1. When should renal replacement therapy (RRT) be initiated?

There are accepted urgent indications for RRT in patients with acute kidney injury (AKI) and generally include: refractory fluid overload, hyperkalemia >6 mEq/L or rapidly rising potassium levels, signs of uremia, severe metabolic acidosis, and certain alcohol and drug intoxications. Although the maintenance of serum creatinine and blood urea nitrogen (BUN) concentrations below arbitrarily set levels is usually a reference for starting dialysis treatment, neither creatinine nor BUN should be used to absolutely determine when to initiate dialysis. BUN reflects factors not directly associated with kidney function, such as catabolic rate and volume status. Serum creatinine is influenced by age, race, muscle mass, and catabolic rate, and its volume of distribution varies in fluid overloaded patients. Other factors such as fluid balance control, nutrition needs, severity of the underlying disease, and acid base and electrolyte balance should guide the decision to start dialysis, as has been suggested by KDIGO AKI guidelines. We favor RRT initiation prior to the development of severe electrolyte disturbances in patients with severe metabolic acidosis (pH < 7.2) despite optimal medical management and with no signs that kidney function or metabolic acidosis is improving; and in patients with positive fluid balance despite aggressive use of diuretics, predominantly if they have increasing oxygen requirements. Therefore it is better to use RRT as a supportive therapy rather than a rescue therapy for late manifestations of AKI.

Since the optimal timing of RRT initiation is controversial, any presumed benefit from early dialysis needs to be balanced by the safety concerns from dialysis including:

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  Risk for infection from an indwelling dialysis catheter

  
  
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  Hypotension

  
  
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  Potential for delayed kidney recovery

  
  
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  Leukocyte activation from contact with dialysis membranes

Randomized, controlled trials that have compared strategies of early versus delayed initiation of RRT (in the absence of absolute indications) have yielded conflicting results. In fact, three of the largest trials have not demonstrated a benefit with earlier initiation of RRT. The best evidence comes from a randomized, controlled trial, which included 620 critically ill patients that had severe AKI (KDIGO stage 3) and required either or both mechanical ventilation and vasopressors (AKIKI Study). Patients were assigned to early RRT (within 6 hours after AKI was identified) or to delayed RRT; the delayed strategy required RRT initiation after the onset of severe hyperkalemia, metabolic acidosis, pulmonary edema, increase in BUN levels >112 mg/dL, or the development of oliguria for more than 72 hours after allocation. The choice of the method of RRT (intermittent or continuous technique, duration and interval between sessions, device setting, and anticoagulation method) was left to the discretion of each study site. The study showed no difference in terms of mortality between patients who received early RRT with a median time of initiation of 2 hours (patients with AKI stage 3 KDIGO without BUN levels >112 mmol/L, pH < 7.15, K levels > 6 mmol/L, and pulmonary edema due to fluid overload) and patients who received late RRT with a median time of initiation of 57 hours. An interesting finding in this study was that kidney recovery marked by increased diuresis was more rapid, and catheter-related infections were lower in the delayed-strategy RRT.

Another study was the ELAIN study: a single center, randomized, controlled trial that enrolled 231 critically ill patients with AKI KDIGO stage 2. All patients had severe sepsis, required vasopressors or catecholamines, or had refractory volume overload. In this study, early RRT (continuous venovenous hemodialfiltration) was started within 8 hours of diagnosis of AKI KDIGO stage 2, and delayed RRT was started within 12 hours of stage 3 AKI, or developed an absolute indication for RRT initiation (serum urea level >100 mg/dL, potassium >6 mEq/L, serum magnesium >8 mEq/L, urine output 200 mL over 12 hours, or diuretic-resistant edema). Compared with delayed or no initiation, early RRT initiation reduced 90-day mortality. In addition, more patients recovered kidney function in the early versus delayed group by 90 days, and both the duration of RRT and the hospital stay were shorter in the early initiation group.

The timing of RRT, a modifiable factor, might exert an important influence on patient survival. We favor utilizing an approach that recognizes that the strategy in treating AKI is to minimize and avoid uremic and volume overload complications. Thus, it is not necessary to wait for progressive uremia to initiate dialytic support; it is better to use RRT as a supportive therapy in the presence of progressive azotemia and oliguria, rather than a rescue therapy for the late manifestation of AKI. Our recommendations to initiate RRT with worsening AKI are listed below:

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  In patients with K >5.8 to 6.0 mEq/L or severe metabolic acidosis despite optimal medical management in patients that demonstrate no sign that kidney function or metabolic acidosis is improving

  
  
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  In patients with positive fluid balance despite aggressive attempts of increasing diuresis, particularly if they have increasing oxygen support requirements

Careful surveillance is mandatory when deciding to wait for RRT initiation in patients with severe AKI, so that any complication will be adequately detected and RRT will be started without delay.

2. Which modalities of RRT are available for treating AKI patients?

The modalities that could be used in the treatment of patients with AKI include:

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  Conventional intermittent hemodialysis (IHD)

  
  
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  Various types of continuous renal replacement therapies (CRRT) such as:

  
  
  
  
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    Continuous venovenous hemofiltration (CVVH)

    
    
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    Continuous venovenous hemodialysis (CVVHD)

    
    
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    Continuous venovenous hemodiafiltration (CVVHDF)

  
  
  
  
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  Prolonged intermittent renal replacement therapies (PIRRT) that combine aspects of both IHD and CRRT, such as slow low-efficiency dialysis (SLED), slow continuous ultrafiltration (SCUF), or extended daily diafiltration.

  
  
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  Peritoneal dialysis (PD).

The removal of solutes can be achieved by convection (hemofiltration), diffusion (hemodialysis), or the combination of the two methods (hemodiafiltration). The amount of solute transported per unit of time (clearance) depends on the molecular weight of the solute, the characteristics of the membrane, and both the dialysate and blood flows. IHD has been used widely for the last four decades to treat end-stage kidney disease (ESKD) and AKI.

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  Diffusive clearance is more effective for small-molecular-weight solutes such as potassium, urea, and creatinine.

  
  
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  Solutes with higher molecular weight (between 500 and 60,000 Da)—so-called middle molecules—are better removed by convection, where hydrostatic pressure forces plasma across a membrane. To provide effective solute clearance, the volume of plasma that must be removed by ultrafiltration is greater than the volume that can be tolerated, so it is replaced partially or completely with a hemofiltration solution. The solution can be infused pre- or post-filter. Intermittent ultrafiltration—in contrast to intermittent hemodiafiltration—can be done with the same machines as IHD, but is used specifically for volume removal. Most nephrologists use isolated ultrafiltration as a method of rapid fluid removal when the major indication for renal replacement or support is pulmonary edema or refractory congestive cardiomyopathy.

Extended daily dialysis (EDD), or SLED, differs from IHD in that dialysate and blood flow are intentionally kept low, but the duration of the treatment is extended. These hybrid modalities can be performed at night for 8 to 12 hours, using intensive care unit (ICU) staff, thereby eliminating an interruption of therapy, reducing staff requirements, and avoiding scheduling conflicts. Studies comparing hybrid modalities to CRRT have revealed favorable hemodynamic tolerance in critically ill patients while achieving dialysis adequacy and ultrafiltration targets, since the fluid removal as well as the solute clearance is more gradual.

There are few studies that have compared PD with other RRT modalities for treating patients with AKI. A single-center randomized trial found that there were no differences in the mortality rate and the recovery of kidney function when PD was compared to daily IHD, although PD was associated with a shorter duration of need for dialysis. Another study, a meta-analysis of eight observational cohorts and four randomized, controlled trials, found no difference in mortality comparing PD to extracorporeal modalities of RRT.

Since RRT can be provided in various forms as shown above, one should consider the use of continuous and intermittent RRT as complementary therapies in AKI patients. CRRT should be used, rather than standard intermittent RRT, for hemodynamically unstable patients. The choice of a specific type of RRT should be based also on the availability of resources, the needs of the patient, and the expertise of the staff.

3. What type of vascular access should be employed?

Guidelines recommend that for acute hemodialysis, access should be obtained by percutaneous placement using the ultrasound guidance of a double lumen catheter in the (order of preferences):

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  Right internal jugular

  
  
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  Femoral

  
  
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  Left internal jugular

  
  
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  Subclavian vein

If RRT is expected to extend beyond several days (>7 days), consideration should be given to early placement of a tunneled catheter in the internal jugular vein. Tunneled catheters have a larger diameter than do non-tunneled catheters, providing higher blood flows, and have a lower incidence of catheter-related bloodstream infections.

Catheter malfunction has a significant impact on the delivered dialysis dose as observed by the investigators of the ATN study; interestingly, one study showed that twin-tunneled catheters in the femoral vein provide better function than a conventional femoral vein catheter. The femoral vein is technically the easiest access to place; nevertheless, concern for infection by this type of access has limited its use. One randomized controlled trial showed that femoral catheters were not associated with an increased risk of infections compared with jugular catheters, except in patients with high body mass indexes. Jugular catheters could be used for prolonged periods of time (usually 3 weeks), with a low risk of bacteremia; on the other hand, femoral catheters—especially in obese and bed-bound patients—should not be used for more than 1 week. Thoracic catheters have the advantage of lower recirculation. However, it should be kept in mind that subclavian vein cannulation is associated with higher rates of both short-term and long-term complications, such as pneumothorax and hemorrhage, and central venous stenosis. Subclavian catheters should be placed only if all the other options are not viable. The use of portable ultrasound machines has improved the success rate of cannulation and decreased the rate of complications, and they should be used if available.

4. Which factors could affect the modality selection of RRT?

There is debate whether continuous modalities are better than intermittent modalities in the treatment of AKI patients. IHD has several advantages:

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  Short duration of therapy

  
  
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  Rapid correction of electrolyte and acid-base disturbances

  
  
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  Rapid fluid removal

  
  
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  Availability of the machines

  
  
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  Availability of trained nurses

Often the machines and nurses available to deploy continuous therapies are not available. However, in intermittent dialysis, the duration of the procedure, 3 to 5 hours, limits the control of fluid regulation and acid-base and electrolyte balance. Patients with hemodynamic instability may not tolerate the high ultrafiltration rates necessary to achieve a fluid balance. CRRT can offer advantages over IHD:

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  Slower fluid removal, which promotes hemodynamic stability

  
  
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  Better solute clearance

  
  
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  Better correction of acid-base and electrolyte abnormalities

  
  
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  Better metabolic control

Some data have suggested that intradialytic hypotensive episodes during IHD could decrease the rate of recovery of kidney function. Still, CRRT can also have some limitations and disadvantages, such as the need for continuous anticoagulation, patient immobilization, and greater human resource requirement, including the need for ICU monitoring. Although there are many arguments that favor the use of CRRT in critically ill patients with AKI, current evidence has not shown any benefit to employing CRRT over IHD in this group of patients. The hybrid modalities, SLED and EDD, can provide the same adequate solute control as IHD can, but require less intensive monitoring and time, compared to CRRT.

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