Management of Acute Kidney InjuryMatthew T. James | Neesh Pannu

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Acute kidney injury (AKI) is associated with prolonged hos-pitalization, substantial resource utilization high mortality, and progressive chronic kidney disease (CKD) and end-stage renal disease (ESRD) in survivors. The principles of management of AKI include early recognition of the prob-lem, identification and correction of the underlying cause, and steps to avoid further kidney injury. After AKI is estab-lished, the therapeutic options are limited, and mortality remains high despite recent technological advancements. Nonetheless, regional and temporal variations in mortality among hospitalizations for AKI suggest that several elements of management, including supportive care, management of complications, and use of renal replacement therapy (RRT), may influence outcomes. This chapter focuses on the management of early or established AKI resulting from prerenal causes or acute tubular necrosis (ATN). Readers are referred elsewhere in the Primer for a review of specific aspects of treatment for acute interstitial nephritis, glo-merulonephritis, urinary obstruction, and systemic diseases involving the kidney.

EARLY RECOGNITION AND INITIAL MANAGEMENT

Timely detection and recognition is desirable as it can allow for prompt implementation of interventions to abort early kidney damage and to avoid the development of severe kid-ney injury and its complications (Box 36.1). AKI is usually identified based on an increase in serum creatinine; however, creatinine is an insensitive early marker of changes in kidney function, and AKI may develop before such changes become apparent. Furthermore, small changes in serum creatinine early in the course of AKI may not be readily appreciated even though they can represent large changes in glomerular filtration rate. Oliguria or anuria is an important sign that can identify AKI before changes in serum creatinine become apparent. Several novel biomarkers for AKI have been iden-tified in recent years including kidney injury molecule-1 (KIM-1), neutrophil gelatinase associated lipocalin (NGAL), interleukin-18 (IL-18), and cystatin C. However, these tests are not yet widely used in clinical practice, and they remain the focus of ongoing studies to determine their appropriate role in guiding management of patients at risk for AKI.

After AKI has been identified, further clinical assessment, investigation, and intervention typically proceed simultane-ously. A thorough history and examination are required to identify potential causes of AKI. Ischemia, sepsis, and expo-sure to nephrotoxic agents are the most common causes of AKI in hospitalized patients. A search for prerenal and

postrenal causes should be performed, as their correction can lead to rapid recovery of kidney function. A number of urine studies have been described to distinguish prerenal AKI from ATN, including the urine sodium concentration, fractional excretion of sodium, and fractional excretion of urea. Unfortunately, all of these tests have limitations in their diagnostic performance, and interpretation is dependent on the clinical context. Clinical examination to assess volume status remains an important aspect of early management. AKI due to hypovolemia may be rapidly reversed by the admin-istration of intravenous fluids. Volume status should be fre-quently reassessed to determine the response to intravenous fluids and to avoid volume overload. Stopping medications that impair glomerular filtration, including nonsteroidal antiinflammatory drugs (NSAIDs) and angiotensin convert-ing enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), can help reverse kidney dysfunction, especially in the setting of low effective arterial blood volume. Drugs that cause direct nephrotoxicity, such as aminoglycosides and intravenous radiocontrast, should be avoided. Selected use of renal ultrasound is useful for identifying hydroureter and/or hydronephrosis indicative of a postrenal cause. Lower uri-nary tract obstruction can be identified and treated by blad-der catheterization showing a large postvoid residual urine volume, whereas nephrostomy tubes or ureteric stents can be used to treat upper urinary tract obstruction.

Urinalysis and urine microscopy provide important information about intrinsic renal causes of AKI. Hematu-ria and proteinuria should prompt further investigations for causes of glomerulonephritis, whereas white bloods cell casts should prompt a careful assessment for causes of interstitial nephritis, including a review of medication exposures. The findings of granular casts and/or renal tubular epithelial cells are associated with an increased likelihood of ATN, and help to predict patients at high-est risk for worsening kidney function, the requirement for RRT, or death.

SUPPORTIVE CARE AND MEDICAL MANAGEMENT OF COMPLICATIONS

After AKI is established, management focuses on preventing extension of kidney injury and providing supportive care while awaiting kidney recovery. Attempts are usually made to avoid further exposure to nephrotoxic agents to the great-est extent possible without compromising management of other comorbidities. Doses of medications cleared by the kidney should be adjusted for the level of kidney function. This can be particularly important for antimicrobial agents

so as to maintain appropriate therapeutic levels in patients with sepsis while avoiding drug toxicity. The involvement of a clinical pharmacist may be helpful.

Supportive care in patients with AKI requires maintenance of fluid, electrolyte, and acid-base balance. Disorders of sodium and water handling, metabolic acidosis, and hyper-kalemia are common complications of AKI. Hyponatremia may result from impaired free water excretion, whereas hypernatremia is common in patients with inadequate free water intake, hypotonic fluid losses, or large-volume intra-venous saline infusions for resuscitation. These abnormali-ties may be corrected by modifying free water intake or the composition of intravenous fluids. Acid generation can be reduced by dietary protein restriction, although this may be undesirable in hypercatabolic patients. Alkaline intrave-nous fluids such as sodium bicarbonate may be provided to correct metabolic acidosis, although volume overload and pulmonary edema may limit this intervention. Hyperkale-mia should be treated by discontinuing exogenous sources of potassium. In the presence of ECG changes, calcium gluconate may be administered. Beta-agonists, insulin, and sodium bicarbonate can shift potassium out of the plasma and into cells. Attempts to eliminate potassium through the gastrointestinal tract using ion exchange resins may be used; however, these agents are slow to take effect, have limited efficacy, have been associated with bowl necrosis or perfora-tion, and are unlikely to be adequate in patients with severe hyperkalemia. When medical management of these abnor-malities is unsuccessful, or medical interventions cannot be tolerated by the patient, RRT is usually necessary unless recovery of kidney function is imminent.

INTRAVENOUS FLUIDS AND HEMODYNAMIC SUPPORT

Hypotension is a common contributor to AKI, and after AKI is established renal perfusion may be further dimin-ished through disruption of renal autoregulation. Early cor-rection of hypovolemia and hypotension not only reverses most prerenal causes of AKI, but also likely prevents exten-sion and allows recovery from ATN. Strategies to maintain hemodynamic stability include the use of intravenous flu-ids, vasopressors/inotropic medications, and protocols for

• Timely recognition of changes in urine output or kidney function

• Identification and reversal of underlying cause• Correction of prerenal states and maintenance of hemody-

namic stability• Avoidance of nephrotoxic agents, if possible, and adjust-

ment of medication doses to level of kidney function• Provision of supportive care, including nutrition and medi-

cal interventions to maintain fluid, electrolyte, and acid-base balance

• Initiation of RRT when needed

RRT, Renal replacement therapy.

Box 36.1 Principles of Management of Acute Kidney Injury

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hemodynamic monitoring to guide the use of these thera-pies. Although more aggressive use of intravenous fluids in the initial phase of illness may be beneficial when AKI is vol-ume responsive, excessive fluid repletion in oliguric patients with established ATN can have adverse effects. A positive fluid balance has been associated with increased mortality in observational studies. Targeting a lower central venous pres-sure (6 to 8 cm H2O) may be appropriate in some patients with stable AKI.

Isotonic crystalloids are the principal intravenous fluid for intravascular volume expansion of patients with AKI. Isotonic (0.9%) saline is considered the standard of care for most patients. Colloid solutions such as albumin and starches are theoretically attractive alternatives for intravenous volume expansion given their oncotic properties, but their appro-priate use remains controversial. No differences in the inci-dence or duration of RRT were observed in a randomized trial of critically ill patients comparing treatment with 4% albumin in 0.9% saline with isotonic saline alone. However, a recent systematic review of randomized trials concluded that the use of hyperoncotic albumin solutions reduced the risk of AKI and may be appropriate for some patients, including those with ascites, spontaneous bacterial peritonitis, burns, or following surgery. Hydroxyethyl starch is an alternative colloid solution; however, when compared to crystalloids, hyperoncotic hydroxyethyl starch has been associated with a higher incidence of AKI and features of renal tubular injury (termed osmotic nephrosis) on kidney biopsy, suggesting these solutions may be harmful. As colloids have not been shown to consistently reduce mortality when compared with crys-talloids across all populations who are at high risk of AKI, these solutions are usually reserved for selected patients, or for those with continuing large fluid requirements.

Distributive shock is a common contributor to AKI in patients with sepsis, anaphylaxis, liver failure, and burns. Aggressive fluid resuscitation remains of paramount impor-tance in these patients; however, after intravascular volume has been repleted, vasopressors such as norepinephrine, dopamine, and vasopressin may be required to maintain hemodynamic stability. Following the publication of several recent randomized trials, management strategies that are focused on achieving specific hemodynamic and oxygen-ation parameters have gained increasing prominence for the management of patients at risk for AKI from septic shock or in the perioperative period. One randomized trial showed a reduction in in-hospital mortality for patients with septic shock managed according to a protocol for early provision of intravenous fluids, blood transfusion, vasopressors, and inotropes based on specific goals for blood pressure, cen-tral venous pressure, serum lactate, central venous oxygen saturation, and urine output. Protocol-based therapies to improve oxygenation and prevent hypotension using intrave-nous fluids, vasopressors, and blood products also appear to reduce the incidence of perioperative AKI in high-risk surgi-cal patients, although it remains unclear which elements of these protocols are associated with this benefit.

DIURETICS

Fluid overload is one of the major complications of AKI, and diuretics are often prescribed to control fluid balance. The use of loop diuretics may also aid in the management

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of hyperkalemia and hypercalcemia. It has been proposed that loop diuretics such as furosemide could ameliorate ischemic damage in AKI by reducing the energy require-ments of cells within the loop of Henle. However, diuretics can induce hypovolemia leading to prerenal AKI, and their use has been associated with increased mortality and delays in kidney recovery in observational studies. Some small ran-domized trials of furosemide reported higher risks of AKI when used as a prophylactic agent at the time of imaging and surgical procedures, and systematic reviews of trials that included patients with or at risk for AKI found no significant effects of furosemide on the risks of death, requirement for RRT, or number of dialysis sessions. Furthermore, although furosemide facilitates diuresis, this approach does not appear to improve kidney recovery among patients requir-ing dialysis for AKI. Nonetheless, diuretics can be used effec-tively to achieve fluid balance, and may facilitate mechanical ventilation in volume-overloaded patients.

VASODILATORS AND OTHER PHARMACOLOGIC AGENTS

Several pharmacologic agents with renal vasodilatory prop-erties have been studied with the aim of increasing renal blood flow and ameliorating ischemic damage in AKI. However, none of these agents are proven to improve the clinical outcomes of AKI. Low-dose dopamine is associated with increased renal blood flow, increased urine output, and small improvements in creatinine clearance. However, a systematic review of trials including patients with or at risk for AKI showed that low-dose dopamine had no signifi-cant effect on survival, need for dialysis, or adverse clinical events. Dopamine is associated with arrhythmias and intesti-nal ischemia, and is not currently recommended to prevent or treat AKI. Fenoldopam is a dopamine type 1 receptor agonist that also increases renal blood flow, although it decreases systemic vascular resistance. A metaanalysis sug-gested promising results with the use of fenoldopam in critically ill patients, including reductions in AKI, need for RRT, and in-hospital mortality. However, given its risk of hypotension along with limitations of the existing pub-lished trials, further trials are necessary to support the use of fenoldopam for this indication. Atrial natriuretic peptide (ANP) has favorable renovascular effects that increase the glomerular filtration rate in animals. However, large trials of ANP (0.2 µg/kg/min) in critically ill patients with AKI showed no effects on mortality or dialysis-free survival, but did show a higher incidence of hypotension. One systematic review has suggested that low-dose ANP (0.1 µg/kg/min) is not associated with hypotension and may lead to a reduc-tion in the requirement for RRT. Yet again, further large trials of low-dose ANP will be required before this agent can be recommended for AKI prevention or treatment.

There is inadequate efficacy and safety data to support the use of growth factors for AKI. Although insulin-like growth factor-1 showed promising results on recovery of kidney function in animals, small trials have failed to demonstrate beneficial results in humans. A small trial of erythropoietin for the prevention of AKI following cardiac surgery reported a reduction in incidence of AKI in treated patients; however, a subsequent trial in the intensive care unit (ICU) detected no effect.

NUTRITIONAL SUPPORT

Malnutrition is common in patients with AKI, and has been consistently associated with mortality. Although clini-cal trials assessing the impact of nutrition on clinical end-points are lacking, it is broadly accepted that appropriate nutritional support should be provided to meet the meta-bolic requirements of AKI patients. Total energy consump-tion is not increased in AKI and is only mildly increased above resting energy expenditure in patients with critical illness. A total energy intake of 20 to 30 kcal/kg/day is recommended to maintain nitrogen balance in patients with AKI and to avoid hyperglycemia, hypertriglyceride-mia, and fluid accumulation observed with higher caloric provisions.

The optimal protein intake in the setting of AKI is not known. Given the association between protein-calorie mal-nutrition and mortality in these patients, dietary restriction of protein is not considered appropriate in attempts to delay or prevent the initiation of RRT for azotemia or acidosis. Protein wasting and negative nitrogen balance may occur in patients with AKI because of the inflammatory and physi-ologic stresses that accompany acute illnesses, particularly in critically ill patients. Nutritional protein administration is therefore usually increased to meet the greater metabolic demands of hypercatabolic patients. Furthermore, losses of amino acids and protein occur in the filtrate on continu-ous renal replacement therapy (CRRT) and via peritoneal dialysis resulting in additional nutritional requirements for patients receiving these treatments. It is reasonable to aim for a protein intake of 0.8 to 1.0 g/kg/day in noncatabolic patients not requiring RRT, increasing to a maximum of 1.7 g/kg/day for hypercatabolic patients receiving RRT. Con-sultation with a registered dietician is valuable to estimate the appropriate energy and protein requirements for an individual patient.

Enteral nutrition is the preferred form of support for patients with AKI. If oral feeding is not possible, then enteral (tube) feeding is recommended. Electrolytes (potassium, phosphate) should be monitored following initiation of enteral feeding. Parenteral nutrition may be required in some patients to supplement the enteral route, or in patients without functional gastrointestinal tracts. Potassium, phos-phate, and magnesium are usually withheld from parenteral nutrition in patients with AKI.

RENAL REPLACEMENT THERAPY

MODALITIES

Several modalities are currently used for RRT in AKI, includ-ing peritoneal dialysis, intermittent hemodialysis (IHD), and CRRTs. Peritoneal dialysis is used for AKI in some pediatric settings and in adults in developing countries where infra-structure for hemodialysis is not available. In industrialized countries, IHD and CRRT are the mainstays of RRT for AKI. Available resources, expertise, hemodynamic stability, and patient comorbidities usually influence the decision of renal replacement modality. In institutions where both modalities are available, it is common for patients to transition between

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Table 36.1 Properties of Various Renal Replacement Therapy Modalities Used for Acute Kidney Injury

Modality Solute Removal Blood Flow RatesUltrafiltration Rate Replacement Fluid Rate Dialysate Flow Rate

Continuous Therapies

CVVHF Convection (ultrafiltration)

150 to 250 mL/min 1500 to 2000 mL/hr

1500 to 2000 mL/hr for neutral fluid balance. Ultrafiltration in excess of replacement fluid nec-essary for fluid removal

0

CVVHD Diffusion (dialysis) 150 to 250 mL/min Variable None 1 to 2 L/hrCVVHDF Diffusion and

convection (ultrafiltration and dialysis)

150 to 250 mL/min 1000 to 1500 mL/hr

1000 to 1500 mL/hr for neutral fluid balance. Ultrafiltration in excess of replacement fluid nec-essary for fluid removal

1 to 2 L/hr

Intermittent Therapies

IHD Diffusion (dialysis) 200 to 350 mL/min Variable None 300 to 500 mL/minSLED Diffusion (dialysis) 100 to 300 mL/min Variable None 100 to 300 mL/minSCUF Convection

(ultrafiltration)100 to 200 mL/min Variable None 0

CVVHD, Continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; CVVHF, continuous venovenous hemofiltration; IHD, Intermittent hemodialysis; SCUF, sustained continuous ultrafiltration; SLED, sustained low-efficiency dialysis.

forms of CRRT and IHD depending on various factors and the setting in which the care is being provided.

CRRT is delivered continuously and uses slower blood flow rates that result in slower fluid and solute removal than IHD. Several forms of CRRT exist, including continuous venovenous hemofiltration (CVVHF), continuous venove-nous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF) (Table 36.1). These modalities are usually only available in ICUs. Although CRRT achieves slower removal of solutes per unit time than IHD, total clear-ance during a 24-hour period may exceed that provided by IHD. Furthermore, the slower rate of solute clearance may avoid large fluid shifts between intracellular and extracel-lular fluid compartments. Based on these features, CRRT is often suggested for hemodynamically unstable patients and patients with brain injury at risk of cerebral edema.

IHD is performed for a few hours at a time over spaced intervals. It uses the methods, equipment, and trained nurs-ing staff established for chronic hemodialysis in patients with ESRD. IHD achieves the fastest removal of small solutes and limits the duration a patient is exposed to the extracor-poreal circuit. It is a popular therapeutic option for many patients with severe hyperkalemia, poisoning, and tumor lysis syndrome. In recent years, variants of IHD have been implemented using the IHD equipment (see Table 36.1). These hybrid therapies, known as sustained low-efficiency dialysis (SLED), use an extended duration of dialysis with a lower blood flow rate to provide more gradual solute and fluid removal while maintaining hemodynamic tolerability.

Although most patients with AKI are eligible for either modality, it is broadly perceived that CRRT is preferable to IHD for treatment of hemodynamically unstable patients. However, randomized comparisons of CRRT and IHD have shown heterogeneous effects on hemodynamic measure-ments, with metaanalyses suggesting no significant differ-ences in the risk of hypotension between modalities. Still higher mean arterial blood pressure, and fewer patients

requiring escalation of vasopressor during treatment, were seen with CRRT than with IHD. Experience reported from clinical trials suggests that IHD can be successfully delivered to many patients with hemodynamic instability. Strategies that may help maintain hemodynamic stability during IHD include priming of the dialysis circuit with saline, cooled dialysate, and a high dialysate sodium concentration. Vary-ing the dialysate sodium concentration and ultrafiltration rate during IHD can also improve hemodynamic stability and achieve greater fluid removal.

Several randomized trials and metaanalyses have compared outcomes with CRRT versus IHD in critically ill patients. Data from these trials have demonstrated no significant differences between these modalities in the length of hospitalization, mortality, or the requirement for chronic dialysis in survivors. Although existing data do not provide evidence that either IHD or CRRT results in superior clinical outcomes, further trials remain necessary to compare the hybrid with conven-tional therapies and to better assess the effect of the major renal replacement modalities on time to kidney recovery.

INITIATION OF RENAL REPLACEMENT THERAPY

Initiating RRT is a clinical decision influenced by several factors, including assessment of fluid, electrolyte, and meta-bolic status. Little information from clinical trials is available to guide this decision. It is widely accepted that hyperkale-mia, metabolic acidosis, and volume overload (refractory to medical management) or overt uremic signs and symptoms constitute traditional indications for RRT. However, it is rare for uremic symptoms to develop in the setting of AKI before initiating dialysis. RRT is usually started after AKI is estab-lished and complications are deemed unavoidable. How-ever, in the absence of imminent complications, dialysis may be deferred when there are signs of clinical improvement or kidney recovery. Many patients recover kidney function without the development of absolute indications for RRT,

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and in some patients complications may be adequately man-aged medically. Thresholds for starting RRT appear to be lower when AKI is accompanied by multiple organ failure, the rationale being that earlier initiation will facilitate other aspects of management while maintaining fluid, solute, and metabolic control.

There is considerable practice variation for starting renal replacement in the absence of traditional indications (Table 36.2). In theory, earlier initiation may avoid adverse AKI consequences, including metabolic abnormalities and fluid overload, and could improve outcomes. However, earlier initiation can unnecessarily expose some patients to the risk associated with vascular access (infection, thrombosis), anti-coagulation (hemorrhage), and RRT itself (hypotension, dialyzer reactions). The majority of studies on the effects of earlier initiation of RRT are observational, and the interpre-tation of findings is limited by varying definitions of early treatment, comparison with historical cohorts, and possible confounding. However, a small randomized trial that com-pared early initiation of RRT (oliguria less than 6 hours with creatinine clearance less than 20 mL/min) to conventional

Table 36.2 Traditional and Early Criteria for Renal Replacement Therapy in Acute Kidney Injury

Criteria Comment

Traditional Criteria

Volume overload Pulmonary edema or respiratory failure that cannot be managed with medi-cal therapy including diuretics

Electrolytes Hyperkalemia refractory to medical management, severe (K greater than 6.0 mEq/L) or associated with ECG changes

Acidemia Usually based on severity of meta-bolic acidosis, but no established threshold

Uremia Indications include pericarditis, encephalopathy, or uremic bleeding attributed to platelet dysfunction

Early Criteria

Volume management To minimize fluid overload, and to facilitate administration of nutritional support and intravenous medication that would otherwise lead to fluid accumulation

Electrolytes Proactive use to avoid impending elec-trolyte disorders

Acid-base balance To maintain arterial pH in the setting of permissive hypercapnea in patients with respiratory failure

Solute control Severe AKI that is unlikely to recover imminently

Remove solutes that are difficult to quantify in the setting of AKI

AKI, Acute kidney injury; ECG, electrocardiogram; K, serum potassium concentration.

criteria (pulmonary edema, urea greater than 112 mg/dl [40 mmol/L], serum potassium greater than 6.5 mmol/L) did not show an effect of earlier initiation on mortality. Fur-ther trials are needed in this area to guide practice.

DOSE OF RENAL REPLACEMENT THERAPY

Several limitations exist regarding the use of urea clearance to quantify the intensity of RRT due to the high catabolic rate and changes in the volume of distribution that commonly accompany AKI. Despite these limitations, urea clearance is often used to prescribe and measure the intensity of RRT in AKI. Urea clearance by hemodialysis is expressed as Kt/V, and may be modified by increasing the surface area of the dialyzer, blood flow rate, dialysate flow rate, treatment dura-tion, or frequency. Urea clearance by CRRT is considered equivalent to the effluent flow rate (ultrafiltrate and/or dialy-sate) and can be expressed as mL/kg/h of effluent.

One small trial that evaluated the effect of daily versus alternate-day IHD in AKI reported lower mortality and shorter duration of dialysis in the daily IHD group. However, the delivered dose in the alternate-day group was lower than intended with a weekly mean Kt/V of 3.0. More recently, two larger studies of the dose of renal replacement in AKI have provided major advances in our knowledge of this area. The Veterans Affairs ATN study was a randomized trial that evaluated the intensity of RRT while allowing patients to switch between CRRT, IHD, or SLED. In this trial, IHD was prescribed at a Kt/V of 1.4 (mean delivered dose was 1.3) and was performed six times weekly in the intensive arm and three times weekly in the less intensive arm. CRRT was performed using predilution CVVHDF prescribed with effluent flow rate of 35 mL/kg/h in the intensive arm and 20 mL/kg/h in the less intensive arm. Mortality and recov-ery of kidney function were similar in the intensive and less intensive groups. The RENAL study randomized patients with AKI treated with postdilution CVVHDF to doses of 40 versus 25 mL/kg/h and showed no difference in survival between the two groups.

Based on these results, a delivered dose equivalent to that achieved in the less intensive arm of the ATN study (weekly Kt/V 3.9) appears to be adequate for treatment of patients with IHD. Moreover, a delivered effluent volume consistent with the less intensive arms of the ATN and RENAL stud-ies (20 to 25 mL/kg/h) has been recommended for CRRT. Hemodynamic instability, access failure, technical problems, and time off RRT to perform procedures may reduce the effective time on RRT and result in a lower delivered dose, which may require prescription adjustments. Assessment of the adequacy of renal replacement should also incorporate other factors in addition to small solute (urea) clearance, including fluid management, acid-base status, and electro-lyte balance, as these parameters may influence the pre-scription for RRT. Extracorporeal therapy may be required in some instances for ultrafiltration alone.

VASCULAR ACCESS FOR RENAL REPLACEMENT THERAPY

Venous access is a necessity for CRRT and IHD, and access dysfunction can limit blood flow and the delivery of dialysis.

Because of their large diameter, complications of dialysis catheter insertion (arterial puncture, hematoma, pneumo-thorax, or hemothorax) can be serious. Indwelling cathe-ters also predispose to bacteremia. Nontunneled catheters are the initial choice for most patients starting RRT. Cuffed, subcutaneous tunneled catheters are more complex to insert; however, they may be less prone to dysfunction, infec-tion, or thrombosis, and thus appropriate if longer (greater than 3 week) durations of RRT are anticipated. Subcla-vian vein catheters are associated with the highest risk of venous stenosis. As this may compromise future attempts at permanent vascular access, the internal jugular vein is the preferred upper body insertion site for patients at risk for progression to ESRD. Femoral catheters are another rea-sonable choice, but these restrict mobility and are associ-ated with increased infection in obese patients. Ultrasound guidance is recommended to decrease the risk of insertion complications and to improve the likelihood of successful placement. Insertion should be performed according to infection control protocols, including sterile barrier pre-cautions, skin antisepsis, and catheter use restricted to RRT to minimize the incidence of catheter-related bloodstream infection.

ANTICOAGULATION FOR RENAL REPLACEMENT THERAPY

Clotting of the dialysis filter can lead to extracorporeal blood loss, a reduction in dialysis efficiency, and proce-dural interruptions. Use of anticoagulation for CRRT and IHD may reduce these problems; however, the ben-efits of anticoagulation must be balanced against the risk of bleeding complications in acutely ill AKI patients with significant comorbidities. Patients with coagulopathy and thrombocytopenia may not benefit from additional antico-agulation, and CRRT and IHD can often be provided with-out anticoagulation, aided by intermittent saline flushes of the extracorporeal circuit.

Unfractionated heparin is the most widely used antico-agulant for dialysis. Low molecular weight heparin may also be used, although it has unpredictable clearance in patients with kidney failure. A prolonged half-life requires moni-toring of factor Xa levels. Regional citrate anticoagulation has become more common in recent years, especially for anticoagulation on CRRT. Citrate is infused into the prefil-ter line where it chelates calcium, thereby inhibiting filter coagulation. Some citrate is removed in the extracorporeal circuit, while the citrate returning to the systemic circula-tion is metabolized to produce bicarbonate and calcium. Additional calcium is infused to replace extracorporeal losses and to maintain normal systemic ionized calcium concentrations. The complexity of this procedure necessi-tates close monitoring of acid-base status and calcium (total and ionized) levels, and frequent adjustments to infusion rates. Adequately trained staff and adherence to strict pro-tocols are recommended to minimize the complications of metabolic alkalosis, hypocalcemia, and citrate accumula-tion. Citrate anticoagulation is contraindicated in patients with severely impaired liver function or muscle hypoperfu-sion who are unable to metabolize citrate. Some small tri-als suggest that regional citrate anticoagulation reduces the

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requirement for transfusion and risk of hemorrhage com-pared to systematic heparin.

DIALYZER/HEMOFILTER MEMBRANES

Hollow fiber dialyzers used for IHD or CRRT are character-ized by their surface area, composition, and flux. Synthetic dialysis membranes are associated with less activation of complement than traditional bioincompatible membranes made of unsubstituted cellulose. Metaanalyses have shown no difference in mortality with biocompatible compared to bioincompatible membranes. However, as a higher risk of death has been suggested with unsubstituted cellulose mem-branes, these are typically avoided in AKI. Trials to date have shown no difference in outcomes between high-flux and low-flux membranes in AKI, although the increased perme-ability of high-flux membranes makes them advantageous for hemofiltration.

DIALYSATE AND REPLACEMENT FLUIDS

Dialysate for IHD is produced by the dialysis machine from concentrated electrolyte solutions and treated water from a municipal source. Sterile dialysate and replacement fluid for CRRT may be purchased commercially or produced in local hospital pharmacies. Solutions containing bicarbon-ate, lactate, and acetate are available for use with CRRT or IHD to correct metabolic acidosis. Bicarbonate-containing solutions have become increasingly available in recent years, and they avoid lactate accumulation in patients with shock or liver failure. When citrate is used for anticoagulation, requirements for additional buffer in dialysate or replace-ment fluid are limited.

DISCONTINUING RENAL REPLACEMENT THERAPY

Many patients with AKI will experience partial or complete recovery of kidney function, although recovery is less likely in those with severe injury and preexisting CKD. Little is known about the optimal time to stop RRT; however, increas-ing urine output often identifies patients recovering native kidney function. Changes in interdialytic measurements of serum creatinine, urea, and urinary creatinine clearance can be used to assess native kidney function in patients receiving IHD. For patients receiving a stable prescription of CRRT for several days, urinary creatinine clearance has also been used to measure recovery of native kidney function. Because of the high mortality in patients with AKI accom-panying multiorgan failure, some patients will appropriately discontinue RRT as part of withdrawal from life support measures.

LONG-TERM FOLLOW-UP

Acute kidney injury is associated with an increased risk of progressive CKD and ESRD after hospital discharge. Post-discharge follow-up of kidney function is currently rec-ommended for survivors of AKI. Subsequent long-term management of patients with CKD after AKI usually proceeds according to the principles of CKD management.

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