renal replacement for acute kidney injury patients admitted to the intensive care unit: results of a randomized clinical trial". Nephrol Dial Transplant. vol. 24. 2009. pp. 512-8.

Vanholder, R, Van Biesen, W, Hoste, E, Lameire, N. "Pro/con debate: Continuous versus intermittent dialysis for acute kidney injury: a never-ending story yet approaching the finish?". Crit Care. vol. 15. 2011. pp. 204.

Friedrich, JO, Wald, R, Bagshaw, SM, Burns, KE, Adhikari, NK. "Hemofiltration compared to hemodialysis for acute kidney injury: systematic review and meta-analysis". Crit Care. vol. 16. 2012. pp. R146.

This systematic review and meta-analysis highlights the paucity of data from randomized controlled trials comparing hemofiltration to hemodialysis in the treatment of AKI. Pooled data from a few randomized trials indicate that hemofiltration increases the clearance of medium to larger molecules without improving clinical outcomes, though confidence intervals were wide.

Schefold, JC, von Haehling, S, Pschowski, R, Bender, T, Berkmann, C, Briegel, S, Hasper, D, Jörres, A. "The effect of continuous versus intermittent renal replacement therapy on the outcome of critically ill patients with acute renal failure (CONVINT): a prospective randomized controlled trial". Crit Care. vol. 18. 2014. pp. R11.

This is another single-centered randomized controlled trial that demonstrated no statistically significant differences between CRRT and IHD regarding mortality, renal-related outcome measures, or survival at 14 days after RRT. This adds to the data that intermittent and continuous RRTs may be considered equivalent approaches for critically ill patients with dialysis-dependent AKI.

Renal replacement dose in AKI patients

Palevsky, PM, Zhang, JH, O'Connor, TZ, Chertow, GM, Crowley, ST, Choudhury, D, Finkel, K, Kellum, JA, Paganini, E, Schein, RM, Smith, MW, Swanson, KM, Thompson, BT, Vijayan, A, Watnick, S, Star, RA, Peduzzi, P. "Intensity of renal support in critically ill patients with acute kidney injury". N Engl J Med. vol. 359. 2008. pp. 7-20.

Bellomo, R, Cass, A, Cole, L, Finfer, S, Gallagher, M, Lo, S, McArthur, C, McGuinness, S, Myburgh, J, Norton, R, Scheinkestel, C, Su, S. "Intensity of continuous renal-replacement therapy in critically ill patients". N Engl J Med. vol. 361. 2009. pp. 1627-38.

Bouchard, J, Soroko, SB, Chertow, GM, Himmelfarb, J, Ikizler, TA, Paganini, EP, Mehta, RL. "Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury". Kidney Int. vol. 76. 2009. pp. 422-7.

Claure-Del Granado, R, Mehta, RL. "Assessing and delivering dialysis dose in acute kidney injury". Semin Dial. vol. 24. 2011. pp. 157-163.

Vaara, ST, Korhonen, AM, Kaukonen, KM, Nisula, S, Inkinen, O, Hoppu, S, Laurila, JJ, Mildh, L, Reinikainen, M, Lund, V, Parviainen, I, Pettilä, V. "FINNAKI Study Group: 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. vol. 16. 2012. pp. R197.

The results of this study support the growing body of evidence showing an association between fluid overload and increased risk for mortality.

When to stop renal replacement therapies in AKI patients

Cruz, DN, Ricci, Z, Bagshaw, SM, Piccinni, P, Gibney, N, Ronco, C. "Renal replacement therapy in adult critically ill patients: when to begin and when to stop". Contrib Nephrol. vol. 165. 2010. pp. 263-273.

Gibney, RT, Bagshaw, SM, Kutsogiannis, DJ, Johnston, C. "When should renal replacement theraphy for acute kidney injury be initiated and discontinued?". Blood Purif. vol. 26. 2008. pp. 473-484.

Prognosis of AKI patients requiring renal replacement therapy

Aldawood, A. "Outcome and prognostic factors of critically ill patients with acute renal failure requiring continuous renal replacement therapy". Saudi J Kidney Dis Transpl. vol. 21. 2010. pp. 1106-1110.

Lines, SW, Cherukuri, A, Murdoch, SD, Bellamy, MC, Lewington, AJ. "The outcomes of critically ill patients with acute kidney injury receiving renal replacement therapy". Int J Artif Organs. vol. 34. 2011. pp. 2-9.

Yasuda, H, Kato, A, Fujigaki, Y, Hishida, A. "Incidence and clinical outcomes of acute kidney injury requiring renal replacement therapy in Japan". Ther Apher Dial. vol. 14. 2010. pp. 541 546.

Murray, P, Udani, S, Koyner, JL. "Does renal replacement therapy improve outcome? Controversies in acute kidney injury". Contrib Nephrol. vol. 174. 2011. pp. 212-21.

The role of team care

Martin, RK. "Who should manage CRRT in the ICU? The nursing viewpoint". Am J Kidney Dis. vol. 30. 1997. pp. S105-S108.

Honore, PM, Joannes-Boyau, O, Gressens, B. "CRRT technology and logistics: is there a role for a medical emergency team in CRRT?". Contrib Nephrol. vol. 156. 2007. pp. 354-364.

Pea, F, Viale, P, Pavan, F, Furlanut, M. "Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy". Clin Pharmacokinet. vol. 46. 2007. pp. 997-1038.

Guidelines for renal replacement therapy in AKI patients

"KDIGO clinical practice guidelines for acute kidney injury". Kidney Int Suppl. 2012.

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