Critical Care Medicine

Acute Kidney Injury Requiring Renal Replacement Therapy, Kidney Replacement Therapy, Dialysis, Acute Renal Failure

Acute Kidney Injury Requiring Renal Replacement Therapy

All terms in the glossary

Acute Renal Failure

Azotemia

Acute Kidney Injury

1. Description of the problem

Glossary

Renal Replacement Therapy (RRT): Any method of attempting to purify the blood in the presence of renal dysfunction. Includes continuous, intermittent and peritoneal methods.

Continuous Renal Replacement Therapy (CRRT): Any method attempting to provide extracorporeal blood purification in the presence of renal dysfunction with the aim of 24-hour-per-day support. Older, arteriovenous methods of CRRT relied on the patient's blood pressure to drive filtration, removing arterial blood for purification and returning it to the venous circulation. These may still be used in some centers and in the developing world. Veno-venous methods using a peristaltic pump to generate blood flow are currently the mainstay of such techniques.

Continuous Veno-Venous Hemofiltration (CVVH): Blood is driven around an extra-corporeal circuit by a peristaltic pump generating a sufficient transmembrane pressure to push plasma water across a semi-permeable membrane in a process called ultrafiltration. The ultrafiltrate will contain all the molecules to which the membrane is permeable. This solvent drag removes many toxins, and replacement fluid can be added as necessary to achieve volume and electrolyte homeostasis (Figure 1).

Figure 1.

CVVH

Continuous Veno-Venous Hemodialysis (CVVHD): Blood is driven around the extra-corporeal circuit to a filter, where solute is exchanged by diffusion down electrochemical concentration gradients by counter-current circulation of the blood with dialysate across a semi-permeable membrane. The used dialysate is then discarded (Figure 2).

Figure 2.

CVVHD

Continuous Veno-Venous Hemodiafiltration (CVVHDF): This method of CRRT uses both filtration and dialysis to achieve blood purification by both convective and diffusive means ( Figure 3).

Figure 3.

CVVHDF(Taken from Bagshaw S, Cruz N, Gibney RTN, Ronco C. A proposed algorithm for initiation of renal replacement therapy in adult critically ill patients. Critical Care 2009;13:3127.)

Intermittent Hemodialysis (IHD): This is the primary intermittent method of RRT and is a diffusive technique relying on the solute clearance generated by the counter-current circulation of blood and dialysate on the opposing sides of a semi-permeable membrane. Applying negative pressure on the dialysate side of the membrane can achieve ultrafiltration and controlled fluid removal. Dialysate flow rates are much higher than in CRRT and IHD sessions typically last for 3-6 hours daily in the management of AKI, dictated by clinical need.

Slow Low-Efficiency Extended Dialysis (SLED): This is an extended version of IHD, but with lower dialysate and blood flow rates over an extended time period of 8-10 hours to achieve fluid balance and solute removal goals with a minimum of hemodynamic upset. Filtration can be applied to enhance solute clearance.

Extra-Corporeal Circuit (ECC): A circuit comprising a vascular access catheter allowing removal and return of blood to the systemic circulation, a filter to allow the removed blood to be purified, a pump to move blood around the circuit without depending on patient hemodynamics and the tubing connecting these devices.

Filter/Dialyser: Interchangeable term referring to the device used in RRT circuits that allows solute and fluid removal. Normally a plastic casing surrounding a form of semipermeable membrane.

Vascular Access Catheter: A large-bore plastic catheter, inserted into a central vein, that typically has two lumens - an arterial lumen for outflow of blood and a venous lumen for return of blood to the systemic circulation.

Ultrafiltrate: Water removed from the systemic circulation across a semipermeable membrane during RRT.

Replacement Fluid: Fluid containing buffer and electrolytes to replace the losses induced by RRT.

Post-dilution:Replacement fluid is administered after the filter in the extracorporeal circuit. It avoids dilution of solutes entering the filter but results in hemoconcentration at the filter. This increases the risk of filter clotting and filtration failure.

Pre-dilution: Replacement fluid is administered in the extracorporeal circuit before the filter. This reduces the efficiency of solute removal by diluting the concentration of solutes entering the filter; the size of this effect is determined by the rate of replacement fluid flow as a proportion of the plasma flow rate. However, it will reduce hemoconcentration and has been shown to increase filter lifespan. Despite diminished efficiency it leads to similar solute control as post-dilution.

Effluent: The waste fluid of RRT: ultrafiltrate, spent dialysate or a combination. In CVVH this is the ultrafiltrate. In CVVHD this is the spent dialysate plus any generated ultrafiltrate. In CVVHDF this is the spent ultradiafiltrate.

Dialysate: Fluid containing electolytes and buffer providing a concentration gradient across the membrane to facillate diffusive solvent clearance. Can normally also be used as replacement fluid.

Filtration Fraction(FF): This is the relationship between blood flow and hence plasma flow through the filter and the amount of ultrafiltrate extracted. Blood flow x (1 - hematocrit) gives the rate of plasma flow. The FF is equal to the (filtration rate/plasma flow rate) x 100. If greater than 25%, hemoconcentration occurs with the promotion of filter clotting.

Membrane Sieving Coefficient (SC):The SC of a solute represents the permeability of a membrane to the solute in question. It is estimated by the ratio of the concentration of the solutes on either side of the membrane. A SC of 1.0 indicates complete permeability - urea and creatinine have a Sc of 1.0. However, a SC of 0 indicates complete rejection.

What every clinician needs to know

(See chapters Acute Kidney Injury and Acute on Chronic Kidney Failure.)

Renal replacement therapy

RRT is an artificial method of blood purification involving the use of an artificial or biological extra-renal membrane to remove unwanted solutes and water to allow external, therapeutic control of the internal milieu for as long as is needed. This may be until excretory renal function recovers, or until the patient with end-stage renal failure is established on chronic intermittent therapy. It can be corporeal, as in peritoneal dialysis, or extracorporeal, as in filtration and hemodialysis. The goals of this therapy are outlined in Table I.

Table I.

Goals of Renal Replacement Therapy
Qualitative blood purification
Quantitative blood purification
Restoration of fluid and electrolyte homeostasis
Maintenance of fluid and electrolyte homeostasis
Facillitation of organ recovery
Biologic compatibility
Minimal therapy

Renal supportive therapy

While RRT can replace the physiological functions of the damaged kidney, the same technology can also be used supportively in the context of multiple organ failure. Such renal supportive therapy (RST) can be used to ameliorate the effects of other organ system failure on the critically ill patient. Table II lists some ways in which RST can be used.

Table II.

Examples of Renal Supportive Therapy
Organ System Effect
Lungs/ARDS Optimization of fluid balance
Lungs/ARDS Biochemical correction of respiratory acidosis
GIT/ileus or short-gut Maintenance of nutrition
Cardiovascular/Fluid overload Optimization of fluid balance
Systemic/SIRS or Sepsis Removal of inflammatory mediators
Malignant Hyperthermia Control of resistant hyperpyrexia
Renal/AKI or CKD Removal of radiocontrast in those at risk of contrast nephropathy
Hematological Preventing fluid overload in massive transfusion situations

There are many different forms of RRT. Intermittent hemodialysis (IHD) allows rapid correction of fluid and electrolyte abnormalities over 4-6 hours a day but may result in hemodynamic instability. Continuous renal replacement therapy (CRRT) should allow continuous and tightly regulated control of the internal milieu, even in hemodynamcially unstable patients. There are numerous forms of CRRT, and some hybrid techniques, combining the benefits of continuous and intermittent techniques while supposedly minimizing their disadvantages, also exist.

Principles of renal replacement therapy

Clinical Features

In severe AKI and renal failure symptoms and signs are either the result of the precipitating condition or the accumulation of fluid or toxins. The cardinal features of failure of excretory renal function are rising serum urea and creatinine and oliguria. The clinical sequelae of severe AKI are discussed below.

Oliguria

The natural response to many of the insults classically described as pre-renal causes of AKI - hypovolemia, anemia, reduction in renal blood flow, etc. - and commonly present in the critically ill is renal retention of salt and water through the activation of numerous neurohormonal mechanisms. These mechanisms are most effective with intact tubular function. The relationship between urine output and renal function is complex, particularly given the routine practice of diuretic administration in many ICUs.

Biomarkers

Current widely used biomarkers of renal dysfunction - urea and creatinine - are unreliable surrogate markers of glomerular filtration rate. Indeed, filtration function can be totally lost for 24 hours before there is a doubling in serum creatinine. Recognition that increases of 30 micrograms/l in serum creatinine are associated with a significant increase in mortality suggests a role for frequent creatinine assessment; to our knowledge, this has not been done.

Serum and urinary neutrophil gelatinase-associated lipocalin, and in particular the urinary ratio of the renal to systemic forms of the protein, offer an alternative biomarker for renal dysfunction and the risk of progression to renal failure. Once validated it may help us pinpoint the optimal time to intervene in renal failure to influence outcome.

Key points

  • Severe AKI is associated with a significant increase in ICU, hospital, and long-term mortality and signficantly increases hospital stay and the cost burden of care.

  • Treatment of AKI requiring RRT begins with recognition, stabilization and the prevention of further renal damage.

  • Many of the clinical sequelae can be treated with RRT. RRT can purify the blood, taking over the physiological role of the kidney while promoting optimal control over the internal milieu to facilitate renal recovery. It can also be used to support other failing organ systems by helping optimize their performance.

  • It is a complex process with its own language, skill set and knowledge base, and the provision of safe and effective RRT requires considerable infrastructure and support. It should be prescribed with a dose and specific operational parameters.

  • There is no evidence that timing, dose, modality, technique or the use of diuretics improves outcome in severe AKI requiring RRT. Further clinical studies powered to show differences in mortality and other patient-centered outcomes are required.

  • There is no evidence base to the cessation of RRT, but urine output and falling creatinine in a stable patient on a stable CRRT presciption generally herald return of renal function, though care must be taken that the restored function meets excretory requirements.

2. Emergency Management

The emergency management of severe AKI involves recognition of the risk of severe AKI, resuscitation and stabilization, preventing secondary AKI, preparing for and initiating CRRT and the management of any complications as a consequence of the loss of normal homeostasis.

Recognition

The clinical signs and symptoms of renal failure, particularly in the sedated/intubated patient, may be difficult to detect. ECG changes may herald dangerous hyperkalemia. Oliguria should always prompt further investigation. Urgent renal ultrasound can rule out obstructive uropathy.

Immediate electrolyte results can be obtained from arterial blood gas sampling. Modern blood gas analyzers can measure creatinine with a high degree of accuracy. Patients at particular risk include those with sepsis, underlying CKD and increasing severity of the underlying condition.

Resuscitation and stabilization

Hypovolemia should be corrected by targeted fluid challenge. Invasive monitoring will aid in determining appropriate clinical end-points and in blood sampling. Immediate treatment for hyperkalaemia with calcium chloride, salbutamol and insulin-dextrose can be life-saving. The use of furosemide can promote diuresis and NIV or IPPV may stabilize a patient suffering from fluid overload until RRT can be established.

At this stage there should also be an attempt to identify and/or treat the underlying etiology of the AKI in an attempt to ameliorate the renal insult: in rhabdomyolysis bicarbonate-mannitol diuresis is indicated and in obstruction catheterization or insertion of a nephrostomy may reduce the progression of AKI to RRT. Poisoned patients should be treated with reference to local or national protocols such as Toxbase. Infections should be treated aggressively.

Preventing secondary AKI

Due to sepsis, hemodynamic disturbance, bleeding, systemic inflammation or toxin ingestion, the critically ill patient with AKI can face multiple additional renal insults. Though there is little evidence on their effectiveness it is thought that preventing further renal damage will optimize the chances of renal recovery. Standard management includes excluding renal tract obstruction and the maintenance of euvolemia, particularly in the presence of a post-obstructive diuresis or the so-called diuretic phase of renal recovery. Avoidance of nephrotoxins such as antifungals, NSAIDs and radiocontrast is important. Renal hemodynamics should be optimized, with cardiac output monitoring and the use of vasoactive medications if necessary.

Preparing for and Initiating CRRT

The initiation of CRRT requires mobilization of a team, not just the treating physician. Achieving vascular access in a large central vein, preferably under ultrasound guidance, will require the assistance of at least one nursing colleague, while assembling and priming the CRRT circuit will require two more trained members of staff. Extension of the circulation in anemic patients can compromise tissue oxygen delivery and may provoke hemodynamic instability. An anticoagulation strategy needs to be adopted cognizant of any contraindications to systemic anticoagulation.

Treating the complications of Severe AKI with RRT

Hyperkalemia

Potassium is cleared by all methods of RRT. Severe hyperkalemia may be best treated with IHD to allow rapid correction. Rebound hyperkalemia can occur after such correction, and frequent electrolyte monitoring is mandatory and may require extended dialysis or a second session. Remember that blood products contain a significant quantity of potassium. Emergent therapy as described above may be required.

Acidosis

Underlying causes should be sought and treated. CRRT corrects disturbances of acid-base balance by changing the strong ion difference, mainly by changing the ratio of sodium to chloride, and through loss of weak acids. Removal of chloride by RRT will be neccessary in the anuric hyperchloremic patient.

Fluid balance

Rapid fluid removal is best achieved with IHD. CVVHDF can also achieve rapid fluid removal by controlling fluid replacement and increasing filter blood flow and the rate of ultrafiltration. Care should be taken to avoid hemodynamic upset. Vasoactive support is often required.

Dysnatremias

The treatment of dysnatremia depends on the time scale over which the condition developed and the etiology of the electolyte disturbance. Rapid falls or rises in sodium concentration can be rapidly corrected. Dysnatremias of gradual onset need to be corrected slowly to avoid cerebral edema or central pontine demyelinosis. This can be achieved through the addition or removal or salt, or the addition or removal of water, depending on the etiology.

Hyperphosphatemia and hypocalcemia

Acute severe hyperphosphatemia can be life-threatening, particularly if associated with hypocalcemia. Causes include bisphosphonate use and cell lysis syndrome. Phosphate behaves like a large molecule and is more effectively cleared by convection than the other electrolytes. Calcium containing dialysate/replacement fluid will correct hypocalcemia.

3. Diagnosis

Recognizing the need for RRT

Oliguria is the most common reason prompting RRT initiation, though intitiatory criteria vary widely between countries and indeed between individual practitioners. There is no consensus on the exact figures that should prompt initiation of RRT, but reasonable clinical criteria with pragmatic suggestions for the levels at which RRT should be considered are given in Table III. The general principle is that RRT should be started when the consequences of volume overload or solute accumulation have become dangerous. The indications for RST are even less well defined, but are discussed below.

Table III.

Modern Criteria for Commencing RRT
Oliguria Urine output <200 ml/12 hours
Anuria Urine output 0-50 ml/12 hours
Uremia [Urea] > 35 mmol/l
Uremic Complications Encephalopathy, pericarditis, myopathy
Fluid overload Unresponsive to diuretics
Hyperkalemia [K+] >6.5 mmol/l or rapid increase
Hyper/hyponatremia [Na+] > 160 or < 110 mmol/l
Severe metabolic acidosis pH < 7.1
Hyperpyrexia Temperature > 40°C
Hypercreatininemia [Creatinine] > 400 mcg/l
Overdose with dialysable toxin Lithium, etc.

If one criterion is present then RRT should be considered; if more than one criteria are present then it is strongly recommended.

Oliguria and furosemide

In established olgiuric renal failure, fluid overload can cause a myriad of clinical sequelae, and there is emerging clinical evidence that excessively positive fluid balances are associated with worse patient outcomes. Patients with oliguric renal failure have significantly worse outcomes than those who maintain a urine output.

A subset of patients, when administered the loop diuretic furosemide, may convert from oliguric renal failure to non-oliguric renal failure. It is unclear if furosemide terminates the natural physiological response of salt and water retention in the face of the multiple insults associated with critical illness, a response that may become pathological if allowed to persist, or if this subset of patients suffer from a less severe form of AKI.

What is clear is that the administration of loop diuretic in the setting of oliguric AKI is commonplace. A multinational survey of primarily academic institutions demonstrated that bolused furosemide, titrated to the physiological end-point of urine output, is commonly used in the critically ill population with AKI, most often when AKI is associated with pulmonary edema.

As regards clinical evidence of benefit, post-hoc analysis of the BEST study showed no increase in mortality with the administration of furosemide in over 1700 critically ill patients with AKI. A meta-analysis of randomized controlled trials of the use of loop diuretic in renal failure revealed only five trials of suitable methodological quality for inclusion. Furosemide administration improved urine output and reduced the duration of RRT, but did not reduce mortality or increase RRT independence.

The significant difference between practice and the current evidence suggests clinical equipoise, and the need for high-quality evidence in this area. The SPARK study is a double-blind randomized controlled trial designed to address this issue. At present a furosemide challenge in bolus or infusion form may be given, but the aim should be the promotion of diuresis, rather than renal support or outcome modification.

Timing of RRT

At present the initiation of RRT is not an evidence-based process. The lack of consensus definitions for AKI has, until recently, prevented high-quality synthesis of the trials produced to date, as has variation in the criteria for RRT initiation. Oliguria, acidosis, increasing age and increasing number of organ failures are all strongly associated with an increased mortality risk, and it may be that this population may benefit from early intervention.

A large observational study has shown that increasing length of time from ICU admission to initiation of RRT is associated with an increased risk of mortality. There is no reproducible evidence for altered outcome based on initiation as a result of serum creatinine, urea or other variable.

Clinical decision-making: RRT and RST

At present consensus definitions and large clinical trials are required to assess the impact of timing of RRT on outcome in AKI. The opinion-based clinical algorithm in Figure 4 was recently published to help with clinical decision-making regarding the intitiation of RRT and RST.

Figure 4.

Clinical decision-making: RRT and RST. Taken from Bagshaw S, Cruz N, Gibney RTN, Ronco C. A proposed algorithm for initiation of renal replacement therapy in adult critically ill patients. Critical Care 2009;13:3127.

How do I know this is what the patient has?

Rising serum and creatinine concentrations in the presence of the typical electolyte disturbances found in AKI, with or without oligoanuria, are the key features of AKI representing the loss of filtration and excretory function. Some drugs, notably trimethoprim, can cause elevations in serum creatinine, and urea is elevated in any catabolic state and by the use of steroids.

Urethral obstruction and trigone infiltration causing bilateral ureteric obstruction are potentially ameliorable causes of anuria and AKI. Obviously urinary catheter obstruction should be considered. Bladder scanning and abdominal ultrasound are useful bedside tools for assessing for obstruction of the renal tract.

4. Specific Treatment

Technique

The different forms of RRT vary in intensity, duration, frequency, mechanism of transport, type of filter, vascular access and infrastructure requirements.

IHD has already been described. The theoretical advantages of intermittent techniques are the potential to rapidly correct volume and electrolyte status, reduced monetary cost and reduced duration of specialist/intensive nursing input. The disadvantages are inferior solute and electrolyte control, fluctuations in intracranial pressure secondary to fluid shifts with rapid solute exchange, and increased hemodynamic instability. It should not be used in cases of cerebral edema or fulminant liver failure.

IHD also requires larger catheters and higher blood flows than CRRT to be effective. IHD may also require heavy involvement of the local renal service, which may not be feasible due to service constraints.

The theoretical advantages of CRRT are that they should allow continuous and tightly regulated control of the internal milieu, even in the hemodynamically unstable critically ill patient. Many of the complications of CRRT have been ameliorated by the adoption of veno-venous techniques over arteriovenous methods. It is labor- and cost-intensive. Clotting of the filter results in discontinuous therapy, a loss of fluid and hemoglobin and a reduction in delivered dose.

Despite the theoretical advantages of CRRT, multiple systematic reviews and meta-analyses have failed to demonstrate a mortality benefit in using one technique over the other. Biased selection of patients, with more unwell patients receiving CRRT, may partially explain this finding.

However, the studies have been performed over a 20-year period. Over the past 10 years RRT technologies have evolved into substantially different therapies from their predecessors. The patient demographic admitted to ICU and commenced on RRT is also significantly different, and this may be a more powerful reason for the lack of demonstrated mortality benefit in meta-analysis.

CVVH or CVVHDF?

A direct clinical comparison between CVVHDF and (pre-dilution) CVVH has shown that CVVHDF is superior at clearing small molecules like urea, but the techniques have equivalent clearances for middle molecules, represented experimentally by beta2-microglobulin, at blood flow rates of 125 ml/min. Theoretically one would assume the purely convective method to be superior at clearing middle molecules, and this is likely a function of pre-dilution. The effect of higher blood flows on solute clearances has not yet been demonstrated.

CVVHDF is, at modest flow rates, the most efficent choice of modality to achieve broad solute clearance. Optimal function is likely to be dictated by a specific set of operative conditions, as described below in "Prescribing CRRT."

Dose of CRRT

RRT is a complex intervention, and assessing the efficacy of a modality can be difficult. The most pragmatic method of estimation is the intensity or efficacy of clearance of a surrogate solute, commonly urea, though this is imperfect for reasons outlined elsewhere. There is no evidence to say that control of measured solute is more important than control of tonicity, volume or acid-base status.

There have been numerous studies looking at the effect of delivered dose on renal and patient outcome in the ICU. These have mainly been single-center studies, and of varying methodological quality, using a variety of RRT modalities and recruiting only several hundred patients.

The ATN trial in 2008 and the RENAL trial in 2009 were large, multi-center, randomized controlled trials, each recruiting over 1000 patients. They were designed to specifically examine the effect of delivered dose on patient outcome. Neither trial showed a significant difference in either renal recovery or mortality between the high- and low-dose groups.

A large prospective, multi-center observational study confirmed these results. Three recent meta-analyses reviewing the data for over 3000 patients agree that, although the studies show significant heterogeneity, doses of RRT >25 ml/kg/hr or the equivalent do not reduce mortality or aid renal recovery.

It is unlikely that there is no dose-dependent difference in outcome. It may be that 25 ml/kg/hr is the optimal dose for RRT. It is more likely that we are not considering the correct variables and that timing, modality or other unresolved issues have a significant opposing impact on outcome.

Clinical dosing is another matter. The dose of RRT required to correct dangerous hyperkalemia in one patient will be significantly different from that required for managing fluid overload with hemodynamic instability in another and needs to be tailored to the clinical situation.

Anticoagulation

Essentially, critical illness is a prothrombotic state. Uremic platelet dysfunction can result in bleeding. The components of the ECC in patients undergoing RRT can be prothrombotic, and kinks in the circuit or problems with vascular access can lead to blood stasis. Clotting of the filter or circuit is wasteful, contributes to anemia, and interrupts the delivery of RRT.

A variety of techniques can be used to extend filter life. Simple techniques like post-dilutional transfusion of blood, the use of pre-dilutional fluid replacement, ensuring vascular access is adequate and maintaining blood flows of 200 ml/hr or more have been shown to extend filter life. These are particularly useful in patients with variceal bleeding, recent surgery or intracranial hemorrhage.

Anticoagulation can be local or systemic. Local anticoagulation involves predilutional administration of an anticoagulant with post-dilutional administration of an antidote. This may be heparin/protamine or citrate/calcium. It is more complex than systemic anticoagulation, but so long as the anticoagulant is neutralized, it should be safe in those patients for whom systemic anticoagulation is contraindicated.

Systemic anticoagulation is normally by unfractionated heparin to allow easy monitoring, reversal and titration. Low-molecular-weight heparin is more complex to monitor and needs to be adjusted depending on the effective clearance. They may both cause heparin-induced thrombocytopenia, though it should be noted that there are other causes of thrombocytopenia in patients on CRRT. Heparinoids or prostacycline can be used as alternatives.

Filter clotting should not prompt an automatic escalation in anticoagulation; the etiology must be investigated. Larger-diameter vascular access catheters, reducing the ultrafiltration rate, or increasing blood flows may be more effective, without increasing the risk of hemorrhage.

CRTT in specific circumstances

Hemodynamic or neurological deterioration, other organ dysfunction, impaired endogenous clearance or clinical deterioration despite best supportive care in cases of poisoning may prompt the use of RST in the form of hemodialysis or hemofiltration.

The topic of blood purification for poisoning is not reviewed in detail here. CVVHDF is likely to be the most successful at drug removal. For heavily protein-bound drugs like theophylline and barbiturates, hemoperfusion, an absorptive modality of solute separation, using a charcoal filter may provide superior drug clearance.

Therapeutic plasma exchange, using an ECC much like RRT with the addition of a pheresis machine to separate and return cellular elements to the patient while discarding and replacing the toxin-containing plasma, is occasionally used for the treatment of poisoning where the substance is question is of very high molecular weight or is extremely protein-bound. Examples of such toxins include cisplatin and snake venom.

Immunomodulation

There is a physiological premise supporting the use of specialized convective forms of CRRT in the removal of cytokines and related inflammatory mediators in the middle molecular range. The underlying pathophysiology is too complex for a worthwhile examination here, but Phase I and II studies in humans are ongoing after initial animal models suggested that such intervention may attenuate the inflammatory response responsible for the sepsis syndrome. It is likely to be some time before large-scale, suitably powered, randomized controlled trials are available to assess the impact of such therapies on outcome.

Liver failure

The syndrome of liver failure involves the accumulation of heavily protein-bound toxic substances with profound neurological and systemic effects. CVVHDF is effective at removing water-soluble toxins and may be useful in controlling fluid balance and preventing the accumulation of the uremic toxins, but additional mechanisms of solute removal are required to effectively provide support for the failing liver.

Several techniques of extracorporeal hepatic support have been developed, of which the molecular adsorbents recirculating system (MARS) is best known. Adequately powered clinical trials are awaited: to date there has been no impact on outcome, though they have been shown to be safe and effective at improving biochemistry.

Prescribing renal replacement therapy

RRT is no different from other interventions in critical care: it requires operational parameters to be set. The operational parameters required to achieved a desired efficacy, or dose, of CRRT should be thought of as a prescription with the same requirements for precision and accuracy.

Technique/mode

There will often be only a single mode of RRT offered by a unit. In central units with the infrastructure to offer multiple modalities the desired mode needs to be clearly stated. This will affect both circuit design and set-up.

Dose

Effective dose depends on clearance. Traditionally it is described in ml/kg/hr. Most centers aim for 25-35 ml/kg/hr. This should be stated, and the desired dose will determine the other operational parameters depending on the modality selected.

Fluid balance

Goals should be set for the patient - for example, -1000 ml over the 12 hours from 1200 to 0000 - and for the machine. The administration of drugs needs to be taken into account and the machine goals - for example, -200 ml/h - adjusted to meet the patient goals. Fluid can be administered if a positive balance is sought by increasing replacement fluid or reducing ultrafiltration.

Problems can arise with failure to meet targets due to significant downtime with filter crashes or multiple procedures or investigations requiring cessation of RRT. Incorrect machine settings or periods of low blood flow may also contribute, as may hemodynamic instability precluding fluid removal.

Flow rates

Blood flow, Effluent flow, Dialysis flow and Replacement fluid flow should all be prescribed in accordance to dosing and fluid balance goals.

Anticoagulation

The anticoagulant infusion rate, concentration and the drug itself need to be prescribed clearly, and orders need to be given for the antidote in regional anticoagulation.

Drug dosing in RRT

Changes in drug handling

Severe AKI and its consequences have profound effects on pharmacodynamics and pharmacokinetics. Hypoalbuminemia increases the free fraction of protein-bound drugs available for clearance AKI and critical illness are dynamic process, and the clearance of drugs can vary significantly from day to day. Drug removal by RRT depends on residual renal function, the mode and technique of RRT, the principle of solute removal adopted, and the physicochemical and pharmacokinetic properties of the individual drug.

CVVHDF is likely to be the most effective method of drug clearance. Drugs of low molecular weight, with low volumes of distribution, poor protein binding and high renal clearance, are most effectively cleared by CRRT. Specific dosing information is outside the realms of this work. Prescribing for patients on CRRT requires the support of experienced ICU pharmacists, and texts such as the Renal Drug Handbook, the British National Formulary or other sources should be consulted.

5. Disease monitoring, follow-up and disposition

Response to CRRT

The clearance of uremic toxins can be monitored using urea and creatinine as surrogates. This is imperfect, as discussed elsewhere in this chapter. Patient weight or fluid balance charting will show the efficacy of ultrafiltration in the management of fluid overload. Acid-base status, electrolyte abnormalities, and uremic markers should stabilize after 24-48 hours.

Improvement in the clinical condition of the patient - resolution of uremic encephalopathy, improved hemodynamic stability, improvement in the organ systems for which RST was commenced - is one of the most important methods of monitoring response to therapy.

Metabolic monitoring

Replacement or dialysis fluid contains sodium, chloride, lactate or bicarbonate as a buffer, and calcium and can contain varying concentrations of potassium in order to promote physiological homeostasis as part of RRT. However, after prolonged RRT, magnesium, phosphate and other trace elements may be depleted. Daily monitoring of electrolytes is mandatory, and replacement of phosphate and magnesium will likely be required.

Monitoring anticoagulation

APTT should be checked regularly if using heparin-based anticoagulation, be it local or systemic. Protamine or calcium administration rates can be increased if systemic coagulation is compromised. Local protocols should exist to guide therapeutic anticoagulation to local laboratory standards, particularly if specialist techniques or low-molecular-weight heparins are employed. Platelets should also be monitored.

Ineffective RRT

If the physician and nursing staff prescribing and operating the CRRT system have a sound understanding of the circuit, the modalities, the method of fluid replacement and the choice of anticoagulation, then reliable control of uremia and fluid balance with an adequate filter life and minimal technical issues can be safely and effectively achieved.

Ongoing training and a supportive infrastructure are mandatory in the provision of RRT for 24 hours a day. Rapid recognition of signs heralding machine dysfunction or patient deterioration can ameliorate many problems experienced while running CRRT.

Frequent filter clotting is likely to be the biggest contributor to ineffective RRT. Inadequate vascular access limits blood flows and can limit the effectiveness of solute clearance. It can also lead to reduced filter lifespan, as can sub-therapeutic anticoagulation, high rates of ultrafiltration and post-dilutional fluid replacement. Increasing transmembrane pressure can herald incipient filter failure. Recognition can allow the return of the blood in the ECC to the patient to minimize blood loss.

Cessation of renal replacement therapy

Renal replacement and support

If CRRT has been started as a replacement therapy, for control of electrolyte or fluid disturbance, or for treatment of the uremic syndrome in the presence of AKI, then adequate control of these variables needs to be achieved prior to cessation. The main mechanism of this will be recovery of functional urine output - i.e. recovery of renal excretory function.

Increasing urine output and falling creatinine concentration in the context of a fixed CRRT prescription and a clinically stable patient suggests recovery of excretory function. CRRT commenced in support of other organ dysfunction should be ceased once there is objective evidence of organ recovery.

There is a marked paucity of evidence on this topic. Practices vary significantly. Large clinical trials are badly needed to improve patient care.

Withdrawal of care

In some patients the progression to AKI requiring RRT is used as a ceiling of therapy by physicians. Ongoing deterioration despite maximal therapy to that point is taken as a sign of futility and, depending on the age, predicted mortality, the likelihood of functional recovery, the wishes of the family and the premorbid wishes of the patient, CRRT may not be started. In some cases where expected mortality is very high a trial of therapy over a clearly defined time frame may be indicated.

Where treatment has already begun but clinical deterioration has continued, RRT may be withdrawn along with vasoactive and ventilatory support. This is generally done on medical grounds with the consent of the family and CRRT is stopped.

Monitoring treatment cessation

It should be expected that urea and creatinine will rise after cessation of CRRT. The recovering renal function is unlikely to be as great as that of residual renal function and RRT clearance. They should plateau within 48 hours; continued rise after this time may indicate that CRRT needs to be re-established. The trajectory of the rise should also be considered, as should whether the volume of urine being produced is sufficient to maintain homeostasis.

As mentioned above, furosemide is commonly used to attempt to provoke a diuresis in patients with AKI. A significant number of physicians use furosemide in the recovery phase of AKI post-RRT in an attempt to increase urine output to accelerate weaning from CRRT, though there is no evidence to support this.

Post-hoc analysis of the BEST Kidney study showed that increasing urine output pre-cessation and falling creatinine levels pre-cessation are the best indicators of successful weaning from RRT, though the predictive ability of urine output was adversely affected by the use of diuretics. Early oliguria, prolonged RRT, increasing age and increasing illness severity scoring have been associated with failure to wean from CRRT.

Moving to chronic RRT

There is very little evidence regarding the conversion of CRRT for AKI to IHD once the only requirement for ICU management is non-recovery of renal function. Dialysis dose has been treated as a fixed quantity in the literature. There are no large trials demonstrating either benefit or harm in converting to IHD under these circumstances, even with a significant reduction in dialysis dose.

Most units will wait until the clinical condition has stabilized and reliable control has been achieved over the internal milieu before converting to IHD. There is no evidence to guide practice on this topic, and local practice varies considerably.

Follow-up

Patients with any form of AKI are at substantially higher risk of in-hospital mortality. If there is an ongoing need at discharge from the ICU for further investigation as to the cause of AKI or ongoing RRT is required in the form of IHD for non-recovery of renal function, then the local renal team should become involved. It may be that this requires transfer to another hospital. Even if excretory renal function is recovered, then patients should still be discharged to the care of physicians with acute care experience.

Pathophysiology

Pathophysiological consequences of severe AKI

Resolution of severe AKI can take days, weeks or even months, during which time the loss of filtration function, the retention of fluid and waste products and the loss of the normal mechanisms of hormonal and metabolic homeostasis can lead to profound and complex pathophysiological consequences. Known collectively as the uremic syndrome, this derangement of biochemistry and normal physiology parallels the severity of the AKI and has profound systemic effects.

Cardiovascular

Loss of urine output leads to fluid retention and, in combination with hypoalbuminemia, may lead to congestive cardiac failure. AKI can lead to a SIRS response with the potential for adverse hemodynamic effects. Volume overload can also result in secondary hypertension.

Respiratory

Volume overload and hypoalbuminemia lead to pulmonary edema and pleural effusions. Reno-pulmonary crosstalk can potentiate acute respiratory distress syndrome (ARDS) in those patients at risk with infiltration of the lung tissue by activated cytokines. Uremic inhibition of platelet function can increase the risk of pulmonary hemorrhage.

Immunological

A number of molecules normally excreted in the urine but retained in AKI have the potential to modify the immune response. Fluid retention and hypoalbuminemia cause tissue edema. White cell dysfunction occurs with the promotion of free radical formation and oxidative stress. The net effect is of delayed tissue healing and increased susceptibility to sepsis.

Gastrointestinal

Volume overload and gut edema can lead to impaired barrier function, impaired absorption and abdominal compartment syndrome. The inflammatory and hemodynamic consequences of AKI can lead to gut ischemia and gastroduodenal ulceration.

Hematological

Loss of erythropoietin, increased erythrolysis and impaired erythropoiesis promote anemia. Bleeding may be a significant complication of AKI with uremic inhibition of platelet aggregation.

Neurological

Uremia, disorders of electrolyte homeostasis, malnutrition and altered drug handling can all result in, or propagate, obtundation, oversedation, ICU delirium, prolonged ventilation and myoneuropathy.

Acid-base and electrolyte homeostasis

This can be profoundly deranged with retention of acid, accumulation of organic acid, reduced chloride excretion, hyperkalemia, dilutional hyponatremia, reduced buffering and hypoalbuminemia. Malignant arrhythmias, neurological side effects, marked unantagonized catabolism, hemodynamic dysfunction and lung and gut injury may all occur as a consequence.

Drug handling

Both pharmacodynamics and pharmacokinetics are significantly altered in AKI. Fluid retention significantly increases the volume of distribution, while elimination, protein binding and availability may all be siginifcantly reduced depending on the drug in question. Drug toxicity can occur at much lower doses than in patients with intact excretory function, but conversely, some drugs may be underdosed.

Uremic toxins

Much of the current understanding of the pathophysiology of uremia is extrapolated from work performed in CKD. This is a relatively stable condition without the additional confounders of sepsis, multiple organ dysfunction, and the systemic inflammatory response, which often coexist in the critically ill patient with dynamic AKI.

Both conditions occur as a result of a toxic accumulation of uremic toxins, and so they are likely to share some pathological mechanisms. In addition, the pathophysiological effects of RRT itself can obscure the clinical picture.

Though known as the uremic syndrome, over 90 solutes have been shown to be retained in renal failure. More await identification. It is uncertain how important each of these substances is to the genesis of the syndrome, but it is likely that some or all contribute to the pathophysiological consequences of severe AKI. They can be divided into small and middle molecules on the basis of molecular weight.

It is generally accepted that urea would be toxic only at concentrations higher than those normally found in AKI. However, the clearance of urea is a convenient measure of the efficacy of RRT, despite the different clearances, kinetics and volumes of distribution of each retention product.

Pathophysiological consequences of RRT for severe AKI

Though RRT undoubtedly saves lives and is able to correct many of the adverse pathophysiological consequences of severe AKI and uremia, it may also cause adverse effects in its own right.

Hemodynamic disturbance

The extension of the circulation on initiation of CRRT can drop the hematocrit and may affect tissue oxygen delivery. It may also cause hypovolemia.

Microbiological contamination

Unless a reliable source of ultrapure dialysate or replacement fluid is available, then the risks of infection, pyogenic transfer and a further inflammatory insult are increased. In addition, manufacturing error or deliberate inoculation can lead to contamination of otherwise sterile commercial product.

Membrane compatibility

Older biologic membranes were associated with hemodynamic disturbance and the activation of complement and leukocytes. This lack of biological compatibility was thought to prejudice renal recovery; newer synthetic membranes do not seem to have the same disadvantage.

Vascular access

Inadvertant vascular damage may lead to anemia, hypovolemia and hemodynamic instability. As with any indwelling device, the risk of infection also increases.

Anticoagulation

Prothrombotic factors - inflammatory mediators, immobility, hypoperfusion - vie with anticoagulant factors - uremia, anticoagulants - in the critically ill patient. With AKI requiring RRT the natural clotting mechanisms are further compromised: the RRT circuit may be prothrombotic, while extending filter life to ensure continuous RRT often requires local or systemic anticoagulation.

Specific uremic retention products

Small molecule retention products

These are products with a molecular weight <500 Da. Asymmetric dimethylarginine accumulates, interfering with nitric oxide production and promoting endothelial dysfunction. Creatinine also accumulates in renal failure, though no evidence of toxicity has been demonstrated. Hippuric acid accumulation leads to altered drug protein binding and tubular transport of organic acids. It may push free, active drug concentrations into the toxic range. Indoxyl sulphate has similar effects. Hyperphosphatemia can lead to vascular damage through calcium-phosphate complex deposition. Other small molecules include purines, guanides and homocysteine.

Middle molecule retention products

These are those substances with a molecular weight between 500 and 12,000 Da retained in renal failure. Cytokines are the primary middle molecule to be retained. Septic patients with AKI can develop massive blood concentrations of cytokines, promoting the inflammatory response and subsequent organ dysfunction.

Other middle molecules include peptides that inhibit the activity and function of leukocytes, kappa and lambda light chains, themselves nephrotoxic, parathyroid hormone leading to intracellular calcium influx and beta2-microglobulin, also nephrotoxic and implicated in dialysis-related amyloidosis, though this is unlikely to be of significance in the acute setting.

Epidemiology

The problem with renal failure and AKI

The epidemiological study of AKI has been profoundly hampered by the lack of a consensus definition for the syndrome. Though many studies have been performed, their definitions of acute renal failure are so disparate that synthesis and meaningful review is very difficult. Very few studies to date have looked at early AKI or the importance of small increases in creatinine concentration. The introduction of the RIFLE classification system has provided a consensus upon which future studies can be based. Table IV lists the risk factors for the development of AKI.

Table IV.

Risk Factors for the Development of AKI
Sepsis
Age > 62 years
Race
Increasing Illness Severity Score
Underlying CKD
Admission to a non-ICU ward
Surgical > Medical
Emergency surgery
Cardiovascular disease
Mechanical ventilation

AKI Requiring RRT

Several studies have investigated the incidence of AKI requiring RRT. There has been a substantial increase in the reported incidence of RRT requiring renal failure. In the early 1990s the incidence was around 50 per million people per year. In more recent studies the incidence has been found to be closer to 200 per million people. This may be partially explained by the advent of RST as a therapy, the changing demographics of the ICU patient and perhaps a change in practice regarding selection for RRT.

The healthcare burden of AKI

Hospital-acquired AKI is conservatively estimated to cost in excess of US$10 billion per year. When combined with the costs of prolonged hospital stays, the cost worldwide must be staggering. Even a small increase in serum creatinine is associated with significant additional costs. The problem of definitions again prevents useful meta-analysis on this topic.

Prognosis

Mortality

There has been virtually no improvement in the outcome for AKI since the advent of dialysis. This may be due to the changing demographic of the ICU patient and widened criteria for the use of RRT. ICU mortality in patients with AKI has been reported from 20-70%, with hospital mortality even higher at 25-80%. Even small increases in serum creatinine are associated with significant increases in mortality.

There is a linear association between severity of RIFLE grade of AKI and mortality. Patients with AKI have a significantly greater risk of mortality than those with ESRD on admission, probably due to the increased incidence of multiple organ failure. RRT commencement is strongly associated with a significant increase in mortality. Factors associated with hospital mortality are listed in Table V.

Table V.

Factors Predicting Hospital Mortality in AKI
Underlying CKD
Oliguria
Prolonged RRT
Increasing age
Commencing RRT
Requiring additional organ support
Underlying sepsis

Long-term prognosis

Data is sparse on the long-term outcome of AKI requiring RRT, which is surprising given the scale of the problems and the healthcare burden associated with renal non-recovery. Six-month survival varies from 24% to 45%, 1-year survival from 21% to 53% and 5-year survival from 15% to 35%.

Renal recovery

Mortality reduction is the goal of most ICU interventions, particularly those involving extracorporeal or mechanical support. Other outcomes are often looked at in a post-hoc fashion. For survivors of the ICU who suffered AKI requiring CRRT, RRT dependence can have a profound impact on quality of life. This area has not been extensively studied and suffers from a lack of definition similar to that of AKI prior to the advent of the RIFLE classification.

Underlying CKD and AKI associated with sepsis appear from the sparse literature to be associated with poor renal outcomes. Exact figures vary significantly but, among survivors, the incidence of dialysis dependence appears to be between 8% and 20%.

Length of stay

A large multi-national study has shown that median ICU stay for patients with AKI is 10 days, and 22 days in hospital. AKI is independently associated with an increased hospital stay.

Special considerations for nursing and allied health professionals

N/A

What's the evidence?

General resources

Kellum, JA, Bellomo, R, Ronco, C. Continuous Renal Replacement Therapy. Oxford University Press. 2010.

Bellomo, R, Baldwin, I, Ronco, C, Golper, T. Atlas of Hemofiltration. WB Saunders. 2002.

(These are two excellent resources for understanding and implementing RRT. They provide theoretical, practical and organizational information and a wealth of practical experience.)

Description of the problem

Bellomo, R, Ronco, C, Kellum, JA. "Acute renal failure: definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Conference of the Acute Dialysis Quality Initiative group". Critical Care. vol. 8. 2004. pp. R204-12..

Mehta, RL, Kellum, JA, Shah, SV. "Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury". Critical Care. vol. 11. 2007. pp. R31.

(These are the current accepted consensus definitions for the classification of AKI. Some debate exists as to the validity of a classification system that includes outcome measures, as does the RIFLE classification. To this end, and to incorporate more recent evidence that even small increases in serum creatinine adversely affect outcome, the AKIN criteria were produced. In practice the two systems are very similar, with little to differentiate them.)

Mehta, RL. "Indications for dialysis in the ICU: renal replacement vs. renal support". Blood Purification. vol. 19. 2001. pp. 227-32.

(The initial discussion of renal replacement versus renal replacement, this is a useful review of the non-renal indications for dialysis.)

Diagnosis

Bagshaw, SM, Cruz, DN, Gibney, RT, Ronco, C. "A proposed algorithm for initiation of renal replacement therapy in adult critically ill patients". Critical Care. vol. 13. 2009. pp. 317-25.

(This an opinion piece published in an attempt to produce consensus guidelines for initiation and cessation of RRT and RST. Nonetheless it is a useful summary of the indications for CRRT and may help with clinical decision-making.)

Specific treatment

Ricci, A, Ronco, C, D’amico, G. "Practice patterns in the management of acute renal failure in the critically ill patient: an international survey". Nephrology, Dialysis and Transplantation. vol. 21. 2006. pp. 690-96.

(This article is very interesting, comparing the practice of RRT and management of AKI internationally in both critical care nephrologists and intensive care physicians, and highlights the wide variation in clinical practice and the need for further large-scale trials to provide evidence-based parameters for RRT.)

Rabindranath, KS, Adams, J, MacLeod, AM, Muirhead, N. "Intermittent versus continuous renal replacement therapy for acute renal failure in adults". Cochrane Database of Systematic Reviews. 2007.

(This systematic review is the latest in a series of such articles showing no difference in clinical outcomes between patients undergoing continuous or intermittent RRT.)

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

Bagshaw, SM, Uchino, S, Rellomo, R. "Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury". J Critical Care. vol. 24. 2009. pp. 129-40.

(This well-performed multi-center observational study and the meta-analysis showed no good evidence for timing of RRT affecting patient or renal outcome.)

Palevsky, PM, Hongyuan Zhang, J, O’Connor, TZ. "VA/NIH Acute Renal Failure Trial Network. 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. "RENAL Replacement Therapy Study Investigators. Intensity of continuous renal-replacement therapy in critically ill patients". N Engl J Med. vol. 361. 2009. pp. 1627-38..

Van Wert, R, Friedrich, JO, Scales, DC. "University of Toronto Acute Kidney Injury Research Group. High-dose renal replacement therapy for acute kidney injury: systematic review and meta-analysis". J Critical Care. vol. 38. 2010. pp. 1360-9.

(These are the two largest published trials of high methodological quality comparing high- and low-intensity strategies of RRT. The subsequent meta-analysis is methodologically sound and taken together would appear to indicate that intensity has no effect on clinical outcome. As discussed above, it is likely that we are failing to take into account key variables regarding RRT and outcome.)

Ronco, C, Bellomo, R, Brendolan, A, Pinna, V, LaGreca, G. "Brain density changes during renal replacement in critically ill patients with acute renal failure: continuous hemofiltration versus intermittent hemodialysis". J Nephrol. vol. 12. 1999. pp. 173-8.

Davenport, A, Will, EJ, Davidson, AM. "Improved cardiovascular stability during continuous modes of renal replacement therapy in critically ill patients with acute hepatic and renal failure". Critical Care Med. vol. 21. 1993. pp. 328-38.

(These papers were the foundation for the argument that CRRT, in most situations, is the preferred technique of RRT due to increased hemodynamic stability and reduced fluid shifts. However, over the past two decades there have been considerable advances in both intermittent and continuous technologies, and this may not hold true.)

Bagshaw, SM, Delaney, A, Jones, D. "Diuretics in the management of acute kidney injury: a multinational survey". Contrib Nephrol. vol. 156. 2007. pp. 236-49..

Bagshaw, SM, Delaney, A, Haase, M. "Loop diuretics in the management of acute renal failure: a systematic review and meta-analysis". Critical Care and Resuscitation. vol. 9. 2007. pp. 60-8.

(Clinical equipoise regarding the use of furosemide in the management of AKI and in managing weaning from RRT is well demonstrated by the wide clinical use, but lack of an evidence of benefit presented by this survey and meta-analysis.)

Disease monitoring, follow-up and disposition

Wu, V-C, Ko, W-J, Chang, H-W. "Risk factors of early redialysis after weaning from postoperative acute renal replacement therapy". Intensive Care Med. vol. 34. 2008. pp. 101-8.

(A limited study in many ways, but one of the few to look at factors predictive of weaning failure in RRT.)

Uchino, S, Bellomo, R, Morimatsu, H. "Discontinuation of continuous renal replacement therapy: a post hoc analysis of a prospective multi-centre observational study". Critical Care Med. vol. 37. 2009. pp. 2576-82.

(This provides our best evidence to date for features likely to be indicative of renal recovery and is part of the BEST Kidney series.)

Pathophysiology

Vanholder, R, de Smet, R, Glorieux, G. "Review on uremic toxins: classification, concentration, and interindividual variability". Kidney International. vol. 63. 2003. pp. 1934-43.

(This is a comprehensive article covering the complexities of the uremic syndrome, uremic toxins and their clearance.)

Bellomo, R, Baldwin, I, Ronco, C. "Extracorporeal blood purification therapy for sepsis and systemic inflammation: its biological rationale". Contrib Nephrol. vol. 132. 2001. pp. 367-74.

(This article admirably covers the complexities of the pathophysiology of sepsis and the potential for mediation by hemodiafiltrative extraction of inflammatory mediators.)

Epidemiology and prognosis

Liangos, O, Wald, R, O’Bell, JW. "Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey". Clin J Am Soc Nephrol. vol. 1. 2006. pp. 43-51..

Uchino, S, Kellum, JA, Bellomo, R. "Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study". JAMA. vol. 294. 2005. pp. 813-8..

Silvester, W, Bellomo, R, Cole, L. "Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia". Critical Care Med. vol. 29. 2001. pp. 1910-5.

Thakar, CV, Christianson, A, Freyberg, R. "Incidence and outcomes of acute kidney injury in intensive care patients: A Veterans Administration study". Critical Care Med. vol. 37. 2009. pp. 2552-8.

(These articles look at the incidence and prognosis of AKI and AKI requiring RRT in a variety of populations over the past decade.)
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